This invention relates to quinolin-2-one compounds and their use in therapy. Background of the Invention

Mast cells are known to play an important role in allergic and immune responses through the release of a number of mediators, such as histamine, leukotrienes, cytokines, prostaglandin D ₂ , etc (Boyce; Allergy Asthma Proc, 2004, 25, 27-30). Prostaglandin D ₂ (PGD ₂ ) is the major metabolite produced by the action of cyclooxygenase on arachadonic acid by mast cells in response to allergen challenge (Lewis et al; J. Immunol., 1982, 129, 1627-1631). It has been shown that PGD ₂ production is increased in patients with systemic mastocytosis (Roberts; N. Engl. J. Med., 1980, 303, 1400-1404), allergic rhinitis (Naclerio er a/; Am. Rev. Respir. Dis., 1983, 128, 597-602; Brown et al; Arch. Otolarynol. Head Neck Surg., 1987, 113, 179-183; Lebel et at, J. Allergy Clin. Immunol., 1988, 82, 869-877), bronchial asthma (Murray et al; N. Engl. J. Med., 1986, 315, 800-804; Liu et at. Am. Rev. Respir. Dis., 1990, 142, 126-132; Wenzel et at, J. Allergy Clin. Immunol., 1991, 87, 540-548), and urticaria (Heavey et al; J. Allergy Clin. Immunol., 1986, 78, 458-461). PGD ₂ mediates it effects through two receptors, the PGD ₂ (or DP) receptor (Boie et al; J. Biol. Chem., 1995, 270, 18910-18916) and the chemoattractant receptor-homologous molecule expressed on Th2 (or CRTH2) (Nagata et al; J. Immunol., 1999, 162, 1278-1289; Powell; Prostaglandins Luekot. Essent. Fatty Acids, 2003, 69, 179-185). Therefore, it has been postulated that agents that antagonise the effects of PGD ₂ at its receptors may have beneficial effects in number of disease states.

The CRTH2 receptor has been shown to be expressed on cell types associated with allergic inflammation, such as basophils, eosinophils, and Th2- type immune helper cells (Hirai et al; J. Exp. Med., 2001, 193, 255-261). The CRTH2 receptor has been shown to mediate PGD ₂ -mediated cell migration in these cell types (Hirai et at, J. Exp. Med., 2001 , 193, 255-261 ), and also to play a major role in neutrophil and eosinophil cell recruitment in a model of contact dermatitis (Takeshita et at, Int. Immunol., 2004, 16, 947-959). Ramatroban {(3R)-3-[(4-fluorophenyl)sulphonylamino]-1,2,3,4-tetrahydro- 9H-carbazole-9- propanoic acid}, a dual CRTH2 and thromboxane A ₂ receptor antagonist, has been shown to attenuate these responses (Sugimoto et a/; J. Pharmacol. Exp. Ther., 2003, 305, 347-352; Takeshita et aϊ, op. cit). The potential of PGD ₂ both to enhance allergic inflammation and induce an inflammatory response has been demonstrated in mice and rats. Transgenic mice over expressing PGD ₂ synthase exhibit an enhanced pulmonary eosinophilia and increased levels of Th2 cytokines in response to allergen challenge (Fujitani et a/; J. Immunol., 2002, 168, 443-449). In addition, exogenously administered CRTH2 agonists enhance the allergic response in sensitised mice (Spik et a/; J. Immunol., 2005, 174, 3703-3708). In rats exogenously applied CRTH2 agonists cause a pulmonary eosinophilia but a DP agonist (BW 245C) or a TP agonist (I-BOP) showed no effect (Shirashi et a/; J. Pharmacol. Exp Ther., 2005, 312, 954-960). These observations suggest that CRTH2 antagonists may have valuable properties for the treatment of diseases mediated by PGD ₂ .

In addition to Ramatroban a number of other CRTH2 antagonists have been described. Examples include: benzimidazole-acetic acids (WO2006/021418; WO2006/034418), indole-acetic acids (WO2003/022813; WO2003/066046; WO2003/066047; WO2003/097042; WO2003/097598; WO2003/101961; WO2003/101981; WO2004/007451; WO2004/078719; WO2004/106302; WO2005/019171; GB2407318; WO2005/040112; WO2005/040114; WO2005/044260; WO2005/094816; WO2006/034419; WO2006/036994; WO2006/095183; WO2007/045867), indolizine-acetic acids (WO2006/136859; WO2007/031747), pyrrole-acetic acids (WO2006/063763); pyrrolopyridine-acetic acids (WO2005/054232; WO2005/121141; WO2005/123731; GB2422830; GB2422829; GB2422831); tetrahydroquinolines (EP1413306; EP1435356; WO2004/032848; WO2004/035543;

WO2005/007094; WO2005/100321; WO2006/091674), quinolines (WO2007036743), phenyl-acetic acids (WO2004/058164), phenoxy-acetic acids (WO2004/089884 WO2004/089885; WO2005/018529; WO2005/105727; WO2005/115382; WO2006/056752; WO2006/125593; WO2006/125596), tetrahydropyridoindoles (WO2005/095397) and thiazole-acetic acids (WO2005/116001). Surprisingly, we have now discovered that quinolin-2-one compounds of general formula [1] represent a novel class of compounds active at the CRTH2 receptor. Summary of the Invention

One aspect of the invention provides quinolin-2-one derivatives of general formula [1]:

Ml

in which:

A represents a direct bond, an optionally substituted alkylene or alkenylene group, or a group of formula Z-(optionally substituted)alkylene; B represents a direct bond, an optionally substituted alkylene or alkenylene group, or a group of formula Z-(optionally substituted)alkylene or

(optionally substituted)alkylene-Z;

Z represents an oxygen atom, an NH or N-alkyl group, a group of formula

S(O) _n , in which n = 0 to 2 or a group of formula -0-SO ₂ -; X represents a carboxylic acid, tetrazole, 3-hydroxyisoxazole, hydroxamic acid, phosphinate, phosphonate, phosphonamide, sulfonic acid or a group of formula C(=O)NHSO ₂ Wor SO ₂ NHC(O)W;

W represents an optionally substituted aryl or heteroaryl group or an optionally substituted alkyl group; Y represents an optionally substituted aryl or heteroaryl group, or an optionally substituted aryl-fused-heterocycloalkyl, heteroaryl-fused-cycloalkyl, heteroaryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl or cycloalkyl group;

R ^a , R ^b , and R ^c independently represent hydrogen, acyl, alkoxy, alkylsulphinyl, alkylsulphonyl, alkylthio, -NH ₂ , aminoalkyl, hydroxyalkyl, arylalkyl cyano, dialkylamino, halo, haloalkoxy, haloalkyl, alkyl, alkenyl, -OH, -CHO, -NO ₂ , aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl, aminosulphonyl, acylamino, sulphonylamino, heteroarylalkyl, cyclic amine, aryloxy, heteroaryloxy, arylalkyloxy, and heteroarylalkyloxy; R ^d represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted arylalkyl group or heteroarylalkyl group;

The groups X-A- and Y-B- may be attached to the bicyclic ring core at any available position; and corresponding Λ/-oxides, pharmaceutically acceptable salts, solvates and prodrugs of such compounds.

A second aspect of the invention is a pharmaceutical composition comprising a compound of formula [1] or an Λ/-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with a pharmaceutically acceptable carrier or excipient.

A third aspect of the invention is a compound of formula [1] or an N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof for use in therapy.

A fourth aspect of the invention is the use of a compound of formula [1], or an Λ/-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of a disease in which a

CRTH2 antagonist can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease.

A fifth aspect of the invention is a method for treating a disease in a patient in which a CRTH2 antagonist can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the patient a therapeutically effective amount of compound of formula [1] or an Λ/-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof.

A sixth aspect of the invention is a method of preparing a compound of formula [1] or an Λ/-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof.

A seventh aspect of the invention is a method of making a pharmaceutical composition comprising combining a compound of formula [1], or an Λ/-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, with a pharmaceutically acceptable carrier or excipient. Description of the Preferred Embodiments

For purposes of the present invention, the following definitions as used throughout the description of the invention shall be understood to have the following meanings: "Compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula [1] as hereinbefore described, their N- oxides, their prodrugs, their pharmaceutically acceptable salts and their solvates, where the context so permits. "Patient" includes both human and other mammals.

For purposes of the present invention, the following chemical terms as used above, and throughout the description of the invention, and unless otherwise indicated, shall be understood to have the following meanings:

"Acyl" means a -CO-alkyl group in which the alkyl group is as described herein. Exemplary acyl groups include -COCH ₃ and -COCH(CH ₃ ) ₂ .

"Acylamino" means a -NR-acyl group in which R and acyl are as described herein. Exemplary acylamino groups include -NHCOCH ₃ and N(CH ₃ )COCH ₃ .

"Alkoxy" and "alkyloxy" means an -O-alkyl group in which alkyl is as defined below. Exemplary alkoxy groups include methoxy (OCH ₃ ) and ethoxy (OC ₂ H ₅ ).

"Alkoxycarbonyl" means a -COO-alkyl group in which alkyl is as defined below. Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. "Alkyl" as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain. Exemplary alkyl groups include methyl, ethyl, 1 -propyl and 2-propyl.

"Alkenyl" as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms and one carbon-carbon double bond in the chain. Exemplary alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl.

"Alkylamino" means a -NH-alkyl group in which alkyl is as defined above. Exemplary alkylamino groups include methylamino and ethylamino. "Alkylene means an -alkyl- group in which alkyl is as defined previously.

Exemplary alkylene groups include -CH ₂ -, -(CH ₂ J ₂ - and -C(CH ₃ )HCH ₂ -.

"Alkenylene" means an -alkenyl- group in which alkenyl is as defined previously. Exemplary alkenylene groups include -CH=CH-, -CH=CHCH ₂ -, and -CH ₂ CH=CH-. "Alkylsufinyl" means a -SO-alkyl group in which alkyl is as defined above. Exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.

"Alkylsufonyl" means a -SO ₂ -alkyl group in which alkyl is as defined above. Exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl. "Alkylthio" means a -S-alkyl group in which alkyl is as defined above.

Exemplary alkylthio groups include methylthio and ethylthio.

"Aminoacyl" means a -CO-NRR group in which R is as herein described. Exemplary aminoacyl groups include -CONH ₂ and -CONHCH ₃ .

"Aminoalkyl" means an alkyl-NH ₂ group in which alkyl is as previously described. Exemplary aminoalkyl groups include -CH ₂ NH ₂ .

"Aminosulfonyl" means a -SO ₂ -NRR group in which R is as herein described. Exemplary aminosulfonyl groups include -SO ₂ NH ₂ and -SO ₂ NHCH ₃ .

"Aryl" as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl, and in one embodiment preferably phenyl. The aryl group may be substituted by one or more substituent groups.

"Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C ₁ ^ alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl.

"Arylalkyloxy" means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a C ₁ ^ alkyl moiety. Exemplary arylalkyl groups include benzyloxy. "Aryl-fused-cycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein. Exemplary aryl-fused-cycloalkyl groups include tetrahydronaphthyl and indanyl. The aryl and cycloalkyl rings may each be substituted by one or more substituent groups. The aryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon atom.

"Aryl-fused-heterocycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein. Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl. The aryl and heterocycloalkyl rings may each be substituted by one or more substituent groups. The aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.

"Aryloxy" means an -O-aryl group in which aryl is described above. Exemplary aryloxy groups include phenoxy.

"Cyclic amine" means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein). Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and N- methylpiperazine. The cyclic amine group may be substituted by one or more substituent groups. "Cycloalkyl" means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group may be substituted by one or more substituent groups. "Cycloalkylalkyl" means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

"Dialkylamino" means a -N(alkyl) ₂ group in which alkyl is as defined above. Exemplary dialkylamino groups include dimethylamino and diethylamino.

"Halo" or "halogen" means fluoro, chloro, bromo, or iodo.

"Haloalkoxy" means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy. "Haloalkyl" means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl.

"Heteroaryl" as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups. The heteroaryl group may be substituted by one or more substituent groups. The heteroaryl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom. "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.

Ηeteroarylalkyloxy" means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Preferred heteroarylalkyloxy groups contain a lower alkyl moiety. Exemplary heteroarylalkyloxy groups include pyridylmethyloxy.

"Heteroaryloxy" means a heteroaryloxy- group in which the heteroaryl is as previously described. Exemplary heteroaryloxy groups include pyridyloxy. Ηeteroaryl-fused-cycloalkyl" means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a cycloalkyl group, in which heteroaryl and cycloalkyl are as previously described. Exemplary heteroaryl-fused-cycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl. The heteroaryl and cycloalkyl rings may each be substituted by one or more substituent groups. The heteroaryl-fused-cycloaikyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.

"Heteroaryl-fused-heterocycloalkyl" means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which heteroaryl and heterocycloalkyl are as previously described. Exemplary heteroaryl-fused-heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyridinyl and dioxolopyridinyl. The heteroaryl and heterocycloalkyl rings may each be substituted by one or more substituent groups. The heteroaryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom.

Ηeterocycloalkyl" means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR and CONRCO (examples of such groups include succinimidyl and 2- oxopyrrolidinyl). The heterocycloalkyl group may be substituted by one or more substituent groups. The heterocycloalkyl group may be attached to the remainder of the compound of formula [1] by any available carbon or nitrogen atom. Ηeterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.

"Hydroxamate" means a group -C(=O)NHOR where R is as described herein. Exemplary groups are -C(=O)NHOH and -C(=O)NHOCH ₃ .

"Lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl (n-propyl or /so-propyl) or butyl (π- butyl, /so-butyl or fert-butyl).

"Phosphinate" means a -P(=O)R(OR) group in which R is as described herein. Exemplary groups are -P(=O)(OH)CH ₃ and -P(=O)(OH)H. "Phosphonate" means a -P(=O)(OH)OR group in which R is as described herein. Exemplary groups are -P(=O)(OH) ₂ and -P(=O)(OH)OC ₂ H ₅ .

"Phosphonamide" means a -P(=O)(OR)NR ₂ group in which R is as described herein. An exemplary group is -P(=O)(OH)NH ₂ .

"Sulfonate" means a -S(=O) ₂ OR group where R is as described herein. Exemplary groups are -S(=O) ₂ OH (sulfonic acid) and -S(=O) ₂ OCH ₃ .

"Sulfonylamino" means a -NR-sulfonyl group in which R and sulfonyl are as described herein. Exemplary sulfonylamino groups include -NHSO ₂ CH ₃ .

For the avoidance of doubt the numbering system used for the quinolin-2- one ring system is shown below: As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides, e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L- arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. Specific salts with bases include the benzathine, calcium, diolamine, meglumine, olamine, potassium, procaine, sodium, tromethamine and zinc salts. Those compounds of the invention which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like. Where a compound contains a quaternary ammonium group acceptable counter-ions may be, for example, chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), napadisylates (naphthalene- 1 ,5-disulfonates or naphthalene- 1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2-disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), isethionates (2-hydroxyethylsulfonates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, malates, fumarates, succinates, xinafoates, p- acetamidobenzoates and the like; wherein the number of quaternary ammonium species balances the pharmaceutically acceptable salt such that the compound has no net charge.

Salts are discussed in the "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", P. Heinrich Stahl & Camille G. Wermuth, Wiley- VCH, 2002.

It will be understood that, as used in herein, references to the compounds of formula [1] are meant to also include the pharmaceutically acceptable salts.

The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. It will be understood that, as used in herein, references to the compounds of formula [1] are meant to also include the hydrate and solvate forms.

"Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula [1]. For example an ester prodrug of a compound of formula [1] containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of compounds of formula [1] containing a hydroxy group, are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluene- sulphonates, cyclohexylsulphamates and quinates. As another example an ester prodrug of a compound of formula [1] containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379.

It will be understood that, as used in herein, references to the compounds of formula [1] are meant to also include the prodrug forms.

"Saturated" pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.

The cyclic groups referred to above, namely, aryl, heteroaryl, cycloalkyl, aryl-fused-cycloalkyl, heteroaryl-fused-cycloalkyl, heterocycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl-fused-heterocycloalkyl and cyclic amine may be substituted by one or more substituent groups. Suitable optional substituent groups include acyl (e.g. -COCH ₃ ), alkoxy (e.g. -OCH ₃ ), alkoxycarbonyl (e.g. -COOCH ₃ ), alkylamino (e.g. -NHCH ₃ ), alkylsulfinyl (e.g. -SOCH ₃ ), alkylsulfonyl (e.g. -SO ₂ CH ₃ ), alkylthio (e.g. -SCH ₃ ), -NH ₂ , aminoalkyl (e.g. -CH ₂ NH ₂ ), arylalkyl (e.g. -CH ₂ Ph or -CH ₂ -CH ₂ -Ph), cyano, dialkylamino (e.g. -N(CH ₃ ) ₂ ), halo, haloalkoxy (e.g. -OCF ₃ or -OCHF ₂ ), haloalkyl (e.g. -CF ₃ ), alkyl (e.g. -CH ₃ or -CH ₂ CH ₃ ), -OH, -CHO, -NO ₂ , aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (e.g. -CONH ₂ , -CONHCH ₃ ), aminosulfonyl (e.g. -SO ₂ NH ₂ , -SO ₂ NHCH ₃ ), acylamino (e.g. -NHCOCH ₃ ), sulfonylamino (e.g. -NHSO ₂ CH ₃ ), heteroarylalkyl, cyclic amine (e.g. moφholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy.

Alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g. -OCH ₃ ), alkylamino (e.g. -NHCH ₃ ), alkylsulfinyl (e.g. -SOCH ₃ ), alkylsulfonyl (e.g. -SO ₂ CH ₃ ), alkylthio (e.g. -SCH ₃ ), -NH ₂ , aminoalkyl (e.g. -CH ₂ NH ₂ ), arylalkyl (e.g. -CH ₂ Ph or -CH ₂ -CH ₂ - Ph), cyano, dialkylamino (e.g. -N(CH ₃ J ₂ ), halo, haloalkoxy (e.g. -OCF ₃ or -OCHF ₂ ), haloalkyl (e.g. -CF ₃ ), alkyl (e.g. -CH ₃ or -CH ₂ CH ₃ ), -OH, -CHO ₁ and -NO ₂ . Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and frans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis). With reference to formula [1] above, particular and preferred embodiments are described below.

In one embodiment the group -B-Y is attached to the 3-position of the quinolin-2-one ring system.

In one embodiment the group -B-Y is attached to the 4-position of the quinolin-2-one ring system.

In one embodiment the group -A-X is attached to the 5-position of the quinolin-2-one ring system.

In a further embodiment R ^c represents a lower alkyl group. In a further embodiment R ^d represents a hydrogen atom or a lower alkyl group.

In a further embodiment R ^d represents an arylalkyl group.

In a further embodiment A represents an alkylene group.

In a further embodiment Y represents an aryl or heteroaryl group.

In a further embodiment Y represents a cycloalkyl group. In a further embodiment X represents a carboxylic acid. In a preferred embodiment A represents the group -0-CH ₂ -. In another preferred embodiment A represents the group -CH ₂ -. In another preferred embodiment B represents the group -CH ₂ -. In another preferred embodiment the group -B-Y is attached to the 3- position and the group -A-X is attached to the 5-position of the quinolin-2-one ring system

In another preferred embodiment R ^d is selected from a hydrogen atom or a lower alkyl group. Specific compounds of the invention include those of the Examples herein, and pharmaceutically acceptable salts thereof. Utilities of the Invention

Whilst the compounds of the present invention may be shown to antagonise the effects of the CRTH2 receptor according to the tests described in the Biological Methods section of this document, the mechanism of action by which the compounds act is not a limiting embodiment of the present invention. For example, compounds of the present invention may also have beneficial effects at other prostanoid receptors, such as the PGD ₂ receptor or the thromboxane A ₂ receptor. The therapeutic application of these compounds is pertinent to any disease that is known to be at least partially mediated by the activation of the CRTH2 receptor. Examples of such diseases include, but are not limited to: asthma, chronic obstructive pulmonary disease, bronchitis, cystic fibrosis, emphysema, rhinitis, psoriasis, dermatitis (atopic and non-atopic), Crohn's disease, ulcerative colitis, and irritable bowel disease.

The present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.

The present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions. Combinations

Other compounds may be combined with compounds of this invention of formula [I] for the prevention and treatment of prostaglandin-mediated diseases. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating PGD ₂ -mediated diseases comprising a therapeutically effective amount of a compound of the invention of formula [1] and one or more other therapeutic agents. Suitable therapeutic agents for a combination therapy with compounds of formula [1] include, but are not limited to: (1) corticosteroids, such as fluticasone, ciclesonide or budesonide; (2) β2- adrenoreceptor agonists, such as salmeterol, indacaterol or formoterol; (3) leukotriene modulators, for example leukotriene antagonists such as montelukast, zafirulast or pranlukast or leukotriene biosynthesis inhibitors such as Zileuton or BAY-1005; (4) anticholinergic agents, for example muscarinic-3 (M3) receptor antagonists such as tiotropium bromide; (5) phosphodiesterase-IV (PDE-IV) inhibitors, such as roflumilast or cilomilast; (6) antihistamines, for example selective histamine- 1 (H 1) receptor antagonists, such as fexofenadine, citirizine, loratidine or astemizole; (7) antitussive agents, such as codeine or dextramoφhan; (8) non-selective COX-1/COX-2 inhibitors, such as ibuprofen or ketoprofen; (9) COX-2 inhibitors, such as celecoxib and rofecoxib; (10) VLA-4 antagonists, such as those described in WO97/03094 and WO97/02289; (11) TACE inhibitors and TNF-α inhibitors, for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel; (12) inhibitors of matrix metalloprotease, for example MMP12; (13) human neutrophil elastase inhibitors, such as those described in WO2005/026124, WO2003/053930 and WO06/082412; (14) A2a agonists such as those described in EP1052264 and EP1241176 (15) A2b antagonists such as those described in WO2002/42298; (16) modulators of chemokine receptor function, for example antagonists of CCR3 and CCR8; (17) compounds which modulate the action of other prostanoid receptors, for example a DP receptor antagonist or a thromboxane A ₂ antagonist; and (18) agents that modulate Th2 function, such as PPAR agonists

The weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Pharmaceutical Formulations

The present invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient. The magnitude of prophylactic or therapeutic dose of a compound may be determined by any suitable method known to one skilled in the art. It will be understood, however, that the specific amount for any particular patient will depend upon a variety of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment.

In general, the daily dose range will lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

For use where a composition for the intravenous administration is employed, a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of formula [1] per kg of body weight per day.

In the cases where an oral composition is employed, a suitable dosage range is, for example, from about 0.01 mg to about 300 mg of a compound of formula [1] per day, preferably from about 0.1 mg to about 30 mg per day. For oral administration, the compositions are preferably provided in the form of tablets containing from 0.01 to 1,000 mg, preferably 0.01, 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0 or 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds of the invention may be administered by inhalation at a dose range from 0.0005 mg to 10 mg (preferably 0.005 mg to about 0.5 mg) per kg of body weight per day.

Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable nontoxic bases or acids including inorganic bases or acids and organic bases or acids.

Compounds of the invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which present compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the invention.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route. The compositions include those compositions suitable for routes of administration known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non- aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosage forms for the compounds of formula [1]: Injectable Suspension (I. M.):

Compound of formula [1 ] 10 mg/mL Methylcellulose 5.0 mg/mL

Tween 80 0.5 mg/mL

Benzyl alcohol 9.0 mg/mL

Benzalkonium chloride 1.0 mg/mL

Water for injection to a total volume of q.s. 1mL 500 mg Tablet:

Compound of formula [1] 25 mg/tablet

Microcrystalline Cellulose 415 mg/mL

Povidone 14.0 mg/mL Pregelatinized Starch 43.5 mg/mL

Magnesium Stearate 2.5 mg/mL

600 mg Capsule:

Compound of formula [1] 25 mg/tablet Lactose Powder 573.5 mg/tablet

Magnesium Stearate 1.5 mg/tablet

For delivery by inhalation, the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray-drying, freeze-drying and micronisation. Aerosol generation can be carried out using, for example, pressure-driven jet atomizers or ultrasonic atomizers, preferably using propellant-driven metered aerosols or propellant-free administration of micronized active compounds from, for example, inhalation capsules or other "dry powder" delivery systems.

By way of example, a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI). Propellants suitable for use in a PMDI are known to the skilled person, and include CFC-12,

HFA-134a, HFA-227, HCFC-22 (CCI ₂ F ₂ ) and HFA-152 (CH ₂ F ₂ and isobutane).

Microparticles for delivery by administration may be formulated with excipients that aid delivery and release, such as, for example, propellants (e.g.

Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.

For example, in a dry powder formulation, microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung. Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, a preferred composition is: Compound of the invention 24 mg/canister

Lecithin, NF Liq. Cone. 1.2 mg/canister

Trichlorofluoromethane, NF 4.025 g/canister

Dichlorodifluoromethane, NF 12.15 g/canister For the purposes of inhalation, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321).

In practical use, the compounds of formula [1] can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such, as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. In addition to the common dosage forms set out above, the compounds of formula [1] may also be administered by controlled release means and/or delivery devices such as those described in US patents 3845770, 3916899, 3536809, 3598123, 3630200 and 4008719. Methods of Synthesis

The present invention is also concerned with processes for preparing the compounds of this invention.

The compounds of formula [1] of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The compounds of the invention of formula [1] may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. The free acid form corresponding to isolated salts can be generated by acidification with a suitable acid such as acetic acid and hydrochloric acid and extraction of the liberated free acid into an organic solvent followed by evaporation. The free acid form isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic or aqueous solvent followed by addition of the appropriate base and subsequent evaporation, precipitation, or crystallisation.

It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of formula [1] to avoid their unwanted participation in a reaction leading to the formation of compounds of formula [1]. Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 1999, may be used. Compounds of the invention of general formula [1a], in which group A is represented by a group of formula O-(optionally substituted)alkylene, may conveniently be prepared by the reaction between a compound of formula [2] and a suitable alkylating agent of formula [3], where group LG represents a suitable leaving group (for example, chloro, bromo, or methanesulfonyloxy). Typically, the alkylation reaction is carried out in the presence of a base (for example, potassium carbonate) in an inert solvent (for example, acetone or N ₁ N- dimethylformamide). It will be understood by those who are practiced in the art that it may be convenient to carry out the transformation of intermediate [2] to final compound [1a] using a form of alkylating agent [3] in which one or other of the functionalities on either component is suitably protected. For example, if group X represents a carboxylic acid it may be convenient to carry out the reaction using an alkylating agent in which the acid group is protected as an ester (for example, an ethyl or fert-butyl ester). It is to be understood that if the reaction is carried out on a protected form of alkylating agent [3] an appropriate deprotection step will be required to obtain the desired compound [1 a] of the invention.

[1a]; A = O-(optionally

[2] [3] substrtuted)alkylene

Intermediate compounds of formula [2a] may conveniently be prepared by the reaction between an aminophenol of formula [4] and a β-ketoester of formula [5], in which PG represents an appropriate ester function (such as methyl and ethyl). The reaction may be run neat or in the presence of a suitable dehydrating agent, such as polyphosphoric acid, aluminium chloride, trifluoroacetic acid, hydrochloric acid or sulphuric acid.

Similarly, intermediate compounds of formula [2b] may conveniently be prepared by the reaction between an aminophenol of formula [4] and a β- ketoester of formula [6], in which PG represents an appropriate ester function (such as methyl and ethyl). The reaction may be run neat or in the presence of a suitable dehydrating agent, such as polyphosphoric acid, aluminium chloride, trifluoroacetic acid, hydrochloric acid or sulphuric acid.

[4] [6] [2b]

Compounds of the invention of general formula [1b] may be prepared by the reaction between an intermediate compound of formula [7], in which group T represents a chloro, bromo, or iodo atom, or a trifluoromethanesulfonyloxy group, and 1-(tert-butyldimethylsilyloxy)-1-methoxyethane. The reaction may conveniently be carried out in the presence of a suitable catalyst (for example a palladium compound) and a base (such as sodium acetate).

[7] [1b]

Intermediates of formula [7], in which T is trifluoromethanesulfonyloxy, may be prepared from the reaction of intermediates of formula [2] with N- phenyltrifluoromethanesulfonimide in the presence of a base, such as potassium carbonate.

It will be understood by those practiced in the art that compounds of the invention may be prepared by transformations of other compounds of the invention. For example, compounds of the invention of formula [1d], in which group A represents an optionally substituted alkylene group, may conveniently be prepared by the reduction of compounds of the invention of formula [1c], in which group A represents an optionally substituted alkenylene group. The transformation of compounds of formula [1c] to those of formula [1d] may conveniently be achieved by reduction with hydrogen in the presence of a suitable catalyst, such as palladium supported on carbon. ally )alkylene

Similarly, when R ^d in formula [1e] represents H, compounds of formula [1f] may be conveniently prepared by, for example, the reaction between a compound of formula [1e] and an a Iky I halide in the presence of a suitable base such as potassium carbonate. It will be understood by those who are practiced in the art that it may be convenient to carry out the transformation of intermediate [1e] to final compound [1f] using a form of intermediate [1e] in which the X group is suitably protected (for example, an ethyl or tert-butyl ester). It is to be understood that if the reaction is carried out on a protected form of intermediate [1e] an appropriate deprotection step will be required to obtain the desired compound [1f] of the invention.

[1e]; Rd = H [1f]; R" = (optionally substituted)alkyl Examples

The invention will now be described in detail with reference to the following examples. It will be appreciated that the invention is described by way of example only and modification of detail may be made without departing from the scope of the invention. 1H NMR spectra were recorded at ambient temperature using a Varian

Unity Inova (400 MHz) spectrometer with a triple resonance 5 mm probe spectrometer. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br s = broad singlet, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet. Mass Spectrometry (LCMS) experiments to determine retention times and associated mass ions were performed using the following methods:

Method A: experiments were performed on a Micromass Platform LCT spectrometer with positive ion electrospray and single wavelength UV 254 nm

S detection using a Higgins Clipeus C18 5 μm 100 x 3.0 mm column and a 2 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system was held0 constant for a further 2 minutes.

Method B: experiments were performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/Diode array detection using a Phenomenex Luna C18(2) 30 x 4.6 mm column and a 2 mL/minute flow rate. The solvent system was 95% solvent A and 5% solvent B5 for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes

Microwave experiments were carried out using a Personal Chemistry Smith Synthesizer™. 0 Example 1 : [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid

Preparation 1a: 3-amino-5-methylphenol

A mixture of 5-methylbenzene-1 ,3-diol (6.0 g), ammonium chloride5 (3.0 g), water (9.0 mL) and ammonium hydroxide (6.8 mL, 33% in water) were sealed in a bomb and heated at 180 ⁰ C for 17 hours. The mixture was cooled to room temperature and the resulting precipitate collected by filtration.

Crystallisation from water gave title compound, 1.7 g. ¹ H NMR (DMSO-d6): δ 2.05 (s, 3H), 4.75 (br s, 2H), 5.75-5.80 (m, 3H) ₁ 8.70 (s, 1H).

Preparation 1 b: 3-(4-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2- one A mixture of 3-amino-5-methylphenol (0.25 g) and 2-(4-chlorobenzyl)-3- oxo-butyric acid ethyl ester (0.52 g) was heated at 15O ⁰ C under nitrogen for 7 hours. The mixture was cooled to room temperature and triturated with methanol to give title compound as an off-white solid, 0.32 g.

¹ H NMR (DMSO-d6): δ 2.20 (s, 3H), 2.55 (s, 3H) ₁ 4.00 (s, 2H), 6.40 (m, 1H), 6.55 (m, 1 H) ₁ 7.20 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 10.00 (br s, 1H), 11.50 (br s, 1H).

MS: ESI (+ve) (Method B): 314 (M+H)\ Retention time 3.1 min. Preparation 1 c: [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin- 5-yloxy]acetic acid fert-butyl ester A mixture of 3-(4-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1H-quinolin-2-one

(0.40 g), /V,/V-dimethylforrnamide (8.0 mL), potassium carbonate (0.18 g) and bromoacetic acid terf-butyl ester (0.25 g) was stirred at room temperature overnight. The mixture was diluted with water and the resulting precipitate collected by filtration to give title compound as a white solid, 0.52 g. 1H NMR (DMSO-d6): δ 1.40 (s, 9H), 2.30 (s, 3H), 2.60 (s, 3H), 4.00 (s,

2H), 4.70 (s, 2H), 6.50 (m, 1H), 6.75 (m, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 11.65 (br s, 1H).

MS: ESI (+ve) (Method B): 428 (M+H)\ Retention time 4.1 min. Preparation 1d: [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin- 5-yloxy]acetic acid

[3-(4-Chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid te/f-butyl ester (0.05 g) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (1.5 mL) and the resulting solution was stirred at room temperature overnight. The solution was evaporated to dryness and the residue triturated with diethyl ether. The resulting solid was collected by filtration, washed with diethyl ether and dried to give title compound as a beige solid, 0.038 g. ¹ H NMR (DMSO-d6): δ 2.25 (s, 3H), 2.55 (s, 3H), 3.95 (s, 2H) ₁ 4.70 (s, 2H), 6.50 (m, 1H) ₁ 6.70 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 11.60 (br s, 1 H), 13.00 (br s, 1 H).

MS: ESI (+ve) (Method A): 372 (M+H)\ Retention time 9.5 min. Example 2: [3-(4-chlorobenzyl)-1,4,7-trimethyl-2-oxo-1,2-dihydroquinoli n-5- yloxy]acetic acid

Preparation 2a: [3-(4-chlorobenzyl)-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid tert-butyl ester A mixture of [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid tert-butyl ester (0.10 g), iodomethane (0.40 ml_), potassium carbonate (0.13 g) and acetone (4.0 ml_) was sealed in a tube and heated at 5O ⁰ C for 21 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulphate and concentrated to give a colourless gum. Purification by flash chromatography on silica gel, eluting with dichloromethane gave title compound as a colourless gum, 0.12 g.

¹ H NMR (CDCI ₃ ): δ 1.50 (s, 9H), 2.40 (s, 3H), 2.75 (s, 3H), 3.70 (s, 3H), 4.10 (s, 2H), 4.60 (s, 2H), 6.40 (m, 1H), 6.85 (m, 1H), 7.20 (m, 4H). MS: ESI (+ve) (Method B): 442 (M+H) ⁺ , Retention time 4.4 min.

Preparation 2b: [3-(4-chlorobenzy l)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

[3-(4-Chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid ferf-butyl ester (0.12 g) was dissolved in a 4.0 M solution of hydrogen chloride in dioxane (4.0 mL) and the resulting solution was stirred at 6O ⁰ C for 2 hours. The solution was evaporated to dryness and the residue triturated with diethyl ether. The resulting solid was collected by filtration, washed with diethyl ether and dried to give title compound as a white solid, 0.079 g. ¹ H NMR (DMSO-d6): δ 2.35 (s, 3H), 2.60 (s, 3H), 3.60 (s, 3H), 4.00 (s, 2H), 4.75 (s, 2H), 6.60 (m, 1H) ₁ 6.95 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 13.05 (br s, 1H).

MS: ESI (+ve) (Method A): 386 (M+H) ⁺ , Retention time 10.7 min.

Example 3: [3-(4-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5- yl]acetic acid

Preparation 3a: trifluoromethanesuifonic acid 3-(4-chlorobenzyl)-4,7- dimethyl-2-oxo-1,2-dihydroquinolin-5-yl ester

A mixture of 3-(4-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1H-quinolin-2-one (0.31 g), Λ/-phenyltrifluoromethanesulfonimide (0.36 g), potassium carbonate (0.41 g) and tetrahydrofuran (5.0 mL) was heated by microwave irradiation at 12O ⁰ C for 6 minutes. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogen carbonate solution and then water and dried over sodium sulfate. The solution was evaporated to dryness and the residue purified by column chromatography on silica gel to afford title compound as a white solid, 0.10 g.

¹ H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.50 (s, 3H), 4.05 (s, 2H), 7.05 (m, 1H) 7.20-7.25 (m, 3H), 7.30 (d, J = 8.3 Hz, 2H), 12.15 (br s, 1H).

Preparation 3b: [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin- 5-yl]acetic acid methyl ester

A mixture of trifluoromethanesuifonic acid 3-(4-chlorobenzyl)-4,7- dimethyl-2-oxo-1 ,2-dihydroquinolin-5-yl ester (0.54 g), 1-(terf- butyldimethylsilyloxy)-1-methoxyethene (1.30 mL), sodium acetate (0.12 g), tris(dibenzylideneacetone) dipalladium (0) (0.06 g), 1,1'-bis(diphenylphospino) ferrocene (0) (0.034 g) and Λ/,Λ/-dimethylformamide (7 mL) was heated by microwave irradiation at 12O ⁰ C for 12 minutes. The mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and then water and dried over sodium sulfate. The solution was evaporated to dryness and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (2:3, 3:2 and 1 :0 by volume) to afford title compound as a beige solid, 0.23 g. 1H NMR (CDCI ₃ ): δ 2.35 (s, 3H), 2.50 (s, 3H), 3.70 (s, 3H), 4.05 (s, 2H),

4.20 (s, 2H), 6.85 (m, 1H), 7.00 (m, 1H), 7.15-7.20 (m, 4H), 11.60 (br s, 1H).

Preparation 3c: [3-(4-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yl]acetic acid methyl ester

A mixture of [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yl]acetic acid methyl ester (0.22 g), iodomethane (0.04 ml_), potassium carbonate (0.25 g) and Λ/,Λ/-dimethylformamide (5.0 ml_) was heated at 8O ⁰ C for

2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, evaporated to dryness and the residue purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane to afford title compound, 0.12 g.

¹ H NMR (CDCI ₃ ): δ 2.45 (s, 3H), 2.50 (s, 3H), 3.70 (s, 3H), 3.75 (s, 3H),

4.05 (s, 2H), 4.15 (s, 2H), 6.90 (m, 1H), 7.10-7.20 (m, 5H).

MS: ESI (+ve) (Method B): 384 (M+H)\ Retention time 3.7 min.

Preparation 3d: [3-(4-chlorobenzyl)-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yl]acetic acid

A mixture of [3-(4-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-

5-yl]acetic acid methyl ester (0.11 g), methanol (6.0 ml_), saturated aqueous lithium hydroxide solution (0.3 ml_) and water (0.6 ml_) was stirred at 35 ⁰ C for 3 hours. The pH of the mixture was adjusted to 1 by the addition of 1.0 M aqueous hydrochloric acid (3.0 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether, and then dried to give title compound as a white solid, 0.08 g. 1H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.45 (s, 3H), 3.65 (s, 3H), 4.05 (s,

4H), 7.00 (m, 1H), 7.20 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.30 (m,

1 H), 12.50 (br s, 1 H).

MS: ESI (+ve) (Method A): 370 (M+H)\ Retention time 10.2 min. Example 4: [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yl]acetic acid

A mixture of [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yl]acetic acid methyl ester (0.11 g), methanol (2.0 mL), saturated aqueous lithium hydroxide solution (0.1 mL) and water (0.3 mL) was stirred at 50 ⁰ C for 2.5 hours. The mixture was cooled to room temperature and the pH adjusted to 1 by the addition of 1.0 M aqueous hydrochloric acid (2.0 mL). The resulting precipitate was collected by filtration, washed with water and then dried to give title compound as a white solid, 0.037 g.

¹ H NMR (DMSO-d6): δ 2.30 (s, 3H), 2.45 (s, 3H) ₁ 4.05 (s, 4H), 6.85 (s, 1H), 7.05 (S, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz ₁ 2H), 11.70 (s, 1H), 12.5 (br s, 1H).

MS: ESI (+ve) (Method A): 356 (M+H) ⁺ , Retention time 9.1 min.

MS: ESI (+ve) (Method B): 356 (M+H) ⁺ , Retention time 2.8 min. Example 5: [3-(4-chlorobenzyl)-1-ethyl-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yl]acetic acid

Preparation 5a: [3-(4-chlorobenzyl)-1-ethyl-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yl]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinolin-5 -yl]acetic acid methyl ester and bromoethane.

MS: ESI (+ve) (Method B): 398 (M+H)\ Retention time 3.8 min. Preparation 5b: [3-(4-chlorobenzyl)-1-ethyl-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yl]acetic acid

The title compound was prepared by the method of Preparation 3d using ^-(^chlorobenzyO-i-ethyMJ-dimethyl-Σ-oxo-i ^-dihydroquinolin-S-yllacetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 1.25 (t, J = 7.1 Hz, 3H), 2.40 (s, 3H), 2.45 (s, 3H), 4.05 (s, 2H), 4.10 (s, 2H), 4.35 (q, J = 7.1 Hz, 2H) ₁ 7.00 (s, 1H), 7.20 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz ₁ 2H), 7.35 (s, 1H), 12.5 (br s, 1H).

MS: ESI (+ve) (Method A): 384 (M+H)\ Retention time 10.7 min.

MS: ESI (+ve) (Method B): 384 (M+H)\ Retention time 3.3 min. Example 6: [1-benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yl]acetic acid

Preparation 6a: [1 -benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yl]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinolin-5 -yl]acetic acid methyl ester and bromomethylbenzene.

MS: ESI (+ve) (Method B): 460 (M+H)\ Retention time 4.2 min. Preparation 6b: [1-benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yl]acetic acid

The title compound was prepared by the method of Preparation 3d using [1-benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5-yl]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.25 (s, 3H), 2.50 (s, 3H), 4.05 (s, 2H), 4.15 (s, 2H), 5.60 (br s, 2H), 6.95 (d, J = 1.1 Hz, 1H), 7.15-7.20 (m, 3H) ₁ 7.20-7.25 (m. 3H), 7.30-7.35 (m, 4H), 12.5 (br s, 1H).

MS: ESI (+ve) (Method A): 446 (M+H) ⁺ , Retention time 11.9 min. MS: ESI (+ve) (Method B): 446 (M+H)\ Retention time 3.7 min. Example 7: [3-(4-chlorobenzyl)-4-methyl-2-oxo-7-trifluoromethyl-1 ,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 7a: 3-(4-chlorobenzyl)-5-hydroxy-4-methyl-7-trifluoromethyl- 1 H-quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using 3-amino-5-trifluoromethylphenol and 2-(4-chlorobenzyl)-3-oxo-butyric acid ethyl ester. MS: ESI (+ve) (Method B): 368 (M+H) ⁺ , Retention time 3.9 min.

Preparation 7b: [3-(4-chlorobenzyl)-4-methyl-2-oxo-7-trifluoromethyl-1 ,2- dihydroquinolin-5-yloxy]acetic acid tert-butyl ester

The title compound was prepared by the method of Preparation 1c using 3-(4-chlorobenzyl)-5-hydroxy-4-methyl-7-trifluoromethyl-1 H-quinolin-2-one and bromoacetic acid ferf-butyl ester.

MS: ESI (+ve) (Method B): 482 (M+H) ⁺ , Retention time 4.4 min. Preparation 7c: [3-(4-chlorobenzyl)-4-methyl-2-oxo-7-trifluoromethyl-1 ,2- dihydroquinolin-5-yloxy]acetic acid

A mixture of [3-(4-chlorobenzyl)-4-methyl-2-oxo-7-trifluoromethyl-1 ,2- dihydroquinolin-5-yloxy]acetic acid te/t-butyl ester (0.060 g), water (1 drop) and 10% solution of trifluoroacetic acid in dichloromethane (2.0 mL) was stirred at 4O ⁰ C for 2 days. The mixture was concentrated under reduced pressure and the residue triturated with diethyl ether to afford title compound as a pale yellow solid, 0.031 g. 1H NMR (DMSO-d6): δ 2.45 (s, 3H), 4.05 (s, 2H), 5.25 (s, 2H), 7.00 (d, J

= 1.1 Hz ₁ 1 H), 7.25 (d, J = 8.5 Hz, 2H), 7.30 (br s, 1H), 7.35 (d, J = 8.5 Hz, 2H), 15.60 (s, 1H).

MS: ESI (+ve) (Method A): 426 (M+H)\ Retention time 11.9 min. MS: ESI (+ve) (Method B): 426 (M+H) ⁺ , Retention time 3.8 min. Example 8: [3-(4-chlorobenzyl)-1-ethyl-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 8a: [3-(4-chlorobenzyl)-1-ethyl-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid te/t-butyl ester

The title compound was prepared by the method of Preparation 3c using [3-(4-chlorobenzyl)^7<limethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid terf-butyl ester and bromoethane.

MS: ESI (+ve) (Method B): 456 (M+H)\ Retention time 4.5 min. Preparation 8b: [3-(4-chlorobenzyl)-1-ethyl-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

A mixture of [3-(4-chlorobenzyl)-1-ethyl-4,7-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid terf-butyl ester (0.041 g), trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 ml.) was stirred at 4O ⁰ C for 1 hour. The mixture was concentrated under reduced pressure and the residue triturated with a mixture of ethyl acetate and heptane (1:8 by volume) to afford title compound as a white solid, 0.020 g.

¹ H NMR (DMSO-d6): δ 1.20 (t, J = 7.0 Hz, 3H), 2.40 (s, 3H), 2.60 (s, 3H), 4.05 (S, 2H), 4.30 (q, J = 7.0 Hz, 2H), 4.75 (s, 2H), 6.65 (s, 1H), 7.00 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 13.05 (br s, 1H).

MS: ESI (+ve) (Method A): 400 (M+H) ⁺ , Retention time 11.1 min. MS: ESI (+ve) (Method B): 400 (M+H)\ Retention time 3.4 min. Example 9: [1-benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 9a: [1-benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid tert-butyl ester

The title compound was prepared by the method of Preparation 3c using [S-^-chlorobenzyO^J-dimethyl^-oxo-i^-dihydroquinolin-δ-ylox ylacetic acid terf-butyl ester and bromomethylbenzene.

ESI (+ve) (Method B): 518 (M+H) ⁺ , Retention time 4.7 min. Preparation 9a: [1-benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 8b using [1-benzyl-3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroq uinolin-5- yloxy]acetic acid terf-butyl ester. 1H NMR (DMSO-d6): δ 2.25 (s, 3H) ₁ 2.65 (s, 3H), 4.15 (s, 2H) ₁ 4.75 (s,

2H), 5.55 (br s, 2H), 6.60 (s, 1H) ₁ 6.85 (s, 1H) ₁ 7.15 (m, 2H) 7.20-7.25 (m, 3H), 7.25-7.35 (m, 4H) ₁ 13.10 (br s, 1H).

MS: ESI (+ve) (Method A): 462 (M+H) ⁺ , Retention time 12.2 min.

MS: ESI (+ve) (Method B): 462 (M+H) ⁺ , Retention time 3.8 min. Example 10 and 11: (3-benzyl-1,4,7-trimethyl-2-oxo-1,2-dihydroquinolin-5- yloxy)acetic acid and (3-cyclohexy lmethyl-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy)acetic acid

Preparation 10a and 11a: (3-benzyl-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy)acetic acid and (3-cyclohexylmethyl-i ,4,7- trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid

A mixture of [3-(4-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin- 5-yloxy]acetic acid (0.042 g), palladium, 10 wt. % on activated carbon (0.010 g) and acetic acid (3.0 ml_) was stirred at 7O ⁰ C for 68 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washing with acetic acid and the solvent removed under reduced pressure. The residue was purified by preparative reverse-phase HPLC using a gradient over 80 minutes of acetonitrile in water (20% to 100% of organic modifier) to afford (3-benzyl-1 ,4,7-trimethyl-2- oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid as a white solid, 0.0038 g and (3- cyclohexylmethyl-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid as a white solid, 0.0022 g.

(3-benzyl-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid 1H NMR (CD ₃ OD): δ 2.45 (s, 3H), 2.70 (s, 3H), 3.75 (s, 3H), 4.15 (s, 2H),

4.75 (S, 2H), 4.75 (s, 2H) ₁ 6.65 (s, 1H), 7.05 (s, 1H), 7.10-7.25 (m, 5H). MS: ESI (+ve) (Method A): 452 (M+H)\ Retention time 10.0 min. (S-cyclohexylmethyM ^J-trimethyl^-oxo-i ^-dihydroquinolin-S- yloxy)acetic acid 1H NMR (CD ₃ OD): δ 1.00-1.25 (m, 5H), 1.50-1.75 (m, 6H), 2.45 (s, 3H),

2.65 (d, J = 7.1 Hz, 2H), 2.75 (s, 3H), 3.70 (s, 3H), 4.75 (s, 2H), 6.60 (s, 1 H), 7.00 (s, 1H).

MS: ESI (+ve) (Method A): 458 (M+H) ⁺ , Retention time 11.4 min. Example 12: [3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid

Preparation 12a: 3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1 H-quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using 3-aminophenol and 2-(4-chlorobenzyl)-3-oxo-butyric acid ethyl ester. MS: ESI (+ve) (Method B): 300 (M+H) ⁺ , Retention time 3.0 min. Preparation 12b: [3-(4-chlorobenzyl)-4-methyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid terf-butyl ester

The title compound was prepared by the method of Preparation 1c using 3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid terf-butyl ester.

MS: ESI (+ve) (Method B): 414 (M+H) ⁺ , Retention time 3.9 min. Preparation 12c: [3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid tert-butyl ester The title compound was prepared by the method of Preparation 3c using

[3-(4-chlorobenzyl)-4-methyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid tert- butyl ester and iodomethane.

ESI (+ve) (Method B): 428 (M+H)\ Retention time 4.3 min. Preparation 12d: [3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 8b using [3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid te/t-butyl ester

¹ H NMR (DMSO-d6): δ 2.65 (s, 3H), 3.65 (s, 3H) ₁ 4.10 (s, 2H), 4.80 (s, 2H), 6.80 (dd, J = 0.6, 8.3 Hz, 1H) ₁ 7.15 (dd, J = 0.6, 8.3 Hz ₁ 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.50 (t, J = 8.3 Hz, 1H), 13.10 (br s, 1H).

MS: ESI (+ve) (Method A): 472 (M+H) ⁺ , Retention time 10.3 min.

MS: ESI (+ve) (Method B): 472 (M+H) ⁺ , Retention time 3.3 min.

Example 13: [6-chloro-3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2-dihydro- quinolin-5-yloxy]acetic acid

Preparation 13a: 6-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1 H- quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using 5-amino-2-chlorophenol and 2-(4-chlorobenzyl)-3-oxo-butyric acid ethyl ester. MS: ESI (+ve) (Method B): 334 (M+H) ⁺ , Retention time 3.3 min.

Preparation 13b: [6-chloro-3-(4-chlorobenzyl)-4-methyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

A mixture of 6-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1 H-quinolin- 2-one (0.64 g) and tetrahydrofuran (17 mL) at -4O ⁰ C was treated with 1.0 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (1.9 mL) and the resulting mixture was warmed to O ⁰ C over 1 hour. The mixture was cooled to - 3O ⁰ C and treated with a solution of bromoacetic acid methyl ester (0.29 mL) in tetrahydrofuran (1.0 mL) and the resulting mixture was warmed to room temperature over 90 minutes and then stirred at this temperature for 2 days. The mixture was diluted with 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1 :0 to 0:1 by volume) gave title compound as a white solid, 0.12 g.

Preparation 13c: [6-chloro-3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [6-chloro-3-(4-chlorobenzyl)-4-methyl-2-oxo-1,2-dihydroquino lin-5-yloxy]acetic acid methyl ester and iodomethane.

ESI (+ve) (Method B): 420 (M+H)\ Retention time 4.0 min. Preparation 13d: [6-chloro-3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2- dihydro-quinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [6-chloro-3-(4-chlorobenzyl)-4-methyl-2-oxo-1,2-dihydroquino lin-5-yloxy]acetic acid methyl ester.

¹ H NMR (CD ₃ OD): δ 2.70 (s, 3H), 3.75 (s, 3H), 4.15 (s, 2H), 4.60 (s, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 9.3 Hz, 1 H), 7.65 (d, J = 9.3 Hz, 1H). MS: ESI (+ve) (Method A): 406 (M+H) ⁺ , Retention time 10.6 min.

MS: ESI (+ve) (Method B): 406 (M+H) ⁺ , Retention time 3.3 min. Example 14: [3-(5-fluorobenzothiazol-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 14a: 2-(5-fluorobenzothiazol-2-ylmethyl)-3-oxo-butyric acid methyl ester

A suspension of potassium tert-butoxide (0.79 g) in anhydrous tetrahydrofuran (20 ml.) at O ⁰ C was treated with a mixture of fert-butanol (0.1 mL) and 3-oxo-butyric acid methyl ester (0.76 ml_). The mixture was stirred at O ⁰ C for 30 minutes, treated with 2-bromomethyl-5-fluorobenzothiazole (1.7 g) and then heated at 7O ⁰ C overnight. The mixture was cooled to room temperature, diluted with water and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was removed under reduced pressure and the residue triturated with a mixture of ethanol and pentane, filtered, and the filtrate concentrated under reduced pressure to afford title compound as a yellow oil 1.0 g. Preparation 14b: 3-(5-fluorobenzothiazol-2-ylmethyl)-5-hydroxy-4,7- dimethyl-1 H-quinolin-2-one

The title compound was prepared by the method of Preparation 1b using 3-amino-5-methylphenol and 2-(5-fluorobenzothiazol-2-ylmethyl)-3-oxo-butyric acid methyl ester.

MS: ESI (+ve) (Method B): 355 (M+H)\ Retention time 3.1 min. Preparation 14c: [3-(5-fluorobenzothiazol-2-ylmethyl)-4,7-dimethyl-2-oxo- 1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 3-(5-fluorobenzothiazol-2-ylmethyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.

¹ H NMR (CDCI ₃ ): δ 2.34 (s, 3H), 2.96 (s, 3H), 3.81 (s, 3H) ₁ 4.67 (s, 2H), 4.69 (S, 2H), 6.31 (d, J = 0.9 Hz, 1H), 6.80 (m, 1H), 7.05 (dt, J = 2.5, 8.8 Hz, 1 H), 7.62-7.67 (m, 1H), 8.02 (s, 1H).

Preparation 14d: [3-(5-fluorobenzothiazol-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo- 1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [3-(5-fluorobenzothiazol-2-ylmethyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5- yloxy]acetic acid methyl ester and iodomethane.

¹ H NMR (CDCI ₃ ): δ 2.45 (s, 3H), 2.83 (s, 3H), 3.76 (s, 3H), 3.81 (s, 3H) ₁ 4.65 (S, 2H), 4.71 (s, 2H), 6.40 (d, J = 0.9 Hz, 1H), 6.85 (m, 1H), 7.05 (dt, J = 2.5, 8.8 Hz, 1H), 7.62-7.68 (m, 2H).

Preparation 14e: [3-(5-fluorobenzothiazol-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo- 1 ,2-dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [3-(5-fluorobenzothiazol-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.75 (s, 3H), 3.65 (s, 3H), 4.55 (s, 2H), 4.80 (s, 2H), 6.70 (s, 1H) ₁ 7.00 (s, 1H), 7.25 (dt, J = 2.5, 9.0 Hz ₁ 1H), 7.75 (dd. J = 2.5, 10.0 Hz, 1H), 8.00 (dd. J = 5.4, 9.0 Hz ₁ 1H). MS: ESI (+ve) (Method A): 427 (M+H) ⁺ , Retention time 10.0 min.

Example 15: [3-(6-fluoroquinolin-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 15a: 2-(6-fluoroquinolin-2-ylmethyl)-3-oxo-butyric acid methyl ester

The title compound was prepared by the method of Preparation 14a using 3-oxo-butyric acid methyl ester and 2-chloromethyl-6-fluoroquinoline. MS: ESI (+ve) (Method B): 276 (M+H) ⁺ , Retention time 2.9 min.

Preparation 15b: 3-(6-fluoroquinolin-2-ylmethyl)-5-hydroxy-4,7-dimethyl- 1 H-quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using 3-amino-5-methylphenol and 2-(6-fluoroquinolin-2-ylmethyl)-3-oxo-butyric acid methyl ester.

MS: ESI (+ve) (Method B): 349 (M+H)\ Retention time 2.4 min. Preparation 15c: [3-(6-fluoroquinolin-2-ylmethyl)-4,7-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 3-(6-fluoroquinolin-2-ylmethyl)-5-hydroxy-4,7-dirnethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.

MS: ESI (+ve) (Method B): 421 (M+H) ⁺ , Retention time 2.0 min. Preparation 15d: [3-(6-fluoroquinolin-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester The title compound was prepared by the method of Preparation 3c using

[3-(6-fluoroquinolin-2-ylmethyl)-4,7-dimethyl-2-oxo-1,2-d ihydroquinolin-5- yloxyjacetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method B): 435 (M+H) ⁺ , Retention time 3.2 min. Preparation 15e: [3-(6-fluoroquinolin-2-ylmethyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [3-(6-fluoroquinolin-2-ylmethyl)-1,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.70 (s, 3H), 3.65 (s, 3H), 4.45 (s, 2H), 4.80 (s, 2H) ₁ 6.70 (s, 1 H), 7.00 (s, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 7.65 (dt, J = 2.8, 8.9 Hz, 1 H), 7.75 (dd, J = 2.8, 9.3 Hz, 1H), 8.00 (dd, J = 5.4, 9.3 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H).

MS: ESI (+ve) (Method A): 421 (M+H)\ Retention time 7.6 min. MS: ESI (+ve) (Method B): 421 (M+H) ⁺ , Retention time 2.8 min. Example 16: [8-chloro-3-(4-chlorobenzyl)-1,4-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 16a: [8-chloro-3-(4-chlorobenzyl)-4-methyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid ethyl ester

The title compound was prepared by the method of Preparation 13b using δ-chloro-S-^-chlorobenzyO-δ-hydroxy^-methyl-IH-quinolin^-o ne and bromoacetic acid ethyl ester

MS: ESI (+ve) (Method B): 420 (M+H) ⁺ , Retention time 4.2 min. Preparation 16b: [8-chloro-3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid ethyl ester

The title compound was prepared by the method of Preparation 3c using [8-chloro-3-(4-chlorobenzyl)-4-methyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid ethyl ester and iodomethane. MS: ESI (+ve) (Method B): 434 (M+H)\ Retention time 5.0 min.

Preparation 16c: [8-chloro-3-(4-chlorobenzyl)-1,4-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [8-chloro-3-(4-chlorobenzyl)-1,4-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid ethyl ester.

¹ H NMR (DMSO-d6): δ 2.80 (s, 3H), 4.00 (s, 3H), 4.20 (s, 2H), 4.80 (s, 2H), 6.85 (d, J = 8.8 Hz, 1 H), 7.15 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.70 (d, J= 8.8 Hz, 1H).

MS: ESI (+ve) (Method A): 406 (M+H) ⁺ , Retention time 13.9 min. MS: ESI (+ve) (Method B): 406 (M+H) ⁺ , Retention time 4.6 min. Example 17: [4-(4-chlorobenzyl)-1 ,3,7-trimethyl-2-oxo-1 ,2-dihydroquinolin- 5-yloxy]acetic acid

Preparation 17a: 4-(4-chlorobenzyl)-5-hydroxy-3,7-dimethyl-1 H-quinolin-2- one

The title compound was prepared by the method of Preparation 1b using 3-amino-5-methylphenol and 4-(4-chlorophenyl)-2-methyl-3-oxo-butyric acid ethyl ester.

MS: ESI (+ve) (Method B): 314 (M+H)\ Retention time 3.3 min. Preparation 17b: [4-(4-chlorobenzyl)-3,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1 c using 4-(4-chlorobenzyl)-5-hydroxy-3,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester. MS: ESI (+ve) (Method B): 386 (M+H)\ Retention time 3.6 min.

Preparation 17c: [4-(4-chlorobenzyl)-1,3,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [4-(4-chlorobenzyl)-3,7-dimethyl-2-oxo-1,2-dihydroquinolin-5 -yloxy]acetic acid methyl ester and iodomethane.

Preparation 17d: [4-(4-chlorobenzyl)-1,3,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [4-(4-chlorobenzyl)-1 ,3,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.10 (s, 3H), 2.35 (s, 3H) ₁ 3.65 (s, 3H), 4.35 (s, 2H), 4.70 (s, 2H), 6.50 (s, 1H), 6.95 (s, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H).

MS: ESI (+ve) (Method A): 486 (M+H) ⁺ , Retention time 10.3 min. Example 18: [3-(2-chlorobenzyl)-1,4,7-trimethyl-2-oxo-1,2-dihydroquinoli n- 5-yloxy]acetic acid

Preparation 18a: 3-<2-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2- one

The title compound was prepared by the method of Preparation 1b using 3-amino-5-methylphenol and 2-(2-chlorobenzyl)-3-oxo-butyric acid ethyl ester.

MS: ESI (+ve) (Method B): 314 (M+H) ⁺ , Retention time 3.1 min. Preparation 18b: [3-(2-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1 c using 3-(2-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.

MS: ESI (+ve) (Method B): 386 (M+H)\ Retention time 3.5 min. Preparation 18c: [3-(2-chlorobenzyl)-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [3-(2-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinolin-5 -yloxy]acetic acid methyl ester and iodomethane. MS: ESI (+ve) (Method B): 400 (M+H)\ Retention time 3.9 min.

Preparation 18d: [3-(2-chlorobenzyl)-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [3-(2-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.40 (s, 3H) ₁ 2.55 (s, 3H) ₁ 3.65 (s, 3H), 4.10 (s, 2H), 4.80 (S, 2H) ₁ 6.70 (s, 1H), 6.80 (dd, J = 1.8, 7.5 Hz ₁ 1H), 7.00 (s, 1H), 7.15-7.25 (m, 2H), 7.45 (dd, J = 1.4, 7.8 Hz, 1H), 13.05 (br s, 1H). MS: ESI (+ve) (Method A): 486 (M+H) ⁺ , Retention time 10.7 min. MS: ESI (+ve) (Method B): 486 (M+H) ⁺ , Retention time 3.4 min. Example 19: [3-(2,4-dichlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 19a: 3-(2,4-dichlorobenzyl)-5-hydroxy-4,7-dimethyl-1H- quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using 3-amino-5-methylphenol and 2-(2,4-dichlorobenzyl)-3-oxo-butyric acid ethyl ester.

MS: ESI (+ve) (Method B): 348 (M+H) ⁺ , Retention time 3.4 min. Preparation 19b: [3-(2,4-dichlorobenzyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 3-(2,4-dichlorobenzyl)-5-hydroxy-4,7-dimethyl-1H-quinolin-2- one and bromoacetic acid methyl ester. MS: ESI (+ve) (Method B): 420 (M+H)\ Retention time 3.8 min.

Preparation 19c: [3-(2,4-dichlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [3-(2,4-dichlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinol in-5-yloxy]acetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method B): 434 (M+H) ⁺ , Retention time 4.2 min. Preparation 19d: [3-(2,4-dichlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [3-(2,4-dichlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.55 (s, 3H) ₁ 3.60 (s, 3H), 4.05 (s, 2H) ₁ 4.80 (s, 2H), 6.70 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 7.00 (s, 1H), 7.25 (dd, J = 2.2, 8.3 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H). MS: ESI (+ve) (Method A): 420 (M+H) ⁺ , Retention time 11.6 min.

MS: ESI (+ve) (Method B): 420 (M+H) ⁺ , Retention time 3.9 min. Example 20: [3-(4-fluorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid

Preparation 20a: 3-(4-fluorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2- one

The title compound was prepared by the method of Preparation 1 b using 3-amino-5-methylphenol and 2-(4-fluorobenzyl)-3-oxo-butyric acid methyl ester. MS: ESI (+ve) (Method B): 298 (M+H)\ Retention time 3.0 min.

Preparation 20b: [3-(4-fluorobenzyl)-4,7-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 3-(4-fluorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.

MS: ESI (+ve) (Method B): 370 (M+H) ⁺ , Retention time 3.3 min. Preparation 20c: [3-(4-fluorobenzyl)-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [3-(4-fluorobenzyl)-4,7-dimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method B): 384 (M+H)\ Retention time 3.3 min. Preparation 2Od: [3-(4-fluorobenzyl)-1,4,7-trimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid The title compound was prepared by the method of Preparation 3d using

[3-(4-fluorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester. ¹ H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.60 (s, 3H), 3.60 (s, 3H), 4.05 (s, 2H), 4.80 (S ₁ 2H) ₁ 6.65 (s, 1H), 7.00 (s, 1H), 7.05 (m, 2H), 7.20 (m, 2H), 13.05 (br s, 1H).

MS: ESI (+ve) (Method A): 470 (M+H)\ Retention time 10.1 min. MS: ESI (+ve) (Method B): 470 (M+H)\ Retention time 3.2 min.

Example 21 : [3-(3-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin- 5-yloxy]acetic acid

Preparation 21a: 3-(3-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2- one

The title compound was prepared by the method of Preparation 1 b using 3-amino-5-methylphenol and 2-(3-chlorobenzyl)-3-oxo-butyric acid methyl ester

MS: ESI (+ve) (Method B): 314 (M+H) ⁺ , Retention time 3.1 min. Preparation 21b: 3-(3-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 3-(3-chlorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.

MS: ESI (+ve) (Method B): 386 (M+H) ⁺ , Retention time 3.5 min.

Preparation 21c: [3-(3-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using S-φ-chlorobenzyO^J-dimethyl^-oxo-i^-dihydroquinolin-δ-ylox yjacetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method B): 400 (M+H)\ Retention time 3.9 min. Preparation 21 d: [3-(3-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using [3-(3-chlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.65 (s, 3H), 3.65 (s, 3H) ₁ 4.10 (s, 2H), 4.80 (S, 2H), 6.70 (s, 1H), 7.00 (s, 1 H), 7.15 (m, 1H), 7.20 (m, 2H), 7.25 (m, 1H), 13.10 (br s, 1H).

MS: ESI (+ve) (Method A): 486 (M+H)\ Retention time 10.7 min. MS: ESI (+ve) (Method B): 486 (M+H)\ Retention time 3.6 min.

Example 22: [3-(3,4-dichlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 22a: 2-(3,4-dichlorobenzyl)-3-oxo-butyric acid ethyl ester The title compound was prepared by the method of Preparation 14a using

3-oxo-butyric acid ethyl ester and 1 ,2-dichloro-4-chloromethylbenzene

¹ H NMR (CDCI ₃ ): δ 1.23 (t, J = 7.2 Hz, 3H), 2.2 (s, 3H), 3.10 (m, 2H), 3.70

(m, 1H), 4.14-4.20 (m, 2H) ₁ 7.02 (dd, J = 2.1, 8.3 Hz, 1H), 7.28 (d, J = 2.1 Hz,

1H), 7.34 (d, J = 8.3 Hz, 1H). Preparation 22b: 3-(3,4-dichlorobenzyl)-5-hydroxy-4,7-dimethyl-1H- quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using

3-amino-5-methylphenol and 2-(3,4-dichlorobenzyl)-3-oxo-butyric acid ethyl ester. MS: ESI (+ve) (Method B): 348 (M+H)\ Retention time 3.4 min. Preparation 22c: [3-(3,4-dichlorobenzyl)-4,7-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 3-(3,4-dichlorobenzyl)-5-hydroxy-4,7-dimethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.

MS: ESI (+ve) (Method B): 420 (M+H)\ Retention time 4.0 min. Preparation 22d: [3-(3,4-dichlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using ^(S^-dichlorobenzyO^J-dimethyl^-oxo-i^-dihydroquinolin-δ-yl oxylacetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method B): 434 (M+H) ⁺ , Retention time 4.4 min. Preparation 22e: [3-(3,4-dichlorobenzyl)-1 ,4,7-trimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid The title compound was prepared by the method of Preparation 3d using

^-(S^-dichlorobenzyO-I ^J-trimethyl^-oxo-i^-dihydroquinolin-S-yloxyJacetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.40 (s, 3H), 2.65 (s, 3H), 3.65 (s, 3H), 4.05 (s, 2H), 4.80 (s, 2H), 6.70 (s, 1H), 7.00 (s, 1H), 7.15 (dd, J = 2.1 , 8.3 Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H) ₁ 7.50 (d, J = 8.3 Hz, 1H), 13.10 (br s, 1H).

MS: ESI (+ve) (Method A): 420 (M+H) ⁺ , Retention time 11.5 min. Example 23: (1,4,7-trimethyl-3-naphthalen-1-ylmethyl-2-oxo-1,2- dihydroquinolin-5-yloxy)acetic acid

Preparation 23a: 5-hydroxy-4,7-dimethyl-3-naphthalen-1-ylmethyl-1H- quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using 3-amino-5-methylphenol and 2-(3,4-dichlorobenzyl)-3-oxo-butyric acid ethyl ester. MS: ESI (+ve) (Method B): 330 (M+H)\ Retention time 3.5 min. Preparation 23b: (4,7-dimethyl-3-naphthalen-1-ylmethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy)acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 5-hydroxy-4,7-dimethyl-3-naphthalen-1 -ylmethyl-1 H-quinolin-2-one and bromoacetic acid methyl ester.

MS: ESI (+ve) (Method B): 402 (M+H) ⁺ , Retention time 3.9 min. Preparation 23c: (1 ,4,7-trimethyl-3-naphthalen-1-ylmethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy)acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using (4,7-dimethyl-3-naphthalen-1-ylmethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid methyl ester and iodomethane.

¹ H NMR (DMSO-d6): δ 2.48 (s, 3H) ₁ 2.62 (s, 3H), 3.75 (s, 3H), 3.77 (s, 3H), 4.57 (s, 2H), 4.53 (s, 2H), 6.67 (m, 1H), 6.85 (dd, J = 0.9, 7.1 Hz, 1H), 7.09 (m, 1H), 7.26 (dd, J = 7.4, 8.0 Hz, 1H), 7.51 (m, 1H), 7.58 (m, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.87 (m, 1H), 8.27 (d, J = 8.4 Hz, 1H).

Preparation 23d: (1 ,4,7-trimethyl-3-naphthalen-1 -ylmethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy)acetic acid

The title compound was prepared by the method of Preparation 3d using (1 ,4,7-trimethyl-3-naphthalen-1-ylmethyl-2-oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.45 (s, 3H), 2.55 (s, 3H), 3.65 (s, 3H), 4.50 (s, 2H), 4.80 (S, 2H), 6.70 (s, 1H), 6.85 (m, 1H), 7.05 (s, 1H), 7.30 (m, 1H), 7.55- 7.65 (m, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.95 (m, 1H), 8.30 (d, J = 8.4 Hz, 1 H), 13.00 (br s, 1 H). MS: ESI (+ve) (Method A): 402 (M+H) ⁺ , Retention time 11.0 min.

Example 24: [[7-chloro-3-[(4-chlorophenyl)methyl]-1,2-dihydro-1,4- dimethyl-2-oxo-5-quinolinyl]oxy]acetic acid.

Preparation of 24a: 7-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1 H- quinolin-2-one

The title compound was prepared by the method of Preparation 1 b using 2-(4-chlorobenzyl)-3-oxo-butyric acid ethyl ester and 3-amino-5-chlorophenol. 1H NMR (DMSO-d6): δ 2.56 (s, 3H) ₁ 3.98 (s, 2H), 6.58 (d, J = 2.2 Hz, 1 H) ₁

6.80 (d, J = 2.2 Hz, 1H), 7.19 (m, 2H), 7.29 (m, 2H), 10.7 (br s, 1 H), 11.68 (s, 1H).

MS: ESI (+ve) (Method B): 334 (M+H) ⁺ , Retention time 3.32 min. Preparation of 24b: [7-chloro-3-(4-chlorobenzyl)-4-methyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

A mixture of 7-chloro-3-(4-chlorobenzyl)-5-hydroxy-4-methyl-1 H-quinolin-

2-one (0.24 g), Λ/,Λ/-dimethylformamide (9.0 mL), potassium carbonate (0.11 g) and bromoacetic acid methyl ester (0.11 g) was stirred at room temperature for

20 hours. The reaction mixture was diluted with water and the resulting precipitate collected by filtration to give title compound as a white solid, 0.27 g.

MS: ESI (+ve) (Method B): 406 (M+H) ⁺ , Retention time 3.65 min Preparation of 24c: [7-chloro-3-(4-chlorobenzyl)-1,4-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [7-chloro-3-(4-chlorobenzyl)-4-methyl-2-oxo-1,2-dihydroquino lin-5-yloxy]acetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method B): 420 (M+H) ⁺ , Retention time 4.23 min. Preparation of 24d: [7-chloro-3-(4-chlorobenzyl)-1,4-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid A mixture of [7-chloro-3-(4-chlorobenzyl)-1 ,4-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester (0.27 g), methanol (14 mL) and 1.0 M aqueous lithium hydroxide solution (0.7 mL) was stirred at 50 ⁰ C for 3 hours. The mixture was cooled at room temperature, concentrated under reduced pressure and the residue diluted with water. The pH of the resulting mixture was adjusted to 5 by addition of 1.0 M aqueous HCI. The resulting precipitate was collected by filtration to give title compound as a pale yellow solid, 0.149 g.

¹ H NMR (DMSO-d6): δ 2.56 (s, 3H), 3.58 (s, 3H), 4.01 (s, 2H), 4.82 (s, 2H), 6.86 (d, J = 1.9 Hz, 1H), 7.15 (m, 3H), 7.29 (m, 2H). MS: ESI (+ve) (Method A): 406 (M+H) ⁺ , Retention time 11.3 min. Example 25: [8-chloro-1 ,4-dimethy l-2-oxo-3-(4-py razol-1 -ylbenzy l)-1 ,2- dihydroquinolin-5-yloxy]acetic acid

Preparation of 25a: 3-oxo-2-(4-pyrazol-1 -ylbenzy l)thiobutyric acid S-tert- butyl ester

A solution of 3-oxo-thiobutyric acid S-terf-butyl ester (3.7 g) in 1 ,2- dimethoxyethane (5.0 ml_) was added to a stirred suspension of sodium hydride (60% in oil, 0.92 g) in 1 ,2-dimethoxyethane (25 mL) at -10 ⁰ C. The mixture was stirred at 0 ⁰ C for 10 minutes and then a solution of 1-(4-bromomethylphenyl)-1H- pyrazole (5.0 g) in 1 ,2-dimethoxyethane (20 mL) was added dropwise over a period of 10 minutes. The resulting mixture was warmed to room temperature over 30 minutes and then stirred at this temperature for 18 hours. The mixture was diluted with water, pH adjusted to 5 by the addition of glacial acetic acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulphate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane, dichloromethane and ethyl acetate (1 :3:0 and 0:10:1 by volume) gave title compound as a white solid, 3.6 g. 1H NMR (CDCI ₃ ): δ 1.42 (s, 9H), 2.22 (s, 3H) ₁ 3.16 (m, 2H), 3.88 (t, J = 7.5 Hz, 1H), 6.45 (m, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 1.6 Hz, 1H), 7.89 (m, 1H).

Preparation of 25b: /V-(2-chloro-5-hydroxyphenyl)-3-oxo-2-(4-pyrazol-1- ylbenzyl)butyramide Silver trifluoroacetate (1.46 g) was added in four portions over a period of

1 hour to a stirred solution of 3-amino-4-chlorophenol (0.76 g) and 3-oxo-2-(4- pyrazol-1-yl-benzyl)thiobutyric acid S-terf-butyl ester (1.8 g) in 1.2- dimethoxyethane (10 mL) at room temperature. The mixture was stirred at room temperature for 5 hours and then filtered through hyflo, washing with 1 ,2- dimethoxyethane. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 3:1 by volume) gave title compound as a brown solid, 1.4 g.

¹ H NMR (DMSO-d6): δ 2.26 (s, 3H), 3.10 (m, 2H), 4.23 (m, 1H), 6.52 (m, 1H), 6.60 (dd, J = 2.7, 8.8 Hz, 1 H), 7.03 (d, J = 2.7 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.74 (m, 3H), 8.45 (d, J = 2.1 Hz, 1 H), 9.75 (d, J = 16 Hz, 2H). Preparation of 25c: 8-chloro-5-hydroxy-4-methyl-3-(4-pyrazol-1-ylbenzyl)- 1 H-quinolin-2-one.

A mixture of Λ/-(2-chloro-5-hydroxyphenyl)-3-oxo-2-(4-pyrazol-1- ylbenzyl)butyramide (1.3 g) and methanesulfonic acid (5.6 rnL) was heated at 100 ⁰ C for 10 minutes. The mixture cooled to room temperature and poured into saturated aqueous solution of sodium acetate (20 ml_). The resulting precipitate was collected by filtration, washed with water and dried to afford title compound as a beige solid, 0.81 g.

¹ H NMR (DMSO-d6): δ 2.64 (s, 3H), 4.07 (s, 2H), 6.50 (m, 1H), 6.63 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.70 (m, 3H), 8.40 (m, 1H), 10.3 (br s, 1H).

Preparation of 25d: [8-chloro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 8-chloro-5-hydroxy-4-methyl-3-(4-pyrazol-1 -ylbenzyl)-1 H-quinolin-2-one and bromoacetic acid methyl ester.

MS: ESI (+ve) (Method A): 438 (M+H) ⁺ , Retention time 3.5 min. Preparation 25e: [8-chloro-1 ,4-dimethyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using: [8-chloro-4-methyl-2-oxo-3-(4-pyrazol-1 -ylbenzyl)-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method A): 452 (M+H) ⁺ , Retention time 4.5 min. Preparation 25f: [8-chloro-1 ,4-dimethyl-2-oxo-3-(4-pyrazol-1-yl-benzyl)-1 ,2- dihydroquinolin-5-yloxy]acetic acid

A solution of [8-chloro-1 ,4-dimethyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester (0.35 g), methanol (7 ml_) and saturated solution of lithium hydroxide in water (0.32 mL) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and the residue diluted with water. The pH of the resulting mixture was adjusted to 5 by addition of glacial acetic acid. The resulting precipitate was collected by filtration to give title compound as a pale yellow solid, 0.18 g. 1H NMR (DMSO-d6): δ 2.64 (s, 3H), 3.74 (s, 3H), 4.13 (s, 2H), 4.83 (s,

2H), 6.51 (t, J = 2.0 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 8.6 Hz ₁ 2H), 7.57 (d, J = 9.0 Hz, 1H), 7.70 (m, 3H), 8.4 (d, J = 2.6 Hz, 1H).

MS: ESI (+ve) (Method A): 438 (M+H) ⁺ , Retention time 10.0 min. Example 26: [8-fluoro-1 ,4-dimethyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1 ,2- dihydroquinolin-5-yloxy]acetic acid

Preparation 26a: Λ/-(2-fluoro-5-hydroxyphenyl)-3-oxo-2-(4-pyrazol-1- ylbenzyl)butyramide

The title compound was prepared by the method of Preparation 25b using: 3-amino-4-fluorophenol and 3-oxo-2-(4-pyrazol-1-ylbenzyl)thiobutyric acid S-te/f-butyl ester.

MS: ESI (+ve) (Method B): 368 (M+H)\ Retention time 2.9 min Preparation 26b: 8-fluoro-5-hydroxy-4-methyl-3-(4-pyrazol-1-ylbenzyl)-1 H- quinolin-2-one The title compound was prepared by the method of Preparation 25c using

Λ/-(2-fluoro-5-hydroxyphenyl)-3-oxo-2-(4-pyrazol-1-ylben zyl)butyramide. ¹ H NMR (DMSO-d6): δ 2.65 (s, 3H) ₁ 4.05 (s, 2H), 6.50-6.55 (m, 2H), 7.15 (dd, J = 8.9, 10.2 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.70 (m, 3H) ₁ 8.40 (dd, J = 0.4, 2.5 Hz ₁ 1 H), 10.10 (s, 1 H), 11.40 (s, 1H).

MS: ESI (+ve) (Method B): 368 (M+H)\ Retention time 2.9 min S Preparation 26c: [8-fluoro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 8-fluoro-5-hydroxy-4-methyl-3-(4-pyrazol-1 -ylbenzyl)-1 H-quinolin-2-one and bromoacetic acid methyl ester. 0 MS: ESI (+ve) (Method B): 422 (M+H)\ Retention time 3.3 min

Preparation 26d: [8-fluoro-1 ,4-dimethyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1 ,2- dihydroquinolin-5-yloxy]-acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [8-fluoro-4-methyl-2-oxo-3-(4-pyrazol-1-ylbenzyl)-1 ,2-dihydroquinolin-5-S yloxyjacetic acid methyl ester and iodomethane.

MS: ESI (+ve) (Method B): 436 (M+H) ⁺ , Retention time 3.7 min Preparation 26e: [8-fluoro-1 ,4-dimethyl-2-oxo-3-(4-pyrazol-1 -ylbenzyl)-1 ,2- dihydroquinolin-5-yloxy]acetic acid

The title compound was prepared by the method of Preparation 3d using0 [8-fluoro-4-methyl-2-oxo-3-(4-pyrazol-1 -ylbenzyl)-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.58 (s, 3H), 3.71 (d, J = 10.4 Hz, 3H), 4.06 (s, 2H), 4.71 (S, 2H), 6.43 (t, J = 2.0 Hz, 1H), 6.72 (dd, J = 3.4, 9.1 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.30 (dd, J = 9.1, 14 Hz, 1 H), 7.62 (m, 3H), 8.32 (d, J = 2.4 Hz,5 1H).

MS: ESI (+ve) (Method A): 422 (M+H) ⁺ , Retention time 9.6 min

Example 27: 2-(8-fluoro-1 ,4-dimethyl-3-(4-methylsulfonyl)benzyl)-2-oxo-1 ,2- dihydroquinolin-5-yloxy)acetic acid

Preparation 27a: 2-(4-methanesulfonylbenzyl)-3-oxo-thiobutyric acid S-ferf- butyl ester

The title compound was prepared by the method of Preparation 25a using

3-oxo-thiobutyric acid S-te/t-butyl ester and 1-bromomethyl-4- methanesulfonylbenzene

Preparation 27b: Λ/-(2-fluoro-5-hydroxyphenyl)-2-(4- methanesulfony lbenzyl)-3-oxo-butyramide

The title compound was prepared by the method of Preparation 25b using: 3-amino-4-fluorophenol and 2-(4-methanesulfonylbenzyl)-3-oxo- thiobutyric acid S-te/f-butyl ester.

¹ H NMR (DMSO-d6): δ 2.17 (s, 3H), 3.06-3.18 (m, 5H), 4.21 (dd, 1 H), 6.45 (m, 1 H), 6.97 (dd, 1 H), 7.20 (dd, 1 H) ₁ 7.46 (d, 2H), 7.79 (d, 2H), 9.34 (s,

1 H), 9.94 (s, 1 H).

Preparation 27c: 8-fluoro-5-hydroxy-3-(4-methanesulfonylbenzyl)-4-methyl-

1 H-quinolin-2-one

The title compound was prepared by the method of Preparation 25c sing: Λ/-(2-fluoro-5-hydroxyphenyl)-2-(4-methanesulfonylbenzyl)-3 -oxo-butyramide.

¹ H NMR (DMSO-d6): δ 2.59 (s, 3H), 3.11 (s, 3H), 4.08 (s, 2H), 6.48 (dd, 1 H) ₁

7.06 (dd, 1 H), 7.40 (d, 2H), 7.77 (d, 2H), 11.23 (br s, 1 H).

Preparation 27d: [8-fluoro-3-(4-methanesulfonylbenzyl)-4-methyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester The title compound was prepared by the method of Preparation 1c using

8-fluoro-5-hydroxy-3-(4-methanesulfonylbenzyl)-4-methyl-1 H-quinolin-2-one and bromoacetic acid methyl ester. ¹ H NMR (DMSO-d6): δ 2.60 (s, 3H), 3.12 (s, 3H), 3.66 (s, 3H), 4.14 (s, 2H), 4.84 (S, 2H), 6.64 (dd, 1H), 7.28 (m, 1H), 7.41 (d, 2H), 7.78 (d, 2H), 11.62 (s, 1H).

Preparation 27e: [8-fluoro-3-(4-methanesulfonylbenzyl)-1 ,4-dimethyl-2-oxo- 1 ,2-dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [8-fluoro-3-(4-methanesulfonylbenzyl)-4-methyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester and iodomethane.

¹ H NMR (DMSO-d6): δ 2.59 (s, 3H) ₁ 3.12 (s, 3H), 3.66 (s, 3H), 3.73 (d, 3H), 4.17 (S, 2H), 4.88 (s, 2H), 6.79 (dd, 1H), 7.36 (dd, 1H), 7.40 (d, 2H) ₁ 7.77 (d, 2H)

Preparation 27e: 2-(8-fluoro-1 ,4-dimethyl-3-(4-methylsulfonyl)benzyl)-2- oxo-1 ,2-dihydroquinolin-5-yloxy)acetic acid

The title compound was prepared by the method of Preparation 3d using [[8-fluoro-3-(4-methanesulfonylbenzyl)-1 ,4-dimethyl-2-oxo-1 ,2-dihydroquinolin-5- yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.63 (s, 3H), 3.16 (s, 3H), 3.76 (d, J = 10.0 Hz, 3H), 4.21 (s, 2H), 4.78 (s, 2H), 6.79 (dd, J = 3.5, 9.3 Hz, 1H), 7.38 (dd, J = 9.3, 14.4 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz), 13.1 (br s, 1 H). MS: ESI (+ve) (Method A): 434 (M+H) ⁺ , Retention time 8.6 min.

Example 28: 2-(3-(4-chlorobenzyl)-8-fluoro-1,4-dimethyl-2-oxo-1,2- dihydroquinolin-5-yloxy)acetic acid

Preparation 28a: [3-(4-chlorobenzyl)-8-fluoro-4-methyl-2-oxo-1,2- dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 1c using 3-(4-chlorobenzyl)-8-fluoro-5-hydroxy-4-methyl-1 H-quinolin-2-one and bromo- acetic acid methyl ester. ¹ H NMR (DMSO-d6): δ 2.58 (s, 3H), 3.66 (s, 3H), 4.02 (s, 2H) ₁ 4.84 (s,

2H), 6.63 (dd, 1H), 7.17 (d, 2H), 7.24-7.29 (m, 3H), 11.57 (s, 1H)

Preparation 28b: [3-(4-chlorobenzyl)-8-fluoro-1 ,4-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy]acetic acid methyl ester The title compound was prepared by the method of Preparation 3c using

[3-(4-chlorobenzyl)-8-fluoro-4-methyl-2-oxo-1,2-dihydroqu inolin-5-yloxy]acetic acid methyl ester and iodomethane.

¹ H NMR (DMSO-d6): δ 2.56 (s, 3H), 3.66 (s, 3H), 3.72 (d, 3H) ₁ 4.04 (s,

2H), 4.87 (s, 2H), 6.77 (dd, 1H), 7.15 (d, 2H), 7.26 (d, 2H), 7.34 (dd, 1H). Preparation 28c: 2-(3-(4-chlorobenzyl)-8-fluoro-1 ,4-dimethyl-2-oxo-1 ,2- dihydroquinolin-5-yloxy)acetic acid

The title compound was prepared by the method of Preparation 3d using

[3-(4-chlorobenzyl)-8-fluoro-1,4-dimethyl-2-oxo-1,2-dihyd roquinolin-5- yloxy]acetic acid methyl ester. 1H NMR (DMSO-d6): δ 2.61 (s, 3H), 3.75 (d, J = 10.3 Hz, 3H), 4.07 (s,

2H), 4.77 (s, 2H), 6.77 (dd, J = 3.4, 9.0 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 2H) ₁ 7.30 (d,

J = 8.3 Hz, 2H) ₁ 7.37 (dd, J = 9.0, 14.5 Hz), 13.15 (br s, 1H).

MS: ESI (+ve) (Method A): 390 (M+H)\ Retention time 10.9 min

Example 29: 2-(8-chloro-1 ,4-dimethyl-3-(4-methylsulfonyl)benzyl)-2-oxo-1 ,2- dihydroquinolin-5-yloxy)acetic acid

Preparation 29a: [8-chloro-3-(4-methanesulfonylbenzyl)-1 ,4-dimethyl-2-oxo- 1,2-dihydroquinolin-5-yloxy]acetic acid methyl ester

The title compound was prepared by the method of Preparation 3c using [δ-chloro-S^-methanesulfonylbenzylH-methyl^-oxo-i ^-dihydroquinolin-δ- yloxyjacetic acid methyl ester and iodomethane. ¹ H NMR (DMSO-d6): δ 2.57 (s, 3H) ₁ 3.12 (s, 3H), 3.67 (s, 3H), 3.67 (s, 3H), 4.16 (s, 2H), 4.91 (s, 2H), 6.84 (d, 1H), 7.40 (d, 2H), 7.53 (d, 1 H), 7.77 (d, 2H). Preparation 29b: 2-(8-chloro-1 ,4-dimethyl-3-(4-methylsulfonyl)benzyl)-2- oxo-1,2-dihydroquinolin-5-yloxy)acetic acid

The title compound was prepared by the method of Preparation 3d using [8-chloro-3-(4-methanesulfonylbenzyl)-1,4-dimethyl-2-oxo-1,2 -dihydroquinolin-5- yloxy]acetic acid methyl ester.

¹ H NMR (DMSO-d6): δ 2.62 (s, 3H), 3.16 (s, 3H), 3.72 (s, 3H), 4.19 (s, 2H), 4.82 (s, 2H), 6.86 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.9 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 2H), 13.2 (br s, 1H).

MS: ESI (+ve) (Method A): 450 (M+H) ⁺ , Retention time 8.9 min Biological Methods

Compounds of the invention of formula [1] can be tested using the following biological test methods to determine their ability to displace PGD ₂ from the CRTH2 receptor and for their ability to antagonise the functional effects of PGD ₂ at the CRTH2 receptor. Radioligand Binding Assay

The receptor binding assay is performed in a final volume of 200 μl_ binding buffer [10 mM BES (pH 7.4), 1 mM EDTA ₁ 10 mM manganese chloride, 0.01% BSA] and 1 nM [ ³ H]-PGD ₂ (Amersham Biosciences UK Ltd). Ligands are added in assay buffer containing a constant amount of DMSO (1% by volume). Total binding is determined using 1% by volume of DMSO in assay buffer and non-specific binding is determined using 10 μM of unlabeled PGD ₂ (Sigma). Human embryonic kidney (HEK) cell membranes (3.5 μg) expressing the CRTH2 receptor are incubated with 1.5 mg wheatgerm agglutinin SPA beads and 1 nM [ ³ H]-PGD ₂ (Amersham Biosciences UK Ltd) and the mixture incubated for 3 hours at room temperature. Bound [ ³ H]-PGD ₂ is detected using a Microbeta TRILUX liquid scintillation counter (Perkin Elmer). Compound IC ₅₀ value is determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series. IC ₅₀ calculations are performed using Excel and XLfit (Microsoft), and this value is used to determine a Ki value for the test compound using the Cheng-Prusoff equation. Functional Assay: GTPγS

The GTPγS Assay is performed in a final volume of 200 mL assay buffer (20 mM HEPES pH 7.4, 10 mM MgCI ₂ , 100 mM NaCI, 10 μg/mL saponin). DMSO concentrations are kept constant at 1% by volume. Human embryonic kidney (HEK) cell membranes (3.5 μg) expressing the CRTH2 receptor are incubated with the compounds for 15 min at 3O ⁰ C prior to addition of PGD ₂ (30 nM final concentration) and GTP (10 μM final concentration). The assay solutions are then incubated for 30 minutes at 30 ⁰ C, followed by addition of [ ³⁵ S]- GTPγS (0.1 nM final concentration). The assay plate is than shaken and incubated for 5 minutes at 30 ⁰ C. Finally, SPA beads (Amersham Biosciences, UK) are added to a final concentration of 1.5 mg/well and the plate shaken and incubated for 30 minute at 30 ⁰ C. The sealed plate is centrifuged at 1000g for 10 minutes at 30°C and the bound [ ³⁵ S]-GTPyS is detected on Microbeta scintillation counter (Perkin Elmer). Compound IC ₅₀ value is determined using a 6-point dose response curve in duplicate with a semi-log compound dilution series. IC ₅₀ calculations are performed using Excel and XLfit (Microsoft), and this value is used to determine a Ki value for the test compound using the Cheng- Prusoff equation. Biological Results: The compounds of the Examples above were tested in the CRTH2 radioligand binding described above; the compounds all have Ki values of less than 10 μM in the binding assay. For example, compounds of Examples 5 and 16 have Ki values of 100 and 49 nM, respectively. The compounds also have Ki values of less than 10 μM in the GTPγS functional assay. For example, compounds of Examples 5 and 16 have Ki values of 52 and 140 nM, respectively.