WO2011132017A1 - Pyrido[3,4-d]pyrimidinyl acetamide derivatives as trpa1 modulators - Google Patents

Abstract

Provided are pyrido[3,4-d]pyrimidinyl acetamide derivatives as Transient Receptor Potential Ankyrin (TRPA) modulators. In particular, the compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by Transient Receptor Potential Ankyrin 1 (TRPAl). Also provided herein are processes for preparing the 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. Formula (I).

Description

PYRIDO[3,4-d]PYRIMIDINYL ACETAMIDE DERIVATIVES AS TRPAl

MODULATORS

Related applications

This application claims the benefit of Indian Patent Application Nos 1270/MUM/2010 filed on April 19, 2010 and 1736 MUM/2010 filed on June 07, 2010; and US Provisional Application Nos 61/328,302 filed on April 27, 2010 and 61/355,762 filed on June 17, 2010; all of which are hereby incorporated by reference.

Technical Field

The present patent application relates to pyrido[3,4-d]pyrimidinyl acetamide derivatives with transient receptor potential ankyrin l (TRPA l) 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, ANKTM 1) and TRPN (NOMPC) families. The TRPC family can be divided into 4 subfamilies (i) TRPC 1 (ii) TRPC2 (iii) TRPC 3, TRPC6, TRPC 7 and (iv) TRPC4, TRPC 5 based on sequence functional similarities. Currently the TRPV family has 6 members. TRPV 5 and TRPV6 are more closely related to each other than to TRPV 1 , TRPV2, TRPV 3 or TRPV4. TRPAl is most closely related to TRPV 3 and is more closely related to TRPV 1 and TRPV2 than to TRPV 5 and TRPV6. The TRPM family has 8 members. Constituents include the following: the founding member TRPM1 (melastatin or LTRPC 1 ), TRPM3 ( IAA 1616 or LTRPC3), TRPM7 (TRP-PLIK, Cha ( l ), LTRPC7), TRPM6 (Cha 2), TRPM2 (TRPC 7 or LTRPC2), TRPM8 (TRP-p8 or CMR1 ), TRPM5 (MTR1 or LTRPC5) and TRPM4 (FLJ20041 or LTRPC4). The TRPML family consists of the mucolipins, which include TRPML1 (mucolipin 1 ), TRPML2 (mucolipin 2) and TRPML3 (mucolipin 3). The TRPP family consists of two groups of channels: those predicted to have six transmembrane domains and those that have eleven. TRPP2 (P JD2), TRPP3 (P D2L1 ), TRPP5 (P D2L2) are all predicted to have six transmembrane domains. TRPPl (PKDl , PC I ), PKD-REJ and PKD-l Ll are all thought to have eleven transmembrane domains. The sole mammalian member of the TRPA family is ANKTM1. It is believed TRPA l is expressed in nociceptive neurons. Nociceptive neurons of the nervous system sense the peripheral damage and transmit pain signals. TRPA l 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.TRPA l 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 TRPA l 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 TRPA l 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 (B ) which is released during tissue injury at peripheral terminals

The difference between TRPA l and other TRP receptors is that TRPA l ligand binding persists for hours due to which the physiological response (e.g., pain) is greatly prolonged. Hence to dissociate the electrophile, an effective antagonist is required.

WO 2009/158719, WO 2009/002933, WO 2008/0949099, WO 2007/073505, WO 2004/055054 and WO 2005/089206 describe the TRP channels as the targets for the treatment of pain and related conditions.

In efforts to discover better analgesics for the treatment of both acute and chronic pain and to develop treatments for various neuropathic and nociceptive pain states, there exists a need for a more effective and safe therapeutic treatment of diseases, conditions and/or disorders modulated by TRPAl .

Summary of the Invention

The present invention relates to compounds of the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein,

R¹ and R² are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyi, heterocyclylalkyl, and - (CR^xR^y)_nOR^x;

at each occurrence, R³ is selected from hydrogen, halogen, cyano, hydroxyl, amino, alkylamino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyi, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl

R^a and R^b are independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, hydroxyalkyl, substituted or unsubstituted cycloalkyl and cycloalkylalkyl;

U, V, W and Y are independently selected from CR^C, N, O and S in such a way that it forms stable five-membered heterocyclic ring;

at each occurrence, R^c is selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyi, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; or

R^c is absent;

at each occurrence, R^x and R are independently selected from hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyi, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;

'n' is selected from 0 to 2, both inclusive; and

'p' is selected 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 one embodiment, specifically provided are compounds of the formula (II)

(Π)

or a pharmaceutically acceptable salt thereof,

wherein,

R° is selected from hydrogen, halogen, cyano, hydroxyl, nitro, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyi, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl;

at each occurrence, R³ is selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, alkylamino, substituted or unsubstituted alkyl, alkoxy, haloalkyi, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and

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

According to another embodiment, specifically provided are compounds of the formula (I) wherein R¹ and R² are alkyl preferably methyl.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R^a and R^b are hydrogen.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which Y and W are nitrogen and U and V are carbon.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which U and Y are nitrogen, W is carbon and V is oxygen.

According to yet another embodiment, specifically provided are compounds of the formula (I) in which R^c is hydrogen or absent.

According to one embodiment, specifically provided are compounds of the formula (I) in which each occurrence of R³ is selected from halogen (for example F, CI or Br), haloalkyi (for example CF3), haloalkoxy (for example OCHF₂ or OCF3,), alkylamino (for example methyamino or ethylamino), dialkylamino (for example dimethylamino or diethylamino) and heterocyclic ring (for example morpholinyl).

Particularly contemplated are compounds of the formulas (I) and (II), which possess IC50 of less than 250 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to TRPAl activity as measured by method as described in the present patent application.

It should be understood that the formulas (I) and (II), structurally encompasses all stereoisomers, enantiomers and diastereomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

The compound of the present invention as TRPAl modulator is used herein because it is more selective for one TRP isoform than others, e.g., 2-fold, 5-fold, 10-fold, and more preferably at least 20, 40, 50, 60, 70, 80, or at least 100- or even 1000-fold more selective for TRPAl over one or more of TRPC6, TRPV5, TRPV6, TRPM8, TRPV1, TRPV2, TRPV4 and/or TRPV3.

More specifically the compound of the present invention are more selective as

TRPAl modulator over TRPV4 for e.g., 2-fold, 5-fold, 10-fold, and more preferably at least 20, 40, 50, 60, 70, 80, or even 100- fold more selective.

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 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 TRPA 1 receptors, wherein modulation is believed to be related to a variety of disease states.

The compounds of the present invention can be administered alone or in combination with other therapeutic agents. For instance, the TRPA1 modulator is administered conjointly with one or more of an anti-inflammatory agent, anti-acne agent, anti-wrinkle agent, anti-scarring agent, anti-psoriatic agent, anti-proliferative agent, antifungal agent, anti-viral agent, anti-septic agent, anti-migraine agent, keratolytic agent, or a hair growth inhibitor

In accordance with another aspect, the present patent application further provides a method of inhibiting TRPA 1 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 (te -butyl). The term "C| _ alkyl" refers to an alkyl chain having 1 to 6 carbon atoms. Unless set forth or recited to the contrary, all alkyl groups described herein may be straight chain or branched, substituted or unsubstituted

The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched chain having 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l - propenyl, 1 -butenyl and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "alkynyl" refers to a straight or branched chain hydrocarbyl radical having at least one carbon-carbon triple bond and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred) e.g., ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, all alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted. The term "alkoxy" refers to a straight or branched, saturated aliphatic hydrocarbon radical bonded to an oxygen atom that is attached to a core structure. Examples of alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, 3-methyl butoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.

The term "haloalkyl" and "haloalkoxy" means alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms, where alkyl and alkoxy groups are as defined above. The term "halo" is used herein interchangeably with the term "halogen" means F, CI, Br or I. Examples of "haloalkyl" include but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl 4,4,4-trifluorobutyl, chloromethyl, dichloromethyl, trichloromethyl, 1 -bromoethyl and the like. Examples of "haloalkoxy" include but are not limited to fluoromethoxy, 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 is (C3_6)cycloalkyl-(Ci. ₆)alkoxy. Preferably, cyclopropylmethoxy, 1 - or 2-cyclopropylethoxy, 1 -, 2- or 3- cyclopropylpropoxy, 1 -, 2-, 3- or 4-cycIopropyl-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-cycIohexylethoxy and 1-, 2- or 3- cyclohexylpropoxy. Unless set forth or recited to the contrary, all cycloalkylalkoxy groups described herein may be substituted or unsubstituted.

The term "cycloalkenyl" refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described herein may be substituted or unsubstituted.

The term "aryl" means a carbocyclic aromatic system containing one, two or three fused or linked aromatic rings (i.e., biaryl, aryl-substituted aryl, etc). If the rings are fused, one of the rings must be fully unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated. The term "fused" means that a second ring is present (ie, attached or formed) by having two adjacent atoms in common (i.e., shared) with the first ring. The term "fused" is equivalent to the term "condensed". The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Unless set forth or recited to the contrary, all aryl groups described herein may be substituted or unsubstituted.

The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C6H₅ or -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.

The term "heterocyclic ring" or "heterocyclyl" refers to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoqinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamoφholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclic ring described herein may be substituted or unsubstituted.

The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described herein may be substituted or unsubstituted.

The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroaryl groups described herein may be substituted or unsubstituted.

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyl groups described herein may be substituted or unsubstituted.

Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or more or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, -COOR", -C(0)R^x, -C(S)R^X, -C(0)NR^xR^y*, -C(0)ONR^xR^y', -NR^xCONR^yR^z, -N(R^x')SOR^y', -N(R^x')S0₂R^y', (=N-N(R^x')R^y ), -NR^x'C(0)OR^y', -NR^x R^y, -NR^xC(0)R^y', -NR^xC(S)R^y', -NR^xC(S)NR^y R^z', -SONR^x R^y, -S0₂NR^x R^y', -OR"', -OC(0)R^x, -OC(0)NR^x R^y', -SR^X', -SOR^x', -S0₂R^x' and - ON0₂, wherein R ' 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. "IC50" refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity.

The compounds described in the present patent application may form salts. Non- limiting examples of pharmaceutically acceptable salts forming part of this patent application include salts derived from inorganic bases salts of organic bases, salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids.

Certain compounds of the present invention, including compounds of formula (I), and (II) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers). The present invention includes these stereoisomeric forms (including diastereomers and enantiomers) and mixtures thereof. The various stereoisomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.

Pharmaceutical Compositions

The pharmaceutical composition of the present patent application includes at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition includes the compound(s) described herein in an amount sufficient to inhibit TRPA I in a subject (e.g., a human). The inhibitory activity of compounds falling within the formulas (I) and (II) 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 tieatable by inhibition of TRPA l . 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 TRPA l receptors: pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, chemotherapy - induced neuropathies, eye - irritation, bronchial - irritation, skin - irritation (atopic dermatitis), Frost - bites (cold - bite), spasticity, catatonia, catalepsy, parkinsons, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory disorder like airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and paracetamol-induced asthma, cough, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), overactive bladder, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus. Digestive organ diseases like irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, constipation, diarrhea, and vomiting. The connection between therapeutic effect and inhibition of TRPAl is illustrated, for example, in Story, G. M. et al. Cell, 2003, 1 12, 819-829; McMahon, S.B. and Wood, J. N., Cell, 2006, 124, 1 123-1 125; Voorhoeve, P. M. et al. Cell, 2006, 124, 1 169-1 181 ; 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 ( . M. Foley, Pain, in Cecil Textbook of Medicine; J. C. Bennett & F. Plum (eds.), 20th ed., 1996, 100- 107). The sensation of pain can be triggered by any number of physical or chemical stimuli and the sensory neurons which mediate the response to this harmful stimulus are termed as "nociceptors". Nociceptors are primary sensory afferent (C and Αδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal and proton (pH<6) modalities. Nociceptors are the nerves which sense and respond to parts of the body which suffer from damage. They signal tissue irritation, impending injury, or actual injury. When activated, they transmit pain signals (via the peripheral nerves as well as the spinal cord) to the brain.

Chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the sensory nerves of the peripheral or central nervous system and is maintained by aberrant somatosensory processing. The pain is typically well localized, constant and often with an aching or throbbing quality. Visceral pain is the subtype of nociceptive pain that involves the internal organs. It tends to be episodic and poorly localized. Nociceptive pain is usually time limited, meaning when the tissue damage heals, the pain typically resolves (arthritis is a notable exception in that it is not time limited).

General Methods of Preparation

The compounds described herein, including compounds of general formula (I) and (II), and specific examples, can be prepared by techniques known to in the art, for example, through the reaction scheme depicted in Schemes 1 -9. 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 pyrido[3,4-i/]pyrimidinyl acetamide derivatives of the general formula (I), wherein R¹, R², R³, R^a, R^b, U, V, W, Y and 'p' are as defined above in description can depicted in Scheme 1. The carboxylic acid (when R is hydrogen) or its ester derivative (when R is alkyl) of the formula (1) is coupled with amine of formula (2) in presence of a suitable coupling agent (for R = H) or a suitable base such as sodium hydride (for R = alkyl) in a suitable solvent or a mixture of solvents to afford compounds of the formula (I).

Scheme 1

A general approach for the synthesis of pyrido[3,4-c/]pyrimidinyl acetamide derivatives of the general formula (la), wherein U, V, W, Y, R³ and 'p' are as defined above can depicted in Scheme 2. The known 6-methyl-l,3-dimethyluracil derivative (3) can be prepared by two different methods. In one approach N,N-dimethyl urea is condensed with acetic anhydride in presence of dry pyridine as reported by Egg, H. et al in Synthesis, 1982, 1071 -1073. Alternatively, intermediate (3) can be prepared by alkylation of 6-methyluracil according to the procedure reported by Siverman, R. B. et al, J. Am. Chem. Soc, 1982, 104, 6434-6439. Friedel-Crafts acylation of intermediate (3) in the presence of catalytic amount of Lewis acid e.g., ZnCI₂ gives compounds of the formula (4) [Tsupak, E. B. et al in J. Chemistry heterocyclic compounds, 2003, 39, 953- 959]. The condensation of compounds of the formula (4) with triethylorthoformate gives compound of the formula (5). Oxidative cleavage of olefenic double in intermediate (5) using a suitable reagent such as NaI0 or NalCVOsC^ or CuCl/DMF/0₂ gives desired aldehyde of formula (6). The aldehyde of formula (6) can be transformed into aldehyde amine of the formula (7) in three steps. Cyclisation of aldehyde amine (7) gives desired pyrido[3,4-d]pyrimidine-5-one of the formula (8). The aromatization of compound (8) using phosphorous oxyhalide such as phosphorous oxychloride or phosphorous oxybromide in dry toluene in the presence of suitable base such as N,N-dimethyl aniline gives compounds of halo pyrido[3,4-d]pyrimidine of the formula (9). Suzuki-Miyaura coupling of halo compound (9) with allylboronic acid ester followed by oxidative cleavage can give corresponding pyrido[3,4-i/]pyrimidinyl acetic acid of the formula ( Γ) [ otha et al., in Synlett, (2005), 12, 1877-1890 and Sharpless, . B. et al. in J. Org. Chem., ( 1981 ), 3936-3938]. The coupling of compounds of formula ( Γ) with amines of formula (2) by using a standard amide coupling method can give compounds of general formula (la).

Scheme 2

In another approach pyrido[3,4-i/]pyrimidinyl acetamide derivatives of the general formula (la), wherein U, V, W, Y, R³ and 'p' are as defined above, can be prepared from a pyridine derivative as depicted in Scheme 3. Thus, commercially available 3,5- dibromopridine-4-carbaldehyde of the formula (10) is converted to the corresponding nitrile of formula (1 1) by a known approach using ammonia in the presence of iodine. Selective displacement of bromo compound (1 1) with methyl amine hydrochloride in the presence of suitable base gives compounds of the formula (12). The nitrile of formula ( 12) is converted to the corresponding amide of the formula (13) by using standard procedure as reported in the literature. Cyclisation of compounds of the formula ( 13) with triphosgene or carbonyl dimidazole in the presence of suitable solvent gives the compounds of the formula (14), which on selective N-alkylation afforded compounds of the formula ( 15). Aryl bromide of formula (15) on reaction with allylboronic acid pinacol ester of the formula ( 16) in the presence of Pd(0) catalyst gives ally! pyrido[3,4- i ]pyrimidinedione of the formula (17). Oxidative cleavage of the terminal olefinic bond of intermediate ( 17) using sodium metaperiodate in the presence of catalytic amounts of ruthenium (III) chloride (Sharpless, . B. et al. in J. Org. Chem., (1981 ), 3936-3938) can give the desired pyrido[3,4-</|pyrimidinyl acetic acid derivative of the formula ( Γ). The coupling of compounds of formula ( ) with amines of formula (2) by using a standard amide coupling method can give compounds of general formula (la).

Scheme 3

Another approach for the synthesis of for the synthesis of pyrido[3,4- c/]pyrimidinyl acetamide derivatives of the general formula (la), wherein U, V, W, Y, R³ and 'p' are as defined above can be depicted in Scheme 4. Suzuki-Miyaura coupling of bromo compound (13) with allylboronic acid ester (16) in the presence of Pd(0) catalyst gives allyl compounds of the formula (18). Cyclisation of compounds of the formula (18) with triphosgene gives compounds of the formula ( 19). The selective N-methylation of (19) gives compounds of the formula (17). Oxidative cleavage of the terminal olefinic bond of intermediate ( 17) using sodium metaperiodate in the presence of catalytic amounts of ruthenium (III) chloride can give the desired pyrido[3,4-i/]pyrimidinyl acetic acid of the formula ( ). The coupling of compounds of formula ( Γ) with amines of formula (2) by using a standard amide coupling method gives compounds of general formula (la).

Scheme 4

An alternative approach for the synthesis of pyrido[3,4-c/)pyrimidinyl acetamides of general formula (la) is shown in Scheme 5. Thus, reaction of 5-bromo pyrido[3,4- ] pyrimidinedione (15) with dialkyl malonate of the formula (20) in the presence of suitable base such as sodium hydride in suitable solvent such as dry DMSO gives the adduct (21) which on dealkoxycarboxylation using suitable base gives pyrido[3,4- i/]pyrimidinyl ester of the formula (22). A similar approach is reported by Koomen, G. J. et al Tetrahedron ( 1985), 41, 1893-1904. The coupling reaction of ethyl pyrido[3,4- i/]pyrimidinyl acetate of the formula (22) with amine of the formula (2) mediated by 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 (la).

Scheme 5 oxylation

Another approach for the synthesis of pyrido[3,4-i/]pyrimidinyl acetamides of general formula (la) is shown in Scheme 6. Thus, reaction of 6-methyl-l,3-dimethyluracil of general formula (3) with N,N-dimethylformamide dimethyl acetal of formula (23) in the presence of a suitable solvent (DMF) affords enamine of general formula (24). The compound of general formula (24) on oxidative cleavage of aliphatic olefinic bond using sodium periodate in presence of a suitable solvent gives formyl uracil of general formula (25). Condensation of compound of formula (25) with aminoacetaldehyde dimethylacetal of formula (26) gives intermediate of general formula (27). Reaction of compound of formula (27) with glyoxylic acid under acidic conditions, preferably con. HCI, followed by esterification affords ethyl pyrido[3,4-d]pyrimidinyl acetate of the formula (22). A similar approach is reported by Walter, J. G. et al. in J. Org. Chem., (40), 733-739, 1975. The coupling reaction of ethyl pyrido[3,4-i/jpyrimidinyl acetate of the formula (22) with amine of the formula (2) using suitable base such as sodium hydride in presence of a suitable solvent such as toluene or xylene affords compounds of the general formula (la).

Scheme 6

(3) (23)

Scheme 7 depicts synthesis of 2-amino-4-arylthiazoles of the formula (34) from aryl alkyl ketone of the formula (33) using known approaches. Certain di-and tri- substituted aryl alkyl ketone were not commercially available and they were prepared from the corresponding benzoic acid derivative of formula (29) in three steps. Thus, acid of formula (29) was converted to the corresponding acid chloride of formula (30) using oxalyl chloride in the presence of catalytic amounts of DMF in dry dichloromethane. The acid chloride of formula (30) was converted to corresponding Weinerb amide of formula (32) by treating with N,0-dimethylhydroxylamine hydrochloride of formula (31) in the presence of a suitable base such as triethylamine. The addition of methyl magnesium iodide to Weinreb amide of formula (32) afforded aryl alkyl ketone derivative of formula (33). Conversion of aryl alkyl ketone derivative of formula (33) to 2-amino-4- substituted arylthiazole of the formula (34) can be effected by two approaches as described in Scheme 7. In the first case aryl alkyl ketone was converted to the corresponding a-bromo ketone, which in turn was reacted with thiourea in a suitable solvent such as tetrahydrofuran at refluxing condition. Alternatively, aryl alkyl ketone derivative of formula (33) can be converted to 2-amino-4-aryl thiazole (34) 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 7

R^cCH₂Mgl ether

(34) thiourea, l₂ EtOH

5-Amino- 3-aryloxadiazoles of the formula (38) were prepared as shown in Scheme 8. The reaction of aryl nitrile of the formula (35) with dry ethanol in presence of dry HCl gas in dry diethyl ether gives imido ester hydrochloride of formula (36). The cyclisation of imido ester hydrochloride (36) using cyanamide and hydroxyl amine hydrochloride in presence of a suitable solvent gives desired oxadiazole amine of the formula (38).

Scheme 8 se, solvent

(37) OS) 3-Amino-l-arylpyrazoles of the formula (41) were prepared as shown in Scheme 9. Reaction of phenyl hydrazine derivative of formula (39) with acrylonitrile in the presence of a suitable base such as sodium ethoxide in refluxing ethanol affords the dihydro derivative of compound of formula (40). Intermediate (40) on oxidation with N- bromosuccinamide as described by Duffin, G. F. et al. J. Chem. Soc. ( 1954), 408-415, gives 3-amino- I -aryIpyrazoles derivative of formula (41).

Scheme 9

3 ^ NH H₂ ^C _t "^2Ν^ ^ _Ρ 3ν NBS . H₂N^¾

(^R J NaOEt/EtOH <^R Toluene "HQ^

(39) (40) (41 )

The intermediates and examples described in the present invention are prepared using the procedure described below. However, it is understood that these intermediates and examples can be prepared by alternate approaches which are within the scope of the present invention. EXPERIMENTAL

Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses. The following abbreviations are used in the text: DMSO-i/₆: 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

Ethyl pyrido[3,4-i/]pyrimidinyl acetate used for the preparation of compounds of the present invention, is prepared according to the synthetic schemes provided in 'General Methods of Preparation'. However, this intermediate can 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. 2-Amino-4-arylthiazoles were prepared by known literature methods starting from either substituted acetophenone or substituted benzoic acid as shown below.

Intermediate 1

Ethyl ( l ,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrido[3,4-i/]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 (1 10.92 g, 907.955 mmol) in dry pyridine (1.4 L) was added acetic anhydride (905.86 g, 2996.254 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for overnight. The excess of solvent was distilled under reduced pressure, quenched with 2 N HC1 (1000 ml) and extracted with chloroform (3 x 300 ml). The organic layer was washed with 2 N HCI ( 1000 ml) followed by saturated solution of sodium bicarbonate ( 1000 ml) and dried Na₂SC> ). The solvent was evaporated under reduced pressure to give 95.15 g of the product as a white solid;Ή-NMR (300 MHz, CDCI₃) δ 2.24 (s, 3H), 3.33 (s, 3H), 3.41 (s, 3H), 5.62 (s, 1 H).

Step 2: 6-[(£)-2-(Dimethylamino)vinyl]- l,3-dimethylpyrimidine-2,4(lH,3H)-dione: A mixture of Step 1 intermediate (40.0 g, 259.70 mmol) and N,N-dimethyl formamide dimethyl acetal (206 ml, 1549.12 mmol) in dry DMF (80 ml) was heated at 90°C for 48 h. 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 34 g of product as off-white solid. Ή-NMR (300 MHz, CDCI₃) δ 2.95 (s, 6H), 3.33 (s, 3H), 3.43 (s, 3H), 4.62 (d, J = 12.6 Hz, 1 H), 5.58 (s, 1 H), 7.03 (d, J = 12.6 Hz, l H).

Step 3: l ,3-Dimethyl-2,6-dioxo-l ,2,3,6-tetrahydropyrimidine-4-carbaldehyde: Sodium periodate ( 104.30 g, 488.01 mmol) was slowly added to a well stirred solution of Step 2 intermediate (34.0 g, 162.67 mmol) in a mixture of THF-water (650 ml). The reaction mixture was stirred at room temperature for 3 h. Chloroform ( 1000 ml) was added to the reaction mixture and stirred for 1 h after which it was filtered to remove the inorganic material. The filtrate was extracted with chloroform, dried (Na₂S0₄) and concentrated to yield the crude product. The compound was purified by tituration with diethyl ether ( 100 ml) to yield 17.80 g of product as off-white solid; Ή-NMR (300 MHz, CDC1₃) δ 3.39 (s, 3H), 3.68 (s, 3H), 6.29 (s, 1H), 9.56 (s, 1H).

Step 4: 6-{(£)-[(2,2-Dimethoxyethyl)imino]methyl}-l,3-dimethylpyrimidine-2,4(lH,3H)- dione: To a well stirred solution of Step 3 intermediate (30 g, 178.57 mmol) in dry toluene (615 ml) was added aminoacetaldehyde dimethylacetal (29.10 ml, 267.75 mmol) and was refluxed overnight. After completion of the reaction toluene was distilled out under reduced pressure to yield 42 g of crude product as brown oil; Ή-NMR (300 MHz, CDC1₃) δ 3.36-3.45 (m, 9H), 3.61 (s, 3H), 3.80 (d, J = 5.1 Hz, 2H), 4.67 (t, J = 4.8 Hz, 1H), 6.04 (s, l H), 8.07 (s, 1 H).

Step 5: 6- { [(2,2-Dimethoxyethyl)amino]methy 1 } - 1 ,3-dimethylpyrimidine-2,4( 1 H,3H)- dione: To a well stirred solution of Step 4 intermediate (42.0 g, 164.70 mmol) in dry methanol (41 1 ml), sodium borohydride (9.3 g, 247.05 mmol) was added portion wise at 0-5°C and the reaction was further stirred for 5 h at room temperature. The reaction mixture was then quenched with acetic acid and the excess of solvent was distilled out under reduced pressure. The reaction mass was diluted with water (500 ml) and extracted with dichloromethane (750 ml x 3). The combined organic layers were washed with water (200 ml), brine (200 ml), dried and concentrated to yield 42.0 g of the product as brown oil. Ή-NMR (300 MHz, CDC1₃) δ 2.77 (d, J = 5.4 Hz, 2H), 3.34 (s, 3H), 3.40 (s, 6H), 3.46 (s, 3H), 3.62 (s, 2H), 4.44 (t, J = 5.4 Hz, 1 H), 5.82 (s, 1 H).

Step 6: (l ,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-i/|pyrimidin-5-yl)acetic acid hydrochloride: To a well stirred solution of Step 5 intermediate (42.0 g, 163.40 mmol) in a mixture of concentrated hydrochloric acid (326 ml) and ethanol (326 ml) was added a solution of glyoxylic acid ( 1.8 g, 19.688 mmol) in ethanol (326 ml) and the reaction mixture was refluxed for 1 h. The excess of solvent was removed under reduced pressure to yield 67 g of crude product which was used directly for the next step.

Step 7: Ethyl (l ,3-dimethyl-2,4-dioxo-l ,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5- yl)acetate: To a well stirred solution of Step 6 intermediate (67.0 g, 234.50 mmol) in dry ethanol (670 ml) was added concentrated sulfuric acid (6 ml) and the reaction mixture was refluxed overnight. The excess of solvent was distilled out under reduced pressure, the reaction mass was diluted with water (200 ml) and neutralized by saturated sodium bicarbonate solution. The product was extracted with dichloromethane (500 ml x 3) and the combined organic layers were washed with water (150 ml x 2), brine (100 ml) and dried (Na₂SC»4) and concentrated to yield the crude product. The compound was purified by silica gel column chromatography to yield 1.75 g of product as off-white solid; Ή- NMR (300 MHz, CDC1₃) δ 1.29 (t, J =6.9 Hz, 3H), 3.44 (s, 3H), 3.69 (s, 3H), 4.14 (s, 1 H), 4.20 (q, J = 6.6 Hz, 2H), 8.33 (s, 1 H), 8.71 (s, 1 H).

Intermediate 2

5-[3-Fluoro-4-(trifluoromethyl)phenyl]- 1 ,2,4-oxadiazol-3-amine:

N O =x

F

Step 1 ; 3-Fluoro-4-(trifluoromethyl)benzamide: To a stirred solution of 3-fluoro-4- (trifluoromethyl)benzoic acid (2.8 g, 13.46 mmol), dry DMF ( 1 -2 drops) in dry dichloromethane (30 ml) was added oxalyl chloride (1.4 ml, 16.15 mmol) drop wise at 0- 5°C and stirred at room temperature for 2 h. The excess of solvent was evaporated under reduced pressure. The acid chloride was dissolved in dry acetone and was added to aqueous ammonia solution (50 ml) at 0-5°C. Reaction mixture was stirred at room temperature for 2 h and resulting solid was filtered and dried to yield 2.51 g of white solid.'H-NMR (300 MHz, DMSO-d₆) δ 7.79 (br s, 1H), 7.86- 7.95 (m, 3H), 8.26 (br s, 1 H).

Step 2: 3-Fluoro-4-(trifluoromethyl)benzonitrile: To a stirred solution of Step 1 intermediate (2.5 g, 12.077 mmol) in dry pyridine (25 ml) was added phosphorous pentachloride (3.01 g, 14.49 mmol) and refluxed for 2 h. The reaction mass was then quenched into 1 N HCl and extracted in ethyl acetate (25 ml x 3). The combined organic layer was washed with water, brine, dried (Na₂S0₄) and concentrated to yield 1.55 g of the product as yellow solid. Ή-NMR (300 MHz, DMSO-d₆) δ 7.96 (d, J = 8.4 Hz, l H), 8.04 (t, J = 7.8 Hz, 1 H), 8.24 (d, J = 10.5 Hz, 1 H).

Step 3: Ethyl 3-fluoro-4-(trifluoromethyl)benzenecarboximidoate hydrochloride: To a stirred solution of Step 2 intermediate (1.5 g, 7.93 mmol) in dry diethyl ether (15 ml) was added dry ethanol (0.5 ml). The solution was cooled (0-5°C) and dry HCl gas was bubbled through for 2 h. Reaction mass was kept in refrigerator for 3 days and then stirred for 2 h at room temperature. To the reaction mixture was added diethyl ether (20 ml) and solid thus obtained was filtered and dried to yield 1.21 g of off-white solid as a product. Ή-NMR (300 MHz, DMSO-d₆) δ 1.18 (t, J = 7.2 Hz, 3H), 4.07 (q, J = 7.2 Hz, 2H), 7.68 (br s, 3H), 12.30 (br s, 1 H). Step 4: N-Cyano-3-fluoro-4-(trifluoromethyl)benzenecarboximidamide: To a stirred solution of Step 3 intermediate (1.2 g, 4.418 mmol) in dry ethanol (9 ml) was added tri ethyl amine (750 L) and cooled at 0-5°C. Cyanamide (222 mg, 5.303 mmol) was then added and stirred at room temperature for overnight. Excess of solvent was evaporated under reduced pressure, diluted with water, solid obtained was filtered and dried to yield 810 mg of off-white solid as a product. Ή-NMR (300 MHz, DMSO-d₆) δ 7.95-8.80 (m, 3H), 9.05 (br s, 1H), 9.41 (br s, 1 H).

Step 5; 5-[3-Fluoro-4-(trifluoromethyl)phenyl]-l,2,4-oxadiazol-3-amine: To a stirred solution of hydroxy! amine hydrochloride (292 mg, 4.210 mmol) in dry ethanol (12 ml). were added triethylamine (590 ih, 4.210 mmol) and Step 4 intermediate (800 mg, 3.508 mmol) in dry ethanol dropwise at 0-5 °C and temperature of the reaction mass was then gradually increased to room temperature and stirred for overnight. Excess of solvent was evaporated under reduced pressure, diluted with water, precipitated solid was filtered and dried to obtain crude product. The crude product was purified by Si0₂ column chromatography to give 428 mg of white solid as a product. Ή-NMR (300 MHz, DMSO- d₆) δ 7.23 (br. s, 2H), 7.78 (d, J = 5.4 Hz, 2H), 8.57 (d, J = 4.8 Hz, 2H).

Intermediate 3

Preparation of l -[3-(Trifluoromethyl)phenyl]-lH-pyrazol-3-amine Step 1 : l -[3-(Trifluoromethyl)phenyl]-4,5-dihydro-lH-pyrazol-3-amine: To a freshly prepared sodium ethoxide (1 17 mg, 5.08 mmol) in dry ethanol (4.3 ml) were added acrylonitrile (900 mg, 16.96 mmol), 3-trifluoromethyl phenyl hydrazine (3.07 g, 17.46 mmol) and resulting reaction mixture was refluxed for 24 h. The reaction mixture was concentrated, diluted with water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The combined organic layer was washed with brine (25 ml), dried (Na₂S0₄) and evaporated under reduced pressure. The crude product was purified by column chromatography to yield 900 mg of pale yellow solid as a product. Ή NMR (300 MHz, CDC1₃) δ 2.93 (t, J = 9.3 Hz, 2H), 3.72 (t, J = 9.6 Hz, 2H), 4.08 (br s, 2H), 6.94-7.00 (m, 2H), 7.13 (s, 1 H), 7.25-7.33 (m, 1 H).

Step 2: l -[3-(Trifluoromethyl)phenyl]-lH-pyrazol-3-amine: To a well stirred solution of step 1 intermediate (720 mg, 3.144 mmol) in dry toluene ( 1 1 ml) was added N- bromosuccinimide (558 mg, 3.134 mmol) and reaction mixture was refluxed for 1 h. The reaction mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 x 25 ml). Combined organic layer was washed with brine (25 ml), dried (Na₂S04) and solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to yield 180 mg of pale yellow solid.Ή NMR (300 MHz, CDC1₃) δ 3.27 (br s, 2H), 5.87 (s, 1 H), 7.38 (d, J = 7.5 Hz, 1 H), 7.48 (t, J = 7.8 Hz, 1 H),- 7.73-7.68 (m, 2H), 7.82 (s, 1H).

General procedure for the preparation of 2-amino-4-aryl thiazoles:

Method A

A solution of acetophenone derivative (1.0 equiv.) in glacial acetic acid (5 vol) was added liquid bromine ( 1.0 equiv.) at 0°C 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 Na₂SC>4. 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 HCI to result salt formation of the amine. The precipitated salt was collected by filtration. The salt was then treated with saturated solution of NaHCC to re-generate the amine. The mixture was extracted with dichloromethane (2x 50 ml) and the combined organic extracts were washed with water and brine. The solvent was evaporated under reduced pressure to afford the 2-amino-4-aryl-thiazole derivative.

Method B

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 HCI and precipitated salt was collected by filtration. The free amine was regenerated as described in Method A given above.

All the 2-amino-4-arylthiazole derivatives were prepared by either Method A or Method B starting from appropriate aryl alkyl ketones. Structure information and characterization data for selected intermediates are given in Table 1.

Table 1 : Structural details and H NMR data of selected 2-aminothiazole intermediates

S No Structure Mol. Formula Ή NMR (δ ppm, 300 MHz)

The illustrative examples described herein are synthesized by coupling Intermediates 1 with appropriate aryl amines intermediate. EXAMPLES

The compounds of invention represented by the general structure (I) can be prepared by coupling ethyl pyrido[3,4-d]pyrimidinyl acetate derivative with an appropriate amine of the formula (2) using the general procedure given below. General procedure for the preparation of Examples: To a stirred solution of appropriate thiazoleamine (1.2 equiv.) in dry toluene, sodium hydride (60 % dispersion in mineral oil, 1.4 equiv.) was added and after stirring for 30 min at room temperature ethyl pyrido[3,4- djpyrimidinyl acetate ( 1.0 equiv.) was added and the mixture was heated to reflux for overnight. The mixture was acidified to pH 6.0 by the 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

N-{4-[4-(Diethylamino)phenyl]-l ,3-thiazol-2-yl}-2-(l,3-dimethyl-2,4-dioxo-l ,2,3,4- tetrahydropyrido[3,4-i/]pyri

The title compound was prepared according to the general procedure by coupling Intermediate 1 (80 mg, 0.288 mmol) with 4-[4-(diethylamino)phenyl]-l,3-thiazol-2-amine (71 mg, 0.288 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 23 mg, 0.577 mmol) in dry toluene (3 ml) to yield product (32 mg) as brown solid; Ή- NMR (300 MHz, CDC1₃) δ 1.18 (t, J=6.9 Hz, 6H), 3.34-3.42 (m, 4H), 3.47 (s, 3H), 3.68 (s, 3H), 4.25 (s, 2H), 6.60-6.80 (m, 2H), 6.89 (br s, 1 H), 7.6-0-7.75 (m, 2H), 8.43 (s, 1H), 8.72 (s, 1 H), 10.32 (br s, 1 H); ESI-MS (m/z) 479 (M+H)⁺.

Example 2

N-[4-(4-Chlorophenyl)- 1 ,3-thiazol-2-y l]-2-( 1 ,3-dimethy 1-2,4-dioxo- 1 ,2,3,4- tetrahydropyrido[3,4-i/]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 105 mg, 0.379 mmol) with 4-(4-chlorophenyl)-l,3-thiazol-2-amine (98 mg, 0.379 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 30 mg, 0.758 mmol) in dry toluene (4 ml) to yield product (53 mg) as off white solid. Ή- NMR (300 MHz, DMSO-i/₆) δ 3.23 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.64 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2H), 8.42 (s, 1 H), 8.88 (s, 1H), 12.52 (s, 1 H); APCI (m/z) 442.17 (M+H)⁺.

Example 3

2-( 1 ,3-Dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydropyrido[3,4-i/Jpyrimidin-5-yl)-N- {4-[3- (trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 (150 mg, 0.541 mmol) with 4-[3-(trifluoromethyl)phenyl]-l,3-thiazol-2- amine (132 mg, 0.541 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43.32 mg, 1.083 mmol) in dry toluene (5 ml) to yield 13 mg of product as off- white solid; ¹ H-NMR (300 MHz, DMSO-cfe) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.69 (d, J= 4.5 Hz, 2H), 7.84 (s, 1H), 8.20-8.27 (m, 2H), 8.42 (s, 1 H), 8.89 (s, 1H), 12.59 (s, 1 H); ESI-MS (m/z) 476.29 (M+H)⁺.

Example 4

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 150 mg, 0.541 mmol) with 4-[3-(trifluoromethoxy)phenyl]-l ,3-thiazol-2- amine (141 mg, 0.541 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43.1 mg, 1.083 mmol) in dry toluene (5 ml) to yield 1 1 mg of product as off- white solid; ¹ H-NMR (300 MHz, DMSO-</₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.33 (d, J=8.1 Hz, 1H), 7.58 (t, J=8.1 Hz, 1 H), 7.77 (s, l H), 7.88 (s, 1 H), 7.95

Hz, 1 H), 8.42 (s, 1 H), 8.88 (s, 1 H), 12.56 (s, 1 H); ESI-MS (m/z) 490.06 (M-H)\

Example 5

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (150 mg, 0.541 mmol) with 4-[3-(trifluoromethoxy)phenyl]-l ,3-thiazol-2- amine (140 mg, 0.541 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43.32 mg, 1.083 mmol) in dry toluene (6 ml) to yield 13 mg of product as off- white solid; ¹ H-NMR (300 MHz, DMSO-<&) δ 3.23 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.67 (s, 1 H), 8.03 (d, J=9.0 Hz, 2H), 8.42 (s, 1H), 8.88 (s, 1 H), 12.55 (s, 1 H); APCI (m/z) 492.10 (M+H)⁺.

Example 6

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (75 mg, 0.270 mmol) with 4-[4-(diethylamino)-3-fluorophenyl]-l ,3- thiazol-2-amine (72 mg, 0.270 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 22 mg, 0.541 mmol) in dry toluene (3 ml) to yield product (27 mg) as off- white solid; ¹ H-NMR (300 MHz, DMSO- ₆) δ 1.05 (t, J=6.9 Hz, 6H), 3.14-3.24 (m, 4H), 3.25 (s, 3H), 3.61 (s, 3H), 4.33 (s, 2H), 7.01 (t, J=8.7 Hz, 1 H), 7.45 (s, 1 H), 7.55-7.62 (m, 2H), 8.41 (s, 1 H), 8.88 (s, 1 H), 12.46 (s, 1H); ESI-MS (m/z) 497.32 (M+H)⁺.

Example 7 2-( l ,3-Dimethyl-2,4-dioxo-l ,2,3,4-tetrahydropyrido[3,4- ]pyrimidin-5-yl)-N-{4-[2- fluoro-3-(trifluoromethyl)phenyl]-l ,3-thiazol-2-yl}-acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 (105 mg, 0.379 mmol) with 4-[2-fIuoro-3-(trifluoromethyI)phenyI]-l ,3- thiazol-2-amine (99 mg, 0.379 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 30.3 mg, 0.758 mmol) in dry toluene (4 ml) to yield 25 mg of product as off-white solid. Ή-NMR (300 MHz, CDCI₃) δ 3.51 (s, 3H), 3.71 (s, 3H), 4.38 (s, 2H), 7.32 (d, J = 8.1 Hz, 1 H), 7.46 (s, 1 H), 7.55 (t, J = 7.2 Hz, 1 H), 8.29 (t, J = 7.5 Hz, 1 H), 8.55 (s, 1 H), 8.76 (s, 1 H), 10.03 (s, 1 H); ESI-MS (m/z) 494.04 (M+H)⁺.

Example 8

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (1 14 mg, 0.41 1 mmol) with 4-[2-fluoro-4-(trifluoromethyl)phenyl]-l ,3- thiazol-2 -amine ( 107 mg, 0.41 1 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 33 mg, 0.822 mmol) in dry toluene (4 ml) to yield 33 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO-c ₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.35 (s, 2H), 7.68-7.76.(m, 2H), 7.82 (t, J = 1 1.7 Hz, 1 H), 8.28 (t, J = 7.8 Hz, 1 H), 8.43 (s, 1 H), 8.89 (s 1 H), 12.65 (s, 1 H); ESI-MS (m/z) 494.33 (M+H)⁺.

Example 9

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (115 mg, 0.415 mmol) with 4-[3-fluoro-4-(trifluoromethyl)phenyl]-l,3- thiazol-2-amine (109 mg, 0.415 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 34 mg, 0.83 mmol) in dry toluene (4 ml) to yield 40 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO-i ) δ 3.20 (s, 3H), 3.59 (s, 3H), 4.32 (s, 2H), 7.85 (t, J= 7.8 Hz, IH), 7.86-8.00 (m, 3H), 8.40 (s, IH), 8.87 (s, IH), 12.61 (s, IH); ESI-MS (m/z) 494.03 (M+H)⁺.

Example 10

2-(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)-N-{4-[4- fluoro-3-(trifluoromethyl)phen -l,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 (115 mg, 0.415 mmol) with 4-[4-fluoro-3-(trifluoromethyl)phenyl]-l,3- thiazol-2-amine (108 mg, 0.415 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 34 mg, 0.83 mmol) in dry toluene (5 ml) to yield 57 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO-i₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.33 (s, 2H), 7.62 (t, J= 9.6 Hz, IH), 7.81 (s, IH), 8.28 (d, J= 6.9 Hz, 2H), 8.42 (s, IH), 8.88 (s, IH), 12.59 (s, IH); ESI-MS (m/z) 493.96 (M+H)⁺.

Example 11

2-(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-i]pyrimidin-5-yl)-N-{4-[3- fluoro-5-(trifluoromethyl)phen -l,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 (105 mg, 0.379 mmol) with 4-[3-fluoro-5-(trifluoromethyl)phenyl]-l ,3- thiazoI-2-amine (99 mg, 0.379 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 30.3 mg, 0.758 mmol) in dry toluene (4 ml) to yield 40 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO- /₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.65 (d, J = 6.0 Hz, I H), 7.96 (s, IH), 8.07 (d, J = 9.0 Hz, I H), 8.14 (s, I H), 8.42 (s, I H), 8.88 (s, I H), 12.61 (s, I H); ESI-MS (m/z) 494.05 (M+H)⁺.

Example 12

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 150 mg, 0.541 mmol) with 4-[2-fluoro-5-(trifluoromethyl)phenyl]-l ,3- thiazol-2-amine ( 142 mg, 0.541 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43 mg, 1.083 mmol) in dry toluene (6 ml) to yield 16 mg of product as yellow solid; Ή-NMR (300 MHz, DMSO- δ 3.23 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.56-7.67 (m, 2H), 7.72-7.81 (m, I H), 8.40-8.45 (m, 2H), 8.89 (s, I H), 12.63 (s, I H); ESI-MS (m/z) 492.15 (M-H)⁺.

Example 13

N- {4-[3-Chloro-4-(trifluoromethyl)pheny 1]- 1 ,3-thiazol-2-yl } -2-( 1 ,3-dimethy 1-2,4-dioxo- l ,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 (80 mg, 0.288 mmol) with 4-[3-chloro-4-(trifluoromethyl)phenyl]-l ,3- thiazol-2-amine (80.4 mg, 0.288 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 23.1 mg, 0.577 mmol) in dry toluene (3 ml) to yield 25 mg of product as white solid; Ή-NMR (300 MHz, DMSO-cfe) δ 3.23 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.92-7.99 (m, 2H), 8.07 (d, J=8.1 Hz, 1 H), 8.23 (s, 1 H), 8.42 (s, 1 H), 8.89 (s, 1 H), 12.63 (s, 1 H); APCI (m/z) 510.12 (M+H)⁺.

Example 14

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (80 mg, 0.288 mmol) with 4-[4-chloro-3-(trifluoromethyl)phenyl]-l ,3- thiazol-2-amine (201 mg, 0.722 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 23.1 mg, 0.577 mmol) in dry toluene (3 ml) to yield 55 mg of product as white solid; Ή-NMR (300 MHz, DMSO-i/₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.82 (d, J=8.4 Hz, 1 H), 7.89 (s, 1 H), 8.22 (d, J=8.1 Hz, 1 H), 8.36 (s, 1 H), 8.42 (s, 1 H), 8.89 (s, 1H), 12.61 (s, 1 H); APCI (m/z) 510 (M+H)⁺.

Example 15

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (200 mg, 0.722 mmol) with 4-[3-chloro-5-(trifluoromethyl)phenyl]- l ,3- thiazol-2-amine (201 mg, 0.722 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 57.7 mg, 1.441 mmol) in dry toluene (7 ml) to yield 35 mg of product as off-white solid; Ή-NMR (300 MHz, DMSO-i4) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.83 (s, IH), 8.01 (s, I H), 8.24 (s, I H), 8.31 (s, I H), 8.42 (s, IH), 8.89 (s, I H), 12.61 (s, IH); ESI-MS (m/z) 510.07 (M+H)⁺.

Example 16

2-( l ,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)-N-{4-[3- fluoro-4-(trifluoromethoxy)phenyl]-l,3-thiazol-2-yl}acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 1 15 mg, 0.415 mmol) with 4-[3-fluoro-4-(trifluoromethoxy)phenyl]-l ,3- thiazol-2-amine ( 1 15 mg, 0.415 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 68 mg, 1.66 mmol) in dry toluene (4 ml) to yield 60 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO-</₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.65 (t, J = 7.8 Hz, IH),) 7.80 (s, IH), 7.86 (d, J = 8.4 Hz, I H), 7.98 (d, J = 12.3 Hz, I H), 8.42 (s, I H), 8.88 (s, I H), 12.59 (s, I H); ESI-MS (m/z) 510.02 (M+H)⁺.

Example 17

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 105 mg, 0.379 mmol) with 4-[4-fluoro-3-(trifluoromethoxy)phenyl]-l ,3- thiazol-2-amine ( 105 mg, 0.379 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 30.32 mg, 0.758 mmol) in dry toluene (4 ml) to yield 46 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO-</₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.33 (s, 2H), 7.60 (t, J = 9.3Hz, I H),) 7.76 (s, I H), 7.98-8.06 (m,2H), 8.42 (s, I H), 8.88 (s, I H), 12.57 (s, IH); ESI-MS ( /z) 508.14 (M-H)\

Example 18

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (95 mg, 0.342 mmol) with 4-[3-chloro-4-(trifluoromethoxy)phenyl]-l ,3- thiazol-2-amine ( 101 mg, 0.342 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 27.4 mg, 0.6858 mmol) in dry toluene (4 ml) to yield 13 mg of product as pale yellow solid. Ή-NMR (300 MHz, DMSO-i/₆) δ 3.23 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.66 (d, J = 8.1 Hz, 1 H), 7.83 (s, 1 H), 8.01 (d, J = 8.1 Hz, 1 H), 8.20 (s, 1 H), 8.42 (s, 1 H), 8.89 (s, 1 H), 12.59 (br s, 1 H); ESI-MS (m/z) 526.13 (M+H)⁺.

Example 19

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (80 mg, 0.288 mmol) with 4-[4-chloro-3-(trifluoromethoxy)phenyl]-l ,3- thiazol-2-amine (85 mg, 0.288 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 23 mg, 0.577 mmol) in dry toluene (3 ml) to yield 50 mg of product as off- white solid. Ή-NMR (300 MHz, DMSO-c ) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.77 (d, J = 8.1 Hz, 1 H), 7.85 (s, 1 H), 7.98 (d, J = 8.1 Hz, 1 H), 8.04 (s, 1 H), 8.42 (s, 1 H), 8.89 (s, 1 H), 12.60 (s, 1 H); ESI-MS (m/z) 524.1 1 (M-H)\

Example 20

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 150 mg, 0.5415 mmol) with 4-[3-chloro-5-(trifluoromethoxy)phenyl]- l,3- thiazol-2-amine (160 mg, 0.5415 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 43.16 mg, 1.083 mmol) in dry toluene (5 ml) to yield 10 mg of product as off-white solid; Ή-NMR (300 MHz, DMSO- ₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.34 (s, 2H), 7.53 (s, I H), 7.88 (s, IH), 7.94 (s, I H), 8.06 (s, I H), 8.42 (s, I H), 8.89 (s, I H), 12.59 (s, I H); ESI-MS (m/z) 526.04(M)⁺

Example 21

N-{4-[4-(Difluoromethoxy)-3-fluorophenyl]-l,3-thiazol-2-yl}-2-(l,3-dimethyI-2,4-dioxo- l,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 (80 mg, 0.288 mmol) with 4-[4-(difluoromethoxy)-3-fluorophenyl]-l ,3- thiazol-2-amine (75 mg, 0.288 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 23 mg, 0.577 mmol) in dry toluene (3 ml) to yield 29 mg of product as off- white solid; Ή-NMR (300 MHz, DMSO-cfe) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.33 (s, 2H), 7.29 (t, J=73.2 Hz, IH), 7.45 (t, J =8.4 Hz, IH), 7.71 (s, I H), 7.79 (d, J= 9.0 Hz, IH), 7.89 (d, J =13.8 Hz, I H), 8.42 (s, I H), 8.88 (s, I H), 12.56 (s, I H); ESI-MS (m/z) 492 (M+H)⁺.

Example 22

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 (100 mg, 0.361 mmol) with 4-[3-fluoro-4-(morpholin-4-yl)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 yield 29 mg of product as off-white solid; ¹ H-NMR (300 MHz, DMSO-i/₆) δ 3.05 (br s, 4H), 3.23 (s, 3H),

3.61 (s, 3H), 3.76 (br s, 4H), 4.33 (s, 2H), 7.09 (t, J=9.0 Hz, IH), 7.52 (s, IH), 7.60-7.69 (m, 2H), 8.41 (s, I H), 8.88 (s, I H), 12.46 (s, IH); ESI-MS (m/z) 51 1.25 (M)⁺.

Example 23

N-{4-[4-(Dimethylamino)-3,5-difluorophenyl]-l ,3-thiazol-2-yl }-2-(l ,3-dimethyl-2,4- dioxo- 1 ,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 100 mg, 0.361 mmol) with 4-[4-(dimethylamino)-3,5-difluorophenyl]- l ,3-thiazol-2-amine (92 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 yield 70 mg of product as off-white solid; ¹ H-NMR (300 MHz, DMSO-<4) δ 2.85 (s, 6H), 3.23 (s, 3H), 3.61 (s, 3H), 4.33 (s, 2H), 7.51 (s, IH), 7.54 (s, I H), 7.63 (s, I H), 8.41 (s, I H), 8.87 (s, I H), 12.48 (s, I H); ESI-MS (m/z) 487.1 1 (M+H)⁺.

Example 24

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 1 15 mg, 0.415 mmol) with 4-[2,3-difluoro-4-(trifluoromethyl)phenyl]- l ,3-thiazol-2-amine (1 16 mg, 0.415 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 68 mg, 1.66 mmol) in dry toluene (4 ml) to yield 48 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO-i/₆) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.35 (s, 2H), 7.72-7.78 (m, 2H), 8.03 (t, J = 6.9 Hz, 1 H), 8.42 (s, 1H), 8.89 (s, 1H), 12.67 (s, 1 H); ESI-MS (m/z) 51 1.91 (M+H)⁺.

Example 25

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 -i/]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 100 mg, 0.361 mmol) with 4-[2,4-difluoro-3-(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 (5 ml) to yield 15 mg of product as off-white solid.Ή-NMR (300 MHz, CDC1₃) δ 3.51 (s, 3H), 3.71 (s, 3H), 4.37 (s, 2H), 7.08 (t, J = 9.0 Hz, 1H), 7.39 (s, l H), 8.27 (q, J = 9.0 Hz, 1H), 8.55 (s, 1 H), 8.76 (s, 1H), 9.98 (br s, 1 H); ESI-MS (m/z) 512.25 (M+H)⁺.

Example 26

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[3,4-i ]pyrimidin-5-yl)acetamide

The title compound was prepared according to the general procedure by coupling Intermediate 1 (105 mg, 0.379 mmol) with 4-[3,5-difluoro-4-(trifluoromethyl)phenyl]- l ,3-thiazol-2-amine ( 106 mg, 0.379 mmol) in the presence of sodium hydride (60 % dispersion in mineral oil, 30.3 mg, 0.758 mmol) in dry toluene (4 ml) to yield 65 mg of product as off-white solid. Ή-NMR (300 MHz, DMSO-ofe) δ 3.22 (s, 3H), 3.61 (s, 3H), 4.35 (s, 2H), 7.84 (s, 1 H), 7.83 (s, 1 H), 8.06 (s, 1 H), 8.42 (s, 1 H), 8.89 (s, 1 H), 12.65 (s, 1 H); ESI-MS (m/z) 512.02 (M+H)⁺.

Example 27

2-( 1 ,3-Dimethyl-2,4-dioxo- 1 ,2.3,4-tetrahydropyrido[3,4-d]pyrim idi n-5-yl)-N- { I -[3- (trifluoromethyl)phenyl]- I H-pyrazol-3-yl } acetamide

The title compound was prepared according to the general procedure by coupling

Intermediate 1 (100 mg, 0.361 mmol) with l -( 3-trifluoromethylphenyl)-lH-pyrazol-3- amine (Intermediate 3) (81.90 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 yield 59 mg of product as off white solid; Ή-NMR (300 MHz, CDC ) δ 3.51 (s, 3H), 3.70 (s, 3H), 4.31 (s, 2H), 6.93 (s, 1 H), 7.47-7.60 (m, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.84 (s, 1 H), 7.90 (s, 1 H), 8.55 (s, 1 H), 8.73 (s, 1H), 8.85 (br s, 1 H) ; ESI-MS (m/z) 459.40 (M+H)⁺.

Example 28

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

The title compound was prepared according to the general procedure by coupling Intermediate 1 ( 100 mg, 0.361 mmol) with 5-[3-fluoro-4-(trifluoromethyl)phenyl]- 1 ,2,4- oxadiazol-3-amine (Intermediate 2) (89 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 yield 12 mg of product as off-white solid; Ή-NMR (300 MHz, DMSO-c ) δ 3.24 (s, 3H), 3.61 (s, 3H), 4.32 (s, 2H), 8.09-8.19 (m, 3H), 8.41 (s, 1 H), 8.88 (s, 1 H), 1 1.65 (s, 1 H); ESI-MS (m/z) 477 (M-H)\ Pharmacological activity

The illustrative examples of the present invention are screened for TRPA l activity according to a modified procedure described in (a) Toth, A. et al. Life Sciences, 2003, 73, 487-498. (b) McNamara C, R. et al, Proc. Natl. Acad. Sci. U.S.A., 2007, 104, 13525- 13530. The screening of the compounds can be carried out by other methods and procedures known to persons skilled in the art.

Screening for TRPA l antagonist using the ^4¾Calcium uptake assay:

The inhibition of TRPAl receptor activation was measured as inhibition of ally 1 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 TRPA l expressing CHO cells were grown in F- 12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 / ml of G-418. Rat TRPA l expressing CHO cells were grown in F-12 DMEM medium with 10% FBS, 1% penicillin-streptomycin solution, and 400 μg / ml of Zeocin. Cells were seeded 24 h prior to the assay in 96 well plates so as to get ~ 50,000 cells per well on the day of experiment. Cells were treated with the test compounds for 10 minutes followed by the addition of AITC at a final concentration of 30 μΜ (for human TRPAl) and / or 10 μΜ (for rat TRPAl) and 5 μθι^'/πιΐ ⁴⁵Ca⁺² for 3 minutes. Cells were washed and lysed using a buffer containing 1% Triton X-100, 0.1 % deoxycholate and 0.1% SDS. Radioactivity in the lysate was measured in a Packard TopCount after addition of liquid scintillant. (Toth et al, Life Sciences (2003) 73, 487-498; McNamara CR et al, Proceedings of the National Academy of Sciences, (2007) 104 , 13525-13530).

Concentration response curves were plotted as a % of maximal response obtained in the absence of test antagonist. ICs₀ 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 μΜ and 10.0 μΜ are given in the table along with IC50 (nM) details for selected examples. The IC50 (nM) values of the compounds are set forth in Table 3 wherein "A" refers to an IC₅₀ value of less than 50 nM, "B" refers to IC₅₀ value in range of 50.01 to 100.0 nM and "C" refers to IC₅₀ value of more than 100.0 nM Table 2: In-vitro screening results of compounds of invention

Claims

WE CLAIM:

1. A compound of the formula (I)

or a pharmaceutically acceptable salt thereof,

wherein,

R¹ and R² are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heterocyclylalkyl, and - (CR^xR^y)_nOR^x;

at each occurrence, R³ is selected from hydrogen, halogen, cyano, hydroxyl, amino, alkylamino, substituted or unsubstituted alkyl, alkoxy, haloalkyi, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl

R^a and R^b are independently selected from hydrogen, hydroxyl, cyano, halogen, substituted or unsubstituted alkyl, haloalkyi, hydroxyalkyi, substituted or unsubstituted cycloalkyl and cycloalkylalkyl;

U, V, W and Y are independently selected from CR^C, N, O and S in such a way that it forms stable five-membered heterocyclic ring;

at each occurrence, R^c is selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted alkyl, alkoxy, haloalkyi, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; or

R^c is absent;

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;

'n' is selected from 0 to 2, both inclusive; and

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

2. The compound according to claim 1 , wherein R¹ and R² are (C| -C4)alkyl.

3. The compound according to claim 2, wherein (Ci-C4)alk l is methyl.

4. The compound according to any of claims 1 to 3, wherein R^a and R^b are hydrogen.

5. The compound according to any of claims 1 to 4, wherein U is sulfiir, Y is nitrogen and, V and W are carbon.

6. The compound according to any of claims 1 to 4, wherein W and Y are nitrogen and, U and V are carbon.

7. The compound according to any of claims 1 to 4, wherein U and Y are nitrogen, V is oxygen and W is carbon.

8. The compound according to any of claims 1 to 7, wherein R³ is halogen, haloalkyl, haloalkoxy, alkylamino, dialkylamino or heterocyclic ring.

9. The compound according to any of claims 1 to 8, wherein 'p' is 1, 2 or 3.

10. A compound of formula (II)

(Π)

or a pharmaceutically acceptable salt thereof,

wherein,

R° is 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, R³ is selected from the group comprising of hydrogen, halogen, cyano, hydroxyl, nitro, amino, alkylamino, substituted or unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocyclic ring and heterocyclylalkyl; and

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

1 1. The compound according to claim 10, wherein R^c is hydrogen.

12. The compound according to any of claim 10 or 1 1 , wherein R³ is halogen, haloalkyl, haloalkoxy, alkylamino, dialkylamino or heterocyclic ring.

13. The compound according to any of claims 10 to 12, wherein 'p' is 1 , 2 or 3.

14. The compound selected from:

N- {4-[4-(Diethy lamino)pheny 1]- 1 ,3-thiazol-2-yl } -2-( 1 ,3-dimethy 1-2,4-dioxo- l ,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)acetamide;

N-[4-(4-Chloropheny 1)- 1 ,3-thiazol-2-yl]-2-( 1 ,3-dimethy 1-2,4-dioxo- 1 ,2,3,4- tetrahydropyrido[3,4-i/]pyrimidin-5-yl)acetamide;

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

2-( l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-i/Ipyrimidin-5-yl)-N-{4- [3-(trifluoromethoxy)phenyl]- l,3-thiazol-2-yl}acetamide;

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

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

2-( l ,3-Dimethyl-2,4-dioxo-l ,2,3,4-tetrahydropyrido[3,4-i |pyrimidin-5-yl)-N-{4- [2-fluoro-3-(tri fluoromethy l)pheny I]- 1 ,3-thiazol-2-y 1 } -acetamide;

2-( 1 ,3-Dimethyl-2,4-dioxo- 1 ,2,3,4-tetrahydropyrido[3,4-i/)pyrimidin-5-yl)-N-{4- [2-fluoro-4-(trifluoromethyl)phenyl]-l,3-thiazoI-2-yl}-acetamide;

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

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

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

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

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

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

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

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

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

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

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

2-(l ,3-DimethyI-2,4-dioxo-l ,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)-N-{4- [3-fluoΓO-4-(mo holin-4-yl)phenyl]-l,3-thiazol-2-yl}acetamide;

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

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

N- {4-[3,5-Difluoro-4-(trifluoromethy l)pheny 1]- 1 ,3-thiazol-2-yl } -2-( 1 ,3-dimethy 1-

2,4-dioxo-l ,2,3,4-tetrahydropyrido[3,4-i/]pyrimidin-5-yl)acetamide;

2-(l,3-Dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrido[3,4-d]pyrimidin-5-yl)-N-{ l - [3-(trifluoromethyl)phenyl]-l H-pyrazol-3-yl}acetamide; and

N- { 5-[3-Fluoro-4-(trifluoromethyI)pheny 1]- 1 ,2,4-oxadiazol-3-y 1 } -2-( 1 ,3-dimethy 1- 2,4-dioxo-l ,2,3,4-tetrahydropyrido[3,4-i ]pyrimidin-5-yl)acetamide;

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising one or more compounds selected from the compounds of any one of claims 1 to 14, and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.

16. A method for treating disease or condition associated with TRPA1 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 14.

17. The method according to claim 16, wherein the symptoms of a disease or condition associated with TRPA 1 function is selected from pain, chronic pain, complex regional pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, migraine, neuropathies, chemotherapy - induced neuropathies, eye - irritation, bronchial - irritation, skin - irritation (atopic dermatitis), Frost - bites (cold - bite), spasticity, catatonia, catalepsy, parkinsons, diabetic neuropathy, sciatica, HIV-related neuropathy, post-herpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, respiratory disorder like airway inflammation, asthma, emphysema, bronchitis, COPD, sinusitis, rhinitis, cough, respiratory depression, reactive airways dysfunction syndrome (RADS), acute respiratory distress syndrome (ARDS), irritant induced asthma, occupational asthma, sensory hyper-reactivity, multiple chemical sensitivity, and paracetamol-induced asthma, cough, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), overactive bladder, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer and pruritus; digestive organ diseases like irritable bowel syndrome, inflammatory bowel disease, functional dyspepsia, constipation, diarrhea, and vomiting.

18. The method according to claim 17, wherein the symptoms of a disease or condition is associated with chronic pain.

19. The method according to claim 17, wherein the symptoms of a disease or condition is associated with neuropathic pain.

20. The method according to claim 17, wherein the symptoms of a disease or condition is associated with rheumatoid arthritic pain or osteoarthritic pain.

21. The method according to claim 17, wherein the symptoms of a disease or condition is associated with COPD.

22. The method according to claim 17, wherein the symptoms of a disease or condition is associated with asthma.