WO2011114184A1 - Amides of heterocyclic compounds as trpa1 inhibitors - Google Patents

Amides of heterocyclic compounds as trpa1 inhibitors Download PDF

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Publication number
WO2011114184A1
WO2011114184A1 PCT/IB2010/002218 IB2010002218W WO2011114184A1 WO 2011114184 A1 WO2011114184 A1 WO 2011114184A1 IB 2010002218 W IB2010002218 W IB 2010002218W WO 2011114184 A1 WO2011114184 A1 WO 2011114184A1
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Prior art keywords
thiazol
acetamide
phenyl
dioxo
dimethyl
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PCT/IB2010/002218
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French (fr)
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Sachin Sundarlal Chaudhari
Sukeerthi Kumar
Abraham Thomas
Nisha Parag Patil
Ashok Bhausaheb Kadam
Nayan Taterao Waghmare
Neelima Khairatkar-Joshi
Indranil Mukhopadhyay
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Glenmark Pharmaceuticals S.A.
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Publication of WO2011114184A1 publication Critical patent/WO2011114184A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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

Definitions

  • the present patent application relates to amides of heterocyclic compounds with transient receptor potential ankyrinl (TRPA1) activity.
  • TRP channels or receptors are pain receptors. They have been classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin, ANKTM1) and TRPN (NOMPC) families.
  • TRPC canonical
  • TRPV vanilloid
  • TRPM melastatin
  • TRPP polycystin
  • TRPML mucolipin
  • TRPA ankyrin, ANKTM1
  • TRPN nuclear factor-associated TRPN
  • TRPV5 and TRPV6 are more closely related to each other than to TRPV1, TRPV2, TRPV3 or TRPV4.
  • TRPAl is most closely related to TRPV3 and is more closely related to TRPVl and TRPV2 than to TRPV5 and TRPV6.
  • the TRPM family has 8 members.
  • Constituents include the following: the founding member TRPMl (melastatin or LTRPC1), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (TRP-p8 or CMR1), TRPM5 (MTR1 or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4).
  • TRPMl melastatin or LTRPC1
  • TRPM3 KAA1616 or LTRPC3
  • TRPM7 TRP-PLIK, ChaK(l), LTRPC7
  • TRPM6 ChoK2
  • TRPM2 TRPC7 or LTRPC2
  • TRPM8 TRP-p8 or CMR1
  • TRPM5 MTR1 or LTRPC5
  • TRPM4 FLJ20041 or LTRPC4
  • TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have eleven.
  • TRPP2 PPD2
  • TRPP3 PPD2L1
  • TRPP5 PPD2L2
  • TRPPl PPDl, PCI
  • PKD-REJ PKD-REJ
  • PKD-lLl The sole mammalian member of the TRPA family is ANKTM1. It is believed TRPAl is expressed in nociceptive neurons. Nociceptive neurons of the nervous system sense the peripheral damage and transmit pain signals. TRPAl is membrane bound and most likely acts as a heterodimeric voltage gated channel.
  • TRPAl is activated by a variety of noxious stimuli, including cold temperatures (activated at 17°C), pungent natural compounds (e.g., mustard, cinnamon and garlic) and environmental irritants (MacPherson, L. J. et al., Nature, 2007, 445; 541-545). Noxious compounds activate TRPAl ion channels through covalent modification of cysteines to form covalently linked adducts. Variety of endogenous molecules produced during tissue inflammation / injury have been identified as pathological activators of TRPAl receptor.
  • TRPAl is also activated in receptor dependant fashion by Bradykinin (BK) which is released during tissue injury at peripheral terminals
  • TRPAl and other TRP receptors The difference between TRPAl and other TRP receptors is that TRPAl ligand binding persists for hours due to which the physiological response (e.g., pain) is greatly prolonged. Hence to dissociate the electrophile, an effective antagonist is required.
  • WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO 2004/055054 and WO 2005/089206 describe the TRP channels as the targets for the treatment of pain and related conditions.
  • the present invention relates to compounds of the formula (I):
  • Q is a heterocycle selected from the group consisting of
  • U is selected from -(CR x R y ) n -, substituted or unsubstituted aryl, substituted or unsubstituted heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles, 1,2,3-triazoles and 1, 2, 4-triazole, pyrimidine, pyridine and pyridazine;
  • V is selected from hydrogen, cyano, nitro, -NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl
  • R 1 , R 2 and R 3 which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR x R y ) complicatOR x , COR", COOR x , CONR x R y ,and (CH 2 ) n CHR x R y ;
  • R 4 is halogen
  • R x and R y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyi, heterocyclic ring and heterocyclylalkyl;
  • 'n' is selected from 0 to 2, both inclusive.
  • R 1 , U and V are as defined above in formula (I)
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), haloalkoxy (for example OCHF 2 , OCH 2 CF 3j or OCH 2 CH 2 CF 3 ), cycloalkylalkoxy (for example cyclobutylmethoxy) and cycloalkyl (for example cyclohexyl).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • haloalkoxy for example OCHF 2 , OCH 2 CF 3j or OCH 2 CH 2 CF 3
  • cycloalkylalkoxy for example cyclobutylmethoxy
  • cycloalkyl for example cyclohexyl
  • R 1 , U and V are as defined above in formula (I).
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), alkoxy (for example OCH 2 C(CH 3 ) 3 ) and haloalkoxy (for example OCH 2 CF 3 ).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • alkoxy for example OCH 2 C(CH 3 ) 3
  • haloalkoxy for example OCH 2 CF 3
  • R 1 , R 2 , U and V are as defined above in formula (I). According to another embodiment, specifically provided are compounds of the formula (Ic) wherein R 1 and R 2 are alkyl preferably methyl.
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), alkoxy (for example OCH 2 C(CH 3 ) 3 ) and haloalkoxy (for example OCF 3 or OCH 2 CF 3 ).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • alkoxy for example OCH 2 C(CH 3 ) 3
  • haloalkoxy for example OCF 3 or OCH 2 CF 3
  • R 1 , R 2 , R 3 , U and V are as defined above in formula (I).
  • R 1 and R 2 are alkyl preferably methyl.
  • R 3 is alkyl, preferably (C 1 -C4) alkyl.
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), alkoxy (for example OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH(CH 3 ) 2 , OCH 2 C(CH 3 ) 3 or OCH 2 CH 2 CH(CH 3 ) 2 ), haloalkoxy (for example OCHF 2 , OCF 3 , OCH 2 CF 3> or OCH 2 CH 2 CF 3 ) and cycloalkylalkoxy (for example cyclopropylmethoxy or cyclobutylmethoxy).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • alkoxy for example OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH 2 CH 2 CH 2 CH 3 , OCH
  • R 1 , R 2 , R 4 , U and V are as defined above in formula (I).
  • R 4 is halogen preferably fluorine, chlorine or bromine.
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF 3 ), dialkylamino (for example diethylamino), and haloalkoxy (for example OCF 3 ).
  • halogen for example F, CI or Br
  • haloalkyl for example CF 3
  • dialkylamino for example diethylamino
  • haloalkoxy for example OCF 3
  • R 1 , R 2 , U and V are as defined above in formula (I).
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), alkyl [for example CH 2 CH(CH 3 )2], haloalkyl (for example CF 3 ), alkoxy (for example OCH 3 ) and haloalkoxy (for example OCF 3 or OCH 2 CF 3 ).
  • halogen for example F, CI or Br
  • alkyl for example CH 2 CH(CH 3 )2
  • haloalkyl for example CF 3
  • alkoxy for example OCH 3
  • haloalkoxy for example OCF 3 or OCH 2 CF 3
  • R 1 , R 2 , U and V are as defined above in formula (I).
  • R 1 and R 2 are alkyl preferably methyl.
  • 'LP is substituted or unsubstituted aryl, preferably phenyl.
  • substituent on phenyl is halogen (for example F)
  • phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), alkyl (for example wo-propyl) haloalkyl (for example CF 3 ), haloalkoxy (for example OCF 3 ) and optionally substituted aryloxy (for example methylphenoxy).
  • halogen for example F, CI or Br
  • alkyl for example wo-propyl
  • haloalkyl for example CF 3
  • haloalkoxy for example OCF 3
  • optionally substituted aryloxy for example methylphenoxy
  • Another preferred embodiment is compounds of formula (Ha) to (Ilg):
  • R ⁇ R 2 and R 3 which may be the same or different, are independently selected from hydrogen or substituted or unsubstituted alkyl;
  • R 4 is halogen selected from F, CI, Br or I; at each occurrence, R 5 is selected from hydrogen, halogen or substituted or unsubstituted alkyl;
  • R 6 is selected from hydrogen, cyano, nitro, -NR x R y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(0)OR x , -OR x , -C(0)NR x R y and -C(0)R x ;
  • 'm' is selected from 0 to 5, both inclusive.
  • Particularly contemplated are compounds of the formulas (I), (Ia)-(Ig) and (Ila)- (Ilg), which possess IC 5 o of less than 250 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to TRPAl activity as measured by method as described in the present patent application.
  • the present patent application 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 of the present invention can be administered as pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be the doctor's discretion.
  • Compounds of the present invention may be used in the manufacture of medicaments for the treatment of any diseases disclosed herein.
  • the compounds and pharmaceutical compositions described herein are useful for modulating TRPA1 receptors, wherein modulation is believed to be related to a variety of disease states.
  • the compound of the present invention can be administered alone or in combination with other therapeutic agents.
  • the TRPA1 modulator is administered conjointly with one or more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, antifungal agent, anti-viral agent, anti-septic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor
  • the present patent application further provides a method of inhibiting TRPA1 receptors 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 includes fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, 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 (tert-butyl).
  • Ci ⁇ alkyl refers to an alkyl chain having 1 to 6 carbon atoms.
  • alkyl groups described herein may be straight chain or branched, substituted or unsubstituted
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl and 2-butenyl.
  • alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred) e.g., ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy refers to a straight or branched, saturated aliphatic hydrocarbon radical bonded to an oxygen atom that is attached to a core structure.
  • alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl and haloalkoxy means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms, where alkyl and alkoxy groups are as defined above.
  • halo is used herein interchangeably with the term “halogen” means F, CI, Br or I.
  • haloalkyl include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl 4,4,4-trifluorobutyl, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl and the like.
  • haloalkoxy examples include but are not limited to fluoromethoxy, difiuoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy, 1-bromoethoxy and the like. Unless set forth or recited to the contrary, all "haloalkyl” and “haloalkoxy” groups described herein may be straight chain or branched, substituted or unsubstituted.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, 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 sprirobicyclic groups, e.g., spiro(4,4) non-2-yl. Unless set forth or recited to the contrary, all cycloalkyi groups described herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • 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 herein may be substituted or unsubstituted.
  • cycloalkylalkoxy is used to denote alkoxy substituted with cycloalkyi, wherein 'alkoxy' and 'cycloalkyi' are as defined above (either in the broadest aspect or a preferred aspect). Examples of 'cycloalkylalkoxy' groups is
  • all cycloalkylalkoxy groups described herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described herein may be substituted or unsubstituted.
  • aryl means a carbocyclic aromatic system containing one, two or three fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc). If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated.
  • fused means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. The term “fused” is equivalent to the term “condensed”.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Unless set forth or recited to the contrary, all aryl groups described, herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 or -C 2 H4C 6 H 5 . Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.
  • aryloxy means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • heterocyclic ring refers to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic 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.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl).
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoqinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl
  • 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 heterocyclic ring described herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • 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 herein may be substituted or unsubstituted.
  • heteroaryl refers to an aromatic heterocyclic ring radical.
  • 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. Unless set forth or recited to the contrary, all heteroaryl groups described herein may be substituted or unsubstituted.
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • 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 herein may be substituted or unsubstituted.
  • 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.
  • IC50 refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity.
  • 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 the present invention including compounds of formula (I), (Ia)-(Ig) and (Ila)-(IIg) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers).
  • the present invention includes these stereoisomeric forms (including diastereomers and enantiomers) and mixtures thereof.
  • the various stereoisomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • the pharmaceutical composition of the present patent application 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 includes the compound(s) described herein in an amount sufficient to inhibit TRPAl in a subject (e.g., a human).
  • the inhibitory activity of compounds falling within the formulas (I), (Ia)-(Ig) and (Ila)-(IIg) may be measured by an assay provided below.
  • the compound of the present invention 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.
  • a pharmaceutically acceptable excipient such as a carrier or a diluent
  • the pharmaceutical compositions may be prepared by techniques known in the art.
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the compounds and pharmaceutical compositions of the present invention can be administered to treat any disorder, condition, or disease treatable by inhibition of TRPAl.
  • the compounds and pharmaceutical compositions of the present invention are suitable for treatment or prophylaxis of the following diseases, conditions and disorders mediated or associated with the activity of TRPAl receptors: pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, chemotherapy - induced neuropathies, eye - irritation, bronchial - irritation, skin - irritation (atopic dermatitis), Frost - bites (cold - bite), spasticity, catatonia, catalepsy, parkinsons, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain,
  • the sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors".
  • Nociceptors are primary sensory afferent (C and ⁇ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal and proton (pH ⁇ 6) modalities. Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.
  • 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).
  • carboxylic acid ester of formula (1) [when R a is alkyl] can be coupled with amines of general formula (2) by using suitable base (e.g., sodium hydride) and in suitable solvent (e.g. toluene, xylene) to give compounds of the general formula
  • Compound of formula (3) can be converted to substituted triazinedione ester of general formula (4) by reaction with N-(chlorocarbonyl)isocyanate in the presence of suitable base (e.g., triethylamine, diisopropylethylamine) in a suitable solvent such as dichloromethane or tetrahydrofuran followed by alkylation with alkylating agent of formula R'X in the presence of suitable base (e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine) in suitable solvent such as DMF or THF.
  • suitable base e.g., triethylamine, diisopropylethylamine
  • suitable solvent such as dichloromethane or tetrahydrofuran
  • suitable base e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine
  • the carboxylic acid of a formula (5) is coupled with amine of a formula (2) under appropriate conditions using a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) to give compound of a general formula (la).
  • a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP)
  • Compound of formula (3') can be converted to substituted triazinedione ester of general formula (4') by reaction with N-(chlorocarbonyl)isocyanate in the presence of suitable base (e.g., triethylamine, diisopropylethylamine) in a suitable solvent such as dichloromethane or tetrahydrofuran followed by alkylation with alkylating agent of formula R'X in the presence of suitable base (e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine) in suitable solvent such as DMF or THF.
  • suitable base e.g., triethylamine, diisopropylethylamine
  • suitable solvent such as dichloromethane or tetrahydrofuran
  • suitable base e.g., K 2 C0 3 , Cs 2 C0 3 or diisopropylethylamine
  • the carboxylic acid of a formula (5') can be coupled with amine of a formula (2) under appropriate conditions using a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) to give compound of a general formula (la').
  • a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP)
  • intermediate of the general formula (4) can also be prepared as shown is Scheme 4.
  • 2-amino-4-methylthiazole (6) can be converted to substituted triazinedione of general formula (7) in two steps as described in Scheme 3.
  • LDA Lithium diisopropylamide
  • LHMDS lithium hexamethyldisilazide
  • Intermediate (1 1) can also be alkylated stepwise using alkyl halide R'X followed by R 2 X to afford unsymmetrical Intermediate (12) in presence of a suitable base and solvent.
  • Formylation of (12) using phosphorusoxychloride and N,N-dimethylformamide followed by one carbon homologation using methoxymethyltriphenylphosphonium chloride (13) in the presence of a strong base under Wittig reaction conditions affords the enol ether (14).
  • Hydrolysis of enol ether (14) under acidic condition e.g., hydrochloric acid, boron tribromide
  • Oxidation of acetaldehyde intermediate (15) with suitable oxidizing agent e.g., Jones reagent, chromic acid, sodium chlorite
  • suitable oxidizing agent e.g., Jones reagent, chromic acid, sodium chlorite
  • carboxylic acid (16) Coupling of triazinedione acetic acid (16) with amine of a formula (2) under appropriate conditions with the help of a suitable coupling agent (e.g., DCC, EDCI, HATU, HBTU) gives compounds of the general formula (Ic).
  • 6-chloro-l,3-dialkyl-2,4(lH,3H)-dione of the formula (17) is commercially available or can be prepared according to a known literature methods. Nitration of compounds of the general formula (17) using an appropriate mixture of nitric acid and sulfuric acid followed by coupling with an appropriate amine of formula (18) affords the amino nitro compound of the formula (19).
  • a similar approach for the synthesis of intermediate (19) is described by Senda, S. et al, in J. Am. Chem. Soc. 1978, 100(24), 7661-7664. Reduction of nitro group of formula (19) using palladium catalyst gives diamino compound (20).
  • N-bromosuccinimde, N- chlorosuccinimide, F-TEDA [N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate)] ⁇ gives halo-furo[2,3-c ]pyrimidinetrione of formula (26).
  • compound of formula (26) can also be prepared from compound of formula (25) using dihaloacetyl chloride such as dichloroacetyl chloride or dibromoacetyl chloride.
  • dihaloacetyl chloride such as dichloroacetyl chloride or dibromoacetyl chloride.
  • Halo-furo[2,3-iflpyrimidinetrione compounds of formula (26) was converted into furo[2,3-i/]pyrirnidinedione ester of compounds of general formula (27) by reaction with the lithium salt of ethyl acetate (generated from dry ethyl acetate and LHMDS) followed by dehydration and isomerization under acidic conditions. Hydrolysis of furo[2,3-c/ ⁇ pyrimidinedione ester of general formula (27) under basic conditions affords corresponding carboxylic acid of general formula (28).
  • the carboxylic acid intermediate of the general formula (28) can be prepared as described in Scheme 10.
  • reaction of (cyanomethyl)lithium with furo[2,3-i ]pyrimidinetrione of formula (26) (where R 4 is halogen) in a suitable solvent gives furo[2,3-i ]pyrimidinyl acetonitrile of the formula (29).
  • This intermediate on hydrolysis under acidic conditions gives intermediates of the formula (28) required for the synthesis of compounds of the general formula (Ie).
  • the carboxylic acid (38) is coupled with an amine using standard amide coupling method to give compounds of formula (39).
  • Cyclisation of (39) with triphosgene produced the fused pyrimidine diene intermediate (40).
  • Intermediate (40) on alkylation using alkyl halide furnished intermediate (41).
  • Hydrolysis of ester of formula (41) with aqueous acid gives compounds of the formula (42).
  • the coupling of compounds of formula (42) with an amine of formula (2) by using a standard amide coupling method gives compounds of general formula (Ig).
  • Scheme 16 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (54) (wherein R 5 , R 6 and 'm' are as defined above in description) which is prepared from acetophenones of the formula (53) using known approaches. Certain di-and tri-substituted acetophenones were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (49) in three steps. Thus, acid of formula (49) was converted to the corresponding acid chloride of formula (50) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (50) was converted to corresponding Weinerb amide of formula
  • ketone (56) can also be synthesized in two steps by a-bromination of ketone (55) using bromine in acetic acid followed by condensation with thiourea in a suitable solvent such as ethyl alcohol at elevated temperature.
  • the 2-amino-4-aryl thiazole (56) is coupled with haloacetyl halide (e.g., chloroacetyl chloride or bromoacetyl bromide) of formula (57) in presence of suitable solvent such as dichloromethane gives aryl thiazolyl acetamide of the general formula (58).
  • haloacetyl halide e.g., chloroacetyl chloride or bromoacetyl bromide
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • DMSO-i& Hexadeuterodimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • J Coupling constant in units of Hz
  • RT or rt room temperature (22-26°C)
  • Aq. aqueous
  • AcOEt ethyl acetate
  • Step 1 Ethyl (2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l ,3,5]triazin-6-yl)acetate: To a stirred suspension of ethyl (2-amino-l,3-thiazol-4-yl)acetate (0.500 g, 2.685. mmol) in anhydrous dichloromethane (10 ml), was added dropwise at 0°C, a solution of N- (chlorocarbonyl) isocyanate (0.425 g, 4.027 mmol) in anhydrous dichloromethane (10 ml) under nitrogen atmosphere.
  • Step 2 Ethyl (3-methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6- yl)acetate: To a magnetically stirred solution of step 1 intermediate (150 mg, 0.588 mmol) in anhydrous DMF (2.0 ml) was added diisopropyl ethylamine (DIPEA) (0.076 g, 0.588 mmol) followed by iodomethane (0.167 g, 1.176 mmol) at room temperature. Resulting suspension was further stirred for 18 hours under nitrogen atmosphere.
  • DIPEA diisopropyl ethylamine
  • Step 3 (3-Methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2- ][l,3,5]triazin-6-yl)acetic acid: A mixture of step 2 intermediate (0.700 g, 2.60 mmol) and concentrated HC1 (5.0 ml) was heated at 90 °C for 2 h.
  • Step 1 Ethyl (l, l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6] thiatriazin-7- yl)acetate: To a stirred and cooled (0°C) suspension of ethyl (2-amino-l,3-thiazol-4- yl)acetate (7.0 g, 37.587 mmol) in anhydrous dichloromethane (35 ml) was added dropwise a solution of chlorosulfonyl isocyanate (4.91 ml, 56.381 mmol) in anhydrous dichloromethane (15 ml) under nitrogen atmosphere.
  • Step 2 Ethyl (2-methyl-l, l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6] thiatriazin-7-yl)acetate: To a magnetically stirred solution of Step 1 intermediate (2.0 g, 6.865 mmol) in anhydrous DMF (10.0 ml) was added N ⁇ V-diisopropylethylamine (DIPEA) (1.2 ml, 6.865 mmol) followed by iodomethane (0.85 ml, 13.739 mmol) at room temperature under nitrogen atmosphere.
  • DIPEA N ⁇ V-diisopropylethylamine
  • Step 3 2-MethyI-l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7- yl)acetic acid: A mixture of Step 2 intermediate (680 mg, 2.227 mmol) and concentrated HC1 (3.0 ml) was heated at 90°C for 2 h. The reaction mixture was cooled to room temperature.
  • Step 1 l,3-Dimethylimidazo[l,2-a][l,3,5]triazine-2,4(lH,3H)-dione: To a stirred solution of sodium hydroxide (8.8 g, 221.879 mmol) in water (135 ml) was added imidazo[l,2- ][l,3,5]triazine-2,4(lH,3H)-dione (13.50 g, 88.757 mmol) at 0°C and the reaction mixture was stirred at the same temperature for 30 min. Dimethyl sulphate (21.0 ml, 221.879 mmol) was added dropwise at the same temperature and the resulting mixture was slowly warmed to room temperature.
  • Step 2 l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazine-6- carbaldehyde: Phosphorous oxychloride (5.1 ml) was added slowly to a solution of dry DMF (20.0 ml) at room temperature. Step 1 intermediate (4.0 g, 22.202 mmol) was added portion wise and the resulting reaction mixture was heated overnight at 80 °C. The excess of phosphorous oxychloride and DMF were distilled off under reduced pressure. The viscous residue obtained was poured into ice-cold water (100 ml) and neutralized with NaHC0 3 solution.
  • the aqueous layer was extracted with ethyl acetate (3 x 75 ml) and the combined organic layers were washed with saturated solution of NaHC0 3 (50 ml), followed by brine (50 ml), dried over Na 2 S0 4 and filtered.
  • Step 4 ( 1 ,3-Dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydroimidazo[ 1 ,2-a] [ 1 ,3,5]triazin-6-y 1) acetaldehyde: 1 N HC1 (1 ml) was added to a stirred solution of Step 3 intermediate (625 mg, 2.645 mmol) in THF (10 ml) at room temperature to give a turbid solution. After stirring for 2 h, the excess of solvent was evaporated and the residue obtained was neutralized with saturated solution of NaHC0 3 and extracted with ethyl acetate (3 x 75 ml).
  • Step 5 (l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2- ][l,3,5]triazin-6- yl)acetic acid: To a solution of Step 4 intermediate (575 mg, 2.587 mmol) and sulphamic acid (376 mg, 3.881 mmol) in acetone (10.0 ml) was added sodium chlorite (292 mg, 3.234 mmol) in water (4.0 ml) at 0 °C. After stirring for 1 h at room temperature, excess of solvent was distilled out. The residue obtained was diluted with brine and extracted with ethyl acetate (3 x 50 ml).
  • Step 1 6-Chloro-l,3-dimethyl-5-nitropyrimidine-2,4(lH,3H)-dione: 6-Chloro-l,3- dimethylpyrimidine-2,4(lH,3H)-dione (13.0 g, 74.464 mmol) was added portion wise to a stirred and cooled (15°C) solution of concentrated sulphuric acid (40 mL). The reaction temperature was maintained below 10 °C. Fuming nitric acid (15 mL) was added dropwise into the above reaction mixture and then stirred for 2 h at the same temperature.
  • Step 2 l,3-Dimethyl-6-(methylamino)-5-nitropyrimidine-2,4(lH3H)-dione: To a stirred solution of Step 1 intermediate (1 1.00 g, 50:095 mmol) in anhydrous chloroform (90 mL) was added dropwise a solution of 40 % aqueous methylamine (7.76 ml, 100.191 mmol) in anhydrous dichloromethane (20 mL) at room temperature under nitrogen atmosphere. After stirring for 1 h the reaction mixture was distilled under vacuo to give crude product.
  • Step 3 5-Amino-l,3-dimethyl-6-(methylamino)pyrimidine-2,4(lH,3H)-dione: To a stirred solution of Step 2 intermediate (13.5 g, 63.034 mmol) in methanol (700 mL) was added 10 % Palladium on carbon (50 % wet, 5.0 g) under hydrogen balloon atmosphere at room temperature. After overnight stirring, the reaction mixture was filtered through celite bed.
  • Step 4 l,3,9-Trimethyl-7,9-dihydro-lH-purine-2,6,8(3H)-trione: To a magnetically stirred solution of Step 3 intermediate (2.0 g, 10.857 mmol) in anhydrous THF (50.0 mL) was added ⁇ , ⁇ -carbonyldiimidazole (2.1 g, 13.029 mmol) at room temperature under nitrogen atmosphere. After refluxing for 18 h the excess of solvent was distilled under reduced pressure. The residue obtained was diluted with ethyl acetate (100 ml) and water (100 ml).
  • the aqueous layer was extracted with ethyl acetate (2 x 75 ml) and the combined organic layers were washed with water (2 x 25 ml) followed by brine (25 ml), dried (Na 2 S0 4 ) and filtered. The filtrate was concentrated under reduced pressure.
  • Step 1 6-Chloro-l,3-dimethylfiiro[2,3-i/lpyrimidine-2,4,5(lH,3H,6H)-trione: To a stirred solution of l,3-dimethylfuro[2,3-i ]pyrimidine-2,4,5(lH,3H,6H)-trione (5.0 g, 25.489 mmol) and azobisisobutyronitrile (AIBN) (83.71 mg, 0.509 mmol) in carbon tetrachloride (50 mL) was added N-chlorosuccinimide (4.084 g, 30.587 mmol). The resulting mixture was refluxed for 24 h.
  • AIBN azobisisobutyronitrile
  • reaction mixture was then cooled to room temperature and diluted with chloroform (100 mL) and water (100 mL). The layers were separated. Aqueous layer was extracted with chloroform (2 x 50 ml) and the combined organic layers were washed with brine (2 x 50 ml), dried (Na 2 S0 4 ) and filtered. The filtrate was concentrated under reduced pressure.
  • Step 2 Ethyl (2Z)-(6-chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5(6H)-ylidene)acetate: Anhydrous THF (100 mL) was cooled to -78°C. A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 2.5 g, 14.94 mmol) was added under nitrogen atmosphere. Then dry ethyl acetate (1.313 g, 14.94 mmol) was added and the resulting mixture was stirred at the same temperature for 1 h.
  • LiHMDS lithium bis(trimethylsilyl)amide
  • Step 3 Ethyl (2Z)-(6-chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5-yl)acetate: A mixture of Step 2 intermediate (1.0 g, 0.003 mmol) and glacial acetic acid (15.0 mL) was refluxed for 4 h.
  • Step 4 (6-Chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-i
  • Step 1 6-Bromo-l,3-dimethylfuro[2,3-i jpyrimidine-2,4,5(lH,3H,6H)-trione:
  • the title compound was prepared by reaction of l,3-dimethylfuro[2,3-c/)pyrirnidine- 2,4,5(1 H,3H,6H)-trione (500 mg, 2.548 mmol) and azobisisobutyronitrile (AIBN) (8.0 mg, 0.049 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (544 mg, 3.056 mmol) as described in the procedure of intermediate 8 step 1 to obtain 200 mg of the product as a white solid; ⁇ NMR (300 MHz, CDC1 3 ) ⁇ 3.36 (s, 3H), 3.53 (s, 3H), 6.55 (s, 1H); APCI (m/z) 275 (M) + .
  • Step 2 Ethyl (2Z)-(6-bromo-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5(6H)-ylidene)acetate:
  • the title comopund was prepared by the reaction of 6-bromo-l,3-dimethylfuro[2,3-i ]pyrirnidine-2,4,5(lH,3H,6H)-trione (3.5 g, 12.62 mmol) with lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 3.169 g, 18.94 mmol) and dry ethyl acetate (1.829 g, 18.94 mmol) in dry THF (200 mL) as described for the preparation of step 2 of intermediate 8 to give 150 mg of the product as an off-white solid; ⁇ NMR (300 MHz, CDC1 3 ) ⁇ 1.28-1.36
  • Step 3 Ethyl (2Z)-(6-bromo-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i/]pyrimidin-5-yl)acetate:
  • the title compound was prepared according to procedure described for step 3 of intermediate 8 by using step 2 intermediate (150 mg, 0.473 mmol) and glacial acetic acid (5.0 mL) to give 65 mg of the product as an off-white solid;
  • Step 4 (6-Bromo-l,3-dimethyl-2,4-dioxo-l ,2,3,4-tetrahydrofuro[2,3-i ]pyrimidin-5- yl)acetic acid:
  • This intermediate was prepared according to procedure described for step 3 of intermediate 8 by using step 2 intermediate (60 mg, 0.189 mmol) to yield 45 mg of the product as an off- white solid.
  • Step 1 6-Chloro-l,3-dimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of 1,3- dimethylbarbituric acid (20.0 g, 128.09 mmol) in water (10 ml), phosphorous oxychloride (80 ml) was added slowly by externally cooling and reaction was then refluxed for 3 h. The reaction mixture was allowed to cool to 0°C and quenched with ice cold water (350 ml).
  • Step 2 6-(Hydroxyamino)-l,3-dimethylpyrimidine-2,4(lH,3H)-dione:
  • a solution of Step 1 intermediate (10 g, 57.261 mmol), hydroxylamine hydrochloride (12.15 g, 176.361 mmol) and sodium acetate (33.81 g, 412.28 mmol) in isopropyl alcohol (280 ml) were refluxed for 4 h.
  • the reaction mixture was concentrated under reduced pressure, diluted with water and stirred for 1 h.
  • Step 3 3,5,7-Trimethylisoxazolo[3,4-i/]pyrimidine-4,6(5H,7H)-dione: A mixture of Step 2 intermediate (9.5 g, 55.555 mmol) and acetic anhydride (48 ml) in dry pyridine (92 ml) were refluxed for 6 h under nitrogen atmosphere.
  • Step 4 Methyl (5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[3,4-i ]pyrimidin-3- yl)acetate: To a stirred solution of Step 3 intermediate (8.0 g, 41.02 mmol) in dimethylcarbonate (12.6 ml) was added sodium hydride (60 % dispersion in mineral oil, 3.93 g, 163.75 mmol) and mixture was refluxed overnight under nitrogen atmosphere.
  • Step 5 (5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[3,4-i/] rjyrimidin-3-yl)acetic acid: A mixture of Step 4 intermediate (9.0 g, 35.55 mmol) and 6 N H 2 S0 4 (88.93 ml) in dioxane (90 ml) stirred at reflux temperature for 1 h to give a homogeneous pale yellow solution. This solution was cooled, diluted with water and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, dried over Na 2 S0 4 and concentrated.
  • Step 1 tert-Butyl cyanoacetate: To a stirred solution of cyanoacetic acid (110 g, 1293.20 mmol) in dry diethyl ether (650 ml), phosphorus pentachloride was added in portions at 0 °C and stirred at room temperature for 3 h. The excess of solvent and phosphorus oxychloride were distilled out under reduced pressure.
  • the acid chloride was dissolved in dry diethyl ether (150 ml) and cooled 0-5 °C, ⁇ , ⁇ -dimethyl aniline (165 ml, 1293.20 mmol) and tert butanol (122.88 ml, 1293.20 mmol) in dry diethyl ether (150 ml) was added dropwise during 30 min and refluxed for 2 h and subsequently stirred at room temperature for overnight. The reaction mixture was then diluted with water and the product was extracted in ethyl acetate (200 ml x 2).
  • Step 2 1-fert-Butyl 5-ethyl (2£)-3-amino-2-cyanopent-2-enedioate: To a stirred solution of step 1 intermediate (114 g, 808.5 mmol) and ethyl (3£)-3-ethoxy-3-iminopropanoate hydrochloride (158.20 g, 808.5 mmol) in dry chloroform was added triethyl amine (588.24 ml, 4041.2 mmol) and mixture was vigoruosly stirred and heated to reflux for 72 h under nitrogen atomosphere.
  • step 1 intermediate 114 g, 808.5 mmol
  • ethyl (3£)-3-ethoxy-3-iminopropanoate hydrochloride 158.20 g, 808.5 mmol
  • triethyl amine 588.24 ml, 4041.2 mmol
  • Step 3 tert-Butyl 5-amino-3-(2-ethoxy-2-oxoethyl)-l,2-oxazole-4-carboxylate: A mixture of step 2 intermediate (105 g, 413 mmol), hydroxylamine hydrochloride (57.44 g, 826.77 mmol) and sodium acetate (122.07 g, 1488.16 mmol) in dry ethanol (830 ml) was stirred and refluxed for overnight. The excess of ethanol was distilled off under reduced pressure, diluted with water (250 ml) and extracted with ethyl acetate (3x500 ml) and dried (Na 2 S0 4 ).
  • Step 4 5-Amino-3-(2-ethoxy-2-oxoethyl)-l,2-oxazole-4-carboxylic acid: To a stirred solution of step 3 intermediate (45.8 g, 169.6 mmol) in dichloromethane was added trifluoro acetic acid (274 ml) at 0 °C and subsequently stirred at room temperature for 2 h. The reaction solvent was removed under reduced pressure, diluted with water, it was adjusted to PH 6.4 with saturated sodium hydrogen carbonate aqueous solution.
  • Step 5 Ethyl [5-amino-4-(methylcarbamoyl)-l,2-oxazol-3-yl]acetate: To a stirred solution of step 4 intermediate (26.5 g, 123.8 mmol) in 1,2-dichloroethane (310 ml) was added EDCI.HC1 (28.48 g, 148.5 mmol) and HOBt (16.7 g, 123.7 mmol). The reaction mixture was then stirred at room temperature for 30 min. Methyl amine (33% in dry ethanol) (23.3 ml, 247.5 mmol) was added at 15-20 °C and stirred at room temperature for 24 h.
  • Step 6 Ethyl (5-methyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3- yl)acetate: To a stirred solution of Step 5 intermediate (17.5 g, 77.09 mmol) in dry THF (256 ml) was added triphosgene (1 1.43 g, 38.51 mmol) and mixture was refluxed for overnight.
  • Step 7 Ethyl(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-d]pyrimidin-3- yl)acetate: A solution of Step 6 intermediate (7.5 g, 29.64 mmol) in dry acetone (185 ml) was added anhydrous K 2 C0 3 (5.33 g, 38.53 mmol) and the mixture was stirred at room temperature for 15 min. Methyl iodide (9.24 ml, 147.9 mmol) was added slowly with stirring and further stirred at room temperature for 4 h.
  • Step 8 (5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[5,4-i/]pyrimidin-3-yl)acetic acid: A mixture of Step 7 intermediate (5.5 g, 20.59 mmol) and 6 N H 2 S0 4 (50 ml) in 1,4- dioxane (50 ml) was stirred at reflux temperature for 2.5 h to give a homogeneous pale yellow solution. The solvent was evaporated completely under reduced pressure, diluted with water and extracted with dichloromethane (3 x 100 ml). The combined organic layers were washed with water, dried over Na 2 S0 4 and concentrated.
  • the salt was then treated with saturated solution of NaHC0 3 to re-generate the amine.
  • the mixture was extracted with dichloromethane (2x 50 mL) and the combined organic extracts were washed with water and brine. The solvent was evaporated under reduced pressure to afford the 2-amino-4-aryl-thiazole derivative.
  • Step 1 A mixture of appropriate aryl alkyl ketone (1.0 equiv.), thiourea (2.0 eqiv.) and iodine (1.0 equiv.) in dry ethanol (5 volumes) was refluxed for 24 h. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of sodium thiosulphate. The organic layer was treated with IN HCl and the precipitated salt was collected by filtration. The salt was then treated with saturated solution of NaHC0 3 and extracted with dichloromethane, washed with brine, dried over sodium sulfate and the solvent was evaporated to afford the 2-aminothiazole derivative.
  • Step 2 To a stirred and cooled (0°C) solution of appropriate amine (1.0 equiv.) and pyridine (1.2 equiv.) in dichloromethane (5 vol.) was added bromoacetyl bromide (1.2 eq.) over 5 min and the resulting mixture was allowed to warm to room temperature. After stirring for 2 h, the reaction mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water, followed by brine, dried (Na 2 S0 4 ) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5-10% ethyl acetate in petroleum ether to obtain the desired product as an off-white solid.
  • Method A To a stirred solution of isoxazole acetic acid (1.0 equiv.) in 1,2-dichloroethane was added EDCI (1.2 equiv.), HOBt (0.3 equiv.) and 4-dimethylaminopyridine (0.1 equiv.) and the mixture was stirred at room temperature for 10-15 min. An appropriate amine (1.0 equiv.) was then added and mixture was stirred under nitrogen atmosphere at the same temperature for 48 h or heated at reflux temperature for 24 h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with methanol and stirred at room temperature for 30 min. The solid separated out was collected by filtration. The solid product was further purified by recrystalisation from isopropanol or methanol to give the desired products.
  • Method B To a stirred solution of isoxazole acetic acid (1.1 equiv.) in dry dichloromethane were added appropriate amine (1.1 equiv.), HOBt (0.37), N-methyl morpholine (1.16) and EDCI (1.16) 0-5° C and stirred at the same temperature for 30 min. The temperature of the reaction mixture was then gradually increased to room temperature and stirred for overnight. The reaction mass was directly loaded on silica gel column chromatography to give the desried product.
  • the illustrative examples of the present invention are screened for TRPAl activity according to a modified procedure described in (a) Toth, A. et al. Life Sciences, 2003, 73, 487-498. (b) McNamara C, R. et al, Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13525- 13530.
  • the screening of the compounds can be carried out by other methods and procedures known to persons skilled in the art.
  • TRPAl receptor activation was measured as inhibition of allyl isothiocyanate (AITC) induced cellular uptake of radioactive calcium.
  • Test compounds were dissolved in 100% DMSO to prepare 10 mM stock and then diluted using plain medium with 0.1% BSA and 1.8 mM CaCl 2 to get the desired concentration. The final concentration of DMSO in the reaction was 0.5% (v/v).
  • Human TRPAl expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 ⁇ g / ml of G-418.
  • Rat TRPAl expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 ⁇ g / ml of Zeocin.
  • Test compound is formulated immediately prior to dosing by making a suspension
  • Example 29 (2.5 ⁇ 7 ⁇ Tween-80 and 0.5 % methylcellulose suspension in geometric dilution).
  • the animals were provided with food and water ad libitum throughout the study period.
  • Male rats SD are administered orally a dose of 10 mg/kg (dose volume lOmL/kg body weight) of test compound by a gavage needle.
  • Blood samples (approximately 250 ⁇ ) were collected from retro orbital sinus using rat capillary tubes at regular intervals of 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 24.0 hrs after dose administration into rat. Samples were centrifuged immediately at lOOOg for 10 min at 4°C. Plasma samples were processed and analyzed by LCMS/MS as per standard operating procedures. Plasma concentration of test compound was recorded and used to calculate the pharmacokinetic parameters such as C max , area under the curve, T max etc using Pharsight Winonlin software.
  • the pharmacokinetic profile of Example 29 is depicted

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Abstract

Amides of heterocyclic compounds as Transient Receptor Potential subfamily A (TRPA) modulators are provided In particular, compounds described herein are useful for treating or preventing diseases, conditions and/ or disorders modulated by TRPA1 (Transient Receptor Potential subfamily A, member 1) Also provided herein are processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPA1. (I).

Description

AMIDES OF HETEROCYCLIC COMPOUNDS AS TRPA1 INHIBITORS
Related applications
This application claims the benefit of Indian Patent Application Nos 681 /MUM/2010 filed on March 15, 2010; 679/MUM/2010 filed on March 15, 2010; 762/MUM/2010 filed on March 22, 2010; 1108/MUM/2010 filed on April 1, 2010; and US Provisional Application Nos 61/314,820 filed on March 17, 2010; 61/314,823 filed on March 17, 2010; 61/317,385 filed on March 29, 2010; 61/329,290 filed on April 29, 2010 all of which are hereby incorporated by reference.
Technical Field
The present patent application relates to amides of heterocyclic compounds with transient receptor potential ankyrinl (TRPA1) activity.
Background of the Invention
The transient receptor potential (TRP) channels or receptors are pain receptors. They have been classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin, ANKTM1) and TRPN (NOMPC) families. The TRPC family can be divided into 4 subfamilies (i) TRPC1 (ii) TRPC2 (iii) TRPC3, TRPC6, TRPC 7 and (iv) TRPC4, TRPC5 based on sequence functional similarities. Currently the TRPV family has 6 members. TRPV5 and TRPV6 are more closely related to each other than to TRPV1, TRPV2, TRPV3 or TRPV4. TRPAl is most closely related to TRPV3 and is more closely related to TRPVl and TRPV2 than to TRPV5 and TRPV6. The TRPM family has 8 members. Constituents include the following: the founding member TRPMl (melastatin or LTRPC1), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (TRP-p8 or CMR1), TRPM5 (MTR1 or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4). The TRPML family consists of the mucolipins, which include TRPML1 (mucolipin 1), TRPML2 (mucolipin 2) and TRPML3 (mucolipin 3). The TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have eleven. TRPP2 (PKD2), TRPP3 (PKD2L1), TRPP5 (PKD2L2) are all predicted to have six transmembrane domains. TRPPl (PKDl, PCI), PKD-REJ and PKD-lLl are all thought to have eleven transmembrane domains. The sole mammalian member of the TRPA family is ANKTM1. It is believed TRPAl is expressed in nociceptive neurons. Nociceptive neurons of the nervous system sense the peripheral damage and transmit pain signals. TRPAl is membrane bound and most likely acts as a heterodimeric voltage gated channel. It is believed to have a particular secondary structure, its N-terminus is lined with a large number of ankyrin repeats which are believed to form a spring-like edifice.TRPAl is activated by a variety of noxious stimuli, including cold temperatures (activated at 17°C), pungent natural compounds (e.g., mustard, cinnamon and garlic) and environmental irritants (MacPherson, L. J. et al., Nature, 2007, 445; 541-545). Noxious compounds activate TRPAl ion channels through covalent modification of cysteines to form covalently linked adducts. Variety of endogenous molecules produced during tissue inflammation / injury have been identified as pathological activators of TRPAl receptor. These include hydrogen peroxide which is produced due to oxidative stress generated during inflammation, alkenyl aldehyde 4-HNE - an intracellular lipid peroxidation product and cyclopentenone prostaglandin 15dPGJ2 which is produced from PGD2 during inflammation / allergic response. TRPAl is also activated in receptor dependant fashion by Bradykinin (BK) which is released during tissue injury at peripheral terminals
The difference between TRPAl and other TRP receptors is that TRPAl ligand binding persists for hours due to which the physiological response (e.g., pain) is greatly prolonged. Hence to dissociate the electrophile, an effective antagonist is required.
WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO 2004/055054 and WO 2005/089206 describe the TRP channels as the targets for the treatment of pain and related conditions.
In efforts to discover better analgesics for the treatment of both acute and chronic pain and to develop treatments for various neuropathic and nociceptive pain states, there exists a need for a more effective and safe therapeutic treatment of diseases, conditions and/or disorders modulated by TRPAl .
Summary of the Invention
The present invention relates to compounds of the formula (I):
O
Q-CH2 C-NH-U-V
(I)
or a pharmaceutically acceptable salt thereof,
wherein, Q is a heterocycle selected from the group consisting of
Figure imgf000004_0001
U is selected from -(CRxRy)n-, substituted or unsubstituted aryl, substituted or unsubstituted heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles, 1,2,3-triazoles and 1, 2, 4-triazole, pyrimidine, pyridine and pyridazine; V is selected from hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyi, heterocyclic ring and heterocyclylalkyl, -C(0)OR , -ORx, -C(0)NRxRy, -C(0)Rx and -S02NRxRy; or
at each occurrence, R1, R2 and R3, which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CRxRy)„ORx, COR", COORx, CONRxRy,and (CH2)nCHRxRy;
R4 is halogen;
at each occurrence, Rx and Ry are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyi, heterocyclic ring and heterocyclylalkyl;
at each occurrence, 'n' is selected from 0 to 2, both inclusive.
The embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of the formula (la)
Figure imgf000005_0001
(la)
or a pharmaceutically acceptable salt thereof,
wherein,
R1, U and V are as defined above in formula (I)
According to another embodiment, specifically provided are compounds of the formula (la) wherein R1 is alkyl preferably methyl.
According to another embodiment, specifically provided are compounds of the formula (la) wehrein 'LP is five membered heterocycle, preferably thiazole.
According to yet another embodiment, specifically provided are compounds of the formula (la) wherein 'V is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent(s) on phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF3), haloalkoxy (for example OCHF2, OCH2CF3j or OCH2CH2CF3), cycloalkylalkoxy (for example cyclobutylmethoxy) and cycloalkyl (for example cyclohexyl).
According to one embodiment, specifically provided are compounds of the formula (lb)
Figure imgf000006_0001
(lb)
or a pharmaceutically acceptable salt thereof,
wherein,
R1, U and V are as defined above in formula (I).
According to another embodiment, specifically provided are compounds of the formula (lb) wherein R1 is alkyl preferably methyl.
According to yet another embodiment, specifically provided are compounds of the formula (lb) wherein 'U' is five membered heterocycle, preferably thiazole.
According to yet another embodiment, specifically provided are compounds of the formula (lb) wherein 'V is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent(s) on phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF3), alkoxy (for example OCH2C(CH3)3) and haloalkoxy (for example OCH2CF3).
According to one embodiment, specifically provided are compounds of the formula (Ic)
Figure imgf000006_0002
(Ic)
or a pharmaceutically acceptable salt thereof,
wherein,
R1, R2, U and V are as defined above in formula (I). According to another embodiment, specifically provided are compounds of the formula (Ic) wherein R1 and R2 are alkyl preferably methyl.
According to yet another embodiment, specifically provided are compounds of the formula (Ic) wherein 'U' is five membered heterocycle, preferably thiazole.
According to yet another embodiment, specifically provided are compounds of the formula (Ic) wherein 'V is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent(s) on phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF3), alkoxy (for example OCH2C(CH3)3) and haloalkoxy (for example OCF3 or OCH2CF3).
According to one embodiment, specifically provided are compounds of the formula (Id)
Figure imgf000007_0001
(Id)
or a pharmaceutically acceptable salt thereof,
wherein,
R1, R2, R3, U and V are as defined above in formula (I).
According to another embodiment, specifically provided are compounds of the formula (Id) wherein R1 and R2 are alkyl preferably methyl.
According to yet another embodiment, specifically provided are compounds of the formula (Id) wherein R3 is alkyl, preferably (C1 -C4) alkyl.
According to yet another embodiment, specifically provided are compounds of the formula (Id) wherein 'LP is five membered heterocycle, preferably thiazole.
According to yet another embodiment, specifically provided are compounds of the formula (Id) wherein 'V is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent(s) on phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF3), alkoxy (for example OCH2CH3, OCH2CH2CH3, OCH2CH2CH2CH3, OCH(CH3)2, OCH2CH(CH3)2, OCH2C(CH3)3 or OCH2CH2CH(CH3)2), haloalkoxy (for example OCHF2, OCF3, OCH2CF3> or OCH2CH2CF3) and cycloalkylalkoxy (for example cyclopropylmethoxy or cyclobutylmethoxy). According to one embodiment, specifically provided are compounds of the formula (Ie)
Figure imgf000008_0001
(Ie)
or a pharmaceutically acceptable salt thereof,
wherein,
R1, R2, R4, U and V are as defined above in formula (I).
According to another embodiment, specifically provided are compounds of the formula (Ie) wherein R1 and R2 are alkyl preferably methyl.
According to yet another embodiment, specifically provided are compounds of the formula (Ie) wherein R4 is halogen preferably fluorine, chlorine or bromine.
According to yet another embodiment, specifically provided are compounds of the formula (Ie) wherein 'U' is five membered heterocycle, preferably thiazole.
According to yet another embodiment, specifically provided are compounds of the formula (Ie) wherein 'V is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent(s) on phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), haloalkyl (for example CF3), dialkylamino (for example diethylamino), and haloalkoxy (for example OCF3).
According to one embodiment, specifically provided are compounds of the formula (If)
Figure imgf000008_0002
(if)
or a pharmaceutically acceptable salt thereof,
wherein,
R1, R2, U and V are as defined above in formula (I).
According to another embodiment, specifically provided are compounds of the formula (If) wherein R1 and R2 are alkyl preferably methyl. According to yet another embodiment, specifically provided are compounds of the formula (If) wherein 'U' is five membered heterocycle, preferably thiazole.
According to yet another embodiment, specifically provided are compounds of the formula (If) wherein 'V is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent(s) on phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), alkyl [for example CH2CH(CH3)2], haloalkyl (for example CF3), alkoxy (for example OCH3) and haloalkoxy (for example OCF3 or OCH2CF3 ).
According to one embodiment, specifically provided are compounds of the formula (Ig)
Figure imgf000009_0001
(Ig)
or a pharmaceutically acceptable salt thereof,
wherein,
R1, R2, U and V are as defined above in formula (I).
According to another embodiment, specifically provided are compounds of the formula (Ig) wherein R1 and R2 are alkyl preferably methyl.
According to yet another embodiment, specifically provided are compounds of the formula (Ig) wherein 'LP is five membered heterocycle, preferably thiazole.
According to yet another embodiment, specifically provided are compounds of the formula (Ig) wherein 'U' is -CH2-CH2- linker.
According to yet another embodiment, specifically provided are compounds of the formula (Ig) wherein 'LP is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent on phenyl is halogen (for example F)
According to yet another embodiment, specifically provided are compounds of the formula (Ig) wherein 'V is substituted or unsubstituted aryl, preferably phenyl. In this embodiment the substituent(s) on phenyl may be one or more and are independently selected from halogen (for example F, CI or Br), alkyl (for example wo-propyl) haloalkyl (for example CF3), haloalkoxy (for example OCF3) and optionally substituted aryloxy (for example methylphenoxy). According to yet another embodiment, specifically provided are compounds of the formula (Ig) wherein 'V is halogen (for example fluorine).
Another preferred embodiment is compounds of formula (Ha) to (Ilg):
Figure imgf000010_0001
(Ha) (lib)
Figure imgf000010_0002
(Ilf)
Figure imgf000010_0003
(Ilg)
or a pharmaceutically acceptable salt thereof,
wherein,
at each occurrence, R\ R2 and R3, which may be the same or different, are independently selected from hydrogen or substituted or unsubstituted alkyl;
R4 is halogen selected from F, CI, Br or I; at each occurrence, R5 is selected from hydrogen, halogen or substituted or unsubstituted alkyl;
at each occurrence, R6 is selected from hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(0)ORx, -ORx, -C(0)NRxRy and -C(0)Rx;
at each occurrence, 'm' is selected from 0 to 5, both inclusive.
Particularly contemplated are compounds of the formulas (I), (Ia)-(Ig) and (Ila)- (Ilg), which possess IC5o of less than 250 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to TRPAl activity as measured by method as described in the present patent application.
It should be understood that the formulas (I), (Ia)-(Ig) and (Ila)-(IIg), structurally encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.
Below are representative compounds, which are illustrative in nature only and are not intended to limit to the scope of the invention.
N-[4-(4-Difluoromethoxy-3,5-difluorophenyl)-l,3-thiazol-2-yl]-2-(3-methyl-2,4- dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a]triazin-6-yl)acetamide;
N-{4-[3,5-Dichloro-4-(3,3,3-trifluoropropoxy)phenyl]-l,3-thiazol-2-yl}-2-(3- methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide;
N-[4-(3,5-Dichloro-4-cyclobutylmethoxyphenyl)-l,3-thiazol-2-yl]-2-(3-methyl- 2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2- ][l,3,5]triazin-6-yl)acetamide;
N-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(3-methyl-2,4- dioxo-3,4-dihydro-2H-[l ,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide;
N-[4-(4-Cyclohexylphenyl)-l,3-thiazol-2-yl]-2-(3-methyl-2,4-dioxo-3,4-dihydro- 2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide;
N-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(3- methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-fl][l,3,5]triazin-6-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(3-methyl-2,4- dioxo-3,4-dihydro-2H-[l ,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide; N-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,l-dioxido-3-oxo-2,3- dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide;
N-{4-[3 -Fluoro-4-(trifluoromethyl)pheny 1]- 1 ,3-thiazol-2-yl} -2-(2-methy 1- 1,1- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-l,3-thiazol-2-yl}-2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3-chlorophenyl]-l,3-thiazol-2-yl}-2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide;
N-[4-(2,3,4-Trichlorophenyl)- 1 ,3 -thiazol-2-yl]-2-(2-methyl- 1 , 1 -dioxido-3 -oxo-
2.3- dihydro[l,3]thiazolo[3,2-*][l,2,4,6]thiatriazin-7-yl)-acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl}-2-(2-methyl- 1 , 1 - dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6]thiatriazin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(2- methyl-l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6]thiatriazin-7- yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(2- methyl-l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6]thiatriazin-7- yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}-2-(2- methy 1- 1 , 1 -dioxido-3-oxo-2,3-dihydro[ 1 ,3]thiazolo[3,2-Z>] [ 1 ,2,4,6]thiatriazin-7- yl)acetamide;
N-{4-[3-Chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(2- methyl-l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7- yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}2-(l,3-Dimethyl-2,4- dioxo- 1 ,2,3,4-tetrahydroimidazo[ 1 ,2-a] [1 ,3,5]triazin-6-yl)- acetamide;
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}2-(l,3-dimethyl-
2.4- dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide;
N- {4-[3-Chloro-4-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl} 2-( 1 ,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2- ][l,3,5]triazin-6-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide; N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide;
AT-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-fl][l,3,5]triazin-6-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide;
N-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo- 1 ,2,3,4-tetrahydroimidazo[ 1 ,2-a] [ 1 ,3, 5]triazin-6-yl)acetamide;
N-{4-[4-(Trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide;
N-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(l,3,9-trimethyl-2,6,8-trioxo- l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-isobutoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-neopentyloxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(cyclobutylmethoxy)-phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6, 8-trioxo- 1 ,2,3 ,6, 8, 9-hexahydro-7H-purin-7-y l)acetamide ;
N-{4-[3,5-Dichloro-4-ethoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide; N-{4-[3,5-Dichloro-4-propoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
AT.{4-[3-Chloro-5-fluoro-4-propoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-butoxy-phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
Af-{4-[3-Chloro-4-butoxy-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-isopropoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-isopropoxy-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-(2-methylpropoxy)phenyl]- 1 ,3-thiazol-2-yl} -2-( 1 ,3,9- trimethyl-2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2-methylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-5-fluoro-4-isobutoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}-2- (l,3,9-trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-(3-methylbutoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(3-methylbutoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-(Cyclopropylmethoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6, 8-trioxo- 1 ,2,3 ,6, 8,9-hexahydro-7H-purin-7-yl)acetamide; N-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(cyclopropylmethoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}-2- (l,3,9-trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
A -{4-[4-(Cyclobutylmethoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
A/-{4-[4-(Cyclobutylmethoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(cyclobutylmethoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}-2- (l,3,9-trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l ,3-thiazol-2-yl}-2- (l ,3,9-trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-ethyl-l,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(9-ethyl- l,3-dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-ethyl-l,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-isopropyl-l,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(9- isopropyl-l,3-dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl} -2-(9-isobutyl- 1 ,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(9- isobutyl-l,3-dimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide; N-{4-[3-Chloro-4-(trifluoroinethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[4-(Diethylamino)phenyl]-l ,3-thiazol-2-yl}2-(6-chloro-l ,3-dimethyl-2,4- dioxo- 1 ,2,3,4-tetrahydrofiiro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofUro[2,3-d]pyrimidin-5-yl)acetamide;
N- {4-[3-Fluoro-5-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl } -2-(6-chloro- 1,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(6-chloro-l ,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofiiro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl} -2-(6-chloro- 1,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydroniro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}2-(6-bromo-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}2-(6-bromo-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofiiro[2,3-d]pyrimidin-5-yl)acetaniide;
N-[4-(4-Bromophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[ 1 ,2]oxazolo[3,4-i |pyrimidin-3-yl)acetamide;
N-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)- N-{4-[4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)- N-{4-[3-(trifluoromethyI)phenyl]-l,3-thiazoI-2-yI}acetamide; 2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)- N-{4-[3-(trifluoromethoxy)phenyl]-l ,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)- N-[4-(4-isobutylphenyl)-l,3-thiazol-2-yl]acetamide;
N-[4-(3,5-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydrof 1 ,2]oxazolo[3,4-i/)pyrimidin-3-yl)acetamide;
N-[4-(2,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide;
N-[4-(2,3-Difluorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide;
N-[4-(3-Chloro-2-fluorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo- 4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)- N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)- N-{4-[4-fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)- N-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)- N-{4-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)- N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
N-[4-(3,5-Difluoro-4-methoxyphenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6- dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)acetamide;
N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl- 4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl- 4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)- N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide; 2-(5,7-Dirnethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)- N-{4-[2-fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3-yl)- N-{4-[2-fluoro-3-(triiluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3-yl)- N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)- N- {4-[3-fluoro-4-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/|pyrimidin-3-yl)- N-{4-[4-fluoro-3-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl} acetamide;
N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl- 4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyriniidin-3-yl)- N-{4-[3-fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
N-{4-[2,4-Difluoro-3-(trifluorornethyl)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl- 4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyriniidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)- N-[4-(propan-2-yl)phenyl]acetamide;
N-[2-(4-Chlorophenyl)ethyl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)- N-[3-fluoro-4-(trifluoromethyl)phenyl]acetamide;
N-[2,4-Difluorophenyl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)acetamide; and
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[5,4-i/]pyrimidin-3-yl)-N- [4-(4-methylphenoxy)phenyl]-acetamide;
or a pharmaceutically acceptable salt thereof,
In accordance with another aspect, the present patent application 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 of the present invention can be administered as pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier. The ultimate dose will depend on the condition being treated, the route of administration and the age, weight and condition of the patient and will be the doctor's discretion.
Compounds of the present invention may be used in the manufacture of medicaments for the treatment of any diseases disclosed herein. The compounds and pharmaceutical compositions described herein are useful for modulating TRPA1 receptors, wherein modulation is believed to be related to a variety of disease states.
The compound of the present invention can be administered alone or in combination with other therapeutic agents. For instance, the TRPA1 modulator is administered conjointly with one or more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, antifungal agent, anti-viral agent, anti-septic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor
In accordance with another aspect, the present patent application further provides a method of inhibiting TRPA1 receptors 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 terms "halogen" or "halo" includes fluorine, chlorine, bromine or iodine.
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, 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 (tert-butyl). The term "Ci^ alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described herein may be straight chain or branched, substituted or unsubstituted The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred) e.g., ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "alkoxy" refers to a straight or branched, saturated aliphatic hydrocarbon radical bonded to an oxygen atom that is attached to a core structure. Examples of alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "haloalkyl" and "haloalkoxy" means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms, where alkyl and alkoxy groups are as defined above. The term "halo" is used herein interchangeably with the term "halogen" means F, CI, Br or I. Examples of "haloalkyl" include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl 4,4,4-trifluorobutyl, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl and the like. Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difiuoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy, 1-bromoethoxy and the like. Unless set forth or recited to the contrary, all "haloalkyl" and "haloalkoxy" groups described herein may be straight chain or branched, substituted or unsubstituted.
The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, 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 sprirobicyclic groups, e.g., spiro(4,4) non-2-yl. Unless set forth or recited to the contrary, all cycloalkyi groups described herein may be substituted or unsubstituted.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group. 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 herein may be substituted or unsubstituted.
The term "cycloalkylalkoxy" is used to denote alkoxy substituted with cycloalkyi, wherein 'alkoxy' and 'cycloalkyi' are as defined above (either in the broadest aspect or a preferred aspect). Examples of 'cycloalkylalkoxy' groups is
Figure imgf000021_0001
6)alkoxy. Preferably, cyclopropylmethoxy, 1- or 2-cyclopropylethoxy, 1-, 2- or 3- cyclopropylpropoxy, 1-, 2-, 3- or 4-cyclopropyl-butoxy, cyclobutylmethoxy, 1- or 2- cyclobutylethoxy, 1-, 2- or 3- cyclobutylpropoxy, 1-, 2-, 3- or 4-cyclobutylbutoxy, cyclopentylmethoxy, 1- or 2-cyclopentylethoxy, 1-, 2- or 3- cyclopentylpropoxy, 1-, 2-, 3- or 4- cyclopentylbutoxy, cyclohexylmethoxy, 1- or 2-cyclohexylethoxy and 1-, 2- or 3- cyclohexylpropoxy. Unless set forth or recited to the contrary, all cycloalkylalkoxy groups described herein may be substituted or unsubstituted.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described herein may be substituted or unsubstituted.
The term "aryl" means a carbocyclic aromatic system containing one, two or three fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc). If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Unless set forth or recited to the contrary, all aryl groups described, herein may be substituted or unsubstituted. The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6H5 or -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.
The term "aryloxy" means an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
The term "heterocyclic ring" or "heterocyclyl" refers to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic 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; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoqinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl and isochromanyl. 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 heterocyclic ring described herein may be substituted or unsubstituted.
The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. 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 herein may be substituted or unsubstituted.
The term "heteroaryl" refers to an aromatic heterocyclic ring radical. 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. Unless set forth or recited to the contrary, all heteroaryl groups described herein may be substituted or unsubstituted.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. 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 herein may be substituted or unsubstituted.
Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or more 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 alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR", -C(0)Rx, -C(S)RX', -C(0)NRxRy', -C(0)ONRxRy', -NRxCONRyRz, -N(Rx')SORy', -N(Rx')S02Ry', (=N-N(Rx')Ry), -NRxC(0)ORy', -NRxRy , -NRxC(0)Ry', -NRxC(S)Ry', -NRxC(S)NRy Rz', -SONRxRy , -S02NRxRy', -ORx', -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 or substituted or unsubstituted heterocyclic ring. 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.
"IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity.
The compounds 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 the present invention, including compounds of formula (I), (Ia)-(Ig) and (Ila)-(IIg) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). The present invention includes these stereoisomeric forms (including diastereomers and enantiomers) and mixtures thereof. The various stereoisomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
Pharmaceutical Compositions
The pharmaceutical composition of the present patent application 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 includes the compound(s) described herein in an amount sufficient to inhibit TRPAl in a subject (e.g., a human). The inhibitory activity of compounds falling within the formulas (I), (Ia)-(Ig) and (Ila)-(IIg) may be measured by an assay provided below.
The compound of the present invention 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 pharmaceutical compositions may be prepared by techniques known in the art. For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.
The pharmaceutical compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
Methods of Treatment
The compounds and pharmaceutical compositions of the present invention can be administered to treat any disorder, condition, or disease treatable by inhibition of TRPAl. For instance, the compounds and pharmaceutical compositions of the present invention are suitable for treatment or prophylaxis of the following diseases, conditions and disorders mediated or associated with the activity of TRPAl receptors: pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, chemotherapy - induced neuropathies, eye - irritation, bronchial - irritation, skin - irritation (atopic dermatitis), Frost - bites (cold - bite), spasticity, catatonia, catalepsy, parkinsons, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory disorder like airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and paracetamol-induced asthma, cough, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), overactive bladder, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus. Digestive organ diseases like irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, constipation, diarrhea, and vomiting. The connection between therapeutic effect and inhibition of TRPAl is illustrated, for example, in Story, G. M. et al. Cell, 2003, 1 12, 819-829; McMahon, S.B. and Wood, J. N., Cell, 2006, 124, 1 123-1125; Voorhoeve, P. M. et al. Cell, 2006, 124, 1169-1181; Wissenbach, U, Niemeyer, B. A. and Flockerzi, V. Biology of the Cell, 2004, 96, 47-54; and the references cited therein.
Pain can be acute or chronic. While acute pain is usually self-limiting, chronic pain 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 (K. M. Foley, Pain, in Cecil Textbook of Medicine; J. C. Bennett & F. Plum (eds.), 20th ed., 1996, 100-107). 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.
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).
General Methods of Preparation The compounds described herein, including compounds of general (I), (Ia)-(Ig) and (Ila)-(IIg) and specific examples, can be prepared by techniques known to in the art, for example, through the reaction scheme depicted in Scheme 1-19. Furthermore, in the following scheme, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may also 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 scheme may be of insufficient purity. These compounds can be purified by any of the methods for purification of organic compounds known in the art, for example, crystallization or silica gel or alumina column chromatography using different solvents in suitable ratios. All possible stereoisomers are envisioned within the scope of this invention.
A general approach for the synthesis of acetamide derivatives of the general formula (I), wherein ring Q, U and V are as defined above in the general description can be prepared as described in Scheme 1. Coupling reaction of a carboxylic acid of the formula (1) [when Ra is hydrogen] with amines of the general formula (2) in the presence of a suitable coupling agent such as l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) using a suitable base and solvent gives compounds of the generalformula (I). Alternatively carboxylic acid ester of formula (1) [when Ra is alkyl] can be coupled with amines of general formula (2) by using suitable base (e.g., sodium hydride) and in suitable solvent (e.g. toluene, xylene) to give compounds of the general formula
(I).
Scheme 1
o V-U-NH2 (2)
Q-CH2 C ORA ∞"P'i"9 agent, solvent Q^.^.^
or ^
^ base, solvent ^
An approach for the synthesis of compounds of the general formula (la) wherein R1, U and V are as defined above is depicted in Scheme 2. The starting 2-aminothiazole ester of formula (3) (wherein Ra is alkyl) is commercially available or can be prepared according to methods known to one skilled in the art (Campaigne, E. et al., J. Hetrocyclic Chem., (1980), 17, 1255-1257; Marugan, J. et al., J. Med. Chem. (2005), 48, 926-934). Compound of formula (3) can be converted to substituted triazinedione ester of general formula (4) by reaction with N-(chlorocarbonyl)isocyanate in the presence of suitable base (e.g., triethylamine, diisopropylethylamine) in a suitable solvent such as dichloromethane or tetrahydrofuran followed by alkylation with alkylating agent of formula R'X in the presence of suitable base (e.g., K2C03, Cs2C03 or diisopropylethylamine) in suitable solvent such as DMF or THF. Hydrolysis of triazinedione ester of formula (4) under acidic condition affords the corresponding carboxylic acid of formula (5). The carboxylic acid of a formula (5) is coupled with amine of a formula (2) under appropriate conditions using a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) to give compound of a general formula (la).
Scheme 2 .
O 1. CICONCO, base
-A solvent
Figure imgf000028_0001
solvent
(4) (5)
Figure imgf000028_0002
(la)
A similar approach is depicted in Scheme 3 for the synthesis of compounds of the general formula (la') wherein R1, U and V are as defined above. The starting 2- aminooxazole ester of formula (3') (wherein RA is alkyl) is commercially available or can be prepared according to methods known to one skilled in the art (Campaigne, E. et al., J. Hetrocyclic Chem., (1980), 17, 1255-1257; Marugan, J. et al., J. Med. Chem. (2005), 48, 926-934). Compound of formula (3') can be converted to substituted triazinedione ester of general formula (4') by reaction with N-(chlorocarbonyl)isocyanate in the presence of suitable base (e.g., triethylamine, diisopropylethylamine) in a suitable solvent such as dichloromethane or tetrahydrofuran followed by alkylation with alkylating agent of formula R'X in the presence of suitable base (e.g., K2C03, Cs2C03 or diisopropylethylamine) in suitable solvent such as DMF or THF. Hydrolysis of triazinedione ester of formula (4') under acidic condition affords the corresponding carboxylic acid of formula (5'). The carboxylic acid of a formula (5') can be coupled with amine of a formula (2) under appropriate conditions using a coupling agent such as N- ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazol-1- yloxytris(dimethylamino)phosphoniumhexafluorophosphate (BOP) to give compound of a general formula (la').
Figure imgf000029_0001
da')
Alternatively, intermediate of the general formula (4) can also be prepared as shown is Scheme 4. Thus, commercially available 2-amino-4-methylthiazole (6) can be converted to substituted triazinedione of general formula (7) in two steps as described in Scheme 3. Intermediate (7) can be metalated using suitable base such as Lithium diisopropylamide (LDA) or lithium hexamethyldisilazide (LHMDS) and reacted with diethyl carbonate (Ra = ethyl) to give triazinedione ester of general formula (4).
Scheme 4
o OR
Figure imgf000029_0002
base
solvent
(6) (7) (4)
An approach for the synthesis of compounds of the general formula (lb) wherein R1, U and V are as defined above is shown in Scheme 5. Thus, 2-aminothiazole ester of the formula (3) (wherein Ra is alkyl) on reaction with N-(chlorosulfonyl)isocyanate in the presence of suitable base such as triethylamine or N,N-diisopropylethylamine in a suitable solvent (e.g., dichloromethane, tetrahydrofuran) gives triazinedione- 1,1 ' -dioxide ester of general formula (8). A similar synthetic approach is described by Karady, S. et al. in Heterocycles 1979, 12(6), 815-818. The intermediate (8) on N-alkylation with an alkyl halide of the formula R X in the presence of suitable base gives intermediate of formula (9). Hydrolysis of ester of general formula (9) under acidic conditions affords the corresponding carboxylic acid of formula (10). Carboxylic acid (10) is coupled with amine of formula (2) under appropriate conditions using a coupling agent (e.g., DCC, EDCI, HATU, HBTU) to give compound of a general formula (lb).
Scheme 5
Figure imgf000030_0001
(10) (lb)
A similar approach is depicted in Scheme 6 for the synthesis of compounds of the general formula (lb') wherein R1, U and V are as defined above. Thus, 2-aminooxazole ester of the formula (3') (wherein RA is alkyl) on reaction with N- (chlorosulfonyl)isocyanate in the presence of suitable base such as triethylamine or N,N- diisopropylethylamine in a suitable solvent (e.g., dichloromethane, tetrahydrofuran) gives triazinedione- 1, 1 '-dioxide ester of general formula (8'). A similar synthetic approach is described by arady, S. et al. in Heterocycles 1979, 12(6), 815-818. The intermediate (8') on N-alkylation with an alkyl halide of the formula R'X in the presence of suitable base gives intermediate of formula (9'). Hydrolysis of ester of general formula (9') under acidic conditions affords the corresponding carboxylic acid of formula (10'). Carboxylic acid (10') is coupled with amine of formula (2) under appropriate conditions using a coupling agent (e.g., DCC, EDCI, HATU, HBTU) to give compound of a general formula (lb').
Scheme 6
Figure imgf000030_0002
(101) (lb') A general approach for the synthesis of compounds of the general formula (Ic) wherein R1, R2, U and V are as defined above is shown in Scheme 7. The starting imidazotriazinediones (11) required for the synthesis is commercially available from Aldrich Chemical Company. Alternatively, it can be prepared according to the procedure described by Revankar, G. R. et al, in J. Med. Chem. 1978, 21(9), 883-889. Intermediate (1 1) on reaction with excess of alkylating agent such as dialkyi sulfate (where R1 = R2 = alkyl group) gives the symmetrical dialkyi derivative (12). Alternatively, Intermediate (1 1) can also be alkylated stepwise using alkyl halide R'X followed by R2X to afford unsymmetrical Intermediate (12) in presence of a suitable base and solvent. Formylation of (12) using phosphorusoxychloride and N,N-dimethylformamide followed by one carbon homologation using methoxymethyltriphenylphosphonium chloride (13) in the presence of a strong base under Wittig reaction conditions affords the enol ether (14). Hydrolysis of enol ether (14) under acidic condition (e.g., hydrochloric acid, boron tribromide) affords triazinedione acetaldehyde (15). Oxidation of acetaldehyde intermediate (15) with suitable oxidizing agent (e.g., Jones reagent, chromic acid, sodium chlorite) gives corresponding carboxylic acid (16). Coupling of triazinedione acetic acid (16) with amine of a formula (2) under appropriate conditions with the help of a suitable coupling agent (e.g., DCC, EDCI, HATU, HBTU) gives compounds of the general formula (Ic).
Scheme 7
Figure imgf000031_0001
(15) (16) (Ic)
An approach for the synthesis of the compounds of general formula (Id) wherein
R1, R2, R3, U and V are as defined above is depicted in Scheme 8. The starting compound,
6-chloro-l,3-dialkyl-2,4(lH,3H)-dione of the formula (17) is commercially available or can be prepared according to a known literature methods. Nitration of compounds of the general formula (17) using an appropriate mixture of nitric acid and sulfuric acid followed by coupling with an appropriate amine of formula (18) affords the amino nitro compound of the formula (19). A similar approach for the synthesis of intermediate (19) is described by Senda, S. et al, in J. Am. Chem. Soc. 1978, 100(24), 7661-7664. Reduction of nitro group of formula (19) using palladium catalyst gives diamino compound (20). Cyclization of diamino compound of formula (20) with a 1,1- carbonyldiimidazole gives the uric acid derivative of formula (21). The compounds of the formula (21) on alkylation with suitable halo acetamide of general formula (22) in the presence of suitable base preferably cesium carbonate or sodium hydride in a suitable solvent such as Ν,Ν-dimethylformamide, tetrahydrofuran or dimethylsulfoxide gives compounds of general formula (Id).
Scheme 8
Figure imgf000032_0001
(21 ) (Id)
A general approach for the synthesis of furo[2,3-i ]pyrimidinyl acetamides of formula (Ie) wherein R1, R2, U and V are as defined above is prepared as shown in Scheme 9. Coupling reaction of 1,3-dialkylbarbaturic acid derivative of the formula (23) with haloacetyl chloride derivative (24) in the presence of a suitable base like sodium hydride and in a suitable solvent like tetrahydrofuran gives l,3-dimethylfuro[2,3- i/jpyrimidine-2,4,5(lH,3H,6H)-trione of general formula (25) as an intermediate which on halogenation using suitable halogenating agent such as {e.g. N-bromosuccinimde, N- chlorosuccinimide, F-TEDA [N-chloromethyl-N'-fluorotriethylenediammonium bis(tetrafluoroborate)]} gives halo-furo[2,3-c ]pyrimidinetrione of formula (26). Alternatively compound of formula (26) can also be prepared from compound of formula (25) using dihaloacetyl chloride such as dichloroacetyl chloride or dibromoacetyl chloride. A similar approach is described by Strekowski, L. et al. in J. Heterocyclic Chem. 2001, 38, 359-363. Halo-furo[2,3-iflpyrimidinetrione compounds of formula (26) was converted into furo[2,3-i/]pyrirnidinedione ester of compounds of general formula (27) by reaction with the lithium salt of ethyl acetate (generated from dry ethyl acetate and LHMDS) followed by dehydration and isomerization under acidic conditions. Hydrolysis of furo[2,3-c/}pyrimidinedione ester of general formula (27) under basic conditions affords corresponding carboxylic acid of general formula (28). Coupling of carboxylic acid of formula (28) with amine of the general formula (2) using a suitable coupling agents [e.g., N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), benzotriazol-l-yloxytris (dimethylamino) phosphonium hexafluorophosphate [BOP]) in suitable solvent or mixture of solvents (e.g., N,N-dimethyl formamide, tetrahydrofuran, dichloromethane etc. affords compounds of the general formula (Ie).
Scheme 9
Figure imgf000033_0001
1. UCH2CO2C2H5
2. H+
Figure imgf000033_0002
Alternatively, the carboxylic acid intermediate of the general formula (28) can be prepared as described in Scheme 10. Thus, reaction of (cyanomethyl)lithium with furo[2,3-i ]pyrimidinetrione of formula (26) (where R4 is halogen) in a suitable solvent gives furo[2,3-i ]pyrimidinyl acetonitrile of the formula (29). This intermediate on hydrolysis under acidic conditions gives intermediates of the formula (28) required for the synthesis of compounds of the general formula (Ie).
Scheme 10
Figure imgf000033_0003
A general approach for the synthesis of isoxazolo[3,4-i/]pyrimidinyl acetamides of the formula (If), wherein R1, R2, U and V are as defined above is prepared as described in Scheme 1 1. Thus, 1,3-dialkyl substituted barbituric acid of the formula (23) on treatment with phosphorous oxychloride gives 6-chloro dialkyluracil derivative of the formula (17), which is then treated with hydroxylamine in the presence of a suitable base to afford the hydroxylamino compound of the formula (30) in accordance with a reported procedure (Hirota, K. et al, Chem. Pharm. Bull., 2003, 51, 1451-1454). Cyclisation of compound of the formula (30) with acetic anhydride in dry pyridine gave methyl isoxazolo [3,4-d] pyrimidinedione of the formula (31) in excellent yield. A similar procedure is reported by Furukawa, Y. et al Chem. Pharm. Bull. 1977, 25, 2974-2982. Compound of formula (31) on reaction with dialky carbonate in the presence of a suitable base such as sodium hydride under reflux gives the desired ester of formula (32) (wherein R is alkyl). Ester of formula (32) is hydrolyzed under acidic conditions to furnish isoxazolo[3,4-i/]pyrimidinyl acetic acid (33) in good yield. The carboxylic acid (33) is coupled with amine of formula (2) by using a standard amide coupling method to give compounds of general formula
(if).
Scheme 11
Figure imgf000034_0001
(33) (If)
A general approach for the synthesis of isoxazolo[5,4-i ]pyrimidinyl acetamides of the formula (Ig), wherein R!, R2, U and V are as defined above is depicted in Scheme 12. Acrylonitrile derivative of formula (36) is prepared by the reaction of tertiary butyl cyanoacetate (34) with an imido ester hydrochloride of the formula (35) in presence of a suitable base such as triethyl amine. A similar approach is reported by Nadia.S.I et al Archive Dev Pharmazie (1988), 321, 569-570. Reaction of intermediate (36) with hydroxyl amine hydrochloride in the presence of suitable base gives isoxazole ester derivative (37). A similar approaches are reported by a) Sherif M.F et al Synthesis, (1982), 490-493, b) England, D. C et al Journal of Fluorine Chemistry, 1981 , vol. 17, p. 265-288; and c) Abd-Elaal et. al Monatshefte fuer Chemie, 1984, 1 15, 573-580. The t- butyl ester group of intermediate (37) is selectively cleaved to corresponding acid (38) by using trifluoroacetic acid under homogenous conditions. The carboxylic acid (38) is coupled with an amine using standard amide coupling method to give compounds of formula (39). Cyclisation of (39) with triphosgene produced the fused pyrimidine diene intermediate (40). Intermediate (40) on alkylation using alkyl halide furnished intermediate (41). Hydrolysis of ester of formula (41) with aqueous acid gives compounds of the formula (42). The coupling of compounds of formula (42) with an amine of formula (2) by using a standard amide coupling method gives compounds of general formula (Ig).
Scheme 12
Figure imgf000035_0001
(41) (42) (Ig)
The alternative synthesis of key intermediate (37) is depicted in scheme 13. In this approach tert-butyl cyanoactetate (34) is condensed with the ester (43) in reflux condition with acetic anhydride to give acrylonitrile derivative (44). Intermediate (44) on reaction with hydroxyl amine under basic condition gives the amino isoxazole derivative (37).
Scheme 13 t Bu
Figure imgf000036_0001
(34) (44) (37)
Another approach for the synthesis of advanced intermediate (39) is given in Scheme 14. In this approach N-alkyl cyanoacetamide (45) is coupled with an imido ester hydrochloride of formula (35) in presence of a suitable base such as triethyl amine in a suitable solvent to give aminoacrylonitrile derivative (46). Intermediate (46) is then reacted with hydroxyl amine under basic conditions to furnish the desired amino isoxazole intermediates (39).
Scheme 14
Figure imgf000036_0002
(45) (46) (39)
Another approach for the synthesis of isoxazolo[5,4-i/]pyrimidinyl acetic acid of the formula (42) is as shown in scheme 15. Thus, reaction of commercially available 1,3- dialkylbarbituric acid of the formula (23) with malonic acid (47) in the presence of suitable solvent gives compounds of the formula (48). Posner reaction of (48) by using hydroxy lamine hydrochloride in the presence of suitable base gives isoxazole [3,4-
< ]pyrimidinyl acetic acid of the formula (42) (Posner, T. et. al. Chem. Ber., 1913, 46,
3816).
Scheme 15
Figure imgf000036_0003
(23) (48) (42)
Scheme 16 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (54) (wherein R5, R6 and 'm' are as defined above in description) which is prepared from acetophenones of the formula (53) using known approaches. Certain di-and tri-substituted acetophenones were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (49) in three steps. Thus, acid of formula (49) was converted to the corresponding acid chloride of formula (50) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (50) was converted to corresponding Weinerb amide of formula
(52) by treating with N,0-dimethylhydroxylamine hydrochloride of formula (51) in the presence of a suitable base such as triethylamine. The addition of alkyl magnesium iodide (R5 is hydrogen or alkyl) to Weinreb amide of formula (52) afforded acetophenone derivative of formula (53).
Conversion of acetophenone derivative of formula (53) to 2-amino-4-substituted aryl thiazole of the formula (54) can be effected by two approaches as described in Scheme 16. In the first case acetophenone was converted to the corresponding phenacyl bromide, which in turn was reacted with thiourea in a suitable solvent such as tetrahydrofuran at refluxing condition. Alternatively, acetophenone derivative of formula
(53) can be converted to 2-amino-4-aryl thiazole (54) in one step by its reaction with thiourea and iodine in refluxing ethanol (Carroll, K. et al, J. Am. Chem. Soc, 1950, 3722 and Naik, S. J.; Halkar, U. P., ARKIVOC, 2005, xiii, 141-149).
Scheme 16
oa CH3ONHCH3.HCI
Figure imgf000037_0001
base' solvent
(49) (50)
? D O 11. RBrr2. // AArcTOlHH S~f- R5
N(CH3)OCH3 CH2Mgl Y ^C 2 2. thiourea.THF 2 N
ether " (R >™ "
(52) (53) thiourea, l2, EtOH, (M)
An approach for the synthesis of the intermediates of general formula (58) is depicted in Scheme 17. Thus, reaction of substituted aryl alkyl ketone of general formula
(55) with thiourea in the presence of iodine in a suitable solvent such as ethyl alcohol at elevated temperature gives aryl thiazoleamine of formula (56). Alternatively, intermediate
(56) can also be synthesized in two steps by a-bromination of ketone (55) using bromine in acetic acid followed by condensation with thiourea in a suitable solvent such as ethyl alcohol at elevated temperature. The 2-amino-4-aryl thiazole (56) is coupled with haloacetyl halide (e.g., chloroacetyl chloride or bromoacetyl bromide) of formula (57) in presence of suitable solvent such as dichloromethane gives aryl thiazolyl acetamide of the general formula (58).
Scheme 17
Figure imgf000038_0001
(55) 2. thiourea (56) (58)
A general approach for the synthesis of acetamide derivatives of the general formula (lla), (lib), (lie), (He), (Ilf) and (Ilg) wherein R1, R2, R4, R5, R6 and 'm' are as defined above in the general description can be prepared as described in Scheme 18. Coupling reaction of a carboxylic acid of the formula (5), (10), (16), (28), (33) and (42) with amines of the general formula (54) in the presence of a suitable coupling agent such as l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) using a suitable base and solvent gives corresponding amides of general formula (lla), (lib), (He),
(He), (Ilf) and (Ilg).
Scheme 18
Figure imgf000039_0001
An approach for the synthesis of the compounds of the general formula (lid) wherein R1, R2, R3, R5, R6 and ' m' are defined above is depicted in scheme 19. Coupling reaction of compound of formula (21) with a suitable halo acetamide of general formula (58) (wherein X is halogen) in the presence of suitable base such as cesium carbonate or sodium hydride in suitable solvent such aas Ν,Ν-dimethylformamide, tetrahydroiuran or dimethylsulfoxide gives compounds of general formula (lid) Scheme 19
Figure imgf000040_0001
(21 ) (58) (lid)
The intermediates and examples described in the present invention are prepared using the procedure described below. However, it is understood that these intermediates and examples can be prepared by alternate approaches which are within the scope of the present invention.
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, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses. The following abbreviations are used in the text: DMSO-i&: Hexadeuterodimethyl sulfoxide; DMF: N,N-dimethylformamide; J: Coupling constant in units of Hz; RT or rt: room temperature (22-26°C); Aq.: aqueous; AcOEt: ethyl acetate; equiv. or eq.: equivalents.
2-(4-Chlorophenyl)ethanamine, 4-(propan-2-yl)aniline, 4-fluoro-3-
(trifiuoromethyl)aniline and 2,4-difluoroaniline were purchased from Aldrich. 4-(4- Methylphenoxy)aniline was prepared according to the known literature. The several of the 2-amino-4-aryl thiazoles were also commercial available. The commercially unavailable 2-amino-4-aryllthiazoles were prepared by known literature methods starting from either substituted acetophenone or substituted benzoic acid as shown in 'General Synthetic Methods'
INTERMEDIATES
Intermediate 1
(3-Methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetic acid
Figure imgf000041_0001
Step 1 : Ethyl (2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l ,3,5]triazin-6-yl)acetate: To a stirred suspension of ethyl (2-amino-l,3-thiazol-4-yl)acetate (0.500 g, 2.685. mmol) in anhydrous dichloromethane (10 ml), was added dropwise at 0°C, a solution of N- (chlorocarbonyl) isocyanate (0.425 g, 4.027 mmol) in anhydrous dichloromethane (10 ml) under nitrogen atmosphere. After stirring for 2 hours at room temperature, triethylamine (0.2 ml) was added to the reaction mixture. The reaction mixture was stirred for an additional 4 hour and the solvent was evaporated under vacuo to give crude product which was further purified by column chromatography to give 220 mg of product as off- white soild; IR (KBr) 321 1, 1749, 1710, 1554, 1379, 1219 cm 1; Ή NMR (300 MHz, DMSO-i e) δ 1.16 (t, J = 6.9 Hz, 3H), 3.95 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 6.94 (s, 1H), 1 1.66 (s, 1H); ESI-MS (m/z) 256.48 (M+H)+.
Step 2: Ethyl (3-methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6- yl)acetate: To a magnetically stirred solution of step 1 intermediate (150 mg, 0.588 mmol) in anhydrous DMF (2.0 ml) was added diisopropyl ethylamine (DIPEA) (0.076 g, 0.588 mmol) followed by iodomethane (0.167 g, 1.176 mmol) at room temperature. Resulting suspension was further stirred for 18 hours under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (100 ml), washed with water (25 ml), brine (25 ml), dried (Na2S04), and concentrated under reduced pressure to give crude product which was purified by column chromatography to afford 105 mg of product as an off-white solid; IR (KBr) 3109, 1738, 1667, 1422, 1224, 1027 cm 1; Ή NMR (300 MHz, DMSO-4 δ 1.17 (t, J = 6.9 Hz, 3H), 3.16 (s, 3H), 3.99 (s, 2H), 4.08 (q, J= 6.9 Hz, 2H), 7.01 (s, 1H); ESI-MS (m/z) 268.14 (M-HV.
Step 3: (3-Methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2- ][l,3,5]triazin-6-yl)acetic acid: A mixture of step 2 intermediate (0.700 g, 2.60 mmol) and concentrated HC1 (5.0 ml) was heated at 90 °C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and the precipitated solid was filtered, washed with acetone and dried to give 0.450 g of product as a white solid; IR (KBr) 3442, 2936, 1720, 1566, 1371, 1176, 997 cm"1; Ή NMR (300 MHz, DMSO-<¾ δ 3.17 (s, 3H), 3.92 (s, 2H), 6.99 (s, 1H); ESI-MS (m/z) 242.13 (M+H)+. Intermediate 2
2-Methyl- 1 , 1 -dioxido-3-oxo-2,3-dihydro[ 1 ,3]thiazolo[3,2-Z>] [ 1 ,2,4,6]thiatriazin-7- yl)acetic acid
Figure imgf000042_0001
Step 1 : Ethyl (l, l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6] thiatriazin-7- yl)acetate: To a stirred and cooled (0°C) suspension of ethyl (2-amino-l,3-thiazol-4- yl)acetate (7.0 g, 37.587 mmol) in anhydrous dichloromethane (35 ml) was added dropwise a solution of chlorosulfonyl isocyanate (4.91 ml, 56.381 mmol) in anhydrous dichloromethane (15 ml) under nitrogen atmosphere. After stirring for 2 h at room temperature, triethylamine (9.4 ml, 67.658 mmol) was added to the reaction mixture. The reaction mixture was stirred for another 4 h and evaporated in vacuo to give crude product which was further purified by column chromatography to give 2.25 g of the product as a white solid; Ή NMR (300 MHz, DUSO-d6) δ 1.16 (t, J= 6.9 Hz, 3H), 3.96 (s, 3H), 4.05 (q, J = 6.9 Hz, 2H), 6.96 (s, 1H), 1 1.70 (br s, 1H, exchangeable with D20); APCI-MS (m/z) 288.04 (M-H).
Step 2: Ethyl (2-methyl-l, l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6] thiatriazin-7-yl)acetate: To a magnetically stirred solution of Step 1 intermediate (2.0 g, 6.865 mmol) in anhydrous DMF (10.0 ml) was added N^V-diisopropylethylamine (DIPEA) (1.2 ml, 6.865 mmol) followed by iodomethane (0.85 ml, 13.739 mmol) at room temperature under nitrogen atmosphere. After stirring for 18 h the resulting suspension was diluted with ethyl acetate (500 ml), washed with water (250 ml), brine (100 ml) and dried (Na2S04). The crude product obtained after evaporation of the solvent was purified by column chromatography to afford 700 mg of the product as an off-white solid; Ή NMR (300 MHz, DMSO-cfc) δ 1.17 (t, J= 6.9 Hz, 3H), 3.16 (s, 3H), 3.99 (s, 2H), 4.09 (q, J= 6.9 Hz, 2H), 7.02 (s, 1H); APCI-MS (m/z) 268.14 (M-35)+.
Step 3: 2-MethyI-l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7- yl)acetic acid: A mixture of Step 2 intermediate (680 mg, 2.227 mmol) and concentrated HC1 (3.0 ml) was heated at 90°C for 2 h. The reaction mixture was cooled to room temperature. Precipitated solid was filtered, washed with acetone and dried well to give 350 mg of the product as a white solid; Ή NMR (300 MHz, OMSO-d6) δ 3.17 (s, 3H), 3.92 (s, 2H), 6.99 (s, 1H); APCI-MS (m/z) 242.1 1 (M-35)+. Intermediate 3
(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetic acid
Figure imgf000043_0001
Step 1 : l,3-Dimethylimidazo[l,2-a][l,3,5]triazine-2,4(lH,3H)-dione: To a stirred solution of sodium hydroxide (8.8 g, 221.879 mmol) in water (135 ml) was added imidazo[l,2- ][l,3,5]triazine-2,4(lH,3H)-dione (13.50 g, 88.757 mmol) at 0°C and the reaction mixture was stirred at the same temperature for 30 min. Dimethyl sulphate (21.0 ml, 221.879 mmol) was added dropwise at the same temperature and the resulting mixture was slowly warmed to room temperature. After overnight stirring the reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (3 x 250 ml). The combined organic layers were washed with brine (100 ml), dried (Na2S04) and concentrated to give the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.47 (s, 3H), 3.62 (s, 3H), 7.01 (s, 1H), 7.36 (s, 1H); APCI-MS (m/z) 181.10 (M+H)+.
Step 2: l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazine-6- carbaldehyde: Phosphorous oxychloride (5.1 ml) was added slowly to a solution of dry DMF (20.0 ml) at room temperature. Step 1 intermediate (4.0 g, 22.202 mmol) was added portion wise and the resulting reaction mixture was heated overnight at 80 °C. The excess of phosphorous oxychloride and DMF were distilled off under reduced pressure. The viscous residue obtained was poured into ice-cold water (100 ml) and neutralized with NaHC03 solution. The reaction mixture was extracted with ethyl acetate (3 x 75 ml) and the combined organic extracts were dried over Na2S04 and concentrated. The crude product obtained was then purified by column chromatography using ethyl acetate in chloroform to obtain 4.15 g of the product as an off-white solid; Ή NMR (300 MHz,
CDC13) δ 3.53 (s, 3H), 3.68 (s, 3H), 7.85 (s, lH), 10.40 (br s, 1H); ESI-MS (m/z) 209.24
(M+H)+
Step 3: 6-[(£/2 2-Methoxyvinyl]-l,3-dime
dione: To a stirred solution of (methoxymethyl)triphenyl phosphine (0.92 g, 23.0591 mmol) in dry THF (50 ml) was added sodium hydride (60 % dispersion in mineral oil, 23 mg, 0.576 mmol) under nitrogen atmosphere and stirred for 30 min. Then a solution of Step 2 intermediate (4.0 g, 19.216 mmol) in THF (50 ml) was added. After overnight stirring at room temperature the reaction mixture was diluted with ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (3 x 75 ml) and the combined organic layers were washed with saturated solution of NaHC03 (50 ml), followed by brine (50 ml), dried over Na2S04 and filtered. The filtrate was evaporated and the residue obtained was purified by column chromatography to afford 1.6 g of the product as a white solid; Ή NMR (300 MHz, CDC13) δ 3.46 (s, 3H), 3.60 (s, 3H), 3.69 (s, 3H), 5.63 (d, J = 12.9 Hz, 1H), 7.05 (s, 1H), 7.33 (d, J = 12.9 Hz, 1H); ESI-MS (m/z) 237.21 (M+H)+.
Step 4: ( 1 ,3-Dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydroimidazo[ 1 ,2-a] [ 1 ,3,5]triazin-6-y 1) acetaldehyde: 1 N HC1 (1 ml) was added to a stirred solution of Step 3 intermediate (625 mg, 2.645 mmol) in THF (10 ml) at room temperature to give a turbid solution. After stirring for 2 h, the excess of solvent was evaporated and the residue obtained was neutralized with saturated solution of NaHC03 and extracted with ethyl acetate (3 x 75 ml). The combined organic layers were washed with brine (50 ml), dried over Na2S04 and filtered. The filtrate was distilled out and the residue obtained was purified by column chromatography to afford 586 mg of the product as a yellow solid; Ή NMR (300 MHz, CDC13) δ 3.46 (s, 3H), 3.60 (s, 3H), 3.69 (s, 2H), 7.32 (s, 1H), 9.81 (br s, 1H); ESI-MS (m/z) 223.20 (M+H)+.
Step 5: (l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2- ][l,3,5]triazin-6- yl)acetic acid: To a solution of Step 4 intermediate (575 mg, 2.587 mmol) and sulphamic acid (376 mg, 3.881 mmol) in acetone (10.0 ml) was added sodium chlorite (292 mg, 3.234 mmol) in water (4.0 ml) at 0 °C. After stirring for 1 h at room temperature, excess of solvent was distilled out. The residue obtained was diluted with brine and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na2S04 and filtered. The filtrate was evaporated and the residue obtained was purified by column chromatography to afford 370 mg of the product as a yellow solid; Ή NMR (300 MHz, CDC13) δ 3.33 (s, 3H), 3.55 (s, 3H), 3.69 (s, 2H), 7.37 (s, 1H); APCI-MS (m/z) 239.13 (M+H)+.
Intermediate 4
l,3,9-Trimethyl-7,9-dihydro-lH-puri -2,6,8(3H)-trione
Figure imgf000044_0001
Step 1 : 6-Chloro-l,3-dimethyl-5-nitropyrimidine-2,4(lH,3H)-dione: 6-Chloro-l,3- dimethylpyrimidine-2,4(lH,3H)-dione (13.0 g, 74.464 mmol) was added portion wise to a stirred and cooled (15°C) solution of concentrated sulphuric acid (40 mL). The reaction temperature was maintained below 10 °C. Fuming nitric acid (15 mL) was added dropwise into the above reaction mixture and then stirred for 2 h at the same temperature. The reaction mixture was then poured onto the ice cold water (500 mL) and extracted with chloroform (2 x 250 mL). The combined organic extracts were washed with water (250 mL), dried (Na2S04) and concentrated to obtain 12.3 g of the product as a yellow solid; Ή NMR (300 MHz, CDC13) δ 3.41 (s, 3H), 3.38 (s, 3H); APCI-MS (m/z) 185.99 (M-35)+.
Step 2: l,3-Dimethyl-6-(methylamino)-5-nitropyrimidine-2,4(lH3H)-dione: To a stirred solution of Step 1 intermediate (1 1.00 g, 50:095 mmol) in anhydrous chloroform (90 mL) was added dropwise a solution of 40 % aqueous methylamine (7.76 ml, 100.191 mmol) in anhydrous dichloromethane (20 mL) at room temperature under nitrogen atmosphere. After stirring for 1 h the reaction mixture was distilled under vacuo to give crude product. The crude obtained was triturated with ether, solid obtained was collected by filtration, washed with ether and dried well to obtain 13.6 g of the product as a yellow solid; Ή NMR (300 MHz, CDC13) δ 3.21 (s, 3H), 3.35 (s, 3H), 3.57 (s, 3H), 9.74 (br s, 1H); APCI- MS (m/z) 215.15 (M+H)+.
Step 3: 5-Amino-l,3-dimethyl-6-(methylamino)pyrimidine-2,4(lH,3H)-dione: To a stirred solution of Step 2 intermediate (13.5 g, 63.034 mmol) in methanol (700 mL) was added 10 % Palladium on carbon (50 % wet, 5.0 g) under hydrogen balloon atmosphere at room temperature. After overnight stirring, the reaction mixture was filtered through celite bed. The filtrate was concentrated to afford 5.2 g of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 2.48 (br s, 2H), 2.89 (d, J = 5.4 Hz, 3H), 3.36 (s, 3H), 3.45 (s, 3H), 4.94 (br s, 1H); APCI-MS (m/z) 185.24 (M+H)+.
Step 4: l,3,9-Trimethyl-7,9-dihydro-lH-purine-2,6,8(3H)-trione: To a magnetically stirred solution of Step 3 intermediate (2.0 g, 10.857 mmol) in anhydrous THF (50.0 mL) was added Ι,Γ-carbonyldiimidazole (2.1 g, 13.029 mmol) at room temperature under nitrogen atmosphere. After refluxing for 18 h the excess of solvent was distilled under reduced pressure. The residue obtained was diluted with ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (2 x 75 ml) and the combined organic layers were washed with water (2 x 25 ml) followed by brine (25 ml), dried (Na2S04) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the distillation of the solvent was purified by silica gel column chromatography using methanol in chloroform to obtain 1.2 g of the product as a white solid; 1H NMR (300 MHz, DMSO-cfe) δ 3.19 (s, 3H), 3.48 (s, 3H), 3.63 (s, 1H), 1 1.12 (br s, 1H); APCI-MS (m/z) 21 1.21 (M+H)+.
Intermediate 5
l,3-Dimethyl-9-ethyl-7,9-dihydro-lH-purine-2,6,8(3H)-trione
Figure imgf000046_0001
The title compound was prepared in 3 steps as described in Intermediate 4 by using 6- Chloro-l,3-dimethyl-5-nitropyrimidine-2,4(lH,3H)-dione (2.5 g, 1 1.385 mmol) and ethylamine hydrochloride (1.39 g, 17.045 mmol) to give 900 mg of the desired product as an off-white solid; Ή NMR (300 MHz, DMSO-<&) δ 1.21 (d, J = 6.1 Hz, 3H), 3.20 (s, 3H), 3.60 (s, 3H), 3.94-4.00 (m, 2H), 11.15 (br s, 1H); APCI-MS (m/z) 225 (M+H)+.
Intermediate 6
9-Isopropyl-l,3-dimethyl-7,9-dihyd (3H)-trione
Figure imgf000046_0002
The title compound was prepared in 3 steps as described in Intermediate 4 from 6-Chloro- l,3-dimethyl-5-nitropyrimidine-2,4(lH,3H)-dione (2.5 g, 1 1.385 mmol) and isopropylamine hydrochloride (2.69 g, 45.541 mmol) to give 600 mg of the desired product as an off-white solid; Ή NMR (300 MHz, DMSO-afe) δ 1.49 (d, J= 6.0 Hz, 6H), 3.19 (s, 3H), 3.57 (s, 3H), 4.60-4.71 (m, 1H), 1 1.02 (br s, 1H); APCI-MS (m/z) 239.08 (M+H)+.
Intermediate 7
9-Isobutyl-l,3-dimethyl-7,9-dihydro-lH-purine-2,6,8(3H)-trione
Figure imgf000046_0003
The title compound was prepared in 3 steps as described in Intermediate 4 from 6-chloro- l,3-dimethyl-5-nitropyrimidine-2,4(lH,3H)-dione (5.0 g, 22.770 mmol) and isobutylamine hydrochloride (3.3 g, 45.529 mmol) to give 700 mg of the desired product as an off-white solid; Ή NMR (300 MHz, DMSO-i/6) δ 0.85 (d, J = 6.3 Hz, 6H), 1.88- 1.95 (m, 1H), 3.20 (s, 3H), 3.56 (s, 3H), 3.76 (d, J= 7.5 Hz, 2H), 11.18 (br s, 1H); APCI- MS (w/z) 253.13 (M+H)+.
Intermediate 8
(6-Chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-i ]pyrimidin-5-yl)acetic acid
Figure imgf000047_0001
Step 1 : 6-Chloro-l,3-dimethylfiiro[2,3-i/lpyrimidine-2,4,5(lH,3H,6H)-trione: To a stirred solution of l,3-dimethylfuro[2,3-i ]pyrimidine-2,4,5(lH,3H,6H)-trione (5.0 g, 25.489 mmol) and azobisisobutyronitrile (AIBN) (83.71 mg, 0.509 mmol) in carbon tetrachloride (50 mL) was added N-chlorosuccinimide (4.084 g, 30.587 mmol). The resulting mixture was refluxed for 24 h. The reaction mixture was then cooled to room temperature and diluted with chloroform (100 mL) and water (100 mL). The layers were separated. Aqueous layer was extracted with chloroform (2 x 50 ml) and the combined organic layers were washed with brine (2 x 50 ml), dried (Na2S04) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to obtain 2.3 g of the product as a white solid; 1H NMR (300 MHz, CDC13) δ 3.35 (s, 3H), 3.53 (s, 3H), 6.22 (s, 1H); ESI-MS (m/z) 231 (M+H)+.
Step 2: Ethyl (2Z)-(6-chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5(6H)-ylidene)acetate: Anhydrous THF (100 mL) was cooled to -78°C. A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 2.5 g, 14.94 mmol) was added under nitrogen atmosphere. Then dry ethyl acetate (1.313 g, 14.94 mmol) was added and the resulting mixture was stirred at the same temperature for 1 h. A solution of 6-chloro-l,3-dimethylfuro[2,3-i/]pyrimidine-2,4,5(lH,3H,6H)-trione (2.3 g, 10 mmol) in a mixture of THF and dichloromethane (1 :3, 80.0 mL) was added dropwise to the above solution and the resulting mixture was stirred at -78°C for 2.5 h. The reaction mixture was then acidified with IN HCl (75 mL). The temperature was allowed to rise gradually until reaching room temperature and was extracted with dichloromethane (200 mL). The organic extracts were washed with IN HCl (75 mL), water (100 mL) brine (100 mL), dried (Na2S04). Excess of solvent was evaporated under reduced pressure and the residue obtained was purified with column chromatography by using 10 % ethyl acetate in chloroform to obtain 1.1 g of product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 1.25-1.33 (m, 3H), 3.37 (br s, 3H), 3.53 (s, 3H), 4.18-4.27 (m, 2H), 6.48 (s, 1H), 7.58 (s, 1H); APCI-MS ( n/z) 301 (M+H)+.
Step 3: Ethyl (2Z)-(6-chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5-yl)acetate: A mixture of Step 2 intermediate (1.0 g, 0.003 mmol) and glacial acetic acid (15.0 mL) was refluxed for 4 h. Excess of acid was evaporated under vacuum and the residue obtained after evaporation of the solvent was purified by silica gel column chromatography by using 2 % methanol in chloroform to obtain 800 mg of the product as white solid; Ή NMR (300 MHz, CDC13) δ 1.29 (t, J = 7.2 Hz, 3H), 3.36 (s, 3H), 3.53 (s, 3H), 3.67 (s, 2H), 4.21 (q, J= 7.2 Hz, 2H); APCI-MS (m/z) 301 (M+H)+. Step 4: (6-Chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-i |pyrimidin-5- yl)acetic acid: A mixture of Step 3 intermediate (800 mg, 2.666 mmol) in 1 : 1 solution of glacial acetic acid (5.0 mL) and concentrated hydrochloric acid (5.0 mL) was refluxed for 5 h. Excess of solvent was evaporated under reduced pressure and the crude residue obtained was titurated with hexane to yield 590 mg of off- white solid. Ή NMR (300 MHz, DMSO-<&) δ 3.19 (s, 3H), 3.40 (s, 3H), 3.56 (s, 2H), 2H), 12.60 (br s, 1H); APCI- MS (m/z) 273 (M+H)+.
Intermediate 9
(6-Bromo-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-i ]pyrimidin-5-yl)acetic acid
Figure imgf000048_0001
Step 1 : 6-Bromo-l,3-dimethylfuro[2,3-i jpyrimidine-2,4,5(lH,3H,6H)-trione: The title compound was prepared by reaction of l,3-dimethylfuro[2,3-c/)pyrirnidine- 2,4,5(1 H,3H,6H)-trione (500 mg, 2.548 mmol) and azobisisobutyronitrile (AIBN) (8.0 mg, 0.049 mmol) in carbon tetrachloride (10 mL) was added N-bromosuccinimide (544 mg, 3.056 mmol) as described in the procedure of intermediate 8 step 1 to obtain 200 mg of the product as a white solid; Ή NMR (300 MHz, CDC13) δ 3.36 (s, 3H), 3.53 (s, 3H), 6.55 (s, 1H); APCI (m/z) 275 (M)+.
Step 2: Ethyl (2Z)-(6-bromo-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i ]pyrimidin-5(6H)-ylidene)acetate: The title comopund was prepared by the reaction of 6-bromo-l,3-dimethylfuro[2,3-i ]pyrirnidine-2,4,5(lH,3H,6H)-trione (3.5 g, 12.62 mmol) with lithium bis(trimethylsilyl)amide (LiHMDS) (1.0 M in THF, 3.169 g, 18.94 mmol) and dry ethyl acetate (1.829 g, 18.94 mmol) in dry THF (200 mL) as described for the preparation of step 2 of intermediate 8 to give 150 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 1.28-1.36 (m, 5H), 3.32 (s, 3H), 3.53 (s, 1H), 3.65 (s, 1H), 4.13 4.22 (m, 3H); APCI-MS (m/z) 345 (M)+.
Step 3: Ethyl (2Z)-(6-bromo-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3- i/]pyrimidin-5-yl)acetate: The title compound was prepared according to procedure described for step 3 of intermediate 8 by using step 2 intermediate (150 mg, 0.473 mmol) and glacial acetic acid (5.0 mL) to give 65 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 1.29 (t, J = 7.5 Hz, 3H), 3.36 (s, 3H), 3.53 (s, 3H), 3.67 (s, 2H), 4.21 (q, J= 6.9 Hz, 2H); APCI-MS (m/z) 345 (M)+.
Step 4: (6-Bromo-l,3-dimethyl-2,4-dioxo-l ,2,3,4-tetrahydrofuro[2,3-i ]pyrimidin-5- yl)acetic acid: This intermediate was prepared according to procedure described for step 3 of intermediate 8 by using step 2 intermediate (60 mg, 0.189 mmol) to yield 45 mg of the product as an off- white solid. 1H NMR (300 MHz, DMSO) δ 3.15-3.23 (m, 3H), 3.34- 3.40 (m, 3H), 3.56 (s, 2H), 12.62 (br s, 1H); APCI-MS (m/z) 273 (M-C02)~.
Intermediate 10
(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[3,4-i ]pyrimidin-3-yl)acetic acid
Figure imgf000049_0001
Step 1 : 6-Chloro-l,3-dimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of 1,3- dimethylbarbituric acid (20.0 g, 128.09 mmol) in water (10 ml), phosphorous oxychloride (80 ml) was added slowly by externally cooling and reaction was then refluxed for 3 h. The reaction mixture was allowed to cool to 0°C and quenched with ice cold water (350 ml). The reaction mixture was extracted with chloroform (2 x 200 ml) and the combined organic extracts were washed with water, dried over Na2S04 and concentrated to obtain 21.0 g of the product as a pale brown solid; Ή NMR (300 MHz, CDC13) δ 3.33 (s, 3H), 3.57 (s, 3H), 5.94 (s, 1H).
Step 2: 6-(Hydroxyamino)-l,3-dimethylpyrimidine-2,4(lH,3H)-dione: A solution of Step 1 intermediate (10 g, 57.261 mmol), hydroxylamine hydrochloride (12.15 g, 176.361 mmol) and sodium acetate (33.81 g, 412.28 mmol) in isopropyl alcohol (280 ml) were refluxed for 4 h. The reaction mixture was concentrated under reduced pressure, diluted with water and stirred for 1 h. The precipitated solid was collected by filtration, washed with water (25 ml) and dried to obtain 9.56 g of the product as a pale brown solid; Ή NMR (300 MHz, DMSO-i/6) δ 3.07 (s, 3H), 3.16 (s, 3H), 3.67 (s, 2H), 10.45 (br s, lH). Step 3: 3,5,7-Trimethylisoxazolo[3,4-i/]pyrimidine-4,6(5H,7H)-dione: A mixture of Step 2 intermediate (9.5 g, 55.555 mmol) and acetic anhydride (48 ml) in dry pyridine (92 ml) were refluxed for 6 h under nitrogen atmosphere. The reaction mixture was cooled to 0°C and acidified with IN HC1 (100 ml). The solid obtained was collected by filtration, washed with 1 N HC1 (25 ml), water (25 ml) and dried to give 8.05 g of the product as a white solid; Ή NMR (300 MHz, CDC13) δ 2.75 (s, 3H), 3.36 (s, 3H), 3.49 (s, 3H).
Step 4: Methyl (5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[3,4-i ]pyrimidin-3- yl)acetate: To a stirred solution of Step 3 intermediate (8.0 g, 41.02 mmol) in dimethylcarbonate (12.6 ml) was added sodium hydride (60 % dispersion in mineral oil, 3.93 g, 163.75 mmol) and mixture was refluxed overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched into 1 N HC1 (75 ml), extracted with chloroform (3 x 100 ml) and the combined organic layers were washed with water (2 x 100 ml), dried over Na2S04 and concentrated. The residue obtained was triturated in hexane, solid obtained was filtered to give 9.5 g of the product as a white solid; 'H NMR (300 MHz, CDC13) δ 3.36 (s, 3H), 3.51 (s, 3H), 3.77 (s, 3H), 4.19 (s, 2H). Step 5: (5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[3,4-i/] rjyrimidin-3-yl)acetic acid: A mixture of Step 4 intermediate (9.0 g, 35.55 mmol) and 6 N H2S04 (88.93 ml) in dioxane (90 ml) stirred at reflux temperature for 1 h to give a homogeneous pale yellow solution. This solution was cooled, diluted with water and extracted with ethyl acetate (2 x 50 ml). The combined organic layers were washed with water, dried over Na2S04 and concentrated. The residue obtained was triturated in diethyl ether, solid obtained was collected by filtration to give 6.0 g of the product as a white solid; Ή NMR (300 MHz, DMSO-</6) δ 3.18 (s, 3H), 3.33 (s, 3H), 4.20 (s, 2H), 13.20 (br s, 1H).
Intermediate 1 1
(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[5,4-i |pyrimidin-3-yl)acetic acid
Figure imgf000050_0001
Step 1 : tert-Butyl cyanoacetate: To a stirred solution of cyanoacetic acid (110 g, 1293.20 mmol) in dry diethyl ether (650 ml), phosphorus pentachloride was added in portions at 0 °C and stirred at room temperature for 3 h. The excess of solvent and phosphorus oxychloride were distilled out under reduced pressure. The acid chloride was dissolved in dry diethyl ether (150 ml) and cooled 0-5 °C, Ν,Ν-dimethyl aniline (165 ml, 1293.20 mmol) and tert butanol (122.88 ml, 1293.20 mmol) in dry diethyl ether (150 ml) was added dropwise during 30 min and refluxed for 2 h and subsequently stirred at room temperature for overnight. The reaction mixture was then diluted with water and the product was extracted in ethyl acetate (200 ml x 2). The combined organic layers were washed with I N HCl (200 ml), saturated solution of sodiumbicarbonate (200 ml), water (200 ml) and dried (Na2S04). The crude product was purified by fractional distillation to give 114.3 g of the product as as yellow liquid; Ή NMR (300 MHz, CDC13) δ 1.50 (s, 9H), 3.37 (s, 2H).
Step 2: 1-fert-Butyl 5-ethyl (2£)-3-amino-2-cyanopent-2-enedioate: To a stirred solution of step 1 intermediate (114 g, 808.5 mmol) and ethyl (3£)-3-ethoxy-3-iminopropanoate hydrochloride (158.20 g, 808.5 mmol) in dry chloroform was added triethyl amine (588.24 ml, 4041.2 mmol) and mixture was vigoruosly stirred and heated to reflux for 72 h under nitrogen atomosphere. The reaction mixture was cooled at room temperature, diluted with water, extracted in chloroform (3x750 ml), washed with water, dried over Na2S04 and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using petroleum ether and ethyl acetate to give 105.3 g of the product as yellow oil; Ή NMR (300 MHz, CDC13) δ 1.20-1.34 (m, 3H), 1.50 (s, 9H), 3.60 (s, 2H), 4.23 (q, J= 7.2 Hz, 2H), 7.27 (br s, 1H), 9.36 (br s, 1H).
Step 3: tert-Butyl 5-amino-3-(2-ethoxy-2-oxoethyl)-l,2-oxazole-4-carboxylate: A mixture of step 2 intermediate (105 g, 413 mmol), hydroxylamine hydrochloride (57.44 g, 826.77 mmol) and sodium acetate (122.07 g, 1488.16 mmol) in dry ethanol (830 ml) was stirred and refluxed for overnight. The excess of ethanol was distilled off under reduced pressure, diluted with water (250 ml) and extracted with ethyl acetate (3x500 ml) and dried (Na2S04). The crude product was purified by column chromatography using 20% ethyl acetate in petroleum ether to obtain 40 g of the desired product as off white solid; Ή NMR (300 MHz, DMSO-rf6) δ 1.26 (t, J= 6.9 Hz, 3H), 1.51 (s, 9H), 3.74 (s, 2H), 4.19 (q, J= 6.9 Hz, 2H), 5.92 (br s, 2H). Step 4: 5-Amino-3-(2-ethoxy-2-oxoethyl)-l,2-oxazole-4-carboxylic acid: To a stirred solution of step 3 intermediate (45.8 g, 169.6 mmol) in dichloromethane was added trifluoro acetic acid (274 ml) at 0 °C and subsequently stirred at room temperature for 2 h. The reaction solvent was removed under reduced pressure, diluted with water, it was adjusted to PH 6.4 with saturated sodium hydrogen carbonate aqueous solution. The solid obtained was collected by Alteration to give 26.7 g of the product as off white solid; Ή NMR (300 MHz, DMSO-<&) δ 1.16 (t, J= 6.9 Hz, 3H), 3.65 (s, 2H), 4.07 (q, J= 7.5 Hz, 2H), 7.69 (s, 2H), 12.28 (br s, 1H).
Step 5: Ethyl [5-amino-4-(methylcarbamoyl)-l,2-oxazol-3-yl]acetate: To a stirred solution of step 4 intermediate (26.5 g, 123.8 mmol) in 1,2-dichloroethane (310 ml) was added EDCI.HC1 (28.48 g, 148.5 mmol) and HOBt (16.7 g, 123.7 mmol). The reaction mixture was then stirred at room temperature for 30 min. Methyl amine (33% in dry ethanol) (23.3 ml, 247.5 mmol) was added at 15-20 °C and stirred at room temperature for 24 h. The excess of solvent was distilled under reduced pressure and crude product obtained was purified by column chromatography to give 15.6 g of white solid; Ή NMR (300 MHz, DMSO-i/e) δ 1.16 (t, J = 7.5 Hz, 3H), 2.65 (d, J = 4.2 Hz, 3H), 3.77 (s, 2H), 4.06 (q, J= 6.9 Hz, 2H), 6.98 (br s, 1H), 7.46 (s, 2H).
Step 6: Ethyl (5-methyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3- yl)acetate: To a stirred solution of Step 5 intermediate (17.5 g, 77.09 mmol) in dry THF (256 ml) was added triphosgene (1 1.43 g, 38.51 mmol) and mixture was refluxed for overnight. The reaction mixture cooled to room temperature, filtered, solvent was concentrated and purified by column chromatography using 6% methanol in chloroform to give 7.61 g of the desired product as off white solid; Ή NMR (300 MHz, DMSO-i 6) δ 1.18 (t, J = 7.5 Hz, 3H), 3.13 (s, 3H), 3.91 (s, 2H), 4.11 (q, J = 6.9 Hz, 2H), 13.75 (br s, 1H).
Step 7: Ethyl(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-d]pyrimidin-3- yl)acetate: A solution of Step 6 intermediate (7.5 g, 29.64 mmol) in dry acetone (185 ml) was added anhydrous K2C03 (5.33 g, 38.53 mmol) and the mixture was stirred at room temperature for 15 min. Methyl iodide (9.24 ml, 147.9 mmol) was added slowly with stirring and further stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (100 ml x 3). The combined organic layer was dried (Na2S04) and evaporated under reduced pressure. The crude product obtained was purified by column chromatography to give 5.5 g of white solid; Ή NMR (300 MHz, DMSO-ί/δ) δ 1.29 (t, J = 6.9 Hz, 3H), 3.36 (s, 3H), 3.60 (s, 3H), 3.92 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H).
Step 8: (5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[5,4-i/]pyrimidin-3-yl)acetic acid: A mixture of Step 7 intermediate (5.5 g, 20.59 mmol) and 6 N H2S04 (50 ml) in 1,4- dioxane (50 ml) was stirred at reflux temperature for 2.5 h to give a homogeneous pale yellow solution. The solvent was evaporated completely under reduced pressure, diluted with water and extracted with dichloromethane (3 x 100 ml). The combined organic layers were washed with water, dried over Na2S04 and concentrated. The crude product was purified by Si02 column chromatography using 0.3% methanol in chloroform to obtain 2.54 g of product as off-white solid.'H NMR (300 MHz, DMSO-</6) δ 3.18 (s, 3H), 3.43 (s, 3H), 3.84 (s, 2H), 12.87 (br s, 1H).
General procedure for the preparation of 2-amino-4-aryl thiazoles:
Method 1
A solution of acetophenone derivative (1.0 eq) in glacial acetic acid (5 vol) was added liquid bromine (1.0 eq) at 0 °C and reaction mixture was stirred at room temperature for 2h. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with brine and dried over Na2S04. The crude product obtained upon concentration was dissolved in dry THF (10 vol) and thiourea (2.0 eq) was added and refluxed for overnight. The reaction mixture was diluted with ethyl acetate, washed with sodium thiosulfate solution and organic layer was treated with IN HC1 to result salt formation of the amine. The precipitated salt was collected by filtration. The salt was then treated with saturated solution of NaHC03 to re-generate the amine. The mixture was extracted with dichloromethane (2x 50 mL) and the combined organic extracts were washed with water and brine. The solvent was evaporated under reduced pressure to afford the 2-amino-4-aryl-thiazole derivative.
Method 2
A solution of acetophenone derivative (1.0 equiv.), thiourea (2.0 equiv.) and iodine (1.0 equiv.) in dry ethanol (5 vol.) was refluxed for 24 h. The reaction mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with sodium thiosulfate solution to remove iodine. The ethyl acetate solution was treated with IN HC1 and precipitated salt collected by filtration. The free amine was re-generated as described in Method 1 given above. All the 2-amino-4-aryl-thiazole derivatives were prepared by either Method 1 or Method 2 starting from appropriate aryl alkyl ketones. Structure information and characterization data for selected intermediates are given in Table 1.
Table 1: Structural details and Ή NMR data of selected 2-aminothiazole intermediates
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
General procedure for the preparation of 2-bromo-N-thiazolyl acetamide derivatives
Figure imgf000057_0001
Step 1 : A mixture of appropriate aryl alkyl ketone (1.0 equiv.), thiourea (2.0 eqiv.) and iodine (1.0 equiv.) in dry ethanol (5 volumes) was refluxed for 24 h. The reaction mixture was diluted with ethyl acetate and washed with saturated solution of sodium thiosulphate. The organic layer was treated with IN HCl and the precipitated salt was collected by filtration. The salt was then treated with saturated solution of NaHC03 and extracted with dichloromethane, washed with brine, dried over sodium sulfate and the solvent was evaporated to afford the 2-aminothiazole derivative.
Step 2: To a stirred and cooled (0°C) solution of appropriate amine (1.0 equiv.) and pyridine (1.2 equiv.) in dichloromethane (5 vol.) was added bromoacetyl bromide (1.2 eq.) over 5 min and the resulting mixture was allowed to warm to room temperature. After stirring for 2 h, the reaction mixture was diluted with dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were washed with water, followed by brine, dried (Na2S04) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 5-10% ethyl acetate in petroleum ether to obtain the desired product as an off-white solid.
Structure information and characterization data for selected 2-bromo-N-thiazolyl acetamide intermediates are given in Table 2.
Table 2: Structural details and 1H NMR data of selected 2-bromo-N-thiazolyl acetamides
Figure imgf000057_0002
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
For further illustration of methods of preparing the compounds of the present invention, the following examples are disclosed below.
Example 1
N-[4-(4-Difluoromethoxy-3,5-difluorophenyl)-l,3-thiazol-2-yl]-2-(3-methyl-2,4-dioxo- 3,4-dihydro-2H-[l,3]thiazoIo[3,2- ]triazin-6-yl)acetamide
Figure imgf000061_0002
To a magnetically stirred solution of Intermediate 1, (80 mg, 0.332 mmol) in a mixture of DMF (2.0 ml) and THF (2.0 ml), were added 4-[4-(difluoromethoxy)-3,5- difluorophenyl]-l,3-thiazol-2-amine (92 mg, 0.332 mmol), EDCI (127 mg, 0.664 mmol) and 4-dimethylaminopyridine (DMAP) (8.0 mg, 0.066 mmol) at 90 °C temperature and stirred for 18 h. The reaction mixture was concentrated and the residue diluted with ethyl acetate (100 ml). Combined organic layers were washed with water, saturated solution of sodium bicarbonate and brine to yield a residue which was purified by column chromatography to afford 36 mg of the product as white solid; IR (KBr) 3445, 2959, 1741, 1651, 1494, 1280, 1 106, 771 cm"1 ; Ή NMR (300 MHz, DMSO-i¾ δ 3.16 (s, 3H), 4.21 (s, 4H), 7.06 (s, 1H), 7.28 (t, J = 71.9 Hz, 1H), 7.79 (d, J= 9.9 Hz, 2H), 7.89 (s, 1H), 12.52 (s, 1H); APCI-MS (m/z) 501.93 (M+H)+.
Example 2
N-{4-[3,5-dichloro-4-(3,3,3-trifluoropropoxy)phenyl]-l,3-thiazol-2-yl}-2-(3-methyl-2,4- dioxo-3,4-dihydro-2H-[l ,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide
Figure imgf000062_0001
The title compound was prepared as described in Example 1 using Intermediate 1 (80 mg, 0.332 mmol), 4-[3,5-dichloro-4-(3,3,3-trifluoropropoxy)phenyl]-l,3-thiazol-2-amine (1 18 mg, 0.332 mmol), EDCI (127 mg, 0.664 mmol) and 4-dimethylaminopyridine (DMAP) (8.0 mg, 0.066 mmol) in mixture of anhydrous DMF (2.0 ml), THF (2.0 ml) to give 30 mg of product as an off-white solid; IR (Neat) 2926, 1642, 1542, 1215, 759 cm"1; Ή NMR (300 MHz, DMSO- 6) δ 2.80-3.00 (m, 2H), 3.13 (s, 3H), 4.20 (s, 4H), 7.06 (s, 1H), 7.86 (s, 1H), 8.03 (s, 2H), 12.48 (s, 1H); ESI-MS (m/z) 578.06 (M-H)\
Example 3
N-[4-(3,5-Dichloro-4-cyclobutylmethoxyphenyl)-l,3-thiazol-2-yl]-2-(3-methyl-2,4- dioxo-3,4-dihydro-2H-[l ,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide
Figure imgf000062_0002
The title compound was prepared as described in Example 1 using Intermediate 1 (80 mg, 0.332 mmol), 4-[3,5-dichloro-4-(cyclobutylmethoxy)phenyl]-l,3-thiazol-2 -amine (109 mg, 0.332 mmol), EDCI (127 mg, 0.664 mmol) and 4-dimethylaminopyridine (DMAP) (8.0 mg, 0.664 mmol) in mixture of anhydrous DMF (2.0 ml), THF (2.0 ml) to give 20 mg of product as an white solid; IR (KBr) 3420, 1742, 1562, 1370, 1266, 978 cm"1; Ή NMR (300 MHz, DMSO-c¾ δ 1.80-2.00 (m, 3H), 2.01-2.12 (m, 2H), 2.70-2.90 (m, 2H), 3.13 (s, 3H), 3.99-4.01 (m, 2H), 4.20 (s, 2H), 7.06 (s, 1H), 7.83 (s, 1H), 8.00 (s, 2H), 12.46 (s, 1H); APCI-MS (m/z) 551.90 (M+H)+.
Example 4
N-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(3-methyl-2,4-dioxo-3,4- dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide
Figure imgf000062_0003
The title compound was prepared as described in Example 1 using Intermediate 1 (80 mg, 0.332 mmol), 4-[4-chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (93 mg, 0.332 mmol), EDCI (127 mg, 0.664 mmol) and 4-dimethylaminopyridine (DMAP) (8.0 mg, 0.066 mmol) in mixture of anhydrous DMF (2.0 ml), THF (2.0 ml) to give 25 mg of product as an off-white solid; IR (KBr) 3445, 1741, 1651, 1552, 1378, 1 127 cm"1; Ή NMR (300 MHz, DMSO-</<5) δ 3.13 (s, 3H), 4.21 (s, 2H), 7.06 (s, 1H), 7.80-7.82 (m, 1H), 7.94 (s, 1H), 8.19-8.22 (m, 1H), 8.34 (s, 1H), 12.54 (s, 1H); APCI-MS (m/z) 499.99 (M- H)\
Example 5
N-[4-(4-Cyclohexylphenyl)-l,3-thiazol-2-yl]-2-(3-methyl-2,4-dioxo-3,4-dihydro-2H- [l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide
Figure imgf000063_0001
The title compound was prepared as described in Example 1 using Intermediate 1 (80 mg, 0.332 mmol), 4-(4-cyclohexylphenyl)-l,3-thiazol-2-amine (86 mg, 0.332 mmol), EDCI (127 mg, 0.664 mmol) and 4-dimethylaminopyridine (DMAP) (8.0 mg, 0.066 mmol) in mixture of anhydrous DMF (2.0 ml), THF (2.0 ml) to give 40 mg of product as an off- white solid; IR (KBr) 3414, 2923, 1736, 1682, 1660, 1554, 1427, 1369, 1 148, 765 cm 1 ; Ή NMR (300 MHz, DMSO-i¾ δ 1.20-1.50 (m, 6H), 1.60-1.90 (m, 5H), 3.12 (s, 3H), 4.18 (s, 2H), 7.02 (s, 1H), 7.25 (s, 2H), 7.50 (s, 1H), 7.76 (s, 2H), 12.38 (s, 1H); APCI- MS (m/z) 482.06 (M+H)+.
Example 6
N-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(3-methyl- 2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide
Figure imgf000063_0002
The title compound was prepared as described in Example 1 using Intermediate 1 (65 mg, 0.269 mmol), 4-[3-chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-amine (88 mg, 0.269 mmol), EDCI (103 mg, 0.538 mmol) and 4-dimethylaminopyridine (DMAP) (6.6 mg, 0.053 mmol) in mixture of anhydrous DMF (2.0 ml), THF (2.0 ml) to give 22 mg of product as a white solid; IR (Neat) 3370, 2945, 1667, 1450, 1 1 14, 1030, 758 cm'1 ; Ή NMR (300 MHz, DMSO-^) δ 3.13 (s, 3H), 4.20 (s, 2H), 4.85 (q, J = 8.7 Hz, 2H), 7.06 (s, 1H), 7.82-7.91 (m, 3H), 12.48 (s, 1H); APCI-MS (m/z) 547.97 (M-H)\
Example 7
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(3-methyl-2,4-dioxo-3,4- dihydro-2H-[l,3]thiazolo[3,2-o][l,3,5]triazin-6-yl)acetamide
Figure imgf000064_0001
The title compound was prepared as described in Example 1 using Intermediate 1 (65 mg, 0.269 mmol), 4-[3-fiuoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (71 mg, 0.269 mmol), EDCI (103 mg, 0.538 mmol) and 4-dimethylaminopyridine (DMAP) (6.6 mg, 0.053 mmol) in mixture of anhydrous DMF (2.0 ml), THF (2.0 ml) to give 15 mg of product as an off-white solid; IR (Neat) 3366, 2964, 2834, 1666, 1660, 1450, 1422, 1218, 11 14, 1027, 758 cm"1; Ή NMR (300 MHz, DMSO-i/e) δ 3.13 (s, 3H), 4.21 (s, 2H), 7.06 (s, 1H), 7.57 (s, 1H), 7.70 (s, 1H), 7.80-7.99 (m, 2H), 12.55 (s, 1H); APCI-MS (m/z) 484.04 (M-H)".
Example 8
N-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l, l-dioxido-3-oxo-2,3- dihydro[l,3]thiazolo[3,2-i>][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000064_0002
To a magnetically stirred solution of Intermediate 2 (150 mg, 0.541 mmol) in 1,2- dichloroethane (3 ml) was added EDCI hydrochloride (124 mg, 0.649 mmol), HOBt (22 mg, 0.162 mmol) and 4-dimethylaminopyridine (DMAP) (7 mg, 0.054 mmol) and the mixture was stirred at room temperature for 10-15 min. 4-(3,4-dichlorophenyl)-l,3- thiazol-2 -amine (132 mg, 0.541 mmol) was then added and mixture was stirred for 24 h. The solvent was distilled under reduced pressure and the mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, IN hydrochloric acid solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography to give 48 mg of the product as a white solid; Ή NMR (300 MHz, DMSO-i&) δ 3.15 (s, 3H), 4.21 (s, 2H), 7.06 (s, 1H), 7.71 (d, J= 8.7 Hz, 1H), 7.84 (s, 1H), 7.89 (d, J= 7.5 Hz, 1H), 8.15 (s, 1H), 12.49 (br s, 1H, exchangeable with D20); ESI-MS (m/z) 468.00 (M- 35)+.
Example 9
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(2-methyl-l,l-dioxido-3- oxo-2,3-dihydro[l,3]thiazolo[ -6][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000065_0001
The title compound was prepared as described in Example 8 using Intermediate 2 (150 mg, 0.541 mmol), 4-[3-fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (142 mg, 0.541 mmol) in the presence of EDCI hydrochloride (124 mg, 0.649 mmol), HOBt (22 mg, 0.162 mmol) and DMAP (7 mg, 0.054 mmol) in 1,2-dichloroethane (5 ml) to give 52 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-i¾ δ 3.13 (s, 3H), 4.21 (s, 2H), 7.06 (s, 1H), 7.85-8.00 (m, 4H), 12.55 (br s, 1H, exchangeable with D20); ESI-MS (m/z) 485.99 (M-35)+.
Example 10
N- {4-[4-(2,2-Dimethy lpropoxy)-3-fluoropheny 1]- 1 ,3-thiazol-2-yl } -2-(2-methyl- 1,1- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000065_0002
The title compound was prepared as described in Example 8 using Intermediate 2 (120 mg, 0.433 mmol), 4-[4-(2,2-dimethylpropoxy)-3-fluorophenyl]-l,3-thiazol-2-amine (121 mg, 0.433 mmol) in the presence of EDCI hydrochloride (100 mg, 0.519 mmol), HOBt (18 mg, 0.130 mmol) and DMAP (5 mg, 0.043 mmol) in 1,2-dichloroethane (5 ml) to give 25 mg of the product as an off white solid; Ή NMR (300 MHz, OMSO-d6) δ 1.01 (s, 9H), 3.13 (s, 3H), 3.74 (s, 2H), 4.19 (s, 2H), 7.05 (s, 1H), 7.21 (t, J= 8.7 Hz, 1H), 7.56 (s, 1H), 7.62-7.74 (m, 2H), 12.41 (br s, 1H, exchangeable with D20); APCI-MS ( /z) 504.06 (M-35)+.
Example 11 N- {4-[4-(2,2-Dimethylpropoxy)-3-chlorophenyl]- 1 ,3-thiazol-2-yl}-2-(2-methyl- 1,1- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000066_0001
The title compound was prepared as described in Example 8 using Intermediate 2 (120 mg, 0.433 mmol), 4-[4-(2,2-dimethylpropoxy)-3-chlorophenyl]-l,3-thiazol-2-amine (129 mg, 0.433 mmol) in the presence of EDCI hydrochloride (100 mg, 0.519 mmol), HOBt (18 mg, 0.130 mmol) and DMAP (5 mg, 0.043 mmol) in 1,2-dichloroethane (5 ml) to give 34 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-cfc) δ 1.04 (s, 9H), 3.13 (s, 3H), 3.75 (s, 2H), 4.20 (s, 2H), 7.06 (s, 1H), 7.19 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 12.42 (br s, 1H, exchangeable with D20); APCI-MS (m/z) 520.04 (M-35)+.
Example 12
N-[4-(2,3,4-Trichlorophenyl)-l,3-thiazol-2-yl]-2-(2-methyl-l,l-dioxido-3-oxo-2,3- dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)-acetamide
Figure imgf000066_0002
The title compound was prepared as described in Example 8 using Intermediate 2 (120 mg, 0.433 mmol), 4-(2,3,4-trichlorophenyl)-l,3-thiazol-2-amine (121 mg, 0.433 mmol) in the presence of EDCI hydrochloride (100 mg, 0.519 mmol), HOBt (18 mg, 0.130 mmol) and DMAP (5 mg, 0.043 mmol) in 1,2-dichloroethane (5 ml) to give 90 mg of the product as an off white solid; 1H NMR (300 MHz, DMSO-tf6) δ 3.14 (s, 3H), 4.20 (s, 2H), 7.06 (s, 1H), 7.68 (s, 1H), 7.75-7.81 (m, 1H), 8.34 (s, 1H), 12.51 (br s, 1H, exchangeable with D20); ESI-MS (m/z) 501.91 (M-35)+.
Example 13
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(2-methyl-l,l- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2- >][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000066_0003
The title compound was prepared as described in Example 8 using Intermediate 2 (150 mg, 0.541 mmol), 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (152 mg, 0.541 mmol) in the presence of EDCI hydrochloride (124 mg, 0.649 mmol), HOBt (22 mg, 0.162 mmol) and DMAP (6 mg, 0.054 mmol) in 1,2-dichloroethane (5 ml) to give 56 mg of the product as a white solid; Ή NMR (300 MHz, OMSO-d6) δ 3.15 (s, 3H), 4.14 (s, 2H), 7.06 (s, 1H), 7.52 (t, J = 9.6 Hz, 1H), 7.64 (s, 1H), 8.30-8.38 (m, 1H), 12.54 (br s, 1H, exchangeable with D20); APCI-MS (m/z) 503.98 (M-35)+.
Example 14
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(2-methyl-l, l- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-Z>][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000067_0001
The title compound was prepared as described in Example 8 using Intermediate 2 (70 mg, 0.252 mmol), 4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-amine (79 mg, 0.252 mmol) in the presence of EDCI hydrochloride (97 mg, 0.505 mmol) and DMAP (6.2 mg, 0.050 mmol) in the mixture of THF: DMF (1 : 1, 4 ml) to give 15 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-ak) δ 3.13 (s, 3H), 4.20 (s, 2H), 4.86 (q, J = 8.7 Hz, 2H), 7.06 (s, 1H), 7.52 (d, J = 9.3 Hz, 2H), 7.81 (s, 1H), 12.49 (br s, 1H, exchangeable with £>20); APCI-MS (m/z) 533.94 (M-35)+.
Example 15
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(2-methyl-l, l- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000067_0002
The title compound was prepared as described in Example 8 using Intermediate 2 (150 mg, 0.541 mmol), 4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-amine (161 mg, 0.541 mmol) in the presence of EDCI hydrochloride (124 mg, 0.649 mmol), HOBt (22 mg, 0.162 mmol) and DMAP (7 mg, 0.053 mmol) in 1,2-dichloroethane (5 ml) to give 84 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-i/«$) δ 1.01 (s, 9H), 3.13 (s, 3H), 3.80 (s, 2H), 4.20 (s, 2H), 7.06 (s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.75 (s, 1H), 12.46 (br s, 1H, exchangeable with D20); APCI-MS (m/z) 521.97 (M- 35)+.
Example 16
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}-2-(2-methyl-l,l- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000068_0001
The title compound was prepared as described in Example 8 using Intermediate 2 (120 mg, 0.433 mmol), 4-[4-(2,2-dimethylpropoxy)-3,5-dichlorophenyl]-l,3-thiazol-2 -amine (143 mg, 0.433 mmol) in the presence of EDCI hydrochloride (100 mg, 0.519 mmol), HOBt (18 mg, 0.130 mmol) and DMAP (5 mg, 0.043 mmol) in 1 ,2-dichloroethane (5 ml) to give 76 mg of the product as a white solid; Ή NMR (300 MHz, DMSO-i¾ δ 1.07 (s, 9H), 3.13 (s, 3H), 3.67 (s, 2H), 4.20 (s, 2H), 7.05 (s, 1H), 7.83 (s, 1H), 8.00 (s, 2H), 12.46 (br s, 1H, exchangeable with D20); APCI-MS (m/z) 553.92 (M-35)+.
Example 17
N-{4-[3-Chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(2-methyl- l,l-dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetamide
Figure imgf000068_0002
The title compound was prepared as described in Example 8 using Intermediate 2 (120 mg, 0.433 mmol), 4-[3-chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]-l,3-thiazol-2- amine (136 mg, 0.433 mmol) in the presence of EDCI hydrochloride (100 mg, 0.519 mmol), HOBt (18 mg, 0.130 mmol) and DMAP (5 mg, 0.043 mmol) in 1,2- dichloroethane (5 ml) to give 51 mg of the product as a white solid; Ή NMR (300 MHz, DMSO-i e) δ 1.04 (s, 9H), 3.13 (s, 3H), 3.78 (s, 2H), 4.20 (s, 2H), 7.05 (s, 1H), 7.74-7.80 (m, 2H), 7.85 (s, 1H), 12.45 (br s, 1H, exchangeable with D20); APCI-MS (m/z) 538.04 (M-35)+.
Example 18
N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}2-(l,3-Dimethyl-2,4-dioxo- l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)- acetamide
Figure imgf000069_0001
The title compound was prepared as described in Example 8 using Intermediate 3 (100 mg, 0.419 mmol), 4-[3-fluoro-4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-amine (121 mg, 0.461 mmol) in the presence of EDCI hydrochloride (136 mg, 0.710 mmol), HOBt (24 mg, 0.178 mmol) and DMAP (5 mg, 0.041 mmol) in 1,2-dichloroethane (4 ml) to give 13 mg of the product as an off white solid; 1H NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.73 (s, 3H), 3.80 (s, 2H), 7.33 (s, IH), 7.60-7.70 (m, 4H), 10.54 (br s, IH); APCI-MS (m/z) 483.16 (M+H)+.
Example 19
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydroimidazo[l,2-cr][l,3,5]triazin-6-yl)acetamide
Figure imgf000069_0002
The title compound was prepared as described in Example 8 using Intermediate 3 (70 mg, 0.293 mmol), 4-[3-fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (90 mg, 0.323 mmol) in the presence of EDCI hydrochloride (96 mg, 0.499 mmol), HOBt (17 mg, 0.124 mmol) and DMAP (3.6 mg, 0.029 mmol) in 1,2-dichloroethane (4 ml) to give 10 mg of the product as an off white solid; lH NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.72 (s, 3H), 3.79 (s, 2H), 7.71 (s, IH), 7.30-7.36 (m, 2H), 7.58 (d, J= 9.8 Hz, IH), 7.64-7.70 (m, IH), 10.45 (br s, IH); APCI-MS (m/z) 499.21 (M+H)+.
Example 20
N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydroimidazo[l,2-o][l ,3,5]triazin-6-yl)acetamide
Figure imgf000069_0003
The title compound was prepared as described in Example 8 using Intermediate 3 (70 mg, 0.293 mmol), 4-[3-chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (95 mg, 0.323 mmol) in the presence of EDCI hydrochloride (96 mg, 0.499 mmol), HOBt (17 mg, 0.124 mmol) and DMAP (3.6 mg, 0.029 mmol) in 1,2-dichloroethane (4 ml) to give 10 mg of the product as an off white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.72 (s, 3H), 3.79 (s, 2H), 7.17 (s, 1H), 7.32-7.38 (m, 2H), 7.68-7.75 (m, 1H), 7.94 (s, 1H), 10.41 (br s, 1H); APCI-MS (m/z) 513.21 (M-H)\
Example 21
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo- 1 ,2,3,4-tetrahydroimida - ][l ,3,5]triazin-6-yl)acetamide
Figure imgf000070_0001
The title compound was prepared as described in Example 8 using Intermediate 3 (100 mg, 0.419 mmol), 4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (129 mg, 0.461 mmol) in the presence of EDCI hydrochloride (136 mg, 0.710 mmol), HOBt (24 mg, 0.178 mmol) and DMAP (5 mg, 0.041 mmol) in 1,2-dichloroethane (4 ml) to give 7 mg of the product as an off white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.72 (s, 3H), 3.79 (s, 2H), 7.02-7.12 (m, 1H), 7.33 (s, 1H), 7.42 (s, 1H), 8.20-8.26 (m, 1H), 10.43 (br s, 1H); APCI-MS (m/z) 500.99 (M+H)+.
Example 22
N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydroimidazo[l,2-o][l,3,5]triazin-6-yl)acetamide
Figure imgf000070_0002
The title compound was prepared as described in Example 8 using Intermediate 3 (70 mg, 0.293 mmol), 4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (90 mg, 0.323 mmol) in the presence of EDCI hydrochloride (96 mg, 0.499 mmol), HOBt (17 mg, 0.124 mmol) and DMAP (3.6 mg, 0.029 mmol) in 1,2-dichloroethane (4 ml) to give 9 mg of the product as an off white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.73 (s, 3H), 3.80 (s, 2H), 7.29-7.34 (m, 2H), 7.42-7.53 (m, 2H), 10.54 (br s, 1H); APCI-MS (jn/z) 499.30 (M-H)~.
Example 23
iV-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l ,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide
Figure imgf000071_0001
The title compound was prepared as described in Example 8 using Intermediate 3 (75 mg, 0.314 mmol), 4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-amine (103 mg, 0.346 mmol) in the presence of EDCI hydrochloride (102 mg, 0.533 mmol), HOBt (18 mg, 0.133 mmol) and DMAP (4 mg, 0.031 mmol) in 1,2-dichloroethane (4 ml) to give 12 mg of the product as an off white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.72 (s, 3H), 3.78 (s, 2H), 7.06 (s, lH), 7.30-7.38 (m, 3H), 10.37 (br s, 1H); APCI- MS (m/z) 519.08 (M+H)+.
Example 24
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l ,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide
The ing Intermediate 3 (75 mg,
Figure imgf000071_0002
0.314 mmol), 4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-amine (107 mg, 0.346 mmol) in the presence of EDCI hydrochloride (102 mg, 0.533 mmol), HOBt (18 mg, 0.133 mmol) and DMAP (4 mg, 0.031 mmol) in 1,2-dichloroethane (4 ml) to give 7.5 mg of the product as an off white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.72 (s, 3H), 3.79 (s, 2H), 4.47 (q, J = 7.8 Hz, 2H), 7.1 1 (s, 1H), 7.32 (s, 1H), 7.39 (d, J= 8.7 Hz, 2H), 10.42 (br s, 1H); APCI-MS (m/z) 531.06 (M+H)+.
Example 25
N-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l ,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydroimidazo[l,2-o][l,3,5]triazin-6-yl)acetamide
Figure imgf000072_0001
The title compound was prepared as described in Example 8 using Intermediate 3 (1 10 mg, 0.4617 mmol), 4-[3-chloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (141 mg, 0.507 mmol) in the presence of EDCI hydrochloride (150 mg, 0.785 mmol), HOBt (26 mg, 0.196 mmol) and DMAP (6 mg, 0.0461 mmol) in 1,2-dichloroethane (4 ml) to give 15 mg of the product as a pale yellow solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.73 (s, 3H), 3.80 (s, 2H), 7.28 (s, 1H), 7.33 (s, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.97 (s, 1H), 10.45 (br s, 1H); APCI-MS (m/z) 499.09 (M+H)+.
Example 26
c
N-{4-[4-(Trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydroimidazo[l,2-a][l,3,5]triazin-6-yl)acetamide
Figure imgf000072_0002
The title compound was prepared as described in Example 8 using Intermediate 3 (1 10 mg, 0.462 mmol), 4-[4-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (124 mg, 0.508 mmol) in the presence of EDCI hydrochloride (150 mg, 0. 785 mmol), HOBt (26 mg, 0. 196 mmol) and DMAP (6 mg, 0.0461 mmol) in 1,2-dichloroethane (4 ml) to give 16 mg of the product as a pale yellow solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.72 (s, 3H), 3.79 (s, 2H), 7.27 (s, 1H), 7.33 (s, 1H), 7.65 (d, J= 7.8 Hz, 2H), 7.92 (d, J= 7.8 Hz, 2H), 10.80 (br s, 1H); APCI-MS (m/z) 465.13 (M+H)+.
General procedure for the preparation of Examples (27-66):
To a stirred mixture of l ,3,9-trimethyl-7,9-dihydro-lH-purine-2,6,8(3H)-trione (1.0 eq.) and cesium carbonate (2.0 eq.) in dry N,N-dimethylformamide (1.0 ml/g) was added 2- bromo-N-(phenyl-l,3-thiazol-2-yl)-acetamide (1.2 eq.) at room temperature, the reaction mixture was stirred for 30 min. The reaction mixture was heated overnight at 100°C. After this time, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and water. Two layers were formed. Aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried (Na2S04) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using methanol in chloroform to obtain the product as a white solid. Following examples were prepared according to this general procedure by coupling Intermediates with appropriate 2-bromo-N-thiazolyl acetamide intermediate.
Example 27
N-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(l,3,9-trimethyl-2,6,8-trioxo-l,2,3,6,8,9- hexahydro-7H-purin-7-yl)acetamide
Figure imgf000073_0001
To a stirred solution of Intermediate 4 (100 mg, 0.475 mmol) in dry N,N- dimethylformamide (5.0 mL) was added cesium carbonate (310 mg, 0.951 mmol) at room temperature and the reaction mixture was stirred for 30 min. 2-Bromo-N-{4-(3,4- dichlorophenyl)-l,3-thiazol-2-yl}acetamide (200 mg, 0.523 mmol) was added to the above reaction mixture at the same temperature. After overnight stirring at 100°C, excess of solvent was distilled under reduced pressure and the residue was diluted with ethyl acetate (50 ml) and water (50 ml). Aqueous layer was extracted with ethyl acetate (2 x 15 ml) and the combined organic layers were washed with water (2 x 10 ml), dried (Na2S04) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after the distillation of the solvent was purified by silica gel column chromatography using methanol in chloroform to obtain 60 mg of the product as a white solid; Ή NMR
(300 MHz, DMSC s) δ 3.16 (s, 3H), 3.60 (s, 3H), 3.68 (s, 3H), 4.86 (s, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.87 (s, 2H), 8.14 (s, 1H), 12.68 (br s, 1H); ESI-MS (m/z) 495.19 (M)+.
Example 28
N-{4-[3-Chloro-4-isobutoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8-trioxo- l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000074_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.238 mmol) with 2-bromo-N-{4-[3-chloro-4- isobutoxyphenyl]-l,3-thiazol-2-yl}acetamide (1 15 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (15 mL) to give 25 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-c ) δ 1.01 (d, J = 6.9 Hz, 6H), 2.02-2.08 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.87 (d, J= 6.3 Hz, 2H), 4.85 (s, 2H), 7.20 (d, J = 9 Hz, 1H), 7.62 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H), 12.60 (s, 1H); ESI-MS (m/z) 533 (M)+.
Example 29
N-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000074_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (70 mg, 0.333 mmol) with 2-bromo-N-{4-[4-(2,2- dimethylpropoxy)-3-fluorophenyl]-l,3-thiazol-2-yl}acetamide (160 mg, 0.399 mmol) in the presence of cesium carbonate (217 mg, 0.666 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 30 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-</6) δ 1.02 (s, 9H), 3.17 (s, 3H), 3.68 (s, 3H), 3.74 (s, 3H), 3.77 (s, 2H), 4.86 (s, 2H), 7.22 (t, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.67-7.75 (m, 2H), 12.59 (br s, 1H); APCI-MS (m/z) 531.39 (M+H)+.
Example 30
N-{4-[3-Chloro-4-neopentyloxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8-trioxo- l,2,3,6,8,9-hexahydro-7 -purin-7-yl)acetamide
Figure imgf000074_0003
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.238 mmol) with 2-bromo-N-{4-[3-chloro-4- neopentyloxyphenyl]-l,3-thiazol-2-yl}acetamide (1 15 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (15 mL) to give 1 1 mg of product as a off-white solid; Ή NMR (300 MHz, OMSO-d6) δ 1.03 (s, 9H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.85 (s, 2H), 7.19 (d, J = 9 Hz, 1H), 7.62 (s, 1H), 7.81 (d, J= 7.2 Hz, 1H), 7.95 (s, 1H), 12.60 (s, 1H); ESI -MS (m/z) 547 (M)+.
Example 31
N-{4-[3-Chloro-4-(cyclobutylmethoxy)-phenyl]-l,3-thiazol-2-yl}-2-(l ,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000075_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3-chloro-4- (cyclobutylmethoxy)-phenyl]-l,3-thiazol-2-yl}acetamide (1 18 mg, 0.283 mmol) in the presence of cesium carbonate (154 mg, 0.475 mmol) in anhydrous N,N- dimethylformamide (10 mL) to give 40 mg of product as a off-white solid; Ή NMR (300
MHz, DMSO- δ 1.90-1.96 (m, 4H), 2.08 (d, J = 6.3 Hz, 2H), 2.72-2.77 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.07 (d, J = 6.3 Hz, 2H), 4.85 (s, 2H), 7.21 (d, J = 8.7 Hz, 1H),7.62 (s, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H) 12.60 (s, 1H); ESI-MS (m/z)
545 (M)+.
Example 32
N-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro- -purin-7-yl)acetamide
Figure imgf000075_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (70 mg, 0.333 mmol) with 2-bromo-N-{4-[3-chloro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (159 mg, 0.399 mmol) in the presence of cesium carbonate (217 mg, 0.666 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 35 mg of product as an off-white solid; H NMR
(300 MHz, DMSO-i tf) δ 3.17 (s, 3H), 3.60 (s, 3H), 3.69 (s, 3H), 4.87 (s, 2H), 7.23 (d, J = 8.4 Hz, 1H), 8.03-8.09 (m, 2H), 8.22 (s, 1H), 12.74 (br s, 1H); APCI-MS (m/z) 529.16 (M+H)+.
Example 33
N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7 -purin-7-yl)acetamide
Figure imgf000076_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (70 mg, 0.333 mmol) with 2-bromo-N-{4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (153 mg, 0.399 mmol) in the presence of cesium carbonate (217 mg, 0.666 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 40 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-cfe) δ 3.17 (s, 3H), 3.60 (s, 3H), 3.69 (s, 3H), 4.86 (s, 2H), 7.61 (t, J = 9.9 Hz, 1H), 7.88 (s, 1H), 8.26 (d, J = 6.9 Hz, 2H), 12.70 (br s, 1H); APCI-MS (m/z) 513.20 (M+H)+.
Example 34
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l ,2,3,6,8,9-hexahydro- -purin-7-yl)acetamide
Figure imgf000076_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (200 mg, 0.523 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 65 mg of product as a white solid; Ή NMR (300 MHz, DMSO- tf) δ 3.17 (s, 3H), 3.60 (s, 3H), 3.69 (s, 3H), 4.87 (s, 2H), 7.82-7.96 (m, 3H), 8.02 (s, 1H), 12.74 (br s, 1H); APCI-MS (m/z) 513.18 (M+H)+.
Example 35 ^-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo- 1 ,2,3,6,8,9-hexahydro- -purin-7-yl)acetamide
Figure imgf000077_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (70 mg, 0.333 mmol) with 2-bromo-N-{4-[3-chloro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}acetamide (152 mg, 0.366 mmol) in the presence of cesium carbonate (217 mg, 0.666 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 35 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-i/e) δ 3.17 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.87 (s, 2H), 7.65 (d, J = 8.7 Hz, 1H), 7.89 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H), 8.19 (s, 1H), 12.70 (br s, 1H); APCI- MS (m/z) 545.29 (M+H)+.
Example 36
N-{4-[3,5-Dichloro-4-ethoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000077_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3,5-dichloro-4- ethoxyphenyl]-l,3-thiazol-2-yl}acetamide (1 17 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (10 mL) to give 45 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-i/6) δ 1.39 (t, J = 6.9 Hz, 3H), 3.16 (s, 3H), 3.60 (s, 3H), 3.68 (s, 3H), 4.05-4.12 (m, 2H), 4.86 (s, 2H), 7.86 (s, 1H), 8.00 (s, 2H), 12.67 (s, 1H); APCI-MS (m/z) 539.20 (M)+.
Example 37
N-{4-[3,5-Dichloro-4-propoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8-trioxo- l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000078_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3,5-dichloro-4- propoxyphenyl]-l,3-thiazol-2-yl}acetamide (121 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (10 mL) to give 45 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-c ) δ 1.04 (t, J = 7.2 Hz, 3H), 1.76-1.83 (br s, 2H), 3.16 (s, 3H), 3.60 (s, 3H), 3.68 (s, 3H), 3.97 (t, J = 6.3 Hz, 2H), 4.86 (s, 2H), 7.86 (s, 1H), 8.00 (s, 2H), 12.66 (s, 1H); APCI-MS (m/z) 553.14 (M+H)+.
Example 38
N-{4-[3-Chloro-5-fluoro-4-propoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000078_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3-chloro-5-fluoro-4- propoxyphenyl]-l,3-thiazol-2-yl}acetamide (116 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (10 mL) to give 20 mg of product as a off-white solid; lU NMR (300 MHz, DMSO-</6) δ 1.01 (t, J = 7.2 Hz, 3H), 1.74 (q, J = 6.9 Hz, 2H), 3.17 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.08 (t, J = 6.3 Hz, 2H), 4.86 (s, 2H), 7.6-7.85 (m, 3H), 12.63 (s, 1H); APCI-MS (m/z) 537 (M+H)+.
Example 39
N-{4-[3,5-Dichloro-4-butoxy-phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8-trioxo- 1,2,3, 6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000079_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3,5-dichloro-4- butoxy-phenyl]-l,3-thiazol-2-yl}acetamide (125 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (10 mL) to give 30 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-ck) δ 0.95 (t, J = 7.2 Hz, 3H), 1.47-1.55 (m, 2H), 1.71 -1.78 (m, 2H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.01 (t, J = 6.0 Hz, 2H), 4.86 (s, 2H), 7.85 (s, 1H), 7.99 (s, 2H), 12.63 (s, 1H); ESI- MS (m z) 567 (M)+.
Example 40
N-{4-[3-Chloro-4-butoxy-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000079_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.287 mmol) with 2-bromo-N-{4-[3-chloro-4-butoxy-5- fluorophenyl]-l,3-thiazol-2-yl}acetamide (120 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (10 mL) to give 40 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-i/tf) δ 0.93 (t, J = 7.2 Hz, 3H), 1.44-1.54 (m, 2H), 1.66-1.75 (m, 2H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.10 (t, J = 6.3 Hz, 2H), 4.86 (s, 2H), 7.75-7.84 (m, 3H), 12.60 (s, lH); APCI-MS (m/z) 551 (M+H)+.
Example 41
N-{4-[3,5-Dichloro-4-isopropoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000080_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3,5-dichloro-4- isopropoxyphenyl]-l ,3-thiazol-2-yl}acetamide (121 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N-dimethylformamide (10 mL) to give 25 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-^) δ 1.32 (d, J = 6.0 Hz, 6H), 3.17 (s, 3H), 3.60 (s, 3H), 3.68 (s, 3H), 4.58-4.62 (m, 1H), 4.86 (s, 2H), 7.85 (s, 1H), 8.00 (s, 2H), 12.65 (s, 1H); APCI-MS (m/z) 553 (M+H)+.
Example 42
N-{4-[3-Chloro-4-isopropoxy-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(l ,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000080_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.2378 mmol) with 2-bromo-N-{4-[3-chloro-4- isopropoxy-5-fluorophenyl]-l,3-thiazol-2-yl}acetamide (1 16 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N- dimethylformamide (10 mL) to give 40 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-c ) δ 1.31 (d, J= 5.7 Hz, 6H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.44- 4.50 (m, 1H), 4.86 (s, 2H), 7.76-7.86 (m, 3H), 12.64 (s, 1H); APCI-MS (m/z) 535 (M-H)\
Example 43
N-{4-[3,5-Dichloro-4-(2-methylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000080_0003
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(2- methylpropoxy)phenyl]-l,3-thiazol-2-yl}acetamide (229 mg, 0.570 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 55 mg of product as a white solid; Ή NMR (300 MHz, DMSO-i e) δ 1.04 (d, J= 6.9 Hz, 6H), 1.98-2.13 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.79 (d, J= 6.3 Hz, 2H), 4.86 (s, 2H), 7.86 (s, 1H), 8.00 (s, 2H), 12.65 (br s, 1H); APCI-MS (m/z) 567.19 (M)+.
Example 44
N- {4-[3,5-Difluoro-4-(2-methylpropoxy)phenyl]- 1 ,3-thiazol-2-yl} -2-(l ,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000081_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(2- methylpropoxy)phenyl]-l,3-thiazol-2-yl}acetamide (231 mg, 0.570 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 60 mg of product as a white solid; Ή NMR (300 MHz, DMSO-i/6) δ 0.98 (d, J= 6.9 Hz, 6H), 1.93-2.03 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.91 (d, J= 6.3 Hz, 2H), 4.86 (s, 2H), 7.64 (d, J= 9.3 Hz, 2H), 7.77 (s, 1H), 12.64 (br s, 1H); APCI-MS (m/z) 535.23 (M+H)+.
Example 45
N-{4-[3-Chloro-5-fluoro-4-isobutoxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000081_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediated (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3-chloro-5-fluoro-4- isobutoxyphenyl]-l,3-thiazol-2-yl}acetamide (120 mg, 0.284 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous NN-dimethylformamide (10 mL) to give 60 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-</<j) δ 1.01 (d, J = 6.9 Hz, 6H), 1.99-2.07 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.89 (d, J = 6.3 Hz, 2H), 4.86 (s, 2H), 7.75-7.85 (m, 3H), 12.64 (s, 1H); ESI-MS (m/z) 551.18 (M+H)+.
Example 46
N-{4-[3,5-Dichloro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000082_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(2,2- dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}acetamide (258 mg, 0.570 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous NN- dimethylformamide (5.0 mL) to give 70 mg of product as a white solid; Ή NMR (300 MHz, DMSO-i/6) δ 1.07 (s, 9H), 3.16 (s, 3H), 3.59 (s, 3H), 3.62-3.70 (m, 5H), 4.86 (s, 2H), 7.86 (s, 1H), 8.00 (s, 2H), 12.65 (br s, 1H); APCI-MS (m/z) 581.15 (M+H)+.
Example 47
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l ,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000082_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[4-(2,2- dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}acetamide (230 mg, 0.570 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 70 mg of product as a white solid; Ή NMR (300 MHz, DMSO-Jtf) δ 1.01 (s, 9H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.80 (s, 2H), 4.86 (s, 2H), 7.65 (d, J = 9.6 Hz, 2H), 7.78 (s, 1H), 12.65 (br s, 1H); APCI-MS (m/z) 549.25 (M+H)+.
Example 48
N-{4-[3-Chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000083_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3-chloro-4-(2,2- dimethylpropoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}acetamide (241 mg, 0.570 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 75 mg of product as a white solid; Ή NMR (300 MHz, DMSO-i/e) δ 1.04 (s, 9H), 3.17 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.78 (s, 2H), 4.86 (s, 2H), 7.75-7.86 (m, 3H), 12.64 (br s, 1H); APCI-MS (m/z) 565.27 (M+H)+.
Example 49
N-{4-[3,5-Dichloro-4-(3-methylbutoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000083_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(3- methylbutoxy)phenyl]-l,3-thiazol-2-yl}acetamide (258 mg, 0.571 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) to give 85 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-cfo) δ 0.95 (d, J= 6.9 Hz, 6H), 1.65-1.72 (m, 2H), 1.88-1.93 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.04 (d, J= 6.9 Hz, 2H), 4.86 (s, 2H), 7.85 (s, 1H), 8.00 (s, 2H), 12.64 (br s, 1H); APCI-MS (m/z) 581.21 (M)+.
Example 50 N-{4-[3,5-difluoro-4-(3-methylbutoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000084_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(3- methylbutoxy)phenyl]-l,3-thiazol-2-yl}acetamide (230 mg, 0.548 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N-dimethylformamide (10.0 mL) to give 70 mg of product as an off-white solid; Ή NMR (300 MHz, OMSO-d6) δ 0.92 (d, J= 6.9 Hz, 6H), 1.55-1.63 (m, 2H), 1.75-1.84 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.15 (t, J = 6.6 Hz, 2H), 4.86 (s, 2H), 7.64 (d, J = 9.3 Hz, 2H), 7.77 (s, 1H), 12.64 (br s, 1H); APCI-MS (m/z) 549.25 (M+H)+.
Example 51
N-{4-[4-(Cyclopropylmethoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H- urin-7- l)acetamide
Figure imgf000084_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[4- (cyclopropylmethoxy)-3,5-dichloro-phenyI]-l ,3-thiazol-2-yl}acetamide (124 mg, 0.288 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N- dimethylformamide (10 mL) to give 10 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-i/e) δ 0.32 (d, J = 5.1 Hz, 2H), 0.57 (d, J = 7.8 Hz, 2H), 0.83 (br s, 1H), 3.17 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.88 (d, J = 6.9 Hz, 2H), 4.86 (s, 2H), 7.58 (s, 1H), 7.99 (s, 2H), 12.65 (s, 2H); APCI-MS (m/z) 565.15 (M+H)+.
Example 52
N-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l ,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000085_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (70 mg, 0.333 mmol) with 2-bromo-N-{4-[4- (cyclopropylmethoxy)-3,5-difluorophenyl]-l ,3-thiazol-2-yl}acetamide (147 mg, 0.366 mmol) in the presence of cesium carbonate (217 mg, 0.666 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 12 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-i¾ δ 0.23-0.29 (m, 2H), 0.50-0.56 (m, 2H), 1.18-1.24 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.96 (d, J = 7.5 Hz, 2H), 4.86 (s, 2H), 7.64 (d, J = 9.9 Hz, 2H), 7.78 (s, 1 H), 12.65 (br s, 1H); APCI-MS (m/z) 531.21 (M-H)\
Example 53
N- { 4-[3 -Chloro-4-(cyclopropy lmethoxy)-5 -fluorophenyl] - 1 ,3 -thiazol-2-y 1 } -2-( 1 ,3 ,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000085_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[3-chloro-4- (cyclopropylmethoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}acetamide (120 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N- dimethylformamide (10 mL) to give 71 mg of product as a off-white solid; Ή NMR (300 MHz, DMSO-c ) δ 0.28 (d, J = 4:8 Hz, 2H), 0.54 (d, J = 6.9 Hz, 2H), 1.22 (br s, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 3.95 (d, J = 7.2 Hz, 2H), 4.86 (s, 2H), 7.75-7.85 (m, 3H), 12.64 (s, 1H); APCI-MS (m/z) 549.17 (M+H)+.
Example 54
N-{4-[4-(Cyclobutylmethoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000086_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.237 mmol) with 2-bromo-N-{4-[4- (cyclobutylmethoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}acetamide (128 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N- dimethylformamide (10 mL) to give 8 mg of product as a white solid; 1H NMR (300 MHz, DMSO-<¾ δ 1.96 (br s, 4H), 2.07 (br s, 2H), 2.73-2.79 (m, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.00 (d, J = 6.6 Hz, 2H), 4.86 (s, 2H), 7.86 (s, 1H), 8.00 (s, 2H), 12.66 (s, 1H); APCI-MS (m/z) 579.15 (M)+.
Example 55
N-{4-[4-(Cyclobutylmethoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000086_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (70 mg, 0.333 mmol) with 2-bromo-N-{4-[4- (cyclobutylmethoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}acetamide (166 mg, 0.366 mmol) in the presence of cesium carbonate (217 mg, 0.666 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 39 mg of product as an off-white solid; 1H NMR (300 MHz, DMSO-i¾) δ 1.78-1.87 (m, 4H), 1.90-1.98 (m, 2H), 2.62-2.69 (m, 1H), 3.19 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.10 (d, J = 6.9 Hz, 2H), 4.86 (s, 2H), 7.60-7.67 (m, 2H), 7.78 (s, 1H), 12.65 (br s, 1H); APCI-MS (m/z) 547.22 (M+H)+.
Example 56
N- { 4- [3 -Chloro-4-(cyclobuty lmethoxy)-5 -fluorophenyl] - 1 ,3-thiazol-2-yl} -2-( 1 ,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000087_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (50 mg, 0.287 mmol) with 2-bromo-N-{4-[3-chloro-4-( cyclobutylmethoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}acetamide (128 mg, 0.285 mmol) in the presence of cesium carbonate (155 mg, 0.475 mmol) in anhydrous N,N- dimethylformamide (10 mL) to give 27 mg of product as an off-white solid; 1H NMR (300 MHz, DMSO-</6) δ 1.87 (s, 4H), 2.06 (d, J = 8.4 Hz, 2H), 2.72 (br s, 1H), 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.08 (d, J = 6.9 Hz, 2H), 4.86 (s, 2H), 7.75-7.85 (s, 3H), 12.64 (s, 1H); APCI-MS (m/z) 563 (M+H)+.
Example 57
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000087_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3,5-difluoro-4- (2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}acetamide (246 mg, 0.571 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 85 mg of product as an off-white solid; 1H NMR (300 MHz, DMSO-c ) δ 3.16 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.80-4.91 (m, 4H), 7.70 (d, J= 9.3 Hz, 2H), 7.93 (s, 1H), 12.67 (br s, 1H); APCI-MS (m/z) 561.06 (M+H)+.
Example 58
N-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000087_0003
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[3-chloro-5-fluoro-4- (2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}acetamide (255 mg, 0.571 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 75 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-<&) δ 3.17 (s, 3H), 3.59 (s, 3H), 3.68 (s, 3H), 4.78-4.87 (m, 4H), 7.80- 7.90 (m, 3H), 12.66 (br s, 1H); APCI-MS (m/z) 577.07 (M+H)+.
Example 59
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo- 1 ,2,3,6,8,9-hexahydro-7 -purin-7-yl)acetamide
Figure imgf000088_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 4 (100 mg, 0.475 mmol) with 2-bromo-N-{4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (209 mg, 0.523 mmol) in the presence of cesium carbonate (310 mg, 0.951 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 70 mg of product as a white solid; Ή NMR (300 MHz, DMSO-i/a) δ 3.17 (s, 3H), 3.60 (s, 3H), 3.69 (s, 3H), 4.88 (s, 2H), 7.50 (t, J = 9.6 Hz, 1H), 7.67 (s, 1H), 8.28-8.38 (m, 1H), 12.73 (br s, 1H); ESI-MS ( /z) 531.16 (M+H)+.
Example 60
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-ethyl-l,3-dimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000088_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 5 (100 mg, 0.446 mmol) with 2-bromo-N-{4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (205 mg, 0.535 mmol) in the presence of cesium carbonate (290 mg, 0.891 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 75 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-i/6) δ 1.27 (t, J= 6.9 Hz, 3H), 3.17 (s, 3H), 3.65 (s, 3H), 4.05-4.10 (m, 2H), 4.88 (s, 2H), 7.83-8.02 (m, 4H), 12.74 (br s, 1H); APCI-MS (m/z) 527.1 1 (M+H)+.
Example 61
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(9-ethyl-l,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000089_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 5 (100 mg, 0.446 mmol) with 2-bromo-N-{4-[4-(2,2- dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}acetamide (220 mg, 0.535 mmol) in the presence of cesium carbonate (290 mg, 0.891 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 90 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-i/,5) δ 1.01 (s, 9H), 1.27 (t, J= 6.9 Hz, 3H), 3.16 (s, 3H), 3.65 (s, 3H), 3.80 (s, 2H), 4.05-4.10 (m, 2H), 4.87 (s, 2H), 7.63-7.68 (m, 2H), 7.77 (s, 1H), 12.65 (br s, 1H); APCI-MS (m/z) 563.37 (M+H)+.
Example 62
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-ethyl-l,3-dimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000089_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 5 (100 mg, 0.400 mmol) with 2-bromo-N-{4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (200 mg, 0.500 mmol) in the presence of cesium carbonate (260 mg, 0.800 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 1 10 mg of product as a white solid; Ή NMR (300 MHz, OMSO-d6) δ 1.27 (t, J= 6.9 Hz, 3H), 3.17 (s, 3H), 3.65 (s, 3H), 4.00-4.10 (m, 2H), 4.88 (s, 2H), 7.47-7.56 (m, 1H), 7.67 (s, 1H), 8.30-8.36 (m, 1H), 12.72 (br s, 1H); APCI- MS (m/z) 545.26 (M+H)+.
Example 63 N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(9-isopropyl-l,3-dimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000090_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 6 (100 mg, 0.419 mmol) with 2-bromo-N-{4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (176 mg, 0.461 mmol) in the presence of cesium carbonate (273 mg, 0.839 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 60 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-<&) δ 1.53 (d, J= 6.3 Hz, 6H), 3.16 (s, 3H), 3.64 (s, 3H), 4.80-4.86 (m, 3H), 7.94-8.02 (m, 4H), 12.89 (br s, 1H); APCI-MS (m/z) 541.06 (M+H)+.
Example 64
N-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(9-isopropyl-l,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000090_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 6 (75 mg, 0.314 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(2,2- dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}acetamide (145 mg, 0.346 mmol) in the presence of cesium carbonate (205 mg, 0.629 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 60 mg of product as an off-white solid; Ή NMR (300 MHz, DMSO-i/6) δ 1.01 (s, 9H), 1.52 (d, J= 6.6 Hz, 6H), 3.16 (s, 3H), 3.63 (s, 3H), 3.80 (s, 2H), 4.70-4.83 (m, 3H), 7.65 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H), 12.64 (br s, 1H); APCI-MS (m/z) 577.27 (M+H)+.
Example 65
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-isobutyl-l ,3-dimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000091_0001
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 7 (100 mg, 0.396 mmol) with 2-bromo-N-{4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide (182 mg, 0.475 mmol) in the presence of cesium carbonate (250 mg, 0.792 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 70 mg of product as a white solid; Ή NMR (300 MHz, DMSO-i 6) δ 0.90 (d, J= 6.3 Hz, 6H), 1.95-2.02 (m, 1H), 3.16 (s, 3H), 3.61 (s, 3H), 3.87 (d, J = 7.2 Hz, 2H), 4.89 (s, 2H), 7.85 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 8.01 (s, 1H), 12.75 (br s, 1H); APCI-MS (m/z) 555.22 (M+H)+
Example 66
N-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(9-isobutyl-l,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide
Figure imgf000091_0002
The title compound was prepared according to the procedure described in Example 27 by coupling Intermediate 7 (100 mg, 0.396 mmol) with 2-bromo-N-{4-[3,5-difluoro-4-(2,2- dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}acetamide (199 mg, 0.474 mmol) in the presence of cesium carbonate (258 mg, 0.791 mmol) in anhydrous N,N- dimethylformamide (5.0 mL) to give 85 mg of product as an off-white solid; 1H NMR (300 MHz, DMSO-i¼) δ 0.90 (d, J= 6.3 Hz, 6H), 1.01 (s, 9H), 1.95-2.02 (m, 1H), 3.16 (s, 3H), 3.61 (s, 3H), 3.80 (s, 2H), 3.87 (d, J= 7.5 Hz, 2H), 4.88 (s, 2H), 7.65 (d, J= 9.0 Hz, 2H), 7.77 (s, 1H), 12.66 (br s, 1H); APCI-MS (m/z) 591.32 (M+H)+.
General procedure for the preparation of Examples (67-77)
To a stirred solution of Intermediate 8 (1.0 equiv.) or Intermediate 9 (1.0 equiv.) in 1,2- dichloroethane (5 vol.) was added EDCI (1.2 equiv.), HOBt (0.3 equiv.) and 4- dimethylaminopyridine (0.1 equiv.) and the mixture was stirred at room temperature for 10-15 min. An appropriate amine (1.0 equiv.) was then added and mixture was stirred at the same temperature for 24 h. Then EDCI HCl (0.5 equiv.) and HOBt (0.125 equiv.) was added to the reaction mixture and further stirred for 24 h. Excess of solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography using 30 % ethyl acetate in petroleum ether to afford the desired compound.
Example 67
N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3-dimethyl- 2,4-dioxo- 1 ,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide
Figure imgf000092_0001
The title compound was prepared according to the general procedure by coupling Intermediate 8 (90 mg, 0.330 mmol) in EDC (5 mL) with 4-[3-chloro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2 -amine (97 mg, 0.330 mmol), EDCI.HC1 (76 mg, 0.396 mmol), 4-dimethylaminopyridine (4.0 mg, 0.033), HOBt (14 mg, 0.099 mmol) to give 68 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-cfe) δ 3.16 (s, 3H), 3.42 (s, 3H), 3.85 (s, 2H), 7.66 (d, J= 8.4 Hz, 1H), 7.87 (s, 1H), 8.00 (d, J= 8.7 Hz, 1H), 8.19 (s, 1H), 12.61 (s, 1H); ESI-MS (m/z) 549 (M)+.
Example 68
N-{4-[2,4-Difluoro-3-(trifluromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydrofu -d]pyrimidin-5-yl)acetamide
Figure imgf000092_0002
The title compound was prepared according to the general procedure by coupling Intermediate 8 (50 mg, 0.183 mmol) in EDC (5 mL) with 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (51 mg, 0.183 mmol), EDCI.HC1 (42 mg, 0.219 mmol), 4-dimethylaminopyridine (2.5 mg, 0.020), HOBt (7 mg, 0.051 mmol) to, give 12 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-cfe) δ 3.17 (s, 3H), 3.42 (s, 3H), 3.86 (s, 2H), 7.52 (t, J = 9.3 Hz, 1H), 7.65 (s, 1H), 8.34 (q, J = 8.7 1H), 12.63 (s, 1H); APCI-MS (m/z) 533 (M-H)\
Example 69
N-{4-[4-(Diethylamino)phenyl]-l,3-thiazol-2-yl}2-(6-chloro-l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yI)acet^mide
Figure imgf000093_0001
The title compound was prepared according to the general procedure by coupling Intermediate 8 (50 mg, 0.183 mmol) in EDC (5 mL) with 4-[4-(diethylamino)phenyl]-l,3- thiazol-2-amine (45 mg, 0.183 mmol), EDCI.HCl (42 mg, 0.219 mmol), 4- dimethylaminopyridine (2.5, mg, 0.020), HOBt (7 mg, 0.051 mmol) to give 30 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-i 6) δ 1.01 (t, J = 6.9 Hz, 6H), 3.17 (s, 3H), 3.30-3.39 (m, 4H), 3.42 (s, 3H), 3.82 (s, 2H), 6.64 (d, J = 8.7 Hz, 2H), 7.23 (s, 1H), 7.68 (d, J= 9.0 Hz, 2H), 12.43 (s, 1H); APCI (m/z) 502 (M+H)+.
Example 70
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(6-chloro-l ,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide
Figure imgf000093_0002
The title compound was prepared according to the general procedure by coupling Intermediate 8 (50 mg, 0.183 mmol) in EDC (5 mL) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (48 mg, 0.183 mmol), EDCI.HCl (42 mg, 0.219 mmol), 4-dimethylaminopyridine (2.5 mg, 0.020), HOBt (7.6 mg, 0.056 mmol) to give 14 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-</6) δ 3.16 (s, 3H), 3.42 (s, 3H), 3.85 (s, 2H), 7.83-7.90 (m, 1H), 7.93-8.00 (m, 3H), 12.63 (s, 1H); APCI-MS (m/z) 517 (M+H)+. Example 71
N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide
Figure imgf000094_0001
The title compound was prepared according to the general procedure by coupling Intermediate 8 (50 mg, 0.183 mmol) in EDC (5 . mL) with 4-[3-fluoro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (48 mg, 0.183 mmol), EDCI.HC1 (42 mg, 0.219 mmol), 4-dimethylaminopyridine (2.5 mg, 0.020), HOBt (7.4 mg, 0.054 mmol) to give 13 mg of the product as an off white solid;Ή NMR (300 MHz, DMSO-efe) δ 3.16 (s, 3H), 3.42 (s, 3H), 3.85 (s, 2H), 7.66 (d, J = 7.8 Hz, 1H), 8.01-8.13 (m, 3H), 12.64 ( s, 1H); ESI-MS (m/z) 517.1 1 (M+H)+.
Example 72
N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3-dimethyl- 2,4-dioxo-l ,2,3,4-tetrahydrofu -d]pyrimidin-5-yl)acetamide
Figure imgf000094_0002
The title compound was prepared according to the general procedure by coupling Intermediate 8 (50 mg, 0.183 mmol) in EDC (5 mL) with 4-[2-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (48 mg, 0.183 mmol), EDCI.HC1 (42 mg, 0.219 mmol), 4-dimethylaminopyridine (2.2 mg, 0.018), HOBt (7.4 mg, 0.054 mmol) to give 10 mg of the product as an off white solid 1H NMR (300 MHz, DMSO-cfe) δ 3.17 (s, 3H), 3.42 (s, 3H), 3.86 (s, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.78 (t, J = 6.9 Hz, 1H), 8.33 (t, J= 7.2 Hz, 1H), 12.64 ( s, 1H); ESI (m/z) 515 (M-H)\
Example 73
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide
Figure imgf000095_0001
The title compound was prepared according to the general procedure by coupling Intermediate 8 (50 mg, 0.183 mmol) in EDC (5 mL) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2 -amine (51 mg, 0.183 mmol), EDCI.HCl (42 mg, 0.219 mmol), 4-dimethylaminopyridine (2.5 mg, 0.020), HOBt (7 mg, 0.051 mmol) to give 14 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-cfe) δ 3.16 (s, 3H), 3.42 (s, 3H), 3.85 (s, 2H), 7.65 (t, J = 8.1 Hz, 1H), 7.82-7.89 (m, 2H), 7.98 (d, J =1 1.7 Hz, 1H), 12.60 (s, 1H); APCI-MS (m/z) 533 (M+H)+.
Example 74
N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydrof -d]pyrimidin-5-yl)acetamide
Figure imgf000095_0002
The title compound was prepared according to the general procedure by coupling Intermediate 8 (50 mg, 0.183 mmol) in EDC (5 mL) with 4-[4-fluoro-3- (trifluoromethoxy)phenyl]-l,3-thiazol-2 -amine (51 mg, 0.183 mmol), EDCI.HCl (42 mg, 0.219 mmol), 4-dimethylaminopyridine (2.5 mg, 0.020), HOBt (7 mg, 0.051 mmol) to give 10 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-i/6) δ 3.17 (s, 3H), 3.42 (s, 3H), 3.85 (s, 2H), 7.59 (t, J = 9.3 Hz, 1H), 7.79 (s, 1H), 7.95-8.03 (m, 2H), 12.54 (s, 1H); APCI-MS (m/z) 533 (M)+.
Example 75
N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}2-(6-chloro-l,3- dimethyl-2,4-dioxo-l ,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide
Figure imgf000095_0003
The title compound was prepared according to the general procedure by coupling Intermediate 8 (40 mg, 0.126 mmol) in EDC (3 mL) with 4-[2,3-difluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (51 mg, 0.183 mmol), EDCI.HC1 (42 mg, 0.219 mmol), 4-dimethylaminopyridine (2.5 mg, 0.020), HOBt (7 mg, 0.051 mmol) to give 5 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-cfe) δ 3.17 (s, 3H), 3.42 (s, 3H), 3.86 (s, 2H), 7.74-7.83 (m, 2H), 8.02 (t, J = 1 1.4 Hz, 1H), 12.70 (s, 1H); APCI-MS (m/z) 533 (M-H)".
Example 76
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}2-(6-bromo-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide
Figure imgf000096_0001
The title compound was prepared according to the general procedure by coupling Intermediate 9 (50 mg, 0.126 mmol) in EDC (3 mL) with 4-[2,4-Difiuoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (35 mg, 0.126 mmol), EDCI.HC1 (28 mg, 0.157 mmol), 4-dimethylaminopyridine (1.5 mg, 0.012), HOBt (5.22 mg, 0.053 mmol) to give 15 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-c/6) δ 3.17 (s, 3H), 3.42 (s, 3H), 3.81 (s, 2H), 7.52 (t, J= 10.2 Hz, 1H), 7.98 (s, 1H), 8.34 (q, J= 8.1 Hz, 1H), 12.61 (s, 1H); APCI-MS (m/z) 580 (M+H)+.
Example 77
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}2-(6-bromo-l ,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide
Figure imgf000096_0002
The title compound was prepared according to the general procedure by coupling Intermediate 9 (40 mg, 0.126 mmol) in EDC (5 mL) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (35 mg, 0.126 mmol), EDCI.HC1 (28 mg, 0.151 mmol), 4-dimethylaminopyridine (1.5 mg, 0.012), HOBt (5.22 mg, 0.038 mmol) to give 8 mg of the product as an off white solid; Ή NMR (300 MHz, DMSO-i 6) δ 3.16 (s, 3H), 3.42 (s, 3H), 3.85 (s, 2H), 7.65 (t, J = 8.4 Hz, 1H), 7.82-7.89 (m, 2H), 7.98 (d, J = 1 1.7 Hz, 1H), 12.61 (s, 1H).
General procedure for the preparation of Examples (78-109):
Method A: To a stirred solution of isoxazole acetic acid (1.0 equiv.) in 1,2-dichloroethane was added EDCI (1.2 equiv.), HOBt (0.3 equiv.) and 4-dimethylaminopyridine (0.1 equiv.) and the mixture was stirred at room temperature for 10-15 min. An appropriate amine (1.0 equiv.) was then added and mixture was stirred under nitrogen atmosphere at the same temperature for 48 h or heated at reflux temperature for 24 h. The solvent was evaporated under reduced pressure and the residue obtained was diluted with methanol and stirred at room temperature for 30 min. The solid separated out was collected by filtration. The solid product was further purified by recrystalisation from isopropanol or methanol to give the desired products.
Method B: To a stirred solution of isoxazole acetic acid (1.1 equiv.) in dry dichloromethane were added appropriate amine (1.1 equiv.), HOBt (0.37), N-methyl morpholine (1.16) and EDCI (1.16) 0-5° C and stirred at the same temperature for 30 min. The temperature of the reaction mixture was then gradually increased to room temperature and stirred for overnight. The reaction mass was directly loaded on silica gel column chromatography to give the desried product.
Example 78
N-[4-(4-Bromophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[3,4-i/|pyrimidin-3-yl)acetamide
Figure imgf000097_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(4-bromophenyl)-l,3-thiazol-2- amine (214 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 30 mg of the product as an off-white solid; Ή NMR (300 MHz, DMSO-i 6): δ 3.17 (s, 3H), 3.34 (s, 3H), 4.47 (s, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.75 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 12.80 (br s, 1H); ESI-MS (m/z) 476.01 (M+H)+. Example 79
N-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[ 1 ,2]oxazolo[3,4-i/]pyrimidin-3-yl)acetamide
Figure imgf000098_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(4-chlorophenyl)-l,3-thiazol-2- amine (176 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (40 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2 dichloroethane (8.3 ml) at room temperature to give 36 mg of the product as a white solid; 'H NM (300 MHz, CDC13): δ 3.45 (s, 3H), 3.51 (s, 3H), 4.28 (s, 2H), 7.14 (s, 1H), 7.36 (d, J = 8.7, 2H), 7.75 (d, J = 9.0 Hz, 2H), 10.65 (br s, 1H); APCI-MS (m/z) 432.10 (M+H)+.
Example 80
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)-N-{4-[4- (trifluoromethyl)phenyl]-l,3
Figure imgf000098_0002
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(4-trifluoromethylphenyl)-l,3- thiazol-2-amine (204 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 40 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.45 (s, 3H), 3.51 (s, 3H), 4.30 (s, 2H), 7.27 (s, 1H), 7.65 (d, J = 7.8 Hz, 2H), 7.94 (d, J = 7.5 Hz, 2H), 10.76 (br s, 1H). APCI-MS (m/z) 466.18 (M+H)+.
Example 81
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)-N-{4-[3- (trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide
Figure imgf000099_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(3-trifluoromethylphenyl)-l,3- thiazol-2-amine (204 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 20 mg of the product as an off-white solid; 'H NMR (300 MHz, CDC13): δ 3.46 (s, 3H), 3.52 (s, 3H), 4.32 (s, 2H), 7.25 (s, 1H), 7.50-7.58 (m, 2H), 7.97-8.06 (m, 1H), 8.08-8.13 (m, lH), 12.70 (br s, 1H); ESI-MS (m/z) 466.70 (M+H)+.
Example 82
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-< ]pyrimidin-3-yl)-N-{4-[3- (trifluoromethoxy)phenyl]-l,3
Figure imgf000099_0002
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(3-trifluoromethoxyphenyl)-l,3- thiazol-2-amine (217 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 23 mg of the product as an off-white solid; Ή ΝΜΡν (300 MHz, CDC13): δ 3.46 (s, 3H), 3.52 (s, 3H), 4.31 (s, 2H), 7.18-7.28 (m, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.70-7.76 (m, 2H), 10.75 (br s, 1H). APCI-MS (m/z): 482.14 (M+H)+.
Example 83
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)-N-[4-(4- isobutylphenyl)- 1 ,3-thiaz -2-yl]acetamide
Figure imgf000099_0003
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(4-isobutylphenyl)-l,3-thiazol-2- amine (194 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 22 mg of the product as an off-white solid; 'H NMR (300 MHz, CDC13): δ 0.90 (d, J= 6.3 Hz, 6H), 1.80-1.92 (m, 1H), 2.48 (d, J = 6.9 Hz, 2H), 3.40 (s, 3H), 3.49 (s, 3H), 3.96-4.12 (m, 2H), 7.1 1 (s, 1H), 7.18 (d, J = 7.8 Hz, 2H), 7.71 (d, J= 7.2 Hz, 2H), 1 1.29 (br s, 1H); ESI-MS (m/z): 454 (M+H)+.
Example 84
N-[4-(3,5-Dichlorophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[ 1 ,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide
Figure imgf000100_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(3,5-dichlorophenyl)-l,3-thiazol- 2-amine (204 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 30 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.46 (s, 3H), 3.51 (s, 3H), 4.32 (s, 2H), 7.20-7.29 (m, 2H), 7.09 (s, 2H), 10.68 (br s, 1H); ESI-MS (m/z) 464.01 (M-H) \
Example 85
N-[4-(2,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[ 1 ,2]oxazolo[3,4-i |pyrimidin-3-yl)acetamide
Figure imgf000100_0002
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(2,4-difluorophenyl)-l ,3-thiazol- 2-amine (178 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 35 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.45 (s, 3H), 3.51 (s, 3H), 4.31 (s, 2H), 6.87-7.00 (m, 2H), 7.37 (s, 1H), 7.78-8.16 (m, 1H), 10.66 (br s, 1H); APCI-MS (m/z) 434 (M+H)+.
Example 86
N-[4-(2,3-Difluorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)acetamide
Figure imgf000101_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(2,3-difluorophenyl)-l,3-thiazol- 2-amine (177 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 30 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.45 (s, 3H), 3.51 (s, 3H), 4.31 (s, 2H), 7.10-7.16 (m, 2H), 7.47 (s, 1H), 7.78-7.84 (m, 1H), 10.63 (br s, 1H); APCI-MS (m/z): 434 (M+H)+.
Example 87
N-[4-(3-Chloro-2-fluorophenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide
Figure imgf000101_0002
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(3-chloro-2 -fluorophenyl)- 1,3- thiazol-2 -amine (200 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2- dichloroethane (8.3 ml) at room temperature to give 21 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.45 (s, 3H), 3.51 (s, 3H), 4.31 (s, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.28-7.37 (m, 1H), 7.47 (s, 1H), 7.94-8.05 (m, 1H), 10.64 (br s, 1H); ESI- MS (m/z) 450 (M+H)+. Example 88
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)-N-{4-[3- fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide
Figure imgf000102_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-[3-fiuoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (220 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2-dichloroethane (8.3 ml) at room temperature to give 35 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.47 (s, 3H), 3.52 (s, 3H), 4.33 (s, 2H), 7.29 (s, 1H), 7.61-7.71 (m, 3H), 10.69 (br s, 1H); APCI-MS (m/z): 484.01 (M+H)+.
Example 89
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)-N-{4-[4- fluoro-3-(trifluoromethoxy)phenyl]-l ,3-thiazol-2-yl}acetamide
Figure imgf000102_0002
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(4-fluoro-3- (trifluoromethoxy)phenyl)-l,3-thiazol-2 -amine (232 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2-dichloroethane (8.3 ml) at room temperature to give 1 1 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.45 (s, 3H), 3.52 (s, 3H), 4.33 (s, 2H), 7.13 (s, 1H), 7.19-7.30 (m, 1H), 7.69-7.83 (m, 2H), 10.88 (br s, 1H); APCI- MS (m/z) 500.02 (M+H)+.
Example 90
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-cQpyrimidin-3-yl)-N-{4-[3- fluoro-4-(trifluoromethoxy)phenyl]-l ,3-thiazol-2-yl}acetamide
Figure imgf000103_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2 -amine (232 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2-dichloroethane (8.3 ml) at room temperature to give 25 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.46 (s, 3H), 3.52 (s, 3H), 4.32 (s, 2H), 7.18 (s, 1H), 7.28-7.38 (m, 1H), 7.58-7.72 (m, 2H), 10.68 (br s, 1H); ESI- MS (m/z): 500.21 (M+H)+.
Example 91
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i/]pyrimidin-3-yl)-N-{4-[3- fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}acetamide
Figure imgf000103_0002
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-(3-fluoro-4-(2,2,2- trifluoroethoxy)phenyl)-l,3-thiazol-2 -amine (244 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1 ,2- dichloroethane (8.3 ml) at room temperature to give 44 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.45 (s, 3H), 3.51 (s, 3H), 4.28 (s, 2H), 4.40-4.48 (m, 2H), 7.02-7.10 (m, 2H), 7.52-7.63 (m, 2H), 10.69 (br s, 1 H); APCI-MS (m/z): 514.15 (M+H)+.
Example 92
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)-N-{4-[4- fiuoro-3-(trifluoromethyl)phen -l,3-thiazol-2-yl}acetamide
Figure imgf000103_0003
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (220 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2-dichloroethane (8.3 ml) at room temperature to give 45 mg of the product as an off-white solid; 1H NMR (300 MHz, CDC13): δ 3.47 (s, 3H), 3.52 (s, 3H), 4.32 (s, 2H), 7.17 (s, 1H), 7.18-7.28 (m, 1H), 7.94-8.05 (m, 1H), 8.08 (d, J = 6.3 Hz, 1H), 10.69 (br s, 1H); APCI-MS (m/z) 484.08 (M+H)+.
Example 93
N-[4-(3,5-Difluoro-4-methoxyphenyl)-l,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo- 4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-i/]pyrimidin-3-yl)acetamide
Figure imgf000104_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (250 mg, 1.045 mmol) with 4-(3,5-difluoro-4-methoxyphenyl)- l,3-thiazol-2-amine (253 mg, 1.045 mmol) in the presence of EDCI hydrochloride (240 mg, 1.254 mmol), HOBt (42 mg, 0.313 mmol) and DMAP (12.7 mg, 0.104 mmol) in 1 ,2- dichloroethane (10.5 ml) at room temperature to give 40 mg of the product as an off- white solid; 1H NMR (300 MHz, DMSO-rf6): δ 3.46 (s, 3H), 3.51 (s, 3H), 4.02 (s, 2H), 4.31 (s, 3H), 7.08 (s, 1H), 7.32-7.43 (m, 2H), 10.72 (br s, 1H); ESI-MS (m/z): 464.08 (M+H)+.
Example 94
N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6- dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i |pyrimidin-3-yl)acetamide
Figure imgf000104_0002
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-[3,5-difluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (234 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1,2-dichloroethane (8.3 ml) at room temperature to give 20 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13): δ 3.48 (s, 3H), 3.52 (s, 3H), 4.32 (s, 2H), 7.31 (s, lH), 7.44-7.53 (m, 2H), 10.75 (br s, 1H); APCI-MS (m/z): 500.34 (M-H) \
Example 95
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6- dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide
Figure imgf000105_0001
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 10 (200 mg, 0.836 mmol) with 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazoI-2-amine (235 mg, 0.836 mmol) in the presence of EDCI hydrochloride (192 mg, 1.003 mmol), HOBt (34 mg, 0.250 mmol) and DMAP (10 mg, 0.083 mmol) in 1 ,2-dichloroethane (8.3 ml) at room temperature to give 45 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.46 (s, 3H), 3.52 (s, 3H), 4.33 (s, 2H), 7.09 (t, J = 9.0 Hz, 1H), 7.44 (s, 1H), 8.30 (q, J = 8.4 Hz, 1H), 10.76 (br s, 1H); ESI-MS (m/z) 500.43 (M-H) ".
Example 96
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)-N-{4-[3- fluoro-4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl } acetamide
Figure imgf000105_0002
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (50 mg, 0.209 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2 -amine (60 mg, 0.229 mmol) in the presence of HOBt (10 mg, 0.077 mmol), N-methyl morpholine (27 μί, 0.242 mmol] and EDCI hydrochloride (46 mg, 0.242 mmol) in dichloromethane (1 ml) to give 8 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.62 (s, 3H), 4.01 (s, 2H), 7.28 (s, 1H), 7.58-7.72 (m, 3H), 1 1.01 (br s, 1H); ESI-MS (m/z) 484.17 (M+H) +.
Example 97
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrirnidin-3-yl)-N-{4-[2- fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide
Figure imgf000106_0001
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (95 mg, 0.397 mmol) with 4-[2-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (1 14 mg, 0.435 mmol) in the presence of HOBt (20 mg, 0.148 mmol), N-methyl morpholine (51 h, 0.460 mmol) and EDCI hydrochloride (88 mg, 0.460 mmol) in dichloromethane (2 ml) at 0-5° C to give 7.2 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.47 (s, 3H), 3.62 (s, 3H), 4.09 (s, 2H), 7.39 (d, J = 1 1.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H ), 8.25 (t, J= 7.8 Hz, 1H), 10.93 (br s, 1H); ESI-MS (m/z) 482.19 (M-H) ".
Example 98
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-i ]pyrimidin-3-yl)-N-{4-[2- fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide
Figure imgf000106_0002
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) in dichloromethane (4 ml) with 4-[2- fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-amine (241 mg, 0.920 mmol) in the presence of HOBt (41 mg, 0.303 mmol), Ν-methyl morpholine (51 L, 0.460 mmol) and EDCI hydrochloride (186 mg, 0.970 mmol) in dichloromethane (2 ml) to give 45 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.62 (s, 3H), 4.09 (s, 2H), 7.27-7.38 (m, 1H), 7.48-7.59 (m, 2H), 8.33 (t, J = 8.8 Hz, 1H), 10.88 (br s, 1H); ESI-MS (m/z) 484.53 (M+H)+. Example 99
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)-N-{4-[4- fluoro-3-(trifluoromethyl)phen -l,3-thiazol-2-yl}acetamide
Figure imgf000107_0001
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) with 4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2 -amine (241 mg, 0.920 mmol) in the presence of HOBt (41 mg, 0..309 mmol), N-methyl morpholine (107.8 [iL, 0.970 mmol) and EDCI hydrochloride (186 mg, 0.970 mmol) in dichloromethane (4 ml) to give 44 mg of the product as white solid; Ή NMR (300 MHz, CDC13): δ 3.48 (s, 3H), 3.62 (s, 3H), 4.09 (s, 2H), 7.15 (s, 1H), 7.18-7.25 (m, 1H), 7.97-8.05 (m, 1H ), 8.09 (d, J = 6.3 Hz, 2H), 10.90 (s, 1H); ESI-MS (m/z) 482.30 (M-H) \
Example 100
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/jpyrimidin-3-yl)-N-{4-[3- fluoro-4-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl} acetamide
Figure imgf000107_0002
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2 -amine (255 mg, 0.920 mmol) in the presence of HOBt (42 mg, 0.3096 mmol), N-methyl morpholine (107 [iL, 0.460 mmol) and EDCI hydrochloride (88 mg, 0.460 mmol) in dichloromethane (4 ml) at to give 20 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.49 (s, 3H), 3.62 (s, 3H), 4.09 (s, 2H), 7.17 (s, 1H), 7.25-7.36 (m, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.70 (d, J = 1 1.1 Hz, 1H), 10.95 (s, 1H); ESI-MS (m/z) 500.05 (M+H) +.
Example 101
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3-yl)-N-{4-[4- fluoro-3-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl} acetamide
Figure imgf000108_0001
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) with 4-[4-fluoro-3- (trifluoromethoxy)phenyl]-l,3-thiazol-2 -amine (255 mg, 0.920 mmol) in the presence of HOBt (41.79 mg, 0.309 mmol), N-methyl morpholine (107.89 [iL, 0.9706 mmol) and EDCI hydrochloride (186 mg, 0.9706 mmol) in dichloromethane (4 ml) to give 40 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.47 (s, 3H), 3.62 (s, 3H), 4.08 (s, 2H), 7.12 (s, 1H ), 7.18-7.27 (m, 1H), 7.70-7.73 (m, 1H), 7.81 (d, J= 7.5 Hz, 1H), 10.91 (s, 1H); ESI-MS (m/z) 498.07 (M-H) \
Example 102
N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6- dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)acetamide
Figure imgf000108_0002
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (160 mg, 0.669 mmol) with 4-[3-chloro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2 -amine (217 mg, 0.736 mmol) in the presence of HOBt (33 mg, 0.247 mmol), N-methyl morpholine (86 [iL, 0.776 mmol) and EDCI hydrochloride (149 mg, 0.776 mmol) in dichloromethane (3 ml) to give 22 mg of the product as white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.62 (s, 3H), 4.09 (s, 2H), 7.17 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.96 (s, 1H), 10.88 (s, 1H); ESI-MS (m/z) 514.33 (M-H)\
Example 103
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)-N-{4-[3- fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide
Figure imgf000109_0001
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) with 4-[3-fluoro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (241 mg L, 0.920 mmol) in the presence of HOBt (41 mg, 0.309 mmol), N-methyl morpholine (107.8 pL, 0.970 mmol) and EDCI hydrochloride (186 mg, 0.970 mmol) in dichloromethane (4 ml) to give 10 mg of the product as an off-white solid; Ή NMR (300 MHz, DMSO-i 6) δ 3.32 (s, 3H), 3.43 (s, 3H), 4.1 1 (s, 2H), 7.64 (d, J = 7.5 Hz, 1H), 8.00-8.13 (m, 3H), 12.77 (s, 1H); ESI-MS (m/z) 482.77 (M-H) ".
Example 104
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl-4,6- dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)acetamide
Figure imgf000109_0002
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) with 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (258 mg, 0.920 mmol) in the presence of HOBt (41.79 mg, 0.309 mmol), N-methyl morpholine (107.89 ML, 0.970 mmol) and EDCI hydrochloride (186 mg, 0.970 mmol) in dichloromethane (4 ml) to give 33 mg of the product as white solid; Ή NMR (300 MHz, CDC13) δ 3.48 (s, 3H), 3.45 (s, 3H), 4.08 (s, 2H), 7.08 (t, J = 9.3 Hz, 1H), 7.42 (s, 1H), 8.30 (q, J = 8.1 Hz, 1H), 10.89 (s, 1H); ESI-MS (m/z) 502 (M+H) +.
Example 105
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i ]pyrimidin-3-yl)-N-[4- (propan-2-yl)phenyl]acetamide
Figure imgf000110_0001
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) with 4-isopropyl-aniline (125 mg, 0.925 mmol) in the presence of HOBt (41 mg L, 0.309 mmol), N-methyl morpholine (107.8 pL, 0.970 mmol) and EDCI hydrochloride (186 mg, 0.970 mmol) in dichloromethane (4 ml) to give 160 mg of the product as white solid; Ή NMR (300 MHz, CDC13) δ 1.20 (d, J = 6.9 Hz, 6H), 2.80-2.92 (m, 1H), 3.43 (s, 3H), 3.60 (s, 3H), 3.91 (s, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.46 (d, J= 8.1 Hz, 2H), 9.33 (s, 1H); ESI-MS (m/z) 357.25 (M+H)+.
Example 106
N-[2-(4-Chlorophenyl)ethyl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)acetamide
Figure imgf000110_0002
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (150 mg, 0.627 mmol) with 2-(4-chlorophenyl)ethanamine (107 mg, 0.690 mmol) in the presence of HOBt (31 mg, 0.232 mmol), N-methyl morpholine (80.91 iL, 0.7280 mmol) and EDCI hydrochloride (139 mg, 0.7280 mmol) in dichloromethane (4 ml) to give 140 mg of the product as white solid; Ή NMR (300 MHz, CDC13) δ 2.80 (t, J = 6.9 Hz, 2H), 3.32 (s, 3H), 3.54 (q, J = 6.6 Hz, 2H), 3.62 (s, 3H), 3.68 (s, 2H), 6.99 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.1 Hz, 2H); ESI-MS (m/z) 3773.33 (M+H) +.
Example 107
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)-N-[3- fluoro-4-(trifluoromethyl)phenyl]acetamide
Figure imgf000111_0001
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 11 (150 mg, 0.627 mmol) with 4-fluoro-3-trifluoromethyl aniline (123 mg, 0.690 mmol) in the presence of HOBt (31 mg, 0.232 mmol), N-methyl morpholine (80.91 L, 0.728 mmol) and EDCI hydrochloride (140 mg, 0.728 mmol) in dichloromethane (3 ml) to give 100 mg of the product as an off-white solid; Ή NMR
(300 MHz, CDCls) δ 3.46 (s, 3H), 3.61 (s, 3H), 3.93 (s, 2H), 7.13 (t, J = 9.3 Hz, 1H), 7.73-7.82 (m, 2H), 9.82 (br s, 1H); ESI-MS (m/z) 401.39 (M+H) +.
Example 108
N-[2,4-Difluorophenyl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4- </]pyrimidin-3-yi)acetamide
Figure imgf000111_0002
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (200 mg, 0.837 mmol) with 2,4-fluoroaniline (1 18 mg, 0.920 mmol) in the presence of HOBt (41 mg, 0.309 mmol), N-methyl morpholine (107.87 μΐ,, 0.970 mmol) and EDCI hydrochloride (186 mg, 0.970 mmol) in dichloromethane (4 ml) to give 60 mg of the product as an off-white solid; Ή NMR (300 MHz, CDC13) δ 3.42 (s, 3H), 3.61 (s, 3H), 3.99 (s, 2H), 6.84 (t, J= 8.7 Hz, 2H), 8.14 (q, J= 8.1 Hz, 1H), 9.04 (br s, 1H); (ESI-MS m/z) 351 (M+H) +.
Example 109
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[5,4-i/|pyrimidin-3-yl)-N-[4-(4- methylphenoxy)phenyl]-acetamide
Figure imgf000111_0003
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 1 (150 mg, 0.627 mmol) with 4-(4-methylphenoxy)aniline (137 mg, 0.690 mmol) in the presence of HOBt (31 mg, 0.232 mmol), N-methyl morpholine (81 L, 0.73 mmol) and EDCI hydrochloride (140 mg, 0.73 mmol) in dichloromethane (3 ml) to give 170 mg of the product as white solid; Ή NMR (300 MHz, DMSO-<&) δ 2.31 (s, 3H), 3.44 (s, 3H), 3.61 (s, 3H), 3.91 (s, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.4, 2H), 7.49 (d, J = 9.3 Hz, 2H), 9.48 (s, 1H); ESI-MS (m/z) 421 (M+H) +.
Pharmacological activity
The illustrative examples of the present invention are screened for TRPAl activity according to a modified procedure described in (a) Toth, A. et al. Life Sciences, 2003, 73, 487-498. (b) McNamara C, R. et al, Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13525- 13530. The screening of the compounds can be carried out by other methods and procedures known to persons skilled in the art.
Screening for TRPAl antagonist using the 45Calcium uptake assay:
The inhibition of TRPAl receptor activation was measured as inhibition of allyl isothiocyanate (AITC) induced cellular uptake of radioactive calcium.
Test compounds were dissolved in 100% DMSO to prepare 10 mM stock and then diluted using plain medium with 0.1% BSA and 1.8 mM CaCl2 to get the desired concentration. The final concentration of DMSO in the reaction was 0.5% (v/v). Human TRPAl expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 μg / ml of G-418. Rat TRPAl expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 μg / ml of Zeocin. Cells were seeded 24 h prior to the assay in 96 well plates so as to get ~ 50,000 cells per well on the day of experiment. Cells were treated with the test compounds for 10 minutes followed by the addition of AITC at a final concentration of 30 μΜ (for human TRPAl) and / or 10 μΜ (for rat TRPAl) and 5 μθί/πιΐ 45Ca+2 for 3 minutes. Cells were washed and lysed using a buffer containing 1% Triton X-100, 0.1 % deoxycholate and 0.1% SDS. Radioactivity in the lysate was measured in a Packard TopCount after addition of liquid scintillant. (Toth et al, Life Sciences (2003) 73, 487-498; McNamara CR et al, Proceedings of the National Academy of Sciences, (2007) 104 , 13525-13530).
- I l l - Concentration response curves were plotted as a % of maximal response obtained in the absence of test antagonist. IC50 values can be 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 3. Percentage inhibition at concentrations of 1.0 μΜ and 10.0 μΜ are given in the table along with IC5o (nM) details for selected examples. The IC50 (nM) values of the compounds are set forth in Table 3 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC50 value in range of 50.01 to 100.0 nM and "C" refers to IC50 value of more than 100.0 nM
Table 3: In-vitro screening results of compounds of invention:
Figure imgf000113_0001
10.37 42.54 — ~ — —
27.72 34.86 — ~ — —
81.50 98.95 C — — —
89.15 99.78 c — —
65.37 98.90 — — — —
59.07 97.86 — — — —
86.06 100.0 c — — —
99.87 100.0 A 93.68 97.91 C
75.30 99.66 c — — —
94.46 99.9 A 80.02 98.54 c
94.64 99.16 A 66.44 98.72 c
98.92 98.87 A 92.55 100.0 B
98.92 98.62 A 96.06 99.0 B
69.21 96.83 - — — —
69.17 99.37 - — —
60.10 98.80 - — — —
90.94 99.66 C — —
81.99 97.75 C — — ■ —
95.17 100.0 A 67.9 99.2 —
94.78 99.73 B — — —
95.50 99.76 B — — —
72.44 99.59 C — — — ·
91.19 98.58 C — — —
84.03 99.75 C — — —
85.95 99.61 C — — —
95.21 99.14 B — — —
88.84 96.72 C ~ — —
35.58 98.71 ■ — ~ — —
86.30 90.47 C — — ~
86.33 99.78 c — — —
90.42 99.87 c — — ...
31.00 92.47 — — — —
80.89 99.38 c — — —
96.43 99.58 c — ~ —
73.64 99.80 — — —
91.42 99.89 c — — —
86.88 99.74 A — — —
96.70 100.00 A — — C 89.03 99.79 C — — —
93.84 99.62 C — — -
92.26 99.32 C — — —
94.18 99.60 A ~ — —
92.92 99.84 C — — —
94.93 98.76 C — —
67.15 99.41 — — — ~
98.15 98. 48 A 99.69 99.73 A
100 100 A 97.25 97.34 A
100 100 B — — —
100 100 A 95.54 97.26 A
100 100 A 98.57 99.61 A
100 100 A ~ — —
100 99.85 A 99.9 99.74 A
99.03 99.84 A 100.0 100.0 A
99.97 99.77 A 100.0 100.0 A
100 100 A 100.0 100.0 A
99.88 99.59 A 100.0 100.0 A
99.08 96.88 B 82.87 99.40 --
96.84 98.83 B 86.85 91.36 -
99.21 93.01 A 69.5 99.24 —
92.60 99.86 B 94.24 100.0 C
75.43 99.52 C 62.6 99.8
81.89 97.83 C 92.28 100.0 C
92.49 100.00 C 86.56 98.43 c
65.88 94.45 - — — —
68.27 94.37 C 79.98 100.0 c
96.42 99.05 c — — —
92.08 99.82 B 72.9 95.4 —
93.49 97.56 C 96.33 100.0 c
92.01 99.28 C 60.78 100.0 c
94.71 99.59 A 79.74 100.0 c
96.15 99.95 A 90.76 100.0 —
97.81 99.61 A 44.3 99.6 —
92.10 100.00 A 57.5 99.9 —
97.64 99.80 A 98.38 99.32 B
98.59 99.88 C 89.7 100.0 C
98.93 99.97 C 92.77 99.27 ~ 98 98.29 100.00 C 100.0 98.99 ~
99 98.67 100.00 C 97.93 99.88 C
100 98.75 100.00 C 93.48 98.17 C
101 98.89 100.00 C 97.78 99.88 c
102 99.27 100.00 C 98.09 100.0 c
103 99.89 100.00 C 95.03 96.83 c
104 99.47 100.00 C 99.27 99.63 c
105 1 1.44 68.50 ~ ~ — —
106 0.00 9.95 — — — —
107 1.21 18.74 — — — —
108 0.97 4.35 — - — — —
109 32.99 88.5 — — — —
Oral PK profile of Example 29
Test compound is formulated immediately prior to dosing by making a suspension
(2.5 μΙ7πιΙν Tween-80 and 0.5 % methylcellulose suspension in geometric dilution). The animals were provided with food and water ad libitum throughout the study period. Male rats SD are administered orally a dose of 10 mg/kg (dose volume lOmL/kg body weight) of test compound by a gavage needle. Blood samples (approximately 250 μΐ) were collected from retro orbital sinus using rat capillary tubes at regular intervals of 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, and 24.0 hrs after dose administration into rat. Samples were centrifuged immediately at lOOOg for 10 min at 4°C. Plasma samples were processed and analyzed by LCMS/MS as per standard operating procedures. Plasma concentration of test compound was recorded and used to calculate the pharmacokinetic parameters such as Cmax, area under the curve, Tmax etc using Pharsight Winonlin software. The pharmacokinetic profile of Example 29 is depicted in Table 4 below.
Table 4: Pharmacokinetic profile of Example 29
Figure imgf000116_0001

Claims

WE CLAIM:
1. A compound of the formula (I)
O
Q-CH2-C NH-U-V
(I)
or a pharmaceutically acceptable salt thereof,
wherein, Q is a heteroc cle selected from the rou consistin of
Figure imgf000117_0001
o o . o ,o . O J o >,/
Figure imgf000117_0002
Figure imgf000118_0001
U is selected from -(CRxRy)n- substituted or unsubstituted aryl, substituted or unsubstituted heterocycles selected from the group consisting of thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrroles, 1,2,3-triazoles and 1, 2, 4-triazole, pyrimidine, pyridine and pyridazine;
V is selected from hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(0)ORx, -ORx, -C(0)NRxRy, -C(0)Rx and -S02NRxRy; or
at each occurrence, R1, R2 and R3, which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkylalkyl, arylalkyl, (CRxRy)nORx, CORx, COORx, CONRxRy,and (CH2)nCHRxRy;
R4 is halogen;
at each occurrence, Rx and Ry are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloaikyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;
at each occurrence, 'n' is selected from 0 to 2, both inclusive.
2. The compound according to claim 1, wherein U is heterocycle.
3. The compound according to claim 2, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
4. The compound according to any of claims 1 to 3, wherein V is substituted or unsubstituted aryl.
5. The compound according to claim 4, wherein aryl is phenyl.
6. The compound according to any of claims 1 to 5, wherein R1, R2 and R3 are (d- C4)alkyl.
7. The compound according to claim 6, wherein (Cj-C4)alkyl is methyl.
8. The compound according to any of claims 1 to 7, wherein R4 is fluorine, chlorine or bromine.
9. The compound of claim 1 having the formula (la):
Figure imgf000119_0001
(la)
10. The compound according to claim 9, wherein R is (Ci-C- alkyl.
11. The compound according to claim 10, wherein (C!-C4)alkyl is methyl.
12. The compound according to any of claims 9 to 11, wherein U is heterocycle.
13. The compound according to claim 12, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
14. The compound according to any of claims 9 to 13, wherein V is substituted or unsubstituted aryl.
15. The compound according to claim 14, wherein aryl is phenyl.
16. The compound of claim 1 having the formula (lb):
Figure imgf000119_0002
(lb)
17. The compound according to claim 16, wherein R1 is (Ci-C4)alkyl.
18. The compound according to claim 17, wherein (Ci-C alkyl is methyl.
19. The compound according to any of claim 16 to 18, wherein U is heterocycle.
20. The compound according to claim 19, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
21. The compound according to any of claims 16 to 20, wherein V is substituted or unsubstituted aryl.
22. The compound according to claim 21 , wherein aryl is phenyl.
23. The compound of claim 1 having the formula (Ic):
Figure imgf000119_0003
(Ic)
24. The compound according to claim 23, wherein R1 and R2 are (Ci-C4)alkyl.
25. The compound according to claim 24, wherein (Ci-C4)alkyl is methyl.
26. The compound according to any of claim 23 to 25, wherein U is heterocycle.
27. The compound according to claim 26, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
28. The compound according to any of claims 23 to 27, wherein V is substituted or unsubstituted aryl.
29. The compound according to claim 28, wherein aryl is phenyl.
30. The compound of claim 1 having the formula (Id):
Figure imgf000120_0001
(Id)
31. The compound according to claim 30, wherein R , R and R are (C1-C4)alkyl.
32. The compound according to claim 31 , wherein (C1-C4)alkyl is methyl.
33. The compound according to any of claims 30 to 32, wherein U is heterocycle.
34. The compound according to claim 33, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
35. The compound according to any of claims 30 to 34, wherein V is substituted or unsubstituted aryl.
36. The compound according to claim 35, wherein aryl is phenyl.
37. The compound of claim 1 having the formula (Ie):
Figure imgf000120_0002
(Ie)
The compound according to claim 37, wherein R and R are (Ci-C4)alkyl.
The compound according to claim 38, wherein (Ci-C4)alkyl is methyl.
40. The compound according to any of claims 37 to 39, wherein R4 is fluorine, chlorine or bromine.
41. The compound according to any of claims 37 to 40, wherein U is heterocycle.
42. The compound according to claim 41, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
43. The compound according to any of claims 37 to 42, wherein V is substituted or unsubstituted aryl.
44. » The compound according to claim 43, wherein aryl is phenyl.
45. The compound of claim 1 having the formula (If):
Figure imgf000121_0001
(if)
46. The compound according to claim 45, wherein R1 and R2 are (C]-C4)alkyl.
47. The compound according to claim 46, wherein (Ci-C4)alkyl is methyl.
48. The compound according to any of claims 45 to 47, wherein U is heterocycle.
49. The compound according to claim 48, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
50. The compound according to any of claims 45 to 49, wherein V is substituted or unsubstituted aryl.
51. The compound according to claim 50, wherein aryl is phenyl.
52. The compound of claim 1 having the formula (Ig):
Figure imgf000121_0002
(Ig)
53. The compound according to claim 52, wherein R1 and R2 are (C1-C4)alkyl.
54. The compound according to claim 53, wherein (C1-C4)alkyl is methyl.
55. The compound according to any of claims 52 to 54, wherein U is heterocycle.
56. The compound according to claim 55, wherein heterocycle is selected from a group consisting of thiazole, imidazole, isoxazole, pyrazole, thiadiazole or pyrimidine.
57. The compound according to any of claims 52 to 54, wherein U is aryl.
58. The compound according to claim 57, wherein aryl is phenyl.
59. The compound according to any of claims 52 to 54, wherein U is -CH2-CH2-. 60. The compound according to any of claims 52 to 59, wherein V is substituted or unsubstituted aryl.
61. The compound according to claim 60, wherein aryl is phenyl.
62. A compound according to claim 1 wherein the compound of formula (I) is
Figure imgf000122_0001
(Ila) (lib)
Figure imgf000122_0002
(lie) (lid)
Figure imgf000122_0003
He) (Ilf)
Figure imgf000122_0004
(Ilg) or a pharmaceutically acceptable salt thereof,
wherein,
at each occurrence, R1, R2 and R3, which may be the same or different, are independently selected from hydrogen or substituted or unsubstituted alkyl;
R4 is halogen selected from F, CI, Br or I;
at each occurrence, R5 is selected from hydrogen, halogen or substituted or unsubstituted alkyl;
at each occurrence, R6 is selected from hydrogen, cyano, nitro, -NRxRy, halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl, -C(0)ORx, -ORx, -C(0)NRxRy and -C(0)Rx;
at each occurrence, 'm' is selected from 0 to 5, both inclusive.
63. The compound selected from:
N-[4-(4-Difluoromethoxy-3,5-difluorophenyl)-l,3-thiazol-2-yl]-2-(3-methyl-2,4- dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a]triazin-6-yl)acetamide;
N- {4-[3 ,5-Dichloro-4-(3 ,3 ,3 -trifluoropropoxy)phenyl] - 1 ,3-thiazol-2-yl } -2-(3- methyl-2,4-dioxo-3 ,4-dihydro-2H-[ 1 ,3]thiazolo[3,2-a] [ 1 ,3,5]triazin-6-yl)acetamide;
N-[4-(3,5-Dichloro-4-cyclobutylmethoxyphenyl)-l,3-thiazol-2-yl]-2-(3-methyl- 2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide;
N-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(3-methyl-2,4- dioxo-3 ,4-dihydro-2H- [ 1 ,3]thiazolo[3 ,2-a] [ 1 ,3 ,5]triazin-6-yl)acetamide;
N-[4-(4-Cyclohexylphenyl)-l,3-thiazol-2-yl]-2-(3-methyl-2,4-dioxo-3,4-dihydro- 2H- [ 1 ,3 ]thiazolo[3 ,2-a] [ 1 ,3 ,5]triazin-6-yl)acetamide;
N-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(3- methyl-2,4-dioxo-3,4-dihydro-2H-[l,3]thiazolo[3,2-a][l,3,5]triazin-6-yl)acetamide;
N- { 4- [3 -Fluoro-4-(trifluoromethyl)phenyl] -1,3 -thiazol-2-yl } -2-(3 -methyl-2,4- dioxo-3 ,4-dihydro-2H- [ 1 ,3]thiazolo [3 ,2-a] [ 1 ,3 ,5]triazin-6-yl)acetamide;
N-[4-(3 ,4-Dichlorophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl- 1 , 1 -dioxido-3-oxo-2,3- dihydro[ 1 ,3]thiazolo[3,2-6] [ 1 ,2,4,6]thiatriazin-7-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(2-methyl-l,l- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-0][l,2,4,6]thiatriazin-7-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-l,3-thiazol-2-yl}-2-(2-methyl- 1 , 1 -dioxido-3 -oxo-2,3 -dihydro [ 1 ,3 ]thiazolo[3 ,2-b] [ 1 ,2,4,6]thiatriazin-7-yl)acetamide; N-{4-[4-(2,2-Dimethylpropoxy)-3-chlorophenyl]- 1 ,3-thiazol-2-yl}-2-(2-methyl- 1 , 1 -dioxido-3 -oxo-2,3 -dihydro [ 1 ,3]thiazolo[3 ,2-b] [ 1 ,2,4,6]thiatriazin-7-yl)acetamide;
N-[4-(2,3,4-Trichlorophenyl)- 1 ,3-thiazol-2-yl]-2-(2-methyl-l , 1 -dioxido-3-oxo-
2.3- dihydro[ 1 ,3]thiazolo[3,2-6] [1 ,2,4,6]thiatriazin-7-yl)-acetamide;
N- {4-[2,4-Difluoro-3 -(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } -2-(2-methyl- 1,1- dioxido-3-oxo-2,3-dihydro[l,3]thiazolo[3,2-6][l,2,4,6]thiatriazin-7-yl)acetarnide;
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(2- methyl- 1 , 1 -dioxido-3-oxo-2,3-dihydro[ 1 ,3]thiazolo[3,2-6] [ 1 ,2,4,6]thiatriazin-7- yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(2- methyl- 1 , 1 -dioxido-3-oxo-2,3-dihydro[ 1 ,3]thiazolo[3,2-i>] [ 1 ,2,4,6]thiatriazin-7- yl)acetamide;
^-{4-[4-(2,2-Dimethylpropoxy)-3,5-dichlorophenyl]-l,3-thiazol-2-yl}-2-(2- methyl-1, 1 -dioxido-3-oxo-2,3-dihydro[l ,3]thiazolo[3,2-6][l ,2,4,6]thiatriazin-7- yl)acetamide;
N-{4-[3-Chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]-l,3-thiazol-2-yl}-2-(2- methyl- 1 , 1 -dioxido-3-oxo-2,3-dihydro[ 1 ,3]thiazolo[3,2-&] [ 1 ,2,4,6]thiatriazin-7- yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}2-(l,3-Dimethyl-2,^ dioxo-1 ,2,3, 4-tetrahydroimidazo[l ,2-a] [1 ,3,5]triazin-6-yl)- acetamide;
N- {4-[3 -Fluoro-4-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl } 2-( 1 ,3 -dimethyl-
2.4- dioxo- 1 ,2,3 ,4-tetrahydroimidazo [ 1 ,2-a] [ 1 ,3 ,5]triazin-6-yl)acetamide;
N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}2-(l ,3-dimethyl- 2,4-dioxo- 1 ,2,3,4-tetrahydroimidazo[l ,2-a][l ,3,5]triazin-6-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l ,2,3,4-tetrahydroimidazofl ,2-a][l ,3,5]triazin-6-yl)acetamide;
N-{4- [3 ,5 -Difluoro-4-(trifluoromethyl)phenyl]- 1 ,3 -thiazol-2-yl } -2-( 1 ,3 -dimethyl- 2,4-dioxo-l ,2,3,4-tetrahydroimidazo[l ,2-a][l ,3,5]triazin-6-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l,3-thiazol-2-yl}-2-(l ,3- dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydroimidazo[ 1 ,2-a] [ 1 ,3 ,5]triazin-6-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3- dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydroimidazo [ 1 ,2-a] [ 1 ,3 ,5]triazin-6-yl)acetamide;
N- { 4- [3 -Chloro-4-(trifluoromethy l)phenyl] - 1 ,3-thiazol-2-yl } -2-( 1 ,3-dimethyl-2,4- dioxo-l ,2,3,4-tetrahydroimidazo[l,2- ][l,3,5]triazin-6-yl)acetamide; and N-{4-[4-(Trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(l ,3-dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydroimidazofl ,2-α][1 ,3,5]triazin-6-yl)acetamide;
or a pharmaceutically acceptable salt thereof,
64. The compound selected from:
N-[4-(3,4-Dichlorophenyl)-l ,3-thiazol-2-yl]-2-(l ,3,9-trimethyl-2,6,8-trioxo- l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-isobutoxyphenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9-trimethyl-2,6,8- trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-(2,2-Dimethylpropoxy)-3-fluorophenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo- 1 ,2,3 ,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-neopentyloxyphenyl]-l,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(cyclobutylmethoxy)-phenyl]-l ,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo- 1 ,2,3 ,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4- [4-Fluoro-3-(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } -2-( 1 ,3 ,9-trimethyl- 2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- { 4- [3 -Fluoro-4-(trifluoromethy l)phenyl] - 1 ,3-thiazol-2-yl } -2-(l ,3,9-trimethyl- 2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3 -Chloro-4-(trifluoromethoxy)phenyl]- 1 ,3 -thiazol-2-yl } -2-( 1 ,3 ,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-ethoxyphenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9-trimethyl-2,6,8- trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-propoxyphenyl]-l ,3-thiazol-2-yl}-2-(l,3,9-trimethyl-2,6,8- trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4-[3-Chloro-5-fluoro-4-propoxyphenyl]- 1 ,3-thiazol-2-yl} -2-( 1 ,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-butoxy-phenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9-trimethyl-2,6,8- trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-4-butoxy-5-fluorophenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9-trimethyl- 2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-isopropoxyphenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9-trimethyl- 2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide; N-{4-[3-Chloro-4-isopropoxy-5-fluorophenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-(2-methylpropoxy)phenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2-methylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-5-fluoro-4-isobutoxyphenyl]-l ,3-thiazol-2-yl}-2-(l,3,9-trimethyl- 2,6,8-trioxo- 1 ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-(2,2-dimethylpropoxy)phenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4-[4-(2,2-Dimethylpropoxy)-3 ,5-difluorophenyl] - 1 ,3 -thiazol-2-yl } -2-( 1 ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4-[3-Chloro-4-(2,2-dimethylpropoxy)-5-fluorophenyl]- 1 ,3-thiazol-2-yl} -2- (l ,3,9-trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Dichloro-4-(3-methylbutoxy)phenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4-[3 ,5-Difluoro-4-(3-methylbutoxy)phenyl]- 1 ,3-thiazol-2-yl} -2-( 1 ,3 ,9- trirnethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4- [4-(Cyclopropylmethoxy)-3 ,5 -dichlorophenyl] - 1 ,3 -thiazol-2-yl } -2-( 1 ,3 ,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-(Cyclopropylmethoxy)-3,5-difluorophenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4- [3 -Chloro-4-(cyclopropylmethoxy)-5-fluorophenyl] - 1 ,3-thiazol-2-yl } -2- (l ,3,9-trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4-[4-(Cyclobutylmethoxy)-3,5-dichlorophenyl]- 1 ,3-thiazol-2-yl } -2-( 1 ,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[4-(Cyclobutylmethoxy)-3,5-difluorophenyl]-l ,3-thiazol-2-yl}-2-(l ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetarnide;
N- {4- [3 -Chloro-4-(cyclobutylmethoxy)-5 -fluorophenyl] -1 ,3 -thiazol-2-yl } -2- (l ,3,9-trirnethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]- 1 ,3-thiazol-2-yl } -2-( 1 ,3,9- trimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3-Chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l ,3-thiazol-2-yl}-2- (l ,3,9-trirnethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetarnide; A^-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3,9- trimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
^-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-ethyl-l,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
7V-{4-[4-(2,2-Dimethylpropoxy)-3,5-difluorophenyl]-l ,3-thiazol-2-yl}-2-(9-ethyl- l ,3-dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(9-ethyl-l,3- dimethyl-2,6,8-trioxo-l ,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N- {4- [3 -Fluoro-4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl } -2-(9-isopropyl- 1,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(9- isopropyl-l,3-dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide;
N-{4-[3 -Fluoro-4-(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } -2-(9-isobutyl- 1,3- dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)acetamide; and
N- {4- [3 ,5-Difluoro-4-(2,2-dimethylpropoxy)phenyl]- 1 ,3 -thiazol-2-yl } -2-(9- isobutyl-l,3-dimethyl-2,6,8-trioxo-l,2,3,6,8,9-hexahydro-7H-purin-7-yl)ace1amide;
or a pharmaceutically acceptable salt thereof,
65. The compound selected from:
N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[2,4-Difluoro-3-(trifluromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(6-chloro- 1 ,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N- {4-[4-(Diethylamino)phenyl]- 1 ,3-thiazol-2-yl } 2-(6-chloro- 1 ,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N- {4-[3-Fluoro-4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl} -2-(6-chloro- 1 ,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6-chloro-l ,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide; N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}2-(6-chloro-l ,3- dimethyl-2,4-dioxo-l ,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
N- {4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl } 2-(6-bromo- 1 ,3- dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydrofiiro[2,3-d]pyrimidin-5-yl)acetamide; and
N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l ,3-thiazol-2-yl}2-(6-bromo-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide;
or a pharmaceutically acceptable salt thereof,
66. The compound selected from:
jV.[4-(4-Bromophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[l ,2]oxazolo[3,4-i Jpyrimidin-3-yl)acetamide;
N-[4-(4-Chlorophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro[ 1 ,2]oxazolo[3,4-^pyrimidin-3-yl)acetamide;
2-(5 ,7-Dimethyl-4,6-dioxo-4,5 ,6,7-tetrahydro [ 1 ,2]oxazolo[3 ,4-^pyrimidin-3 -yl)- N-{4- [4-(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } acetamide ;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-if|pyrimidin-3-yl)- N- { 4- [3 -(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } acetamide ;
2-(5 ,7-Dimethyl-4,6-dioxo-4,5 ,6,7-tetrahydro [ 1 ,2]oxazolo[3 ,4-</]pyrimidin-3 -yl)- N- {4-[3-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl }acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i¾pyrimidin-3-yl)- N-[4-(4-isobutylphenyl)- 1 ,3-thiazol-2-yl]acetamide;
N-[4-(3,5-Dichlorophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro [1,2] oxazolo [3 ,4-if]pyrimidin-3 -yl)acetamide ;
N-[4-(2,4-Difluorophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro [ 1 ,2] oxazolo [3 ,4-<i]pyrirnidin-3 -yl)acetamide;
N-[4-(2,3-Difluorophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro [ 1 ,2] oxazolo [3 ,4-c/]pyrimidin-3 -yl)acetamide ;
N-[4-(3-Chloro-2-fluorophenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo- 4,5,6,7-tetrahydro[l ,2]oxazolo[3,4- ]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-i ]pyrimidin-3-yl)- N- {4-[3-fluoro-4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl } acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-£ ]pyrimidin-3-yl)- N- {4-[4-fluoro-3-(trifluoromethoxy)phenyl]- 1 ,3-thiazol-2-yl} acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[3,4-i )pyrimidin-3-yl)- N- { 4-[3-fluoro-4-(trifluoromethoxy)phenyl] - 1 ,3 -thiazol-2-yl } acetamide; 2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-(^]pyrimidin-3-yl)- N-{4-[3-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l ,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-i ]pyrimidin-3-yl)- N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]- l ,3-thiazol-2-yl}acetamide;
N-[4-(3,5-Difluoro-4-methoxyphenyl)-l ,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6- dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-i¾pyrimidin-3-Tyl)acetainide;
N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(5,7-dimethyl- 4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-i/lpyrimidin-3-yl)acetamide;
iV-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(5,7-dimethyl- 4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[3,4-i ]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-ii]pyriinidin-3-yl)- N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)- N-{4-[2-fluoro-4-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}acetamide;
2-(5 ,7-Dimethyl-4,6-dioxo-4,5 ,6,7-tetrahydro[ 1 ,2]oxazolo[5 ,4-i ]pyrimidin-3 -yl)- N- { 4-[2-fluoro-3-(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-i/]pyrimidin-3-yl)- N-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-i ]pyrimidin-3-yl)- N- { 4- [3 -fluoro-4-(trifluoromethoxy)phenyl] - 1 ,3 -thiazol-2-y 1 } acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-^pyrimidin-3-yl)- N- { 4- [4-fluoro-3 -(trifluoromethoxy)phenyl] -1,3 -thiazol-2-yl } acetamide;
N- { 4- [3 -Chloro-4-(trifluoromethoxy)phenyl] - 1 ,3 -thiazol-2-yl } -2-(5 ,7-dimethyl- 4,6-dioxo-4,5,6,7-tetrahydro[l,2]oxazolo[5,4-i/]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-i ]pyrimidin-3-yl)- N- { 4- [3 -fluoro-5 -(trifluoromethyl)phenyl] - 1 ,3 -thiazol-2-yl } acetamide ;
N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-2-(5,7-dimethyI- 4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-i ]pyrimidin-3-yl)acetamide;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-if]pyrimidin-3-yl)- N- [4-(propan-2-yl)pheny 1] acetamide ;
N-[2-(4-Chlorophenyl)ethyl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydro [1 ,2] oxazolo [5 ,4-i/]pyrimidin-3 -yl)acetamide ;
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydro[l ,2]oxazolo[5,4-i ]pyrimidin-3-yl)- N-[3-fluoro-4-(trifluoromethyl)phenyl]acetamide; N-[2,4-Difluorophenyl]-2-(5,7-dimethyl-4,6-dioxo-4,5,6,7- tetrahydrofl ,2]oxazolo[5,4-<flpyrimidin-3-yl)acetamide; and
2-(5,7-Dimethyl-4,6-dioxo-4,5,6,7-tetrahydroisoxazolo[5,4-</]pyrimidin-3-yl)-N- [4-(4-methylphenoxy)phenyl] -acetamide ;
or a pharmaceutically acceptable salt thereof,
67. The compound having the structures:
Figure imgf000130_0001
68. A pharmaceutical composition comprising one or more compounds selected from the compounds of any one of claims 1 to 66, and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.
69. A method for treating disease or condition associated with TRPAl function in a subject in need thereof comprising administering to the subject an effective amount of a compound according to any of claims 1 to 66.
70. The method according to claim 69, wherein the symptoms of a disease or condition associated with TRPAl function is selected from pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, chemotherapy - induced neuropathies, eye - irritation, bronchial - irritation, skin - irritation (atopic dermatitis), Frost - bites (cold - bite), spasticity, catatonia, catalepsy, parkinsons, diabetic neuropathy, sciatica, HIV -related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory disorder like airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and paracetamol-induced asthma, cough, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), overactive bladder, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus; digestive organ diseases like irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, constipation, diarrhea, and vomiting.
71. The method according to claim 70, wherein the symptoms of a disease or condition is associated with chronic pain.
72. The method according to claim 70, wherein the symptoms of a disease or condition is associated with neuropathic pain.
73. The method according to claim 70, wherein the symptoms of a disease or condition is associated with rheumatoid arthritic pain or osteoarthritic pain.
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