WO2010125469A1 - Pyrimidinedione-fused heterocyclic compounds as trpa1 modulators - Google Patents

Abstract

The present invention is related to novel pyrimidinedione-fused heterocyclic compounds as TRPA (Transient Receptor Potential subfamily A) modulators. 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.

Description

PYRIMIDINEDIONE-FUSED HETEROCYCLIC COMPOUNDS AS TRPAl

MODULATORS

Related applications

This application claims the benefit of Indian Patent Application Nos 1139/MUM/2009 filed on April 29, 2009; 2888/MUM/2009 filed on December 15, 2009; 2889/MUM/2009 filed on December 15, 2009 and US Provisional Application Nos 61/180,191 filed on May 21, 2009; 61/294,465 filed on January 12, 2010 and 61/300,290; filed on February 01, 2010 all of which are hereby incorporated by reference.

Technical Field

The present patent application relates to pyrimidinedione-fused heterocyclic compounds with transient receptor potential ankyrinl (TRPAl) 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, ANKTMl) and TRPN (NOMPC) families. The TRPC family can be divided into 4 subfamilies (i) TRPCl (ii) TRPC2 (iii) TRPC3, TRPC6, TRPC7 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 TRPVl, TRPV2, TRPV3, or TRPV4. TRPAl is most closely related to TRPV3, and is more closely related to TRPVl and TRPV2 than to TRP V5 and TRPV6. The TRPM family has 8 members. Constituents include the following: the founding member TRPMl (melastatin or LTRPCl), TRPM3 (KIAAl 616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK(l), LTRPC7), TRPM6 (ChaK2), TRPM2 (TRPC7 or LTRPC2), TRPM8 (TRP-p8 or CMRl), TRPM5 (MTRl or LTRPC5), and TRPM4 (FLJ20041 or LTRPC4). The TRPML family consists of the mucolipins, which include TRPMLl (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, PCl), PKD-REJ and PKD-ILl are all thought to have eleven transmembrane domains. The sole mammalian member of the TRPA family is ANKTMl. 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 2010/036821, WO 2010/039289, WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO 2004/055054 and WO 2005/089206 describe various TRP channels modulators.

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):

(I) or pharmaceutically acceptable salt thereof, wherein,

A₁, A₂ and A₃ are independently selected from N and CR^a; with the proviso that A₁, A₂ and A3 simulteneously are not CR^a at any given instance and when Ai is CR^a, A₂ is N, then A₃ is not CR^a;

R^a is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, (CR^xR^y)_nOR^x, COOR^X, CONR^xR^y, S(O)_mNR^xR^y, NR^x(CR^xR^y)_nOR^x, (CH₂)_nNR^xR^y, (CH₂)_nCHR^xR^y, NR^x(CR^xR^y)_nCONR^xR^y, (CH₂)_nNHCOR^x, (CH₂)_nNH(CH₂)_nSO₂R^x and (CH₂)_nNHSO₂R^x;

L is a linker selected from -(CR^xR^y)_n-, -O-(CR^xR^y)_n-, -C(O)-, -NR^X-, -S(O)_mNR^x-, -NR^x(CR^xR^y)n- and -S(O)_mNR^x(CR^xR^y)_n;

R¹ and R², which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR^xR^y)_nOR^x, COR^X, COOR^X, C0NR^xR^y, (CH₂)_nNR^xR^y, (CH₂)_nCHR^xR^y and (CH₂)_nNHC0R^x;

R³ is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and cycloalkenyl;

U is selected from -(CR^xR^y)_n-, substituted or unsubstituted aryl, substituted or unsubstituted five membered 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, or substituted or unsubstituted six membered heterocycle selected from the group consisting of pyrimidine, pyridine and pyridazine;

V is selected from hydrogen, cyano, nitro, -NR^xR^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(O)OR^X, -OR^X, -C(0)NR^xR^y, -C(O)R^X and -SO₂NR^xR^y; or alternatively, U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring that may optionally include one or more heteroatoms selected from O, S and N; at each occurrence, R^x and R^y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and at each occurrence, 'm' and 'n' are independently selected from 0 to 2, both inclusive.

The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

According to one embodiment, there is provided a compound of the formula (Ia):

(Ia) or pharmaceutically acceptable salt thereof, wherein, at each occurrence, R^a is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and cycloalkylalkyl;

U is substituted or unsubstituted five membered heterocycle, for example selected from the group consisting of

at each occurrence, R^b is independently selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; at each occurrence, R^z is independently selected from halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, COOR^X, C0NR^xR^y, S(O)_mNR^xR^y, NR^x(CR^xR^y)_nOR^x, (CH₂)_nNR^xR^y, NR^x(CR^xR^y)_nCONR^xR^y, (CH₂)_nNHCOR^x, (CH₂)_nNH(CH₂)_nSO₂R^x and (CH₂)_nNHSO₂R^x; at each occurrence, R^x and R^y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;

at each occurrence, 'm' and 'n' are independently selected from 0 to 2, both inclusive; and

'p' is independently selected from from 0 to 5, 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 another embodiment, specifically provided are compounds of the formula (Ia) in which each occurance of R^a is independently hydrogen or alkoxy preferably methoxy.

According to yet another embodiment, specifically provided are compounds of the

formula (Ia) in which U is

in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the

formula (Ia) in which U is

; wherein R in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the formula (Ia) in which each of R^z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C₄)alkyl], haloalkyl (for example -CF₃), haloalkoxy (for example -OCF₃, or -OCH₂CF₃) and dialkyl amine (for example diethylamine).

According to one embodiment, there is provided a compound of the formula (Ib):

(Ib) or pharmaceutically acceptable salt thereof, wherein,

R^a, R^z, U and 'p' are as defined herein above.

The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.

According to another embodiment, specifically provided are compounds of the formula (Ib) in which each occurance of R^a is hydrogen.

According to yet another embodiment, specifically provided are compounds of the

formula (Ib) in which U is

; wherein R h in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the

formula (Ib) in which U is

; wherein R in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the formula (Ib) in which each of R^z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C₄)alkyl], alkoxy [for example -OCH₃, -OCH₂C(CH₃)₃], haloalkyl (for example CF₃), haloalkoxy (for example -OCF₃ or -OCH₂CF₃) and dialkyl amine (for example diethylamine).

According to one embodiment, there is provided a compound of the formula (Ic):

(Ic) or pharmaceutically acceptable salt thereof, wherein,

R^a, R^z, U and 'p' are as defined herein above.

The embodiment 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 (Ic) in which R^a is hydrogen or alkyl preferably methyl.

According to yet another embodiment, specifically provided are compounds of the

formula (Ic) in which U is

; wherein R^b in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the formula (Ic) in which each of R^z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C₄)alkyl], haloalkyl (for example CF₃), and haloalkoxy (for example OCF₃).

According to one embodiment, there is provided a compound of the formula (Id):

(Id) or pharmaceutically acceptable salt thereof, wherein,

R^a, R^z, U and 'p' are as defined herein above.

The embodiment 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 (Id) in which R^a is hydrogen.

According to yet another embodiment, specifically provided are compounds of the

formula (Id) in which U

; wherein R b in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the

formula (Id) in which U

; wherein R in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the formula (Id) in which each of R^z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C₄)alkyl], haloalkyl (for example CF₃), and haloalkoxy (for example OCF₃).

According to one embodiment, there is provided a compound of the formula (Ie):

(Ie) or pharmaceutically acceptable salt thereof, wherein,

R^a, R^z, U and 'p' are as defined herein above.

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 (Ie) in which R^a is hydrogen.

According to yet another embodiment, specifically provided are compounds of the

formula (Ie) in which U is

; wherein R b in this ring is hydrogen or alkyl (for example methyl).

According to yet another embodiment, specifically provided are compounds of the formula (Ie) in which each of R^z is independently selected from halogen (for example F, Cl or Br), alkyl [for example (Ci-C₄)alkyl], haloalkyl (for example CF₃) and haloalkoxy (for example OCF₃).

Particularly contemplated are compounds of the formulas (I), (Ia), (Ib), (Ic), (Id) and (Ie) which possess IC50 of less than 1000 nM, preferably, less than 250 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), (Ib), (Ic), (Id) and (Ie) structurally encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

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. The compounds and pharmaceutical compositions of the present invention are useful for modulating TRPAl receptors, which modulation is believed to be related to a variety of disease states.

In an embodiment, the compound of the present invention may also modulate one or more receptor such as TRPVl, TRPV3, TRP V4 and TRPM8 along with TRPAl receptor.

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 TRPAl 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 TRPAl 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 TRPAl 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_₆ 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, Cl, Br or I. Examples of "haloalkyl" include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl 4,4,4-trifluorobutyl, 4,4-difluorocyclohexyl, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl and the like. Examples of "haloalkoxy" include but are not limited to fluoromethoxy, difluoromethoxy, 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 cycloalkyl 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 cycloalkyl, wherein 'alkoxy' and 'cycloalkyl' are as defined above (either in the broadest aspect or a preferred aspect). Examples of cycloalkylalkoxy groups include 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. Preferably, 'cycloalkylalkoxy' is (C3-6)cycloalkyl-(Ci_6)alkoxy. 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 rings wherein such rings may be fused. 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., -CH₂CeH₅ or -C₂H₄CeH₅. Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.

The term "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. 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, A- 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 "heterocyclyl" refers to a heterocyclic ring radical as defined above. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described 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 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, -C00R^x', -C(O)R^X', -C(S)R^*', -C(0)NR^xR^y', -C(0)0NR^xR^y', -NR^x'CONR^yR^z', - N(R^x')S0R^y', -N(R^x')S0₂R^y', -(=N-N(R^x')R^y), -NR^x'C(0)0R^y', -NR^xR^y', -NR^x'C(0)R^y', - NR^x'C(S)R^y', -NR^x'C(S)NR^yR^z', -S0NR^xR^y', -S0₂NR^xR^y', -OR^X', -0R^x'C(0)NR^yR^z', - 0R^x'C(0)0R^y', -0C(0)R^x', -0C(0)NR^x'R^y', -R^xNR^y'C(0)R^z', -R^x'θR^y', -R^x'C(0)0R^y', - R^x'C(0)NR^y'R^z', -R^x'C(0)R^y', -R^x'θC(O)R^y', -SR^X', -SOR^X', -SO₂R^X' and -ONO₂, wherein R^x' R^y and R^z 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.

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), (Ib), (Ic), (Id) and (Ie) 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 of them. 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), (Ib), (Ic), (Id) and (Ie) 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, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus. The connection between therapeutic effect and inhibition of TRPAl is illustrated, for example, in Story, G. M. et al. Cell, 2003, 112, 819-829; McMahon, S.B. and Wood, J. N., Cell, 2006, 124, 1123-1125; 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 Aδ 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 Method of Preparation

The compounds described herein, including compounds of general formulas (I), (Ia), (Ib), (Ic), (Id), (Ie) and specific examples, can be prepared by techniques known to in the art, for example, through the reaction scheme depicted in Schemes 1-13. 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 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 pyrimidinedione-fused heterocyclic compounds of the general formula (I), wherein A₁, A₂, A₃, R¹, R², R³, U, V and L are as defined above in the general description can be prepared as shown in Scheme 1. Coupling reaction of a carboxylic acid or its ester derivative of the formula (1) with amines of the general formula (2) in the presence of a suitable coupling agent such as l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride (for R = H) or in the presence of a suitable strong base such as sodium hydride (for R = alkyl group) in a suitable solvent gives compounds of the formula (3). The selective N-alkylation of the compounds of the formula (3) with suitable alkylating agent of the formula (4) in the presence of base and solvent gives compounds of the general formula (I).

Scheme 1

An approach for the synthesis of pyrido[2,3-fiT]pyrimidinyl acetamides of general formula (Ia-I) wherein, R^a, R^z, U and 'p' are as defined herein above is prepared as shown in Scheme 2. Thus, 6-amino-l,3-dimethyluracil derivative of formula (5) on condensation with 2-cyano-3-ethoxyacrylic acid ethyl ester of formula (6) in the presence of a suitable base such as potassium carbonate gives the desired enamine derivative (7) in excellent yield. Thermal cyclisation of enamine (7) gives the bicyclic ester of the formula

(8) (Heber, D. et al. Pharmazie, (1993), 48 (7), 509-513, and Heber, D. et al. Biorganic & Medicinal Chemistry Letters. (2006), 14, 2837-2849). The ester group in compound of formula (8) is hydrolyzed using aqueous hydrobromic acid to give the amino acid derivative of formula (9) [procedure is similar to that is described by Tominaga, Y. et al. in Chem. Pharm. Bull. Chem. (1984), 32, 122-129). The decarboxylation of amino acid

(9) using copper in the presence of quinoline at elevated temperature gives 5-amino- pyrido[2,3-<i]pyrimidinedione of the formula (10) (Ludo. E. J. Kennis. et al. Biorg. & Med. Chem. Lett, (2000), 10, 71-74, and Mashraqui, S. H. et al. Tetrahedron, (2005), 61, 3507-3513). The diazotization of 5-amino pyrido[2,3-fiT]pyrimidinedione formula (10) followed by halide substitution of the resulting diazo compound (Hannaford, A. J.; Smith, P.W.G.; Tatchell, A. R., Vogel's Textbook of Practical Organic Chemistry 5^th Ed. (2006) pp. 936-937) affords 5-halo pyrido[2,3-<i]pyrimidinedione of the formula (11). The compound of formula (11) is coupled with allylic boronic acid (12) in the presence of a palladium (0) catalyst to give the allyl derivative of formula (13) using a Suzuki-Miyaura coupling procedure described by Kotha et al., in Synlett, (2005), U, 1877-1890. Oxidative cleavage of the terminal olefinic bond of intermediate (13) using sodium metaperiodate in the presence of catalytic amounts of ruthenium (III) chloride (Sharpless, K. B. et al. in J. Org. Chem., (1981), 3936-3938) gives pyrido[2,3-fiT]pyrimidinyl acetic acid derivative of the formula (14). The coupling reaction of pyrido[2,3-fiT]pyrimidinyl acetic acid derivative of the formula (14) with the various amines of the formula (16) using a suitable coupling agent such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the presence of a suitable activating agent such as HOBt (1- hydroxybenzotriazole) and in a suitable solvent or a mixture of solvents to afford compounds of the formula (Ia-I). Alterantively, pyrido[2,3-fiT]pyrimidinyl acetic acid (14) can also be converted to the corresponding ester (15) by using well known esterification methods. Sodium hydride mediated coupling reaction of (15) with various amines of the general formula (16) gives amides of the general formula (Ia-I).

Scheme 2

Another approach for the synthesis of pyrido[2,3-(f|pyrimidinyl acetic acid ester of the formula (15) wherein R^a is independently hydrogen, methyl, ethyl etc is shown in Scheme 3. Thus, reaction of 5-halo pyrido[2,3-<i]pyrimidinedione of the formula (11) with dialkyl malonoate in the presence of suitable base such as sodium hydride in a suitable solvent gives the diester (wherein R is alkyl) of the formula (17). Dealkoxycarbonylation of diester (17) using suitable base affords the desired pyrido[2,3- <i]pyrimidinyl etser (15').

Scheme 3

An approach for the synthesis of pyrido[2,3-fiT]pyrimidinyl acetamides of general formula (Ia-2) wherein R^z, U and 'p' are as defined herein above is prepared as shown in Scheme 4. Thus, the known pyrido[2,3-d]pyrimidinetrione of the formula (18) was prepared from readily available 6-amino-l,3-dimethyluracil of formula (5) using procedure described by Khattab, A. F. et al. Monatshefte fuer chemie, 1996, 127 (8/9), 917-926. The selective O-alkylation of the formula (18) using a suitable alkylating agent such as methyl iodide in the presence of a suitable base gives 7-methoxypyrido[2,3- <i]pyrimidinedione of the formula (19). The hydroxyl group of intermediate (19) is then transformed into triflate derivative (20) by treatment with trifluoromethanesulfonic anhydride in the presence of a suitable base and solvent. Palladium(O) catalyzed coupling of triflate (20) with allylboronic acid ester of formula (12) followed by oxidative cleavage of the vinyl group under Sharpless condition as described in Scheme 2 afforded the desired 7-methoxy pyrido[2,3-<i]pyrimidinyl acetic acid of the formula (22). The coupling of compound of formula (22) with amines of formula (16) by using a standard amide coupling method gives compound of general formula (Ia-2).

Scheme 4

H₃ Tf₂O OCH₃ base, solvent

(5) (18) (19)

(20) (21 )

(22) (Ia-2)

An approach for the synthesis of pyrido[4,3-(f|pyrimidinyl acetamides of the formula (Ib-I) wherein R^a, R^z, U and 'p' are as defined herein above is prepared as shown in Scheme 5. The known 6-methyluracil derivative (23) can be prepared by two different methods. In one approach N,N-dimethyl urea is condensed with acetic anhydride in presence of pyridine as reported by Egg, H. et al. in Synthesis, 1982, 1071-1073. Alternatively, intermediate (23) can be prepared by alkylation of 6-methyluracil according to the procedure reported by Siverman, R. B. et al. in J. Am. Chem. Soc, 1982, 104, 6434-6439. The formylation of uracil derivative (23) using phosphorous oxychloride and dry DMF gives the formyl uracil derivative (24) according to a procedure described by Shirahashi, M. et al. Yakugaku Z. 1971, 91, 1372. The formyl group of formula (24) was convertd to the corresponding cyano group in two steps by treatment with hydroxylamine hydrochloride followed by dehydration using phosphorous oxychloride (Hirota, K. et al. Heteocycle, 1998, 47, 871-882). Condensation of cyano derivative (25) with an acetal of the formula (26) in dry DMF gives the condensed product (27). Cyclisation of compounds of the formula (27) using 75% aqueous sulfuric acid or dimethylamine hydrochloride in dry pyridine according to a known protocol (Kouichiro, G. et al. US4808618A, 1989 and Klemmkurt et al. Chemische Berichte, 1981, 2001- 2018) affords 5-hydroxylpyrido[4,3-<i]pyrimidinedione (28) in excellent yield. The hydroxyl group in (28) was converted to a halide to give intermediate (29) by using phosphorous oxychloride or phosphorous oxybromide in dry toluene in the presence of suitable base such as N,N-dimethylaniline. 5-Allylpyrido[4,3-fiT]pyrimidinedione (30) is obtained by Suzuki-Miyaura coupling reaction of 5-halopyrido pyrimidinedione (29) with allyl boronic acid of the formula (12). Oxidative cleavage of terminal olefinic bond in intermediate (30) under Sharpless reaction conditions proceeds smoothly to give pyrido[4,3-<i]pyrimidinyl acetic acid derivative of the formula (31). The coupling of compounds of formula (31) with an amine of formula (16) by using a standard amide coupling method gives compounds of general formula (Ib-I).

Scheme 5

An alternative approach for the synthesis of pyrido[4,3-<i]pyrimidinyl acetamides of the general formula (Ib-I) is shown in Scheme 6. Thus, reaction of 5-halo pyridopyrimidinedione (29) with dialkyl malonate in the presence of suitable base such as sodium hydride in suitable solvent such as dry DMSO gives the coupled product (33) which on dealkoxycarboxylation using suitable base gives pyrido[4,3-fiT]pyrimidinyl ester of the formula (35). A similar approach is reported by Koomen, G. J. et al Tetrahedron (1985), 41, 1893-1904. The ester (35) is also prepared by coupling 5-halo pyridopyrimidinedione (29) with a beta keto ester such as ethyl acetoacetate (34) in the presence of suitable base such as sodium hydride followed by deacetylation using a suitable base. The reaction proceeds via a retro Claisen reaction as reported by Hamamichi, N. et al. J. Heterocyclic Chem. (1990), 27, 2011-2015 and Yamazaki, M. et al. J. Heterocyclic Chem. (2001), 38, 269-21 A). The direct coupling of ester (35) with amines of the formula (16) using a suitable base such as sodium hydride in the presence of a suitable solvent such as toluene or xylene affords compounds of the general formula (Ib-I). Alternatively, pyrido[4,3-<i]pyrimidinyl ester (35) can be hydro lysed to corresponding acid and coupled with amines of the formula (16) using a suitable coupling agent gives compounds of general formula (Ib-I).

Scheme 6

(29) (33)

1 . H₃CCOCH₂CO₂R (34) base, solvent

2. NEt₃/H₂O

C^H3

(Ib-I)

A general approach for the synthesis of pyrimido[4,5-fiT]pyrimidinyl acetamides of general formula (Ic) wherein R^a, R^z, U and 'p' are as defined herein above, is prepared as shown in Scheme 7. Thus, commercially available 1,3-methyllbarbituric acid of the formula (36) was converted to known 6-chloro-5-formyl-l,3-dimethyluracil (37) using the reported procedure (Singh, J. S. et al. Synthesis 1988, 342-344) using POCl₃ and dry DMF. Treatment of ό-chloro-S-formyl-l^-dialkyluracil (37) with hydroxylamine in methanol and followed by dehydration with phosphorous oxychloride give the cyano derivative (38). The intermediate (38) on reaction with sodium azide in DMF followed by reduction using SnCl₄ in a mixture of ethanol and water gives the amino derivative (39). Condensation of (39) with an acetal of the formula (39) in dry DMF gives compounds of the formula (41). Compound (41) was treated with 75% aqueous sulphuric acid to afford the desired 5-hydroxypyrimido[4,5-d] pyrimidinedione (42) in good yield. This approach is similar to the procedure described by Klemmkurt et al. in Chemische Berichte, 1981, 2001-2018). Reaction of hydroxyl intermediate (42) with phosphorous oxyhalide or phosphorous oxybromide in dry toluene in the presence of suitable base such as N, N- dimethyl aniline gives 5-halo pyrimido[4,5-d]pyrimidinedione (43). Suzuki-Miyaura coupling reaction of halide (43) with allyl boronic acid ester (12) gives 5-allyl pyrimido [4, 5 -<i]pyrimidinedione (44). The oxidative cleavage of the olefin group of intermediate (44) gives the carboxylic acid derivative (45). The coupling reaction of acid (45) with an amine of the formula (16) using a suitable coupling agent affords compounds of the formula (Ic).

Scheme 7

_LJ ^ ? „ ° „ „ 1. NH₂OKHCl/ KOH ₁ _ ? „..

^H3C"N ^| POCI_3^ H₃C_N A^CHO MeOH / H₂O ^H3^u _N " γ^UN 1. azide formation

O^N ^O ^DMF O^ΛN Cl 2. POCI₃ / DMF O^N Cl 2. reduction

CH₃ CH₃ CH₃

(36) (37) (38)

(45) (Ic)

Another approach for the synthesis of pyrimido[4,5-<i]pyrimidinyl acetamides of general formula (Ic) is depicted in Scheme 8. Thus, reaction of 5-halo pyrimido pyrimidinedione (43) with dialkyl malonate in the presence of suitable base such as sodium hydride in suitable solvent such as dry DMSO gives the coupled product (46) which on dealkoxycarboxylation using suitable base gives the mono ester (47). Alternatively, the reaction of 5-halo pyrimido pyrimidinedione (43) with a beta keto ester such as ethyl acetoacetate (34) in the presence of suitable base such as sodium hydride followed by deacetylation gives the desired ester (47). Sodium hydride mediated coupling reaction of ester (47) with an amine of the formula (16) in a suitable solvent such as toluene or xylene affords compounds of the general formula (Ic). Alternatively, compound of formula (47) can be hydrolysed to corresponding acid and coupled with amines of the formula (16) using a suitable coupling agent gives compounds of general formula (Ic).

Scheme 8

^H3 base, solvent

^neat

CH₃ CH₃

(43) (46)

An approach for the synthesis of pyrimido[4,5-c]pyridazinyl acetamide of formula (Id-I) R^z, U and 'p' are as defined herein above, is described in Scheme 9. Thus, 1,3- dimethylbarbituric acid of the formula (36) on treatment with phosphorous oxy chloride gives 6-chloro uracil derivative (48), which on treatment with hydrazine hydrate gives intermediate (49). Cyclisation of hydrazine derivative (49) with glyoxylic acid using the procedure reported by Aleksandrova G. A. et. al. in Pharmaceutical Chemistry, 18, 322- 325, 1984 gives intermediate of the formula (50). Halogenation and aromatisation of (50) using phosphorous oxybromide or phosphorous oxychloride in dry toluene in the presence of suitable base such as N,N-dimethylaniline affords 4-halo pyrimido[4,5- c]pyridazinedione of the formula (51). Reaction of intermediate (51) with ethyl ethynyl ether in the presence of dichlorobis(triphenylphosphine)palladium [PdCl₂(Pli3)₂] and cuprous iodide in dry DMF in the presence of triethylamine gave (52). The hydration of (52) in the presence of aqueous H₂SO₄ afforded the desried pyrimido[4,5-c]pyridazinyl acetic ethyl ester (53) in good yield. This conversion is similar to a method reported by Sakamoto T. et. al. in Chem. Pharm. Bull. Chem. (1994), 42, 2032-2035. Sodium hydride mediated coupling reaction of (53) with amines of the general formula (16) gives compounds of the general formula (Id-I).

Scheme 9 CHOCOOH S^θlV6nt

An alternative approach for the synthesis of pyrimido[4,5-c]pyridazinyl acetamide of formula (Id-I) R^z, U and 'p' are as defined herein above, is depicted in Scheme 10. Thus, reaction of 4-halo pyrimido[4,5-c]pyridazinedione of the formula (51) with allylboronic acid pinacol ester of the formula (12) under Suzuki-Miyaura coupling conditions gives the allyl pyrimido[4,5-c]pyridazinedione (54). Oxidative cleavage of the terminal olefinic bond of intermediate (54) gives pyrimido[4,5-c]pyridazinyl acetic acid of the formula (55). Coupling reaction of compounds of formula (55) with amines of formula (16) by using an appropriate coupling agent gives compounds of general formula (Id-I).

Scheme 10

^ solvennTt ^

CH₃ (Id-I)

A general approach for the synthesis of pyrimido[4,5-<f]pyridazinyl acetamide of formula (Ie-I) wherein R^z, U and 'p' are as defined herein above, is depicted in Scheme 11. The formylation of compounds of the formula (23) using phosphorous oxychloride in the presence of dry DMF gives the 5-formyl uracil derivative as described in Shirahashi, M. et al. in Yakugaku Zasshi 1971, 91, 1372. Oxidation of formyl group with potassium persuphate in the presence of a catalytic amount of silver nitrate gives pyrimidine-5- carboxylic acid (56). This reaction is similar to the procedure reported by Kanatomo, S. et.al. Chem. Pharm.Bull. 1988, 2042-2049. Esterification of (56) followed by bromination using literature procedure [Thomas F, et. al in J. Heterocyclic Chem. 15, 687-688 (1978)] gives dibromo ester of the formula (58). Cyclisation of dibromo ester (58) using hydrazine hydrate in a suitable solvent gives pyrimido[4,5-<i]pyradizine trione of the formula (59) as described by Sanjay Batra, et. al in Tetrahedron 2004, 60, 2301-2310). Halogenatiopn and aromatisation of (59) using phosphorous oxychloride or phosphorous oxybromide in dry toluene in the presence of suitable base such as N,N-dimethyl aniline gives 5-halo-pyrimido[4,5-<i]pyridazinedione of the formula (60). The reaction of aryl halide (60) with dialkyl malonate in the presence of suitable base gives diester of the formula (61). Dealkoxycarbonylation of (61) as desribed in Scheme 3 gives the desried pyrimido[4,5-fiT]pyridazinyl acetic ester of the formula (62). The coupling of pyrimido[4,5-<i]pyridazinyl acetic ester of the formula (62) with amines of formula (16) by using a suitable base and solvent gives compounds of general formula (Ie-I).

Scheme 11

(23) (56) (57)

Scheme 12 depicts synthesis of 2-amino-4-aryl thiazoles of the formula (68) from acetophenones of the formula (67) 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 (63) (wherein R^z and 'p' are as defined in description) in three steps. Thus, acid of formula (63) was converted to the corresponding acid chloride of formula (64) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (64) was converted to corresponding Weinerb amide of formula (66) by treating with N, O- dimethylhydroxylamine hydrochloride of formula (65) in the presence of a suitable base such as triethylamine. The addition of methyl magnesium iodide to Weinreb amide of formula (66) afforded acetophenone derivative of formula (67).

Conversion of acetophenone derivative of formula (67) to 2-amino-4-substituted aryl thiazole of the formula (68) can be effected by two approaches as described in Scheme 12. In the first case acetophone 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 (67) can be converted to 2-amino-4-aryl thiazole (68) 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 12 _z JT if CO₂ ²H / (_nC_oO_rC;_hl)_o2, _n D_MM_FF _ CH₃ONHCH₃.HCI (65)

CH₂CI₂ or SOCI₂

base, solvent

(63) (64)

5-Aryl-lH-imidazol-2-amines of the formula (70) were prepared as shown in Scheme 13. The reaction of acetophenones of the formula (67) (wherein R^z and 'p' are as defined above in scheme 12) with bromine in acetic acid to give the alpha bromo intermediate, which on reaction with acetyl guanidine in acetonitrile at reflux condition give compounds of the formula (69). The deacetylation of (69) in the presence of catalytic amount of concentrated sulphuric acid using suitable solvent afforded desired 5-Aryl-lH- imidazol-2-amine of the formula (70). (This is similar to procedure reported by Thomas, L. et al., J. Org. Chem., 1994, 59, 7299-7305).

Scheme 13

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-fife: 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.

INTERMEDIATES Pyrido[2,3-<i]pyrimidinyl acetic acid, ethyl pyrido[2,3-<i]pyrimidinyl acetate, 7- methoxy-pyrido[2,3-<i]pyrimidinyl acetic acid, ethyl pyrido[4,3-<i]pyrimidinyl acetate, ethyl pyrimido[4,5-fiT]pyrimidinyl acetate, ethyl pyrimido[4,5-c]pyridazinyl acetate and ethyl pyrimido[4,5-<i]pyridazinyl acetate were used for the preparation of compounds of the present invention, were prepared according to the synthetic schemes provided in 'General Methods of Preparation'. However, these intermediates may be prepared by alternative approaches reported in the literature or by methods known to people skilled in the art of organic synthesis. Detailed experimental procedures for the synthesis of intermediates are given below.

Intermediate 1

(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetic acid

Step 1 Ethyl (2£)-2-cyano-3-[(l,3-dimethyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4- yl)amino]acrylate: A solution of 6-amino-l,3-dimethyl uracil (80.0 g, 515.596 mmol) and ethyl 2-cyano-3-ethoxyacrylate (87.22 g, 515.596 mmol) in anhydrous N,N-dimethyl formamide (1.0 lit.) was added anhydrous potassium carbonate (106.8 g, 773.395 mmol) and the mixture was heated to 90⁰C under nitrogen atmosphere for 2 h. The reaction mixture was cooled to room temperature, poured into crushed ice, acidified with acetic acid till the solid precipitates out. The solid obtained was filtered, washed with water and dried to give 75.23 g of the product as an off white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.37 (t, J= 6.9, 3H), 3.35 (s, 3H), 3.56 (s, 3H), 4.35 (q, J= 6.9, 2H), 5.56 (br s, IH), 7.77 (d, J= 10.5, IH), 11.16 (d, J= 9.3, IH).

Step 2 Ethyl 5-amino-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-<i] pyrimidine- 6-carboxylate: A solution of Step 1 intermediate (75.0 g, 269.532 mmol) and diphenyl ether (539 ml) was refluxed for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature. Hexane was added to the reaction mixture and solid obtained was filtered, washed with diethyl ether to give pure 45.12 g of the product as an off white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.39 (t, J= 6.9, 3H), 3.43 (s, 3H), 3.67 (s, 3H), 4.36 (q, J= 7.2, 2H), 8.63 (br s, IH), 8.85 (s, IH), 9.42 (br s, IH). Step 3 5-Amino-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidine-6- carboxylic acid: A mixture of Step 2 intermediate (40.0 g, 147.745 mmol), acetic acid (718 ml) and 40 % HBr (287 ml) was refluxed for 18 h. After evaporation of solvent under reduced pressure, solid obtained was filtered, washed with hexane and dried to obtain 34.11 g of the product as an off white solid; ¹H-NMR (300 MHz, CDCl₃) δ 3.25 (s, 3H), 3.51 (s, 3H), 8.66 (br s, IH), 8.72 (s, IH), 9.27 (br s, IH).

Step 4 5-Amino-l,3-dimethylpyrido[2,3-(i]pyrimidine-2,4(lH,3H)-dione: Copper powder (2.714 g, 396.0 g atom) was added to a suspension of Step 3 intermediate (33.0 g, 132.0 mmol) in quinoline (660 ml) and the resulting mixture was stirred and heated at 235- 240⁰C for 3 h under nitrogen. The reaction mixture was cooled to room temperature, diluted with chloroform, filtered to remove insoluble residue. The solvent was evaporated and crude product was purified by silica gel column chromatography by using 10% ethyl acetate in petroleum ether to give 30.0 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.23 (s, 3H), 3.46 (s, 3H), 6.42 (d, J= 6.0, IH), 7.63 (br s, IH), 7.95 (d, J= 5.4, IH), 8.24 (br s, IH).

Step 5 5-Iodo-l,3-dimethylpyrido[2,3-(i]pyrimidine-2,4(lH,3H)-dione: To a stirred solution of tert-butyl nitrite (6.0 ml, 50.971 mmol) in acetonitrile (135.9 ml) was added copper iodide (7.76 g, 40.776 mmol) slowly during 10-15 min. Step 4 intermediate (7.0 g, 33.981 mmol) was added portion-wise at room temperature. The reaction was heated at 65°C for 3 h. The mixture was cooled to room temperature and quenched with saturated solution of sodium thiosulphate (150 ml) and extracted with ethyl acetate (2 x 250 ml). The combined organic layers were washed with water, dried over sodium sulphate and concentrated. The crude product obtained was then purified by silica gel column chromatography using 5% ethyl acetate in chloroform to give 5.1 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSCM₆) δ 3.27 (s, 3H), 3.53 (s, 3H), 7.91 (d, J = 5.1 Hz, IH), 8.19 (d, J= 5.4 Hz, IH); ESI-MS (m/z) 318.14 (M+H)⁺. Step 6 5-Allyl-l,3-dimethylpyrido[2,3-βT|pyrimidine-2,4(lH,3H)-dione: To a stirred solution of Step 5 intermediate (5.0 g, 15.772 mmol) in dry TΗF (80 ml) was added cesium fluoride (4.79 g, 31.545 mmol) and allyl boronic acid pinacol ester (5.31 ml, 28.231 mmol) under nitrogen atmosphere and the mixture was degassed for 10 min. Tetrakis(triphenylphosphine)palladium(0) (1.82 g, 1.577 mmol) was added and the mixture was stirred at reflux temperature for 24 h under nitrogen atmosphere. The reaction mixture was diluted with water (80 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were concentrated and the residue obtained was purified by silica gel column chromatography using 10% ethyl acetate in pet ether to give 2.67 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSCM₆) δ 3.46 (s, 3H), 3.72 (s, 3H), 4.06 (d, J= 6.3, 2H), 5.06-5.16 (m, 2H), 5.98-6.09 (m, IH), 7.04 (d, J= 5.4 Hz, IH), 8.49 (d, J= 4.8 Hz, IH); ESI-MS (m/z) 232.28 (M+H)⁺. Step 7 (l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetic acid: To a stirred solution of Step 6 intermediate (2.5 g, 10.822 mmol) in a 1 :3:3 mixture of water, acetonitrile and carbon tetrachloride (56.1 ml) at room temperature was added sodium metaperiodate (14.4 g, 67.324 mmol) and ruthenium (III) chloride hydrate (46 mg, 0.216 mmol). The biphasic mixture was stirred vigorously at room temperature for 24 h. The mixture was cooled and filtered. The solid containing the product was refluxed in ethyl acetate and the hot mixture is filtered. The filtrate containing the product was evaporated to give 2.2 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.26 (s, 3H), 3.58 (s, 3H), 4.12 (s, 2H), 7.22 (d, J= 4.8 Hz, IH), 8.62 (d, J =

5.1 Hz, IH), 12.35 (br s, IH,); APCI-MS (m/z) 250.18 (M+H)⁺.

Intermediate 2 Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetate

CH₃

Route 1:

Step 1 : Diethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5- yl)malonate: To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.883 g, 22.04 mmol) in dry DMSO (28 ml) was added dropwise diethyl malonate (3.36 ml, 22.04 mmol) at room temperature. After evolution of hydrogen ceased, Step 5 of intermediate 1 (3.5 g, 11.02 mmol) was added and heated at 80⁰C for 4h. The reaction mixture was cooled to room temperature and diluted with water (50 ml), extracted with ethyl acetate (3x25 ml). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated. Purification of crude product by silica gel column chromatography to obtain 3.7 g of the product as a off white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 1.19 (t, J= 6.9 Hz, 6H), 3.26 (s, 3H), 3.59 (s, 3H), 4.19 (q, J= 6.9 Hz, 4H),

6.02 (s, IH), 7.11 (d, J= 5.4 Hz, IH), 8.72 (d, J= 5.1 Hz, IH). Step 2: Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5- yl)acetate: To a stirred solution of Step 1 intermediate (2.67 g, 7.646 mmol) in dry ethanol (38 ml) was added a catalytic amount of sodium hydride (60% dispersion in mineral oil, 30 mg, 0.767 mmol) at room temperature and reaction was refluxed for 2 h. Excess of solvent was removed under reduced pressure and diluted with water, precipitated solid was collected by filtration to give 1.48 g of the desired product as a white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 1.17 (t, J= 6.6 Hz, 3H), 3.25 (s, 3H), 3.58 (s, 3H), 4.09 (q, J = 6.9 Hz, 2H), 4.17 (s, 2H), 7.23 (d, J = 4.8 Hz, IH), 8.63 (d, J = 4.8 Hz, IH).

Route 2: Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5- yl)acetate: To a stirred solution of Intermediate 1 (490 mg, 1.756 mmol) in dry ethanol (15 ml) was added catalytic amount of concentrated sulphuric acid (2 drops) and the reaction was refluxed for 3 h. The excess of solvent was evaporated and water was added, precipitated solid filtered to obtain 425 mg of the product as off-white solid. ¹H-NMR (300 MHz, DMSO-(Z₆) δ 1.17 (t, J = 6.6 Hz, 3H), 3.25 (s, 3H), 3.58 (s, 3H), 4.09 (q, J = 6.9 Hz, 2H), 4.17 (s, 2H), 7.23 (d, J= 4.8 Hz, IH), 8.63 (d, J= 4.8 Hz, IH).

Intermediate 3 (7-Methoxy-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetic acid

Step 1 5-Hydroxy-l,3-dimethylpyrido[2,3-d]pyrimidine-2,4,7(lH,3H,8H)-trione: A mixture of 6-amino- 1,3 -dimethyl uracil (16.0 g, 103.12 mmol) and dimethyl malonate (33.036 g, 206.25 mmol) in diphenyl ether (80 ml) was refluxed for 2 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, precipitated solid was collected by filtration and crude solid was purified by silica gel column chromatography by using 3 % ethyl acetate in chloroform to obtain 9.8 g of the product; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.25 (s, 3H), 3.46 (s, 3H), 5.87 (s, IH), 11.89 (s, IH), 12.17 (br s, IH); APCI-MS (m/z) 224.26 (M+H)⁺.

Step 2 5-Hydroxy-7-methoxy-l,3-dimethylpyrido[2,3-(i]pyrimidine-2,4(lH,3H)-dione: A solution of Step 1 intermediate (9.6 g, 43.049 mmol) in dry DMF (70 ml) was added anhydrous cesium carbonate (14.026 g, 43.049 mmol) and the mixture was stirred at room temperature for 15 min. Methyl iodide (6.111 g, 43.049 mmol) was added slowly with stirring and further stirred at room temperature for overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2x100 ml). The combined organic layers were washed with water (75 ml), brine (75 ml), dried over Na₂SO₄ and concentrated. The crude residue obtained was purified by silica gel column chromatography using 20% ethyl acetate in petroleum ether to obtain 4.3 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSCM₆) δ 3.26 (s, 3H), 3.51 (s, 3H), 3.93 (s, 3H), 6.08 (s, IH), 12.15 (br s, IH); APCI-MS (m/z) 238.21 (M+H)⁺. Step 3 7-Methoxy-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl trifluoromethanesulfonate: To a stirred solution of Step 2 intermediate (4.2 g, 18.834 mmol) in dry dichloromethane (10 ml) was added triethylamine (2.86 g, 28.251 mmol) at room temperature and reaction mixture was cooled to 0⁰C. Triflic anhydride (6.38 g, 22.601 mmol) was added slowly and reaction was allowed to warm to room temperature. After overnight stirring reaction mixture was diluted water (150 ml) and extracted with ethyl acetate (3x50 ml). The organic layers were washed with water, brine, dried and concentrated. The crude residue was purified by silica gel column chromatography using 10% ethyl acetate in petroleum ether to give 7.75 g of the product as a white solid; ¹H- NMR (300 MHz, DMSO-^₆) δ 3.26 (s, 3H), 3.57 (s, 3H), 4.05 (s, 3H), 6.84 (s, IH); APCI-MS (m/z) 369.99 (M)⁺.

Step 4 5-Allyl-7-methoxy-l,3-dimethylpyrido[2,3-d]pyrimidine-2,4(lH,3H)-dione: The title compound was prepared according to the procedure as described for Intermediate 1, by coupling of Step 3 intermediate (7.7 g, 20.867 mmol) with allyl boronic acid pinacol ester (6.3 g, 37.561 mmol) in the presence of tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.982 mmol) and cesium fluoride (6.34 g, 41.734 mmol) in 1,4-dioxane (80 ml) to give 3.65 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.44 (s, 3H), 3.68 (s, 3H), 3.95-4.02 (m, 5H), 5.00-5.13 (m, 2H), 6.00-6.06 (m, IH), 6.44 (s, IH); APCI-MS (m/z) 262.23 (M+H)⁺.

Step 5 (7-Methoxy-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5- yl)acetic acid: The title compound was prepared according to procedure as described for Intermediate 1 by oxidative cleavage of Step 4 intermediate (3.5 g, 14.171 mmol) using ruthenium(III) chloride hydrate (0.06 g, 0.283 mmol) and sodium metaperiodate (18.2 g, 85.026 mmol) in mixture of water, acetonitrile and carbon tetrachloride to give 2.2 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.23 (s, 3H), 3.56 (s, 3H), 3.98 (s, 3H), 4.02 (s, 2H), 6.65 (s, IH), 12.27 (br s, IH); APCI-MS (m/z) 280.10 (M+H)⁺.

Intermediate 4

Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-βT|pyrimidin-5-yl)acetate

Step 1 l,3,6-Trimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of N, N- dimethyl urea (80.0 g, 907.955 mmol) and 4-dimethylaminopyridine (110.92 g, 907.955 mmol) in dry pyridine (1.4 lit.), acetic anhydride (905.86 g, 2996.254 mmol) was added dropwise at 0⁰C. The reaction mixture was stirred at room temperature for overnight. The excess of solvent was evaporated under reduced pressure and quenched into 2 Ν HCl (1.0 lit.) and extracted with chloroform (3 x 300 ml). The organic layer was washed with 2 Ν HCl (1.0 lit.) and saturated aqueous sodium hydrogen carbonate solution (1.0 lit.), dried over anhydrous sodium suphate. The solvent was evaporated under reduced pressure to give 95.15 g of the product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 2.24 (s, 3H), 3.33 (s, 3H), 3.41 (s, 3H), 5.62 (s, IH).

Step 2 l,3,6-trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde: To a stirred solution of Step 1 intermediate (95.00 g, 616.883 mmol) in dry DMF (94 ml) was added phosphorous oxychloride (118 ml) dropwise at 0⁰C and reaction mixture was heated at 120⁰C for 4 h. The reaction mixture was allowed to room temperature and extracted with chloroform (3x250 ml). The combined organic extracts were dried over Na₂SO₄ and concentrated. The crude material obtained was then stirred in ethanol (100 ml) and preceipitated solid was collected by filteration to give 28.7 g of the product as an off white solid; ¹H-NMR (300 MHz, CDCl₃) δ 2.78 (s, 3H), 3.40 (s, 3H), 3.53 (s, 3H), 10.28 (br s, IH).

Step 3 l,3,6-Trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime: A mixture of Step 2 intermediate (28.7 g, 157.692 mmol), hydroxylamine hydrochloride (13.05 g, 189.231 mmol) and triethylamine (19.14 g, 157.692 mmol) in ethanol (300 ml) was stirred at room temperature for 3 h. The resulting precipitates were filtered and recrystallized from ethanol to give 29.9 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 2.55 (s, 3H), 3.19 (s, 3H), 3.40 (s, 3H), 8.04 (s, IH), 10.10 (br s, IH).

Step 4 l,3,6-Trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbonitrile: Step 3 of intermediate (29.7 g, 150.616 mmol) was added portion-wise to phosphorous oxychloride (267.3 ml) at room temperature and reaction was stirred further for 1 h. The excess of phosphorous oxychloride was evaporated under reduced pressure. The crude residue obtained was washed with diethyl ether several times and triturated with water. The solid obtained was filtered, washed with methanol and dried to give 24.1 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSCM₆) δ 2.53 (s, 3H), 3.18 (s, 3H), 3.39 (s, 3H). Step 5 6-[(£)-2-(Dimethylamino)vinyl]-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydro pyrimidine-5-carbonitrile: A mixture of Step 4 intermediate (20.00 g, 111.731 mmol) and N,N-dimethyl formamide dimethyl acetal (15.95 g, 134.078 mmol) in dry DMF (40 ml) was heated at 80⁰C for 2h. The reaction mixture was cooled to room temperature and diluted with diethyl ether (100 ml). The precipitated solid was filtered, washed with diethyl ether (2 x 50 ml) and dried to obtain 24.0 g of the product as a white solid; ¹H- ΝMR (300 MHz, CDCl₃) δ 3.09 (s, 6H), 3.34 (s, 3H), 3.51 (s, 3H), 4.64 (d, J= 12.6 Hz, IH), 8.05 (d, J= 12.0 Hz, IH).

Step 6 5-Hydroxy-l,3-dimethylpyrido[4,3-(i]pyrimidine-2,4(lH,3H)-dione: To a stirred solution of 75 % sulfuric acid (291 ml), Step 5 intermediate (23.5 g, 102.174 mmol) was added portion-wise and the reaction was then heated at 90⁰C for 4 h. The reaction mixture was cooled to room temperature and diluted with ice cold water (500 ml). The solid precipitated out was collected by filtration and dried to give 16.00 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSCM₆) δ 3.18 (s, 3H), 3.42 (s, 3H), 6.30 (d, J = 7.5 Hz, IH), 7.67 (d, J= 6.9 Hz, IH), 11.89 (br s, IH).

Step 7 5-Bromo-l,3-dimethylpyrido[4,3-(i]pyrimidine-2,4(lH,3H)-dione: A solution of Step 6 intermediate (5.0 g, 24.154 mmol) in dry toluene (80 ml) were added N, N- dimethylaniline (2.93 g, 24.154 mmol) followed by phosphorous oxybromide (8.3 g, 29.014 mmol). The reaction mixture was refluxed for 24 h. The solvent was completely evaporated under reduced pressure and diluted with water (400 ml). The solid precipitated out was filtered and purified by silica gel column chromatography by using 9 % ethyl acetate in chloroform to obtain 1.92 g of the product as a white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.27 (s, 3H), 3.48 (s, 3H), 7.47 (d, J = 5.7 Hz, IH), 8.43 (d, J = 5.7 Hz, IH). Step 8 Diethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5- yl)malonate: The title comopound was prepared by following the procedure as described for step 1 of Intermediate 2 by the reaction of Step 7 intermediate (1.9 g, 7.063 mmol), sodium hydride (60% dispersion in mineral oil, 0.339 g, 14.126 mmol), diethyl malonate (2.26 g, 14.126 mmol) and dry DMSO (15 ml) to give 1.73 g of the product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.30 (t, J= 7.2 Hz, 6H), 3.43 (s, 3H), 3.60 (s, 3H), 4.30 (q, J= 7.5 Hz, 4H), 5.88 (s, IH), 7.09 (d, J= 6.0 Hz, IH), 8.65 (d, J= 5.7 Hz, IH). Step 9 Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5- yl)acetate: The title comopound was prepared by following the procedure as described for step 2 of Intermediate 2 by Step 8 intermediate (1.67 g, 4.785 mmol), sodium hydride (60% dispersion in mineral oil, 11.5 mg, 0.478 mmol) and dry ethanol (32 ml) to obtain 630 mg of the desired product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.28 (t, J = 7.5 Hz, 3H), 3.44 (s, 3H), 3.60 (s, 3H), 4.20 (q, J= 9.0 Hz, 2H), 4.40 (s, 2H), 7.06 (d, J = 6.0 Hz, IH), 8.62 (d, J= 6.3 Hz, IH).

Intermediate 5

Ethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetate

CH₃

Stepjj_. 6-Chloro- 1 ,3 -dimethyl-2,4-dioxo- 1 ,2,3 ,4-tetrahydropyrimidine-5-carboxaldehyde: Phosphorous oxychloride (1.720 lit.) was added slowly to dry DMF (450 ml) at 0⁰C. The mixture was then allowed to warm to room temperature. 1,3-Dimethylbarbituric acid (150 g, 960.737 mmol) was added portion wise and the resultant mixture refluxed for 45 min. The excess of phosphorous oxychloride and DMF were distilled off under reduced pressure and the viscous residue was poured into ice-cold water (3000 ml). The reaction mixture was allowed cooled to room temperature and extracted with chloroform (3 x 2000 ml). The combined organic extracts were dried over Na₂SO₄ and concentrated. The crude material obtained was then stirred in 10 % ethyl acetate in hexane (500 ml) to obtain 131 g of the product as the pale yellow solid; ¹H NMR (300 MHz, CDCl₃) δ 3.41 (s, 3H), 3.69 (s, 3H), 10.18 (br s, IH).

Step 2: 6-Chloro-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde oxime: To a mixture of Step 1 intermediate (120 g, 594.059 mmol) and hydroxylamine hydrochloride (51.6 g, 742.574 mmol) in methanol (1.2 lit.) was added dropwise a solution of KOH (41.6 g, 742.574 mmol) in water (75 ml) over a period of 1 h, while reaction mixture was maintained below 10⁰C. The mixture was stirred at room temperature for 1 h, and the resulting precipitated oxime was collected by filtration, washed with water (2 x 500 ml), methanol (2 x 250 ml) and dried to give 95.52 g of the product as a pale yellow solid; ¹H NMR (300 MHz, DMSCM₆) δ 3.14 (s, 3H), 3.51 (s, 3H), 7.93 (s, IH), 11.39 (br s, IH).

Step 3 6-Chloro- 1 ,3-dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydropyrimidine-5-carbonitrile: The title compound was prepared following the procedure as described for step 4 of Intermediate 4 by the reaction of Step 2 intermediate (95 g, 436.560 mmol) with phosphorous oxychloride (850 ml) to give 78.63 g of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆ ): δ 3.38 (s, 3H), 3.69 (s, 3H).

Step 3: ό-Azido-l^-dimethyl^^-dioxo-l^^^-tetrahydropyrimidine-S-carbonitrile: To a stirred solution of Step 3 of intermediate (20.0 g, 103.092 mmol) in dry ethanol (103 ml), sodium azide (8.042 g, 123.711 mmol) was added and the mixture was further stirred for 2 h at room temperature. Solid precipitated out was collected by filtration, washed with ethanol and dried to give 24.1 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.17 (s, 3H), 3.30 (s, 3H).

Step 4: ό-Amino-l^-dimethyl^^-dioxo-l^^^-tetrahydropyrimidine-S-carbonitrile: To a stirred solution of Step 3 intermediate (17.9 g, 89.27 mmol) in mixture of ethanol (357 ml) and water (5.5 ml), stannous chloride (30.21 g, 40.229 mmol) was added and mixture was stirred at room temperature for 2 h. The solvent was evaporated completely under reduced pressure, diluted with water, solid obtained was filtered and dried to give 7.12 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.10 (s, 3H), 3.28 (s, 3H), 7.98 (s, 2H).

Step 5: N^l-(5-Cyano-l,3-dimethyl-2,6-dioxo-l,2,3,6-tetrahydropyrimidin-4-yl)-N,N- dimethylimidoformamide: The title compound was prepared according to the procedure as described for step 5 of Intermediate 4 by the reaction of Step 4 intermediate (7.0 g, 40.229 mmol) with N,N-dimethylformamide dimethyl acetal (19.1 g, 160.919 mmol) in dry DMF (80 ml) to give 8.75 g of the product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 3.15 (s, 3H), 3.24 (s, 3H), 3.34 (s, 3H), 3.41 (s, 3H), 8.12 (s, IH). Step 6: 5-Hydroxy-l,3-dimethylpyrimido[4,5-(i]pyrimidine-2,4(lH,3H)-dione: The title compound was prepared following the procedure as described for Intermediate 4 by cycisation of Step 5 intermediate (8.75 g, 37.234 mmol) using 75 % sulfuric acid (106 ml) to give 6.1 g of the product as an off-white solid; ¹H-NMR (300 MHz, DMSCM₆) 5 3.18 (s, 3H), 3.46 (s, 3H), 8.39 (s, IH), 12.89 (br s, IH).

Step 7: 5-Bromo-l,3-dimethylpyrimido[4,5-d]pyrimidine-2,4(lH,3H)-dione: The title compound was prepared according to the procedure described for Intermediate 4 by reaction of Step 6 intermediate (5.38 g, 25.844 mmol) with phosphorous oxybromide (8.87 g, 31.013 mmol) in dry toluene (103 ml) and N,N-dimethylaniline (3.29 ml, 25.844 mmol) to obtain 3.98 g of the product as a white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.27 (s, 3H), 3.52 (s, 3H), 8.87 (s, IH).

Step 8: Diethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(/]pyrimidin-4- yl)malonate: The title compound was prepared according to the procedure described for Intermediate 2 by the reaction of Step 7 intermediate (3.0 g, 11.071 mmol) with diethyl malonate (3.37 ml, 22.140 mmol) using sodium hydride (60% dispersion in mineral oil, 0.850 g, 22.140 mmol) in dry DMSO (30.7 ml) to obtain 3.62 g of the product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.31 (t, J= 6.6 Hz, 6H), 3.43 (s, 3H), 3.70 (s, 3H), 4.30 (q, J= 6.9 Hz, 4H), 5.84 (s, IH), 9.04 (s, IH).

Step 9: Ethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-<i]pyrimidin-4- yl)acetate: The title compound was obtained by following the procedure as described for Intermediate 2 by deethoxycarbonylation of Step 8 intermediate (3.5 g, 10.00 mmol) in dry ethanol (71 ml) using a catalytic amount of sodium hydride (60% dispersion in mineral oil, 38.4 mg, 1.00 mmol) to obtain 2.45 g of the desired product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.24-1.32 (m, 3H), 3.44 (s, 3H), 3.70 (s, 3H), 4.24 (q, J = 7.2 Hz, 2H), 4.38 (s, 2H), 9.05 (s, IH).

Intermediate 6

Ethyl (2,6,8-trimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetate

Stepl : (lZ)-N'-(5-cyano-l,3-dimethyl-2,6-dioxo- 1,2,3, 6-tetrahydropyrimidin-4-yl)-N,N- dimethylethanimidamide: The title compound was prepared according to the procedure as described for Intermediate 4 by the reaction 6-Amino-l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-carbonitrile (10.5 g, 60.34 mmol) with N,N-dimethylacetamide dimethyl acetal (32.1 g, 241.37 mmol) in dry DMF (21 ml) to give 6.50 g of the product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 2.24 (s, 3H), 3.16 (s, 3H), 3.19 (s, 3H), 3.34 (s, 6H).

Step 2: 5-Hydroxy-l,3,7-trimethylpyrimido[4,5-(i]pyrimidine-2,4(lH,3H)-dione: The title compound was prepared according to the procedure described for Intermediate 4 by cycisation of Step 1 intermediate (1.10 g, 4.41 mmol) using 75 % sulfuric acid (12.57 ml) to give 460 mg of the product as an off-white solid.

Step 3: 5-Bromo-l,3,7-trimethylpyrimido[4,5-(i]pyrimidine-2,4(lH,3H)-dione: The title compound was prepared according to the procedure described for Intermediate 4 by reaction of Step 2 intermediate (4.35 g, 19.55 mmol) with phosphorous oxybromide (6.72 mg, 23.51 mmol) in dry toluene (65 ml) and N,N-dimethylaniline (2.4 g, 19.55 mmol) to obtain 400 mg of the product as a white solid; ¹H-NMR (300 MHz, CDC13) δ 2.73 (s, 3H), 3.46 (s, 3H), 3.68 (s, IH).

Step 4: Diethyl (2,6,8-trimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4- yl)propanedioate: The title compound was prepared according to the procedure described for Intermediate 2 by the reaction of Step 3 intermediate (470 mg, 1.65 mmol) with diethyl malonate (529 mg, 3.30 mmol) using sodium hydride (60% dispersion in mineral oil, 79 mg, 3.30 mmol) in dry DMSO (2.2 ml) to obtain 470 mg of the product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.31 (t, J= 6.6 Hz, 6H), 2.71 (s, 3H), 3.40 (s, 3H), 3.67 (s, 3H), 4.30 (q, J= 7.5 Hz, 4H), 5.75 (s, IH).

Step 5: ethyl (2,6,8-trimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4- yl)acetate: The title compound was obtained by following the procedure as described for Intermediate 2 by deethoxycarbonylation of Step 4 intermediate (470 mg, 1.29 mmol) in dry ethanol (9 ml) using a catalytic amount of sodium hydride (60% dispersion in mineral oil, 6.4 mg, 0.12 mmol) to obtain 180 mg of the product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.26 (t, J= 6.6 Hz, 3H), 2.41 (s, 3H), 3.38 (s, 3H), 3.57 (s, 3H), 3.67 (s, 2H), 4.16 (q, J= 6.9 Hz, 2H).

Intermediate 7

Ethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetate

CH₃ 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 0⁰C and quenched with ice cold water (350 ml). The reaction mixture was extracted with chloroform (2x 200 ml) and the combined organic extracts were washed with water, dried over Na₂SO₄ and concentrated. The residue obtained was purified by silica gel column chromatography using 5% ethyl acetate in chloroform to obtain 21 g of the product as a pale brown solid; ¹H NMR (300 MHz, CDCl₃): δ 3.33 (s, 3H), 3.57 (s, 3H), 5.94 (s, IH).

Step 2 6-Hydrazino-l,3-dimethylpyrimidine-2,4(lH,3H)-dione: To a stirred solution of Step 1 intermediate (10.0 g, 57.30 mmol) in isopropanol (30 ml) was added hydrazine hydrate (30 ml, 573.00 mmol). After stirring for 4 h at room temperature the precipitated white solid was filtered off and washed with water (2 x 15 ml), dried well to obtain 11.8 g of the product as a white solid; ¹H-NMR (300 MHz, DMSCM₆) δ 3.08 (s, 3H), 3.21 (s, 3H), 4.38 (br s, 2H), 5.10 (s, IH), 8.07 (br s, IH).

Step 3 6,8-Dimethylpyrimido[4,5-c]pyridazine-4,5,7(lH,6H,8H)-trione: To a stirred solution of Step 2 intermediate (5.0 g, 29.411 mmol) in dry ethanol (50 ml) was added glyoxylic acid (2.9 g, 32.35 mmol) at room temperature and the resulting suspension was refluxed till a clear solution was obtained. Immediately heating was stopped and the reaction mixture was cooled to room temperature. Precipitated solid obtained was filtered and washed with ethanol (2 x 10 ml) to obtain 3.0 g of the product as a yellow solid; ¹H- NMR (300 MHz, DMSCM₆) δ 3.24 (s, 3H), 3.34 (s, 3H, overlapped with DMSO peak), 7.36 (s, IH), 13.20 (br s, IH).

Step 3 4-Bromo-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-dione: The title compound was prepared according the the same procedure as described for Initermediate 4 by the reaction of Step 2 intermediate (3.0 g, 14.423 mmol) with phosphorous oxybromide (4.96 g, 17.307 mmol) in dry toluene (30 ml) and N,N-dimethylaniline (1.75 g, 14.423 mmol) to afford 2.6 g of the product as an off-white solid; ¹H-NMR (300 MHz, CDCl₃) δ 3.50 (s, 3H), 3.86 (s, 3H), 8.25 (s, IH).

Step 4 Ethyl (6,8-dimethyl-5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4- yl)acetate: To a stirred suspension of Step 3 of intermediate (3.0 g, 11.070 mmol) in a mixture of dry N,N-dimethylformamide and triethylamine (1 : 1, 36 ml) were sequentially added bis(triphenylphosphine)Pd(II) chloride (0.16 g, 0.221 mmol), copper(I)iodide (21 mg, 0.110 mmol) and ethyl ethynyl ether (40% solution in hexane, 1.16 g, 16.605 mmol) at room temperature. The resulted black colored reaction mixture was stirred for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water (50 ml), brine (50 ml) and dried over anhydrous Na₂SO₄. The solvent was evaporated under reduced pressure and crude residue was purified by silica gel column chromatography using 25 % ethyl acetate in pet ether to give 1.5 g of the product as a yellow solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.29 (t, J= 7.5 Hz, 3H), 3.50 (s, 3H), 3.89 (s, 3H), 4.16 (s, 2H), 4.22 (q, J= 7.5 Hz, 2H), 8.16 (s, IH).

Intermediate 8

Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5-(i]pyridazin-5-yl)acetate

CH₃

Step 1 l^jό-Trimethyl^^-dioxo-l^^^-tetrahydropyrimidine-S-carboxylic acid: To a stirred of l,3,6-trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carbaldehyde (Step 2 of Intermediate 4) (17.0 g, 93.406 mmol) and sulphamic acid (18.13 g, 186.81 mmol) in acetone (467 ml) was added sodium chlorite (12.67 g, 140.109 mmol) in water (93 ml) and reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and diluted with water and acidified with IN HCl, solid obtained was filtered and dried to give 14.6 g of title compound as a white solid. ¹H-NMR (300 MHz, CDCl₃) δ 2.55 (s, 3H), 3.21 (s, 3H), 3.41 (s, 3H), 13.41 (br s, IH).

Step 2 Methyl l,3,6-trimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate: The title compound was prepared according the procedure described for Intermediate 2 (Route 2) by refluxing Step 1 intermediate (14.0 g, 70.646 mmol) in dry methanol (350 ml) in the presence of cone. H₂SO₄ (1.5 ml) for 24 h to give 11.46 g of the product as an off-white solid; ¹H-NMR (300 MHz, CDCl₃) δ 2.36 (s, 3H), 3.34 (s, 3H), 3.47 (s, 3H), 3.89 (s, 3H). Step 3 Methyl 6-(dibromomethyl)-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine- 5-carboxylate: A mixture of Step 2 intermediate (11.46 g, 54.056 mmol), N- bromosuccinimide (28.86 g, 162.169 mmol), glacial acetic acid (22.92 ml) and carbon tetrachloride (450 ml) was stirred and refluxed for 75 h. The mixture was then cooled, washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. The crude mixture was purified by silica gel column chromatography using 20% ethyl acetate in pet ether to give 7.1 g of the less polar product as a white solid; ¹H-NMR (300 MHz, CDCl₃) δ 3.39 (s, 3H), 3.85 (s, 3H), 3.95 (s, 3H), 7.07 (s, IH). APCI-MS (m/z) 371.16 (M+H)⁺.

Step 4 l,3-Dimethylpyrimido[4,5-uT]pyridazine-2,4,5(lH,3H,6H)-trione: To a stirred solution of Step 3 intermediate (5.0 g, 13.513 mmol) in glacial acetic acid (50 ml) was added hydrazine hydrate (2.36 g, 47.297 mmol) at room temperature. The reaction mixture was refluxed for 75 h. The acetic acid was evaporated under under reduced pressure. The sticky mass obtained was dissolved in chloroform, dried over Na₂SO₄ and filtered. The filtrate was concentrated and and residue obtained was as used for the next step.

Step 5 5-Bromo-l,3-dimethylpyrimido[4,5-<i]pyridazine-2,4(lH,3H)-dione: The title compound was prepared according to the procedure described for Intermedaite 4 by using Step 4 intermediate (7.1 g, 34.134 mmol), dry toluene (70 ml), N,N-dimethyl aniline (4.13 g, 34.134 mmol) and phosphorusoxybromide (9.78 g, 34.134 mmol) to obtain 137 mg of the product as a light yellow solid; ¹H-NMR (300 MHz, CDCl₃) δ 3.50 (s, 3H), 3.71 (s, 3H), 9.27 (s, IH). APCI-MS (m/z) 271.21 (M)⁺.

Step 6 Diethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5- yl)propanedioate: The title compound was prepared following the same procedure as described for Intermediate 2 by the reaction of Step 5 intermediate (225 mg, 0.830 mmol), diethylmalonate (267 mg, 1.060 mmol), sodium hydride (60 % dispersion in mineral oil, 67 mg, 1.661 mmol) in dry DMSO (2.3 ml) to obtain 115 mg of the product as a yellow solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.31 (t, J = 6.9 Hz, 6H), 3.48 (s, 3H), 3.70 (s, 3H), 4.32 (q, J = 6.9 Hz, 4H), 5.81 (s, IH), 9.35 (s, IH). ESI-MS (m/z) 351.09 (M+H)⁺.

Step 7 Ethyl (l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5- yl)acetate: The title compound was prepared according to procedure described for Intermediate 2 by deethoxycarbonylation of Step 6 intermediate (110 mg, 0.314 mmol) in dry ethanol (2.1 ml) in the presence of a catalytic amount of sodium hydride (60% dispersion in mineral oil, 1.5 mg, 0.314 mmol) to give 60 mg of the product as an off- white solid; ¹H-NMR (300 MHz, CDCl₃) δ 1.29 (t, J= 7.5 Hz, 3H), 3.46 (s, 3H), 3.70 (s, 3H), 4.21 (q, J= 7.2 Hz, 2H), 4.54 (s, 2H), 9.33 (s, IH). APCI-MS (m/z) 279.11 (M+H)⁺.

Intermediate 9

4-[3-Fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-amine

Step 1 N-{4-[3-fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl}acetamide: To a stirred solution of 2-bromo-l-[3-fluoro-4-(trifluoromethyl)phenyl]ethanone (4.5 g, 15.73 mmol) in acetonitrile (45 ml) was added acetyl guanidine (2.38 g, 23.60 mmol). The reaction mixture was stirred and refluxed for overnight. The solvent was evaporation under reduced pressure and diluted with water and extracted with ethyl acetate (75 ml x 3) and organic layers were washed with brine, dried (Na₂SO₄) and filtered. The filtrate was concentrated under reduced pressure and the residue obtained after the evaporation of the solvent was purified by silica gel column chromatography using 2 % methanol in chloroform to obtain 1.15 g of the product as a yellow solid; ¹H NMR (300 MHz, DMSO- d₆): δ 2.07 (s, 3H), 7.58 (s, IH), 7.69-7.78 (m, 3H), 11.31 (br s, IH), 11.91 (br s, IH).

Step 2 4-[3-Fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-amine: To a stirred solution of Step 1 intermediate (1.1 g, 3.829 mmol) in a mixture of methanol (20 ml) and water (20 ml) was added cone. H₂SO₄ (2 ml) and the resulting mixture was refluxed for 24 h. The reaction mixture was cooled to room temperature, saturated solution of potassium carnonate was added and extracted with ethyl acetate (2 x 50 ml). The organic layers were combined and dried over Na₂SO₄ 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 % methanol in chloroform to obtain 290 mg of the product as a yellow solid; ¹H NMR (300 MHz, DMSO-^₆): δ 5.55 (br s, 2H), 7.32 (s, IH), 7.59-7.67 (m, 3H), 11.30 (br s, IH). 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 0⁰C and reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with brine and dried over Na₂SO₄. The crude product obtained upon concentration was dissolved in dry THF (10 vol) and thiourea (2.0 eq) was added to the reaction mixture. After overnight refluxing the reaction mixture was diluted with ethyl acetate and washed with sodium thiosulfate solution. The organic layer was treated with IN HCl to result salt formation of the amine. The precipitated salt was collected by filtration. The salt was then treated with saturated solution Of NaHCO₃ to re-generate the amine. The mixture was extracted with dichloromethane (2 x 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 HCl and precipitated salt was collected by filtration. The free amine was regenerated 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. 5-(4-bromophenyl) isoxazol-3 -amine is purchased from Aldrich. Table 1 : Structural details and ¹H NMR data of selected 2-aminothiazole intermediates

7.5 Hz, 6H).

For further illustration of methods of preparing the compounds of the present invention, the following examples are disclosed below.

EXAMPLES

General procedure for the preparation of Examples Method A:

To a stirred solution of pyrido[2,3-<i] pyrimidinyl acetic acid or 7-methoxy-pyrido[2,3- <i]pyrimidinyl acetic acid derivatives (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 at the same temperature for 48h. 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 pyrido[2,3-<i] pyrimidinyl acetic acid or 7-methoxy-pyrido[2,3- βT]pyrimidinyl acetic acid derivatives (1.0 equiv.) in a mixture of tetrahydrofuran and N₅N- dimethylformamide (3: 1) was added EDCI (2.0 equiv.) and the mixture was stirred for 30 min. An appropriate amine (1.0 equiv.) and DMAP (0.2 equiv.) was added and mixture was maintained at 80⁰C under stirring for another 24 h. Most of the tetrahydrofuran is evaporated under reduced pressure and the mixture was acidified to pH 6.0 by addition of 2N hydrochloric acid. The solid precipitated out was collected by filtration. The product was further purified by crystallization or by silica gel column chromatography using methanol-chloroform mixture. Method C:

To a stirred solution of appropriate thiazoleamine (1.2 equiv.) in dry toluene or xylene, sodium hydride (60 % dispersion in mineral oil, 1.4 equiv.) was added and after stirring for 30 min at room temperature ethyl pyrido[2,3-<i]pyrimidinyl acetate or ethyl pyrido[4,3-fiT]pyrimidinyl acetate or ethyl pyrimido[4,5-fiT]pyrimidinyl acetate or ethyl pyrimido[4,5-c]pyridazinyl acetate or ethyl pyrimido[4,5-<i]pyridazinyl acetate (1.0 equiv.) was added and heated to reflux for overnight. The mixture was acidified to pH 6.0 by addition of 2N hydrochloric acid. The solid precipitated out was collected by filtration. The product was further purified by crystallization or by silica gel column chromatography using methanol-chloroform mixture.

Example 1 iV-{[4-(4-Ethylphenyl)]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-(4-ethylphenyl)-l,3-thiazol-2- amine (164 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32.5 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1,2- dichloroethane (8 ml) to give 70 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 1.17-1.24 (m, 3H), 2.60-2.66 (m, 2H), 3.23 (s, 3H), 3.60 (s, 3H), 4.39 (s, 2H), 7.25-7.31 (m, 3H), 7.51 (s, IH), 7.82 (d, J = 7.8 Hz, 2H), 8.66 (d, J = 5.1, IH), 12.50 (br s, IH); APCI-MS (m/z) 436.10 (MH)⁺.

Example 2

N-{[4-(4-Isopropylphenyl)]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-(4-isopropylphenyl)-l,3-thiazol-2- amine (175 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32.5 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1,2- dichloroethane (8 ml) to give 80 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSO-έfe) δ 1.23 (d, J = 6.9, 6H), 2.86-3.05 (m, IH), 3.23 (s, 3H), 3.59 (s, 3H), 4.39 (s, 2H), 7.25-7.33 (m, 3H), 7.50 (s, IH), 7.82 (d, J = 8.4 Hz, 2H), 8.65 (d, J = 4.8 Hz, IH), 12.50 (br s, IH); APCI-MS (m/z) 450.35 (MH)⁺. Example 3

N-{[4-(4-Isobutylphenyl)]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-(4-isobutylphenyl)-l,3-thiazol-2- amine (186 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1,2- dichloroethane (8 ml) to give 90 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 0.88 (d, J = 6.3 Hz, 6H), 1.82-1.97 (m, IH), 2.47 (d, J = 7.5, 2H), 3.23 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.22 (d, J= 7.8 Hz, 2H), 7.28 (d, J= 4.2 Hz, IH), 7.51 (s, IH), 7.81 (d, J = 7.5 Hz, 2H), 8.65 (d, J = 4.5 Hz, IH), 12.50 (br s, IH); APCI- MS (m/z) 464.11 (MH)⁺.

Example 4 iV-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-(4-chlorophenyl)-l,3-thiazol-2- amine (169 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (33 mg, 0.240 mmol) and DMAP (10 mg, 0.080 mmol) in 1,2- dichloroethane (8 ml) to give 75 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.22 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.30 (d, J= 5.1 Hz, IH), 7.50 (t, J= 8.4 Hz, IH), 7.66 (s, IH), 7.93 (d, J= 8.4 Hz, IH), 8.66 (d, J= 5.1 Hz, IH), 12.54 (br s, IH); APCI-MS (m/z) 442.06 (M+H)⁺.

Example 5 N-{4-[3-(Trifluoromethoxy)plienyl]-l,3-thiazol-2-yl}-2-(l,3-dimetliyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)- acetamide

CH₃

The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 1 (150 mg, 0.602 mmol) with 4-[3-(trifluoromethoxy)phenyi]-l,3- thiazol-2-amine (156 mg, 0.602 mmol) in the presence of EDCI hydrochloride (231 mg, 1.204 mmol), DMAP (14.7 mg, 0.120 mmol) in the mixture of THF: DMF (3: 1, 2.8 ml) to give 22 mg of the product as an off-white solid; ¹H-NMR (300 MHz, DMSCM₆) δ 3.23 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.24-7.36 (m, 2H), 7.58 (t, J= 7.8 Hz, IH), 7.77-7.98 (m, 3H), 8.66 (d, J= 4.8 Hz, IH), 12.57 (br s, IH). APCI-MS (m/z) 492.08 (MH)⁺.

Example 6

N-[4-(4-Diethylaminophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (100 mg, 0.361 mmol) with 4-[4-(diethylamino)phenyl]-l,3- thiazol-2 -amine (89 mg, 0.361 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 17 mg, 0.722 mmol) in dry toluene (4 ml) to give 70 mg of the product as an off-white solid; ¹H ΝMR (300 MHz, CDCl₃) δ 1.17 (t, J= 6.9 Hz, 6H), 3.38 (q, J= 6.9 Hz, 4H), 3.51 (s, 3H), 3.73 (s, 3H), 4.35 (s, 2H), 6.68 (d, J = 8.7 Hz, 2H), 6.85 (s, IH), 7.18 (d, J = 4.8 Hz, IH), 7.65 (d, J = 8.7 Hz, 2H), 8.57 (d, J = 5.1 Hz, IH), 10.29 (br s, IH); APCI-MS (m/z) 479.19 (M+H)⁺.

Example 7

N-[4-(2,3-Difluorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-(2,3-difluorophenyi)-l,3-thiazol-2- amine (170 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32.5 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1,2- dichloroethane (8 ml) to give 38 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.40 (s, 2H), 7.27-7.45 (m, 3H), 7.58 (s, IH), 7.80-7.86 (m, IH), 8.66 (d, J= 5.1 Hz, IH), 12.60 (br s, IH); APCI-MS (m/z) 444.09 (MH)⁺.

Example 8

N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (50 mg, 0.180 mmol) with 4-[2-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (47 mg, 0.185 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 14 mg, 0.361 mmol) in dry toluene (2 ml) to give 25 mg of the product as an off-white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.41 (s, 2H), 7.29 (d, J= 5.1 Hz, IH), 7.54 (t, J= 7.8 Hz, IH), 7.66 (s, IH), 7.78 (t, J = 7.2 Hz, IH), 8.34 (t, J = 7.2 Hz, IH), 8.66 (d, J = 5.1 Hz, IH), 12.62 (s, IH); APCI-MS (m/z) 494.01 (M+H)⁺.

Example 9

N-[4-(2,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-(2,4-difluorophenyi)-l,3-thiazol-2- amine (170 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32.5 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1,2- dichloroethane (8 ml) to give 60 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSO-rfβ) δ 3.23 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.20-7.48 (m, 4H), 8.04-8.12 (m, IH), 8.66 (d, J= 4.5 Hz, IH), 12.56 (br s, IH); APCI-MS (m/z) 444.03 (MH)⁺.

Example 10

N-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (90 mg, 0.324 mmol) with 4-(2-fluoro-4- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (90 mg, 0.324 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 0.649 mmol) in dry toluene (3 ml) to give 105 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.41 (s, 2H), 7.29 (d, J= 4.2 Hz, IH), 7.69-7.87 (m, 3H), 8.27 (t, J = 7.8 Hz, IH), 8.66 (d, J = 4.8 Hz, IH), 12.64 (s, IH); APCI-MS (m/z) 493.99 (M+H)⁺.

Example 11

N-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-(3,4-dichlorophenyl)-l,3-thiazol-2- amine (196 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32.5 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1,2- dichloroethane (8 ml) to give 30 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-(Z₆) δ 3.22 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.27 (s, IH), 7.68-7.93 (m, 3H), 8.15 (s, IH), 8.66 (d, J = 4.8 Hz, IH), 12.56 (br s, IH); APCI-MS (m/z) 476.00 (M+H)⁺.

Example 12 N-[4-(3-Chloro-4-(trifluoromethyl)phenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (100 mg, 0.361 mmol) with 4-[3-chloro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (101 mg, 0.361 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.722 mmol) in dry toluene (3.6 ml) to give 85 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.38 (s, 2H), 7.26 (d, J= 4.8 Hz, IH), 7.92 (d, J= 8.4 Hz, 2H), 8.05 (d, J = 8.1 Hz, IH), 8.21 (s, IH), 8.64 (d, J = 5.1 Hz, IH), 12.54(br s, IH); APCI- MS (m/z) 510.09 (M)⁺.

Example 13 iV-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)- acetamide

CH₃

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (100 mg, 0.401 mmol) with 4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (105 mg, 0.401 mmol) in the presence of EDCI hydrochloride (92 mg, 0.481 mmol), HOBt (16.2 mg, 0.120 mmol) and DMAP (4.9 mg, 0.040 mmol) in 1 ,2-dichloroethane (4 ml) to give 30 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.22 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.28 (d, J= 4.8 Hz, IH), 7.61 (t, J= 9.0 Hz, IH), 7.82 (s, IH), 8.28 (d, J= 6.3 Hz, 2H), 8.66 (d, J= 4.8 Hz, IH), 12.59 (br s, IH). APCI-MS (m/z) 493.99 (MH)⁺.

Example 14

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)- acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (100 mg, 0.401 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (105 mg, 0.401 mmol) in the presence of EDCI hydrochloride (92 mg, 0.481 mmol), HOBt (16.2 mg, 0.120 mmol) and DMAP (4.9 mg, 0.040 mmol) in 1 ,2-dichloroethane (4 ml) to give 12 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-^₆,) δ 3.22 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H); 7.29 (d, J = 5.1 Hz, IH), 7.82-8.02 (m, 4H), 8.66 (d, J = 4.5 Hz, IH), 12.63 (br s, IH); APCI-MS (m/z) 493.98 (M+H)⁺.

Example 15

N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (100 mg, 0.360 mmol) with 4-[4-fluoro-3- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (101 mg, 0.360 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.722 mmol) in dry toluene (4 ml) to give 45 mg of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-fik) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.40 (s, 2H), 7.28 (d, J= 4.2 Hz, IH), 7.60 (t, J= 9.3 Hz, IH), 7.76 (s, IH), 7.97-8.06 (m, 2H), 8.66 (d, J= 4.8 Hz, IH), 12.56 (s, IH); APCI-MS (m/z) 510.05 (M+H)⁺.

Example 16

N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (223 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32.5 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1 ,2-dichloroethane (8 ml) to give 17 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.40 (s, 2H), 7.28 (d, J = 5.1 Hz, IH), 7.66 (t, J = 8.4 Hz, IH), 7.81 (s, IH), 7.86 (d, J= 8.4 Hz, IH), 7.98 (d, J = 9.0 Hz, IH), 8.66 (d, J = 4.8 Hz, IH), 12.58 (br s, IH); APCI-MS (m/z) 510.17 (M+H)⁺.

Example 17

N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-βf]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (50 mg, 0.180 mmol) with 4-[3-chloro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (53 mg, 0.180 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 14 mg, 0.361 mmol) in dry toluene (2 ml) to give 36 mg of the product as an off-white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.40 (s, 2H), 7.28 (d, J= 4.8 Hz, IH), 7.65 (d, J= 8.1 Hz, IH), 7.82 (s, IH), 8.00 (d, J= 8.7 Hz, IH), 8.19 (s, IH), 8.65 (d, J= 4.8 Hz, IH), 12.58 (br s, IH); APCI-MS (m/z) 524.05 (M-H)^".

Example 18 iV-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (75 mg, 0.270 mmol) with 4-[4-chloro-3- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (80 mg, 0.270 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 21 mg, 0.540 mmol) in dry toluene (3 ml) to give 47 mg of the product as an off-white solid; ¹H NMR (300 MHz, DMSO-^) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.40 (s, 2H), 7.28 (d, J= 4.8 Hz, IH), 7.77 (d, J= 8.4 Hz, IH), 7.84 (s, IH), 7.95-8.04 (m, 2H), 8.66 (d, J = 5.1 Hz, IH), 12.57 (br s, IH); APCI-MS (m/z) 526.16 (M+H)⁺.

Example 19

N-{4-[3-Chloro,5-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (75 mg, 0.270 mmol) with 4-[3-chloro,5- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (80 mg, 0.270 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 22 mg, 0.541 mmol) in toluene (3 ml) to give 50 mg of the product as an yellow SoIi(Ij¹H-NMR (300 MHz, DMSCM₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.39 (s, 2H), 7.27 (d, J = 4.8 Hz, IH), 7.80 (s, IH), 7.95 (s, IH), 8.22 (s, IH), 8.29 (s, IH), 8.65 (d, J = 4.8 Hz, IH), 12.58 (br s, IH); APCI-MS (m/z) 524.14 (M+H)⁺.

Example 20

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (100 mg, 0.361 mmol) with 4-(3-Fluoro-5- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (95 mg, 0.361 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.72 mmol) in dry toluene (4 ml) to give 135 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSO-fifo) δ 3.22 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.28 (d, J= 4.8 Hz, IH), 7.65 (d, J= 8.1 Hz, IH), 7.97 (s, IH), 8.07 (d, J = 9.9 Hz, IH), 8.13 (s, IH), 8.66 (d, J = 4.8 Hz, IH), 12.61 (s, IH); APCI-MS (m/z) 494.20 (M+H)⁺.

Example 21

N-{4-[2,4-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 4-[2,4-difluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (224 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32.5 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1 ,2-dichloroethane (8 ml) to give 10 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.40 (s, 2H), 7.29 (d, J = 5.1 Hz, IH), 7.53 (t, J = 9.0 Hz, IH), 7.62 (s, IH), 8.35 (q, J= 8.7 Hz, IH), 8.66 (d, J= 4.8 Hz, IH), 12.62 (br s, IH); APCI-MS (m/z) 512.14 (MH)⁺.

Example 22

N-[4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (100 mg, 0.361 mmol) with 4-(2,3-difluoro-4- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (101 mg, 0.361 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.722 mmol) in dry toluene (4 ml) to give 100 mg of the product as an white solid; ¹H ΝMR (300 MHz, DMSO-fik) δ 3.23 (s, 3H), 3.60 (s, 3H), 4.41 (s, 2H), 7.29 (d, J= 4.8 Hz, IH), 7.72-7.79 (m, 2H), 8.03 (t, J = 6.6 Hz, IH), 8.67 (d, J = 4.8 Hz, IH), 12.68 (s, IH); APCI-MS (m/z) 510.04 (M- H)-.

Example 23

N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 2 (100 mg, 0.361 mmol) with 4-(3,5-difluoro-4- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (101 mg, 0.361 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.722 mmol) in dry toluene (4 ml) to give 38 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-d₆) δ 3.22 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 7.28 (d, J = 4.8 Hz, IH), 7.84 (s, IH), 7.88 (s, IH), 8.06 (s, IH), 8.66 (d, J= 5.1 Hz, IH), 12.65 (s, IH); APCI-MS (m/z) 510.07 (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-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (100 mg, 0.401 mmol) with 4-[3,5-difluoro-4-(2,2,2- trifluoroethoxy)phenyl]-l,3-thiazol-2-amine (124 mg, 0.401 mmol) in the presence of EDCI hydrochloride (92 mg, 0.481 mmol), HOBt (16.2 mg, 0.120 mmol) and DMAP (4.9 mg, 0.040 mmol) in 1 ,2-dichloroethane (4 ml) to give 23 mg of the product as an off white solid; ¹H-NMR (300 MHz, DMSO-^₆) δ 3.22 (s, 3H), 3.59 (s, 3H), 4.40 (s, 2H), 4.86 (q, J= 8.7 Hz, 2H), 7.28 (d, J = 4.8 Hz, IH), 7.71 (d, J = 9.0 Hz, 2H), 7.78 (s, IH), 8.66 (d, J= 4.8 Hz, IH), 12.56 (br s, IH). APCI-MS (m/z) 542.10 (M+H)⁺.

Example 25

N-[5-(4-Bromophenyl)isoxazol-3 -yl]-2-( 1 ,3 -dimethyl-2,4-dioxo- 1 ,2,3 ,A- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (200 mg, 0.803 mmol) with 5-(4-bromophenyl)isoxazol-3 -amine (191 mg, 0.803 mmol) in the presence of EDCI hydrochloride (184 mg, 0.963 mmol), HOBt (32 mg, 0.240 mmol) and DMAP (9.8 mg, 0.080 mmol) in 1 ,2-dichloroethane (8 ml) to give 93 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSO-fifo) δ 3.24 (s, 3H), 3.59 (s, 3H), 4.34 (s, 2H), 7.27 (d, J= 4.8 Hz, IH), 7.31 (s, IH), 7.72 (d, J = 9.0 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 8.65 (d, J = 4.8 Hz, IH), 11.36 (br s, IH); APCI- MS (m/z) 471.95 (MH)⁺.

Example 26 N-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(7-methoxy-l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 3 (200 mg, 0.716 mmol) with 4-(4-chlorophenyl)-l,3-thiazol-2- amine (133 mg, 0.716 mmol) in the presence of EDCI hydrochloride (164 mg, 0.860 mmol), HOBt (29 mg, 0.215 mmol) and DMAP (8.7 mg, 0.0716 mmol) in 1,2- dichloroethane (4 ml) to give 102 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSO-rfβ) δ 3.20 (s, 3H), 3.58 (s, 3H), 4.00 (s, 3H), 4.30 (s, 2H), 6.71 (s, IH), 7.49 (d, J = 8.4 Hz, 2H), 7.64 (s, IH), 7.92 (d, J = 8.4 Hz, 2H), 12.47 (br s, IH); APCI-MS (m/z) 471.91 (M+H)⁺.

Example 27

N-[4-(3-Fluoro-4-trifluoromethylphenyl)-l,3-thiazol-2-yl]-2-(7-methoxy-l,3-dimethyl- 2,4-dioxo- 1,2,3 ,4-tetrahydropyrido[2,3-uT|pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 3 (150 mg, 0.537 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (140 mg, 0.537 mmol) in the presence of EDCI hydrochloride (123 mg, 0.645 mmol), HOBt (21 mg, 0.161 mmol) and DMAP (8.7 mg, 0.0716 mmol) in 1,2-dichloroethane (4 ml) to give 18 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.19 (s, 3H), 3.58 (s, 3H), 4.01 (s, 3H), 4.31 (s, 2H), 6.72 (s, IH), 7.81 (d, J = 8.1 Hz, IH), 7.93-8.01 (m, 3H), 12.56 (br s, IH); APCI-MS (m/z) 523.89 (M+H)⁺.

Example 28

N-[4-(2,4-Difluoro-3-trifluoromethylphenyl)-l,3-thiazol-2-yl]-2-(7-methoxy-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 3 (150 mg, 0.537 mmol) with 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (150 mg, 0.537 mmol) in the presence of EDCI hydrochloride (123 mg, 0.645 mmol), HOBt (21 mg, 0.161 mmol) and DMAP (8.7 mg, 0.0716) in 1,2-dichloroethane (4 ml) to give 14.7 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSO-έfc) δ 3.20 (s, 3H), 3.59 (s, 3H), 4.01 (s, 3H), 4.31 (s, 2H), 6.72 (s, IH), 7.48-7.62 (m, 2H), 8.32-8.38 (m, IH), 12.55 (br s, IH); APCI-MS (m/z) 542.01 (MH)⁺.

Example 29 iV-{4-[4-(Trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[4-(trifluoromethyl)phenyl]-l,3- thiazol-2-amine (105 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 24 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.49 (s, 2H), 7.43 (d, J = 6.0 Hz, IH), 7.78-7.85 (m, 3H), 8.12 (d, J = 8.4 Hz, 2H), 8.63 (d, J= 5.7 Hz, IH), 12.55 (br s, IH); APCI-MS (m/z) 474.18 (M-H).

Example 30 N-{4-[3-(tert-Butyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.358 mmol) with 4-[3-(tert-butyl)phenyl]-l,3-thiazol- 2-amine (99 mg, 0.429 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 19.2 mg, 0.501 mmol) in dry toluene (4 ml) to give 84 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-d₆) δ 1.31 (s, 9H), 3.25 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.40-7.53 (m, 4H), 7.82 (d, J = 8.4 Hz, 2H), 8.63 (d, J = 5.7 Hz, IH), 12.47 (br s, IH); APCI-MS (m/z) 492.05 (M+H)⁺.

Example 31

N-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-(4-chlorophenyl)-l,3-thiazol-2- amine (91 mg, 0.433 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 100 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.43 (d, J= 6.0 Hz, IH), 7.50 (d, J= 8.4 Hz, 2H), 7.66 (s, IH), 7.92 (d, J= 9.0 Hz, 2H), 8.63 (d, J= 6.0 Hz, IH), 12.50 (br s, IH); APCI-MS (m/z) 442.07 (M+H)⁺.

Example 32 N-{4-[3-(Trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (50 mg, 0.179 mmol) with 4-[3-(trifluoromethoxy)phenyl]-l,3- thiazol-2-amine (56 mg, 0.215 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 5.16 mg, 0.215 mmol) in dry toluene (2 ml) to give 30 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.49 (s, 2H), 7.33 (d, J = 8.1 Hz, IH), 7.43 (d, J= 5.7 Hz, IH), 7.58 (t, J = 7.8 Hz, IH), 7.78 (s, IH), 7.87 (s, IH), 7.95 (d, J = 7.8 Hz, IH), 8.62 (d, J = 5.7 Hz, IH), 12.52 (br s, IH); APCI-MS (m/z) 492.05 (MH)⁺.

Example 33 iV-[4-(4-Diethylaminophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[4-(diethylamino)phenyl]-l,3- thiazol-2 -amine (89 mg, 0.361 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 17 mg, 0.722 mmol) in dry toluene (4 ml) to give 35 mg of the product as an off-white solid; ¹H NMR (300 MHz, CDCl₃) δ 1.19 (t, J= 7.5 Hz, 6H), 3.37 (q, J= 6.9 Hz, 4H), 3.45 (s, 3H), 3.59 (s, 3H), 4.60 (s, 2H), 6.67 (d, J = 8.4 Hz, 2H), 6.84 (s, IH), 7.05 (d, J= 6.0 Hz, IH), 7.63 (d, J= 8.7 Hz, 2H), 8.67 (d, J= 6.0 Hz, IH), 10.66 (s, IH); APCI-MS (m/z) 479 (M+H)⁺.

Example 34

N-{4-[2,4-Dichlorophenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (150 mg, 0.541 mmol) with 4-(2,4-dichlorophenyl)-l,3-thiazol-2- amine (159 mg, 0.649 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43 mg, 1.08 mmol) in dry toluene (5 ml) to give 40 mg of the product as an yellow solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.43 (d, J= 6.0 Hz, IH), 7.53 (d, J= 8.4 Hz, IH), 7.63 (s, IH), 7.73 (s, IH), 7.88 (d, J = 8.7 Hz, IH), 8.63 (d, J= 5.7 Hz, IH), 12.52 (s, IH); APCI-MS (m/z) 476.10 (M+H)⁺.

Example 35

N-{4-[2,4-Difluorophenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (150 mg, 0.541 mmol) with 4-(2,4-difluorophenyl)-l,3-thiazol-2- amine (134 mg, 0.649 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43 mg, 1.08 mmol) in dry toluene (5 ml) to give 110 mg of the product as an off white solid; ¹H ΝMR (300 MHz, CD₃COD) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.22 (t, J= 6.6 Hz, IH), 7.35-7.47 (m, 3H), 8.07 (q, J = 6.9, IH), 8.62 (d, J = 5.7 Hz, IH), 12.52 (s, IH); APCI-MS (m/z) 444.23 (M+H)⁺.

Example 36

2-(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-βT|pyrimidin-5-yl)-N-{4-[2- fluoro-4-(trifluoromethyl)phenyl]- 1 ,3 -thiazol-2-yl} acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[2-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (113 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 95 mg of the product as a pale yellow solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.50 (s, 2H), 7.43 (d, J = 6.0 Hz, IH), 7.69-7.86 (m, 3H), 8.27 (t, J = 7.8 Hz, IH), 8.63 (d, J = 5.7 Hz, IH), 12.59 (br s, IH); APCI-MS (m/z) 494.12 (MH)⁺.

Example 37

2-(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-ύT|pyrimidin-5-yl)-N-{4-[2- fluoro-3 -(trifluoromethyl)phenyl]- 1 ,3 -thiazol-2-yl} acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[2-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (133 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 25 mg, 0.501 mmol) in dry toluene (4 ml) to give 50g of the product as an off white solid; ¹H ΝMR (300 MHz, CDCl₃) δ 3.49 (s, 3H), 3.61 (s, 3H), 4.66 (s, 2H), 7.10 (d, J = 5.7 Hz, IH), 7.26-7.33 (m, IH), 7.46 (s, IH), 7.51 (t, J = 6.3 Hz, IH), 8.29 (t, J= 6.9, IH), 8.71 (d, J = 6.0 Hz, IH), 10.17 (br s, IH); APCI-MS (m/z) 494.05 (M+H)⁺. Example 38

N-[4-(3-Methyl-4-chlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (150 mg, 0.541 mmol) with 4-(3-methyl-4-chlorophenyl)-l,3- thiazol-2-amine (145 mg, 0.649 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 30mg, 0.758 mmol) in dry toluene (5 ml) to give 112 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 2.34 (s, 3H), 3.25 (s, 3H), 3.51 (s, 3H), 4.41 (s, 2H), 7.22 (s, IH), 7.31-7.39 (m, 2H), 7.68 (d, J= 8.4 Hz, IH), 7.83 (s, IH), 8.58 (d, J= 5.7 Hz, IH), 14.20 (br s, IH);; APCI-MS (m/z) 456.03 (M+H)⁺.

Example 39

N-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (150 mg, 0.541 mmol) with 4-(3,4-dichlorophenyl)-l,3-thiazol-2- amine (159 mg, 0.649 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43 mg, 1.08 mmol) in dry toluene (5 ml) to give 81 of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-Cl₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.42 (d, J= 6.0 Hz, IH), 7.70 (d, J= 8.7 Hz, IH), 7.80 (s, IH), 7.89 (d, J= 6.6 Hz, IH), 8.14 (s, IH), 8.62 (d, J= 6.0 Hz, IH), 12.49 (br s, IH); APCI-MS (m/z) 476.08 (MH)⁺.

Example 40

N-[4-(3,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (150 mg, 0.541 mmol) with 4-(3,4-difluorophenyi)-l,3-thiazol-2- amine (138 mg, 0.649 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43 mg, 1.08 mmol) in dry toluene (5 ml) to give 90 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.42 (d, J = 5.7 Hz, IH), 7.48-7.57 (m, IH), 7.69 (s, IH), 7.74-7.77 (m, IH), 7.85-7.95 (m, IH), 8.62 (d, J= 5.7 Hz, IH), 12.49 (s, IH); APCI-MS (m/z) 444.08 (M+H)⁺.

Example 41

N-[4-(3-Fluoro-4-methoxyphenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (150 mg, 0.541 mmol) with 4-(3-fluoro-4-methoxyphenyl)-l,3- thiazol-2-amine (146 mg, 0.649 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43 mg, 1.08 mmol) in dry toluene (5 ml) to give 80 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-Cl₆) δ 3.24 (s, 3H), 3.51 (s, 3H), 3.87 (s, 3H), 4.48 (s, 2H), 7.22 (t, J= 8.4 Hz, IH), 7.41 (d, J= 6.0 Hz, IH), 7.52 (s, IH), 7.68 (s, IH), 7.72 (d, J= 5.7 Hz, IH), 8.61 (d, J = 6.0 Hz, IH), 12.42 (s, IH); APCI-MS (m/z) 456.02 (M+H)⁺.

Example 42

N-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (200 mg, 0.722 mmol) with 4-(4-chloro-3- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (241 mg, 0.866 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 58 mg, 1.44 mmol) in dry toluene (7 ml) to give 190 mg of the product as an off white solid; ¹H NMR (300 MHz, CDC13) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.43 (d, J= 6.0 Hz, IH), 7.81 (d, J= 8.4 Hz, IH), 7.90 (s, IH), 8.21 (d, J = 7.5 Hz, IH), 8.35 (s, IH), 8.63 (d, J = 5.7 Hz, IH), 12.57 (s, IH); APCI-MS (m/z) 510.92 (M+H)⁺.

Example 43

N-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl) acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-(3-chloro-4-[trifluoromethyl] phenyl)-l,3-thiazol-2-amine (121 mg, 0.433 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 28 mg, 0.722 mmol) in dry toluene (4 ml) to give 114 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSO-έfe) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.49 (s, 2H), 7.43 (d, J= 5.7 Hz, IH), 7.94 (d, J= 8.4 Hz, IH), 7.99 (s, IH), 8.07 (d, J = 8.4 Hz, IH), 8.23 (s, IH), 8.63 (d, J = 5.7 Hz, IH) 12.58 (s, IH); APCI-MS (m/z) 510.06 (M+H)⁺.

Example 44

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (50 mg, 0.179 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (56 mg, 0.215 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 5.16 mg, 0.215 mmol) in dry toluene (4 ml) to give 15 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.49 (s, 2H), 7.43 (d, J= 6.3 Hz, IH), 7.83-8.03 (m, 4H), 8.63 (d, J= 6.3 Hz, IH), 12.58 (br s, IH); APCI-MS (m/z) 494.02 (M+H)⁺.

Example 45

N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (113 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 22 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-Cl₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.43 (d, J= 6.0 Hz, IH), 7.61 (t, J= 9.9 Hz, IH), 7.82 (s, IH), 8.27 (d, J = 6.3 Hz, 2H), 8.62 (d, J = 5.7 Hz, IH), 12.54 (br s, IH); APCI- MS (m/z) 494.12 (M+H)⁺.

Example 46

N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<f]pyrimidin-5-yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (200 mg, 0.722 mmol) with 4[3-Chloro-4- (trifluoromethoxy)phenyl] -l,3-thiazol-2-amine (255 mg, 0.866 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 57.7 mg, 1.44 mmol) in dry toluene (7 ml) to give 170 of the product as an off white solid; ¹H NMR (300 MHz, OMSO-d₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.42 (s, 2H), 7.37 (d, J= 6.0 Hz, IH), 7.53-7.60 (m, 2H), 7.94 (d, J = 8.4 Hz, IH), 8.13 (s, IH), 8.60 (d, J = 5.7 Hz, IH) 12.57 (br s, IH); APCI-MS (m/z) 526.01 (M+H)⁺.

Example 47

N-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<f]pyrimidin-5-yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (200 mg, 0.722 mmol) with 4-(4-Chloro-3- [trifluoromethoxy]phenyl)-l,3-thiazol-2-amine (255 mg, 0.866 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 57 mg, 1.44 mmol) in dry toluene (7 ml) to give 155 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.42 (d, J= 6.3 Hz, IH), 7.77 (d, J= 8.7 Hz, IH), 7.85 (s, IH), 7.98 (d, J = 8.1 Hz, IH), 8.03 (s, IH), 8.62 (d, J = 6.0 Hz, IH), 12.55 (s, IH); APCI-MS (m/z) 526.05 (M+H)⁺.

Example 48

N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (120 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 76 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-d₆) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.49 (s, 2H), 7.42 (d, J= 6.0 Hz, IH), 7.65 (t, J= 8.4 Hz, IH), 7.80 (s, IH), 7.86 (d, J= 9.0 Hz, IH), 7.95-8.02 (m, IH), 8.62 (d, J= 6.3 Hz, IH), 12.54 (br s, IH); APCI-MS (m/z) 508.36 (M-H) ^".

Example 49

N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[4-fluoro-3- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (120 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 40 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-Cl₆) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.42 (d, J= 6.3 Hz, IH), 7.60 (t, J= 8.4 Hz, IH), 7.77 (s, IH), 7.97-8.06 (m, 2H), 8.62 (d, J = 6.0 Hz, IH), 12.52 (br s, IH); APCI-MS (m/z) 510.03 (M+H)⁺.

Example 50 N-{4-[2-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[2-fluoro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (113 mg 0.430mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 24 mg, 0.501 mmol) in dry toluene (4 ml) to give 75 g of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-Cl₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.49 (s, 2H), 7.42 (d, J= 6.0 Hz, IH), 7.59 (t, J= 8.7 Hz, IH), 7.66 (s, IH), 7.78 (s, IH), 8.42 (d, J= 6.3 Hz, IH), 8.63 (d, J= 5.7 Hz, IH), 12.57 (br s, IH); APCI-MS (m/z) 494.08 (M+H)⁺.

Example 51 N-{4-[3-Chloro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (200 mg, 0.722 mmol) with 4-[3-Chloro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (241 mg, 0.866 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 57 mg, 1.44 mmol) in dry toluene (7 ml) to give 103 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.25 (s, 3H), 3.53 (s, 3H), 4.51 (s, 2H), 7.48 (d, J = 5.7 Hz, IH), 7.82 (s, IH), 8.02 (s, IH), 8.23 (s, IH), 8.30 (s, IH), 8.66 (d, J= 6.3 Hz, IH), 12.49 (br s, IH); APCI-MS (m/z) 510.08 (M+H)⁺.

Example 52

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[3-fluoro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (113 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 63 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.24 (s, 3H), 3.52 (s, 3H), 4.48 (s, 2H), 7.43 (d, J= 5.7 Hz, IH), 7.65 (d, J= 7.8 Hz, IH), 7.98 (s, IH), 8.06 (d, J= 9.6 Hz, IH), 8.13 (s, IH), 8.63 (d, J= 5.7 Hz, IH), 12.57 (br s, IH); APCI-MS (m/z) 508.36 (MH)⁺.

Example 53 N-{4-[3-Chloro-5-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<f]pyrimidin-5-yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (200 mg, 0.722 mmol) with 4-[3-Chloro-5- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (255 mg, 0.866 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 57.7 mg, 1.44 mmol) in dry toluene (7 ml) to give 120 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-di) δ 3.22 (s, 3H), 3.49 (s, 3H), 4.44 (s, 2H), 7.39 (d, J = 5.4 Hz, IH), 7.48 (s, IH), 7.84 (s, 2H), 8.01 (s, IH), 8.59 (d, J = 5.4 Hz, IH), 12.54 (br s, IH); APCI-MS (m/z) 526.14 (MH)⁺.

Example 54 N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<f]pyrimidin-5-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (122 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 35 mg, 0.5054 mmol) in dry toluene (4 ml) to give 35 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-d₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.49 (s, 2H), 7.43 (d, J= 5.7 Hz, IH), 7.52 (t, J= 9.9 Hz, IH), 7.61 (s, IH), 8.35 (q, J = 8.7 Hz, IH), 8.63 (d, J = 5.7 Hz, IH), 12.56 (br s, IH); APCI- MS (m/z) 512.00 (M+H)⁺. Example 55 N- {4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl} -2-(l ,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[2,3-difluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (121 mg, 0.433 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.722 mmol) in dry toluene (4 ml) to give 123 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.25 (s, 3H), 3.52 (s, 3H), 4.50 (s, 2H), 7.42 (d, J= 6.0 Hz, IH), 7.70-7.79 (m, 2H), 8.02 (t, J = 7.2 Hz, IH), 8.62 (d, J = 5.7 Hz, IH), 12.57 (s, IH); APCI-MS (m/z) 512.03 (M+H)⁺.

Example 56

N-{4-[3,5-difluoro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxol,2,3,4-tetrahydropyrido[4,3-<f]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (75 mg, 0.270 mmol) with N-{4-[3,5-difluoro-4-(2,2- dimethylpropoxy)phenyl]-l,3-thiazol-2-amine (97 mg, 0.324 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.9 mg, 0.324 mmol) in dry toluene (4 ml) to give 160 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSO-fik) δ 1.01 (s, 9H), 3.24 (s, 3H), 3.52 (s, 3H), 3.80 (s, 2H), 4.48 (s, 2H), 7.42 (d, J = 6.0 Hz, IH), 7.65 (d, J = 9.6 Hz, 2H), 7.71 (s, IH), 8.62 (d, J = 5.7 Hz, IH), 12.49 (br s, IH); APCI-MS (m/z) 530.25 (MH)⁺.

Example 57 N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-Dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-(3,5-difluoro-4- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (121 mg, 0.433 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.722 mmol) in dry toluene (4 ml) to give 16 mg of the product as an yellow solid; ¹H ΝMR (300 MHz, DMSO-fifc) δ 3.24 (s, 3H), 3.51 (s, 3H), 4.49 (s, 2H), 7.42 (br s, IH), 7.85 (d, J= 10.8 Hz, 2H), 8.06 (br s, IH), 8.32 (br s, IH), 12.60 (br s, IH); APCI-MS (m/z) 512.07 (M+H)⁺.

Example 58

N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(7-methoxy-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (100 mg, 0.361 mmol) with 4-[3,5-difluoro-4-(2,2,2- trifluoroethoxy)phenyl]-l,3-thiazol-2-amine (133 mg, 0.430 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 12.04 mg, 0.501 mmol) in dry toluene (4 ml) to give 150 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.23 (s, 3H), 3.50 (s, 3H), 4.35 (s, 2H), 4.78 (q, J= 8.7 Hz, 2H), 7.25-7.33 (m, 2H), 7.59 (d, J= 9.6 Hz, 2H), 8.55 (d, J= 5.7 Hz, IH); APCI-MS (m/z) 542.22 (M+H)⁺.

Example 59

N-[4-(4-Chlorophenyl)-5-methyl-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (200 mg, 0.722 mmol) with 4-(4-Chlorophenyl)-l,3-thiazol-2- amine (195 mg, 0.866 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 57 mg, 1.44 mmol) in dry toluene (7 ml) to give 140 mg of the product as an off white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 2.43 (s, 3H), 3.24 (s, 3H), 3.51 (s, 3H), 4.44 (s, 2H), 7.41 (d, J= 5.1 Hz, IH), 7.50 (d, J= 7.5 Hz, 2H), 7.67 (d, J= 7.2 Hz, 2H), 8.61 (d, J= 4.8 Hz, IH), 12.30 (br s, IH); APCI-MS (m/z) 456.14 (M+H)⁺.

Example 60

N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-5-methy-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (30 mg, 0.108 mmol) with 4-(4-fluoro-3- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (30 mg, 0.108 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 9 mg, 0.216 mmol) in dry toluene (1 ml) to give 25 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 2.46 (s, 3H), 3.48 (s, 3H), 3.61 (s, 3H), 4.62 (s, 2H), 7.10 (d, J= 6.0 Hz, IH), 7.20-7.25 (m, IH), 7.74-7.79 (m, IH), 7.86 (d, J= 6.9 Hz, IH), 8.70 (d, J= 5.7, IH), 10.05 (br s, IH); APCI- MS (m/z) 508.09 (M+H)⁺.

Example 61

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 4 (200 mg, 0.722 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-lH-imidazol-2-amine (Intermediate 9) (212 mg, 0.866 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 40 mg, 1.011 mmol) in dry toluene (8 ml) to give 45 mg of the product as a yellow solid; ¹H NMR (300 MHz, DMSO-έfe) δ 3.22 (s, 3H), 3.58 (s, 3H), 4.48 (s, 2H), 7.48 (d, J = 6.3 Hz, IH), 7.64 (s, IH), 7.72-7.86 (m, 3H), 8.68 (d, J = 5.7 Hz, IH), 11.58 (br s, IH), 11.87 (br s, IH); APCI-MS (m/z) All. U (MH)⁺.

Example 62

N-[4-(4-Isopropylphenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-fiT]pyrimidin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (200 mg, 0.719 mmol) with 4-(4-isopropylpheny)-l,3-thiazol-2- amine (188 mg, 0.863 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 33 mg, 0.863 mmol) in dry xylene (7 ml) to give 21 mg of the product as yellow solid; ¹H ΝMR (300 MHz, CF₃CO₂D) δ 1.26 (d, J = 6.6 Hz, 6H), 2.92-2.99 (m, IH), 3.50 (s, 3H), 3.91 (s, 5H), 7.29 (s, IH), 7.41 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 8.1 Hz, 2H), 9.38 (s, IH), 11.50 (br s, IH, overlapped with residual TFA peak); APCI-MS (m/z) 451.05 (M+H)⁺.

Example 63

N-[4-(4-tert-Butylphenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-fiT]pyrirnidin-4-yl)- acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (160 mg, 0.575 mmol) with 4-(4-tert-butylphenyl)-l,3-thiazol-2- amine (160 mg, 0.690 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 46 mg, 0.690 mmol) in dry xylene (6 ml) to give 40 mg of the product as yellow solid; ¹H NMR (300 MHz, CF₃CO₂D) δ 1.56 (s, 9H), 3.72 (s, 3H), 4.13 (s, 3H), 4.25 (s, 2H), 7.52 (s, IH), 7.76-7.85 (m, 4H), 9.60 (s, IH), 11.50 (br s, IH, overlapped with residual TFA peak); APCI-MS (m/z) 465.12 (M+H)⁺.

Example 64

N-{4-[3-(Trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-fiT]pyrimidin-4-yl)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (200 mg, 0.719 mmol) with 4-[3-(trifluoromethyl)phenyl]-l,3- thiazol-2-amine (210 mg, 0.862 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 33 mg, 0.862 mmol) in dry xylene (7 ml) to give 43 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSO-έfe) δ 3.46 (s, 3H), 3.86 (s, 5H), 7.43 (s, IH), 7.62-7.69 (m, IH), 7.75-7.85 (m, 2H), 7.87 (s, IH), 9.34 (s, IH), 11.50 (s, IH, overlapped with residual TFA peak); APCI-MS (m/z) 477.09 (M-H)^".

Example 65

N-[4-(4-Trifluoromethylphenyl)-l,3-thiazol-2-yl] -2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-fiT]pyrimidin-4-yl)acetamide

CH₃ The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (200 mg, 0.719 mmol) with 4-(4-trifluoromethylphenyl)-l,3- thiazol-2-amine (210 mg, 0.862 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 33 mg, 0.862 mmol) in dry xylene (7 ml) to give 135 mg of the product as yellow solid; ¹H NMR (300 MHz, CF₃CO₂D) δ 3.91 (s, 3H), 4.32 (s, 3H), 4.44 (s, 2H), 7.90 (s, IH), 8.20-8.29 (m, 4H), 9.80 (s, IH), 11.50 (br s, IH, overlapped with residual TFA peak); APCI-MS (m/z) 465.12 (M+H)⁺.

Example 66

N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -<i]pyrimidin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (200 mg, 0.719 mmol) with 4-[2-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (226 mg, 0.863 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 35 mg, 0.863 mmol) in dry xylene (7 ml) to give 140 mg of the product as an yellow solid; ¹H ΝMR (300 MHz, OMSO-Cl₆) δ 3.45 (s, 3H), 3.85 (s, 5H), 7.39-7.42 (m, IH), 7.58 (s, 2H), 7.75-7.81 (m, IH), 9.33 (s, IH), 11.50 (br s, overlapped with residual TFA peak); APCI-MS (m/z) 494.95 (M+H)⁺.

Example 67

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -<i]pyrimidin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (180 mg, 0.653 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (218 mg, 0.784 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 18 mg, 0.784 mmol) in dry xylene (7 ml) to give 60 mg of the product as an off white solid; ¹H ΝMR (300 MHz, CF₃CO₂D) δ 3.66 (s, 3H), 4.06 (s, 3H), 4.19 (s, 2H), 7.65-7.74 (m, 3H), 7.94-8.00 (m, IH), 9.54 (s, IH), 11.50 (br s, IH, overlapped with residual TFA peak); APCI-MS (m/z) 493.05 (M-H)^".

Example 68

N-{4-[4-Fluoro-3-(trifluoromethyl)plienyl]-l,3-tliiazol-2-yl}-2-(6,8-dimetliyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -<i]pyrimidin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (200 mg, 0.719 mmol) with 4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (226 mg, 0.863 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 21 mg, 0.863 mmol) in dry xylene (7 ml) to give 60 mg of the product as yellow solid; ¹H ΝMR (300 MHz, CF₃CO₂D) δ 3.52 (s, 3H), 3.93 (s, 3H), 4.05 (s, 2H), 7.39-7.46 (m, 2H), 7.86-7.95 (m, 2H), 9.41 (s, IH), 11.50 (br s, IH, overlapped with residual TFA peak); APCI-MS (m/z) 495.08 (M+H)⁺.

Example 69

N-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6,8-Dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -<i]pyrimidin-4-y l)acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (180 mg, 0.653 mmol) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (218 mg, 0.784 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 18 mg, 0.784 mmol) in dry xylene (7 ml) to give 12 mg of the product as an off white solid; ¹H ΝMR (300 MHz, CF₃CO₂D) δ 3.54 (s, 3H), 3.94 (s, 5H), 7.45-7.54 (m, 4H), 9.42 (s, IH), 11.80 (br s, IH, overlapped with residual TFA peak); APCI-MS (m/z) 511.02 (M+H)⁺.

Example 70 N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -<i]pyrimidin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 5 (200mg, 0.719 mmol) with 4-[3-fluoro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (226 mg, 0.863 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 33 mg, 0.863 mmol) in dry xylene (7 ml) to give 55 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.80 (s, 3H), 4.20 (s, 5H), 7.65-7.87 (m, 3H), 8.03 (s, IH), 9.68 (s, IH), 11.80 (br s, IH); APCI-MS (m/z) 494.98 (M+H)⁺.

Example 71

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(2,6,8-trimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-<i]pyrimidin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 6 (150 mg, 0.513 mmol) with 4-(3-fluoro-4- [trifluoromethyl]phenyl)-l,3-thiazol-2-amine (162 mg, 0.616 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 30 mg, 0.616 mmol) in dry xylene (5 ml) to give 80 mg of the product as an off white solid; ¹H ΝMR (300 MHz, CF₃CO₂D) δ 3.01 (s, 3H), 3.45 (s, 3H), 3.57 (s, 2H), 3.85 (s, 3H), 7.47-7.57 (m, 3H), 7.73-7.83 (m, IH); 11.50 (br s, IH, overlapped with residual TFA peak) APCI-MS (m/z) 509.12 (M+H)⁺.

Example 72 iV-[4-(4-Isobutylphenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-(4-isobutylphenyl)-l,3-thiazol-2- amine (150 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 95 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 0.90 (d, J = 6.6 Hz, 6H), 1.82-1.93 (m, IH), 2.49 (d, J = 7.2 Hz, 2H), 3.50 (s, 3H), 3.90 (s, 2H), 4.22 (s, 2H), 7.09 (s, IH), 7.18 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 8.16 (s, IH), 10.41 (br s, IH); APCI-MS (m/z) 465.16 (M+H)⁺.

Example 73

N-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-(4-chlorophenyl)-l,3-thiazol-2- amine (136 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 68 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.90 (s, 3H), 4.23 (s, 2H), 7.13 (s, IH), 7.35 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 8.1 Hz, 2H), 8.15 (s, IH), 10.51 (br s, IH); APCI-MS (m/z) 441.18 (M+H)⁺.

Example 74

N-{4-[3-(trifluoromethoxy)phenyl]-l,3-thiazol -2-yl}-2-(6,8-Dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-[3-(trifluoromethoxy)phenyi]-l,3- thiazol-2-amine (168 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 85 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.92 (s, 3H), 4.30 (s, 2H), 7.13-7.25 (m, 2H), 7.43 (t, J= 8.1 Hz, IH), 7.68-7.76 (m, 2H), 8.20 (s, IH), 10.28 (br s, IH); ESI-MS (m/z) 493.34 (M+H)⁺.

Example 75

N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (100 mg, 0.359 mmol) with 4-[2-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (113 mg, 0.431 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.719 mmol) in dry toluene (5 ml) to give 75 mg of the product as an off-white solid; ¹H ΝMR (300 MHz, OMSO-d₆) δ 3.31 (s, 3H), 3.69 (s, 3H), 4.37 (s, 2H), 7.54 (t, J= 7.8 Hz, IH), 7.73 (s, IH), 7.78 (t, J = 6.6 Hz, IH), 8.27 (s, IH), 8.33 (t, J = 7.2 Hz, 1H),12.81 (s,lH); APCI-MS (m/z) 494.57 (M+H)⁺.

Example 76

N-[4-(2,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (100 mg, 0.359 mmol) with 4-[2,4-dichlorophenyl]-l,3-thiazol-2- amine (106 mg, 0.431 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.719 mmol) in dry toluene (5 ml) to give 70 mg of the product as an off-white solid; ¹H NMR (300 MHz, OMSO-Cl₆) δ 3.31 (s, 3H), 3.69 (s, 3H), 4.36 (s, 2H), 7.55 (d, J= 8.4 Hz, IH), 7.69 (s, IH), 7.74 (s, IH), 7.87 (d, J= 8.4 Hz, IH), 8.26 (s, IH), 12.76 (s, IH); APCI-MS (m/z) 477.03 (M)⁺.

Example 77

N-[4-(2,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (100 mg, 0.35 mmol) with 4-[3,4-difluorophenyl]-l,3-thiazol-2- amine (91 mg, 0.35 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 17 mg, 0.72 mmol) in dry toluene (7 ml) to give 65 mg of the product as an yellow solid; ¹H ΝMR (300 MHz, CDCl₃) δ 3.52 (s, 3H), 3.92 (s, 3H), 4.31 (s, 2H), 6.86-6.94 (m, 2H), 7.36 (s, IH), 8.04 (q, J= 8.1 Hz, IH), 8.21 (s, IH), 10.32 (br s, IH); APCI-MS (m/z) 445.04 (M+H)⁺.

Example 78

N-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (100 mg, 0.359 mmol) with 4-[2-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (113 mg, 0.432 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 17 mg, 0.719 mmol) in dry toluene (5 ml) to give 80 mg of the product as an off white solid; ¹H ΝMR (300 MHz, OMSO-Cl₆) δ 3.31 (s, 3H), 3.69 (s, 3H), 4.38 (s, 2H), 7.70-7.86 (m, 3H), 8.20-8.28 (m, 2H), 12.83 (br s, IH); APCI-MS (m/z) 494.99 (M+H)⁺.

Example 79 N-[4-(3,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,^ tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (120 mg, 0.431 mmol) with 4-(3,5-dichlorophenyl)-l,3-thiazol-2- amine (127 mg, 0.518 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 20.17 mg, 0.863 mmol) in dry toluene (5 ml) to give 75 mg of the product as an off white solid; ¹H ΝMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.91 (s, 3H), 4.30 (s, 2H), 7.17 (s, IH), 7.45 (d, J= 8.7 Hz, IH), 7.63 (d, J= 8.7 Hz, IH), 7.93 (s, IH), 8.19 (s, IH); APCI-MS (m/z) 475.14 (M)⁺.

Example 80

N-[4-(3,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-(3,4-difluorophenyl)-l,3-thiazol-2- amine (137 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 110 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSCM₆) δ 3.33 (s, 3H, overlapped with DMSO peak), 3.69 (s, 3H), 4.36 (s, 2H), 7.50 (d, J = 8.7 Hz, IH), 7.74-7.80 (m, 2H), 7.87-7.96 (m, IH), 8.25 (s, IH), 12.70 (br s, IH); APCI-MS (m/z) 445.01(M+H)⁺.

Example 81

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-Dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (140 mg, 0.504 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (158 mg, 0.604 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 24 mg, 1.007 mmol) in dry toluene (6 ml) to give 65 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.92 (s, 3H), 4.32 (s, 2H), 7.24-7.30 (m, IH), 7.64-7.72 (m, 3H), 8.21 (s, IH), 10.31 (br s, IH); APCI-MS (m/z) 493.15 (M-H)^".

Example 82 iV-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (140 mg, 0.504 mmol) with 4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (158 mg, 0.604 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 24 mg, 1.007 mmol) in dry toluene (6 ml) to give 55 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.92 (s, 3H), 4.32 (s, 2H), 7.16 (s, IH), 7.19-7.28 (m, IH), 7.95-8.02 (m, IH), 8.08-d, J= 6.3 Hz, IH), 8.21 (s, IH), 10.31 (br s, IH); APCI-MS (m/z) 494.99 (M+H)⁺.

Example 83 iV-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (100 mg, 0.359 mmol) with 4-[4-chloro-3-(trifluoromethyl) phenyl]-l,3-thiazol-2-amine (121 mg, 0.432 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 29 mg, 0.719 mmol) in dry toluene (5 ml) to give 60 mg of the product as off white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.92 (s, 3H), 4.32 (s, 2H), 7.23 (s, , IH), 7.53 (d, J = 8.4 Hz, IH), 7.90 (d, J = 8.4 Hz, IH), 8.16 (s, IH), 8.32 (s, IH), 10.31 (s, IH); APCI-MS (m/z) 509.14 (M-H)^".

Example 84

N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-[3-fluoro-4- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (180 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 62 mg of the product as an off white solid; ¹H ΝMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.92 (s, 3H), 4.31 (s, 2H), 7.17 (s, IH), 7.32 (t, J = 8.4 Hz, IH), 7.59 (d, J= 8.4 Hz, IH), 7.65-7.71 (m, IH), 8.20 (s, IH), 10.28 (br s, IH); APCI-MS (m/z) 511.03 (M+H)⁺.

Example 85

N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-[4-fluoro-3- (trifluoromethoxy)phenyl]-l,3-thiazol-2-amine (180 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 120 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.51 (s, 3H), 3.91 (s, 3H), 4.30 (s, 2H), 7.13 (s, IH), 7.17-7.27 (m, IH), 7.68-7.75 (m, IH), 7.79 (d, J = 7.5 Hz, IH), 8.20 (s, IH), 10.21 (br s, IH); APCI-MS (m/z) 510.98 (M+H)⁺.

Example 86

N-[4-(3,5-Difluorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.540 mmol) with 4-(3,5-difluorophenyl)-l,3-thiazol-2- amine (137 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 80 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSCM₆) δ 3.33 (s, 3H, overlapped with DMSO peak), 3.69 (s, 3H), 4.36 (s, 2H), 7.18-7.25 (m, IH), 7.60 (d, J = 6.9 Hz, 2H), 7.89 (s, IH), 8.25 (s, IH), 12.73 (br s, IH); APCI-MS (m/z) 443.15 (M-H) .

Example 87

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-[3-fluoro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (169 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 90 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSO-^₆) δ 3.31 (s, 3H), 3.69 (s, 3H), 4.37 (s, 2H), 7.64 (d, J= 8.4 Hz, IH), 8.01-8.13 (m, 3H), 8.26 (s, IH), 12.77 (br s, IH); ESI-MS (m/z) 494.98 (M+H)⁺.

Example 88

N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-[2,3-difluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (181 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (6 ml) to give 90 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSO-^₆) δ 3.31 (s, 3H), 3.69 (s, 3H), 4.38 (s, 2H), 7.74 (t, J= 7.8 Hz, IH), 7.83 (s, IH), 8.01 (t, J = 7.2 Hz, IH), 8.27 (s, IH), 12.83 (br s, IH); APCI-MS (m/z) 512.93 (M)⁺.

Example 89

N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (140 mg, 0.503 mmol) with 4-[2,4-difluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (169 mg, 0.604 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 24 mg, 1.007 mmol) in dry toluene (6 ml) to give 24 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSO-^₆) δ 3.51 (s, 3H), 3.91 (s, 3H), 4.32 (s, 2H), 7.09 (t, J= 9.9 Hz, IH), 7.43 (s, IH), 8.21 (s, IH), 8.27 (q, J= 9.0 Hz, IH), 10.63 (br s, IH); APCI-MS (m/z) 513.04 (M+H)⁺.

Example 90 N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)-acetamide

CH₃

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (100 mg, 0. 359 mmol) with 4-[3,5-difluoro-4-(trifluoromethyl) phenyl]-l,3-thiazol-2-amine (121 mg, 0.432 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 18 mg, 0.863 mmol) in dry toluene (5 ml) to give 70 mg of the product as an off white solid; ¹H NMR (300 MHz, CDCl₃) δ 3.52 (s, 3H), 3.93 (s, 3H), 4.32 (s, 2H), 7.31 (s, IH), 7.47 (d, J = 10.8 Hz, 2H), 8.21 (s , IH), 10.37 (s, IH); APCI-MS (m/z) 511.14 (M-H)^".

Example 91

N- {4-[3-Fluoro-4-(trifluoromethyl)phenyl]- lH-imidazol-2-yl} -2-(6,8-dimethyl-5,7-dioxo- 5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)-acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 7 (150 mg, 0.539 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]- lH-imidazol-2-amine (Intermediate 9) (159 mg, 0.647 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 1.079 mmol) in dry toluene (5 ml) to give 30 mg of the product as an off white solid; ¹H NMR (300 MHz, DMSO-(Z₆) δ 3.31 (s, 3H), 3.69 (s, 3H), 4.26 (s, 2H), 7.62 (s, IH), 7.72 -7.83 (m, 3H), 8.26 (s,lH), 11.75 (br s, IH), 11.98 (br s, IH); APCI-MS (m/z) 478.05 (M+H)⁺.

Example 92

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrimido[4,5-<f]pyridazin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 8 (60 mg, 0.215 mmol) with 4-[3-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (68 mg, 0.258 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 17 mg, 0.431 mmol) in dry toluene (2.5 ml) to give 13 mg of the product as a brown solid; ¹H NMR (300 MHz, DMSO-^₆) δ 3.24 (s, 3H), 3.61 (s, 3H), 4.59 (s, 2H), 7.83-8.03 (m, 4H), 9.64 (s, IH), 12.72 (br s, IH); APCI-MS (m/z) 495.08 (M+H)⁺.

Example 93

N-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrimido[4,5-<f]pyridazin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 8 (90 mg, 0.323 mmol) with 4-[2-fluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (102 mg, 0.388 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 0.646 mmol) in dry toluene (4 ml) to give 60 mg of the product as a off-white solid; ¹H ΝMR (300 MHz, CDCl₃) δ 3.46 (s, 3H), 3.71 (s, 3H), 4.78 (s, 2H), 7.39 (d, J= 11.7 Hz, IH), 7.46-7.51 (m, 2H), 8.22 (t, J = 7.8 Hz, IH), 9.37 (s, IH), 9.78 (br s, IH); APCI-MS (m/z) 494.95 (M)⁺.

Example 94

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrimido[4,5-<f]pyridazin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 8 (70 mg, 0.251 mmol) with 4-[3-fluoro-5- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (79 mg, 0.302 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 20 mg, 0.503 mmol) in dry toluene (4 ml) to give 37 mg of the product as a brown solid; ¹H NMR (300 MHz, DMSO-^₆) δ 3.25 (s, 3H), 3.61 (s, 3H), 4.59 (s, 2H), 7.65 (d, J= 8.7 Hz, IH), 7.99 (s, IH), 8.07 (d, J= 9.0, IH), 8.14 (s, IH), 9.63 (s, IH), 12.70 (br s, IH); APCI-MS (m/z) 495.00 (M+H)⁺.

Example 95

N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrimido[4,5-<f]pyridazin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 8 (90 mg, 0.323 mmol) with 4-[4-fluoro-3- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (102 mg, 0.388 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 26 mg, 0.646 mmol) in dry toluene (2.5 ml) to give 73 mg of the product as a off-white solid; ¹H ΝMR (300 MHz, CDCl₃) δ 3.46 (s, 3H), 3.71 (s, 3H), 4.79 (s, 2H), 7.12 (s, IH), 7.21 (d, J= 9.3 Hz, IH), 7.96 (br s, IH), 8.07 (d, J = 5.4 Hz, IH), 9.37 (s, IH), 9.88 (br s, IH), 12.72 (br s, IH); APCI-MS (m/z) 495.19 (M+H)⁺.

Example 96

N-{4-[3-Fluoro-4-(trifluoromethoxyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 8 (125 mg, 0.449 mmol) with 4-[3-Fluoro-4- (trifluoromethoxyl)phenyl]-l,3-thiazol-2-amine (150 mg, 0.539 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 36 mg, 0.898 mmol) in dry toluene (5 ml) to give 75 mg of the product as an light brown solid; ¹H NMR (300 MHz, CDCl₃) δ 3.46 (s, 3H), 3.71 (s, 3H), 4.77 (s, 2H), 7.14 (s, IH), 7.32 (t, J= 7.8 Hz, IH), 7.59 (d, J = 9.0 Hz, IH), 7.67 (d, J = 11.1 Hz, IH), 9.37 (s, IH), 9.91 (br s, IH); APCI-MS (m/z) 510.98 (M+H)⁺.

Example 97

N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 8 (125 mg, 0.449 mmol) with 4-[2,3-Difluoro-4- (trifluoromethyl)phenyl]-l,3-thiazol-2-amine (151 mg, 0.539 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 36 mg, 0.899 mmol) in dry toluene (5 ml) to give 90 mg of the product as an off white solid; ¹H ΝMR (300 MHz, DMSO-fik) δ 3.25 (s, 3H), 3.61 (s, 3H), 4.60 (s, 2H), 7.72-7.81 (m, 2H), 8.04 (t, J = 7.5 Hz, IH), 9.64 (s, IH), 12.75 (s, IH); APCI-MS (m/z) 511.15 (M-H)^".

Example 98

N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5-yl)acetamide

The title compound was prepared according to the general procedure (Method C) by coupling Intermediate 8 (125 mg, 0.449 mmol) with 4-[2,4-Difluoro-3-(trifluoromethyl) phenyl]-l,3-thiazol-2-amine (151 mg, 0.539 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 36 mg, 0.899 mmol) in dry toluene (5 ml) to give 90 of the product as an light brown solid; ¹H ΝMR (300 MHz, CDCl₃) δ 3.47 (s, 3H), 3.72 (s, 3H), 4.79 (s, 2H), 7.08 (t, J= 9.3 Hz, IH), 7.40 (s, IH), 8.28 (q, J= 8.1 Hz, IH), 9.38 (s, IH), 9.63 (s, IH); APCI-MS (m/z) 512.98 (M+H)⁺.

Pharmacological activity

The illustrative examples of the present invention are screened for TRPAl activity according to a modified procedure described in (a) Tόth, 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 μM (for human TRPAl) and / or 10 μM (for rat TRPAl) and 5 μCi/ml 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).

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 2. Percentage inhibition at concentrations of 1.0 μM / 10.0 μM and IC50 (nM) details for selected examples are illustrated below. The IC50 (nM) values of the compounds are set forth in Table 2 wherein "A" refers to an IC50 value of less than 50 nM, "B" refers to IC₅₀ value in range of 50.01 to 250.0 nM and "C" refers to IC50 value of more than 250.0 nM

Table 2: In-vitro screening results of compounds of invention:

Claims

WE CLAIM:

1. A compound of the formula (I)

(I) or pharmaceutically acceptable salt thereof, wherein,

A₁, A₂ and A3 are independently selected from N and CR^a; with the proviso that A₁, A₂ and A₃ simulteneously are not CR^a at any given instance and when Ai is CR^a, A₂ is N, then A3 is not CR^a;

R^a is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, (CR^xR^y)_nOR^x, COOR^X, C0NR^xR^y, S(O)_mNR^xR^y, NR^x(CR^xR^y)_nOR^x, (CH₂)_nNR^xR^y, (CH₂)_nCHR^xR^y, NR^x(CR^xR^y)_nCONR^xR^y, (CH₂)_nNHC0R^x, (CH₂)_nNH(CH₂)_nSO₂R^x and (CH₂)_nNHSO₂R^x;

L is a linker selected from -(CR^xR^y)_n-, -O-(CR^xR^y)_n-, -C(O)-, -NR^X-, -S(O)_mNR^x-, -NR^x(CR^xR^y)_n- and -S(O)_mNR^x(CR^xR^y)_n;

R¹ and R², which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR^xR^y)_nOR^x, COR^X, COOR^X, C0NR^xR^y, (CH₂)_nNR^xR^y, (CH₂)_nCHR^xR^y and (CH₂)_nNHC0R^x;

R³ is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl and cycloalkenyl;

U is selected from -(CR^xR^y)_n-, substituted or unsubstituted aryl, substituted or unsubstituted five membered 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, or substituted or unsubstituted six membered heterocycle selected from the group consisting of pyrimidine, pyridine and pyridazine; V is selected from hydrogen, cyano, nitro, -NR^xR^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(O)OR^X, -OR^X, -C(0)NR^xR^y, -C(O)R^X and -SO₂NR^xR^y; or alternatively, U and V together may form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring that may optionally include one or more heteroatoms selected from O, S and N; at each occurrence, R^x and R^y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and at each occurrence, 'm' and 'n' are independently selected from O to 2, both inclusive.

2. The compound according to claim 1, wherein Ai is N and both A₂ and A₃ are CR^a.

3. The compound according to claim 1, wherein A3 is N and both Ai and A₂ are CR^a.

4. The compound according to claim 1, wherein both Ai and A₂ are N and A₃ is CR^a.

5. The compound according to claim 1, wherein both Ai and A₃ are N and A₂ is CR^a.

6. The compound according to claim 1, wherein both A₂ and A₃ are N and Ai is CR^a.

7. The compound according to any of claims 2 to 6, wherein R^a is hydrogen.

8. The compound according to any of claims 2 to 6, wherein R^a is alkyl.

9. The compound according to claim 8, wherein alkyl is methyl.

10. The compound according to any of claims 2 to 6, wherein R^a is alkoxy.

11. The compound according to claim 10, wherein alkoxy is methoxy.

12. The compound according to any of claims 1 to 11, wherein L is -CH₂-

13. The compound according to any of claims 1 to 12, wherein R¹ and R² are (C₁- C₆)alkyl.

14. The compound according to claim 13, wherein (Ci-C₆)alkyl is methyl.

15. The compound according to any of claims 1 to 14, wherein R₃ is hydrogen.

16. The compound according to any of claims 1 to 15, wherein U is heteroaryl.

17. The compound according to claim 16, wherein heteroaryl is selected from the

group consisting

18. The compound according to any of claims 1 to 17, wherein V is substituted or unsubstituted aryl.

19. The compound according to claim 18, wherein aryl is phenyl.

20. A compound of the formula (Ia)

(Ia) or pharmaceutically acceptable salt thereof, wherein, at each occurrence, R^a is selected from hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and cycloalkylalkyl;

U is substituted or unsubstituted five membered heterocycle, for example selected from the group consisting of

at each occurrence, R >b is independently selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; at each occurrence, R^z is independently selected from halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring, heterocyclylalkyl, COOR^X, CONR^xR^y, S(O)_mNR^xR^y, NR^x(CR^xR^y)_nOR^x, (CH₂)_nNR^xR^y, NR^x(CR^xR^y)_nCONR^xR^y, (CH₂)_nNHCOR^x, (CH₂)_nNH(CH₂)_nSO₂R^x and (CH₂)_nNHSO₂R^x; at each occurrence, R^x and R^y are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; at each occurrence, 'm' and 'n' are independently selected from 0 to 2, both inclusive; and

'p' is independently selected from from 0 to 5, both inclusive.

21. The compound according to claim 20, wherein R^a is hydrogen.

22. The compound according to claim 20, wherein R^a is alkoxy.

23. The compound according to claim 22, wherein alkoxy is methoxy.

24. The compound according to any of claims 20 to 23, wherein U « is

25. The compound according to any of claims 20 to 23, wherein U is

26. The compound according to any of claim 24 or 25, wherein R^b is hydrogen.

27. The compound according to any of claims 20 to 26, wherein R^z at each occurrence is independently selected from the group consisting of hydrogen, alkyl, halogen, alkoxy, haloalkyl, haloalkoxy and dialkylamino.

28. The compound according to claim 27, wherein alkyl is (Ci-Ce)alkyl.

29. The compound according to claim 27, wherein alkoxy is methoxy,

30. The compound according to claim 27, wherein haloalkyl is trifluoromethyl.

31. The compound according to claim 27, wherein haloalkoxy is trifluoromethoxy or trifluoroethoxy.

32. The compound according to claim 27, wherein dialkylamino is diethylamino.

33. A compound of the formula (Ib)

(Ib) or pharmaceutically acceptable salt thereof, wherein,

R^a, R^z, U and 'p' are as defined herein above in claim 20.

34. The compound according to claim 33, wherein R^a is hydrogen.

35. The compound according to any of claim 33 or 34, wherein U is

36. The compound according to any of claim 33 or 34, wherein U is

*

37. The compound according to any of claim 35 or 36, wherein R^b is hydrogen.

38. The compound according to any of claim 35 or 36, wherein R is methyl.

39. The compound according to any of claims 33 to 38, wherein R^z at each occurrence is independently selected from the group consisting of hydrogen, alkyl, halogen, alkoxy, haloalkyl, haloalkoxy and dialkylamino.

40. The compound according to claim 39, wherein alkyl is (Ci-C₆)alkyl.

41. The compound according to claim 39, wherein alkoxy is methoxy,

42. The compound according to claim 39, wherein haloalkyl is trifluoromethyl.

43. The compound according to claim 39, wherein haloalkoxy is trifluoromethoxy or trifluoroethoxy.

44. The compound according to claim 39, wherein dialkylamino is diethylamino.

45. A compound of the formula (Ic)

(Ic) or pharmaceutically acceptable salt thereof, wherein,

R^a, R^z, U and 'p' are as defined herein above in claim 20.

46. The compound according to claim 45, wherein R^a is hydrogen or (Ci-C₆)alkyl.

47. The compound according to claim 46, wherein (Ci-Ce)alkyl is methyl.

48. The compound according to any of claims 45 to 47, wherein U is

Y

49. The compound according to claim 48, wherein R^b is hydrogen.

50. The compound according to any of claims 45 to 49, wherein R^z at each occurrence is independently selected from the group consisting of hydrogen, alkyl, halogen, alkoxy, haloalkyl and haloalkoxy.

51. The compound according to claim 50, wherein alkyl is (Ci-C6)alkyl.

52. The compound according to claim 50, wherein alkoxy is methoxy,

53. The compound according to claim 50, wherein haloalkyl is trifluoromethyl.

54. The compound according to claim 50, wherein haloalkoxy is trifluoromethoxy.

55. A compound of the formula (Id)

(Id) or pharmaceutically acceptable salt thereof, wherein, R^a, R^z, U and 'p' are as defined herein above in claim 20.

56. The compound according to claim 55, wherein R^a is hydrogen.

57. The compound according to any of claim 55 or 56, wherein U is

58. The compound according to any of claim 55 or 56, wherein U is

*

59. The compound according to any of claim 57 or 58, wherein R^b is hydrogen.

60. The compound according to any of claims 55 to 59, wherein R^z at each occurrence is independently selected from the group consisting of hydrogen, alkyl, halogen, alkoxy, haloalkyl and haloalkoxy.

61. The compound according to claim 60, wherein alkyl is (Ci-Ce)alkyl.

62. The compound according to claim 60, wherein alkoxy is methoxy,

63. The compound according to claim 60, wherein haloalkyl is trifluoromethyl.

64. The compound according to claim 60, wherein haloalkoxy is trifluoromethoxy.

65. A compound of the formula (Ie)

(Ie) or pharmaceutically acceptable salt thereof, wherein,

R^a, R^z, U and 'p' are as defined herein above in claim 20.

66. The compound according to claim 65, wherein R^a is hydrogen.

67. The compound according to any of claim 65 or 66, wherein U is

*

68. The compound according to claim 67, wherein R is hydrogen.

69. The compound according to any of claims 65 to 68, wherein R^z at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkoxy, haloalkyl and haloalkoxy.

70. The compound according to claim 69, wherein alkoxy is methoxy.

71. The compound according to claim 69, wherein haloalkyl is trifluoromethyl.

72. The compound according to claim 69, wherein haloalkoxy is trifluoromethoxy.

73. The compound selected from: N-{[4-(4-Ethylphenyl)]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide;

N-{[4-(4-Isopropylphenyl)]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide;

N-{[4-(4-Isobutylphenyl)]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide; iV-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide;

N-{4-[3-(Trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-<i]pyrimidin-5-yl)- acetamide;

N-[4-(4-Diethylaminophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-d]pyrimidin-5-yl)acetamide;

N-[4-(2,3-Difluorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<i]pyrimidin-5-yl)acetamide;

N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-[4-(2,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide;

N-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-^-CS^-DichlorophenyO-l^-thiazol^-y^^-Cl^-dimethyl^^-dioxo-l^^^- tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-[4-(3-Chloro-4-(trifluoromethyl)phenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide; N-{4-[4-Fluoro-3-(trifluoromethyl)plienyl]-l,3-tliiazol-2-yl}-2-(l,3-dimetliyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)- acetamide;

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)- acetamide;

N-{4-[4-Fluoro-3-(trifluoromethoxy)plienyl]-l,3-tliiazol-2-yl}-2-(l,3-dimetliyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-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-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-{4-[4-Chloro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-{4-[3-Chloro,5-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide;

N-{4-[2,4-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-^-P^-Difluoro^-CtrifluoromethyOpheny^-l^-thiazol^-y^^-Cl^-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-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-tetrahydropyrido[2,3-(i]pyrimidin-5-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-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-[5-(4-Bromophenyl)isoxazol-3-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[2,3-<f]pyrimidin-5-yl)acetamide;

N-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(7-methoxy-l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide;

N-^-CS-Fluoro^-trifluoromethylphenyO-l^-thiazol^-y^^-CV-methoxy-l^- dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide; and

N-[4-(2,4-Difluoro-3-trifluoromethylphenyl)-l,3-thiazol-2-yl]-2-(7-methoxy-l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[2,3-(i]pyrimidin-5-yl)acetamide; or pharmaceutically acceptable salt thereof.

74. The compound selected from:

N-{4-[4-(Trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide;

N-{4-[3-(tert-Butyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-(i]pyrimidin-5-yl)- acetamide; iV-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide;

N-{4-[3-(Trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)- acetamide;

N-[4-(4-Diethylaminophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide;

N-{4-[2,4-Dichlorophenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide;

N-{4-[2,4-Difluorophenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide;

2-(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-βT|pyrimidin-5-yl)-N-{4- [2-fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl} acetamide;

2-(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-βT|pyrimidin-5-yl)-N-{4- [2-fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl} acetamide;

N-[4-(3-Methyl-4-chlorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-yl)acetamide;

N-^-CS^-DichlorophenyO-l^-thiazol^-y^^-Cl^-dimethyl^^-dioxo-l^^^- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide; iV-[4-(3,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo-l,2,3,4- tetrahydropyrido [4,3 -<i]pyrimidin-5 -yl)acetamide;

N-[4-(3-Fluoro-4-methoxyphenyl)-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)acetamide;

N-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide;

N-{4-[3-Chloro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide;

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<f]pyrimidin-5-yl)acetamide; N-{4-[4-Fluoro-3-(trifluoromethyl)plienyl]-l,3-tliiazol-2-yl}-2-(l,3-dimetliyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)- acetamide;

N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide;

N-{4-[4-Chloro-3-(trifluoromethoxy)plienyl]-l,3-tliiazol-2-yl}-2-(l,3-dimetliyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-<i]pyrimidin-5-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-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)- acetamide;

N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)- acetamide;

N-{4-[2-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)- acetamide;

N-{4-[3-Chloro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide;

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrido[4,3-<f]pyrimidin-5-yl) acetamide;

N-{4-[3-Chloro-5-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide;

N- {4-[2,4-Difluoro-3 -(trifluoromethyl)phenyl]- 1 ,3 -thiazol-2-yl} -2-( 1 ,3 -dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)acetamide;

N- {4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]- 1,3 -thiazol-2-yl} -2-( 1,3 -dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)acetamide;

N-{4-[3,5-difluoro-4-(2,2-dimethylpropoxy)phenyl]-l,3-thiazol-2-yl}-2-(l,3- dimethyl-2,4-dioxol,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-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-tetrahydropyrido[4,3-(i]pyrimidin-5-yl) acetamide;

N-{4-[3,5-Difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-l,3-thiazol-2-yl}-2-(7- methoxy-l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5- yl)acetamide;

N-[4-(4-Chlorophenyl)-5-methyl-l,3-thiazol-2-yl]-2-(l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[4,3-(/]pyrimidin-5-yl)acetamide;

N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-5-methy-l,3-thiazol-2-yl}-2-(l,3- dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-(i]pyrimidin-5-yl)acetamide; and N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrido[4,3-d]pyrimidin-5-yl)acetamide; or pharmaceutically acceptable salt thereof.

75. The compound selected from: N-[4-(4-Isopropylphenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-<f]pyrimidin-4-yl)acetamide;

N-[4-(4-tert-Butylphenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-<i]pyrimidin-4-yl)- acetamide;

N-{4-[3-(Trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7-dioxo- 5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide;

N-[4-(4-Trifluoromethylphenyl)-l,3-thiazol-2-yl] -2-(6,8-dimethyl-5,7-dioxo- 5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide;

N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide;

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide;

N-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide;

N-{4-[3-fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6,8-Dimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide;

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide; and

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(2,6,8-trimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-(i]pyrimidin-4-yl)acetamide; or pharmaceutically acceptable salt thereof.

76. The compound selected from: N-[4-(4-Isobutylphenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-[4-(4-Chlorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[3-(trifluoromethoxy)phenyl]-l,3-thiazol -2-yl}-2-(6,8-Dimethyl-5,7-dioxo- 5,6,7 , 8-tetrahy dropyrimido [4,5 -c]pyridazin-4-y l)acetamide; N-{4-[2-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-[4-(2,4-Dichlorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-[4-(2,4-Difluorophenyl)-l,3-thiazol-2-yl]-2-(6,8-dimethyl-5,7-dioxo-5,6,7,8- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide; iV-^-CS^-DichlorophenyO-l^-thiazol^-y^^-Cό^-dimethyl-SJ-dioxo-S^J^- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide; iV-^-CS^-DifluorophenyO-l^-thiazol^-y^^-Cό^-dimethyl-SJ-dioxo-S^J^- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-Dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide; iV-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide; iV-{4-[4-Chloro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[3-Fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[4-Fluoro-3-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-^-CS^-DifluorophenyO-l^-thiazol^-y^^-Cό^-dimethyl-SJ-dioxo-S^J^- tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl-5,7- dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)acetamide;

N-{4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(6,8-dimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)-acetamide; and

N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl}-2-(6,8-dimethyl- 5,7-dioxo-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-4-yl)-acetamide;

- I l l - or pharmaceutically acceptable salt thereof.

77. The compound selected from: N-{4-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5-yl)acetamide;

N-{4-[2-Fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5-yl)acetamide;

N-{4-[3-Fluoro-5-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrimido[4,5-(i]pyridazin-5-yl)acetamide; iV-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4- dioxo-l,2,3,4-tetrahydropyrimido[4,5-<i]pyridazin-5-yl)acetamide;

N-{4-[3-Fluoro-4-(trifluoromethoxyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5-(i]pyridazin-5-yl)acetamide;

N-{4-[2,3-Difluoro-4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5-(i]pyridazin-5-yl)acetamide; and

N-{4-[2,4-Difluoro-3-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyl- 2,4-dioxo-l,2,3,4-tetrahydropyrimido[4,5-(i]pyridazin-5-yl)acetamide; or pharmaceutically acceptable salt thereof.

78. A pharmaceutical composition comprising one or more compounds selected from the compounds of any one of claims 1 to 77, and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.

79. 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 77.

80. The method according to claim 79, 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, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory diseases, asthma, cough, COPD, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus.

81. The method according to claim 80, wherein the symptoms of a disease or condition is associated with chronic pain.

82. The method according to claim 80, wherein the symptoms of a disease or condition is associated with neuropathic pain.

83. The method according to claim 80, wherein the symptoms of a disease or condition is associated with rheumatoid arthritic pain or osteoarthritic pain.