WO2013038308A1 - SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS AS mPGES-1 INHIBITORS - Google Patents
SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS AS mPGES-1 INHIBITORS Download PDFInfo
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- WO2013038308A1 WO2013038308A1 PCT/IB2012/054612 IB2012054612W WO2013038308A1 WO 2013038308 A1 WO2013038308 A1 WO 2013038308A1 IB 2012054612 W IB2012054612 W IB 2012054612W WO 2013038308 A1 WO2013038308 A1 WO 2013038308A1
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- WIPO (PCT)
- Prior art keywords
- chloro
- phenyl
- mmol
- amino
- trifluoromethyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Definitions
- the present patent application relates to substituted bicyclic heteroaryl compounds as mPGES-1 inhibitors.
- Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis. Inflammation is also a common cause of pain.
- COX cyclooxygenase
- PGE 2 is particularly known to be a strong proinflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE 2 , inclding u “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
- COX-2 inhibitors selective COX-2 inhibitors
- drugs which act by inhibition of COXs are therefore known / suspected to cause adverse biological effects.
- the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
- Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
- PGE 2 A combination of pharmacological, genetic and neutralizing antibody approaches demonstrates the importance of PGE 2 in inflammation.
- the conversion of PGH 2 to PGE 2 by prostaglandin E synthases (PGES) may therefore represent a pivotal step in the propagation of inflammatory stimuli.
- Microsomal prostaglandin E synthase- 1 (mPGES-1) is an inducible PGES after exposure to pro-inflammatory stimuli.
- mPGES-1 is induced in the periphery and CNS by inflammation and represents therefore a target for acute and chronic inflammatory disorders.
- PGE 2 is a major prostanoid, produced from arachidonic acid liberated by phospholipases (PLAs), which drives the inflammatory processes.
- Arachidonic acid is transformed by the action of prostaglandin H synthase (PGH synthase, cycloxygenase) into PGH2 which is a substrate for mPGES-1 , which is the terminal enzyme transforming PGH2 to the pro-inflammatory PGE 2 .
- PGH synthase prostaglandin H synthase
- PGH 2 may be transformed to PGE 2 by prostaglandin E synthases (PGES).
- PGES prostaglandin E synthases
- mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
- cPGES cytosolic prostaglandin E synthase
- agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE 2 are likely to be of benefit in the treatment of inflammation.
- agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma and COPD.
- PGE 2 is involved in malignant growth. PGE 2 facilitates 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 the intestinal tumourogenesis (Nakanishi et. al., Cancer Research 2008, 68(9), 3251-9). In human beings, mPGES-1 is also upregulated in cancers such as colorectal cancer (Schroder Journal of Lipid Research 2006, 47, 1071-80).
- Myositis is chronic muscle disorder characterized by muscle weakness and fatigue. Proinflammatory cytokines and prostanoids have been implicated in the development of myositis. In skeletal muscle tissue from patients suffering from myositis an increase in cyclooxygenases and mPGES-1 has been demonstrated, implicating mPGES-1 as a target for treating this condition. (Korotkova Annals of the Rheumatic Diseases 2008, 67, 1596- 1602).
- Atherosclerosis inflammation of the vasculature leads to atheroma formation that eventually may progress into infarction.
- carotid atherosclerosis an increase in mPGES-1 in plaque regions have been reported (Gomez -Hernandez Atherosclerosis 2006, 187, 139-49).
- mice lacking the mPGES-1 receptor were found to show a retarded atherogenesis and a concomitant reduction in macrophage-derived foam cells together with an increase in vascular smooth muscle cells (Wang, Proceedings of National Academy of Sciences 2006, 103(39), 14507-12).
- WO2010/100249 disclose numerous heterocyclic compounds which are shown to be inhibitors of microsomal prostaglandin E synthase- 1 (mPGES-1) enzyme.
- the present invention is directed to novel compounds that are selective inhibitors of the mPGES-1 enzyme and would therefore be useful for the treatment of pain and inflammation in a variety of diseases or conditions.
- A is selected from C 3 _i 2 cycloalkyl, C 6 _i4aryl, 5- 14 membered heteroaryl and 3-15 membered heterocyclyl;
- L is selected from bond, -(CR x R y ) n C(0)NR p -, -(CR x R y ) n C(0)0-, -(CR x R y ) n -, - (CR x R y ) n -NR p C(0)-, -(CR x R y ) n -NR p C(0)NR p -, -(CR x R y ) n -NR p C(0)0- -(CR x R y ) n NR p S0 2 -, -(CR x R y ) n -OC(0)-, -(CR x R y ) clearlyOC(0)0-, -(CR x R y ) n OC(0)NR p -, -(CR x R y ) n S(0)-, - (CR x R y ) n S0 2 -, -(CR x R y
- W is selected from hydrogen, substituted or unsubstituted Ci_galkyl, C 2 _ioalkenyl, C 2 _ l oalkynyl, Ci-galkoxy, Ci_ 8 alkyloxyCi_ 8 alkyl, haloCi-salkyl, hydroxyCi-galkyl, haloCi-galkoxy, C3-i 2 cycloalkyl, C3-i 2 cycloalkylCi_ 8 alkyl, C3-i 2 cycloalkenyl, C3-i 2 cycloalkenylCi_ 8 alkyl, Ce- naryl, Ce-narylCi-salkyl, 3-15 membered heterocyclyl, 3- 15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi.galkyl;
- R 1 is selected from substituted or unsubstituted Ci.galkyl, C3_i 2 cycloalkyl, C3_ i 2 cycloalkylCi_ 8 alkyl, C3_i 2 cycloalkenyl, C3_i 2 cycloalkenylCi_ 8 alkyl, Ce-naryl, Ce-narylCi- galkyl, 3- 15 membered heterocyclyl, 3-15 membered heterocyclylCi-galkyl, 5- 14 membered heteroaryl and 5-14 membered heteroarylCi- 8 alkyl;
- R 2 is independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci-salkyl, C 2 _ioalkenyl, C 2 _ioalkynyl, Ci-galkyloxyCi- galkyl, haloCi-salkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3_i 2 cycloalkyl, C 3 _i 2 cycloalkylCi- 8 alkyl, C3_i 2 cycloalkenyl, C3_i 2 cycloalkenylCi_ 8 alkyl, C6-i4ar l, Ci-saryloxy, C6-i4arylCi_ 8 alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_ 8 alkyl
- R 3 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci_ 8 alkyl, haloCi-salkyl, haloCi_galkoxy, and hydroxyCi-salkyl; at each occurrence, R p is selected from hydrogen, substituted or unsubstituted Ci-salkyl and C6-i4arylCi_ 8 alkyl;
- R a , R b and R c which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci-salkyl, Ci_8alkyloxyCi- galkyl, haloCi-galkyl, hydroxyCi-salkyl, C3_i 2 cycloalkyl, Ce-naryl, 5-14 membered heteroaryl and 3- 15 membered heterocyclyl; or R a and R b or R b and R c together with the atom to which they are attached, form a cyclic ring, which is substituted or unsubstituted cyclic rings and cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
- R x and R y are independently selected from hydrogen, substituted or unsubstituted Ci-galkyl, C3_i 2 cycloalkyl, Ce-naryl, Ce- narylCi-salkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylalkyl, 5-14 membered heteroaryl, and 5- 14 membered heteroarylCi_salkyl; or R x and R y together with the atom to which they are attached, form a substituted or unsubstituted 3 to 12 membered cyclic ring and cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
- 'm' is an integer ranging from 0 to 4, both inclusive;
- 'n' is an integer ranging from 1 to 3, both inclusive;
- 'q' is an integer ranging from 0 to 2, both inclusive.
- 'r' is an integer ranging from 0 to 4, both inclusive.
- the compounds of formula (I) may involve one or more embodiments.
- Embodiments of formula (I) include compounds of formula (II), and compounds of formula (III) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, 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 R p is hydrogen (according to an embodiment defined below) and X is S (according to another embodiment defined below).
- R 2 is halogen (e.g. F, CI or Br), Ci_ 8 alkyl (e.g. methyl, ethyl) or Ci_galkoxy (e.g. methoxy, ethoxy).
- halogen e.g. F, CI or Br
- Ci_ 8 alkyl e.g. methyl, ethyl
- Ci_galkoxy e.g. methoxy, ethoxy
- R 2 is chloro, fluoro, methyl or methoxy.
- R 2 is chloro, fluoro, methyl or methoxy and m is 1 or 2.
- R 1 is substituted or unsubstituted C 6 _i 4 aryl or C 3 _i 2 cycloalkyl.
- R 1 is substituted or unsubstituted C6 -14 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.
- substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi-salkyl (e.g. trifluoromethyl, difluoromethyl).
- R 1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), C 1-4 alkyl (e.g. methyl, ethyl) and haloCi-salkyl (e.g. trifluoromethyl, difluoromethyl).
- halogen e.g. F, CI or Br
- C 1-4 alkyl e.g. methyl, ethyl
- haloCi-salkyl e.g. trifluoromethyl, difluoromethyl
- R 1 is substituted or unsubstituted C3_i 2 cycloalkyl (e.g. cyclobutyl).
- R 1 is 4-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-5- trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3 -fluorophenyl, 3- trifluoromethylphenyl or cyclobutyl.
- W is substituted or unsubstituted Ci_ 8 alkyl (e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan-l-yl, ie/t-butyl or 2-methylpropan-2-yl).
- Ci_ 8 alkyl e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan-l-yl, ie/t-butyl or 2-methylpropan-2-yl.
- W is substituted or unsubstituted hydroxyCi-salkyl (e.g. 2-hydroxy propan-2-yl or 2-hydroxy propanyl).
- C3_i 2 cycloalkyl e.g. cyclopropyl, cyclobutyl
- substituents on C3_i 2 cycloalkyl are Ci galkyl (e.g. methyl), and hydroxy.
- W is C 3 _i 2 cycloalkyl (e.g. cyclopropyl, cyclobutyl) optionally substituted with one or more substituents selected from Ci.salkyl (e.g. methyl), and hydroxyl.
- W is substituted or unsubstituted 3-15 membered heterocyclyl, (e.g. tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl).
- heterocyclyl e.g. tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
- W is substituted or unsubstituted Ci-salkyl, hydroxyCi-salkyl, C 3 - i 2 cycloalkyl or 3-15 membered heterocyclyl.
- W is isopropyl, propan-2-yl, isobutyl, 2-methylpropan-l-yl, ieri-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2-hydroxy propanyl, cyclopropyl, cyclobutyl, 1- methylcyclopropyl, 1 -hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
- IC5 0 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM with respect to mPGES-1 activity as measured by method described in the present patent application.
- the application also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
- X is selected from O, and S(0) q ;
- G 1 is N
- G 2 and G 3 are CR 3 ;
- W is selected from substituted or unsubstituted Ci-salkyl, C 2 -ioalkenyl, C 2 -ioalkynyl, Ci_
- R 1 is selected from substituted or unsubstituted Ci_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3 _ i2cycloalkylCi_ 8 alkyl, C 3 _i2cycloalkenyl, C 3 -i 2 cycloalkenylCi_ 8 alkyl, C6_Haryl, C6_i4aryl Ci_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi.galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi-salkyl; R 1 is selected from substituted or unsubstituted Ci_ 8 alkyl, C 3 _i 2 cycloalkyl, C 3 _ i2cycloalkylCi_ 8 alkyl, C 3 _i2cycloalkenyl, C 3 3 _i2cycloalkenyl, C 3 _i2cycloalkenyl, C
- R 2 is independently selected from halogen, cyano, hydroxyl, substituted or unsubstituted Ci_galkyl, Ci_galkoxy, haloCi_ 8 alkyl, haloCi.galkoxy and hydroxyC- i_ 8 alkyl;
- R 3 is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted Ci_8alkyl, haloCi-salkyl and haloCi-salkoxy;
- R p is selected from hydrogen, substituted or unsubstituted Ci_ 8 alkyl and C 6 _i4arylCi_ 8 alkyl;
- 'm' is an integer ranging from 0 to 4, both inclusive;
- 'n' is an integer ranging from 1 to 4, both inclusive;
- 'q' is an integer ranging from 0 to 2, both inclusive.
- the compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, or any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments.
- the invention provides compounds of formula (II) as defined above wherein X is S (according to an embodiment defined below), R p is hydrogen (according to an embodiment defined below), R 2 is chloro, fluoro, methyl or methoxy (according to another embodiment defined below) and m is 1 or 2 (according to yet another embodiment defined below).
- R 2 is halogen (e.g. F, CI or Br), Ci-salkyl (e.g. methyl, ethyl) or Ci-galkoxy (e.g. methoxy, ethoxy).
- halogen e.g. F, CI or Br
- Ci-salkyl e.g. methyl, ethyl
- Ci-galkoxy e.g. methoxy, ethoxy
- R 2 is chloro, fluoro, methyl or methoxy and m is 1 or 2.
- R 1 is substituted or unsubstituted Ce naryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.
- substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi_ 8 alkyl (e.g. trifluoromethyl, difluoromethyl).
- R 1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi_galkyl (e.g. trifluoromethyl, difluoromethyl).
- halogen e.g. F, CI or Br
- Ci_4 alkyl e.g. methyl, ethyl
- haloCi_galkyl e.g. trifluoromethyl, difluoromethyl
- R 1 is substituted or unsubstituted C 3 _i 2 cycloalkyl (e.g. cyclobutyl).
- R 1 is 4-trifiuoromethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-5- trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3 -fluorophenyl, 3- trifluoromethylphenyl or cyclobutyl.
- W is substituted or unsubstituted Ci_galkyl (e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan-l-yl, ieri-butyl or 2-methylpropan-2-yl).
- W is substituted or unsubstituted hydroxyCi-salkyl (e.g. 2-hydroxy propan-2-yl or 2-hydroxy propanyl).
- C 3 _i 2 cycloalkyl e.g. cyclopropyl, cyclobutyl
- substituents on C 3 -i 2 cycloalkyl e.g. cyclopropyl, cyclobutyl
- Ci_8alkyl e.g. methyl
- W is C 3 _i 2 cycloalkyl (e.g. cyclopropyl, cyclobutyl) optionally substituted with one or more substituents selected from Ci_8alkyl (e.g. methyl), and hydroxyl.
- Ci_8alkyl e.g. methyl
- W is substituted or unsubstituted 3-15 membered heterocyclyl, (e.g. tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl).
- heterocyclyl e.g. tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
- W is isopropyl, propan-2-yl, isobutyl, 2-methylpropan-l-yl, tert-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2-hydroxy propanyl, cyclopropyl, cyclobutyl, 1- methylcyclopropyl, 1 -hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
- the application also provides a compound of formula (III), which is an embodiment of a compound of formula (I).
- W is substituted or unsubstituted Ci_ 8 alkyl, hydroxyCi_ 8 alkyl, C 3 _i 2 cycloalkyl, or 3-15 membered heterocyclyl;
- R 1 is substituted or unsubstituted Ce-naryl or C3_i 2 cycloalkyl
- R 2 is halogen, Ci_4 alkyl, or Ci-galkoxy
- 'm' is an integer ranging from 0 to 4, both inclusive.
- the compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, 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 2 is chloro, fiuoro, methyl or methoxy (according to an embodiment defined below) and m is 1 or 2 (according to another embodiment defined below).
- R 2 is halogen (e.g. F, CI or Br), Ci.galkyl (e.g. methyl, ethyl) or Ci-salkoxy (e.g. methoxy, ethoxy).
- R 2 is chloro, fluoro, methyl or methoxy.
- R 1 is substituted or unsubstituted C6 -14 aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl.
- substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi_salkyl (e.g. trifluoromethyl, difluoromethyl).
- R 1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), C 1-4 alkyl (e.g. methyl, ethyl) and haloCi-salkyl (e.g. trifluoromethyl, difluoromethyl).
- halogen e.g. F, CI or Br
- C 1-4 alkyl e.g. methyl, ethyl
- haloCi-salkyl e.g. trifluoromethyl, difluoromethyl
- R 1 is substituted or unsubstituted C 3 _i 2 cycloalkyl (e.g. cyclobutyl).
- R 1 is 4-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-5- trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3 -fluorophenyl, 3- trifluoromethylphenyl or cyclobutyl.
- W is substituted or unsubstituted Ci-galkyl (e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan- 1 -yl, ie/t-butyl or 2-methylpropan-2-yl).
- Ci-galkyl e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan- 1 -yl, ie/t-butyl or 2-methylpropan-2-yl.
- W is substituted or unsubstituted hydroxyCi-galkyl (e.g. 2-hydroxy propan-2-yl or 2-hydroxy propanyl).
- C 3 _i 2 cycloalkyl e.g. cyclopropyl, cyclobutyl
- substituents on C 3 _i 2 cycloalkyl are Ci_salkyl (e.g. methyl), and hydroxy.
- W is C 3 _i 2 cycloalkyl (e.g. cyclopropyl, cyclobutyl) optionally substituted with one or more substituents selected from Ci.galkyl (e.g. methyl), and hydroxyl.
- W is substituted or unsubstituted 3-15 membered heterocyclyl, (e.g.
- W is substituted or unsubstituted Ci.galkyl, hydroxyCi.galkyl, C _ i 2 cycloalkyl or 3-15 membered heterocyclyl.
- W is isopropyl, propan-2-yl, isobutyl, 2-methylpropan-l-yl, ieri-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2-hydroxy propanyl, cyclopropyl, cyclobutyl, 1 - methylcyclopropyl, 1 -hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
- compounds of formula (III) with an IC50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM with respect to mPGES-1 activity as measured by method described in the present patent application.
- the present application also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
- the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
- the compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
- the compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of mPGES-1, which is believed to be related to a variety of disease states.
- the present patent application further provides a method of inhibiting mPGES-1 in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
- halogen or halo means fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo).
- alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms (i.e. Ci-salkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, and 1 , 1 -dimethylethyl (t- butyl). Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
- alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms (i.e. C2 ioalkenyl) and including at least one carbon-carbon double bond.
- alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), 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 10 carbon atoms (i.e. C2_ioalkynyl).
- alkynyl groups include ethynyl, propynyl, and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
- alkoxy denotes an alkyl group attached via an oxygen linkage to the rest of the molecule (i.e. Ci_ 8 alkoxy).
- Representative examples of such groups are -OCH 3 and - 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.
- 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_ 8 alkyl or Ci_ 8 alkyloxyCi_ 8 alkyl).
- alkoxyalkyl moiety includes, but are not limited to, - CH2OCH 3 and -CH2OC2H5. Unless set forth or recited to the contrary, all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
- haloalkyl refers to at least one halo group (selected from F, CI, Br or I), linked to an alkyl group as defined above (i.e.haloCi-salkyl).
- haloalkyl moiety include, but are not limited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
- haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e.haloCi-salkoxy).
- haloalkoxy include but are not limited to fiuoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafiuoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1 -bromoethoxy.
- all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
- hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi_ 8 alkyl).
- hydroxyalkyl moiety include, but are not limited to -CH 2 OH, -C2H4OH and -CH(OH)C 2 H 4 OH.
- cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, for example C 3 _i2cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl.
- C 3 _ 6 cycloalkyl refers to the cyclic ring having 3 to 6 carbon atoms. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
- cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 12 carbon atoms directly attached to an alkyl group, for example C 3 _i2cycloalkylCi_ 8 alkyl.
- the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
- Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
- cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 12 carbon atoms with at least one carbon-carbon double bond, for example C 3 _i2cycloalkenyl, such as 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 12 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C3_i2cycloalkenylCi_ 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.
- arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C6-i 4 arylCi_galkyl, 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.
- aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. Ce naryloxy).
- aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
- heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur.
- the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
- heterocyclic ring or heterocyclyl may optionally contain one or more olefmic bond(s).
- heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
- heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described or claimed herein may be substituted or unsubstituted.
- heterocyclylalkyl refers to a heterocyclic ring radical, as defined above, directly bonded to an alkyl group (i.e. heterocyclylCi-salkyl).
- the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
- heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
- 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, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indoli
- heteroarylalkyl refers to a heteroaryl ring radical, as defined above, directly bonded to an alkyl group (i.e. heterarylCi-salkyl).
- the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
- salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
- treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
- subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
- domestic animals e.g., household pets including cats and dogs
- non-domestic animals such as wildlife.
- a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
- the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
- Nociceptors are primary sensory afferent (C and ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH ⁇ 6) modalities.
- Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.
- chronic pain usually refers to pain which persists for 3 months or longer and can lead to significant changes in a patient's personality; lifestyle, functional ability and overall quality of life.
- Chronic pain can be classified as either nociceptive or neuropathic.
- Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis.
- Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant, and often with an aching or throbbing quality.
- Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized.
- Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).
- the compound described in the present patent application may form salts.
- Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.
- Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) the present patent application extends to these stereoisomeric forms and to mixtures thereof.
- CDCI3 deuterated chloroform
- DIPEA NN-diisopropylethylamine
- PCI5 phosphorous pentachloride
- the compounds of the invention are typically administered in the form of a pharmaceutical composition.
- Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention.
- the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
- the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
- the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
- suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
- the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
- compositions may be in conventional forms, for example, capsules, tablets, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present invention may be formulated so as to provide desired release profile.
- Administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
- the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
- Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular, or topical.
- Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
- Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injectable liquids, such as suspensions or solutions.
- Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
- compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
- Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
- Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms, and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
- Compounds of the present invention are particularly useful because they may selectively inhibit the activity of prostaglandin E synthases ⁇ and particularly microsomal prostaglandin E synthase-1 (mPGES-1) ⁇ , i.e., they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit mPGES-1 modulating effect.
- Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
- inflammation will be understood by those skilled in the art to include any condition characterized by a localized or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow.
- inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
- the term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
- the compounds of the present invention may also be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, chronic pain, acute pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g.
- hyperprostaglandin E syndrome classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory
- Compounds of the invention may also have effects that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject.
- Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.
- the compounds of Formula I 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
- the pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy - induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy & chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease like multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neurode
- Such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
- Compounds of Formula I may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.
- Compounds of the present invention may 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 Myeloprolifer
- Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
- the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
- the daily dosage of the compound of the invention may be in the range from 0.05 mg/kg to 100 mg/kg.
- the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, EDCI 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 suitable coupling reagent known to those skilled in the art for example, EDCI 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.
- the reaction can be performed using a suitable reagent such as isobutyl chloro formate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.
- a suitable reagent such as isobutyl chloro formate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF
- a suitable base such as DIPEA.
- the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
- a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
- compound of formula (6) can also be prepared by treatment of compound of formula (5) with an appropriate amine (R 1 -NH 2 ) optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or methanol (MeOH). Removal of the protecting group (PG) from compound of formula (6) under conditions known to those skilled in the art such as with trifluoroacetic acid or hydrochloric acid in a suitable solvent such as methanol or dioxane in the temperature range of 0-200°C can provide the compound of formula (7).
- a suitable base such as sodium hydride or potassium carbonate
- a suitable solvent such as DMF or methanol (MeOH).
- Coupling of compound of (11) with compound of formula (12) can provide compound of formula (III) under the conditions as described in scheme 1.
- the synthesis of the compound of formula (III) (wherein W, R 1 , R 2 and m are as defined above for compound of formula (III)) can be accomplished as described in synthetic scheme 4.
- the removal of the protecting group (PG) from compound of formula (3) (wherein Y is CI, Br or I and PG is an appropriate protecting group such as 4-methoxybenzyl) under conditions known to those skilled in the art such as with trifluoroacetic acid or hydrochloric acid in a suitable solvent such as methanol or dioxane in the temperature range of 0-200°C can provide the compound of formula (13) (wherein Y is CI, Br or I).
- compound of formula (III) can also be prepared by treatment of compound of formula (16) with an appropriate amine ( 1 -NH 2 ) optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or methanol (MeOH).
- a suitable base such as sodium hydride or potassium carbonate
- a suitable solvent such as DMF or methanol (MeOH).
- reaction of compound of formula (17) under suitable conditions such as treatment with an appropriate halide or pseudohalide in the presence of a suitable palladium catalyst in a suitable solvent such as DMF or dioxane in the temperature range of 20-200°C can provide the compound of formula (18).
- a suitable palladium catalyst in a suitable solvent such as DMF or dioxane in the temperature range of 20-200°C
- the compound of formula (18) can also be prepared by treatment of compound of formula (17) with an appropriate halide or pseudohalide optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or THF.
- the compound of formula (18) can also be prepared with an appropriate carbonyl compound in presence of a suitable acid such as acetic acid in a suitable solvent such as dichloromethane and an appropriate reducing agent such as sodium triacetoxyborohydride in the temperature range 20-200 °C.
- a suitable acid such as acetic acid in a suitable solvent such as dichloromethane
- an appropriate reducing agent such as sodium triacetoxyborohydride in the temperature range 20-200 °C.
- Removal of the protecting group (PG) from compound of formula (18) under conditions known to those skilled in the art such as with trifluoroacetic acid or hydrochloric acid in a suitable solvent such as methanol or dioxane in the temperature range of 0-200°C can provide the compound of formula (19).
- the synthesis of the compound of formula (IV) can be accomplished as described in synthetic scheme 6.
- the reaction of the compound of formula (14) (wherein Y is CI, Br or I) with a suitable reagent such as acetohydroxamic acid or p- nitrobenzophenoneoxime or acetoxime in presence of a suitable base such as potassium carbonate or potassium ieri-butoxide in a suitable solvent such as DMF or THF in the temperature range of 20-250°C can provide the compound of formula (20).
- compound of formula (IV) can also be prepared by treatment of compound of formula (20) with an appropriate halide or pseudohalide optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or THF.
- a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or THF.
- the compound of formula (IV) can also be prepared with an appropriate carbonyl compound in presence of a suitable acid such as acetic acid in a suitable solvent such as dichloromethane and an appropriate reducing agent such as sodium triacetoxyborohydride in the temperature range 20-200 °C.
- a suitable acid such as acetic acid
- a suitable solvent such as dichloromethane
- an appropriate reducing agent such as sodium triacetoxyborohydride in the temperature range 20-200 °C.
- the compound of formula (8) can be prepared following the pathway described in synthetic scheme 8 wherein the compound of formula (23) (where LG represent OH) can be converted to the compound of formula (24) by incorporating appropriate protecting group (PG) under the standard conditions known to those skilled in the art.
- the esterification of the compound of formula (24) under the standard conditions can provide the compound of formula (25) (wherein LG' represents O-alkyl, O-aryl).
- Subsequent liberation of the amino group to provide the compound of formula (26) and the acylation of compound of formula (26) with appropriate acylating agent can provide the compound of formula (27).
- the hydrolysis of the compound of formula (27) under the standard conditions can provide the compound of formula (8) (wherein LG represents OH).
- the synthesis of the compound of formula (23) (wherein LG represents OH) and/or (26) (wherein LG represents O-alkyl, O-aryl) can be achieved starting from the compound of formula (31)).
- the reaction of compound of formula (31) with a suitable base such as n BuLi and a formylating agent such as DMF in a suitable solvent such as THF in the temperature range -100 to 20 °C can provide the compound of formula (32).
- the formyl group in (32) can be converted to the corresponding hydroxylamino compound of formula (33) by reacting with a hydroxylamineoxime in a suitable solvent such as methanol in the temperature range 20-200 °C.
- the reduction of the compound of formula (33) under standard conditions known to those skilled in the art can provide the compound of formula (23)/(26).
- the synthesis of compound of formula (26) can also be performed following the pathway described in synthetic scheme 11 by standard reduction of compound of formula (34).
- the compound of formula (34) can be obtained from compound of formula (32) using the procedure known those skilled in the art.
- the synthesis of compound of formula (32) can be performed as described above or it can also be prepared from compound of formula (28) by direct oxidation or via compound of formula (35) (where Y' is Br or I) using known conditions.
- work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate (Na 2 S0 4 ), filtration and evaporation of the solvent under reduced pressure.
- Purification includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase.
- Step 1 Preparation of 3 -bromo-4-chloropyridine 1 -oxide
- Step 4 Preparation of 3-bromo-N-( -methoxybenzyl)[l ,2]thiazolo[4,5- ⁇ ]pyridin-7-amine
- Step 5 Preparation of N 7 -(4-methoxybenzyl)-N 3 -[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- 3 ⁇ 4]pyridine-3 ,7-diamine O
- Step 6 Preparation of N -[4-(trifluoromethyl)phenyl][l,2]thiazolo[4,5-&]pyridine-3,7-diamine
- N 7 -(4-methoxybenzyl)-N 3 -[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- b]pyridine-3,7-diamine 150 mg, 0.35 mmol
- trifluoroacetic acid 3 mL
- Step 1 Preparation of 2-chloro-5- ⁇ [(trifluoroacetyl)amino]methyl ⁇ benzoic acid
- 2-chlorobenzoic acid 500 mg, 3.49 mmol
- 2,2,2- trifluoro-N-(hydroxymethyl)acetamide 547 mg, 3.49 mmol.
- the reaction mixture was poured into ice-water and stirred for 2 h.
- the precipitate was collected by filtration, dried and recrystallized from toulene/butan-2-one (7: 1) to afford 800 mg of the title product.
- Step 2 Preparation of 5- ⁇ [(ieri-butoxycarbonyl)amino]methyl ⁇ -2-chlorobenzoic acid
- Step 1 Preparation of methyl 5-(((ieri-butoxycarbonyl)amino)methyl)-2-chlorobenzoate
- Step 3 Preparation of methyl 2-chloro-5-((l-methylcyclopropanecarboxamido)methyl) benzoate
- Step 4 Preparation of 2-chloro-5-((l -methylcyclopropanecarboxamido)methyl)benzoic acid
- methyl 2-chloro-5-((l-methylcyclopropanecarboxamido)methyl) benzoate 240 mg, 0.857 mmol
- NaOH 68 mg, 1.7 mmol
- the reaction mass was stirred at rt for 2 h before it was concentrated and neutralized with IN HC1 at 0°C.
- the precipitated obtained was filtered and dried to afford 200 mg of the title product.
- Step 1 Preparation of methyl 2-chloro-5-(isobutyramidomethyl)benzoate
- step-2 of intermediate-4 200 mg, 0.911 mmol
- DIPEA 183 mg, 1.36 mmol
- 1- isobutyryl chloride 145 mg, 1.36 mmol
- Step 1 Preparation of methyl 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoate
- step-2 of Intermediate-4 200 mg, 0.91 1 mmol
- DIPEA 361 mg, 2.70 mmol
- cyclopropanecarboxylic acid 125 mg, 1.45 mmol
- oxalyl chloride 221 mg, 1.74 mmol
- a drop of DMF in CH 2 CI 2 3 mL
- Step 1 Preparation of methyl 2-chloro-5-(cyclobutanecarboxamidomethyl)benzoate
- Step 1 Preparation of methyl 2-chloro-5-((tetrahydrofuran-2-carboxamido) methyl) benzoate
- step-2 intermediate-4, 200 mg, 0.847 mmol
- DIPEA 473 mg, 3.3 mmol
- tetrahydrofuran-2-carboxylic acid 160 mg, 1.37 mmol
- oxalyl chloride 210 mg, 1.65 mmol
- a drop of DMF in CH2CI2 3 mL
- Step 2 Preparation of 2-chloro-5-((tetrahydrofuran-2-carboxamido)methyl)benzoic acid
- the title compound was prepared following the procedure described in step-4 of Intermediate- 4 using methyl 2-chloro-5-((tetrahydrofuran-2-carboxamido)methyl)benzoate (250 mg, 0.875 mmol) in THF:MeOH:water (3 :2: 1 , 6 mL) and NaOH (70 mg, 1.75 mmol) to afford 160 mg of the title product.
- Step 1 Preparation of methyl 2-chloro-5-((tetrahydrofuran-3-carboxamido)methyl) benzoate
- Step 2 Preparation of 2-chloro-5-((tetrahydrofuran-3-carboxamido)methyl)benzoic acid
- the title compound was prepared following the procedure described in step-4 of intermediate- 4 using methyl 2-chloro-5-((tetrahydrofuran-3-carboxamido)methyl)benzoate (250 mg, 0.875 mmol) in THF:MeOH:water (3 :2: 1 , 6 mL) and NaOH (70 mg, 1.75 mmol) to afford 150 mg of the title product.
- Step 1 Preparation of methyl 2-chloro-5-((3-methylbutanamido)methyl)benzoate
- step-2 intermediate-4, 1.80 g, 6.00 mmol
- DIPEA 3.096 g, 2.4 mmol
- pivaloyl chloride 1.2 mL, 9.0 mmol
- Step 1 Preparation of N 7 -(4-methoxybenzyl)-N -[3-(trifluoromethyl)phi
- step-4 intermediate -1, 300 mg, 0.86 mmol
- 3-trifluoromethylaniline 208 mg, 1.29 mmol
- CS2CO 3 840 mg, 2.58 mmol
- 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes 150 mg, 0.26 mmol
- tris(dibenzylideneacetone)dipalladium(0) 79 mg, 0.086 mmol
- dioxane 5 mL
- Step 2 Preparation of N 3 -[3-(trifluoromethyl)phenyl][l,2]thiazolo[4,5-3 ⁇ 4]pyridine-3,7-diamine
- the title compound was prepared following the procedure described in step-6 of intermediate- 1 using N 7 -(4-methoxybenzyl)-N 3 -[3-(trifluoromethyl)phenyl] [l ,2]thiazolo[4,5-&]pyridine- 3,7-diamine (150 mg, 0.35 mmol) and trifluoroacetic acid (3 mL) to afford 100 mg of the title product.
- Step 1 Preparation of N -(5-fluoro-2-methylphenyl)-N 7 -(4-methoxybenzyl)isothiazolo[4,5- b]pyridine-3 ,7-diamine
- Step 2 Preparation of N 3 -(5-fluoro-2-methylphenyl)isothiazolo[4,5-fc]pyridine-3,7-diamine
- the title compound was prepared following the procedure described in step-6 of intermediate- 1 using N 3 -(5 -fluoro-2-methylphenyl)-N 7 -(4-methoxybenzyl)isothiazolo [4,5 -&]pyridine-3 ,7- diamine (200 mg, 0.527 mmol), trifluoroacetic acid (5 mL) to afford 90 mg of the title product.
- Step 1 Preparation of N -(2-fluoro-5-(trifluorometriyl)phenyl)-N 7 -(4-methoxybenzyl) isothiazolo[4,5- ⁇ ]pyridine-3, -diamine
- Step 2 Preparation of N -(2-fluoro-5-(trifluoromethyl)phenyl)isothiazolo[4,5-&]pyridine-3,7- diamine
- Step 1 Preparation of N 3 -cyclobutyl-N 7 -(4-methoxybenzyl)isothiazolo[4,5-Z?]pyridine-3,7- diamine
- Step 1 Preparation of (1R, 5 S)-et yl 2-oxo-3-oxabicyclo[3.1.0]hexane-l-carboxylate
- Step 2 Preparation of (lS,2S)-ethyl l,2-bis(hydroxymethyl)cyclopropanecarboxylate
- Step 4 Preparation of (i5,55)-3-oxabicyclo[3.1.0]hexane-l-carboxylic acid
- a solution of (i5,55)-ethyl 3-oxabicyclo[3.1.0]hexane-l-carboxylate (200 mg, 1.28 mmol) in THF-H 2 0 5: 1, 6 mL
- LiOH 108 mg, 2.56 mmol
- the reaction mixture was stirred at rt for 5-6 h.
- the reaction mixture was quenched with water and the organic impurities were extracted in Et 2 0.
- the aqueous layer was neutralized with IN HCl and was extracted with CH 2 CI 2 .
- Step 1 Preparation of N 3 -(3-fluorophenyl)-N 7 -(4-methoxybenzyl)isothiazolo[4,5- ?]pyridine- 3,7-diamine
- Step 2 Preparation of N -(3-fluorophenyl)isothiazolo[4,5- ⁇ ]pyridine-3,7-diamine
- Step 1 Preparation of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate
- Step 2 Preparation of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate
- Step 1 Preparation of 2,6-dimethyl-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid
- Step 1 Preparation of 2-chloro-6-methyl-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid
- the reaction mixture was extracted with 5% MeOH in CHCI 3 .
- the organic layer was separated, dried, filtered and concentrated.
- the concentrate was dissolved in CH 3 CN (20 mL) and the solution was treated with K2CO3 (1.60 g, 11.50 mmol) and CH3I (11.50 mmol) at rt. Then the reaction mixture was heated at 50 °C for 1-2 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The concentrated was purified by column chromatography to provide 1.4 g of the title product and methyl 3-(((ierf-butoxycarbonyl)amino)methyl)-6-chloro-2- methylbenzoate as mixture of products.
- Step 1 Preparation N 3 -(2-fiuoro-4-(trifluoromethyl)phenyl)-N 7 -(4- methoxybenzyl)isothiazolo -b]pyridine-3,7-diamine
- Step 1 Preparation of N 7 -(4-methoxybenzyl)isoxazolo[4,5-&]pyridine-3 ,7-diamine
- Step 2 Preparation of N 7 -(4-methoxybenzyl)-N 3 -(4-(trifluoromethyl)phenyl)isoxazolo[4,5- £>]pyridine-3 ,7-diamine
- Step 3 Preparation of N -(4-(trifluoromethyl)phenyl)isoxazolo[4,5- ⁇ ]pyridine-3,7-diamine
- the title compound was prepared following the procedure described in step-6 of Intermediate- 1 using N 7 -(4-methoxybenzyl)-N 3 -(4-(trifluoromethyl)phenyl)isoxazolo[4,5- ⁇ ]pyridine-3,7- diamine (300 mg, 0.724 mmol), H 2 S0 4 (5 mL) to afford 120 mg of the title product.
- Step 1 Preparation of N 7 -(4-methoxybenzyl)-N -(3-(trifluoromethyl)prienyl)isoxazolo[4,5- b]pyridine-3 ,7-diamine
- Step 2 Preparation of N -(3-(trifluoromethyl)phenyl)isoxazolo[4,5-Z?]pyridine-3,7-diamine
- the title compound was prepared following the procedure described in step-6 of intermediate- 1 using N 7 -(4-methoxybenzyl)-N 3 -(3-(trifluoromethyl)phenyl)isoxazolo[4,5- ⁇ ]pyridine-3,7- diamine (380 mg, 0.92 mmol), H 2 S0 4 (5 mL) to afford 160 mg of the title product.
- reaction mixture was stirred at rt for 2 h.
- the reaction mixture was diluted with EtOAc and was washed with H 2 0 and brine.
- the organic layer was separated, dried, filtered and concentrated. The residue was purified by preparative TLC to afford 10 mg of the title product.
- the title compound was prepared following the procedure as described in example-3 using N 3 -[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- ⁇ ]pyridine-3,7-diamine (intermediate 1 , 70 mg, 0.222 mmol), 2-chloro-5-(isobutyramidomethyl)benzoic acid (intermediate-5, 150 mg, 0.581 mmol), DIPEA (223 mg, 1.75 mmol), isobutyl chloroformate (160 mg, 1.17 mmol), NaH (27 mg, 0.555 mmol) and THF (8 mL) to afford 10 mg of the title product.
- Step-1 Preparation of feri-butyl ⁇ 4-chloro-3-[(3- ⁇ [3-(trifluoromethyl) phenyl]amino ⁇ [l,2]thiazolo[4,5- ?]pyridin-7-yl)carbamoyl]benzyl ⁇ carbamate
- the title compound was prepared following the procedure described in example-3 using 5- ⁇ [(ieri-butoxycarbonyl)amino]methyl ⁇ -2-chlorobenzoic acid (intermediate-2, 128 mg, 0.451 mmol), N 3 -[3-(trifluoromethyl)phenyl][l,2]thiazolo[4,5-l?]pyridine-3,7-diamine (intermediate -13, 100 mg, 0.322 mmol), DIPEA (0.165 mL, 0.966 mmol), isobutyl chloroformate (0.052 mL, .386 mmol), NaH (80 mg, 2.00 mmol) and THF (10 mL) to afford 35 mg of the title product.
- Step-2 2-chloro-5- ⁇ [(2,2-dimethylpropanoyl)amino]methyl ⁇ -N-(3- ⁇ [3- (trifluoromethyl)phenyl] amino ⁇ [1 ,2]thiazolo[4,5- ⁇ ]pyridin-7-yl)benzamide
- Step 1 5-(Aminomethyl)-2-chloro-N-(3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- &]pyridin-7-yl)benzamide hydrochloride
- Step 2 (R)-N-(4-chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridine- 7-yl)carbamoyl)benzyl)tetrahydrofuran-2-carboxamide
- step-2 of example- 12 The title compound was prepared following the procedure described in step-2 of example- 12 using (5)-tetrahydrofuran-2-carboxylic acid chloride (22 mg, 0.194 mmol), 5-(aminomethyl)- 2-chloro-N-(3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-&]pyridin-7-yl)benzamide hydrochloride (step- 1 , example 12, 50 mg, 0.097 mmol), DIPEA (62 mg, 0.485 mmol) and THF (1 mL) to afford 13 mg of the title product.
- reaction mixture was stirred for 30 mins and then added to a solution of 5-(aminomethyl)-2-chloro-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ⁇ ]pyridin-7-yl)benzamide hydrochloride (step- 1, example 12, 60 mg, 0.103 mmol) and DIPEA (62 mg, 0.485 mmol) in THF (1 mL) at 0- 5 °C.
- the reaction mixture was stirred at rt for 1- 2 h.
- the reaction mixture was concentrated and was neutralized with IN HCl.
- the precipitate obtained was collected by filtration, dried and purified by column chromatography to afford 13 mg of the title product.
- step- 1 example 12, 60 mg, 0.103 mmol
- benzotriazole-l-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate 68 mg, 0.155 mmol
- DIPEA 62 mg, 0.485 mmol
- Step-1 Preparation of ieri-butyl 4-chloro-3-((3-((5-fluoro-2-methylphenyl)amino) isothiazolo[4,5-Z?]pyridin-7-yl)carbamoyl)benzylcarbamate
- the title compound was prepared following the procedure as described in example-3 using N 3 -(5-fluoro-2-methylphenyl)isothiazolo[4,5-Z?]pyridine-3,7-diamine (intermediate 14, 83 mg, 0.306 mmol), 5- ⁇ [(ieri-butoxycarbonyl)amino]methyl ⁇ -2-chlorobenzoic acid (intermediate-2, 122 mg, 0.428 mmol), DIPEA (1 16 mg, 0.918 mmol), isobutyl chloroformate (50 mg, 0.367 mmol), NaH (36 mg, 1.520 mmol) and THF (10 mL) to afford 50 mg of the title product.
- Step-2 Preparation of 2-chloro-N-(3-((5-fluoro-2-methylphenyl)amino)isothiazolo[4,5- b]pyridin-7-yl)-5 -(pivalamidomethyl)benzamide
- Step 1 Preparation of ieri-butyl 4-chloro-3-((3-((2-fluoro-5-(trifluoromethyl)phenyl) amino)isothiazolo[4, -/7]pyridin-7-yl)carbamoyl)benzylcarbamate
- the title compound was prepared following the procedure as described in example-3 using N 3 -(2-fluoro-5-(trifluoromethyl)phenyl)isothiazolo[4,5- ?]pyridine-3,7-diamine (intermediate 15, 100 mg, 0.304 mmol), 5- ⁇ [(ieri-butoxycarbonyl)amino]methyl ⁇ -2-chlorobenzoic acid (intermediate-2, 121 mg, 0.426 mmol), DIPEA (1 15 mg, 0.912 mmol), isobutyl chloroformate (49 mg, 0.364 mmol), NaH (60 mg, 2.5 mmol) and THF (10 mL) to afford 80 mg of the title product.
- Step 1 Preparation of ieri-butyl 4-((4-chloro-3-((3-((4-(trifluoromethyl)phenyl)amino) isothiazolo[4,5- ?] ridin-7-yl)carbamoyl)benzyl)carbamoyl)piperidine-l-carboxylate
- the title compound was prepared following the procedure described in example- 14 using 1- Boc-piperidine-4-carboxylic acid (35 mg, 0.155 mmol), 5-(aminomethyl)-2-chloro-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- >]pyridin-7-yl)benzamide hydrochloride (step- 1, example 12, 60 mg, 0.103 mmol), benzotriazole-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (68 mg, 0.155 mmol), and DIPEA (62 mg, 0.485 mmol) in DMF (2 mL) to afford 35 mg of the title product.
- 1- Boc-piperidine-4-carboxylic acid 35 mg, 0.155 mmol
- Step 2 Preparation of N-(4-chloro-3-((3-((4-(trifiuoromethyl)phenyl)amino)isothiazolo[4,5- 3 ⁇ 4]pyridin-7-yl)carbamoyl)benzyl)piperidine-4-carboxamide dihydrochloride
- 4-((4-chloro-3-((3-((4-(trifiuoromethyl)phenyl)amino)isothiazolo[4,5- &]pyridin-7-yl)carbamoyl)benzyl)carbamoyl)piperidine-l-carboxylate 35 mg, 0.051 mmol
- Step 1 Preparation of tert-butyl 4-chloro-3-((3-(cyclobutylamino)isothiazolo[4,5-Z?]pyridin-7- yl)carbamoyl)benzylcarb
- the title compound was prepared following the procedure as described in example-3 using N 3 -cyclobutylisothiazolo[4,5-Z?]pyridine-3,7-diamine (intermediate 16, 120 mg, 0.545 mmol), 5- ⁇ [(feri-butoxycarbonyl)amino]methyl ⁇ -2-chlorobenzoic acid (intermediate-2, 217 mg, 0.763 mmol), DIPEA (207 mg, 1.63 mmol), isobutyl chloroformate (88 mg, 0.654 mmol), NaH (65 mg, 4.54 mmol) and THF (10 mL) to afford 72 mg of the title product.
- Step 2 Preparation of 2-chloro-N-(3-(cyclobutylamino)isothiazolo[4,5- ?]pyridin-7-yl)-5- (pivalamidomethyl)benzamide
- Step 2 Preparation of 6-chloro-2-fluoro-N-(3-((3-fluorophenyl)amino)isothiazolo[4,5- 3 ⁇ 4]pyridin-7-yl)-3-(pivalamidomethyl)benzamide
- Step 2 Preparation of 2,6-dimethyl-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide
- the title compound was prepared following the procedure described in step 2 of example 21 using N 3 -[3-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- ?]pyridine-3,7-diamine (intermediate- 13, 50 mg, 0.161 mmol), 4-nitrophenyl 2,6-dimethyl-3-(pivalamidomethyl)benzoate (124 mg, 0.322 mmol), NaH (32 mg, 0.81 mmol, 60% in mineral oil) and DMF (3 mL) to afford 30 mg of the title product.
- Step 1 Preparation of 4-nitrophenyl 2-chloro-6-methyl-3-(pivalamidomethyl)benzoate
- Step 2 Preparation of 2-chloro-6-methyl-3-(pivalamidomethyl)-N-(3-((3- (trifiuoromethyl)phenyl)amino)isothiazolo[4,5- ⁇ ]pyridin-7-yl)benzamide
- Step 1 Preparation of 2-chloro-5 -(pivalamidomethyl)benzoic acid
- Step 1 Preparatio ethyl)benzoate
- the title compound was prepared following the procedure described in example -27, step-2 using 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid (intermediate-24, 200 mg, 0.668 mmol), EDCI (128 mg, 0.668 mmol), p-nitrophenol (93 mg, 0.668 mmol) and DIPEA (340 mg, 2.67 mmol) in THF (5 mL) to afford 250 mg of the title product.
- Step 2 Preparation of 6-chloro-2-methoxy-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide
- mPGES-1 microsomal prostaglandin E synthase-1
- PGH 2 prostaglandin H 2
- product PGE 2 prostaglandin E 2
- GSH reduced glutathione
- mPGES-1 inhibitors were screened by assessing their ability to inhibit formation of PGE 2 from PGH 2 in presence of mPGES-1 using anti-PGE 2 antibody based detection method.
- Recombinant human mPGES-1 was generated in-house by expressing in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489 - 495).
- Assay was set up using crude microsomal fractions at protein concentration of 40-60 ⁇ g mL.
- Test compounds were prepared in 100 % dimethyl sulfoxide (DMSO) to obtain 20 mM stock solution and then diluted using assay buffer comprising 0.1 M Potassium phosphate buffer with 2 mM EDTA. Final concentration of DMSO in reaction was 0.5 % (v/v).
- Negative controls comprised of all assay reagents except the enzyme.
- Positive controls comprised of enzyme reaction in the absence of any inhibitor.
- Test compounds were incubated for 10 minutes in assay buffer containing 2.5 mM GSH and mPGES-1 enzyme followed by addition of PG3 ⁇ 4 at a concentration of 15 ⁇ for 1 minute.
- Inhibition of mPGES-1 enzyme activity was measured using percent of reaction occurring in the positive control. Concentration response curves were plotted using percent inhibition of maximum enzyme reaction. IC5 0 value was calculated from 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 IC50 (nM) details for selected examples.
- the compounds prepared were tested using the above assay procedure and were found to have IC5 0 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM.
- the IC5 0 (nM) values of the compounds are set forth in Table 1 wherein "A” refers to an IC5 0 value of less than 20 nM, "B” refers to IC 50 value in range of 20.01 to 50.0 nM and "C” refers to IC 50 values more than 50 nM.
- A549 cell line was monitored as inhibition of IL- ⁇ induced PGE 2 release.
- A549 cells were maintained in DMEM medium with 10% FBS and 1%) Penicillin-Streptomycin Solution in 5% C0 2 at 37°C. Cells were seeded 24 h prior to the assay in 96 well plates in DMEM containing 1% Penicillin- Streptomycin and 2% FBS so as to get ⁇ 40,000 cells per well on the day of experiment. Assay was carried out in a total volume of 200 ⁇ . Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and then diluted using plain DMEM. Final concentration of DMSO in the reaction was 0.55% (v/v).
- DMSO dimethyl sulfoxide
- Concentration response curves were plotted as % of maximal response obtained in the absence of test antagonist. IC5 0 value was calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
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Abstract
The present invention relates to bicyclic compounds of formula (I) or pharmaceutically acceptable salt thereof as mPGES-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 asthama, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases. (I)
Description
SUBSTITUTED BICYCLIC HETEROARYL COMPOUNDS AS mPGES-1
INHIBITORS
Related applications
This application claims benefit of Indian provisional application No(s).
2618/MUM/2011 filed on September 15, 2011; 3222/MUM/2011 filed on November 14, 2011; 1655/MUM/2012 filed on June 5, 2012 and US provisional application No(s). 61/540,390 filed on September 28, 2011; 61/576,798 filed on December 16, 2011; 61/665,281 filed on June 27, 2012. All of which are hereby incorporated by reference in their entirety.
Technical Field
The present patent application relates to substituted bicyclic heteroaryl compounds as mPGES-1 inhibitors.
Background
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 other that in most cells and tissues are 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 proinflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE2, inclding u "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 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 known / 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 , which is 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 likely to be of benefit 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 likely to be of benefit 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, 1 17, 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 the intestinal tumourogenesis (Nakanishi et. al., Cancer
Research 2008, 68(9), 3251-9). In human beings, mPGES-1 is also upregulated in cancers such as colorectal cancer (Schroder Journal of Lipid Research 2006, 47, 1071-80).
Myositis is chronic muscle disorder characterized by muscle weakness and fatigue. Proinflammatory cytokines and prostanoids have been implicated in the development of myositis. In skeletal muscle tissue from patients suffering from myositis an increase in cyclooxygenases and mPGES-1 has been demonstrated, implicating mPGES-1 as a target for treating this condition. (Korotkova Annals of the Rheumatic Diseases 2008, 67, 1596- 1602).
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 have 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).
PCT publication numbers WO2006/063466, WO2007/059610, WO2010/034796, and
WO2010/100249 disclose numerous heterocyclic compounds which are shown to be inhibitors of microsomal prostaglandin E synthase- 1 (mPGES-1) enzyme.
The present invention is directed to novel compounds that are selective 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
A is selected from C3_i2cycloalkyl, C6_i4aryl, 5- 14 membered heteroaryl and 3-15 membered heterocyclyl;
L is selected from bond, -(CRxRy)nC(0)NRp-, -(CRxRy)nC(0)0-, -(CRxRy)n-, - (CRxRy)n-NRpC(0)-, -(CRxRy)n-NRpC(0)NRp-, -(CRxRy)n-NRpC(0)0- -(CRxRy)nNRpS02-, -(CRxRy)n-OC(0)-, -(CRxRy)„OC(0)0-, -(CRxRy)nOC(0)NRp-, -(CRxRy)nS(0)-, - (CRxRy)nS02-, -(CRxRy)nS(0)NRp-, -(CRxRy)nS02NRp- and -(CRxRy)nS-;
W is selected from hydrogen, substituted or unsubstituted Ci_galkyl, C2_ioalkenyl, C2_ loalkynyl, Ci-galkoxy, Ci_8alkyloxyCi_8alkyl, haloCi-salkyl, hydroxyCi-galkyl, haloCi-galkoxy, C3-i2cycloalkyl, C3-i2cycloalkylCi_8alkyl, C3-i2cycloalkenyl, C3-i2cycloalkenylCi_8alkyl, Ce- naryl, Ce-narylCi-salkyl, 3-15 membered heterocyclyl, 3- 15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi.galkyl;
R1 is selected from substituted or unsubstituted Ci.galkyl, C3_i2cycloalkyl, C3_ i2cycloalkylCi_8alkyl, C3_i2cycloalkenyl, C3_i2cycloalkenylCi_8alkyl, Ce-naryl, Ce-narylCi- galkyl, 3- 15 membered heterocyclyl, 3-15 membered heterocyclylCi-galkyl, 5- 14 membered heteroaryl and 5-14 membered heteroarylCi-8alkyl;
at each occurrence, R2 is independently selected from halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci-salkyl, C2_ioalkenyl, C2_ioalkynyl,
Ci-galkyloxyCi- galkyl, haloCi-salkyl, haloCi-galkoxy, hydroxyCi-galkyl, C3_i2cycloalkyl, C3_i2cycloalkylCi- 8alkyl, C3_i2cycloalkenyl, C3_i2cycloalkenylCi_8alkyl, C6-i4ar l, Ci-saryloxy, C6-i4arylCi_8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl, 5-14 membered heteroarylCi_8alkyl, -(CRxRy)rC(0)Ra, -(CRxRy)rC(0)NRaRb, - (CRxRy)rC(0)ORa, -(CRxRy)r-NRaRb, -(CRxRy)r-NRaC(0)Rb, -(CRxRy)r-NRaC(0)NRbRc, - (CRxRy)r-NRaC(0)ORb, -(CRxRy)r-N(Ra)S02Rb, -(CRxRy)rOC(0)Ra, -(CRxRy)rOC(0)ORa, - (CRxRy)rOC(0)NRaRb, -(CRxRy)rS(0)Ra, -(CRxRy)rS02Ra, -(CRxRy)rS(0)NRaRb, - (CRxRy)rS02NRaRb and -(CRxRy)rSRa;
R3 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted Ci_8alkyl, haloCi-salkyl, haloCi_galkoxy, and hydroxyCi-salkyl; at each occurrence, Rp is selected from hydrogen, substituted or unsubstituted Ci-salkyl and C6-i4arylCi_8alkyl;
at each occurrence, Ra, Rb and Rc which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci-salkyl, Ci_8alkyloxyCi- galkyl, haloCi-galkyl, hydroxyCi-salkyl, C3_i2cycloalkyl, Ce-naryl, 5-14 membered heteroaryl and 3- 15 membered heterocyclyl; or Ra and Rb or Rb and Rc together with the atom to which
they are attached, form a cyclic ring, which is substituted or unsubstituted cyclic rings and cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
at each occurrence, Rx and Ry, which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted Ci-galkyl, C3_i2cycloalkyl, Ce-naryl, Ce- narylCi-salkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylalkyl, 5-14 membered heteroaryl, and 5- 14 membered heteroarylCi_salkyl; or Rx and Ry together with the atom to which they are attached, form a substituted or unsubstituted 3 to 12 membered cyclic ring and cyclic ring optionally contains one or more hetero atoms selected from O, N or S;
'm' is an integer ranging from 0 to 4, both inclusive;
'n' is an integer ranging from 1 to 3, both inclusive;
'q' is an integer ranging from 0 to 2, both inclusive; and
'r' is an integer ranging from 0 to 4, both inclusive.
The compounds of formula (I) may involve one or more embodiments. Embodiments of formula (I) include compounds of formula (II), and compounds of formula (III) as described hereinafter. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, 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 Rp is hydrogen (according to an embodiment defined below) and X is S (according to another embodiment defined below).
According to one embodiment, specifically provided are compounds of formula (I), in which X is S(0)q and q is 0.
According to another embodiment, specifically provided are compounds of formula
(I), in which X is S.
According to yet another embodiment, specifically provided are compounds of formula (I), in which X is O.
According to yet another embodiment, specifically provided are compounds of formula (I), in which one of the G1, G2 and G3 is N.
According to yet another embodiment, specifically provided are compounds of formula (I), in which one of the G1, G2 and G3 is CR3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which G1 is N, G2 and G3 are CR3.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R3 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which G1 is N, G2 and G3 are CH.
According to yet another embodiment, specifically provided are compounds of formula (I), in which G1, G2 and G3 are CH.
According to yet another embodiment specifically provided are compounds of formula (I), in which Rp is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which A is C6-14aryl, preferably phenyl.
According to yet another embodiment specifically provided are compounds of formula (I), in which R2 is halogen (e.g. F, CI or Br), Ci_8alkyl (e.g. methyl, ethyl) or Ci_galkoxy (e.g. methoxy, ethoxy).
According to yet another embodiment specifically provided are compounds of formula (I), in which R2 is chloro, fluoro, methyl or methoxy.
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 R2 is chloro, fluoro, methyl or methoxy and m is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is substituted or unsubstituted C6_i4aryl or C3_i2cycloalkyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is substituted or unsubstituted C6-14aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi-salkyl (e.g. trifluoromethyl, difluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), C1-4 alkyl (e.g. methyl, ethyl) and haloCi-salkyl (e.g. trifluoromethyl, difluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is substituted or unsubstituted C3_i2cycloalkyl (e.g. cyclobutyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which R1 is 4-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-5-
trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3 -fluorophenyl, 3- trifluoromethylphenyl or cyclobutyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which L is -(CRxRy)n-NRpC(0)-. In this embodiment Rx, Ry and Rp are hydrogen and n is 1.
According to yet another embodiment specifically provided are compounds of formula (I), in which L is -CH2NHC(0)-.
According to yet another embodiment specifically provided are compounds of formula (I), in which L is a bond and W is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (I), in which W is substituted or unsubstituted Ci_8alkyl (e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan-l-yl, ie/t-butyl or 2-methylpropan-2-yl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which W is substituted or unsubstituted hydroxyCi-salkyl (e.g. 2-hydroxy propan-2-yl or 2-hydroxy propanyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which W is substituted or unsubstituted C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl). In this embodiment, substituents on C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl) are Ci galkyl (e.g. methyl), and hydroxy.
According to yet another embodiment, specifically provided are compounds of formula (I), in which W is C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl) optionally substituted with one or more substituents selected from Ci.salkyl (e.g. methyl), and hydroxyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which W is substituted or unsubstituted 3-15 membered heterocyclyl, (e.g. tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl).
According to yet another embodiment, specifically provided are compounds of formula (I), in which W is substituted or unsubstituted Ci-salkyl, hydroxyCi-salkyl, C3- i2cycloalkyl or 3-15 membered heterocyclyl.
According to yet another embodiment, specifically provided are compounds of formula (I), in which W is isopropyl, propan-2-yl, isobutyl, 2-methylpropan-l-yl, ieri-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2-hydroxy propanyl, cyclopropyl, cyclobutyl, 1- methylcyclopropyl, 1 -hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl,
tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
According to one embodiment, specifically provided are compounds of formula (I) with an IC50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM with respect to mPGES-1 activity as measured by method described in the present patent application.
Further embodiments relating to groups it1, it2, Pvp, A, X, m, n and W (and groups defined therein) are described hereinafter in relation to the compounds of formula (II). It is to be understood that these embodiments are not limited to use in conjunction with formula (II), but apply independently and individually to the compounds of formula (I). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (II) in which Rp is hydrogen, and consequently there is also provided a compound of formula (I) wherein Rp is hydrogen.
The application also provides a compound of formula (II), which is an embodiment of a compound of formula (I).
Accordingly the application provides the compound of formula (II):
(II)
or a pharmaceutically acceptable salt thereof,
wherein,
X is selected from O, and S(0)q;
G1 is N;
G2 and G3 are CR3;
W is selected from substituted or unsubstituted Ci-salkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_
8alkoxy, Ci-galkyloxyCi-galkyl, haloCi-galkyl, hydroxyCi-galkyl, haloCi_galkoxy, C3- i2cycloalkyl, C3-i2cycloalkylCi_8alkyl, C3_i2cycloalkenyl, C3-i2cycloalkenylCi_8alkyl, C6_Haryl, C6_i4aryl Ci_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi.galkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi-salkyl;
R1 is selected from substituted or unsubstituted Ci_8alkyl, C3_i2cycloalkyl, C3_ i2cycloalkylCi_8alkyl, C3_i2cycloalkenyl, C3-i2cycloalkenylCi_salkyl, C6-14aryl, Cg-naryl Ci_ salkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi-salkyl;
at each occurrence, R2 is independently selected from halogen, cyano, hydroxyl, substituted or unsubstituted Ci_galkyl, Ci_galkoxy, haloCi_8alkyl, haloCi.galkoxy and hydroxyC- i_8alkyl;
R3 is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted Ci_8alkyl, haloCi-salkyl and haloCi-salkoxy;
at each occurrence, Rp is selected from hydrogen, substituted or unsubstituted Ci_8alkyl and C6_i4arylCi_8alkyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'n' is an integer ranging from 1 to 4, both inclusive; and
'q' is an integer ranging from 0 to 2, both inclusive.
The compounds of formula (II) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, or any other embodiment defined herein. Thus the invention contemplates all possible combinations and permutations of the various independently described embodiments. For example, the invention provides compounds of formula (II) as defined above wherein X is S (according to an embodiment defined below), Rp is hydrogen (according to an embodiment defined below), R2 is chloro, fluoro, methyl or methoxy (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 X is S and q is 0.
According to another embodiment, specifically provided are compounds of formula (II), in which X is S.
According to yet another embodiment, specifically provided are compounds of formula (II), in which X is O.
According to yet another embodiment specifically provided are compounds of formula (II), in which Rp is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R3 is hydrogen.
According to yet another embodiment, specifically provided are compounds of formula (II), in which G2 and G3 are CH.
According to yet another embodiment, specifically provided are compounds of formula (II), in which A is phenyl.
According to yet another embodiment specifically provided are compounds of formula (II), in which R2 is halogen (e.g. F, CI or Br), Ci-salkyl (e.g. methyl, ethyl) or Ci-galkoxy (e.g. methoxy, ethoxy).
According to yet another embodiment specifically provided are compounds of formula
(II), in which R2 is chloro, fluoro, methyl or methoxy.
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 R2 is chloro, fluoro, methyl or methoxy and m is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is substituted or unsubstituted Ce-naryl or C3_i2cycloalkyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is substituted or unsubstituted Ce naryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi_8alkyl (e.g. trifluoromethyl, difluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi_galkyl (e.g. trifluoromethyl, difluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is substituted or unsubstituted C3_i2cycloalkyl (e.g. cyclobutyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which R1 is 4-trifiuoromethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-5- trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3 -fluorophenyl, 3- trifluoromethylphenyl or cyclobutyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which W is substituted or unsubstituted Ci_galkyl (e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan-l-yl, ieri-butyl or 2-methylpropan-2-yl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which W is substituted or unsubstituted hydroxyCi-salkyl (e.g. 2-hydroxy propan-2-yl or 2-hydroxy propanyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which W is substituted or unsubstituted C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl). In this embodiment, substituents on C3-i2cycloalkyl (e.g. cyclopropyl, cyclobutyl) are Ci_8alkyl (e.g. methyl), and hydroxy.
According to yet another embodiment, specifically provided are compounds of formula (II), in which W is C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl) optionally substituted with one or more substituents selected from Ci_8alkyl (e.g. methyl), and hydroxyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which W is substituted or unsubstituted 3-15 membered heterocyclyl, (e.g. tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl).
According to yet another embodiment, specifically provided are compounds of formula (II), in which W is substituted or unsubstituted
hydroxyCi galkyl, C3 i2cycloalkyl or 3- 1 membered heterocyclyl.
According to yet another embodiment, specifically provided are compounds of formula (II), in which W is isopropyl, propan-2-yl, isobutyl, 2-methylpropan-l-yl, tert-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2-hydroxy propanyl, cyclopropyl, cyclobutyl, 1- methylcyclopropyl, 1 -hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
According to yet another embodiment specifically provided are compounds of formula (II), in which n is 1.
According to yet another embodiment, specifically provided are compounds of formula (II) with an IC50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM with respect to mPGES-1 activity as measured by method described in the present patent application.
Further embodiments relating to groups R1, R2, m and W (and groups defined therein) are described hereinafter in relation to the compounds of formula (III). It is to be understood
that these embodiments are not limited to use in conjunction with formula (III), but apply independently and individually to the compounds of formula (I) or formula (II). For example, in an embodiment described hereinafter, the invention specifically provides compounds of formula (III) in which m is 1 or 2, and consequently there is also provided a compound of formula (I) or formula (II) wherein mis 1 or 2.
The application also provides a compound of formula (III), which is an embodiment of a compound of formula (I).
Accordingly the application provides the compound of formula (III):
(III)
or a pharmaceutically acceptable salt thereof,
wherein,
W is substituted or unsubstituted Ci_8alkyl, hydroxyCi_8alkyl, C3_i2cycloalkyl, or 3-15 membered heterocyclyl;
R1 is substituted or unsubstituted Ce-naryl or C3_i2cycloalkyl;
at each occurrence, R2 is halogen, Ci_4 alkyl, or Ci-galkoxy; and
'm' is an integer ranging from 0 to 4, both inclusive.
The compounds of formula (III) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified. It is also to be understood that the embodiments defined herein may be used independently or in conjunction with any definition, 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 R2 is chloro, fiuoro, methyl or methoxy (according to an embodiment defined below) and m is 1 or 2 (according to another embodiment defined below).
According to one embodiment specifically provided are compounds of formula (III), in which R2 is halogen (e.g. F, CI or Br), Ci.galkyl (e.g. methyl, ethyl) or Ci-salkoxy (e.g. methoxy, ethoxy).
According to another embodiment specifically provided are compounds of formula (III), in which R2 is chloro, fluoro, methyl or methoxy.
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 R2 is chloro, fluoro, methyl or methoxy and m is 1 or 2.
According to yet another embodiment, specifically provided are compounds of formula (III), in which R1 is substituted or unsubstituted C6-14aryl, preferably substituted or unsubstituted phenyl, more preferably substituted phenyl. In this embodiment, substituent(s) on phenyl may be one or more and are independently selected from halogen (e.g. F, CI or Br), Ci_4 alkyl (e.g. methyl, ethyl) and haloCi_salkyl (e.g. trifluoromethyl, difluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which R1 is phenyl optionally substituted with one or more substituents selected from halogen (e.g. F, CI or Br), C1-4 alkyl (e.g. methyl, ethyl) and haloCi-salkyl (e.g. trifluoromethyl, difluoromethyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which R1 is substituted or unsubstituted C3_i2cycloalkyl (e.g. cyclobutyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which R1 is 4-trifluoromethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-5- trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3 -fluorophenyl, 3- trifluoromethylphenyl or cyclobutyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which W is substituted or unsubstituted Ci-galkyl (e.g. isopropyl or propan-2- yl, isobutyl or 2-methylpropan- 1 -yl, ie/t-butyl or 2-methylpropan-2-yl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which W is substituted or unsubstituted hydroxyCi-galkyl (e.g. 2-hydroxy propan-2-yl or 2-hydroxy propanyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which W is substituted or unsubstituted C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl). In this embodiment, substituents on C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl) are Ci_salkyl (e.g. methyl), and hydroxy.
According to yet another embodiment, specifically provided are compounds of formula (III), in which W is C3_i2cycloalkyl (e.g. cyclopropyl, cyclobutyl) optionally substituted with one or more substituents selected from Ci.galkyl (e.g. methyl), and hydroxyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which W is substituted or unsubstituted 3-15 membered heterocyclyl, (e.g. tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl).
According to yet another embodiment, specifically provided are compounds of formula (III), in which W is substituted or unsubstituted Ci.galkyl, hydroxyCi.galkyl, C _ i2cycloalkyl or 3-15 membered heterocyclyl.
According to yet another embodiment, specifically provided are compounds of formula (III), in which W is isopropyl, propan-2-yl, isobutyl, 2-methylpropan-l-yl, ieri-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2-hydroxy propanyl, cyclopropyl, cyclobutyl, 1 - methylcyclopropyl, 1 -hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
According to one embodiment, specifically provided are compounds of formula (III) with an IC50 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM with respect to mPGES-1 activity as measured by method described in the present patent application.
It should be understood that the formulas (I), (II) and (III), 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 in the present patent application may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
The compounds and pharmaceutical compositions of the present invention are useful for inhibiting the activity of mPGES-1, which is believed to be related to a variety of disease states.
The present patent application further provides a method of inhibiting mPGES-1 in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor. Detailed Description of the Invention
Definitions
The invention is defined by the claims and not limited by the description provided herein below. The terms used in the appended claims are defined herein in this glossary section, with the proviso that the claim terms may be used in a different manner if so defined by express recitation.
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-salkyl), 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). 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 10 carbon atoms (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_8alkyl or
Ci_8alkyloxyCi_8alkyl). 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-salkyl). 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 fiuoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafiuoroethoxy, 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 "hydroxyalkyl" refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups (i.e. hydroxyCi_8alkyl). Examples of hydroxyalkyl moiety 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, for example C3_i2cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g., spiro(4,4)non-2-yl. 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 12 carbon atoms directly attached to an alkyl group, for example C3_i2cycloalkylCi_8alkyl. 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 12 carbon atoms with at least one carbon-carbon double bond, for example C3_i2cycloalkenyl,
such as 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 12 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group, for example C3_i2cycloalkenylCi_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 "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, i.e. C6-i4arylCi_galkyl, 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 "aryloxy" refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule (i.e. Ce naryloxy). Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
The term "heterocyclic ring" or "heterocyclyl" unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five hetero atoms selected from nitrogen, phosphorus, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. 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 olefmic 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, oxabicyclo[3.1.0]hexanyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, 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, as defined above, directly bonded to an alkyl group (i.e. heterocyclylCi-salkyl). The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described or claimed herein may be substituted or unsubstituted.
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. 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, 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, as defined above, directly bonded to an alkyl group (i.e. heterarylCi-salkyl). The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described or claimed herein may be substituted or unsubstituted.
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)NRxR , -C(0)ONRxR , - NRxCONRyRz , -N(Rx')SOR , -N(Rx')S02R , -(=N-N(Rx')R ), -NRx C(0)OR , -NRxRy , - NRxC(0)Ry, -NRx'C(S)R -NRxC(S)NRyRz', -SONRxRy, -S02NRxRy -ORx', - OC(0)NR Rz', -OC(0)OR , -OC(0)Rx', -OC(0)NRxRy -SRX', -SORx', -S02Rx', and -ON02, wherein 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 term "acute pain" is usually self-limiting. The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors". Nociceptors are primary sensory afferent (C and 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).
The compound described in the present patent application may form salts. Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of present patent application are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). With respect to the overall compounds described by the general formula (I) the present patent application extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the present patent application may be separated from one another by the method 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 of the invention may exist in solvated forms (such as hydrates) as well as unsolvated forms, and that the invention encompasses all such forms.
Abbreviations used in the description of the chemistry and in the examples that follow are:
Aq. : aqueous;
CHC13 : chloroform;
CDCI3 : deuterated chloroform;
Cs2C03 : cesium carbonate
DMSO : di-methyl sulfoxide;
DCM : dichloromethane;
DMF : NN-Dimethylformamide;
DMA : dimethylacetamide;
DIPEA : NN-diisopropylethylamine
EA : ethyl acetate
EDCI : 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide)
eq. : equivalents
HOBt : hydroxybenzotriazole
h : hours
: coupling constant in units of Hz
K2C03 : potassium carbonate
LDA : lithium diisopropylamide
MeOH : methanol
NaHC03 : sodium bicarbonate
NaOtBu : sodiumtertiarybutoxide
NMP : N-methylpyrrolidinone
PCI5 : phosphorous pentachloride
POCI3 : phosphorous oxychloride
rt or PvT : room temperature (22-26°C)
THF : tetrahydrofuran
TEA : triethylamine
TBAF : tetra-n-butylammonium fluoride
Pharmaceutical Compositions
The compounds of the invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the invention. The pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylene.
The pharmaceutical 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.
Methods of Treatment
Compounds of the present invention are particularly useful because they may selectively inhibit the activity of prostaglandin E synthases {and particularly microsomal prostaglandin E synthase-1 (mPGES-1)} , i.e., they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit mPGES-1
modulating effect. Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
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 of Formula I are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) and dental procedures as well as the preemptive treatment of surgical pain. The pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy - induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy & chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease like multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, 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. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. Compounds of Formula I may also be useful for the treatment or prevention of endometriosis, hemophilic arthropathy and Parkinson's disease.
Compounds of the present invention may 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 compound of the present invention may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of 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, Myelodysplastic 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 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), (IV) and specific examples are prepared using techniques known to one skilled 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 to person skilled in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible geometrical isomers and stereoisomers are envisioned within the scope of this invention.
The starting materials 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 invention may be prepared through the reaction scheme as follows, wherein all symbols are as defined above.
Synthetic scheme 1
The synthesis of compound of formula (I) (wherein X, G1, G2, G3, L, W, A, R1 , R? Rp, and m are as defined above for compound of formula (I)) can be performed as described in synthetic scheme 1, which involves the treatment of amine compound of formula (1) with appropriate acyl compound of formula (2), wherein LG represent OH or CI or O-alkyl or O- aryl or 0(C=0)-alkyl. When LG represents OH the reaction can be performed with a suitable coupling reagent known to those skilled in the art for example, EDCI 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. Alternatively, the reaction can be performed using a suitable reagent such as isobutyl chloro formate, oxalyl chloride or thionyl chloride in a suitable solvent such as DMF, DCM or THF, in the presence of a suitable base such as DIPEA.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. Furthermore, when LG represents O-alkyl or O-aryl or 0(C=0)-alkyl the reaction can be performed with a suitable reagent such as trimethylaluminium or a strong base such as sodium hydride (NaH) in a suitable solvent such as toluene or DMF.
ynthetic scheme 2
The synthesis of the compound of formula (III) (wherein W, R1, R2 and m are as defined above for compound of formula (III)) can be performed as described in synthetic scheme 2. The reaction of appropriately substituted pyridine derivative (3) (wherein Y is CI, Br or I and PG is an appropriate protecting group such as 4-methoxybenzyl) with a thiolating agent such as sodium hydrosulfide or sodium thiomethoxide in a suitable solvent such as DMF or NMP in the temperature range of 20-250°C can provide the compound of formula (4). The reaction of compound of formula (4) under suitable conditions, known to those skilled in the art, such as treatment with bromine in a suitable solvent such as EA in the temperature range of 20-250°C can provide the compound of formula (5). The treatment of compound of formula (5) with an appropriate amine (R1-NH2) under suitable conditions such as in the presence of a suitable palladium catalyst in a suitable solvent such as DMF or dioxane in the temperature range of 20-200°C can provide the compound of formula (6). Alternatively, compound of formula (6) can also be prepared by treatment of compound of formula (5) with an appropriate amine (R1-NH2) optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or methanol (MeOH). Removal of the protecting group (PG) from compound of formula (6) under conditions known to those skilled in the art such as with trifluoroacetic acid or hydrochloric acid in a suitable solvent such as methanol or dioxane in the temperature range of 0-200°C can provide the compound of formula (7). Furthermore, treatment of compound of formula (7) with appropriate acyl compound of formula (8) wherein LG represents OH or CI or O-alkyl or O-aryl or 0(C=0)-alkyl, can provide the compound of formula (III) under the conditions as described in scheme 1.
Synthetic scheme 3
The synthesis of the compound of formula (III) (wherein W, R1, R2 and m are as defined above for compound of formula (III)) can be performed as described in synthetic scheme 3. The coupling of compound of formula (7) with compound of formula (9) (wherein LG represents OH or CI or O-alkyl or O-aryl or 0(C=0)-alkyl) provides compound of formula (10). Further deprotection of compound of formula (10) using a suitable deprotecting agent (for e.g. HCl) provides compound of formula (11). Coupling of compound of (11) with compound of formula (12) (wherein LG represents OH or CI or O-alkyl or O-aryl or 0(C=0)- alkyl) can provide compound of formula (III) under the conditions as described in scheme 1.
Synthetic scheme 4
Alternatively, the synthesis of the compound of formula (III) (wherein W, R1, R2 and m are as defined above for compound of formula (III)) can be accomplished as described in
synthetic scheme 4. The removal of the protecting group (PG) from compound of formula (3) (wherein Y is CI, Br or I and PG is an appropriate protecting group such as 4-methoxybenzyl) under conditions known to those skilled in the art such as with trifluoroacetic acid or hydrochloric acid in a suitable solvent such as methanol or dioxane in the temperature range of 0-200°C can provide the compound of formula (13) (wherein Y is CI, Br or I). The treatment of compound of formula (13) with appropriate acyl compound of formula (8) wherein LG represents OH or CI or O-alkyl or O-aryl or 0(C=0)-alkyl, can provide the compound of formula (14) under the conditions as described in scheme 1. Subsequently, the reaction of compound of formula (14) (wherein Y is CI, Br or I) with a thiolating agent such as sodium hydrosulfide or sodium thiomethoxide in a suitable solvent such as DMF or NMP in the temperature range of 20-250°C can provide the compound of formula (15). The reaction of compound of formula (15) under suitable conditions, known to those skilled in the art, such as treatment with bromine in a suitable solvent such as EA in the temperature range of 20- 250°C can provide the compound of formula (16). The treatment of compound of formula (16) with an appropriate amine (R'-NH^) under suitable conditions such as in the presence of a suitable palladium catalyst in a suitable solvent such as DMF or dioxane in the temperature range of 20-200°C can provide the compound of formula (III). Alternatively, compound of formula (III) can also be prepared by treatment of compound of formula (16) with an appropriate amine ( 1-NH2) optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or methanol (MeOH).
Synthetic scheme 5
(IV) (1 9)
The synthesis of the compound of formula (IV) (wherein W, R1, R2 and m are as defined above for compound of formula (I)) can be performed as described in synthetic scheme 5. The reaction of appropriately substituted pyridine (3) derivative (wherein Y is CI,
Br or I and PG is an appropriate protecting group such as 4-methoxybenzyl) with a suitable reagent such as acetohydroxamic acid or p-nitrobenzophenoneoxime or acetoxime in presence of a suitable base such as potassium carbonate or potassium ieri-butoxide in a suitable solvent such as DMF or THF in the temperature range of 20-250°C can provide the compound of formula (17). The reaction of compound of formula (17) under suitable conditions, known to those skilled in the art, such as treatment with an appropriate halide or pseudohalide in the presence of a suitable palladium catalyst in a suitable solvent such as DMF or dioxane in the temperature range of 20-200°C can provide the compound of formula (18). Alternatively, the compound of formula (18) can also be prepared by treatment of compound of formula (17) with an appropriate halide or pseudohalide optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or THF. The compound of formula (18) can also be prepared with an appropriate carbonyl compound in presence of a suitable acid such as acetic acid in a suitable solvent such as dichloromethane and an appropriate reducing agent such as sodium triacetoxyborohydride in the temperature range 20-200 °C. Removal of the protecting group (PG) from compound of formula (18) under conditions known to those skilled in the art such as with trifluoroacetic acid or hydrochloric acid in a suitable solvent such as methanol or dioxane in the temperature range of 0-200°C can provide the compound of formula (19). Furthermore, treatment of compound of formula (19) with appropriate acyl compound of formula (8) wherein LG represents OH or CI or O-alkyl or O-aryl or 0(C=0)-alkyl, can provide the compound of formula (IV) under the conditions as described in scheme 1.
Synthetic scheme 6
Alternatively, the synthesis of the compound of formula (IV) can be accomplished as described in synthetic scheme 6. The reaction of the compound of formula (14) (wherein Y is CI, Br or I) with a suitable reagent such as acetohydroxamic acid or p- nitrobenzophenoneoxime or acetoxime in presence of a suitable base such as potassium carbonate or potassium ieri-butoxide in a suitable solvent such as DMF or THF in the temperature range of 20-250°C can provide the compound of formula (20). The reaction of compound of formula (20) under suitable conditions, known to those skilled in the art, such as treatment with an appropriate halide or pseudohalide in the presence of a suitable palladium
catalyst in a suitable solvent such as DMF or dioxane in the temperature range of 20-200°C can provide the compound of formula (IV). Alternatively, compound of formula (IV) can also be prepared by treatment of compound of formula (20) with an appropriate halide or pseudohalide optionally in presence of a suitable base such as sodium hydride or potassium carbonate in a suitable solvent such as DMF or THF. The compound of formula (IV) can also be prepared with an appropriate carbonyl compound in presence of a suitable acid such as acetic acid in a suitable solvent such as dichloromethane and an appropriate reducing agent such as sodium triacetoxyborohydride in the temperature range 20-200 °C.
The synthesis of the compound of formula (8) (wherein LG represents and OH, R2, m and W are as defined above) is described in synthetic scheme 7. The reaction of compound of formula (21) with appropriate reagent such as N-(hydroxymethyl)trifluoroacetamide in presence of a strong acid such as H2S04 in the temperature range 20-100 °C can provide the compound of formula (22). Subsequently, compound of formula (23) can be obtained from compound of formula (22) under the standard acidic (e.g. HC1, H2S04) or basic (NaOH, OH) conditions in an appropriate solvent such as THF or dioxane in the temperature range 20-200 °C. The acylation of the compound of formula (23) can be performed using the condition known to those skilled in the art in presence of an appropriate acylating agent in a suitable solvent to provide the compound of formula (8).
Synthetic scheme 8
Alternatively, the compound of formula (8) can be prepared following the pathway described in synthetic scheme 8 wherein the compound of formula (23) (where LG represent
OH) can be converted to the compound of formula (24) by incorporating appropriate protecting group (PG) under the standard conditions known to those skilled in the art. The esterification of the compound of formula (24) under the standard conditions can provide the compound of formula (25) (wherein LG' represents O-alkyl, O-aryl). Subsequent liberation of the amino group to provide the compound of formula (26) and the acylation of compound of formula (26) with appropriate acylating agent can provide the compound of formula (27). The hydrolysis of the compound of formula (27) under the standard conditions can provide the compound of formula (8) (wherein LG represents OH).
(28) (29) (30) (23)/ (26)
The synthesis of the compound of formula (23) (wherein LG represents OH) and/or (26) (wherein LG represents O-alkyl, O-aryl) also can be prepared following the pathway described in synthetic scheme 9 wherein the methyl group of compound (28) can be converted to compound of formula (29) by incorporating an appropriate leaving group Z, preferably a halo or pseudohalo group. Then the treatment of compound of formula (29) with a suitable azide source can provide the compound of formula (30) which can be converted to the compound of formula (23) and/or (26) under standard reduction conditions known to those skilled in the art.
(31 ) (32) (33) (23)/ (26)
The synthesis of the compound of formula (23) (wherein LG represents OH) and/or (26) (wherein LG represents O-alkyl, O-aryl) can be achieved starting from the compound of formula (31)). The reaction of compound of formula (31) with a suitable base such as nBuLi and a formylating agent such as DMF in a suitable solvent such as THF in the temperature range -100 to 20 °C can provide the compound of formula (32). The formyl group in (32) can be converted to the corresponding hydroxylamino compound of formula (33) by reacting with a hydroxylamineoxime in a suitable solvent such as methanol in the temperature range 20-200 °C. The reduction of the compound of formula (33) under standard conditions known to those skilled in the art can provide the compound of formula (23)/(26).
ynthetic scheme 11
(28) (32) (3 ) ^
The synthesis of compound of formula (26) can also be performed following the pathway described in synthetic scheme 11 by standard reduction of compound of formula (34). The synthesis of compound of formula (34) can be accomplished starting from compound of formula (31) (wherein Y' = Br or I) using an appropriate source of cyanating agent such as Zn(CN)2 in presence of a suitable catalyst such as Pd(OAc)2 or Cul in a suitable solvent such as DME or DMF in the temperature range 20-250 °C. Alternatively, the compound of formula (34) can be obtained from compound of formula (32) using the procedure known those skilled in the art. The synthesis of compound of formula (32) can be performed as described above or it can also be prepared from compound of formula (28) by direct oxidation or via compound of formula (35) (where Y' is Br or I) using known conditions.
Experimental
Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate (Na2S04), filtration and evaporation of the solvent under reduced pressure. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase.
Preparation of Intermediates
Intermediate 1
N3-[4-(trifluoromethyl)phenyl][l ,2 3,7-diamine
To a solution of 3-bromo pyridine (25 g, 0.158 mol) in glacial acetic acid (150 mL) was added hydrogen peroxide (50 wt.% in H2O, 150 mL) at 10-20°C and the reaction mixture was stirred at rt for 30 mins and further heated to reflux for 16 h. The reaction mixture was concentrated to obtain 25 g of 3-bromopyridine 1 -oxide which was taken to the next step without further purification. To the solution of 3-bromopyridine 1-oxide (25 g, 0.144 mol) obtained above in cone H2SO4 (175 mL) was added KNO3 (175 g, 1.73 mol) portion wise and the reaction mixture was heated at 110 °C for 12 h. The reaction mixture was slowly poured onto ice and the precipitate obtained was filtered and dried to afford 16 g of 3-bromo-4-nitropyridine 1- oxide. A solution of 3-bromo-4-nitropyridine 1-oxide (16 g, 73.06 mmol) in methanol (50 mL) was saturated with HCl gas and the reaction mixture was stirred at rt for 2 h. The reaction mixture was neutralized with NaHCC and concentrated. The concentrate was extracted with 5% MeOH in CH2CI2. The organic layer was separated, dried, filtered and concentrated to afford 12 g of the title product. XH NMR (300 MHz,CDCl3): δ 8.43 (s, 1H), 8.09-8.06 (d, J = 6.9 Hz, 1H), 7.36-7.28 (d, / = 7.2 Hz, 1H); MS (m/z): 210.12 (M+H)+.
Step 2: Preparation of 3-bromo-4-chloropyridine-2-carbonitrile
To a solution of 3-bromo-4-chloropyridine 1-oxide (7 g, 33.58 mmol) in CH3CN was added trimethylsilyl cyanide (13.35 g, 134.6 mmol) and ΕΪ3 (15.61 g, 117 mmol) and the reaction mixture was heated at 80 °C for 5 h. The reaction was quenched with water and was extracted with ethyl acetate. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 4 g of the title product. H
NMR (300 MHz, CDC13): δ 8.54 (d, /= 4.8 Hz, 1H), 7.63 (d, J = 5.4 Hz, 1H).
Step 3: Preparation of 3-bromo-4-[(4-methoxybenzyl)amino]pyridine-2-carbonitrile
To a solution of 3-bromo-4-chloropyridine-2-carbonitrile (4.0 g, 12.57 mmol) in DMF (20 mL) was added 4-methoxybenzyl amine (2.6 g, 18.86 mmol) and DIPEA (4.4 mL, 25.14 mmol) and the reaction mixture was heated at 70°C for 12 h. The reaction was quenched with water and was extracted with ethyl acetate. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 3.5 g of the title product. !H NMR (300 MHz, DMSO d6): δ 8.06 (d, / = 5.7 Hz, 1H), 7.47 (m, 1H), 7.23 (d, / = 8.4 Hz, 2H), 6.87 (d, J = 8.1 Hz, 2H), 6.68 (d, / = 6 Hz, 1H), 4.41 (d, J = 6.3 Hz, 2H), 3.69 (s, 3H); MS (m/z): 318.30 (M+H)+.
Step 4: Preparation of 3-bromo-N-( -methoxybenzyl)[l ,2]thiazolo[4,5-^]pyridin-7-amine
To a solution of 3-bromo-4-[(4-methoxybenzyl)amino]pyridine-2-carbonitrile (1.0 g, 3.14 mmol) in N-methylpyrrolidinone (5 mL) was added sodium thiomethoxide (550 mg, 7.85 mmol) and the reaction mixture was heated at 130-140°C for 1 h. The reaction was quenched with cone. HC1 at 0°C and the yellow precipitate obtained was filtered and dried to afford 600 mg of 4-[(4-methoxybenzyl)amino]-3-sulfanylpyridine-2-carbonitrile which was taken to the next step without further purification. *H NMR (300 MHz, DMSO d6): δ 13.61 (br s, 1H), 8.40 (m, 1H), 7.79 (d, / = 6.3 Hz, 1H), 7.25 (d, / = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.43 (d, J = 6.3 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H).
To a solution of 4-[(4-methoxybenzyl)amino]-3-sulfanylpyridine-2-carbonitrile (600 mg, 2.21 mmol) in ethyl acetate (5 mL) at 0°C was added bromine (0.137 mL, 2.65 mmol) and the reaction mixture was stirred at rt for 30 min. and further heated to reflux for 2 h. The reaction mixture was concentrated and purified by column chromatography to afford 300 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 8.34 (d, = 5.4 Hz, 1H), 8.17 (m, 1H), 7.31 (d, / = 8.1 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 5.7 Hz, 1H), 4.47 (d, / = 5,1 Hz, 2H), 3.72 (s, 3H).
Step 5: Preparation of N7-(4-methoxybenzyl)-N3-[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- ¾]pyridine-3 ,7-diamine
O
To a solution of 3-bromo-N-(4-methoxybenzyl)[l ,2]thiazolo[4,5-&]pyridin-7-amine (300 mg, 0.86 mmol) in dioxane (5 mL) were added 4-trifluoromethylaniline (208 mg, 1.29 mmol), CS2CO (840 mg, 2.58 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (150 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium(0) (79 mg, 0.086 mmol) under nitrogen. The reaction mixture was heated at 110°C for 2 h. The reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was washed with water and brine. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 150 mg of the title product. H NM (300 MHz, DMSO d6): δ 10.03 (br s, 1H), 8.26 (m, 3H), 7.90 (m, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.31 (d, / = 8.4 Hz, 2H), 6.91 (d, = 8.7 Hz, 2H), 6.58 (d, J = 5.1 Hz, 1H), 4.47 (d, / = 6.0 Hz, 2H), 3.72 (s, 3H); MS (m/z): 431.15 (M+H)+.
Step 6: Preparation of N -[4-(trifluoromethyl)phenyl][l,2]thiazolo[4,5-&]pyridine-3,7-diamine A solution of N7-(4-methoxybenzyl)-N3-[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- b]pyridine-3,7-diamine (150 mg, 0.35 mmol) in trifluoroacetic acid (3 mL) was heated at 80°C for 2 h. The reaction mixture was concentrated and the solid mass was diluted with CHCI3 and was washed with a saturated solution of NaHC03, water and brine. The organic layer was separated, dried, filtered and concentrated to afford 90 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 9.99 (br s, 1H), 8.25 (m, 3H), 7.64 (d, / = 8.4 Hz, 2H), 6.94 (br s, 2H, NH2), 6.62 (d, / = 5.4 Hz, 1H); MS (m/z): 309.27 (M-H)".
Intermediate 2
Step 1 : Preparation of 2-chloro-5-{[(trifluoroacetyl)amino]methyl}benzoic acid
To a solution of 2-chlorobenzoic acid (500 mg, 3.49 mmol) in cone H2S04 was added 2,2,2- trifluoro-N-(hydroxymethyl)acetamide (547 mg, 3.49 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The precipitate was collected by filtration, dried and recrystallized from toulene/butan-2-one (7: 1) to afford 800 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 13.47 (br s, 1H), 10.06 (br s, 1H), 7.71 (s, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.43 (d, / = 9.9 Hz, 1H), 4.42 (d, / = 6.0 Hz, 2H); MS (m/z): 280.18 (M-H)\
Step 2: Preparation of 5- {[(ieri-butoxycarbonyl)amino]methyl} -2-chlorobenzoic acid
A solution of 2-chloro-5- {[(trifluoroacetyl)amino]methyl}benzoic acid (800 mg, 2.84 mmol) in cone. HCl (5 mL) and dioxane (1 mL) was heated at reflux for 12 h. The reaction mixture was concentrated and the concentrate was dissolved in THF (10 mL). The solution was treated with NaOH (284 mg, 7.10 mmol) in H20 (1 mL) at 0°C followed by di-ie/t-butyl dicarbonate (840 mg, 3.00 mmol). The reaction mixture was stirred rt for 16 h. The reaction mixture was acidified with IN HCl and the pH was adjusted to 2-3. The reaction mixture was extracted with 5% MeOH in CHCI3. The organic layer was separated, dried, filtered and concentrated. The concentrate was recrystallized from toulene/butan-2-one (7: 1) to afford 800 mg of the title product. !H NMR (300 MHz, DMSO d6): δ 13.1 (br s, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 4.13 (d, / = 5.7 Hz, 2H), 1.38 (s, 9H); MS (m/z): 283.94 (M-H)~.
Intermediate 3
fert-Butyl {4-chloro-3-[(3- {[4-(trifluoromethyl)phenyl]amino} [ l ,2]thiazolo[4,5- ?]pyridin-7- yl)carbamoyl]benzyl} carbamate
To the solution of 5-{[(½ri-butoxycarbonyl)amino]methyl} -2-chlorobenzoic acid (intermediate 2, 80 mg, 0.280 mmol) in CH2CI2 (2 mL) were added oxalyl chloride (71 mg, 0.560 mmol) and DMF (1 drop). The reaction mixture was stirred at rt for 2 h and concentrated. A solution of the concentrate in CH2CI2 (2 mL) were treated with p-nitrophenol (77 mg, 0.560 mmol) and Et3N (84 mg, 0.331 mmol) at 0°C and the reaction mixture was stirred at rt for 12 h. The reaction mixture was washed with water and brine. The organic layer was separated, dried, filtered and concentrated. The concentrate was used for the next step without further purification.
To the solution of N3-[4-(trifluoromethyl)phenyl][ l ,2]thiazolo[4,5-^]pyridine-3,7-diamine (Intermediate 1 , 43 mg, 0.14 mmol) and the above concentrate in THF (2 mL) was added NaH (1 1 mg, 0.28 mmol) at 0°C and the reaction mixture was stirred at rt for 3 h. The reaction was quenched with H20 and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to obtain 30 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.58 (s, 1H), 10.18 (s, 1H), 9.4 (br s, 1H), 8.72 (d, / = 4.8 Hz, 1H), 8.28 (d, / = 8.4 Hz, 2H), 7.68 (m, 3H), 7.60-7.54 (m, 2H), 7.42 (d, / = 9.3 Hz, 1H), 4.19 (d, J = 6.0 Hz, 2H), 1.20 (s, 9H); MS (m/z): 577.99 (M+H)+.
Intermediate 4
To a solution of 5- {[(ieri-butoxycarbonyl)amino]methyl} -2-chlorobenzoic acid (intermediate- 2, 1.0 g, 3.50 mmol) in DMF (5.0 mL) were added methyl iodide (496 mg, 3.50 mmol) and potassium carbonate (966 mg, 7.00 mmol). The reaction mass was stirred at rt for 18 h. The reaction mass was diluted with EtOAc and the organic layer was washed with water and brine. The organic layer was separated, dried and concentrated. The residue was purified by column chromatography to afford 440 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 7.66 (s, 1H), 7.49-7.52 (m, 2H), 7.42 (d, / = 6.3 Hz, 1H), 4.13 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 1.38 (s, 9H).
A solution of methyl 5-(((ierf-butoxycarbonyl)amino)methyl)-2-chlorobenzoate (100 mg, 0.334 mmol) in EtOAc saturated with HC1 solution (1 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and was triturated with pentane to afford 80 mg of the title
product. H NMR (300 MHz, DMSO d6): δ 8.20 (br s, 3H), 7.95 (s, 1H), 7.67 (s, 2H), 4.00 (s, 2H), 3.88 (s, 3H).
To a solution 1-methylcyclopropanecarboxylic acid (140 mg, 1.39 mmol) in dichloromethane (5.0 mL) were added oxalyl chloride (211 mg, 1.6 mmol) and a drop of DMF. The reaction mass was stirred at rt for 2 h and was added to the solution of methyl 5-(aminomethyl)-2- chlorobenzoate hydrochloride (200 mg, 0.911 mmol) and DIPEA (183 mg, 1.36 mmol) in CH2CI2 (3 mL) at -50°C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water and was extracted with CHCI3. The organic layer was separated, dried and concentrated to afford 250 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 8.19 (m, 1H), 7.65 (s, 1H), 7.52 (d, / = 8.1Hz, 1H), 7.41 (d, / = 8.1Hz, 1H), 4.26 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 1.27 (s, 3H), 0.94 (m, 2H), 0.53 (m, 2H).
Step 4: Preparation of 2-chloro-5-((l -methylcyclopropanecarboxamido)methyl)benzoic acid To a solution of methyl 2-chloro-5-((l-methylcyclopropanecarboxamido)methyl) benzoate (240 mg, 0.857 mmol) in THF:MeOH:water (3:2:1, 6 mL) was added NaOH (68 mg, 1.7 mmol). The reaction mass was stirred at rt for 2 h before it was concentrated and neutralized with IN HC1 at 0°C. The precipitated obtained was filtered and dried to afford 200 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 13.40 (br s, 1H), 8.18 (m, 1H), 7.63 (s, 1H), 7.47 (d, / = 8.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 4.25 (d, / = 6.0 Hz, 2H), 1.27 (s, 3H), 0.94 (s, 2H), 0.53 (s, 2H).
Intermediate 5
To a solution of methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (step-2 of intermediate-4, 200 mg, 0.911 mmol) in THF were added DIPEA (183 mg, 1.36 mmol) and
1- isobutyryl chloride (145 mg, 1.36 mmol) at 0-5°C. The reaction mass was stirred at rt for 2 h before it was quenched with water and was extracted with CHCI3. The organic layer was separated, dried, filtered and concentrated to afford 250 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 8.36 (m, 1H), 7.65 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 6.3 Hz, 1H), 4.26 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 2.37-2.44 (m, 1H), 1.02 (d, J = 6.0 Hz, 6H).
Step 2: Preparation of 2-chloro-5-(isobutyramidomethyl)benzoic acid
The title compound was prepared following the procedure described in step-4 of intermediate- 4 using methyl 2-chloro-5-(isobutyramidomethyl)benzoate (250 mg, 0.970 mmol) in THF:MeOH:water (3 :2: 1 , 6 mL) and NaOH (77 mg, 1.94 mmol) to afford 190 mg of the title product. lH NMR (300 MHz, DMSO d6): δ 13.33 (br s, 1H), 8.35 (m, 1H), 7.63(s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.36 (d, / = 6.3 Hz, 1H), 4.25 (d, / = 6.0 Hz, 2H), 2.77-2.39 (m, 1H), 1.24 (d, J = 6.6 Hz, 6H).
Intermediate 6
Step 1 : Preparation of methyl 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoate
¾ COOMe
The title compound was prepared following the procedure described in step-3 of intermediate- 4 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (step-2 of Intermediate-4, 200 mg, 0.91 1 mmol), DIPEA (361 mg, 2.70 mmol), cyclopropanecarboxylic acid (125 mg, 1.45 mmol), oxalyl chloride (221 mg, 1.74 mmol) and a drop of DMF in CH2CI2 (3 mL) to afford 250 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 8.65 (m, 1H), 7.67 (s, 1H), 7.56 (d, / = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 4.29 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 0.68 (m, 4H).
Step 2: Preparation of 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoic acid
The title compound was prepared following the procedure described in step-4 of intermdiate-4 using methyl 2-chloro-5-cyclopropanecarboxamidomethyl)benzoate (250 mg, 0.934 mmol) and NaOH (45 mg, 1.86 mmol) to afford 105 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 13.25 (br s, 1H), 8.65 (m, 1H), 7.63 (s, 1H), 7.48 (d, / = 8.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 4.28 (d, J = 6.0 Hz, 2H), 1.59 (m, 1H), 0.67 (m, 4H).
Intermediate 7
The title compound was prepared following the procedure described in step-3 of Intermediate- 4 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (Step-2, Intermediate-4, 200 mg, 0.847 mmol), DIPEA (473 mg, 3.3 mmol), cyclobutanecarboxylic acid (105 mg, 1.05 mmol), oxalyl chloride (160 mg, 1.26 mmol) and a drop of DMF in CH2CI2 (3 mL) to afford 250 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 8.25 (m, 1H), 7.64 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.41 (d, / = 7.8 Hz, 1H), 4.25 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 3.07- 2.88 (m, 1H), 2.21-1.76 (m, 6H).
Step 2: Preparation of 2-chloro-5-(cyclobutanecarboxamidomethyl)benzoic acid
The title compound was prepared following the procedure described in step-4 of Intermediate- 4 using methyl 2-chloro-5-(cyclobutanecarboxamidomethyl)benzoate (250 mg, 0.889 mmol) in THF:MeOH:water (3:2: 1, 6 mL) and NaOH (71 mg, 1.177 mmol) to afford 150 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 13.20 (br s, 1H), 8.23 (m, 1H), 7.60 (s, 1H), 7.46 (d, / = 7.8 Hz, 1H), 7.34 (d, / = 6.9 Hz, 1H), 4.23 (d, J = 5.7 Hz, 2H), 3.06- 2.86 (m, 1H), 2.25- 1.71 (m, 6H).
Intermediate 8
The title compound was prepared following the procedure described in step-3 of Intermediate- 4 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (step-2, intermediate-4, 200
mg, 0.847 mmol), DIPEA (473 mg, 3.3 mmol), tetrahydrofuran-2-carboxylic acid (160 mg, 1.37 mmol), oxalyl chloride (210 mg, 1.65 mmol) and a drop of DMF in CH2CI2 (3 mL) to afford 250 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 8.49 (m, 1H), 7.66 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.42 (d, / = 8.4 Hz, 1H), 4.28- 4.23 (m, 3H), 3.91- 3.76 (m, 5H), 1.83- 1.79 (m, 4H).
Step 2: Preparation of 2-chloro-5-((tetrahydrofuran-2-carboxamido)methyl)benzoic acid The title compound was prepared following the procedure described in step-4 of Intermediate- 4 using methyl 2-chloro-5-((tetrahydrofuran-2-carboxamido)methyl)benzoate (250 mg, 0.875 mmol) in THF:MeOH:water (3 :2: 1 , 6 mL) and NaOH (70 mg, 1.75 mmol) to afford 160 mg of the title product. lH NMR (300 MHz, DMSO d6): δ 13.50 (br s, 1H), 8.48 (m, 1H), 7.64 (s, 1H), 7.48 (d, / = 7.8 Hz, 1H), 7.37 (d, / = 7.8 Hz, 1H), 4.27- 4.23 (m, 3H), 3.89- 3.78 (m, 2H), 1.82 (m, 4H).
Intermediate 9
2-Chloro-5-((tetrahydrofuran-3-carboxamido)methyl)benzoic acid
The title compound was prepared following the procedure described in step-3 of Intermediate- 4 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (Step-2, Intermediate-4, 200 mg, 0.847 mmol), DIPEA (473 mg, 3.3 mmol), tetrahydrofuran-3-carboxylic acid (160 mg, 1.37 mmol), oxalyl chloride (210 mg, 1.65 mmol) and a drop of DMF in CH2CI2 (3 mL) to afford 250 mg of the title product H NMR (300 MHz, DMSO d6): δ 8.54 (m, 1H), 7.66 (s, 1H), 7.53 (d, / = 8.1 Hz, 1H), 7.42 (d, / = 8.4 Hz, 1H), 4.28 (d, / = 5.7 Hz, 2H), 3.85 - 3.60 (m, 7H), 3.00- 2.88 (m, 1H), 2.19- 1.97 (m, 2H).
Step 2: Preparation of 2-chloro-5-((tetrahydrofuran-3-carboxamido)methyl)benzoic acid The title compound was prepared following the procedure described in step-4 of intermediate- 4 using methyl 2-chloro-5-((tetrahydrofuran-3-carboxamido)methyl)benzoate (250 mg, 0.875 mmol) in THF:MeOH:water (3 :2: 1 , 6 mL) and NaOH (70 mg, 1.75 mmol) to afford 150 mg of the title product. lH NMR (300 MHz, DMSO d6): δ 13.20 (br s, 1H), 8.54 (m, 1H), 7.64 (s,
1H), 7.49 (d, J =8.1 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 4.28 (d, J
4H), 3.00-2.95 (m, 1H), 2.02-1.97 (m, 2H).
Intermediate 10
The title compound was prepared following the procedure described in step-3 of intermediate- 4 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (step-2, intermediate-4, 200 mg, 0.847 mmol), DIPEA (473 mg, 3.3 mmol ), 3-methylbutanoic acid (139 mg, 1.37 mmol), oxalyl chloride (210 mg, 1.65 mmol) and a drop of DMF in CH2CI2 (3 mL) to afford 255 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 8.40 (br s, 1H), 7.67 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 4.27 (d, J =6.0 Hz, 2H), 3.84 (s, 3H), 2.00 (m, 3H), 090- 0.86 (m, 6H).
Step 2: Preparation of 2-chloro-5-((3-methylbutanamido)methyl)benzoic acid
The title compound was prepared following the procedure described in step-4 of intermediate- 4 using methyl 2-chloro-5-((3-methylbutanamido)methyl)benzoate (250 mg, 0.883 mmol) in THF:MeOH:water (3:2:1, 6 mL) and NaOH (70 mg, 1.76 mmol) to afford 165 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 13.20 (br s, 1H), 8.39 (m, 1H), 7.65 (s, 1H), 7.48 (d, / = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 4.26 (d, J = 5.7 Hz, 2H), 2.00 (m, 3H), 0.89- 0.85 (m, 6H).
Intermediate 11
The title compound was prepared following the procedure described in step-3 of intermediate- 4 using methyl 5-(aminomethyl)-2-chlorobenzoate hydrochloride (step-2, intermediate-4, 1.80 g, 6.00 mmol), DIPEA (3.096 g, 2.4 mmol) and pivaloyl chloride (1.2 mL, 9.0 mmol) to afford 2.0 g of the title product. XH NMR (300 MHz, DMSO d6): 8.16 (m, 1H), 7.65 (s, 1H),
7.53 (d, / = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 4.25 (d, / = 5.7 Hz, 2H), 3.85 (s, 3H), 1.15 (s, 9H).
Intermediate 12
2-Chloro-N-(3-chlorobenzo[d]isothiazol-7-yl)-5-(pivalamidomethyl)benzamide
Step 1 : Preparation of 3-chloro-7-nitrobenzo[d]isothiazole
To a solution of 3-chlorobenzo[d]isothiazole (0.5 00 g, 2.941 mmol) in sulphuric acid (5 mL) was added potassium nitrate (272 mg, 2.69 mmol) portion wise at 0-5°C. The reaction mass was stirred at rt for 12 h. The reaction mass was quenched with water and the precipitate obtained was filtered. The precipitate was purified by column chromatography to afford 220 mg of the title product. XH NMR (300 MHz, CDC13): δ 8.59 (d, J = 7.8 Hz, 1H), 8.40 (d, J = 7.8 Hz, 1H), 7.76 (t, / = 7.8 Hz, 1H).
Step 2: Preparation of 3-chlorobenzo[d]isothiazol-7-amine
To a solution of 3-chloro-7-nitrobenzo[d]isothiazole (220 mg, 1.02 mmol) in ethanol (5.0 mL) was added aqueous ammonium chloride (555 mg, 1.02 mmol in 1 mL of water) and iron powder (157 mg, 3.08 mmol). The reaction mass was heated to reflux for 3 h. The reaction mixture was filtered through celite and the filtrate was concentrated to afford 200 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 7.34 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.80 (d, / = 7.2 Hz, 1H), 6.09 (br s, 2H).
To a solution 3-chlorobenzo[d]isothiazol-7-amine (100 mg,0.54 mmol) in toluene (5.0 mL) was added methyl 2-chloro-5-(pivalamidomethyl)benzoate (intermediate- 11 , 153 mg, 0.54 mmol) and a 2M solution of Me3Al in toluene (195 mg, 2.7 mmol). The reaction mass was heated at 80 C for 3 h. The reaction mass was quenched with water and was extracted with ethyl acetate. The organic layer was separated, dried, filtered, concentrated and purified by column chromatography to afford 129 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.32 (s, 1H), 8.19 (m, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.44- 7.67 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H), 4.30 (d, J = 5.7 Hz, 2H), 1.13 (s, 9H).
Intermediate 13
N3- [3 -(Trifluoromethyl)phenyl] [ 1 ,2]thiazolo [4,5 -Z?]pyridine-3 ,7-diamine
Step 1 : Preparation of N7-(4-methoxybenzyl)-N -[3-(trifluoromethyl)phi
[l,2]thiazolo[4,5-Z?]pyridine- -diamine
The title compound was prepared following the procedure described in step-5 of intermediate- 1 using 3-bromo-N-(4-methoxybenzyl)[l ,2]thiazolo[4,5- ?]pyridin-7-amine (step-4, intermediate -1, 300 mg, 0.86 mmol), 3-trifluoromethylaniline (208 mg, 1.29 mmol), CS2CO3 (840 mg, 2.58 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (150 mg, 0.26 mmol), tris(dibenzylideneacetone)dipalladium(0) (79 mg, 0.086 mmol) and dioxane (5 mL) to afford 160 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 9.99 (s, 1H), 8.59 (s, 1H), 8.27 (m, 2H), 7.89 (m, 1H), 7.53 (t, / = 7.8 Hz, 1H), 7.32-7.26 (m, 3H), 6.90 (d, J = 8.7 Hz, 2H), 6.57 (d, = 5.4 Hz, 1H), 4.47 (d, / = 6.0 Hz, 2H), 3.71 (s, 3H).
Step 2: Preparation of N3-[3-(trifluoromethyl)phenyl][l,2]thiazolo[4,5-¾]pyridine-3,7-diamine The title compound was prepared following the procedure described in step-6 of intermediate- 1 using N7-(4-methoxybenzyl)-N3-[3-(trifluoromethyl)phenyl] [l ,2]thiazolo[4,5-&]pyridine- 3,7-diamine (150 mg, 0.35 mmol) and trifluoroacetic acid (3 mL) to afford 100 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 9.99 (s, 1H), 8.53 (s, 1H), 8.30 (d, / = 5.4 Hz, 1H), 8.22 (d, / = 8.4 Hz, 1H), 7.55 (t, / = 7.8 Hz, 1H), 7.30 (d, J = 7.2 Hz, 2H), 6.69 (br s, 1H), 6.68 (d, / = 5.7 Hz, 1H); MS (m/z): 31 1.05 (M+H)+.
Intermediate 14
N3-(5-Fluoro-2-methylphenyl)isothiazolo[4,5- ?]pyridine-3,7-diamine
Step 1 : Preparation of N -(5-fluoro-2-methylphenyl)-N7-(4-methoxybenzyl)isothiazolo[4,5- b]pyridine-3 ,7-diamine
The title compound was prepared following the procedure described in step-5 of intermediate- 1 using 3-bromo-N-(4-methoxybenzyl)[l ,2]thiazolo[4,5-Z?]pyridin-7-amine (intermediate- 1 , step-4, 200 mg, 0.518 mmol), 5-fluoro-2-methylaniline (87 mg, 0.77 mmol), Cs2C03 (505 mg, 1.554 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (149 mg, 0.259 mmol), tris(dibenzylideneacetone)dipalladium(0) (94 mg, 0.103 mmol) to afford 180 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 8.34 (s, 1H), 8.24 (d, J = 5.4 Hz, 1H), 8.16 (m, 1H), 7.87 (m, 1H), 7.29 (d, / = 8.4 Hz, 2H), 7.14- 7.06 (m, 2H), 6.89 (d, = 8.1 Hz, 2H), 6.55 (d, J = 5.42 Hz, 1H), 4.46 (d, / =5.4 Hz, 2H), 3.71 (s, 3H), 2.32 (s,3H).
Step 2: Preparation of N3-(5-fluoro-2-methylphenyl)isothiazolo[4,5-fc]pyridine-3,7-diamine The title compound was prepared following the procedure described in step-6 of intermediate- 1 using N3-(5 -fluoro-2-methylphenyl)-N7-(4-methoxybenzyl)isothiazolo [4,5 -&]pyridine-3 ,7- diamine (200 mg, 0.527 mmol), trifluoroacetic acid (5 mL) to afford 90 mg of the title
product. ¾ NMR (300 MHz, DMSO d6): δ 8.47 (s, 1H), 8.32 (d, 1H), 8.03 (m, 1H), 7.15- 7.06 (m, 3H), 6.70 (d, = 4.8 Hz, 1H), 6.54 (s, 1H), 2.32 (s, 3H).
Intermediate 15
N3-(2-Fluoro-5-(trifluoromethyl)phenyl)isothiazolo[4,5-&]pyridine-3,7-diamine
Step 1 : Preparation of N -(2-fluoro-5-(trifluorometriyl)phenyl)-N7-(4-methoxybenzyl) isothiazolo[4,5-^]pyridine-3, -diamine
The title compound was prepared following the procedure described in step-5 of intermediate- 1 using 3-bromo-N-(4-methoxybenzyl)[l ,2]thiazolo[4,5-Z?]pyridin-7-amine (intermediate- 1 , step-4, 200 mg, 0.518 mmol), 2-fluoro-5-(trifluoromethyl)aniline (139 mg, 0.772 mmol), CS2CO3 (505 mg, 1.55 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (149 mg, 0.259 mmol), tris(dibenzylideneacetone)dipalladium(0) (94 mg, 0.103 mmol) to afford 180 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 8.92 (d, J = 7.2 Hz, 1H), 8.68 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 8.02 (m, 1H), 7.57 (t, J = 9.0 Hz, 1H), 7.54 (m, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.90 (d, J =5.4 Hz, 2H), 6.60 (d, J = 5.4 Hz, 1H), 4.47 (d, J = 6.0 Hz, 2H), 3.71 (s, 3H).
Step 2: Preparation of N -(2-fluoro-5-(trifluoromethyl)phenyl)isothiazolo[4,5-&]pyridine-3,7- diamine
The title compound was prepared following the procedure described in step-6 of intermediate- 1 using N3-(2-fluoro-5-(trifluoromethyl)phenyl)-N7-(4-methoxybenzyl)isothiazolo[4,5- £>]pyridine-3,7-diamine (200 mg, 0.446 mmol), trifluoroacetic acid (5 mL) to afford 170 mg of the title product. lR NMR (300 MHz, DMSO d6): δ 8.93 (d, / = 6.3 Hz, 2H), 8.32 (d, / = 6.0 Hz, 1H), 7.58 (t, J = 8.7 Hz, 1H), 7.47 (br s, 2H), 6.80 (br s, 1H), 6.70 (d, 7 =5.4 Hz, 1H).
Intermediate 16
N3-Cyclobutylisothiazolo[4,5-fc]pyridine-3,7-diamine
Step 1 : Preparation of N3-cyclobutyl-N7-(4-methoxybenzyl)isothiazolo[4,5-Z?]pyridine-3,7- diamine
To a solution of 3-bromo-N-(4-methoxybenzyl)[l ,2]thiazolo[4,5- ?]pyridin-7-amine (intermediate- 1, step-4, 100 mg, 0.259 mmol) in DMSO (1 mL) were added cyclobutyl amine (73 mg, 1.034 mmol), 2C03 (42 mg, 0.310 mmol), Nal (58 mg, 0.3885 mmol) under nitrogen. The reaction mixture was heated at 120-130°C for 18 h. The reaction mixture was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 40 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 8.12 (d, J = 5.4 Hz, 1H), 7.60 (m, 1H), 7.27 (d, / = 8.1 Hz, 2H), 7.20 (d, J = 8.4Hz, 1H), 6.89 (m, 2H), 6.45 (d, = 6.0 Hz, 1H), 4.48-4.37 (m, 3H), 3.70 (s, 3H), 2.13 (m, 2H), 2.09 (m, 2H), 1.64 (m, 2H).
Step2: Preparation of N -cyclobutylisothiazolo[4,5-Z?]pyridine-3,7-diamine
The title compound was prepared following the procedure described in step-6 of intermediate- 1 using N -cyclobutyl-N7-(4-methoxybenzyl)isothiazolo[4,5-^]pyridine-3,7-diamine (200 mg, 0.588 mmol), trifluoroacetic acid (5 mL) to afford 120 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 8.13 (d, / = 5.4 Hz, 1H), 7.18 (d, / = 7.2 Hz, 1H), 6.82 (br s, 2H), 6.53 (d, 1H), 4.38 (m, 1H), 2.25 (m, 2H), 2.09 (m, 2H), 1.66 (m, 2H).
Intermediate 17
To a cold solution of sodium (0.261 g, 1 1.35 mmol) in ethanol (15 mL) was slowly added diethyl malonate (1.9 g, 1 1.89 mmol) at 0 °C. Then a solution of S-epichlorohydrine (1.0 g, 10.81 mmol) in ethanol was slowly added at rt and the reaction mixture was heated at reflux for 20 h. Then the reaction mixture was filtered and concentrated. The residue was dissolved in CH2C12 and was washed with water. The organic layer was separated, dried and concentrated. The concentrate was purified by column chromatography to afford 850 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 4.36- 4.16 (m, 1H), 4.12- 3.83 (m, 3H), 1.92- 1.88 (m, 1H), 1.48- 1.45 (m, 1H), 1.31- 1.17 (m ,4H).
To a solution of (1R,5S)-Qthyl 2-oxo-3-oxabicyclo[3.1.0]hexane-l-carboxylate (200 mg, 1.17 mmol) in ethanol (5 mL) was added sodium borohydride (35 mg, 0.94 mmol) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with IN HC1 and was extracted with ethyl acetate. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 120 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 4.69 (t, / = 5.1 Hz, 1H), 4.59 (t, / = 5.4 Hz, 1H), 4.16- 4.00 (m, 4H), 3.84- 3.78 (m, 1H), 3.69- 3.59 (m, 1H), 1.17 (m, 1H), 1.21- 1.14 (m ,4H), 0.86- 0.82 (m, 1H).
To a solution of (iS,2S)-ethyl l ,2-bis(hydroxymethyl)cyclopropanecarboxylate (500 mg, 2.87 mmol) in toluene (5 mL) was added p-toluenesulphonic acid (50 mg). The reaction mixture was heated at reflux for 4 h before it was quenched with water and was extracted in Et20. The organic layer was separated, dried, filtered and concentrated to afford 220 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 4.16- 4.12 (m, 2H), 4.09- 3.64 (m, 4H), 2.12- 2.09 (m, 1H), 1.37- 1.23 (m, 1H), 1.22- 1.15 (m ,3H), 0.90- 0.83 (m, 1H).
Step 4: Preparation of (i5,55)-3-oxabicyclo[3.1.0]hexane-l-carboxylic acid
To a solution of (i5,55)-ethyl 3-oxabicyclo[3.1.0]hexane-l-carboxylate (200 mg, 1.28 mmol) in THF-H20 (5: 1, 6 mL) was added LiOH (108 mg, 2.56 mmol). The reaction mixture was stirred at rt for 5-6 h. The reaction mixture was quenched with water and the organic impurities were extracted in Et20. The aqueous layer was neutralized with IN HCl and was extracted with CH2CI2. The organic layer was separated, dried, filtered and concentrated to afford 130 mg of the title product. !H NMR (300 MHz, DMSO d6): δ 12.32 (br s, 1H), 3.86- 3.63 (m, 4H), 2.05 (m, 1H), 1.34- 1.31 (m, 1H), 0.85- 0.81 (m ,1H).
Intermediate 18
N3-(3 -Fluorophenyl)isothiazolo [4,5 -&]pyridine-3 ,7-diamine
Step 1 : Preparation of N3-(3-fluorophenyl)-N7-(4-methoxybenzyl)isothiazolo[4,5- ?]pyridine- 3,7-diamine
The title compound was prepared following the procedure described in step-5 of intermediate- 1 using 3-bromo-N-(4-methoxybenzyl)[l,2]thiazolo[4,5-Z?]pyridin-7-amine (intermediate- 1 , step-4, 300 mg, 0.86 mmol), 3-fiuoroaniline (143 mg, 1.28 mmol), Cs2C03 (838 mg, 2.58 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (249 mg, 0.43 mmol), tris(dibenzylideneacetone)dipalladium(0) (78 mg, 0.086 mmol) to afford 250 mg of the title product. ln NMR (300 MHz, DMSO d6): δ 9.82 (s, 1H), 8.26 (d, J = 4.8 Hz, 1H), 8.05-8.01 (d, / = 12.0 Hz, 1H), 7.87-7.83 (m, 2H), 7.36-7.29 (m, 3H), 6.92-6.89 (d, J = 8.7 Hz, 2H), 6.78-6.73 (t, J = 8.4 Hz, 1H), 6.58-6.56 (d, J = 5.4 Hz, 1H), 4.48-4.46 (d, J = 5.4 Hz, 2H), 3.72 (s, 3H).
Step 2: Preparation of N -(3-fluorophenyl)isothiazolo[4,5-^]pyridine-3,7-diamine
The title compound was prepared following the procedure described in step-6 of intermediate- 1 using N3-(5-fluoro-2-methylphenyl)-N7-(4-methoxybenzyl)isothiazolo[4,5-^]pyridine-3,7- diamine (250 mg, 0.657 mmol), trifluoroacetic acid (5 mL) to afford 150 mg of the title product. lH NMR (300 MHz, DMSO d6): δ 9.82 (s, 1H), 8.26-8.24 (d, / = 5.4 Hz, 1H), 8.05-
8.01 (d, / = 12.3 Hz, 1H), 7.86-7.83 (d, / = 8.7 Hz, 1H), 7.36-7.28 (q, J = 7.8, 15.0 Hz, 1H), 6.95 (s, 2H), 6.77-6.73 (t, / = 6.3 Hz, 1H), 6.64-6.62 (d, / = 5.4 Hz, 1H).
Intermediate 19
To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was addeed "BuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at -78 °C and the reaction mixture was warmed to 0 °C over a period of 1 h. Then the reaction mixture was cooled to -78 °C and a solution of ethyl 2-chloro-6- fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at -78 °C for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at -78 °C for 1 h and then gradually warmed to 0 °C over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3- formylbenzoate. XH NMR (300 MHz, DMSO- ): δ 10.27 (s, 1H), 8.05-8.00 (t, / = 7.8 Hz, 1H), 7.72-7.69 (d, = 8.4 Hz, 1H), 4.53-4.46 (q, / = 6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J = 6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq. solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55 °C for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. XH NMR (300 MHz, DMSO- ): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, J = 8.1 Hz, 1H), 7.49-7.46 (d, J = 8.4 Hz, 1H), 4.44-4.37 (q, 7 = 7.5, 14.1 Hz, 2H), 1.34-1.29 (t, / = 7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HC1 in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3 h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of
NaHCC>3. The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. *H NMR (300 MHz, CDC13): δ 7.54 (t, J = 7.8 Hz, 1H), 7.28 (d, / = 7.8 Hz, 1H), 4.45 (q, J = 7.5, 14.1 Hz, 2H), 4.1 1 (d, J = 3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, / = 7.2 Hz, 3H).
To a solution of ethyl 3-(aminomethyl)-6-chloro-2-fluorobenzoate (70 mg, 0.3 mmol) in THF (3 mL) were added ΕΪ3Ν (105 μί, 0.76 mmol) and pivolyl chloride (38 μί, 0.31 mmol). The reaction mass was stirred at rt for 2 h before it was diluted with EtOAc and was washed with water, and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. XH NMR (300 MHz, DMSO-J6): δ 8.15 (br t, 1H), 7.43 - 7.35 (m, 2H), 4.38 (q, = 7.2 Hz, 2H), 4.26 (d, / = 5.7 Hz, 2H), 1.30 (t, J = 6.9 Hz, 3H), 1.1 1 (s, 9H). Step 3 : Preparation of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid
To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (100 mg, 0.317 mmol) in THF:MeOH:H20 (3 :2: 1 ; 6 mL) was added NaOH (25 mg, 0.634 mmol). The reaction mass was stirred at rt for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. *H NMR (300 MHz, DMSO-d6): δ 14.10 (s, 1H), 8.14 (br t, 1H), 7.38- 7.26 (m, 2H), 4.25 (d / = 5.4 Hz, 2H), 1.1 1 (s, 9H).
Intermediate 20
To a solution of 2,6-dimethyl benzoic acid (2.0 g, 13.33 mmol) in cone H2S04 (4 mL) was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (2.1 g, 13.33 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The
precipitate was collected by filtration and dried to afford 3.2 g of the title product. XH NMR (DMSO-de): δ 9.92 (m, 2H), 7.15- 7.04 (m, 2H), 4.36 (s, 2H), 2.18 (m, 6H).
Step 2: Preparation of 2,6-dimethyl-3-(pivalamidomethyl)benzoic acid
To a solution of 2,6-dimethyl-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid (3.2 g, 11.63 mmol) in THF (15 mL) was added IN HC1 (15 mL) and the reaction mass was heated at reflux for 3 h. The reaction mixture was concentrated and the crude was co-distilled with toluene to afford 2.0 g of the 3-(aminomethyl)-2,6-dimethylbenzoic acid which was used in the next step without further purification. To a solution of 3-(aminomethyl)-2,6- dimethylbenzoic acid (500 mg, 2.46 mmol) in THF was added Ν,Ο- bis(trimethylsilyl)trifluoroacetamide (948 mg, 3.69 mmol) and the reaction mass was heated at reflux for 20 mins. The reaction mass was cooled to 0 °C and Et3N (1.77 mL, 9.85 mmol) was added, followed by pivaloyl chloride (0.44 mL, 3.69 mmol). The reaction mixture was stirred at rt for 18 h before it was quenched with water and was extracted with chloroform. The organic layer was separated, dried, filtered and concentrated to afford 450 mg of the title product. lR NMR (300 MHz, DMSO-ifc): δ 13.15 (br s, 1H), 7.93 (br t, 1H), 7.08- 7.01 (m, 2H), 4.19 (d, / = 5.7 Hz, 2H), 2.21 (s, 3H), 2.17 s, 3H), 1.12 (s, 9H).
Intermediate 21
2-Chloro-6-methyl-3-(pivalamidomethyl)benzoic
To a solution of 2-chloro-6-methylbenzoic acid (2.0 g, 11.72 mmol) in cone H2SO4 (4 mL) was added 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (1.26 g, 8.80 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was poured into ice-water and stirred for 2 h. The precipitate was collected by filtration and dried to afford 1.80 g of the title product and 6- chloro-2-methyl-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid as mixture of products. Step 2: Preparation of methyl 3-(((ieri-butoxycarbonyl)amino)methyl)-2-chloro-6- methylbenzoate
A solution of 2-chloro-6-methyl-3-((2,2,2-trifluoroacetamido)methyl)benzoic acid (1.70 g, 5.75 mmol) in cone. HC1 (10 mL) and dioxane (2 mL) was heated at reflux for 12 h. The reaction mixture was concentrated and the concentrate was dissolved in THF (1 mL). The solution was treated with NaOH (690 mg, 17.25 mmol) in H20 (2 mL) at 0°C followed by iert-butyl dicarbonate (2.51 g, 11.50 mmol). The reaction mixture was stirred rt for 16 h. The reaction mixture was acidified with IN HC1 and the pH was adjusted to 2-3. The reaction mixture was extracted with 5% MeOH in CHCI3. The organic layer was separated, dried, filtered and concentrated. The concentrate was dissolved in CH3CN (20 mL) and the solution was treated with K2CO3 (1.60 g, 11.50 mmol) and CH3I (11.50 mmol) at rt. Then the reaction mixture was heated at 50 °C for 1-2 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The concentrated was purified by column chromatography to provide 1.4 g of the title product and methyl 3-(((ierf-butoxycarbonyl)amino)methyl)-6-chloro-2- methylbenzoate as mixture of products.
A solution of methyl 3-(((ieri-butoxycarbonyl)amino)methyl)-2-chloro-6-methylbenzoate and methyl 3-(((ieri-butoxycarbonyl)amino)methyl)-6-chloro-2 -methylbenzoate (1.40 g, 4.46 mmol) in EtOAc saturated with HC1 (5 mL) was stirred at rt for 2 h. Then the reaction mixture was concentrated, triturated with Et20 and dried. Then the solid mass was dissolved in THF (10 mL) and the solution was treated with pivaloyl chloride (1.07 g, 8.92 mmol) and DIPEA (2.30 g, 17.84 mmol) at rt. Then the reaction mixture was stirred at rt for 2 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 600 mg of the title product and 880 mg of methyl 6-chloro-2- methyl-3 -(pivalamidomethyl)benzoate. Methyl 2-chloro-6-methyl-3 -
(pivalamidomethyl)benzoate : H NMR (300 MHz, DMSO d6): δ 8.09 (br t, 1H), 7.27-7.24 (d, / = 7.8 Hz, 1H), 7.20-7.18 (d, / = 8.4 Hz, 1H), 4.28-4.26 (d, / = 5.4 Hz, 2H), 3.88 (s, 3H), 2.22 (s, 3H), 1.14 (s, 9H); Methyl 6-chloro-2-methyl-3-(pivalamidomethyl)benzoate XH NMR
(300 MHz, DMSO d6): δ 8.02 (br t, 1H), 7.37-7.34 (d, J = 8.1 Hz, 1H), 7.24-7.21 (d, J = 8.4 Hz, 1H), 4.22-4.20 (d, / = 5.4 Hz, 2H), 3.88 (s, 3H), 2.18 (s, 3H), 1.13 (s, 9H).
Step 4: Preparation of 2-chloro-6-methyl-3-(pivalamidomethyl)benzoic acid
To a solution of methyl 2-chloro-6-methyl-3-(pivalamidomethyl)benzoate (600 mg, 2.01 mmol) in THF-MeOH-H20 (3 :2: 1 , 6 mL) was added KOH (338 mg, 6.03 mmol) and the reaction mixture was stirred at 60 °C for 12 h. Then the reaction mixture was neutralized with IN HC1 and concentrated. The residue was dissolved in EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 450 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 13.60 (br s, 1H), 8.00 (br t, 1H), 7.32-
7.30 (d, J = 8.4 Hz, 1H), 7.19-7.16 (d, J = 8.4 Hz, 1H), 4.22-4.20 (d, / = 5.7 Hz, 2H), 2.22 (s 3H), 1.13 (s, 9H).
Intermediate 22
N3-(2-Fluoro-4-(trifluoromethyl)phenyl)isothiazolo[4,5-&]pyridine-3,7-diamine
Step 1 : Preparation N3-(2-fiuoro-4-(trifluoromethyl)phenyl)-N7-(4- methoxybenzyl)isothiazolo -b]pyridine-3,7-diamine
The title compound was prepared following the procedure described in step-5 of intermediate- 1 using 3-bromo-N-(4-methoxybenzyl)[ l ,2]thiazolo[4,5-Z?]pyridin-7-amine (intermediate- 1 , step-4, 100 mg, 0.286 mmol), 2-fluoro-4-(trifiuoromethyl)aniline (77 mg, 0.42 mmol), CS2CO3 (254 mg, 0.78 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (83 mg, 0.143 mmol), tris(dibenzylideneacetone)dipalladium(0) (52 mg, 0.057 mmol) to afford 100 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 8.75 (t, J = 8.4 Hz, 1H), 8.66 (s, 1H), 8.26 (d, / = 5.4 Hz, 1H), 8.00 (t, 1H), 7.75 (d, / = 1 1.7 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.29 (d, / = 8.1 Hz, 2H), 6.88 (d, / = 8.7 Hz, 2H), 6.58 ((d, J = 5.4 Hz, 1H), 4.45 (d, J = 5.4 Hz, 2H), 3.69 (s, 3H); MS (m/z): 449.1 1 (M+H)+.
Step 2: Preparation of N3-(2-fluoro-4-(trifluoromethyl)phenyl)isothiazolo[4,5- >]pyridine-3,7- diamine
The title compound was prepared following the procedure described in step-6 of intermediate- 1 using N3-(2-fluoro-4-(trifluoromethyl)phenyl)-N7-(4-methoxybenzyl)isothiazolo[4,5- b]pyridine-3 ,7-diamine (362 mg, 0.808 mmol), H2SO4 (1 mL) to afford 230 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 8.79 (t, / = 8.4 Hz, 1H), 8.66 (br s, 1H), 8.26 (d, J = 5.4 Hz, 1H), 7.78 (d, / = 1 1.4 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.07 (br s, 2H), 6.66 (d, J = 5.4 Hz, 1H).
Intermediate 23
N3-(4-(Trifluoromethyl)phenyl)isoxazolo[4,5-&]pyridine-3 ,7-diamine
To a solution of 3-bromo-4-[(4-methoxybenzyl)amino]pyridine-2-carbonitrile (intermediate- 1, step-3, 750 mg, 2.31 mmol) in DMF (10 mL) were added 2C03 (979 mg, 7.04 mmol) and acetohydroxamic acid (212 mg, 2.03 mmol) and the reaction mixture was heated at 110 °C for 48 h. The reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with a saturated solution of NaHCC>3, water and brine. The organic layer was separated, dried, filtered and concentrated to afford 400 mg of the title product. LH NMR (300 MHz, DMSO-d6): δ 7.92 (d, / = 5.4 Hz, 1H), 7.79 (s, 1H), 7.47 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.02 (t, 1H), 6.88 (d, / = 8.4 Hz, 2H), 6.48 (d, J = 5.1 Hz, 1H), 4.41 (d, / = 6.0 Hz, 2H), 3.70 (s, 3H).
Step 2: Preparation of N7-(4-methoxybenzyl)-N3-(4-(trifluoromethyl)phenyl)isoxazolo[4,5- £>]pyridine-3 ,7-diamine
The title compound was prepared following the procedure described in step-5 of intermediate- 1 using N7-(4-methoxybenzyl)isoxazolo[4,5-Z?]pyridine-3,7-diamine (240 mg, 0.808 mmol), l-bromo-4-(trifluoromethyl)benzene (239 mg, 1.06 mmol), CS2CO3 (866 mg, 2.66 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (255 mg, 0.44 mmol), tris(dibenzylideneacetone)dipalladium(0) (162 mg, 0.147 mmol) to afford 300 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 10.86 (s, 1H), 8.03 (d, / = 5.7 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.72 (d, / = 8.4 Hz, 2H), 7.36-7.20 (m, 4H), 6.90 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 5.7 Hz, 1H), 4.43 (d, / = 5.7 Hz, 2H), 3.71 (s, 3H).
Step 3: Preparation of N -(4-(trifluoromethyl)phenyl)isoxazolo[4,5-^]pyridine-3,7-diamine The title compound was prepared following the procedure described in step-6 of Intermediate- 1 using N7-(4-methoxybenzyl)-N3-(4-(trifluoromethyl)phenyl)isoxazolo[4,5-^]pyridine-3,7- diamine (300 mg, 0.724 mmol), H2S04 (5 mL) to afford 120 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 10.85 (s, 1H), 8.01 (d, / = 5.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.73-7.66 (m, 2H), 6.76 (d, / = 5.4 Hz, 1H), 6.61 (br s, 1H).
Intermediate 24
To a solution of ethyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (intermediate- 19; step-2, 1.00 g, 3.31 mmol) in THF:MeOH:H20 (2:2: 1 ; 5 mL) was added KOH (0.930 g, 16.57 mmol). The reaction mass was heated in a sealed tube atlOO °C for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 700 mg of the title product. XH NMR (300 MHz, DMSO-d6): δ 13.65 (br s, 1H), 8.08 (t, 1H), 7.29-7.26 (d, / = 8.4 Hz, 1H), 7.22-7.19 (d, J = 8.7 Hz, 1H), 4.25 (d, J = 5.7 Hz, 2H), 3.79 (s, 3H), 1.13 (s, 9H); MS (m/z): 300.05 (M+H)+.
Intermediate 25
N3-(3-(Trifluoromethyl)phenyl)isoxazolo[4,5-&]pyridine-3,7-diamine
Step 1 : Preparation of N7-(4-methoxybenzyl)-N -(3-(trifluoromethyl)prienyl)isoxazolo[4,5- b]pyridine-3 ,7-diamine
The title compound was prepared following the procedure described in step-5 of intermediate- 1 using N7-(4-methoxybenzyl)isoxazolo[4,5- ?]pyridine-3,7-diamine (intermediate-23, step- 1 , 500 mg, 1.84 mmol), l -iodo-3-(trifluoromethyl)benzene (604 mg, 2.20 mmol), Cs2C03 (1.81 g, 5.54 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthenes (538 mg, 0.985 mmol), tris(dibenzylideneacetone)dipalladium(0) (338 mg, 0.34 mmol) to afford 380 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 10.84 (s, 1H), 8.23 (s, 1H), 8.03 (d, / = 5.4 Hz, 1H), 7.91 (d, / = 7.5 Hz, 1H), 7.59 (t, 1H), 7.47-7.20 (m, 4H), 6.90 (d, / = 9.0 Hz, 2H), 6.59 (d, 7 = 6.0 Hz, 1H), 4.45 (d, / = 6.3 Hz, 2H), 3.71 (s, 3H).
Step 2: Preparation of N -(3-(trifluoromethyl)phenyl)isoxazolo[4,5-Z?]pyridine-3,7-diamine The title compound was prepared following the procedure described in step-6 of intermediate- 1 using N7-(4-methoxybenzyl)-N3-(3-(trifluoromethyl)phenyl)isoxazolo[4,5-^]pyridine-3,7- diamine (380 mg, 0.92 mmol), H2S04 (5 mL) to afford 160 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 10.83 (s, 1H), 8.24 (s, 1H), 8.01 (d, 7 = 5.1 Hz, 1H), 7.92 (d, / = 8.4 Hz, 1H), 7.59 (t, J = 8.4 Hz, 1H), 7.46 {A, J = 1.2 Hz, 1H), 6.76 (d, / = 5.4 Hz, 1H), 6.60 (br s, 2H).
Example 1
2-Chloro-6-fluoro-N-(3- {[4-(trifluoromethyl)phenyl]amino} [l ,2]thiazolo[4,5-&]pyridin-7- yl)benzamide
To a solution of 2-chloro-6-fluorobenzoic acid (49 mg, 0.280 mmol) in CH2CI2 (2 mL) were added oxalyl chloride (71 mg, 0.560 mmol) and DMF (1 drop). The reaction mixture was stirred at rt for 2 h and was concentrated. The concentrate in CH2C12 (2 mL) was treated with p-nitrophenol (77 mg, 0.560 mmol) and ΕΪ3Ν (84 mg, 0.331 mmol) at 0°C and the reaction mixture was stirred at rt for 12h. The reaction mixture was washed with water and brine. The
organic layer was separated, dried, filtered and concentrated. The concentrate was used for the next step without further purification.
To the solution of N3-[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5-^]pyridine-3,7-diamine (intermediate 1, 43 mg, 0.14 mmol) and the above concentrate in THF (2 mL) was added NaH (11 mg, 0.28 mmol) at 0°C and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with H20 and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to obtain 22 mg of the title product. H NMR (300 MHz, DMSO de): δ 11.79 (s, 1H), 10.23 (s, 1H), 8.74 (d, J = 5.4 Hz, 1H), 8.26 (d, / = 8.4 Hz, 2H), 7.78 (d, J = 5.4 Hz, 1H), 7.67 (d, / = 8.4 Hz, 2H), 7.58 (m, 1H), 7.52-7.42 (m, 2H); MS (m/z): 465.1 1 (M-H)~.
Example 2
2-Chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-(3-{[4-(trifluoromethyl)phenyl] amino} [ 1 ,2]thiazolo[4,5-&]pyridin-7-yl)benzamide
A solution of ieri-butyl {4-chloro-3-[(3-{[4-(trifluoromethyl)phenyl]amino} [l ,2] thiazolo[4,5-Z?]pyridin-7-yl)carbamoyl]benzyl}carbamate (intermediate 3, 27 mg, 0.047 mmol) in HC1 in dioxane (1 mL) was stirred at rt for 2 h. The reaction mixture was concentrated and the concentrate was dissolved in DMF (1 mL). The solution was treated with DIPEA (33 μϋ, 0.19 mmol) followed by pivaloyl chloride (12 mg, 0.105 mmol) at 0°C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc and was washed with H20 and brine. The organic layer was separated, dried, filtered and concentrated. The residue was purified by preparative TLC to afford 10 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.58 (s, 1H), 10.18 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.28 (d, / = 8.4 Hz, 2H), 8.20 (m, 1H), 7.68 (m, 3H), 7.60-7.54 (m, 2H), 7.42 (d, / = 9.3 Hz, 1H), 4.32 (d, = 6.0 Hz, 2H), 1.13 (s, 9H); MS (m/z): 560.19 (M-H)\
Example 3
2-Chloro-5-((l-methylcyclopropanecarboxamido)methyl)-N-(3-((4-(trifluoromethyl) phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide
To a solution of 2-chloro-5-((l-methylcyclopropanecarboxamido)methyl)benzoic acid (intermediate-4, 110 mg, 0.411 mmol) in THF (5 mL) were added DIPEA (159 mg, 1.20 mmol) and isobutyl chloroformate (112 mg, 0.872 mmol) at 0-5°C. The reaction mass was stirred at 0-5°C for 1 h before it was quenched with water and was extracted with dichloromethane. The organic layer was separated, dried and concentrated. A solution of this residue in THF (1 mL) was added to a solution of N3-[4- (trifluoromethyl)phenyl][l ,2]thiazolo[4,5- ?]pyridine-3,7-diamine (intermediate- 1 , 50 mg, 0.161 mmol) and aH (17 mg, 0.70 mmol, 60% in mineral oil) in THF (5.0 mL). The reaction mass was stirred at rt for 4-6 h before it was quenched with saturated aq. solution of NaHCC^. The precipitate obtained was filtered. The filtrate was concentrated and purified by column chromatography to afford 22 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.57 (s, 1H), 10.18 (s, 1H), 8.72 (d, J = 4.8Hz, 1H), 8.29-8.22 (m, 3H), Ί .69-1.66 (m, 3H), 7.58- 7.55 (m, 2H), 7.42 (d, J = 6.3 Hz, 1H), 4.31 (d, / = 5.4 Hz, 2H), 1.29 (s, 3H), 0.95 (s, 2H), 0.53 (s, 2H); MS (m/z): 560.06 (M+H)+.
Example 4
2-Chloro-5-(isobutyramidomethyl)-N-(3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ¾]pyridin-7-yl)benzamide
The title compound was prepared following the procedure as described in example-3 using N3-[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5-^]pyridine-3,7-diamine (intermediate 1 , 70 mg, 0.222 mmol), 2-chloro-5-(isobutyramidomethyl)benzoic acid (intermediate-5, 150 mg, 0.581 mmol), DIPEA (223 mg, 1.75 mmol), isobutyl chloroformate (160 mg, 1.17 mmol), NaH (27 mg, 0.555 mmol) and THF (8 mL) to afford 10 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.56 (s, 1H), 10.18 (s, 1H), 8.72 (d, J = 4.8Hz, 1H), 8.39 (m, 1H), 8.27 (d, J = 8.7 Hz, 2H), 7.68 (m, 3H), 7.56 (m, 2H), 7.42 (d, J = 8.1 Hz, 1H), 4.31 (d, / = 5.7 Hz, 2H), 2.41 (m, 1H), 1.03 (d, / = 6.9 Hz, 6H); MS (m/z): 546.13 (M-H)\
Example 5
2-Chloro-5-(cyclopropanecarboxamidomethyl)-N-(3-((4-(trifluoromethyl)phenyl)amino) isothiazolo[4,5-^]pyridin- -yl)benzamide
The title compound was prepared following the procedure described in example-3 using N3- [4-(trifiuoromethyl)phenyl] [l ,2]thiazolo[4,5-&]pyridine-3,7-diamine (intermediate 1 , 50 mg, 0.161 mmol), 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoic acid (intermediate-6, 105 mg, 0.414 mmol), DIPEA (160 mg, 1.24 mmol), isobutyl chloroformate (1 13 mg, 0.828 mmol), NaH (17 mg, 0.700 mmol) and THF (5 mL) to afford 12 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 1 1.57 (s, 1H), 10.19 (s, 1H), 8.72 (m, 2H), 8.27 (d, J = 8.4 Hz, 2H), 7.67 (m, 3H), 7.56 (m, 2H), 7.43 (d, / = 8.4 Hz, 1H), 4.34 (d, / = 5.4 Hz, 2H), 1.61 (m, 1H), 1.23-1.15 (m, 4H); MS (m/z): 544.13 (M-H)".
Example 6
2-Chloro-5-(cyclobutanecarboxamidomethyl)-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in example-3 using N3- [4-(trifiuoromethyl)phenyl] [l ,2]thiazolo[4,5-&]pyridine-3,7-diamine (intermediate- 1 , 70 mg, 0.222 mmol), 2-chloro-5-(cyclobutanecarboxamidomethyl)benzoic acid (intermediate-7, 150 mg, 0.560 mmol), DIPEA (289 mg, 2.24 mmol), isobutyl chloroformate (153 mg, 1.12 mmol), NaH (14 mg, 0.555 mmol) and THF (8 mL) to afford 20 mg of the title product. lH NMR (300 MHz, DMSO d6): δ 1 1.54 (s, 1H), 10.16 (s, 1H), 8.70 (d, / = 4.8 Hz, 1H), 8.25 (d, J = 9.0 Hz, 3H), 7.66 (d, J = 7.2 Hz, 3H), 7.57- 7.52 (m, 2H), 7.40 (d, / = 7.8 Hz, 1H), 4.29 (d, J = 6.0 Hz, 2H), 3.02 (m, 1H), 2.15- 1.74 (m, 6H); MS (m/z): 558.18 (M-H)".
Example 7
N-(4-Chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl) carbamoyl)benzyl)tetrahydrofuran-2-carboxamide
The title compound was prepared following the procedure described in example-3 using N3-
[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5-&]pyridine-3,7-diamine (intermediate- 1 , 70 mg, 0.225 mmol), 2-chloro-5-((tetrahydrofuran-2-carboxamido)methyl)benzoic acid (intermediate-8, 160 mg, 0.563 mmol), DIPEA (214 mg, 1.6859 mmol), isobutyl chloroformate (151 mg, 1.12 mmol), NaH (14 mg, 0.562 mmol) and THF (8 mL) to afford 17 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.57 (s, IH), 11.17 (s, IH), 8.72 (d, / = 4.8 Hz, IH), 8.51 (m, IH), 8.27 (d, / = 8.4 Hz, 2H), 7.68 (d, J = 4.8 Hz, 3H), 7.59- 7.54 (m, 2H), 7.43 (d, J = 6.6 Hz, IH), 4.33-4.24 (m, 3H), 3.92-3.76 (m, 2H), 1.87-1.79 (m, 4H); MS (m/z): 576.01 (M)+.
Example 8
N-(4-chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl) carbamoyl)benzyl)tetra
The title compound was prepared following the procedure described in example-3 using N3-
[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5-fc]pyridine-3,7-diamine (intermediate- 1 , 70 mg, 0.225 mmol), 2-chloro-5-((tetrahydrofuran-3-carboxamido)methyl)benzoic acid (intermediate-9, 160 mg, 0.563 mmol), DIPEA (214 mg, 1.6859 mmol), isobutyl chloroformate (151 mg, 1.12 mmol), NaH (0.014 g, 0.562 mmol) and THF (8 mL) to afford 15 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.55 (br s, IH), 10.16 (s, IH), 8.70 (d, J = 5.4 Hz, IH), 8.56 (m, IH), 8.25 (d, / = 8.1 Hz, 2H), 7.68 -7.65 (m, 3H), 7.58-7.54
(m, 2H), 7.41 (d, / = 8.4 Hz, 1H), 7.32 (d, / = 6.0 Hz, 2H), 3.87- 3.60 (m, 4H), 3.00 (m, 1H), 1.98 (q, J =7.5, 6.3 Hz, 2H); MS (m/z): 574.1 1 (M-H)~.
Example 9
2-Chloro-5-((3-methylbutanamido)methyl)-N-(3-((4-(trifluoromethyl)phenyl)amino) isothiazolo[4,5- ]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in example-3 using N3- [4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5-&]pyridine-3,7-diamine (intermediate- 1 , 70 mg, 0.225 mmol), 2-chloro-5-((3-methylbutanamido)methyl)benzoic acid (intermediate- 10, 151 mg, 0.563 mmol), DIPEA (214 mg, 1.6859 mmol), isobutyl chloroformate (151 mg, 1.12 mmol), NaH (14 mg, 0.562 mmol) and THF (10 mL) to afford 14 mg of the title product. H NMR (300 MHz, DMSO d6): δ 11.54 (s, 1H), 10.16 (s, 1H), 8.70 (d, = 5.4 Hz, 1H), 8.43 (m, 1H), 8.25 (d, / = 8.4 Hz, 2H), 7.66 -7.65 (m, 3H), 7.57-7.54 (m, 2H),7.41 (d, J = 4.8 Hz, 1H), 4.30 (d, J = 5.7 Hz, 2H), 2.01 (m, 3H), 1.18- 1.13 (m, 6H); MS (m/z): 562.15 (M)+.
Example 10
2-Chloro-5-(pivalamidomethyl)-N-(3-((4-(trifluoromethyl)phenyl)amino)benzo[d]isothiazol- 7-yl)benzamide
To a solution of 4-(trifluoromethyl) aniline (50 mg, 0.316 mmol) in DMF was added NaH (34 mg, 0.086 mmol) at 0-5°C. The reaction mass was stirred at rt for 30 mins and 2-chloro-N-(3- chlorobenzo[d]isothiazol-7-yl)-5-(pivalamidomethyl)benzamide (intermediate- 12, 125 mg, 0.28 mmol) was added to the reaction mixture. The reaction mixture was heated at 80°C for 3 h before it was quenched with water and was extracted with ethyl acetate. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 13 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 10.99
(s, 1H), 9.96 (s, 1H), 8.36 (d, / = 8.1 Hz, 1H), 8.20- 8.13 (m, 3H), 7.71-7.65 (m, 3H), 7.59- 7.53 (m, 2H), 7.47 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 4.30 (d, / = 5.7 Hz, 2H), 1.14 (s, 9H); MS (m/z): 561.15 (M+H)+.
Example 11
2-Chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-(3-{[3-(trifluoromethyl)phenyl] amino} [ 1 ,2]thiazolo[4,5-&]pyridin-7-yl)benzamide
Step-1 : Preparation of feri-butyl {4-chloro-3-[(3- {[3-(trifluoromethyl) phenyl]amino} [l,2]thiazolo[4,5- ?]pyridin-7-yl)carbamoyl]benzyl} carbamate
The title compound was prepared following the procedure described in example-3 using 5- {[(ieri-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (intermediate-2, 128 mg, 0.451 mmol), N3-[3-(trifluoromethyl)phenyl][l,2]thiazolo[4,5-l?]pyridine-3,7-diamine (intermediate -13, 100 mg, 0.322 mmol), DIPEA (0.165 mL, 0.966 mmol), isobutyl chloroformate (0.052 mL, .386 mmol), NaH (80 mg, 2.00 mmol) and THF (10 mL) to afford 35 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 11.55 (s, 1H), 10.13 (s, 1H), 8.71 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.60-7.53 (m, 4H), 7.42 (d, J = 9.9 Hz, 1H), 7.29 (d, / = 7.5 Hz, 1H), 4.19 (d, / = 6.3 Hz, 2H), 1.39 (s, 9H).
Step-2: 2-chloro-5- { [(2,2-dimethylpropanoyl)amino]methyl} -N-(3- { [3- (trifluoromethyl)phenyl] amino} [1 ,2]thiazolo[4,5-^]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in example-2 using tert- butyl 4-chloro-3-((3-((3-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7- yl)carbamoyl)benzylcarbamate (27 mg, 0.047 mmol), HC1 in EtOAc (1 mL), DIPEA (0.033 mL, 0.19 mmol), pivaloyl chloride (12 mg, 0.105 mmol) and DMF (1 mL) to afford 13 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.55 (s, 1H), 10.13 (s, 1H), 9.40 (s, 1H), 8.71 (d, .7 = 4.8 Hz, 1H), 8.56 (s, 1H), 8.32 (d, .7 = 9.0 Hz, 1H), 8.19 (m, 1H), 7.70 (d, J = 5.1
Hz, IH), 7.55 (t, J = 8.1 Hz, 2H), 7.40 (d, / = 8.4 Hz, IH), 7.29 (d, J = 7.8 Hz, IH), 4.30 (d, J = 6.0 Hz, 2H), 1.15 (s, 9H); MS (m/z): 562.12 (M+H)+.
Example 12
(i?)-N-(4-Chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7- yl)carbamoyl)benzyl)tetrahydrofuran-2-carboxamide
Step 1 : 5-(Aminomethyl)-2-chloro-N-(3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- &]pyridin-7-yl)benzamide hydrochloride
To a solution ieri-butyl {4-chloro-3-[(3- {[4-(trifluoromethyl)phenyl]amino} [l ,2]thiazolo[4,5- ¾]pyridin-7-yl)carbamoyl]benzyl} carbamate (intermediate-3, 100 mg, 0.173 mmol) was added HCl saturated in methanol (2 mL). The reaction mass was heated at 40- 45 C for 2 h. The reaction mixture was concentrated to obtain 100 mg of the title compound which was taken to the next step without further purification.
Step 2: (R)-N-(4-chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridine- 7-yl)carbamoyl)benzyl)tetrahydrofuran-2-carboxamide
To a cold solution of 5-(aminomethyl)-2-chloro-N-(3-((4-(trifluoromethyl)phenyl)amino) isothiazolo[4,5-Z?]pyridin-7-yl)benzamide hydrochloride (50 mg, 0.097 mmol) in THF (1 mL) and DIPEA (62 mg, 0.485 mmol) was added ( ?)-tetrahydrofuran-2-carboxylic acid chloride (22 mg, 0.194 mmol) at 0- 5 C.The reaction mixture was stirred at rt for 1- 2 h. The reaction mixture was concentrated and was neutralized with IN HCl. The precipitate obtained was collected by filtration, dried and triturated with Et20 to afford 9 mg of the title product. LH
NMR (300 MHz, DMSO d6): δ 1 1.58 (s, IH), 10.20 (s, IH), 8.71 (d, IH), 8.52 (m, 2H), 8.27 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 6.3 Hz, 2H), 7.59- 7.56 (m, 2H), 7.44 (d, IH), 4.31 (m, 3H), 3.90 (m, IH), 3.78 (m, IH), 2.12- 1.82 (m, 4H).
Example 13
(5)-N-(4-chloro-3-((3-((4-(trifluoromethyl)phenyl)am
yl)carbamoyl)benzyl)tetrahydrofuran-2-carboxamide
The title compound was prepared following the procedure described in step-2 of example- 12 using (5)-tetrahydrofuran-2-carboxylic acid chloride (22 mg, 0.194 mmol), 5-(aminomethyl)- 2-chloro-N-(3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-&]pyridin-7-yl)benzamide hydrochloride (step- 1 , example 12, 50 mg, 0.097 mmol), DIPEA (62 mg, 0.485 mmol) and THF (1 mL) to afford 13 mg of the title product. lR NMR (300 MHz, DMSO d6): δ 11.59 (s, 1H), 10.20 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 8.53 (m, 1H), 8.27 (d, .7 =8.4 Hz, 2H), 7.68 (d, J = 6.3 Hz, 3H), 7.59- 7.54 (m, 2H), 7.42 (d, / = 7.8 Hz, 1H), 4.32 (m, 3H), 3.92- 3.60 (m, 2H), 2.12- 1.82 (m, 4H); MS (m/z): 576.09(M+H)+.
Example 14
2-Chloro-5-((2-hydroxy-2-methylpropanamido)methyl)-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)benzamide
To a cold solution of a-hydroxyisobutric acid (16 mg, 0.155 mmol) in DMF (1 mL) was added benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (68 mg, 0.155 mmol), DIPEA (66 mg, 0.515 mmol) at 0-5 °C. The reaction mixture was stirred for 30 mins and then added to a solution of 5-(aminomethyl)-2-chloro-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)benzamide hydrochloride (step- 1, example 12, 60 mg, 0.103 mmol) and DIPEA (62 mg, 0.485 mmol) in THF (1 mL) at 0- 5 °C. The reaction mixture was stirred at rt for 1- 2 h. The reaction mixture was concentrated and was neutralized with IN HCl. The precipitate obtained was collected by filtration, dried and purified by column chromatography to afford 13 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 11.58 (s, 1H), 10.19 (s, 1H), 8.71 (d, 1H), 8.42 (m, 1H), 8.32- 8.26 (m, 3H), 7.68 (d, / =5.7 Hz, 2H), 7.55 (m, 2H), 7.45 (d, 1H), 5.47 (s, 1H), 4.31 (d, / = 5.7 Hz, 2H), 1.26 (s, 6H); MS (m/z): 562.09(M-H)\
Example 15
2-Chloro-5-((l-hydroxycyclopropanecarboxamido)methyl)-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in example- 14 using 1- hydroxy- 1 -cyclopropane carboxylic acid (16 mg, 0.155 mmol), 5-(aminomethyl)-2-chloro-N- (3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-&]pyridin-7-yl)benzamide
hydrochloride (step- 1, example 12, 60 mg, 0.103 mmol), benzotriazole-l-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate (68 mg, 0.155 mmol), and DIPEA (62 mg, 0.485 mmol) in DMF (2 mL) to afford 1 1 mg of the title product. XH NMR (300 MHz,
DMSO d6): δ 11.57 (s, 1H), 10.18 (s, 1H), 8.70 (d, / = 5.8 Hz, 1H), 8.64 (m, 1H), 8.25 (d, J = 8.7 Hz, 2H), 7.66 (d, / = 5.7 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.8 Hz, 1H), 6.31 (s, 1H), 4.34 (d, J = 6.0 Hz, 2H), 2.70 (s, 1H), 1.00 (m, 2H), 0.83 (m, 2H); MS (m/z): 562.09(M+H)+.
Example 16
2-Chloro-N-(3-((5-fluoro-2-methylphenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)-5- (pivalamidomethyl)benzamide
Step-1 : Preparation of ieri-butyl 4-chloro-3-((3-((5-fluoro-2-methylphenyl)amino) isothiazolo[4,5-Z?]pyridin-7-yl)carbamoyl)benzylcarbamate
The title compound was prepared following the procedure as described in example-3 using N3-(5-fluoro-2-methylphenyl)isothiazolo[4,5-Z?]pyridine-3,7-diamine (intermediate 14, 83 mg, 0.306 mmol), 5-{[(ieri-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (intermediate-2, 122 mg, 0.428 mmol), DIPEA (1 16 mg, 0.918 mmol), isobutyl chloroformate (50 mg, 0.367 mmol), NaH (36 mg, 1.520 mmol) and THF (10 mL) to afford 50 mg of the title product. 1H
NMR (300 MHz, DMSO d6): δ 1 1.53 (s, 1H), 8.68 (d, J = 4.8 Hz ,1H), 8.53 (s, 1H), 8.15- 8.10 (m, 1H), 7.65 (d, / = 4.8 Hz, 1H),7.59- 7.52 (m, 3H), 7.42 (d, / = 8.4 Hz, 1H), 7.16- 7.08 (m, 2H), 4.18 (d, 7 =6.3 Hz, 2H), 2.34 (s, 3H), 1.36 (s, 9H).
Step-2: Preparation of 2-chloro-N-(3-((5-fluoro-2-methylphenyl)amino)isothiazolo[4,5- b]pyridin-7-yl)-5 -(pivalamidomethyl)benzamide
To a solution tert-b yl 4-chloro-3-((3-((5-fluoro-2-methylphenyl)amino) isothiazolo[4,5- fo]pyridin-7-yl)carbamoyl)benzylcarbamate(50 mg, 0.09 mmol) was added HCl saturated in methanol (2 mL). The reaction mass was heated at 40- 45 C for 2 h. The reaction mixture was concentrated to obtain 30 mg of 5-(aminomethyl)-2-chloro-N-(3-((5-fluoro-2- methylphenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide hydrochloride.
To a solution of 5-(aminomethyl)-2-chloro-N-(3-((5-fluoro-2-methylphenyl)amino)isothiazolo [4,5-^]pyridin-7-yl)benzamide hydrochloride (26 mg, 0.058 mmol) in THF (2 mL) were added DIPEA (29 mg, 0.228 mmol) and pivolyl chloride (15 mg, 0.114 mmol) at 0-5 °C. Then reaction mixture was stirred at rt for 1-2 h before it was neutralized with IN HCl and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 7 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 1 1.51 (s, 1H), 8.66 (d, J = 5.1 Hz ,1H), 8.51 (s, 1H), 8.17- 8.08 (m, 2H), 7.64 (d, / = 4.8 Hz, 1H),7.54 (d, / = 8.4 Hz, 1H), 7.49 (s, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.14- 7.03 (m, 2H), 4.28 (d, / = 6 Hz, 2H), 2.32 (s, 3H), 1.10 (s, 9H). MS (m/z): 526.12(M)+.
Example 17
(i5,55)-N-(4-Chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-Z7]pyridin-7- yl)carbamoyl)benzyl)- -oxabicyclo[3.1.0]hexane-l-carboxamide
The title compound was prepared following the procedure described in example- 14 using (iS,5S)-3-oxabicyclo[3.1.0]hexane-l-carboxylic acid (intermediate 17, 20 mg, 0.155 mmol), 5-(aminomethyl)-2-chloro-N-(3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-/?]pyridin- 7-yl)benzamide hydrochloride (step- 1 , example 12, 60 mg, 0.103 mmol), benzotriazole-l-yl- oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (68 mg, 0.155 mmol), and DIPEA (62 mg, 0.485 mmol) in DMF (2 mL) to afford 10 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.57 (s, 1H),10.19 (s, 1H), 8.72 (d, / = 5.4 Hz, 1H), 8.27 (m, 3H),
7.69 (m, 3H), 7.57 (m, 2H), 7.43 (d, / = 8.7 Hz, 1H), 4.32 (d, J = 5.4 Hz, 2H), 3.90 (d, / = 5.4 Hz, 1H), 3.81 (d, / = 8.4 Hz, 1H), 3.68 (m, 2H), 2.02 (s, 1H), 1.27 (m, 1H), 0.75 (s, 1H); MS (m/z): 588.05 (M)+.
Example 18
2-Chloro-N-(3-((2-fluoro-5-(trifluoromethyl)^
(pivalamidomethyl)benzamide
Step 1 : Preparation of ieri-butyl 4-chloro-3-((3-((2-fluoro-5-(trifluoromethyl)phenyl) amino)isothiazolo[4, -/7]pyridin-7-yl)carbamoyl)benzylcarbamate
The title compound was prepared following the procedure as described in example-3 using N3-(2-fluoro-5-(trifluoromethyl)phenyl)isothiazolo[4,5- ?]pyridine-3,7-diamine (intermediate 15, 100 mg, 0.304 mmol), 5-{[(ieri-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (intermediate-2, 121 mg, 0.426 mmol), DIPEA (1 15 mg, 0.912 mmol), isobutyl chloroformate (49 mg, 0.364 mmol), NaH (60 mg, 2.5 mmol) and THF (10 mL) to afford 80 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 11.64 (s, 1H), 8.87 (s, 2H), 8.72 (d, / = 4.8 Hz, 1H), 7.65- 7.45 (m, 7H), 4.18 (d, / = 5.7 Hz, 2H), 1.38 (s, 9H) .
Step 2: Preparation of 2-chloro-N-(3-((2-fiuoro-5-(trifluoromethyl)phenyl)amino)
isothiazolo[4,5- ?]pyridin-7-yl)-5-(pivalamidomethyl)benzamide
To a solution feri-butyl 4-chloro-3-((3-((2-fluoro-5-
(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)carbamoyl)benzylcarbamate (80 mg, 0.134 mmol) was added HCl saturated in methanol (2 mL). The reaction mass was heated at 40- 45 C for 2 h. The reaction mixture was concentrated to obtain 34 mg of 5- (aminomethyl)-2-chloro-N-(3 -((2-fluoro-5-(trifluoromethyl)phenyl)amino)isothiazolo [4,5- b]pyridin-7-yl)benzamide hydrochloride.
To a solution of 5-(aminomethyl)-2-chloro-N-(3-((2-fluoro-5-
(trifluoromethyl)phenyl)amino)isothiazolo[4,5- >]pyridin-7-yl)benzamide hydrochloride (29 mg, 0.228 mmol) in THF (2 mL) were added DIPEA (31 mg, 0.246 mmol) and pivolyl
chloride (14 mg, 0.173 mmol) at 0-5 C. Then reaction mixture was stirred at rt for 1-2 h before it was neutralized with IN HCl and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 10 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.64 (s, 1H), 8.87 (s, 2H), 8.71 (d, / = 7.8 Hz, 1H), 8.20 (m, 1H), 7.65- 7.53 (m, 4H), 7.48- 7.39 (m, 2H), 4.30 (d, / = 5.1 Hz, 2H), 1.12 (s, 9H); MS (m/z): 580.08 (M)+.
Example 19
N-(4-Chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7- yl)carbamoyl)benzyl)piperidine-4-carboxamide dihydrochloride
Step 1 : Preparation of ieri-butyl 4-((4-chloro-3-((3-((4-(trifluoromethyl)phenyl)amino) isothiazolo[4,5- ?] ridin-7-yl)carbamoyl)benzyl)carbamoyl)piperidine-l-carboxylate
The title compound was prepared following the procedure described in example- 14 using 1- Boc-piperidine-4-carboxylic acid (35 mg, 0.155 mmol), 5-(aminomethyl)-2-chloro-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- >]pyridin-7-yl)benzamide hydrochloride (step- 1, example 12, 60 mg, 0.103 mmol), benzotriazole-l-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate (68 mg, 0.155 mmol), and DIPEA (62 mg, 0.485 mmol) in DMF (2 mL) to afford 35 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.55 (s, 1H), 10.17 (s, 1H), 8.71 (d, / = 4.8 Hz, 1H), 8.46 (m, 1H), 8.27 (d, / = 8.7 Hz, 2H), 7.69 (m, 3H), 7.56 (m, 2H), 7.43 (d, 1H), 4.32 (d, / = 6.0 Hz, 2H), 3.90 (m, 2H), 2.73 (m, 2H), 2.49 (m, 1H), 1.98 (m, 2H), 1.70 (m, 2H), 1.33 (s, 9H).
Step 2: Preparation of N-(4-chloro-3-((3-((4-(trifiuoromethyl)phenyl)amino)isothiazolo[4,5- ¾]pyridin-7-yl)carbamoyl)benzyl)piperidine-4-carboxamide dihydrochloride
To a solution ierf-butyl 4-((4-chloro-3-((3-((4-(trifiuoromethyl)phenyl)amino)isothiazolo[4,5- &]pyridin-7-yl)carbamoyl)benzyl)carbamoyl)piperidine-l-carboxylate (35 mg, 0.051 mmol) was added HC1 saturated in methanol (2 niL). The reaction mass was heated at 40- 45 C for 2 h. The reaction mixture was concentrated and triturated with ΕΪ2Ο to afford 10 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.60 (s, 1H), 10.18 (s, 1H), 8.86 (m, 1H), 8.71 (d, J = 4.8 Hz, 1H), 8.63 (m, 2H), 8.27 (d, 7 =7.8 Hz, 2H), 7.69- 7.59 (m, 3H), 7.55 (m, 2H), 7.42 (d, / = 7.8 Hz, 1H), 4.34 (m, 2H), 3.24 (m, 2H), 2.88 (m, 2H),2.49 (m,2H), 1.86- 1.76 (m, 4H) ; MS (m/z): 589.09 (M)+.
Example 20
Step 1 : Preparation of tert-butyl 4-chloro-3-((3-(cyclobutylamino)isothiazolo[4,5-Z?]pyridin-7- yl)carbamoyl)benzylcarb
The title compound was prepared following the procedure as described in example-3 using N3-cyclobutylisothiazolo[4,5-Z?]pyridine-3,7-diamine (intermediate 16, 120 mg, 0.545 mmol), 5-{[(feri-butoxycarbonyl)amino]methyl}-2-chlorobenzoic acid (intermediate-2, 217 mg, 0.763 mmol), DIPEA (207 mg, 1.63 mmol), isobutyl chloroformate (88 mg, 0.654 mmol), NaH (65 mg, 4.54 mmol) and THF (10 mL) to afford 72 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.35 (s, 1H), 8.56 (d, / = 4.8 Hz, 1H), 7.66 (d, J = 5.4 Hz, 1H), 7.57- 7.39 (m, 4H), 7.15 (m, 1H), 4.40 (m, 1H), 4.17 (d, J = 5.4 Hz, 2H), 2.26 (m, 2H), 2.12 (m, 2H), 1.66 (m, 2H), 1.38 (s, 9H) .
Step 2: Preparation of 2-chloro-N-(3-(cyclobutylamino)isothiazolo[4,5- ?]pyridin-7-yl)-5- (pivalamidomethyl)benzamide
To a solution ieri-butyl 4-chloro-3-((3-(cyclobutylamino)isothiazolo[4,5-i»]pyridin-7- yl)carbamoyl)benzylcarbamate (58 mg, 0.142 mmol) was added HC1 saturated in methanol (2 mL). The reaction mass was heated at 40- 45 C for 2 h. The reaction mixture was
concentrated to obtain 28 mg of 5-(aminomethyl)-2-chloro-N-(3-
(cyclobutylamino)isothiazolo[4,5-&]pyridin-7-yl)benzamide hydrochloride which was taken to the next step without further purification.
To a solution of 5-(aminomethyl)-2-chloro-N-(3-(cyclobutylamino)isothiazolo[4,5- ?]pyridin- 7-yl)benzamide hydrochloride (28 mg, 0.072 mmol) in THF (2 mL) were added DIPEA (73 mg, 0.767 mmol) and pivolyl chloride (34 mg, 0.284 mmol) at 0-5 °C. Then reaction mixture was stirred at rt for 1-2 h before it was neutralized with IN HCl and was extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated. The concentrate was purified by column chromatography to afford 10 mg of the title product. LH NMR (300 MHz, DMSO ife): δ 1 1.32 (s, 1H), 8.55 (d, 7 = 4.8 Hz, 1H), 8.16 (m, 1H), 7.64 (d, 7 = 4.8 Hz, 1H), 7.52 (d, / = 8.4 Hz, 1H), 7.45 (s, 1H), 7.37 (m, 2H), 4.38 (m, 1H), 4.27 (d, 7 = 5.4 Hz, 2H), 2.24 (m, 2H), 2.11 (m, 2H), 1.64 (m, 2H), 1.10 (s, 9H); MS (m/z): 472.08 (M+H)+.
Example 21
6-Chloro-2-fluoro-N-(3-((3-fiuorophenyl)amino)isothiazolo[4,5-0]pyridin
(pivalamidomethyl)benzamide
To a solution of 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (intermediate- 19, 200 mg, 0.695 mmol) in THF (5 mL) were added EDCI (139 mg, 0.723 mmol), p-nitrophenol (101 mg, 0.723 mmol) and DIPEA (363 \\L, 2.085 mmol) and the reaction mixture was stirred at rt for 4 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 120 mg of the title product. lH NMR (300 MHz, DMSO d6): δ 8.42-8.38 (d, 7 = 9.3 Hz, 2H), 8.19 (br t, 1H), 7.64-7.61 (d, 7 = 8.7 Hz, 2H), 7.57-7.49 (m, 2H), 4.34-4.32 (d, 7 = 5.7 Hz, 2H), 1.13 (s, 9H).
Step 2: Preparation of 6-chloro-2-fluoro-N-(3-((3-fluorophenyl)amino)isothiazolo[4,5- ¾]pyridin-7-yl)-3-(pivalamidomethyl)benzamide
To a solution of N -(3-fluorophenyl)isothiazolo[4,5-0]pyridine-3,7-diamine (intermediate- 18, 50 mg, 0.19 mmol) in DMF (2 mL) was added NaH (38 mg, 0.95 mmol, 60% in mineral oil)
at 0 °C and the reaction mixture was stirred at 0-5 °C for 30 mins. Then a solution of 4- nitrophenyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (120 mg, 0.294 mmol) in DMF (1 mL) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at 0 °C - rt for 2 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 30 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.82 (s, IH), 10.06 (s, IH), 8.75-8.73 (d, / = 5.1 Hz, IH), 8.22 (br t, IH), 8.05-8.01 (d, / = 1 1.7 Hz, IH), 7.89-7.86 (d, J = 7.8 Hz, IH), 7.82-7.80 (d, / = 5.4 Hz, IH), 7.50-7.47 (d, / = 8.4 Hz, IH), 7.39-7.34 (m, 2H), 6.81-6.78 (t, / = 7.5 Hz, IH), 4.33-4.31 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 530.07 (M+H)+.
Example 22
2,6-Dimethyl-3-( ivalamidomethyl)-N-(3-((3-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- fo]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 1 of example 21 using 2,6-dimethyl-3-(pivalamidomethyl)benzoic acid (intermediate-20, 200 mg, 0.76 mmol), EDCI (151 mg, 0.79 mmol), p-nitrophenol (110 mg, 0.79 mmol), DIPEA (397 μί, 2.28 mmol) and THF (5 mL) to afford 280 mg of the title product. LH NMR (300 MHz, DMSO d6): δ 8.27-8.24 (d, / = 9.0 Hz, 2H), 7.91 (br t, IH), 7.36-7.33 (d, / = 9.0 Hz, 2H), 7.14-7.11 (d, J = 8.4 Hz, IH), 7.05-7.03 (d, J = 8.1 Hz, IH), 4.17-4.15 (d, J = 5.7 Hz, 2H), 1.12 (s, 9H). Step 2: Preparation of 2,6-dimethyl-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-[3-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- ?]pyridine-3,7-diamine (intermediate- 13, 50 mg, 0.161 mmol), 4-nitrophenyl 2,6-dimethyl-3-(pivalamidomethyl)benzoate (124 mg, 0.322 mmol), NaH (32 mg, 0.81 mmol, 60% in mineral oil) and DMF (3 mL) to afford 30 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.49 (s, IH), 10.12 (s, IH), 8.70 (d, J
= 4.5 Hz, 1H), 8.58 (s, 1H), 8.34-8.31 (d, J = 8.4 Hz, 1H), 8.00 (br t, 1H), 7.64-7.62 (d, = 4.8 Hz, 1H), 7.59-7.53 (t, J = 7.8 Hz, 1H), 7.31-7.28 (d, = 7.2 Hz, 1H), 7.20-7.13 (q, J = 7.8, 16.2 Hz, 2H), 4.25 (m, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 1.15 (s, 9H); MS (m/z): 556.13 (M+H)+.
Example 23
2-Chloro-6-methyl-3-(pivalamidomethyl)-N-(3-((3- (trifiuoromethyl)phenyl)amino)isotliiazolo[4,5- ?]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 1 of Example 21 using 2-chloro-6-methyl-3-(pivalamidomethyl)benzoic acid (intermediate-21 , 200 mg, 0.705 mmol), EDCI (141 mg, 0.733 mmol), p-nitrophenol (102 mg, 0.733 mmol), DIPEA (368 μί, 2.12 mmol) and THF (5 mL) to afford 195 mg of the title product. H NMR (300 MHz, DMSO d6): 88.41-8.38 (d, / = 9.3 Hz, 2H), 8.13 (br t, 1H), 7.66-7.63 (d, J = 8.7 Hz, 2H), 7.50-7.48 (d, / = 8.1 Hz, 1H), 7.36-7.33 (d, / = 8.4 Hz, 1H), 4.29-4.27 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H).
Step 2: Preparation of 2-chloro-6-methyl-3-(pivalamidomethyl)-N-(3-((3- (trifiuoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-[3-(trifluoromethyl)phenyl] [ l ,2]thiazolo[4,5- ?]pyridine-3,7-diamine (intermediate- 13, 100 mg, 0.322 mmol), 4-nitrophenyl 2-chloro-6-methyl-3-(pivalamidomethyl)benzoate (195 mg, 0.482 mmol), NaH (64 mg, 1.61 mmol, 60% in mineral oil) and DMF (5 mL) to afford 12 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 1 1.67 (s, 1H), 10.18 (s, 1H), 8.73-8.71 (d, J = 5.1 Hz, 1H), 8.58 (s, 1H), 8.33 (d, / = 7.8 Hz, 1H), 8.12 (t, 1H), 7.72- 7.70 (d, / = 4.8 Hz, 1H), 7.56 (t, 1H), 7.44-7.42 (d, / = 7.8 Hz, 1H), 7.29 (m, 2H), 4.25 (m, 2H), 2.31 (s, 3H), 1.15 (s, 9H); MS (m/z): 576.22 (M+H)+.
Example 24
6-Chloro-2-fluoro-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-[3-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- ?]pyridine-3,7-diamine (intermediate- 13, 100 mg, 0.322 mmol), 4-nitrophenyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (step-1 , example 21 , 264 mg, 0.645 mmol), NaH (64 mg, 1.61 mmol, 60% in mineral oil) and DMF (5 mL) to afford 60 mg of the title product. lR NMR (300 MHz, DMSO d6): δ 11.80 (s,
1H), 10.19 (s, 1H), 8.73 (d, J = 5.1 Hz, 1H), 8.55 (s, 1H), 8.33-8.30 (d, J = 8.7 Hz, 1H), 8.21- 8.17 (t, J = 6.0 Hz, 1H), 7.81-7.79 (d, J = 5.1 Hz, 1H), 7.57-7.52 (t, J = 8.4 Hz, 1H), 7.48-7.35 (m, 2H), 7.30-7.27 (d, / = 6.9 Hz, 1H), 4.31-4.29 (d, / = 6.0 Hz, 2H), 1.13 (s, 9H); MS (m/z): 580.41 (M+H)+.
Example 25
2,6-Dimethyl-3-(pivalamidomethyl)-N-(3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- fr]pyridin-7-yl)benzami
The title compound was prepared following the procedure described in step 2 of example 21 using N3-[4-(trifluoromethyl)phenyl][l ,2]thiazolo[4,5- ?]pyridine-3,7-diamine (intermediate 1 , 50 mg, 0.161 mmol), 4-nitrophenyl 2,6-dimethyl-3-(pivalamidomethyl)benzoate (example-22, step-1, 100 mg, 0.241 mmol), NaH (25 mg, 0.805 mmol, 60% in mineral oil) and DMF (3 mL) to afford 20 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.49 (s, 1H), 10.14 (s, 1H), 8.70 (d, 7 = 4.8 Hz, 1H), 8.28 (d, / = 8.7 Hz, 2H), 8.00 (t, 1H), 7.68 (d, / = 9.0 Hz, 2H), 7.61 (d, / = 4.8 Hz, 1H), 7.20-7.18 (d, = 7.2 Hz, 1H), 7.15-7.13 (d, / = 7.8 Hz, 1H), 4.24 (s, 2H), 2.29 (s, 3H), 2.27 (s, 3H), 1.15 (s, 9H); MS (m/z): 556.18 (M+H)+.
Example 26
N-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-Z?]pyridin-7-yl)-2,6- dimethyl-3-(pivalamidomethyl)benzamide
The title compound was prepared following the procedure described in step 2 of example using N3-(2-fluoro-4-(trifiuoromethyl)phenyl)isothiazolo[4,5-i>]pyridine-3,7-diamine
(intermediate 22, 100 mg, 0.304 mmol), 4-nitrophenyl 2,6-dimethyl-3- (pivalamidomethyl)benzoate (example-22, step-1 , 189 mg, 0.456 mmol), NaH (37 mg, 1.52 mmol, 60% in mineral oil) and DMF (5 mL) to afford 25 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.54 (s, 1H), 8.81 (s, 1H), 8.78-8.72 (m, 1H), 8.68 (d, 7 = 5.4 Hz, 1H), 7.98 (t, 1H), 7.78 (d, J = 10.5 Hz, 1H), 7.65 (d, 7 = 7.8 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.14 (d, 7 = 7.8 Hz, 1H), 4.22 (br s, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.13 (s, 9H); MS (m/z): 572.40 (M-H)+.
Example 27
2-Chloro-N-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)-5- (pivalamidomethyl)benzamide
To a solution of methyl 2-chloro-5-(pivalamidomethyl)benzoate (intermediate- 11 , 2.00 g, 7.05 mmol) in THF:MeOH:H20 (9:6:3; 18 mL) was added NaOH (0.564 g, 14.1 mmol). The reaction mass was stirred at rt for 3 h. The reaction mass was neutralized with citric acid and concentrated. The residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to afford 1.8 g of the title product. XH NMR (300 MHz, DMSO d6): 12.3 (br s, 1H), 8.14 (br t, 1H), 7.61 (s, 1H), 7.47- 7.44 (d, 7 = 8.1 Hz, 1H), 7.34-7.32 (d, 7 = 7.8 Hz, 1H), 4.22 (d, 7 = 6.0 Hz, 2H), 1.18 (s, 9H). Step 2: Preparation 4-nitrophenyl 2-chloro-5-(pivalamidomethyl)benzoate
To a solution of 2-chloro-5-(pivalamidomethyl)benzoic acid (300 mg, 1.12 mmol) in THF (5 mL) were added EDCI (210 mg, 1.09 mmol), p-nitrophenol (154 mg, 1.10 mmol) and DIPEA (558 mg, 4.39 mmol) and the reaction mixture was stirred at rt for 4 h. Then water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 222 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 8.36 (d, / = 9.0 Hz, 2H), 8.20 (t, 1H), 7.97 (s, 1H), 7.62-7.59 (m, 3H), 7.51 (d, J= 8.1 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 1.1 1 (s, 9H).
Step 3 : Preparation of 2-chloro-N-(3-((2-fiuoro-4-
(trifiuoromethyl)phenyl)amino)isothiazolo [4,5 - ]pyridin-7-yl)-5 - (pivalamidomethyl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-(2-fluoro-4-(trifluoromethyl)phenyl)isothiazolo[4,5-^]pyridine-3,7-diamine (intermediate 22, 100 mg, 0.304 mmol), 4-nitrophenyl 2-chloro-5- (pivalamidomethyl)benzoate (177 mg, 0.457 mmol), NaH (37 mg, 0.1.52 mmol, 60% in mineral oil) and DMF (5 mL) to afford 65 mg of the title product. *H NMR (300 MHz, DMSO d6): δ 1 1.63 (s, 1H), 8.84 (s, 1H), 8.75-8.71 (m, 2H), 8.18 (t, 1H), 7.77 (d, 1H), 7.68- 7.53 (m, 4H), 7.40 (d, J 6.6 Hz, 1H), 4.30 (A, J = 5.1 Hz, 2H), 1.12 (s, 9H); MS (m/z): 580.13 (M+H)+.
Example 28
2,6-Dimethyl-3-( ivalamidomethyl)-N-(3-((4-(trifluoromethyl)phenyl)amino)isoxazolo[4,5- b]pyridin-7-yl)benzami
The title compound was prepared following the procedure described in step 2 of example 21 using N3-(4-(trifluoromethyl)phenyl)isoxazolo[4,5-/?]pyridine-3,7-diamine (intermediate 23, 100 mg, 0.34 mmol), 4-nitrophenyl 2,6-dimethyl-3-(pivalamidomethyl)benzoate (example-22, step-1 , 156 mg, 0.408 mmol), NaH (30 mg, 1.14 mmol, 95%) and DMF (5 mL) to afford 60
mg of the title product. Ή NMR (300 MHz, DMSO d6): δ 1 1.07 (s, 1H), 10.56 (s, 1H), 8.60 (d, / = 5.1 Hz, 1H), 8.00-7.93 (m, 4H), 7.74 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 4.23 (d, J = 5.4 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 1.14 (s, 9H).
Example 29
6-Chloro-2-methoxy-3 -(pivalamidomethyl)-N-(3 -((3 -
(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide
Step 1 : Preparatio ethyl)benzoate
The title compound was prepared following the procedure described in example -27, step-2 using 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid (intermediate-24, 200 mg, 0.668 mmol), EDCI (128 mg, 0.668 mmol), p-nitrophenol (93 mg, 0.668 mmol) and DIPEA (340 mg, 2.67 mmol) in THF (5 mL) to afford 250 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 8.39 (d, J = 8.7 Hz, 2H), 8.13 (t, 1H), 7.60 (d, / = 8.7 Hz, 2H), 7.46-7.43 (d, J = 8.1 Hz, 1H), 7.40-7.37 (d, / = 8.4 Hz, 1H), 4.32 (d, / = 6.0 Hz, 2H), 3.91 (s, 3H), 1.14 (s, 9H). Step 2: Preparation of 6-chloro-2-methoxy-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3- [3 -(trifluoromethyl)phenyl] [ 1 ,2]thiazolo [4,5 -&]pyridine-3 ,7-diamine (intermediate - 13, 100 mg, 0.322 mmol), 4-nitrophenyl 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoate (217 mg, 0.482 mmol), NaH (39 mg, 1.60 mmol, 60% in mineral oil) and DMF (5 mL) to afford 31 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 1 1.65 (s, 1H), 10.16 (s, 1H), 8.73 (d, / = 5.4 Hz, 1H), 8.57 (s, 1H), 8.32 (d, / = 7.8 Hz, 1H), 8.15 (t, 1H), 7.74 (d, / = 5.1 Hz, 1H), 7.56 (t, / = 7.8 Hz, 1H), 7.39-7.28 (m, 3H), 4.30 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 1.15 (s, 9H); MS (m/z): 592.09 (M+H)+.
Example 30
2,6-Dimethyl-3-( ivalamidomethyl)-N-(3-((3-(trifluoromethyl)phenyl)amino)isoxazolo[4,5- £>]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-(3-(trifiuoromethyl)phenyl)isoxazolo[4,5-&]pyridine-3,7-diamine (intermediate 25, 55 mg, 0.187 mmol), 4-nitrophenyl 2,6-dimethyl-3-(pivalamidomethyl)benzoate (example-22, step-1, 143 mg, 0.372 mmol), NaH (19 mg, 0.79 mmol, 60% in mineral oil) and DMF (3 mL) to afford 30 mg of the title product. lH NMR (300 MHz, DMSO d6): δ 1 1.05 (s, 1H), 10.55 (s, 1H), 8.59 (t, 1H), 8.23 (s, 1H), 8.00-7.90 (m, 3H), 7.62 (t, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.12 (m, 2H), 4.24 (d, / = 5.4 Hz, 2H), 2.31 (s, 3H), 2.27 (s, 3H), 1.14 (s, 9H).
Example 31
2-Chloro-5-(pivalamidomethyl)-N-(3-((3-(trifluoromethyl)phenyl)amino)isoxazolo[4,5- b]pyridin-7-yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-(3-(trifluoromethyl)phenyl)isoxazolo[4,5-&]pyridine-3,7-diamine (intermediate 25, 60 mg, 0.204 mmol), 4-nitrophenyl 2-chloro-5-(pivalamidomethyl)benzoate (example-27, step-2, 78 mg, 0.20 mmol), NaH (40 mg, 1.66 mmol, 60% in mineral oil) and DMF (3 mL) to afford 40 mg of the title product. !H NMR (300 MHz, DMSO d6): δ 11.07 (s, 1H), 10.57 (s, 1H), 8.61 (d, / = 5.4 Hz, 1H), 8.23-8.19 (m, 2H), 8.01 (d, J = 5.4 Hz, 1H), 7.90 (d, 1H), 7.63 (t, 1H), 7.54-7.49 (m, 3H), 7.38 (d, / = 8.1 Hz, 1H), 4.30 (d, / = 6.6 Hz, 2H), 1.13 (s, 9H).
Example 32
6-Chloro-2-methoxy-3 -(pivalamidomethyl)-N-(3 -((3 - (trifluoromethyl)phenyl)amino)isoxazolo [4 ,5 -£>]pyridin-7 -yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-(3-(trifiuoromethyl)phenyl)isoxazolo[4,5-&]pyridine-3,7-diamine (intermediate 25, 65 mg, 0.221 mmol), 4-nitrophenyl 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoate
(example-29, step-1 , 185 mg, 0.440 mmol), NaH (44 mg, 1.83 mmol, 60% in mineral oil) and DMF (4 mL) to afford 45 mg of the title product. lR NMR (300 MHz, DMSO d6): δ 11.05 (s, 1H), 10.77 (s, 1H), 8.61 (d, J = 4.8 hz, 1H), 8.23 (s, 1H), 8.12 (t, 1H), 8.03 (d, / = 4.8 Hz, 1H), 7.91 (d, / = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.50 (d, / = 7.2 Hz, 1H), 7.30 (m, 2H), 4.29 (d, J = 5.4 Hz, 2H), 3.87 (s, 3H), 1.14 (s, 9H).
Example 33
6-Chloro-2-fiuoro-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isoxazolo [4 ,5 -&]pyridin-7 -yl)benzamide
The title compound was prepared following the procedure described in step 2 of example 21 using N3-(3-(trifluoromethyl)phenyl)isoxazolo[4,5-&]pyridine-3,7-diamine (intermediate 25, 60 mg, 0.204 mmol), 4-nitrophenyl 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoate (step-1 , example 21 , 166 mg, 0.406 mmol), NaH (50 mg, 2.08 mmol, 60% in mineral oil) and DMF (4 mL) to afford 40 mg of the title product. XH NMR (300 MHz, DMSO d6): δ 11.06 (s, 1H),
10.96 (s, 1H), 8.62 (d, / = 4.8 Hz, 1H), 8.23 (s, 1H), 8.17 (t, 1H), 8.02 (d, 1H), 7.92 (d, / = 8.4 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.44-7.42 (d, J = 8.1 Hz, 1H), 7.38-7.36 (d, J = 7.8 Hz, 1H), 4.30 (d, J = 5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 564.22 (M+H)+.
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 anti-PGE2 antibody based detection method. Recombinant human mPGES-1 was generated in-house by expressing in CHO cells (Ouellet M et al. (2002), Protein Expression and Purification 26: 489 - 495). Assay was set up using crude microsomal fractions at protein concentration of 40-60 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. Final concentration
of DMSO in reaction was 0.5 % (v/v). Negative controls comprised of all assay reagents except the enzyme. Positive controls comprised of enzyme reaction in the absence of any inhibitor. Test compounds were incubated for 10 minutes in assay buffer containing 2.5 mM GSH and mPGES-1 enzyme followed by addition of PG¾ at a concentration of 15 μΜ for 1 minute. 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 percent of reaction occurring in the positive control. Concentration response curves were plotted using percent inhibition of maximum enzyme reaction. IC50 value was calculated from 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 value of less than 1000 nM, preferably, less than 500 nM, more preferably, less than 100 nM. The IC50 (nM) values of the compounds are set forth in Table 1 wherein "A" refers to an IC50 value of less than 20 nM, "B" refers to IC50 value in range of 20.01 to 50.0 nM and "C" refers to IC50 values more than 50 nM.
Table 1 :
s for mPGES-1 inhi ?itors using the A549 cell based assay
The inhibition of mPGES-1 enzyme in A549 cell line was monitored as inhibition of IL-Ιβ 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. Assay was carried out in a total volume of 200 μΕ. Test compounds were dissolved in dimethyl sulfoxide (DMSO) to prepare 2 mM stock solution and then diluted using plain DMEM. Final concentration of DMSO in the reaction was 0.55% (v/v). Cells were treated with test compounds for 30 minutes followed by addition of IL-Ιβ 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 ( -101) (Japan) HTRF plate reader and levels of PGE2 calculated by extrapolation from the standard curve.
Concentration response curves were plotted as % of maximal response obtained in the absence of test antagonist. IC50 value was calculated from concentration response curve by nonlinear regression analysis using GraphPad PRISM software.
Claims
1. A compound of formula (II):
(II)
or a pharmaceutically acceptable salt thereof,
wherein,
X is selected from O, and S(0)q;
G1 is N;
G2 and G3 are CR3;
W is selected from substituted or unsubstituted Ci-salkyl, C2-ioalkenyl, C2-ioalkynyl, Ci_ galkoxy, Ci galkyloxyCi galkyl, haloCi galkyl, hydroxyCi_8alkyl, haloCi_8alkoxy, C3 i2cycloalkyl, C3-i2cycloalkylCi_8alkyl, C3_i2cycloalkenyl, C3_i2cycloalkenylCi_8alkyl, Ce-naryl, C6_i4aryl Ci_galkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi_8alkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi galkyl;
R1 is selected from substituted or unsubstituted Ci-galkyl, C3_i2cycloalkyl, C3- i2cycloalkylCi_8alkyl, C3_i2cycloalkenyl, C3_i2cycloalkenylCi_8alkyl, Cg-naryl, Cg-naryl Ci_ 8alkyl, 3-15 membered heterocyclyl, 3-15 membered heterocyclylCi-salkyl, 5-14 membered heteroaryl and 5-14 membered heteroarylCi_8alkyl;
at each occurrence, R2 is independently selected from halogen, cyano, hydroxyl, substituted or unsubstituted Ci_8alkyl, Ci_8alkoxy, haloCi-salkyl, haloCi_salkoxy and hydroxyC- i_8alkyl;
R3 is independently selected from hydrogen, halogen, cyano, substituted or unsubstituted Ci-salkyl, haloCi_8alkyl and haloCi_8alkoxy;
at each occurrence, Rp is selected from hydrogen, substituted or unsubstituted Ci_8alkyl and C6_i4arylCi_8alkyl;
'm' is an integer ranging from 0 to 4, both inclusive;
'n' is an integer ranging from 1 to 4, both inclusive; and
'q' is an integer ranging from 0 to 2, both inclusive.
2. The compound according to claim 1 , wherein X is S.
3. The compound according to claim 1 , wherein X is O.
4. The compound according to any one of the preceding claims, wherein A is phenyl.
5. The compound according to any one of claims 1 to 4, wherein R2 is halogen, C1- alkyl, or Ci-galkoxy.
6. The compound according to any one of claims 1 to 4, wherein R2 is chloro, fluoro, methyl or methoxy.
7. The compounds according to any one of claims 1 to 6, wherein m is 1 or 2
8. The compound according to any one of claims 1 to 7, wherein W is substituted or unsubstituted Ci_8alkyl, hydroxyCi-salkyl, C3-i2cycloalkyl or 3-15 membered heterocyclyl.
9. The compound according to any one of claims 1 to 7, wherein W is isopropyl, propan-2- yl, isobutyl, 2-methylpropan- 1 -yl, iert-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2- hydroxy propanyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, 1 -hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)-tetrahydrofuran-2-yl, (S)- tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
10. The compound according to any one of claims 1 to 9, wherein R1 is substituted or unsubstituted Ce-naryl or C3_i2cycloalkyl.
11. The compound according to any one of claims 1 to 9, wherein R1 is phenyl, optionally substituted with one or more substituents selected from halogen, Ci-galkyl, and haloCi-galkyl.
12. The compounds according to any one of claims 1 to 9, wherein R1 is 4- trifluoromethylphenyl, 5-fluoro-2-methylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro- 4-trifluoromethylphenyl, 3 -fluorophenyl or 3-trifluoromethylphenyl.
13. The compounds according to any one of claims 1 to 12, wherein Rp is hydrogen.
14. The compounds according to any one of claims 1 to 13, wherein n is 1.
15. A compound having the formula (III):
(III)
or a pharmaceutically acceptable salt thereof,
wherein,
W is substituted or unsubstituted Ci-galkyl, hydroxyCi-galkyl, C3_i2cycloalkyl, or 3-15 membered heterocyclyl;
R1 is substituted or unsubstituted C6-i4aryl or C3_i2cycloalkyl;
at each occurrence, R2 is halogen, Ci_4 alkyl, or Ci_8alkoxy; and
'm' is an integer ranging from 0 to 4, both inclusive.
16. The compound according to claim 15, wherein R2 is chloro, fluoro, methyl or methoxy.
17. The compounds according to claim 1 or 16, wherein m is 1 or 2
18. The compound according to any one of claims 15 to 17, wherein W is isopropyl, propan-2-yl, isobutyl, 2-methylpropan-l-yl, ieri-butyl, 2-methylpropan-2-yl, 2-hydroxy propan-2-yl, 2-hydroxy propanyl, cyclopropyl, cyclobutyl, 1 -methylcyclopropyl, 1- hydroxycyclopropyl, tetrahydrofuryl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, (R)- tetrahydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, piperidinyl, oxabicyclo[3.1.0]hexanyl or piperidinyl.
19. The compound according to any one of claims 1 to 18, wherein R1 is phenyl, optionally substituted with one or more substituents selected from halogen, Ci.galkyl, and haloCi.galkyl.
20. The compounds according to any one of claims 15 to 18, wherein R1 is 4- trifluoromethylphenyl, 5-fluoro-2-methylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2-fluoro- 4-trifluoromethylphenyl, 3 -fluorophenyl or 3-trifluoromethylphenyl.
21. The compound selected from
2-Chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-(3-{[4-(trifiuoromethyl)phenyl] amino} [ 1 ,2]thiazolo[4,5-&]pyridin-7-yl)benzamide;
2-Chloro-5 -(( 1 -methylcyclopropanecarboxamido)methyl)-N-(3 -((4-(trifluoromethyl) phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide;
2-Chloro-5-(isobutyramidomethyl)-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-Z?]pyridin-7-yl)benzamide;
2-Chloro-5-(cyclopropanecarboxamidomethyl)-N-(3-((4-(trifluoromethyl)phenyl)amino) isothiazolo [4 , 5 -Z?]pyridin-7-yl)benzamide ;
2-Chloro-5 -(cyclobutanecarboxamidomethyl)-N-(3 -((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide;
N-(4-Chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-&]pyridin-7-yl) carbamoyl)benzyl)tetrahydrofuran-2-carboxamide;
N-(4-chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- >]pyridin-7-yl) carbamoyl)benzyl)tetrahydrofuran-3-carboxamide;
2-Chloro-5-((3-methylbutanamido)methyl)-N-(3-((4-(trifluoromethyl)phenyl)amino) isothiazolo [4 , 5 -Z?]pyridin-7-yl)benzamide ;
2-Chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}-N-(3-{[3-(trifiuoromethyl)phenyl] amino} [ 1 ,2]thiazolo[4,5-fr]pyridin-7-yl)benzamide;
(R)-N-(4-chloro-3-((3-((4-(trifluorometh^
yl)carbamoyl)benzyl)tetrahydrofuran-2-carboxamide;
(5)-N-(4-chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7^ yl)carbamoyl)benzyl)tetrahydrofuran-2-carboxamide;
2-Chloro-5 -((2-hydroxy-2-methylpropanamido)methyl)-N-(3 -((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide;
2-Chloro-5-((l-hydroxycyclopropanecarboxamido)methyl)-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)benzamide;
2-Chloro-N-(3-((5-fluoro-2-methylphenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)-5- (pivalamidomethyl)benzamide;
(i5',55)-N-(4-Chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-&]pyri^^ yl)carbamoyl)benzyl)-3 -oxabicyclo [3.1.0]hexane- 1 -carboxamide;
2-Chloro-N-(3-((2-fluoro-5-(trifluoromem^
yl)-5-(pivalamidomethyl)benzamide;
N-(4-Chloro-3-((3-((4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5-&]pyridin-7- yl)carbamoyl)benzyl)piperidine-4-carboxamide dihydrochloride;
2-Chloro-N-(3-(cyclobutylamino)isothiazolo[4,5-^]pyridin-7-yl)-5- (pivalamidomethyl)benzamide;
6-Chloro-2-fluoro-N-(3-((3-£luorophenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)-3- (pivalamidomethyl)benzamide;
2,6-Dimethyl-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-Z?]pyridin-7-yl)benzamide;
2-Chloro-6-methyl-3 -(pivalamidomethyl)-N-(3 -((3 - (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide;
6-Chloro-2-fluoro-3-(pivalamidomethyl)-N-(3-((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide;
2,6-Dimethyl-3-(pivalamidomethyl)-N-(3-((4- (trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7-yl)benzamide;
N-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- >]pyridin-7-yl)-2,6- dimethyl-3 -(pivalamidomethyl)benzamide; and
2-Chloro-N-(3-((2-fluoro-4-(trifluoromethyl)phenyl)amino)isothiazolo[4,5- ?]pyridin-7- yl)-5-(pivalamidomethyl)benzamide;
or a pharmaceutically acceptable salt thereof.
22. The compound selected from
2,6-Dimethyl-3-(pivalamidomethyl)-N-(3-((4-
(trifluoromethyl)phenyl)amino)isoxazolo[4,5-&]pyridin-7-yl)benzamide;
6-Chloro-2-methoxy-3 -(pivalamidomethyl)-N-(3 -((3- (trifluoromethyl)phenyl)amino)isothiazolo[4,5-^]pyridin-7-yl)benzamide;
2,6-Dimethyl-3-(pivalamidomethyl)-N-(3-((3- (trifiuoromethyl)phenyl)amino)isoxazolo[4,5-&]pyridin-7-yl)benzamide;
2-Chloro-5 -(pivalamidomethyl)-N-(3 -((3 -(trifluoromethyl)phenyl)amino)isoxazolo [4,5 - ¾]pyridin-7-yl)benzamide;
6-Chloro-2-methoxy-3 -(pivalamidomethyl)-N-(3 -((3- (trifiuoromethyl)phenyl)amino)isoxazolo[4,5-¾]pyridin-7-yl)benzamide; and
6-Chloro-2-fluoro-3-(pivalamidomethyl)-N-(3-((3- (trifiuoromethyl)phenyl)amino)isoxazolo[4,5-&]pyridin-7-yl)benzamide;
or a pharmaceutically acceptable salt thereof.
23. The compound selected from
2-Chloro-6-fluoro-N-(3-{[4-(trifluoromethyl)phenyl]amino} [l ,2]thiazolo[4,5-l?]pyridin-7- yl)benzamide;
2-Chloro-5-(pivalamidomethyl)-N-(3-((4- (trifiuoromethyl)phenyl)amino)benzo[d]isothiazol-7-yl)benzamide;
N3-[4-(Trifluoromethyl)phenyl] [ 1 ,2]thiazolo[4,5-&]pyridine-3 ,7-diamine;
ieri-Butyl {4-chloro-3 - [(3 - { [4-(trifluoromethyl)phenyl]amino } [ 1 ,2]thiazolo [4, -Z?]pyridin- 7-yl)carbamoyl]benzyl} carbamate;
2-Chloro-N-(3-chlorobenzo[d]isothiazol-7-yl)-5-(pivalamidomethyl)benzamide;
N3-[3-(Trifluoromethyl)phenyl] [ 1 ,2]thiazolo[4,5-¾]pyridine-3 ,7-diamine;
N3-(5-Fluoro-2-methylphenyl)isothiazolo[4,5-Z?]pyridine-3,7-diamine;
N3-(2-fluoro-5-(trifiuoromethyl)phenyl)isothiazolo[4,5- ?]pyridine-3,7-diamine;
N3-Cyclobutylisothiazolo[4,5- ?]pyridine-3,7-diamine;
N3-(3-Fluorophenyl)isothiazolo[4,5-&]pyridine-3,7-diamine;
N3-(2-Fluoro-4-(trifluoromethyl)phenyl)isothiazolo[4,5-&]pyridine-3,7-diamine;
N3-(4-(Trifluoromethyl)phenyl)isoxazolo[4,5-Z?]pyridine-3,7-diamine;
N3-(3-(Trifluoromethyl)phenyl)isoxazolo[4,5-Z?]pyridine-3,7-diamine;
2-Chloro-5-((l -methylcyclopropanecarboxamido)methyl)benzoic acid;
2-Chloro-5 -(isobutyramidomethyl)benzoic acid;
2-Chloro-5-(cyclopropanecarboxamidomethyl)benzoic acid;
2-Chloro-5-(cyclobutanecarboxamidomethyl)benzoic acid;
2-Chloro-5-((tetrahydrofuran-2-carboxamido)methyl)benzoic acid;
2-Chloro-5-((tetrahydrofuran-3-carboxamido)methyl)benzoic acid;
2-Chloro-5 -((3 -methylbutanamido)methyl)benzoic acid;
2,6-Dimethyl-3-(pivalamidomethyl)benzoic acid;
6-Chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid; and
(i5',55)-3-Oxabicyclo[3.1.0]hexane-l-carboxylic acid;
or a pharmaceutically acceptable salt thereof.
24. The compound having the structure
or a pharmaceutically acceptable salt thereof.
2 . A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, either as a free base or pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
26. The pharmaceutical composition according to claim 25, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
27. A combination product comprising a compound according to any one of claims 1 to 24 or a pharmaceutically-acceptable salt thereof; and another therapeutic agent, wherein each of the compound according to any one of claims 1 to 24 and the therapeutic agent is formulated in admixture with a pharmaceutically-acceptable excipient.
28. The compound according to any one of claims 1 to 24 for use in prevention or treatment of a mPGES-1 mediated disease, disorder or syndrome in a subject.
29. A method of treatment of disease, disorder, syndrome or condition selected from the group consisting of 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 by administration of a compound according to any one of claims 1 to 24.
30. The method according to claim 29, wherein the symptoms of a disease or condition is associated with pain.
31. The method according to claim 29, wherein the symptoms of a disease or condition is associated with chronic or acute pain.
32. The method according to claim 29, wherein the symptoms of a disease or condition is associated with rheumatoid arthritic pain or osteoarthritic pain.
33. The method according to claim 29, wherein the symptoms of a disease or condition is associated with neurodegenerative diseases selected from Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis.
34. A method of treating, preventing or managing cancer comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1 to 24.
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IN2618/MUM/2011 | 2011-09-15 | ||
IN2618MU2011 | 2011-09-15 | ||
US201161540390P | 2011-09-28 | 2011-09-28 | |
US61/540,390 | 2011-09-28 | ||
IN3222MU2011 | 2011-11-14 | ||
IN3222/MUM/2011 | 2011-11-14 | ||
US201161576798P | 2011-12-16 | 2011-12-16 | |
US61/576,798 | 2011-12-16 | ||
IN1655/MUM/2012 | 2012-06-05 | ||
IN1655MU2012 | 2012-06-05 | ||
US201261665281P | 2012-06-27 | 2012-06-27 | |
US61/665,281 | 2012-06-27 |
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