MX2008004091A

MX2008004091A - Quinolines and their therapeutic use

Info

Publication number: MX2008004091A
Application number: MXMX/A/2008/004091A
Authority: MX
Inventors: Colin Cramp Michael; Arienzo Rosa; Hynd George; Crackett Peter; Griggon Yann; Keith Harrison Trevor; Charles Ray Nicholas; Gary Montana John
Original assignee: Argenta Discovery Ltd; Arienzo Rosa; Crackett Peter; Colin Cramp Michael; Finch Harry; Griffon Yann; Keith Harrison Trevor; Hynd George; Gary Montana John; Charles Ray Nicholas
Priority date: 2005-09-30
Filing date: 2008-03-26
Publication date: 2008-09-02

Abstract

Compounds of formula [1]are CRTH2 antagonists, useful in the treatment of conditions having an inflammatory component;in which:R1, R2, R3, R4and R5are independently hydrogen, C1-C6alkyl, C1- C6fluoroalkyl, cyclopropyl, halo, -S(O)nR6, -SO2NR7R8, -NR7R8, -NR7C(O)R6, -CO2R7, -C(O)NR7R8, -C(O)R6, -NO2, -CN or a group -OR9;wherein each R6is independently C1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, aryl, or heteroaryl;R7, R8are independently C1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, cycloalkyl-(C1-C6alkyl)-, aryl, heteroaryl or hydrogen;R9is hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, cycloalkyl, cylcoalkyl-(C1-C6alkyl)-, or a group -SO2R6;A is -CHR10-, -C(O)-, -S(O)n-, -0-, or -NR10- wherein n is an integer from 0-2 and R10is hydrogen, C1-C3alkyl, or C1-C6fluoroalkyl group;B is a direct bond, or a divalent radical selected from -CH2-, -CH2CH2-, -CHR11-, -CR11R12-, -CH2CHR11-, -CH2CR11R12-, -CHR11CHR12-, and divalent radicals of formula -(CR11R12)P-Z- wherein Z is attached to the ring carrying R1, R2and R3;wherein R11is C1-C3alkyl, cyclopropyl, C1-C6fluoroalkyl;R12is methyl or fluoromethyl;p is independently 1 or 2;and Z is -0-, -NH-, or -S(O)n-, wherein n is an integer from 0-2;X is a carboxylic acid, tetrazole, 3-hydroxyisoxazole, hydroxamic acid, phosphinate, phosphonate, phosphonamide, or sulfonic acid group, or a group of formula C(=O)NHSO2R6or SO2NHC(=O)R6;and Y is aryl, heteroaryl, aryl-fused- heterocycloalkyl, heteroaryl-fused-cycloalkyl, heteroaryl-fused-heterocycloalkyl or aryl-fused-cycloalkyl group.

Description

QUINOLINS AND THERAPEUTIC USE Field of the Invention This invention relates to a class of quinoline compounds that are ligands of the CRTH2 receptor (homologous molecule of the Chemoattractant Receptor expressed on T helper cells type 2) and its use in therapy, in particular the treatment of diseases responsive to the modulation of CRTH2 receptor activity, mainly diseases that have a significant inflammatory component. The invention also relates to novel members of that class of ligands and pharmaceutical compositions containing them. Background of the Invention Baited 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 D2, etc.

(Boyce, Allergy Asthma Proc, 2004, 25, 27-30). Prostaglandin D2 (PGD2) is the major metabolite produced by the action of cyclooxygenase on arachidonic acid by mast cells in response to allergen stimulation (Lewis et al, J. Immunol., 1982, 129, 1627-1631).

It has been shown that the production of PGD2 is increased in patients with systemic mastocytosis (Roberts, N. Engl. J. Med., 1980, 303, 1400-1404), allergic rhinitis (Naclerio et al., Am. Rev. Respir. Dis. 1983, 128, 597-602, Brown et al, Arch Otolarynol, Head Neck Surg., 1987, 113, 179-183, Lebel et al, J. Allergy Clin. Immunol., 1988, 82, 869-877. ), bronchial asthma (Murray et al, N. Engl. J. Med., 1986, 315, 800-804; Liu et al., Am. Rev. Respir Dis., 1990, 142, 126-132; Wenzel et al. J. Allergy Clin.Immunol., 1991, 87, 540-548) and urticaria (Heavey et al., J. Allergy Clin.Immunol., 1986, 78, 458-461). PGD2 mediates its effects through two receptors, the PGD2 (or DP) receptor (Boie et al., J. Biol. Chem., 1995, 270, 18910-18916) and the homologous chemoattractant receptor 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 antagonize the effects of PGD2 on its receptors may have beneficial effects in a 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 helper immune cells (Hirai et al., J. Exp. Med., 2001, 193, 255-261). . The CRTH2 receptor has been shown to mediate the migration of the cell mediated by PGD2 in these cell types (Hirai et al, J. Exp. Med., 2001, 193, 255-261) and also that it plays a greater role in the recruitment of neutrophil and eosinophil cells in a model of contact dermatitis (Takeshita et al., Int. Immunol-, 2004, 16, 947-959). Ramatroban ((3R) -3- [(4-fluorophenyl) sulfonyl-amino] -1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid}, a double antagonist of CRTH2 and of the A2 receptor of thromboxane has been shown to attenuate these responses (Sugimoto et al, J. Pharmacol, Exp. Ther., 2003, 305, 347-352, Takeshita et al., op.cit.) The potential of PGD2 to both increase inflammation allergic to induce an inflammatory response has been demonstrated in mice and rats Transgenic mice that overexpress PGD2 synthase exhibit increased pulmonary eosinophilia and increased levels of Th2 cytokines in response to allergen stimulation (Fujitani et al., J. Immunol. , 2002, 168, 443-449) In addition, exogenously administered CRTH2 agonists increase the allergic response in sensitized mice (Spik et al, J. Immunol., 2005, 174, 3703-3708). CRTH2 applied exogenously cause pulmonary eosinophilia but a DP agonist (BW 245C) or a TP agonist (I-BOP) show no effect (Shirashi et al.; 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 PGD2. In addition to ramatroban a number of other CRTH2 antagonists have been described. Examples include: n-acetic acids (WO 2003/022813, WO 2003/066046, WO 2003/066047, WO 2003/097042, WO 2003/097598, WO 2003/101961, WO 2003/101981, WO 2004/007451, WO 2004 / 078719; WO 2004/106302; WO 2005/019171; GB 2407318; WO 2005/040112; WO 2005/040114; WO 2005/044260); tetrahydroqumolines (EP 1413306; EP 1435356; WO 2004/032848; WO 2004/035543; WO 2005/007094) and phenylacetic acids (WO 2004/058164; WO 2004/089884; WO 2004/089885; WO 2005/018529). The quinoline template is common in the compounds proposed for use as pharmaceutical substances. However, the compounds with which the present invention is concerned have a pattern of substitution on the quinoline template which distinguishes them from specific known quinoline-type pharmaceutical substances or known generally-proposed classes of qumolna-type pharmaceutical substances. DETAILED DESCRIPTION OF THE INVENTION Use of a compound of the formula [1] or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof: wherein: R1, R2, R3, R4 and R5 are independently hydrogen, Ci-Cß alkyl, C6-C6 alkyl completely or partially fluorinated, cyclopropyl, halo, -S (0) nR6, -S02NR7R8, -NRR8, -NR7C ( 0) R6, -C02R7, -C (0) NR7R8, -C (0) R6, -N02, -CN or a group -OR9; wherein each R6 is independently alkyl of C? -C6, C6-C6 alkyl completely or partially fluorinated, cycloalkyl, aplo or heteroaryl; R7, R8 with independently C? -C6 alkyl, Ci-Cd alkyl completely or partially fluorinated, cycloalkyl, cycloalkyl- (C? ~? Alkyl), arrio, heteroaryl or hydrogen; R9 is hydrogen, C6-C6alkyl, fully or partially fluorinated C6-C6alkyl, cycloalkyl, cycloalkyl- (Ci-Ce alkyl) -, or a -S02R6 group; A is -CHR10-, -C (O) -, -S (0) n-, -O- or -NR10- where n is an integer of 0-2 and R10 is hydrogen, alqua lo of C1-C3 or group alqua that of C? -C3 completely or partially fluorinated; B is a direct bond, or a divalent radical selected from -CH2-, -CH2CH2-, -CHR11-, -CRnR12-, -CH2CHRU- in any orientation, -CH2CR11R12- in any orientation, -CHRnCHR12-in any orientation and radicals divalents of the formula - (CRnR12) PZ- wherein Z is attached to the ring bearing R1, R2 and R3; wherein R 11 is C 1 -C 3 alkyl, cyclopropyl or C 1 -C 3 alkyl completely or partially fluorinated; R12 is methyl or methyl completely or partially fluorinated; p is independently 1 or 2; and Z is -0-, -NH- or -S (0) n-, where n is an integer of 0-2; X is a carboxylic acid, tetrazole, 3-hydroxoxazole, hydroxamic acid, phosphmate, phosphonate, phosphonamide or sulfonic acid group, or a group of the formula C (= 0) NHS02R6 or S02NHC (= 0) R6; Y is aryl, heteroaryl, heterocycloalkyl fused with aryl, cycloalkyl fused with heteroaryl, heterocycloalkyl fused with heteroaryl or cycloalkyl group fused with aryl; for the manufacture of a medicament for use in the treatment of responsive conditions for the modulation of CRTH2 receptor activity. The compounds (1) with which the invention is concerned are antagonists of the CRTH2 receptor and are selective on the DP receptor. A second aspect of the invention is a method of treating responsive conditions for the modulation of CRTH2 receptor activity, which comprises administering to a patient suffering from such a disease an effective amount of a compound (I) as defined above, or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof. Important responsive conditions for the modulation of CRTH2 receptor activity include asthma, chronic obstructive pulmonary disease, allergic airway syndrome, bronchitis, cystic fibrosis, emphysema and rhinitis. Other responsive conditions for the modulation of CRTH2 receptor activity include psoriasis, dermatitis (atopic and non-atopic), Crohn's disease, ulcerative colitis and irritable bowel disease. Compounds (1) as defined above except that R4 and R5 are not simultaneously hydrogen and B is not a direct bond and their pharmaceutically acceptable salts, N-oxides, hydrates and solvates are believed to be novel in their proper form and such novel compounds form a third aspect of the invention. The pharmaceutical composition comprising such compounds, in admixture with a pharmaceutically acceptable carrier or excipient and the use of such compounds in therapy, are also aspects of the invention.

Terminology As used herein, the term "(Ca-Cb) alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl. As used herein, the term "fully or partially fluorinated Ca-Cb alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from aab to carbon atoms in which the hydrogen all replaced by fluorine (completely fluorinated) or in which some of the hydrogen atoms are replaced by fluorine (partially fluorinated). The term includes, for example -CF3, -CHF2, -CFH2 and CF3CH2-. As used herein the term "carbocyclic" refers to an optionally substituted mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon and include aryl and cycloalkyl. As used herein the term "cycloalkyl" refers to an optionally substituted monocyclic saturated carbocyclic radical having 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. As used herein the term unsubstituted "aryl" refers to an optionally substituted mono-, bi- or tri-cycl radical and includes radicals having two monocyclic carbocyclic aromatic rings that are directly linked by a covalent bond. The aplo radicals can have, for example, from 6 to 14 carbon atoms in the ring, preferably from 6 to 10 carbon atoms. Illustrative of the aryl radicals are phenyl, biphenyl and naphthyl. As used herein, the term "cycloalkyl fused with aryl" refers to a carbocyclic radical consisting of a monocyclic aplo ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and part of cycloalkyl are are defined in the present. Exemplary aryl fused cycloalkyl groups include tetrahydronaphthyl and mdanyl. The cycloalkyl radical fused to aplo can be attached to the rest of the molecule by any available carbon atom. As used herein the term unsubstantiated "hetero-tile" refers to an optionally substituted mono-, bi- or tri-cyclic radical containing one or more heteroatoms selected from S, N and O including radicals having two such monocyclic rings, or one of such monocyclic ring and a monocyclic ap ring, which are directly linked by a covalent bond. Illustrative of such radicals are thienyl, benzthienyl, fuplo, benzupoule, pyrrolyl, imidazolyl, benzimidozolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl or, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl or, pyridinyl, pyridazmyl, pyrimidmyl, pyridazinyl, triazmyl, indolyl and mdazolyl. As used herein the term "heterocycloalkyl" or "heterocyclyl" or "heterocycloalkyl" includes "heterolalk" as defined above, and also means a non-aromatic mono-, bi- or tri-cyclic radical optionally substituted it contains one or more heteroatoms selected from S, N and O and groups consisting of a non-aromatic monocyclic radical containing one or more such heteroatoms that is covalently linked to another of such radical or a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furan, thienyl, piperidyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, pyrrolidinyl, pyrimidyl, morpholyl, piperazyl, mdolyl, quinolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups. As used herein, the term "heteroallo-fused cycloalkyl" means a heterocyclic radical consisting of the monocyclic heteroaryl group, such as pipdyl or furanyl, fused to a cycloalkyl group, wherein the heteroaryl and cycloalkyl portions are as defined above. define in the present. Exemplary heteroalloy-fused cycloalkyl groups include tetrahydrochmolmyl and tetrahydrobenzofuranyl. The cycloalkyl group fused with heteroatel can be attached to the rest of the molecule by which available carbon or nitrogen atom. As used herein, the term "heterocycloalkyl fused to aplo" refers to a heterocyclic radical consisting of a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl portions are as defined above. Heterocycloalkyl groups fused with aryl include tetrahydroquinolmyl, indolyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl. The heterocycloalkyl radical fused to aplo radical can be attached to the rest of the molecule by any available carbon or nitrogen atom. As used herein, the term "heterocycloalkyl fused with heteroaryl" refers to a heterocyclic radical consisting of a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which the heteroaryl and heterocycloalkyl portions they are as defined in the present. Exemplary heterocycloalkyl or fused heteroaryl groups include dihydrodioxinopyridmyl, dihydropyrrolopyridyl, dihydrofophenidinyl and dioxolopipdinyl. The heterocycloalkyl group fused with heteroaphole can be attached to the rest of the molecule by any available carbon or nitrogen atom. Unless otherwise specified in the context in which this occurs, the term "substituted" as applied to any portion herein means substituted with up to four compatible substituents, each of which may be independently, by example, (Ci-Ce) alkyl, cycloalkyl, (C? -C6) alkoxy, hydroxy, hydroxy (C? -C6) alkyl, mercapto, mercapto-alkyl (C? ~ Ce), alkylthio (Ci-Ce), phenyl, monocyclic heteroaryl having 5 or 6 ring atoms, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitplo (-CN), oxo, -COOH, -COOR0 -C0RA, -S02RA, -CONH2, -S02NH2, -C0NHRA, -S02NHRA, -C0NRARB, -S02NRARB, -NH2, -NHR, -NRARB, -OCONH2, -OCONHRA, -OCONRARB, -NHCORA, -NHCOORA, -NRBCOORA , -NHS02ORA, -NR6S02OH, -NRBS02ORA, -NHCONH2, -NRACONH2, -NHCONHRB, -NRACONHRB, -NHCONRARB or -NRACONRARB wherein RA and RB are independently a (C? -C6) alkyl, (C3-C6) cycloalkyl ), phenyl or group monocyclic heterocyclic having 5 or 6 atoms in the ring-, or RA and RB when they are attached to the same nitrogen atom can form a ring with that nitrogen of 5 or 6 ring atoms, optionally containing ad-selected heteroatoms selected from N, 0 or S (examples which are morpholinyl, piperidyl, piperizmyl, 4-methylpiperizmyl and tetrahydropyrrolyl). An "optional substituent" can be one of the above substituent groups. As used herein the term "salt" includes addition of base, addition of acid and quaternary salts. The compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxide, for example sodium and potassium hydroxides; alkaline earth metal hydroxides eg calcium, barium and magnesium hydroxides; with organic bases for example N-methyl-D-glucamma, tris (hydroxymethyl) ammo-methane, L-argmam, L-lysine, N-ethyl pipepdma, dibenzylamine and the like. The specific salts with bases include the salts of benzatma, calcium, diolamma, meglumma, olamma, potassium, procaine, sodium, tromethamine and zinc. Those compounds (I) which are basic can form salts, which include pharmaceutically acceptable salts with inorganic acids, for example with hydrohalic acids such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid and the like and with organic acids for example with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulfonic, p-toluenesulfonic, benzoic, benzeneunonic, glutamic, lactic and mandelic acids and the like. Additional salt forms are detailed in the "Handbook of Pharmaceutical Salts. Properties, selection and use", P. Heinrich Stahl & Camille G. Wermuth, Wiley-VCH, 2002. Also as used herein: The term "phosphinate" refers to a group of the formula -P (0) R (0R) wherein R is hydrogen or C-alkyl. ? ~ C. Exemplary groups are -P (O) (0H) CH3 and - P (O) (OH) H. The term "phosphonate" refers to a group of the formula -P (O) (OH) OR wherein R is hydrogen or C 1 -C 4 alkyl. Exemplary groups are -P (O) (OH) 2 and - P (O) (OH) OC2H5. The term "phosphonamide" refers to a group of the formula -P (O) (OR) NR2 wherein R is hydrogen or C1-C4 alkyl. An exemplary group is -P (O) (OH) NH2. The compounds with which the invention is concerned which may exist in one or more stereoisomeric forms, because the presence of asymmetric atoms or rotational restrictions and in such cases may exist as a number of stereoisomers with R or S stereochemically at each center chiral or as atropisomers with R or S stereochemically to each chiral axis. The invention includes all such enantiomers and diastereomers and mixtures thereof. The use of prodrugs, such as esters, of the compounds (I) with which the invention is concerned is also part of the invention. "Prodrug" means a compound that is convertible in vivo by metabolic means (for example by hydrolysis, reduction or oxidation) to a compound of the formula (1). For example, an ester prodrug of a compound of the formula (1) may be convertible by hydrolysis in vivo to the target molecule. Suitable esters of the compounds of the formula (1) are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthates, gentisatos, isethionates, -p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 1987, 18, 379. As used herein, references to the compounds of the formula (1) are also proposed to include the prodrug forms. The variables R1 -R5, A, B, X and Y For use according to the invention, the following structural characteristics are currently preferred, in any compatible combination, in the compounds (1): R1, R2, R3, R4 and R5 are independently hydrogen; Ci-Cg alkyl, for example methyl, ethyl or n- or iso-propyl; Ci-Cß alkyl completely or partially fluorinated, for example trifluoromethyl or difluoromethyl; cycloalkyl, for example cyclopropyl or cyclobutyl; halo, for example fluoro, chloro or bromo; -N02; -CN; or a group selected from -S (0) nR6, -S02NR7R8, -NR7R8, -NR7C (0) R6, -C02R7, -C (0) NR7R8, -C (0) R6 or a group -OR9; wherein each R6 is independently alkyl of Ci-Cβ, for example methyl, ethyl or n- or iso-propyl; fully or partially fluorinated C -C6 alkyl, for example, trifluoromethyl or difluoromethyl; cycloalkyl for example cyclopropyl], cyclobutyl, cyclopentyl or cyclohexyl; aryl, for example phenyl; or heteroaryl, for example pyridyl, thienyl or furanyl; R7, R8 are independently Ci-Cg alkyl, for example methyl, ethyl or n- or iso-propyl; fully or partially fluorinated C? -C6 alkyl, for example, trifluoromethyl or difluoromethyl; cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylethyl; ari lo, for example phenyl; or heteroanal, for example piphod, thienyl or furanyl; or hydrogen; R9 is hydrogen, C-Cd alkyl, for example methyl, ethyl or n- or iso-propyl; C6-C6 alkyl completely or partially fluorinated, for example trifluoromethyl or difluoromethyl; cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; cycloalkyl- (C? -C6 alkyl) -, for example cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl or, cyclohexylethyl; or a group S02Rd. Presently preterred examples of R1-R5 are: R1 is fluoro or chloro; R2 is hydrogen, chlorine or methyl; R3 is hydrogen; R 4 is methyl, ethyl, methoxy or difluoromethoxy; R5 is methyl, ethyl, ethoxy, isopropoxy, difluoromethoxy or cyano; A is -CHR10-, -C (0) -, -S (0) n-, -0- or -NR10- wherein n is an integer of 0-2 and R10 is hydrogen, Ci-Cß alkyl, for example methyl, ethyl or n- or iso-propyl; C6-C6 alkyl completely or partially fluorinated, for example, trifluoromethyl or difluoromethyl. Presently preferred examples of A are -CH2-, -O- or -S (0) n- wherein n is 0, 2.B is a direct bond or a divalent radical selected from -CH2-, -CH CH2-, -CHR11-, -CR R12-, -CH2CHRU-in any orientation, -CH2CR1: LR12- in any orientation, -CHR1: LCHR12- in any orientation and divalent radicals of the formula - (CR11R12) PZ- where Z is attached to the ring bearing R1, R2 and R3; wherein R 11 is C 1 -C 6 alkyl, for example methyl, ethyl or n- or iso-propyl; fully or partially fluorinated C? -C6 alkyl, for example trifluoromethyl or difluoromethyl; or cyclopropyl; R 12 is methyl or methyl completely or partially fluorinated, for example trifluoromethyl or difluoromethyl; p is independently 1 or 2; and Z is -0-, -NH- or -S (0) n- where n is an integer of 0-2; Presently preferred examples of B are -CH2-, -OCH (CH3) - or -0CH2- wherein the oxygen is attached to the ring bearing R1, R2 and R3. X is a carboxylic acid, tetrazole, 3-hydroxoxazole, hydroxamic acid, phosphmate, phosphonate, phosphonamide or sulphonic acid group, or a group of the formula C (= 0) NHS02R6 or S02NHC (= 0) R6. Currently preferred are the compounds wherein X is a carboxylic acid group. Of course, prodrugs of such compounds include those wherein the carboxylic acid group is esterified as an ester that is hydrolyzed m vivo to release the carboxylic acid. And it is aryl, such as phenyl; heterolane for example qumolmyl, pyridyl, time, furanyl, azolyl, thiazolyl, diazolyl or imidazolyl, heterocycloalkyl fused with aryl, for example tetrahydroquinoline, molinyl, benzodioxim, benxodioxolyl, dihydrobenzofuranyl and isomodolom; cycloalkyl fused to heteropole, for example tetrahydro-molyl; heterocycloalkyl fused with heteroaryl, for example mdolinyl, benzodioxinyl, benzodioxolyl, dihydrobenzofuranyl or isomodolonyl; or cycloalkyl group fused with aryl such as tetrahydronaphthyl and mdan lo. It is currently preferred that Y be optionally substituted. Presently preferred examples of Y include: 4-fluorophenyl, 4-chlorophenyl, 4-methanesulfonylphenyl, 4-ethanesulfonylphenyl, 4- (morpholm-4-sulfonyl) phenyl, 4- (pyrrolidone-1-carbonyl ) phenyl, 2,4-d? fluorophenyl, 2,4-dichlorophenyl, 2-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methanesulfonylphenyl, 2-chloro-4- (p? r? dm-1-carbon? l) phenyl and 2-chloro-4-cyclobutylcarbamoyl A particularly preferred sub-class of the compounds (1) of the invention consists of those in which R1 is fluoro or chloro; R2 and R3 are hydrogen; R 4 is methyl, ethyl, methoxy or difluoromethoxy; R5 is methyl, ethyl, ethoxy, isopropoxy, difluoromethoxy or cyano; A is -CH2-, -O- or -S (0) n- wherein n is 0, 1 or 2; B is -CH2-, -OCH (CH3) - or -0CII2- wherein the oxygen is attached to the ring bearing R1, R2 and R3; X is -C02H; and Y is 4-fluorophenyl, 4-chlorophenyl, 4-methanesulfonylphenyl, 4-ethanesulfominyl, 4- (morphon-4-sulphonyl) phenyl, 4- (pyrrolidone-1-carbonyl) phenyl, 2,4-d? fluorophenyl, 2,4-dichlorophenyl, 2-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methanesulfonylphenyl, 2-chloro-4- (para? ? dm-1-carbon? l) phenyl and 2-chloro-4-cyclobutylcarbamoyl and pharmaceutically acceptable salts, N-oxides, hydrates or solvates. Specific compounds with which the invention is concerned include those of the Examples herein and pharmaceutically acceptable salts, N-oxides, hydrates or solvates thereof. Compositions As mentioned above, the compounds with which the invention is concerned are antagonists of the CRTH2 receptor and are useful in the treatment of diseases that benefit from such modulation. Examples of such diseases are referred to above, and include asthma, rhinitis, allergic airway syndrome and bronchitis. It will be understood that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, proportion of excretion, combination of drug and the severity of the particular disease that undergoes the treatment. Optimal dose levels and frequency of dosing will be determined by the clinical trial, as required in the pharmaceutical art. In general, the daily dose range will be within the range of about 0.001 mg to about 100 mg per kg of body weight of a mammal, often 0.01 mg to about 50 mg per kg, for example 0.1 to 10 mg per kg, in individual or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. The compounds with which the invention is concerned can be prepared by administration by any route consistent with its pharmacokinetic properties. Orally administrable compositions may be in the form of tablets, capsules, powders, granules, pills, liquid or gel preparations, such as parenterally oral, topical or sterile solutions or suspensions. The tablets and capsules for oral administration may be in unit dose presentation form and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet forming lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch or acceptable wettable agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, hydrogenated gelatin edible fats; emulsification agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxy-benzoate or sorbic acid and, if desired, conventional flavoring or coloring agents. For topical application to the skin, the drug can be made in a cream, lotion or ointment. The cream or ointment formulations that can be used for the drug are conventional formulations well known in the art, for example as described in standard pharmaceutical textbooks such as the British Pharmacopoeia. The drug can also be formulated for inhalation, for example as a nasal spray, or dry powder or aerosol inhalers. For delivery by inhalation, the active compound is preferably in the form of microparticles. They can be prepared by a variety of techniques, including spray drying, freeze drying and micronization. The 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 or other capsules. "dry powder" supply systems. The active ingredient can also be administered parenterally in a sterile medium. Depending on the vehicle and the concentration used, the drug can be either suspended or dissolved in the vehicle. Advantageously, adjuvants such as a local anesthetic, preservative and regulatory agents can be dissolved in the vehicle. Other compounds can be combined with the compounds of this invention of the formula [1] for the prevention and treatment of diseases mediated by prostaglandin. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating diseases mediated with PGD2 comprising a therapeutically effective amount of a compound of the invention of the formula [I] and one or more other therapeutic agents. Suitable therapeutic agents for combination therapy with the compounds of the formula [1] include, but are not limited to: (1) corticosteroids, such as fluticasone, cyclosonide or budesonide; (2) β2-adrenoreceptor agonists, such as salmeterol, indacaterol or formoterol; (3) leukotpene modulators, for example leukotriene antagonists such as montelucast, zafirulast or pranlukast or inhibitors of leukotriene biosynthesis such as Zileuton or BAY-1005; (4) anticolmergic agents, for example muscarin? Co-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 receptor antagonists (Hl), such as fexofenadma, citirizine, loratidma or astemizole; (7) antitussive agents, such as codeine or dextramorphan; (8) non-selective COX-l / 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 WO 97/03094 and WO97 / 02289; (11) TACE inhibitors and TNF-a inhibitors, for example anti-TNF monoclonal antibody, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel; (12) matrix metalloprotease inhibitors, for example MMP12; (13) human neutrophil elastase inhibitors, such as those described in WO 2005/026124, WO 2003/053930 and WO 06/082412; (14) A2a agonists such as those described in EP1052264 and EP1241176 (15) A2b antagonists such as those described, in WO 2002/42298; (16) modulators of chemokine receptor function, for example CCR3 and CCR8 antagonists; (17) compounds that modulate the action of other pro-stanoid receptors, for example a DP receptor antagonist or a thromboxane A2 antagonist; and (18) agents that modulate the function of Th2, such as PPAR agonists. The weight ratio of the compound of the invention to the second active ingredient can be varied and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Synthesis Methods The present invention is also concerned with processes for preparing the compounds of this invention. The compounds of the 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. On the other hand, by using the methods described with the description contained herein, one of ordinary skill in the art can readily prepare the additional compounds of the present invention claimed herein. The compounds illustrated in the examples, however, are not going to be considered as forming the genus only which 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 the formula [la], in which the group B is represented by a group of the formula O-alkylene (optionally substituted) and R 1"5, A, X and Y are as defined above, can conveniently prepared by the reaction between a compound of the formula [2] and a suitable alkylating agent of the formula [3], wherein the LG group represents a suitable leaving group (eg, chlorine, bromine or methanesulfonyloxy). Alkylation reaction is carried out in the presence of a base (eg, potassium carbonate) in an inert solvent (eg, acetone or? J? J-dimethylformamide). It will be understood by those who are practical in the art that it may be convenient to carry out the transformation of intermediates [2] to the final compound [the] using a form of alkylating agent [3] in which one or other of the functionalities on either the component is adequately protected. the G When 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 tert-butyl ester). It is to be understood that if the reaction is carried out on a protected form of the alkylating agent [3] an appropriate deprotection step will be required to obtain the desired compound [la] of the invention (Scheme 1).

Scheme 1 The intermediate compounds of the formula [2] can be conveniently prepared by the reaction between an aminophenol of the formula [4] and a 1,3-dicarbonyl compound of the formula [5] (Scheme 2). The reaction can be carried out neat or in the presence of a suitable dehydrating agent, such as polyphosphoric acid, p-toluenesulfonic acid or methanesulfonic acid. The compounds of the formula [4] and [5] are commercially available or prepared by known methods. [41 [5] [21 Scheme 2 The compounds of the formula [la] in which R is an alkoxy group, such as difluoromethoxy, which can be conveniently prepared from the reaction of aniline of the formula [6] and a β-ketoester of the formula [7] , in which PG represents an appropriate alkyl group (such as methyl and ethyl), after alkylation with chlorodifluoromethane (Scheme 3). It is to be understood that if the reaction is carried out on a protected form of the intermediate [6] an appropriate deprotection step will be required to obtain the desired compound [la]. The ketoesters of the formula [7] are known or can be prepared from known compounds according to the methods for those skilled in the art. [1a] B = 0-a! QutlGno (optionally substituted) R "= OCHF, Scheme 3 The compound of the formula [6] can be prepared from the compounds of the formula [4] by treatment with an alkylating agent of the formula [3] (Scheme 4), using the methods described above for the preparation of the compounds of the formula [la] of the compounds of the formula [2] (Scheme 1) Scheme 4 The compounds of the formula [la] in which R5 is an alkoxy group, such as difluoromethoxy, which can be conveniently prepared from the intermediates of the formula [11] using the methods described above for the preparation of the compounds of the formula [la] of the compounds of the formula [2] (Scheme 1) and the compounds of the formula [la] of the compounds of the formula [8] (Scheme 3). The compounds of the formula [11] can conveniently be the compounds of the formula [10]. The reaction can be carried out in the presence of a suitable dehydrating agent, for example methanesulfonic acid or p-toluenesulfonic acid. The intermediates of the formula [10] can be prepared from the reaction of aminophenols of the formula [4] with β-ketothioesters of the formula [9] in the presence of silver trifluoroacetate. The compounds of the formula [4] and [9] are commercially available or prepared by known methods.

Scheme 5 The compounds of the invention of the formula [Ib], wherein R 1"5, A and Y are as defined above, can be prepared by the reaction between an intermediate compound of the formula [12], in which T represents a chlorine, bromine or iodine atom, or a trifluoromethanesulfonyloxy and 1- (er-butyldimethylsilyloxy) -1-methoxyethane group (Scheme 6) .The reaction can be conveniently carried out in the presence of a suitable catalyst ( example, a palladium compound) and a base, such as sodium acetate.

Scheme 6 The intermediates of the formula [12], in which T is trifluoromethanesulfonyloxy, can be prepared from the reaction of intermediates of the formula [2] with W-phenyl-tpfluoromethanesulfonimide in the presence of a base, such as potassium carbonate. . It will be understood by those skilled in the art that the compounds of the invention can be prepared by transformations of other compounds of the invention. For example, the compounds of the invention of the formula [le], in which the group A represents a sulfonyl group, which can be conveniently prepared by the oxidation of the compounds of the invention of the formula [la], in which Group A represents a sulfanyl group, with a suitable oxidizing agent such as potassium peroxymonosulfate, meta-chloroperoxybenzoic acid or other well-known oxidizing agents. [1a] B = 0-alkyl-substituted (optional substituted) [1c] A = S In a further example, the compounds of the formula [1 b], in which the group R 5 represents a hydrogen atom which can be conveniently prepared by the reduction of the compounds of the formula [Ib], in which the group R 5 represents a halo group such as chlorine or bromine. The transformation can be conveniently achieved by reduction with hydrogen in the presence of a suitable catalyst, such as palladium supported on carbon. EXAMPLES The invention will now be described with reference to the following examples. It will be appreciated that the invention is described by way of example only and the modification of detail can be made without departing from the scope of the invention. 1 H NMR spectra were recorded at room temperature using an Inova spectrometer from Vanan Unit (400MHz) with a 5mm resonance triple probe spectrometer. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br s = singlet to plao, s = sprig, d = doublet, dd = double of doublet, t = triplet, q = quartet, m = multiplet. The Mass Spectrometry (LCMS) experiments to determine the retention times and associated mass ions were performed using the following methods: Method A: the experiments were performed on a micromach platform LCT spectrometer with positive ion electro-dew and detection of individual wavelength of UV 254 nm using a Higgms Clipeus C18 5 μm 100 x 3.0 mm column and a flow rate of 2 mL / minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) during the first minute followed by a gradient of up to 5% solvent A and 95% solvent B for the next 14 minutes. The final solvent system was kept constant for an additional 2 minutes. Method B: the experiments were performed on a Micromass Platform LC spectrometer with positive and negative ion electrocution and detection of ELS / Diode array using a Phenomenex Luna C18 (2) 30 x 4.6 mm column and a flow rate of 2 mL / minute. The solvent system was 95% solvent A and 5% solvent B during the first 0.50 minutes followed by a gradient of up to 5% solvent A and 95% solvent B for the next 4 minutes. The final solvent system remained constant for an additional 0.50 minutes. Microwave experiments were carried out using a Personal Chemistry Smith Synthesizer ™, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures of 40-250 ° C can be achieved and pressures up to 20 bar can be achieved. Two types of bottles are available for this processor, 0.5-2.0 mL and 2.0-5.0 mL. Purifications of preparative reverse phase HPLC were carried out using the stationary phase of silica bonded to C-18 of 7 Gemini strands in columns of 10 cm in length and 2 cm in internal diameter. The mobile phase used was mixtures of acetonitrile and water (both regulated with 0.1% trifluoroacetic acid in v / v) with a flow rate of 10 mL per minute and typical gradients of 40 to 90% of organic modifier raised upwards during 30 40 minutes. The fractions containing the required product (identified by the LC-MS analysis) were accumulated, the organic fraction was removed by evaporation and the remaining aqueous fraction was lyophilized, to give the final product. Example 1: [8-chloro-3- (4-chlorobenzyl) -4-methoxy-2-methylquinolin-5-yloxy] acetic acid Preparation: 8-Chloro-3- (4-chlorobenzyl) -5-hydroxy-2-methyl-1H-quinolin-4-one A mixture of 3-amino-4-chlorophenol (2.5 g), 2-ethyl-2-ethyl ester - (4-chlorobenzyl) t3-oxobutyric (4.7 g) and toluene-4-sulfonic acid (0.3 g) was heated at 160 ° C under nitrogen for 10 hours. The mixture was cooled to room temperature and the residue was triturated with methanol and then crystallized from butan-1-ol to give a beige powder. Purification by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0: 1 to 1: 0 by volume) gave the title compound as a yellow solid, 0.77 g. xti NMR (DMSO-dd): d 2.50 (s, 3H), 3.90 (s, 2H), 6.90 (d, J = 8.6 Hz, ÍH), 7.20-7.30 (m, 4H), 7.60 (d, J = 8.6 Hz, ÍH), 11.05 (s, ÍH), 14.90 (s, ÍH). MS: ESI (+ ve) (Method B): 334 (M + H) 0 Retention time 3.8 min. Preparation Ib: [8-chloro-3- (4-chlorobenzyl) -2-methyl-4-oxo-l, 4-dihydroquinolin-5-yloxy] -acetic acid methyl ester A solution of 8-chloro-3- ( 4-chlorobenzyl) -5-hydroxy-2-methyl-lH-quinolin-4-one (0.56 g) in tetrahydrofuran (7.0 mL) was flushed with nitrogen and cooled to -40 ° C. A 1.0 M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (1.7 mL) was added and the resulting mixture was heated at 0 ° C for 1 hour. The mixture was cooled to -30 ° C and a solution of methyl bromoacetic acid ester (0.26 g) in tetrahydrofuran (1.0 mL) was added and the resulting mixture was warmed to room temperature for 2 hours and then stirred at this temperature for 3 days. The mixture was diluted with 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1:19 to 19: 1 by volume) gave the title compound as a gum, 0.13 g. MS: ESI (+ ve) (Method B): 406 (M + H) +, Retention time 3.1 min. Preparation le: [8-Chloro-3- (4-chlorobenzyl) -4-methox-2-methyl? -quim? -5? Lox?] Acetic acid methyl ester A mixture of acid methyl ester [8-] chloro-3- (4-chlorobenzyl) -2-methyl-4-oxo-l, 4-d? h? droqu? nolm-5-? lox?] -acetic (0.13 g), iodomethane (0.20 mL),? J? 7-d? met? lformamide (1.0 mL) and potassium carbonate (0.14 g) were stirred at room temperature for 22 hours. The mixture was diluted with water and extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1:19 to 19: 1 by volume) gave the title compound as a gum, 0.059 g. MS: ESI (+ ve) (Method B): 420 (M + H) +, Retention time 4.0 min. Preparation Id: acid [8-chloro-3- (4-chlorobenzyl) -4-methox? -2-met? Lqumolm-5-? Lox?] Acetic acid A mixture of methyl ester of acid [8-chloro-3-] (4-chlorobenzyl) -4-methox? -2-met? L? Nol? N-5-? Lox?] Acetic acid (0.059 g), methanol (2.0 mL), aqueous lithium hydroxide solution, saturated ( 0.25 mL) and water (0.4 mL) was stirred at room temperature for 15 hours. The methanol was removed under reduced pressure and the pH of the residue was adjusted to 1 by the addition of 1.0 M aqueous hydrochloric acid. Purification by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water (20% to 80%). % organic modifier) gave the title compound as a yellow solid, 0.060 g. ? NMR (DMSO-d6): d 2.55 (s, 3H), 3.80 (s, 3H), 4.20 (s, 2H), 4.90 (s, 2H), 6.90 (d, J = 8.6 Hz, ÍH), 7.15 ( d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, ÍH). MS: ESI (+ ve) (Method A): 406 (M + H) +, Retention time 11.0 min. MS: ESI (+ ve) (Method B): 406 (M + H) 0 Retention time 3.5 min. Example 2: [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yloxy] acetic acid Preparation 2a: [8-Chloro-3- (4-chlorobenzyl) -2,4-d? Meth? L? Nolm-5? -lox?] Acetic acid methyl ester A mixture of 8-chloro-3- (4-chlorobenzyl) -2,4-d? -chlorobenzyl) -2,4-dimethylquinolin-5-ol (0.23 g), N, N-dimethyl formamide (5.0 mL), potassium carbonate (0.11 g) and bromoacetic acid methyl ester (0.075 mL) was stirred at room temperature environment for 17 hours. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 1 by volume) gave the title compound, 0.11 g. XH? MR (CDC13): d 2.75 (s, 3H), 2.85 (s, 3H), 4.25 (s, 2H), 4.75 (s, 2H), 6.60 (d, J = 8.6 Hz, ÍH), 6.95 (s) d, J = 8.6 Hz, ÍH), 7.20 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H). MS: ESI (tve) (Method B): 404 (M + H) +, Retention time 4.1 min. Preparation 2b: [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yloxy] acetic acid A solution of [8-chloro-3- (4-chlorobenzyl) -2-methyl ester, 4-dimethylquinolin-5-yloxy] acetic acid (0.11 g), acetonitrile (2.0 mL) and 4.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 1 hour. The acetonitrile was removed under reduced pressure and the pH of the residue was adjusted to ~5 by the addition of saturated, aqueous sodium dihydrogen phosphate solution. The resulting mixture was extracted with ethyl acetate and the combined extracts over magnesium sulfate and under concentrated reduced pressure. Purification of the residue by column chromatography on an NH2 flash cartridge, eluting with methanol and then 2.0M ammonia in methanol, gave the title compound, 0.10 g. XH NMR (DMSO-d6): d 2.60 (s, 3H), 2.85 (s, 3H), 4.25 (s, 2H), 4.75 (s, 2H), 6.80 (d, J = 8.6 Hz, ÍH), 7.00 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, ÍH). MS: ESI (+ ve) (Method A): 390 (M + H) +, Retention time 11. 0 min. MS: ESI (+ ve) (Method B): 390 (M + H) +, Retention time 3.5 min. Example 3: [3- (4-Chlorobenzyl) -2-ethoxy-4,7-dimethylquinolin-5-yl] acetic acid Preparation 3a: 3-amino-5-methylphenol A mixture of 5-methylbenzene-1,3-diol (6.0 g), ammonium chloride (3.0 g), water (9.0 mL) and ammonium hydroxide (6.8 mL, 33%) in water) were sealed in a pump and heated at 180 ° C for 17 hours. The mixture was cooled to room temperature and the resulting precipitate was collected by filtration. Crystallization of water gave the title compound, 1.7 g. XH NMR (DMS0-d6): d 2.05 (s, 3H), 4.75 (br s, 2H), 5.75-5.80 (m, 3H), 8.70 (s, ÍH). Preparation 3b: 3- (4-chlorobenzyl) -5-hydroxy-4,7-dimethyl-lH-quinolin-2-one A mixture of 3-amino-5-methylphenol (0.25 g) and ethyl ester of 2- ( 4-chlorobenzyl) -3-oxobutyric acid (0.52 g) was heated at 150 ° C under nitrogen for 7 hours. The mixture was cooled to room temperature and the residue was triturated with methanol to give the title compound as an off-white solid, 0.32 g. XH NMR (DMSO-d6): d 2.20 (s, 3H), 2.55 (s, 3H), 4.00 (s, 2H), 6.40 (m, ÍH), 6.55 (m, ÍH), 7.20 (2H, d, J = 8.6 Hz), 7.30 (2H, d, J = 8.6 Hz), 10.00 (1 H, br s), 11.50 (1 H, br s). MS: ESI (+ ve) (Method B): 314 (M + H) +, Retention time 3.14 min. Preparation 3c: 3- (4-chlorobenzyl) -4,7-dimethyl-2-oxo-1,2-dihydroquinoline-5-yl ester of trifluoromethanesulfonic acid A mixture of 3- (4-chlorobenzyl) -5-hydroxy-4,7-dimethyl-1H-quinolin-2-one (1.4 g), N-phenyltrifluoromethanesulfonimide (1.75 g), potassium carbonate (1.85 g) and tetrahydrofuran (7.0 mL) was heated by microwave irradiation at 120 ° C for 12 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1:25 to 1: 5 by volume) gave the title compound as an off-white solid, 3.3 g. XH NMR (DMS0-d6): d 2.40 (3H, s), 2.60 (s, 3H), 4.15 (s, 2H), 6.95 (m, ÍH), 7.15-7.20 (m, 4H), 7.30 (m, ÍH), 12.0 (s, ÍH). MS: ESI (+ ve) (Method B): 446 (MH-H) +, Retention time 4.1 mm. Preparation 3d: [3- (4-chlorobenzyl) -4,7-d? Met? L-2-oxo-l, 2-d? H? Droquol n-5-? L] methyl ester acetic acid A mixture of 3- (4-chlorobenzyl) -4,7-d? met? l-2-oxo-l, 2-d? -hydroquinoline-5-ethyl ester of t-fluoro-methanesulfonic acid ( 1.1 g), 1- (tert-butyldimethylsilyloxy) -1-methoxethene (2.7 mL), sodium acetate (0.25 g), bis (dibenzylidene ketone) palladium (0.07 g) and 1,1 '-bis (diffemlfospmo) ferrocene (0) (0.07 g) in N, N-dimethylformamide (15.0 mL) was heated by microwave irradiation at 120 ° C for 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0: 1 to 1: 3 by volume) gave the title compound as a pale orange oil, 1.75 g. XH NMR (DMSO-d6): d 2.30 (s, 3H), 2.40 (s, 3H), 3.60 (s, 3H), 4.00 (s, 2H), 4.15 (s, 2H), 6.85 (s, 1H) , 7.10 (s, ÍH), 7.20 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 11.75 (s, ÍH). MS: ESI (+ ve) (Method B): 370 (M + H) +, Retention time 3.4 min. Preparation 3e: [3- (4-Chlorobenzyl) -2-ethoxy-4,7-dimethylquinolin-5-yl] acetic acid methyl ester A mixture of [3- (4-chlorobenzyl) methyl ester-4, 7 -dimeti1-2-oxo-1, 2-dihydroquinolin-5-yl] acetic acid (1.0 g), bromoethane (0.24 mL), potassium carbonate (1.1 g) and N, N-dimethylformamide (10 mL) was heated to 40 ° C for 17 hours. The mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0: 1 to 1: 5 by volume) gave the title compound as a gum, 0.28 g. XH? MR (DMSO-d6): d 1.25 (t, J = 7.0 Hz, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.60 (s, 3H), 4.05 (s, 2H), 4.15 (s, 2H), 4.35 (q, J = 7.0 Hz, 2H), 7.00 (s, 1H), 7.15 (d, J = 8.6 Hz, 2H),7. 30 (d, J = 8.6 Hz, 2H), 7.35 (s, ÍH). MS: ESI (+ ve) (Method B): 398 (Mi-H) +, Retention time 4.7 min. Preparation 3f: [3- (4-chlorobenzyl) -2-ethoxy? -4,7-d? Met? L? Nolm-5? L acetic acid A solution of methyl ester of acid [3- (4 -chlorobenzyl) -2-etox? -4, 7-d? met lqua nol? n-5-? l acetic acid (0.10 g), methanol (2.0 mL), aqueous lithium hydroxide solution, saturated (0.20 mL) and water (0.4 mL) was stirred at 50 ° C for 5 hours. The methanol was removed under reduced pressure and the residue was acidified by the addition of tpfluoroacetic acid. The resulting precipitate was collected by filtration, washed with water and dried to provide the title compound as a white solid, 0. 095 g. XH NMR (DMSO-d6): d 1.30 (t, J = 7.0 Hz, 3H), 2.40 (s, 3H), 2. 60 (s, 3H), 4.10 (s, 2H), 4.15 (s, 2H), 4.40 (q, J = 7.0 Hz, 2H), 7.10 (m, ÍH), 7.15 (m, 2H), 7.30 (m, 2H), 7.50 (m, ÍH), 12.50 (br s, ÍH). MS: ESI (+ ve) (Method A): 384 (M + H) +, Retention time 13. 4 min. MS: ESI (+ ve) (Method B): 384 (M + H) 0 Retention time 4.2 min. Example 4: [3- (4-chlorobenzyl) -2,4,7-tr? Methylquinolin-5-yloxy] acetic acid Preparation 4a: [3-4-chlorobenzyl] -2,4,7-trimethylquinoline-5-yloxy] acetic acid methyl ester A mixture of 3- (4-chlorobenzyl) -2,4,7-trimethylquinoline-5-ol (0.24 g), N, N-dimethylformamide (2.0 mL), potassium carbonate (0.12 g) and methyl bromoacetic acid ester (0.12 mL) was stirred at room temperature for 17 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with diethyl ether and further purification by column chromatography on silica gel, eluting with a mixture of tert-butyl methyl ether and dichloromethane (1: 4 to 3: 7 by volume) gave the title compound, 0.078 g. ? MR (CDC13): d 2.50 (s, 3H), 2.60 (s, 3H), 2.85 (s, 3H), 3.85 (s, 3H), 4.20 (s, 2H), 4.75 (s, 2H), 6.55 (m, ÍH), 6.95 (m, 2H), 7.30 (m, 2H), 7.50 (m, ÍH). MS: ESI (+ ve) (Method B): 384 (M + H) 0 Retention time 2.5 min. Preparation 4b: [3- (4-chlorobenzyl) -2,4,7-trimethylquinolin-5-yloxy] acetic acid A solution of [3- (4-chlorobenzyl) -2,4,7-trimethylquinoline- methyl ester] 5-yloxy] acetic acid (0.045 g), acetonitrile (2.0 mL), tetrahydrofuran (1.0 mL) and 4.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 2 hours. The organic solvents were removed under "reduced pressure and the pH of the residue was adjusted to 5-6 by the addition of saturated aqueous sodium dihydrogenphosphate solution." The resulting mixture was extracted with chloroform and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and trituration of the residue with diethyl ether and then methanol gave the title compound, 0.025 g XH NMR (DMSO-d6): d 2.40 (s, 3H), 2.50 (s, 3H), 2.80 (s, 3H), 4.20 (s, 2H), 4.60 (s, 2H), 6.70 (m, ÍH), 7.05 (d, J = 8.6 Hz, 2H), 7.25 (m, ÍH), 7.30 (d , J = 8.6 Hz, 2H) MS: ESI (+ ve) (Method A): 370 (M + H) +, Retention time 7.5 min MS: ESI (+ ve) (Method B): 370 (M + H) 0 Retention time 2.3 min Example 5: [3- (4-Chlorobenzyl) -2,4,7-trimethylquinolin-5-yl] acetic acid Preparation 5a: 3- (4-chlorobenzyl) -2,4,7-trimethylquinolin-5-ol A mixture of 3-amino-5-metho-phenol (1.0 g), 3- (4-chlorobenzyl) pentane- 2,4-dione (1.7 g) and toluene-4-sulfonic acid (0.30 g) was heated at 160 ° C ba or nitrogen for 3 hours. The mixture was cooled to room temperature and the residue was triturated with methanol to give the title compound, 1.5 g. MS: ESI (+ ve) (Method B): 312 (M + H) +, Retention time 2.3 mm. Preparation 5b: 3- (4-chlorobenzyl) -2, 4, 7-tmetmethoquinol-5-yl ester of tp fluoromethanesulfonic acid A mixture of 3- (4-chlorobenzyl) - 2, 4, 7-tr? Met? Lol? Nolm-5-ol (0.32 g), N-phenyltrifluoromethanesulfonimide (0.36 g), potassium carbonate (0.42 g) and tetrahydrofuran (5.0 mL) was heated by microwave irradiation to 120 ° C for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. The purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and tert-butyl methyl ether (9: 1 by volume) gave the title compound, 0.39 g. XH NMR (CDC13): d 2.55 (s, 3H), 2.65 (s, 3H), 2.75 (s, 3H), 4.25 (s, 2H), 6.90 (m, 2H), 7.25-7.40 (m, 4H) . Preparation 5c: [3- (4-chlorobenzyl) -2,4,7-tr? Met? L? Nolm-5? L] acetic acid methyl ester A mixture of 3- (4-chlorobenzyl) ester ) -2, 4, 7-methyl-1-methyl-3-trifluoromethanesulfonic acid (0.39), 1- (tert-butyldimethylsilyloxy) -1-methoxethene (0.95 mL), sodium acetate ( 0.086 g), tris (dibenzylidene ketone) dipalladium (0) (0.080 g) and 1,1 '-bis (diphenylphosphino) ferrocene (0) (0.048 g) in N, Nd? Met? Lformamide (3.0 mL) was heated by irradiation of microwave at 120 ° C for 10 minutes. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 1 by volume) gave the title compound, 0.11 g. ? NMR (CD3OD): d 2.50 (s, 3H), 2.55 (s, 3H), 2.65 (s, 3H), 3.65 (s, 3H), 4.25 (s, 2H), 4.30 (s, 2H), 7.00 (s) d, J = 8.6 Hz, 2H), 7.25 (m, 3H), 7.70 (m, 1H). Preparation 5d: [3- (4-chlorobenzyl) -2,4,7-tr? Met? L? Nolm-5? L] acetic acid A solution of methyl 3- (4-chlorobenzyl) acid -2, 4, 7-methyl-1-methyl-5-acetic acid (0.10 g), methanol (2.0 mL) and 4.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 2 hours. hours. The methanol was removed under reduced pressure and the pH of the residue was adjusted to 5-6 by the addition of saturated, aqueous sodium dihydrogenphosphate solution. The resulting mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Trituration of the residue with acetonitrile gave the title compound, 0.010 g. XH NMR (DMSO-d6): d 2.55 (s, 3H), 2.80 (s, 3H), 3.05 (s, 3H), 4.25 (s, 2H), 5.30 (s, 2H), 6.85 (m, 2H) , 7.25 (m, 2H), 7.40 (m, ÍH), 8.70 (m, ÍH). MS: ESI (+ ve) (Method A): 354 (M + H) 0 Retention time 7.0 min MS ESI (+ ve) (Method B): 354: M + HI Retention time 2.4 min. Example 6: [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yl] acetic acid Preparation 6a: 8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-ol A mixture of 3-amino-4-chlorophenol (2.2 g), 3- (4-chlorobenzyl) pentane-2, 4-dione (3.4 g) and toluene-4-sulfonic acid (few crystals) was heated at 170 ° C under nitrogen for 10 hours. The mixture was cooled to room temperature and purification by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (1:19 by volume), followed by trituration with diethyl ether gave the title compound as a Pale solid coffee, 0.41 g. XH NMR (DMSO-d6): d 2.55 (s, 3H), 2.80 (s, 3H), 4.25 (s, 2H), 6.85 (d, J = 8.3 Hz, ÍH), 7.05 (d, J = 8.3 Hz , 2H), 7.30 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, ÍH), 10.50 (s, ÍH). MS: ESI (tve) (Method B): 332 (M + H) +, Retention time 3.4 min. Preparation 6b: 8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinoline-5-yl ester of trifluoromethanesulfonic acid A mixture of 8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinoline-5 -ol (0.20 g), N-phenyltrifluoromethanesulfonimide (0.26 g), potassium carbonate (0.25 g) and tetrahydrofuran (2.0 mL) was heated by microwave irradiation at 120 ° C for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:19 by volume) gave the title compound as a beige solid, 0.25. g. XH NMR (CDC13): d 2.70 (s, 3H), 2.75 (s, 3H), 4.30 (s, 2H), 6.90 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H ), 7.40 (d, J = 8.4 Hz, ÍH), 7.80 (d, J = 8.4 Hz, ÍH). Preparation 6c: [8-Chloro-3- (4-chlorobenzyl) -2,4-d? Met? Lqu? N-5? L] acetic acid methyl ester A mixture of 8-chloro-3- ( 4-chlorobenzyl) -2,4-d? Met? L? Nol? N-5-tl? Tfluoromethanesulfonic acid (0.24 g), 1- (tert-butyldimethylsilyloxy) -1-methoxethene (0.56 mL), sodium acetate (0.053 g), tris (dibenzylidene ketone) dipalladium (0) (0.024 g) and 1, 1 '-bis (diphenylphosphino) ferrocene (0) (0.014 g) in N, Nd? met? lformamide (2 mL) was heated by microwave irradiation at 120 ° C for 10 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was removed at reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 9 to 1: 6 by volume) to give the title compound as a pink solid, 0.12 g. 1? MR (CDC13): d 2.60 (s, 3H), 2.70 (s, 3H), 3.70 (s, 3H), 4.20 (s, 2H), 4.25 (s, 2H), 6.90 (d, J = 8.6 Hz, 2H), 7.20-7.25 (m, 3H), 7.70 (d, J = 7.8 Hz, ÍH). MS: ESI (i-ve) (Method B): 388 (MH-H) +, Retention time 4.3 min. Preparation 6d: [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yl] acetic acid A solution of [8-chloro-3- (4-chlorobenzyl) - methyl acid ester 2,4-dimethylquinolin-5-yl] acetic acid (0.11 g), methanol (5.0 mL) and 1.0 M aqueous litoxide hydroxide solution (0.84 mL) was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of the mixture was adjusted to 3-4 by the addition of 1.0 M aqueous hydrochloric acid and the resulting precipitate was collected by filtration and washed with water. Crystallization of industrial methylated spectra gave the title compound as a white solid, 0.056 g. XH NMR (DMSO-d6): d 2.55 (s, 3H), 2.60 (s, 3H), 4.20 (s, 2H), 4.30 (s, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.1 Hz, ÍH). MS: ESI (+ ve) (Method A): 374 (M + H) 0 Retention time 10.9 min. Example 7: [8-chloro-3- (4-chlorophenoxy) -2,4-dimethylquinolin-5-yloxy] acetic acid Preparation 7a: 8-chloro-3- (4-chlorophenoxy) -2, -dimethylquinolin-5-ol A mixture of 3-amino-4-chlorophenol (0.36 g), 3- (4-chlorophenoxy) pentane-2, 4 -dione (0.57 g) and p-toluenesulfonic acid monohydrate (0.020 g) was heated at 125 ° C for 3 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 0: 1 by volume) to give the title compound as an oil. coffee, 0.16 g. XH NMR (CDC13): d 2.55 (s, 3H), 2.70 (s, 3H), 6.70 (d, J = 9.0 Hz, ÍH), 6.75 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, ÍH). MS: ESI (+ ve) (Method B): 334 (M + H) +, Retention time 4.2 min. Preparation 7b: [8-chloro-3- (4-chlorophenoxy) -2,4-dimethylquinolin-5-yloxy] acetic acid methyl ester A mixture of 8-chloro-3- (4-chlorophenoxy) -2,4- dimethylquinolin-5-ol (0.16 g), N, N-dimethylformamide (3.0 mL), potassium carbonate (0.20 g) and bromoacetic acid methyl ester (0.88 g) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, washed with water and dried over magnesium sulfate. 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 5: 1 by volume) gave the title compound as a whitish solid, 0.20 g. MS: ESI (+ ve) (Method B): 406 (M + H) +, Retention time 4.5 min. Preparation 7c: [8-chloro-3- (4-chlorophenoxy) -2,4-dimethylquinolin-5-yloxy] acetic acid A solution of [8-chloro-3- (4-chlorophenoxy) -2-methyl ester, 4-dimethylquinolin-5-yloxy] acetic acid (0.20 g), methanol (5.0 mL), water (1.0 mL) and 5.0 M aqueous sodium hydroxide solution (1.0 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 1 by the addition of 0.1 M hydrochloric acid and the methanol was removed under reduced pressure. The residue was purified by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water (40% to 98% organic modifier) to give the title compound as a yellow-green solid, 0.025 g. XH NMR (DMSO-d6): d 2.45 (s, 3H), 2.70 (s, 3H), 3.55 (s, 2H), 4.85 (s, 2H), 6.85 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.6 Hz, HH), 7.35 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 8.6 Hz HH), 13.15 (br s, HH). MS: ESI (+ ve) (Method A): 392 (M + H) \ Retention time 12.3 min. Example 8: [8-chloro-3-4-chlorophenylsulfane] -2,4-dimethylquinolin-5-yloxy] acetic acid Preparation 8a: 8-chloro-3- (4-chlorophenylsulfañil) -2,4-dimethylquinolin-5- ol A mixture of 3-amino-4-chlorophenol (0.36 g), 3- (4-chlorophenylsulfa il) pentane-2,4-dione (0.61 g) and p-toluenesulfonic acid monohydrate (0.040 g) was heated to 140 ° C for 10 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 0: 1 by volume) to give the title compound as an oil. coffee, 0.050 g MS: ESI (-ve) (Method B): 348 (MH) ", Retention time 4.4 min Preparation 8b: methyl ester of acid [8-chloro-3- (4-chlorophenylsulphanyl) -2,4-dimethylquinoline- 5-yloxy] acetic acid A mixture of 8-chloro-3- (4-chlorophenylsulfane) -2, -dimethylquinolin-5-ol (0.050 g), N, N-dimethylformamide (2.0 mL), potassium carbonate (0.059 g) and bromoacetic acid methyl ester (0.031 g) was stirred at room temperature for 15 hours.The mixture was diluted with dichloromethane and this solution was washed with water and then dried over magnesium sulfate.The solvent was removed under reduced pressure to provide the title compound as a brown solid, 0.11 g MS: ESI (+ ve) (Method B): 422 (MH-H) +, Retention time 4. 8 min. Preparation 8c: [8-chloro-3- (4-chlorophenylsulphanyl) -2,4-dimethylquinolin-5-yloxy] acetic acid A solution of [8-chloro-3- (4-chlorophenylsulfanyl) -2) methyl ester, 4-dimethylquinolin-5-yloxy] acetic acid (0.11 g), methanol (5.0 mL), water (1.0 mL) and 5.0 M aqueous sodium hydroxide solution (0.5 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 1 by the addition of aqueous hydrochloric acid 1. 0 M. The resulting mixture was purified by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water (30% to 90% organic modifier) to give the title compound as a white solid, 0.045 g. 1 H NMR (DMSO-d 6): d 2.70 (s, 3 H), 3.15 (s, 3 H), 5.35 (s, 2 H), 6. 85 (d, J = 8.5 Hz, HH), 7.00 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, HH). MS: ESI (+ ve) (Method A): 408 (M + H) +, Retention time 13. 1 min. Example 9: [8-chloro-3- (4-chlorobenzyl) -4-difluoromethoxy-2-methylquinolin-5-yloxy] acetic acid Preparation 9a: [8-chloro-3- (4-chlorobenzyl) methyl ester] -4-difluoromethoxy-2-methylquinolin-5-yloxy] acetic acid To a mixture of methyl ester of acid [8-chloro-3- (4-chlorobenzyl) -2-methyl-4-oxo-l, 4-dihydroquinoline-5 -alloxy] acetic acid (0.080 g), N, N-dimethylformamide (2.0 mL) and potassium carbonate (0.080 g) at -80 ° C was added chlorodifluoromethane (0.4 mL). The flask was sealed and the resulting mixture was warmed to room temperature and then stirred at this temperature for 17 hours. Excess chlorodifluoromethane was allowed to evaporate and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound as a light brown solid, 0.10 g. MS: ESI (+ ve) (Method B): 456 (M + H) +, Retention time 4.3 min. Example 9b: [8-chloro-3- (4-chlorobenzyl) -4-difluoromethoxy-2-methylquinolin-5-yloxy] acetic acid A solution of [8-chloro-3- (4-chlorobenzyl) - methyl acid ester 4-difluoromethoxy-2-methylquinolin-5-yloxy] -acetic acid (0.10 g), methanol (6.0 mL), water (0.6 mL) and saturated aqueous solution of lithium hydroxide (0.3 mL) was stirred at room temperature for 17 hours. The methanol was removed under reduced pressure and the pH of the residue was adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and washed with water. Purification of the solid by preparative reverse phase HPLC using a gradient for 37 minutes of acetonitrile in water (20% to 95% organic modifier) gave the title compound as a cream solid, 0.020 g. ? ti NMR (DMSO-Ó6): d 2.55 (s, 3H), 4.30 (s, 2H), 4.95 (s, 2H), 7.05 (d, J = 8.7 Hz, ÍH), 7.10 (d, J = 8.5 Hz, 2H), 7.25 (t, J = 75 Hz, ÍH), 7.35 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.7 Hz, ÍH), 13.50 (br s, ÍH). MS: ESI (+ ve) (Method A): 442 (M + H) 0 Retention time 12.5 min. MS: ESI (+ ve) (Method B): 442 (M + H) 0 Retention time 3.9 min. Example 10: [8-chloro-3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid Preparation 10a: [4,8-dichloro-3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid methyl ester A solution of methyl acid acid [8-chloro-3- (4-chlorobenzyl)] -2-methyl-4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid (0.13 g) in phosphorus oxychloride (5.0 mL) was heated at 180 ° C in a microwave reactor for 15 minutes. The mixture was emptied on ice and the pH of the solution was adjusted to 3 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound as a beige solid, 0.12 g. Preparation 10b: [8-chloro-3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid methyl ester A mixture of [4,8-dichloro-3- (4-chlorobenzyl) methyl ester) -2-methylquinolin-5-yloxy] acetic acid (0.12 g), palladium, 5% by weight on activated carbon (0.010 g), ethanol and 1.0 M aqueous hydrochloric acid (1.0 mL) was stirred at room temperature for 17 hours, bathing an atmosphere of hydrogen. The mixture was filtered through hyflo, washed with ethanol and water and the solvent was removed under reduced pressure to give the title compound, 0.11 g. Preparation 10c: [8-chloro-3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid A solution of methyl ester of acid [8-chloro-3- (4-chlorobenzyl) -2- methanol (5-10%), acetic acid (0.10 g), ethanol (6.0 mL), water (2.0 mL) and saturated aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 5 hours. The ethanol was removed under reduced pressure and the pH of the residue was adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and purification by preparative reverse phase HPLC using a gradient for 37 minutes of acetonitrile in water (20% to 95% organic modifier) gave the title compound as a solid whitish, 0.039 mg. 01 NMR (DMSO-d6): d 2.60 (s, 3H), 4.25 (s, 2H), 4.90 (s, 2H), 6.90 (d, J = 8.6 Hz, ÍH), 7.20 (d, J = 8.6 Hz , 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.6 Hz, ÍH), 8.30 (s, ÍH), 13.15 (br s, ÍH). MS: ESI (+ ve) (Method A): 376 (M + H) +, Retention time 11.3 mm. MS: ESI (+ ve) (Method B): 376 (M + H) +, Retention time 3.6 min. Example 11: [7-chloro-3- (4-chlorobenzyl) -2,4-dimethyl-quinolin-5-yl] acetic acid Preparation lia: 7-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-ol A mixture of 3-amino-5-chlorophenol (0.46 g), 3- (4-chlorobenzyl) pentane-2, 4-dione (0.72 g) and p-toluenesulfonic acid monohydrate (0.26 g) was heated at 160 ° C for 2 hours. The mixture was cooled to room temperature, diluted with methanol (5.0 mL) and sonicated. The resulting precipitate was collected by filtration, washed with methanol and dried to provide a 50:50 mixture of the title compound and 5-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-7-ol as a whitish solid, 0.67 g. MS: ESI (+ ve) (Method B): 332 (M + H) 0 Retention time 2.4 min. Preparation 11b: 7-Chloro-3- (4-chlorobenzyl) -2,4-dimethylquinoline-5-yl ester of trifluoromethanesulfonic acid A mixture of 7-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinoline-5 -ol and 5-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-7-ol (0.66 g), N-phenyltrifluoromethanesulfonimide (0.86 g), potassium carbonate (0.82 g) and tetrahydrofuran (10 mL) it was heated by microwave irradiation at 130 ° C for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with 1,2-dichloroethane gave a 50:50 mixture of the title compound and 5-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinoline ester Of trifluoromethanesulfonic acid as a honey-colored gum, 0.86 g. MS: ESI (+ ve) (Method B): 464 (M + H) +, Retention time 4.9 min. Preparation 11c: [7-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yl] acetic acid methyl ester A mixture of 7-chloro-3- (4-chlorobenzyl) -2- -dimethylquinoline-5-yl and trifluoromethanesulfonic acid 5-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinoline-7-yl ester (0.86 g), tert-butyl- (1-methoxyvinyloxy) -dimethyl silane (2.0 mL), sodium acetate (0.18 g), bis (dibenzylideneacetone) palladium (0.05 g) and 1,1 '-bis (diphenylphosphino) ferrocene (0) (0.05 g) in N, N-dimethyl formamide (11.0 mL) was heated by microwave irradiation at 120 ° C for 15 minutes. The mixture was diluted with ethyl acetate and this solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and pentane (4: 0: 1 to 1: 0: 0 to 50). : 1: 0 to 25: 1: 0 to 12.5: 1: 0 by volume) gave the title compound as a honey-colored gum, 0.25 g.

XH NMR (DMS0-d6): d 2.50 (s, 3H), 2.55 (s, 3H), 3.60 (s, 3H), 4.25 (s, 2H), 4.40 (s, 2H), 7.00 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 2.4 Hz, ÍH), 7.90 (d, J = 2.4 Hz, ÍH). MS: ESI (+ ve) (Method B): 388 (M + H) +, Retention time 3.2 min. Preparation lid: acid [7-chloro-3- (4-chlorobenzyl) -2,4-d? Met? Lmol? N-5-? L] acetic acid A mixture of methyl ester of acid [7-chloro-3] - (4-chlorobenzyl) -2,4-d? Met? Lmol? N-5-? L acetic acid (0.24 g), methanol (10 mL), water (2.0 mL) and aqueous lithium hydroxide solution , saturated (1.0 mL) was stirred at room temperature for 17 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol was removed under reduced pressure. The resulting precipitate was collected by filtration and washed with water. Crystallization of the ethyl acetate solid gave the title compound as a fluffy white solid, 0.16 g X NMR (DMS0-d6): d 2.45 (s, 3H), 2.70 (s, 3H), 3.75 (s, 2H) , 4.15 (s, 2H), 7.00 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 2.4 Hz, ÍH), 7.35 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 2.4 Hz, ÍH). MS: ESI (+ ve) (Method A): 374 (M + H) +, Retention time 7.8 mm. MS: ESI (+ ve) (Method B): 374 (M + H) 0 Retention time 2.6 mm.

Example 12: [8-chloro-3- (4-chlorophenylsulphanyl) -2,4-dimethylquinolin-5-yl] acetic acid Preparation 12a: 8-chloro-3- (4-chlorophenylsulfane) -2,4-dimethylquinolin-5-ol A mixture of 3-amino-4-chlorophenol (5.0 g), 3- (4-chlorophenylsulfane) pentane-2, 4-dione (8.4 g), p-toluenesulfonic acid monohydrate (12 g) was heated at 140 ° C for 6 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 1: 1 by volume) to give the title compound as a solid. coffee, 1.3 g MS: ESI (+ ve) (Method B): 350 (M + H) +, Retention time 4.4 min. Preparation 12b: 8-chloro-3- (4-chlorophenylsulphanyl) -2,4-dimethylquinoline-5-yl ester of trifluoromethanesulfonic acid A mixture of 8-chloro-3- (4-chlorophenylsulphane) -2,4-dimethylquinoline-5 -ol (1.3 g), N-phenyltrifluoromethanesulfonimide (1.7 g), potassium carbonate (1.6 g) and tetrahydrofuran (10 mL) was heated by microwave irradiation at 120 ° C for 20 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (9: 1 to 0: 1 by volume) gave the title compound, 0.27 g. MS: ESI (+ ve) (Method B): 482 (M + H) 0 Retention time 5.1 min. Preparation 12c: [8-Chloro-3- (-chlorophenylsulphanyl) -2,4-dimethylquinolin-5-yl] acetic acid methyl ester A mixture of 8-chloro-3- (4-chlorophenylsulphanyl) ester -2, 4- dimethylquinoline-5-yl of trifluoromethanesulfonic acid (0.31 g), tert-butyl- (1-methoxyvinyloxy) dimethyl silane (0.71 mL), sodium acetate (0.064 g), bis (dibenzylidene ketone) palladium (0.018 g) and 1,1'-bis (diphenylphosphino) ferrocene (0) (0.018 g) in N, N-dimethylformamide (4.0 mL) was heated by microwave irradiation at 120 ° C for 15 minutes. The mixture was diluted with ethyl acetate and this solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. 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 cyclohexane (1: 1 to 2: 0 by volume) gave the title compound as a yellow solid. pale, 0.15 g.

XH NMR (DMS0-d6): d 2.75, (s, 3H), 2.90 (s, 3H), 3.60, (s, 3H), 4.40 (s, 2H), 7.00 (d, J = 8.7 Hz, 2H ), 7.35 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 7.7 Hz, ÍH), 7.95 (d, J = 7.7 Hz, ÍH). MS: ESI (+ ve) (Method B): 406 (M + H) +, Retention time 4.5 min. Preparation 12d: [8-chloro-3- (4-chlorophenylsulphanyl) -2,4-dimethylquinolin-5-yl] acetic acid A mixture of [8-chloro-3- (4-chlorophenylsulfanyl) -2-methyl ester, 4-dimethylquinolin-5-yl] acetic acid (0.040 g), methanol (2.0 mL), water (0.4 mL) and saturated aqueous lithium hydroxide solution (0.2 mL) was stirred at room temperature for 17 hours. The solvent was removed under reduced pressure and the residue was diluted with water (2.0 mL) and then the pH was adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and dried to provide the title compound as a gray-brown solid, 0.038 g. XH NMR (DMSO-d6): d 2.70 (s, 3H), 3.00 (s, 3H), 4.15 (s, 2H), 7.00 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.6 Hzx 2H), 7.45 (d, J = 7.8 Hz, ÍH), 7.85 (d, J = 7.8 Hz, ÍH). MS: ESI (+ ve) (Method A): 392 (M + H) +, Retention time 12.4 min. MS: ESI (+ ve) (Method B): 392 (M + H) 0 Retention time 4.1 min.

Example 13: N-. { 2- [8-chloro-3- (4-chlorobenzyl) -2,4-d? Met? L? Nol? N-5-? Lox?] -acetyl} methanesulfonamide Preparation 13a: N-. { 2- [8-chloro-3- (4-chlorobenzyl) -2,4-d? Met? Lqu? N? -5? Lox?] Acetyl} methosulfonamide A mixture of acid [8-chloro-3- (4-chlorobenzyl) -2,4-d? met? lmol? n-5-? lox]] acetic acid (0.050 g), hydrochloride of 1- (3 -d? met? lamoprop?) -3-et? lcarbod ?? m? da (0.037 g), methanesulfonamide (0.020 g) and 4- (N, Nd? met? lammo) pyridm (0.005 g) in dichloromethane (5.0 mL) was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane and the solution was washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitop in water (40% to 95% organic modifier) gave the title compound as a yellow solid, 0.010 g XH? MR (DMSO-d6): d 2.60 (s, 3H), 2.80 (s, 3H), 3.30 (s, 3H), 4.30 (s, 2H), 4.90 (s, 2H), 6.85 (d, J = 8.8 Hz, ÍH), 7.05 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.8 Hz, ÍH), 12.15 (br s, ÍH ).

MS: ESI (+ ve) (Method A): 467 (M + H) +, Retention time 11.0 min. Example 14: N-. { 2- [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yloxy] -acetyl} benzenesulfonamide Preparation 14a: N-. { 2- [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yloxy] acetyl} benzenesulfonamide A mixture of [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yloxy] acetic acid (0.050 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.037) g), benzenesulfonamide (0.030 g) and 4- (N / N-dimethylamino) pyridine (0.005 g) in dichloromethane (5.0 mL) was stirred at room temperature for 1 hour. The mixture was purified by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (1:19 by volume), after trituration with cyclohexane containing a small amount of diethyl ether to give the title compound as a solid suede color, 0.020 g. XH? MR (DMSO-d6): d 2.55 (s, 3H), 2.70 (s, 3H), 4.25 (s, 2H), 4.80 (s, 2H), 6.70 (d, J = 8.6 Hz, ÍH), 7.00 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.60-7.70 (m, 4H), 7.90 (d, J = 8.6 Hz, 2H), 12.55 (br s, ÍH). 70 Preparation 15b: [8-chloro-3- (4-chlorophenoxy) -2,4-d? Met? L? Nolm-5-? Lox?] Acetic acid methyl ester A mixture of 8-chloro-3- ( 4-chlorophenoxy) -2,4-d? Met? L? Mol? N-5-l? T of tnfluoromethanesulfonic acid (0.20 g), tert-butyl- (1-methox? V? N? Lox?) Dimethyl silane (0.40 g), sodium acetate (0.044 g), tris (dibenzylidene ketone) dipalladium (0.020 g) and 1,1 '-bis (diphenylphosphino) ferrocene (0) (0.012 g) in N, N-d-meth lformamide (5.0 mL) was heated by microwave irradiation at 120 ° C for 15 minutes. The mixture was purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (9: 1 to 0: 1 by volume) to give the title compound as a yellow solid, 0.034 g. MS: ESI (+ ve) (Method B): 390 (MH-H) +, Retention time 4.4 in. Preparation 15c: [8-chloro-3- (4-chlorophenoxy?) -2,4-d? Met? Lmol? N-5-? L] acetic acid A mixture of methyl ester of [8-chloro- 3- (4-chlorophenoxy) -2,4-d? Met? L? Nolm-5-? Lox?] Acetic acid (0.035 g), methanol (5.0 mL) and 5.0 M aqueous sodium hydroxide solution (0.36 mL) it was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient for 30 minutes of MS: ESI (+ ve) (Method A): 529 (M + H) +, Retention time 12.4 min. Example 15: [8-chloro-3- (4-chlorophenoxy) -2,4-dimethylquinolin-5-yl] acetic acid Preparation 15a: 8-chloro-3- (4-chlorophenoxy) -2,4-dimethylquinoline-5-yl ester of trifluoromethanesulfonic acid A mixture of 8-chloro-3- (4-chlorophenoxy) -2,4-dimethylquinoline-5 -ol (0.50 g), N-phenyltrifluoromethanesulfonimide (0.68 g), potassium carbonate (0.62 g) and tetrahydrofuran (3.0 mL) was heated by microwave irradiation at 120 ° C for 20 minutes. The mixture was diluted with dichloromethane and this solution was washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1: 9 by volume) to give the title compound as a yellow solid, 0.36 g. MS: ESI (+ ve) (Method B): 466 (M + H) +, Retention time 5.1 min. acetonitrile in water (30% to 95% organic modifier) to provide the title compound as a white solid, 0. 0050 g. ? H NMR (DMSO-d6): d 2.45 (s, 3H), 2.55 (s, 3H), 4.25 (s, 2H), 6.85 (d, J = 9.1 Hz, 2H), 7.35 (d, J = 9.1 Hz, 2H), 7.45 (d, J = 7.8 Hz, ÍH), 7.85 (d, J = 7.8 Hz, ÍH). MS: ESI (+ ve) (Method A): 376 (M + H) 0 Retention time 11. 6 min MS: ESI (+ ve) (Method B): 376 (M + H) +, Retention time 4.0 min. Example 16 and 17: [8-chloro-3- (4-chlorobenzyl) -4-ethyl-2-methylquinolin-5-yloxy] acetic acid and [8-chloro-3- (4-chlorobenzyl) -2-ethyl] acid -4-methylquinolin-5-yloxy] acetic acid Preparation 16a: 3- (4-chlorobenzyl) hexane-2,4-dione A solution of hexane-2,4-dione (5.7 g) in N, N-dimethylformamide (20 mL) was added dropwise over a period of 15 minutes at a stirred suspension of sodium hydride (60% in oil, 2.2 g) in N, N-dimethylformamide (60 mL) at -5 ° C. The mixture was stirred at room temperature for 30 minutes and then a solution of l-bromomethyl-4-chlorobenzene (11 g) in N, N-dimethylformamide (20 mL) was added dropwise over a period of 20 minutes. The resulting mixture was stirred at room temperature for 17 hours and then diluted with 1.0 M aqueous hydrochloric acid (100 mL). The mixture was extracted with diethyl ether and the combined extracts were washed with 1.0 M aqueous hydrochloric acid and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and toluene (1: 1 to 1: 2 to 0: 1 by volume) gave the title compound (55:45 mixture of keto-enol tautomers) as a white solid, 2.6 g. XH NMR (CDC13): d 1.00 (t, J = 7.3 Hz, 3H), 1.05 (t, J = 7.3 Hz, 3H), 2.05 (s, 3H), 2.15 (s, 3H), 2.25-2.50 (m , 4H), 3.05-3.25 (M, 2H), 3.65 (s, 2H), 3.95 (t, J = 7.5 Hz, ÍH), 7.05-7.10 (m, 4H), 7.20-7.30 (m, 4H). Preparation 16b and 17a: 8-chloro-3- (4-chlorobenzyl) -4-ethyl-2-methylquinolin-5-ol and 8-chloro-3- (4-chlorobenzyl) -2-ethyl-4-methylquinolin-5 -ol A mixture of 3-amino-4-chlorophenol (0.72 g), 3- (4-chlorobenzyl) hexane-2,4-dione (1.2 g) and p-toluenesulfonic acid monohydrate (0.10 g) was heated to 160 ° C for 1.5 hours. The mixture was cooled to room temperature and then purified by column chromatography on silica gel, eluting with a mixture of toluene and dichloromethane (2: 1 to 3: 2 to 1: 1 to 2: 3 to 1: 2 to 1: 4 to 0: 1 by volume) to provide the title compounds, 0.25 g. MS: ESI (+ ve) (Method B): 346 (M + H) +, Retention time 3.6 and 3.9 min. Preparation 16c and 17b: [8-chloro-3- (4-chlorobenzyl) -4-ethyl-2-methylquinolin-5-yloxy] acetic acid methyl ester and [8-chloro-3- (4- chlorobenzyl) -2-ethyl-4-methylquinolin-5-yloxy] acetic acid A mixture of 8-chloro-3- (4-chlorobenzyl) -4-ethyl-2-methylquinolin-5-ol and 8-chloro-3- ( 4-chlorobenzyl) -2-ethyl-4-methylquinolin-5-ol (0.25 g), N, N-dimethylformamide (4.0 mL), potassium carbonate (0.12 g) and bromoacetic acid methyl ester (0.12 g) was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compounds as a honey-colored semi-solid, 0.26 g. MS: ESI (+ ve) (Method B): 418 (MH-H) +, Retention time 4.5 and 4.8 min. Preparation 16d and 17c: [8-chloro-3- (4-chlorobenzyl) -4-ethyl-2-methylquinolin-5-yloxy] acetic acid and [8-chloro-3- (4-chlorobenzyl) -2-ethyl] -4-Methylquinolin-5-yloxy] acetic acid A solution of methyl ester of acid [8-chloro-3- (4-chlorobenzyl) -4-et? L-2-met? L? Nolm-5-? Lox ?] acetic acid methyl ester [8-chloro-3- (4-chlorobenzyl) -2-et? l-4-met? lmol? n-5-? lox]] acetic acid (0.26 g), methanol (15 mL), water (1.5 mL) and aqueous lithium hydroxide solution, saturated (1.5 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the methanol was removed under reduced pressure. The resulting precipitate was collected by filtration and purified by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water (40% to 98% organic modifier) to provide acid [8-chloro-3- (4- chlorobenzyl) -4- et? l-2-met? lmol? n-5-? lox?] acetic acid as a yellow foam, 0.049 g and acid [8-chloro-3- (4-chlorobenzyl) -2-et? L-4-met? L? Nolm-5-? Lox?] Acetic as a yellow foam, 0.10 g. Acid [8-chloro-3- (4-chlorobenzyl) -4-et? L-2-met? Lm? N-5-yloxy] acetic XH NMR (DMS0-d6): d 1.15 (t, J = 7.3 Hz, 3H), 2.55 (s, 3H), 3.55 (m, 2H), 4.30 (s, 2H), 4.90 (s, 2H), 6.95 (d, J = 8.6 Hz, ÍH), 7.05 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.6 Hz, ÍH), 13.05 (br s, ÍH). MS: ESI (+ ve) (Method A): 404 (M + H) +, Retention time 11.7 min. Acid [8-chloro-3- (4-chlorobenzyl) -2-et? L-4-met? L? Nolm-5-yloxy] acetic XH NMR (DMS0-d6): d 1.25 (t, J = 7.4 Hz, 3H), 2.80 (s, 3H), 2.90 (q, J = 7.4 Hz, 2H), 4.30 (s, 2H), 4.85 (s, 2H), 6.90 (d, J = 8.5 Hz, ÍH) , 7.05 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, ÍH). MS: ESI (+ ve) (Method A): 404 (M + H) +, Retention time 12.6 min. Example 18 and 19: [8-chloro-4-difluoromethoxy-3- (4-fluorobenzyl) -2-methylquinolin-5-yloxy] acetic acid and [8-chloro-2-difluoromethoxy-3- (4-fluorobenzyl)] acid -4-methylquinolin-5-yloxy] acetic acid Preparation 18a: 2- (4-fluorobenzyl) -3-oxobutyric acid ethyl ester A suspension of potassium tert-butoxide (11.2 g) in anhydrous tetrahydrofuran (200 mL) at 0 ° C was treated with a mixture of tert-butanol (0.2 mL) and 3-oxobutyric acid ethyl ester (12.7 mL). The mixture was heated at 15 ° C over a period of 40 minutes and a solution of l-chloromethyl-4-fluorobenzene (11.9 mL) in tetrahydrofuran (40 mL) was added and the resulting mixture was heated at 70 ° C for 20 hours. . The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by distillation under reduced pressure (boiling point, 102-104 ° C at 0.42 mbar) to afford the title compound as a colorless oil, 12.4 g. H NMR (CDC13): d 1.20 (t, J = 7.2 Hz, 3H), 2.20 (s, 3H), 3.15 (m, 2H), 3.75 (t, J = 7.6 Hz, ÍH), 4.15 (m, 2H ), 6.95-7.00 (m, 2H), 7.10-7.15 (m, 2H). Preparation 18b and 19b: [8-chloro-3- (4-fluorobenzyl) -2-methyl-1-4-oxo-1,4-dihydroquinolin-5-yloxy] -acetic acid methyl ester and [8-] methyl ester of acid chloro-3- (4-fluorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -acetic acid A mixture of (3-amino-4-chlorophenoxy) acetic acid methyl ester (1.3 g) ), 2- (4-fluorobenzyl) -3-oxobutyric acid ethyl ester (7.4 g), polyphosphoric acid (15 g) and dioxane (8.0 mL) was heated at 112 ° C for 5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19: 1 by volume) to provide the title compounds, 0.39 g. XH NMR (CDC13): 52.75 (s, 6H), 3.80 (s, 3H), 3.85 (s, 3H), 4.05 (s, 2H), 4.15 (s, 2H), 4.70 (s, 2H), 4.85 ( s, 2H), 6.50-7.55 (m, 12), 9.00 (br s, ÍH), 9.10 (br s, ÍH). Preparation 18c and 19c: [8-chloro-4-difluoromethoxy-3- (4-fluorobenzyl) -2-methylquinolin-5-yloxy] -acetic acid methyl ester and [8-chloro-2-difluoromethoxy3-] methyl ester (4-fluorobenzyl) -4-methylquinolin-5-yloxy] acetic acid A mixture of [8-chloro-3- (4-fluorobenzyl) -2-methyl-4-oxo-l, 4-dihydroquinoline-5-methyl ester. -alloxy] -acetic acid methyl ester [8-chloro-3- (4-fluorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -acetic acid (0.39 g), N, N-dimethylformamide (70 mL), potassium carbonate (0.41 g) and chlorodifluoromethyl ester of acetic acid (0.22 mL) was stirred at 80 ° C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4: 1 by volume) to give the title compounds as a mixture, 0.26. g. XH? MR (CDCI3): d 2.65 (s, 3H), 2.95 (s, 3H), 3.80 (s, 3H)? 3.85 (s, 3H), 4.20 (s, 2H), 4.35 (S, 2H), 4.75 (s, 2H), 4.85 (s, 2H), 6.60-8.05 (m, 14H). Preparation 18d and 19d: [8-chloro-4-difluoromethoxy-3- (4-fluorobenzyl) -2-methylquinolin-5-yloxy] acetic acid and [8-chloro-2-difluoromethoxy-3- (-fluorobenzyl) acid] 4-Methylquinolin-5-yloxy] acetic acid A solution of [8-chloro-4-difluoromethoxy-3- (4-fluorobenzyl) -2-methylquinolin-5-yloxy] -acetic acid methyl ester and methyl ester of acid [8] -chloro-2-difluoromethoxy3 - (4-fluorobenzyl) -4-methylquinolin-5-yloxy] acetic acid (0.26 g), methanol (5.0 mL), water (3.0 mL) and lithium hydroxide solution (0.13 g mL) it was stirred at room temperature for 1 hour. The solution was acidified by the addition of hydrochloric acidit was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile - (in water to give acid [8-chloro-4-difluoromethoxy-3- (-fluorobenzyl) - 2-Methylquinolin-5-yloxy] acetic acid as a white solid, 0.032 g and [8-chloro-2-difluoromethoxy-3- (4-fluorobenzyl) -4-methylquinolin-5-yloxy] acetic acid as a white solid, 0.029 g Acid [8-Chloro-4-difluoromethoxy-3- (4-fluorobenzyl) -2-methylquinolin-5-yloxy] acetic acid? Ti NMR (DMS0-d6): d 2.55 (s, 3H), 4.30 (s, 2H ), 4.90 (s, 2H), 7. 05 (d, J = 8.6 Hz, ÍH), 7.05-7.15 (m, 4H), 7.25 (t, J = 75 Hz, ÍH), 7.85 (d, J = 8.6 Hz, ÍH), 13.50 (br s, ÍH). MS: ESI (+ ve) (Method A): 426 (M + H) +, Retention time 11.6 min. [8-Chloro-2-difluoromethoxy-3- (4-fluorobenzyl) -4-methylquinolin-5-yloxy] acetic acid H NMR (DMSO-d6): d 2.90 (s, 3H), 4.20 (s, 2H), 4.85 (s, 2H), 7. 00 (d, J = 8.7 Hz, ÍH), 7.00-7.25 (m, 4H), 7.80 (d, J = 8.7 Hz, ÍH), 7.90 (t, J = 72 Hz, ÍH), 13.20 (br s, ÍH). MS: ESI (+ ve) (Method A): 426 (M + H) +, Retention time 12. 6 min Example 20: [8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinolin-5-yloxy] acetic acid Preparation 20a: 3- (4-methanesulfonylbenzyl) pentane-2,4-dione A solution of pentane-2,4-dione (4.4 g) in N, N-dimethylformamide (10 mL) was added dropwise over a period of 15 minutes to a stirred suspension of sodium hydride (60% in oil, 1.7 g) in N, N-dimethylformamide (50 mL) at -5 ° C. The mixture was heated at room temperature for 20 minutes and a solution of l-bromomethyl-4-methanesulfonylbenzene (10 g) in N, N-dimethylformamide (20 mL) was added dropwise over a period of 10 minutes. The resulting mixture was stirred at room temperature for 17 hours and then diluted with 1.0 M aqueous hydrochloric acid (100 mL). The resulting mixture was extracted with a mixture of diethyl ether and ethyl acetate (1: 1 by volume) and the combined extracts were washed with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (2: 1 to 1: 2 by volume) gave the title compound as a colorless gum, 3.7 g. XH? MR (CDC13): d 2.05 (s, 6H), 2.15 (s, 6H), 3.00 (s, 3H), 3.05 (s, 3H), 3.25 (d, J = 7.3 Hz, 2H), 3.75 ( s, 2H), 4.00 (t, J = 7.3 Hz, ÍH), 7.35-7.40 (m, 4H), 7.85-7.90 (m, 4H). Preparation 20b: 8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinolin-5-ol A mixture of 3-amino-4-chlorophenol (0.36 g), 3- (4-methanesulfonylbenzyl) pentane-2, 4-dione (0.5 g) and p-toluenesulfonic acid monohydrate (0.05 g) was heated at 160 ° C for 2.5 hours. The mixture was cooled to room temperature and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (50: 1 to 2: 1 by volume) to provide the title compound (mixture 7). : 10 of keto-enol tautomers) as a beige solid, 0.32 g. MS: ESI (+ ve) (Method B): 376 (M + H) +, Retention time 2.5 min. Preparation 20c: [8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinolin-5-yloxy] acetic acid methyl ester A mixture of 8-chloro-3- (4-methanesulfonylbenzyl) -2,4- dimethylquinolin-5-ol (0.31 g), N, N-dimethylformamide (5.0 mL), potassium carbonate (0.46 g) and bromoacetic acid methyl ester (0.35 g) was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate and this solution was washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1: 1: 0 to 0: 1: 0 and 0: 1). : 1 in volume) gave the title compound as a white solid, 0.20 g. XH? MR (DMSO-dd): d 2.60 (s, 3H), 2.80 (s, 3H), 3.20 (s, 3H), 3.70 (s, 3H), 4.45 (s, 2H), 5.00 (s, 2H) ), 6.95 (d, J = 8.7 Hz, ÍH), 7.30 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.7 Hz, HH), 7.85 (d, J = 8.3 Hz, 2H). MS: ESI (+ ve) (Method B): 448 (M + H) 0 Retention time 3.4 min. Preparation 20d: [8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinolin-5-yloxy] acetic acid A solution of [8-chloro-3- (4-methanesulfonylbenzyl) -2] methyl ester, 4-dimethylquinolin-5-yloxy] -acetic (0.11 g), methanol (5.0 mL)water (1.0 mL) and saturated aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 3 days. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the methanol was removed under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a white solid, 0.08 g. XH NMR (DMSO-d6): d 2.60 (s, 3H), 2.85 (s, 3H), 3.-15 (s, 3H), 4.30 (s, 2H), 4.40 (s, 2H), 6.75 (d , J = 8.5 Hz, ÍH), 7.30 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.5 Hz, ÍH), 7.85 (d, J = 8. 3 Hz, 2H). MS: ESI (+ ve) (Method A): 434 (M + H) +, Retention time 8.1 min. MS: ESI (+ ve) (Method B): 434 (M + H) +, Retention time 2.8 min. Example 21: [8-chloro-3- (4-chlorobenzenesulfonyl) -2,4-dimethylquinolin-5-yloxy] acetic acid Preparation 21a: 8-chloro-3- (4-chlorophenylsulfañyl) -2,4-dimethylquinolin-5 -ol A mixture of 3-amino-4-chlorophenol (5.0 g), 3- (4-chlorophenylsulfane) pentane-2,4-dione (8.4 g), p-toluenesulfonic acid monohydrate (3.20 g) and toluene (150 g) mL) was heated to reflux for 2 days. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. 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 cyclohexane (1: 9 by volume) gave the title compound as a pale yellow solid, 0.99 g . 1 H NMR (DMSO-d 6): d 2.70 (s, 3 H), 3.05 (s, 3 H), 6.95 (d, J = 8.4 Hz, H H), 7.00 (d, J = 8.4 Hz, 2 H), 7.35 (d , J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, ÍH). MS: ESI (+ ve) (Method B): 350 (M + H) +, Retention time 4.5 min. Preparation 21b: [8-chloro-3- (4-chlorophenylsulphanyl) -2,4-dimethylquinolin-5-yloxy] acetic acid methyl ester A mixture of 8-chloro-3- (4-chlorophenylsulfañyl) -2, 4- dimethylquinolin-5-ol (0.99 g), N, N-dimethylformamide (40 mL), potassium carbonate (0.60 g) and methyl bromoacetic acid ester (0.32 mL) was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was diluted with water and this mixture was extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 9 by volume) gave the title compound as a white solid, 0.26. g. XH? MR (CDC13): d 2.85 (s, 3H), 3.20 (s, 3H), 3.80 (s, 3H), 4.76 (s, 2H), 6.70 (d, J = 8.4 Hz, ÍH), 6.90 (s) d, J = 8.9 Hz, 2H), 7.15 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 8.4 Hz, ÍH). MS: ESI (+ ve) (Method B): 421 (M + H) 0 Retention time 4.2 min. Preparation 21c: [8-Chloro-3- (4-chlorobenzenesulfonyl) -2,4-dimethylquinolin-5-yloxy] acetic acid methyl ester and [8-chloro-3- (4-chlorobenzenesulfinyl) -2-methyl ester] , 4-dimethylquinolin-5-yloxy] acetic acid A mixture of [8-chloro-3- (4-chlorophenylsulphane I) -2,4-d? Met? L? Nolm-5-? Lox?] Acetic acid methyl ester (0.050 g), 3-chloroperox-benzoic acid (0.040 g) and chloroform were stirred at room temperature for 2 hours. After evaporation of the solvents the mixture was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99: 1 by volume) to give methyl ester of acid [8-chloro-3- ( 4-chlorobenzenesulfon? L) -2,4-d? Met? Lol? Nolm-5? Lox?] Acetic acid as a white solid, 0.020 g and methyl acid ester [8-chloro-3- (4-chlorobenzenesulfonyl) - 2, 4-d? Met? Lol? Nolm-5-? Lox?] -acetic as a cream solid, 0.056 g. Methyl ester of acid [8-chloro-3- (4-chlorobenzenesulfonyl) -2,4-d? Met? L? Nolm-5? Lox?] Acetic acid MS: ESI (+ ve) (Method B): 454 ( M + H) +, Retention time 4.3 mm. Methyl ester of acid [8-chloro-3- (4-clbrobenzenesulf il) -2,4-d? Met? Lqumolm-5-? Lox] acetic acid MS: ESI (+ ve) (Method B): 438 (M + H) +, Retention time 4.1 min. Preparation 21d: [8-chloro-3- (4-chlorobenzenesulfon? L) -2,4-d? Met? Lmolmol-5? Lox?] Acetic acid A solution of methyl ester of acid [8-chloro-3-] (4-chlorobenzenesulfonyl) -2,4-d? Met? Lmolmol-5? Lox?] Acetic acid (0.020 g), methanol (3.0 mL) and 0.1 M aqueous sodium hydroxide solution (0.22 mL) was stirred at room temperature environment for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water gave the title compound as a pale yellow solid., 0.0025 g. XH NMR "(DMSO-d6): d 3.00 (s, 3H), 3.10 (s, 3H), 4.65 (s, 2H), 6.90 (d, J = 8.9 Hz, ÍH), 7.60 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.9 Hz, ÍH), 7.85 (d, J = 8.5 Hz, 2H), 8.25 (br s, ÍH) MS: ESI (+ ve) (Method A): 440 (M + H) +, Retention time 11.4 min Example 22: [8-chloro-3- (4-chlorobenzenesulfinyl) -2,4-dimethylquinolin-5-yloxy] acetic acid Preparation 22a: [8-chloro-3- (4-chlorobenzenesulfinyl) -2,4-dimethylquinolin-5-yloxy] acetic acid A mixture of [8-chloro-3- (4-chlorobenzenesulfinyl) -2-methyl acid ester, 4-Dimethylquinolin-5-yloxy] acetic acid (0.050 g), methanol (3.0 mL) and 0.1 M aqueous sodium hydroxide solution (0.57 mL) was stirred at room temperature for 3 hours. The pH of the mixture was adjusted to 5 by the addition of formic acid and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water gave the title compound as a pale yellow solid, 0.029 g. XH NMR (DMSO-d6): d 2.65 (s, 3H), 3.30 (s, 3H), 4.85 (s, 2H), 7.00 (d, J = 8.7 Hz, ÍH), 7.50 (d, J = 8.3 Hz , 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H). MS: ESI (+ ve) (Method A): 424 (M + H) 0 Retention time 10.6 min. Example 23: 8-chloro-3- (4-chlorobenzyl) -2,4-dimethyl-5- (1H-tetrazol-5-ylmethoxy) quinoline Preparation 23a: [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yloxy] acetonitrile A mixture of 8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5- ol (0.80 g), N, N-dimethyl formamide (10 mL), potassium carbonate (1.0 g) and bromoacetonitrile (0.25 mL) was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and this mixture was washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound as a light brown solid, 0.90 g. XH NMR (DMSO-d6): d 2.60 (s, 3H), 2.75 (s, 3H), 4.30 (s, 2H), 5.35 (s, 2H), 7.05 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.7 Hz, ÍH), 7.35 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 8.7 Hz, ÍH). MS: ESI (+ ve) (Method B): 371 (M + H) 0 Retention time 4.3 min. Preparation 23b: 8-chloro-3- (4-chlorobenzyl) -2,4-dimethyl-5- (1H-tetrazol-5-ylmethoxy) quinoline A mixture of [8-chloro-3- (4-chlorobenzyl) -2 , 4-dimethylquinolin-5-yloxy] acetonitrile (0.10 g), sodium azide (0.026 g), ammonium chloride (0.022 g) and N, N-dimethylformamide (1.5 mL) was heated by microwave irradiation at 100 ° C for 45 minutes. The mixture was diluted with ethyl acetate (20 mL) and saturated aqueous sodium chloride solution (20 mL). The resulting precipitate was collected by filtration, washed with water and ethyl acetate and dried to give the title compound as a white solid, 0.14 g. XH? MR (DMSO-d6): d 2.55 (s, 3H), 2.70 (s, 3H), 4.25 (s, 2H), 5.30 (s, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, ÍH), 7.35 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, ÍH). MS: ESI (+ ve) (Method B): 414 (M + H) +, Retention time 11.0 min.

Example 24: [8-chloro-3- (4-chlorophenylsulphanyl) -4-difluoromethoxy-2-methyl-quinolin-5-yloxy] acetic acid Preparation 24a: 2- (4-chlorophenylsulfanyl) -3-oxobutyric acid methyl ester To a solution of 2-chloro-3-oxobutyric acid methyl ester (3.5 g) and 4-chlorobenzothiol (4.1 g) in dichloromethane (60 mL ) at 0 ° C triethylamine (4.0 mL) was added. The mixture was warmed to room temperature and then stirred at this temperature for 3 days. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 4 by volume) to give the title compound as a waxy solid, 7.2 g. H NMR (CDC13): d 2.35 (s, 3H), 3.75 (s, 3H), 7.05 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H). Preparation 24b: [8-chloro-3- (4-chlorophenylsulfanyl) -2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy] acetic acid methyl ester A mixture of 3-amino acid methyl ester -4-chlorophenoxy) acetic (2.1 g), 2- (4-chlorophenylsulphanyl) -3-oxobutyric acid methyl ester (2.5 g), polyphosphoric acid (10 g) and dioxane (30 mL) was heated at 130 ° C for 2 days. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water and the resulting precipitate was collected by filtration, washed with water and dichloromethane and dried to give the title compound, 1.6 g. MS: ESI (+ ve) (Method B): 424 (M + H) +, Retention time 3.4 min. Preparation 24c: [8-chloro-3- (4-chlorophenylsulfanyl) -4-difluoromethoxy-2-methylquinolin-5-yloxy] acetic acid methyl ester A mixture of [8-chloro-3- (4- chlorofenilsulfañil) -2-methyl-4-oxo-l, 4-dihidroquinolin-5-yloxy] acetic acid (0.26 g), N, N-dimethylformamide (5.0 mL), potassium carbonate (0.25 g) and chlorodifluoromethyl acetic acid ester (0.13 mL) was stirred at 80 ° C for 17 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (7: 3 by volume) to give the title compound, 0.044 g. MS: ESI (+ ve) (Method B): 474 (M + H) +, Retention time 4.5 min. Preparation 24d: [8-chloro-3- (4-chlorophenylsulphanyl) -4-difluoromethoxy-2-methyl-qumolm-5-? Lox] acetic acid A solution of methyl ester of acid [8-chloro-3- (4 -chlorophenylsulfane) -4-d? fluorometox? -2-met? lmolm-5-yloxy] acetic acid (0.044 g), tetrahydrofuran (3.0 mL) and 0.1 M aqueous sodium hydroxide solution (0.15 mL) was stirred at room temperature for 1 hour. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and this mixture was washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting solid was washed with dichloromethane and dried to give the title compound, 0.024 g. XH NMR (DMSO-d6): d 2.65 (s, 3H), 4.90 (s, 2H), 7.05-7.15 (m, 3H), 7.30 (t, J = 74 Hz, ÍH), 7.35 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.9 Hz, ÍH), 13.5 (br s, ÍH). MS: ESI (+ ve) (Method A): 460 (M + H) +, Retention time 12.7 m n.

Example 25: [8-chloro-3- (4-chlorobenzyl) -4-difluoromethoxy-2-methylquinolin-5-yl] acetic acid Preparation 25a: [8-chloro-3- (4-chlorobenzyl) -2-methyl-4-oxo-1,4-dihydroqui-olin-5-yl] acetic acid A mixture of 3-amino-4-methyl ester -chlorophenyl) acetic acid (1.0 g), 2- (4-chlorobenzyl) -3-oxobutyric acid methyl ester (1.3 g), polyphosphoric acid (5 mL) and dioxane (10 mL) was heated at 130 ° C for 1.5 hours . The mixture was diluted with water and the pH of this solution was adjusted to 3 by the addition of sodium acetate. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and methanol (1: 0: 0 to 10: 1: 0 to 1: 1: 0). at 20: 0: 1 and 0: 0: 1 in volume) to provide the title compound, 0.60 g. XH NMR (DMSO-d6): d 2.40 (s, 3H), 3.35 (s, 3H), 3.90 (s, 2H), 4.10 (s, 2H), 7.00 (d, J = 7.9 Hz, ÍH), 7.20 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 7.9 Hz, ÍH), 10.35 (br s, ÍH). MS: ESI (+ ve) (Method B): 376 (MH-H) +, Retention time 3.6 min.

Preparation 25b: [8-chloro-3- (4-chlorobenzyl) -4-difluoromethoxy-2-methyl-quinol-5-l] acetic acid A mixture of [8-chloro-3- (4-chlorobenzyl) acid l) -2-methyl-4-oxo-l, 4-d? h? droqumolm-5-? l] acetic acid (0.45 g), tetraethylammonium bromide (0.025 g), aqueous sodium hydroxide solution 7.5 M (1.6 mL) and dioxane (25 mL) was heated to 80 ° C and then chlorodifluoromethane was bubbled through this solution for 30 minutes. The mixture was cooled to room temperature and the pH of the solution was adjusted to 5 by the addition of glacial acetic acid. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water (40% to 95% organic modifier) gave the title compound as an off-white solid, 0.003 g. XH NMR (DMSO-d6): d 2.40 (s, 3H), 3.85 (s, 2H), 4.05 (s, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz , 2H), 7.35 (d, J = 8.1 Hz, ÍH), 7.65 (t, J = 57 Hz, ÍH), 7.85 (d, J = 8.1 Hz, ÍH), 12.10 (br s, ÍH). MS: ESI (+ ve) (Method A): 426 (M + H) +, Retention time 11.8 min. MS: ESI (+ ve) (Method B): 426 (M + H) 0 Retention time 3.9 min Example 26: [8-chloro-4-difluoromethoxy-3- (4-methanesulfonylbenzyl) -2-methylquinoline-5 acid -alloxy] acetic Preparation 26a: 2- (4-methanesulfonylbenzyl) -3-oxobutyric acid ethyl ester A suspension of potassium tert-butoxide (4.5 g) in anhydrous tetrahydrofuran (70 mL) at 0 ° C was treated with a mixture of tert-butanol (0.2 mL) and 3-oxobutyric acid ethyl ester (5.2 g). After stirring at 15 ° C for 15 minutes a solution of l-bromomethyl-4-methanesulfonylbenzene (10 g) in tetrahydrofuran (30 mL) was added and the resulting mixture was heated at 70 ° C for 17 hours. The mixture was diluted with saturated aqueous citric acid solution (20 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (2: 1 to 0: 1 by volume) to give the title compound as a gum , 3.5 g.

XH NMR (CDCl 3): d 1.20 (t, J = 6.5 Hz, 3H), 2.25 (s, 3H), 3.05 (s, 3H), 3.25 (m, 2H), 3.85 (t, J = 7.6 Hz, ), 4.10-4.25 (m, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H). Preparation 26b: [8-chloro-3- (4-methanesulfonylbenzyl) -2-methyl-4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid methyl ester A mixture of 3-amino acid methyl ester -4-chlorophenoxy) acetic (0.54 g), 2- (4-methanesulfonylbenzyl) -3-oxobutyric acid ethyl ester (0.75 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130 ° C for 20 hours. The mixture was diluted with water and the pH of this solution was adjusted to 3 by the addition of sodium acetate. The resulting precipitate was collected by filtration and dried to give the title compound as a white solid, 1.0 g. XH NMR (DMSO-d6): d 2.45 (s, 3H), 3.15 (s, 3H), 3.70 (s, 3H), 3.95 (s, 2H), 4.85 (s, 2H), 6.70 (d, J = 8.1 Hz, ÍH), 7.45 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, ÍH), 7.80 (d, J = 8.1 Hz, 2H), 10.15 (br s, ÍH). MS: ESI (+ vé) (Method B): 450 (M + H) +, Retention time 2.7 min. Preparation 26c: [8-chloro-4-difluoromethoxy-3- (4-methanesulfonylbenzyl) -2-methylquinolin-5-yloxy] acetic acid methyl ester A stirred mixture of [8-chloro-3- (4-methyl) methyl ester -methanesulfonylbenzyl) -2-methyl-4-oxo-l, 4-dihydro-quinolin-5-yloxy] acetic acid (0.40 g), N, N-dimethyl formamide (15 mL) and potassium carbonate (0.37 g) was cooled at -80 ° C and chlorodifluoromethane was bubbled through this solution for 30 minutes. The flask was sealed and the resulting mixture was warmed to room temperature for 30 minutes and then stirred at this temperature for 3 days and then at 50 ° C for 6 hours. Excess chlorodifluoromethane was allowed to evaporate and the residue was diluted with ethyl acetate. The mixture was washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 1: 2 by volume) to give the title compound as a colorless gum, 0.41 g. XH? MR (DMSO-d6): d 2.65 (s, 3H), 3.00 (s, 3H), 3.85 (s, 3H), 4.50 (s, 2H), 4.85 (s, 2H), 6.75 (d, J = 8.3 Hz, HH), 7.00 (t, J = 75 Hz, ÍH), 7.30 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.3 Hz, HH), 7.85 (d, J = 8.3 Hz, 2H). MS: ESI (+ ve) (Method B): 500 (M + H) 0 Retention time 3.6 min. Preparation 26d: [8-chloro-4-difluoromethoxy-3- (4-methanesulfonylbenzyl) -2-methylquinolin-5-yloxy] acetic acid A solution of [8-chloro-4-difluoromethoxy-3- (4-methyl) methyl ester -methanesulfonylbenzyl) -2-methylquinolin-5-yloxy] acetic acid (0.13 g), methanol (20 mL), saturated aqueous lithium hydroxide solution (1.0 mL) and water (2.0 mL) was stirred at room temperature for 45 minutes . The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol was removed under reduced pressure. The resulting precipitate was collected by filtration and purified by preparative reverse phase HPLC using a 45 minute gradient of acetonitrile in water (10% to 95% organic modifier) to give the title compound as a pale yellow solid, 0.014. g. XH NMR (DMS0-d6): d 2.55 (s, 3H), 3.15 (s, 3H), 4.45 (s, 2H), 4.95 (s, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.25 (t, J = 75 Hz, ÍH), 7.35 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.6 Hz, ÍH), 13.35 (br Yes H) . MS: ESI (+ ve) (Method A): 486 (M + H) +, Retention time 9.6 min. MS: ESI (+ ve) (Method B): 486 (M + H) +, Retention time 3.6 min. Example 27: [3- (4-chlorobenzyl) -4-difluoromethoxy-8-fluoro-2-methylquinolin-5-yloxy] acetic acid Preparation 27a: [3- (4-chlorobenzyl) -8-fluoro-2-methyl-4-oxo-l, 4-d? H? Droqumolm-5-? Lox?] Acid methyl ester acét? co A mixture of (3-ammo-4-fluorophenoxy) acetic acid methyl ester (0.50 g), 2- (4-chlorobenzyl) -3-oxobutypic acid ethyl ester (7.4 g) and polyphosphoric acid (1.1 g) heated at 130 ° C for 2 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19: 1 by volume) to provide the title compound, 0.29 g. XH NMR (CDC13): d 2.60 (s, 3H), 3.90 (s, 3H), 4.10 (s, 2H), 4.80 (s, 2H), 6.60 (dd, J = 3.6, 8.7 Hz, ÍH), 7.15 -7.25 (m, 5H). Preparation 27b: [3- (4-chlorobenzyl) -4-d? Fluoromethoxy-8-fluoro-2-met? Lmolm-5-? Lox] acetic acid methyl ester A mixture of methyl acid ester [3 - (4-chlorobenzyl) -8-fluoro-2-methyl-4-oxo-l, 4-d? H? Droqumolm-5-yloxy] acetic acid (0.29 g), N, Nd? Met? Lformamide (10 mL), potassium carbonate (0.62 g) and chlorodifluoromethyl ester of acetic acid (0.31 mL) was stirred at 70 ° C for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4: 1 by volume) gave the title compound, 0.18 g. MS: ESI (+ ve) (Method B): 439 (M + H) +, Retention time 4.1 min. Preparation 27c: [3- (4-chlorobenzyl) -4-difluoromethoxy-8-fluoro-2-methylquinolin-5-yloxy] acetic acid A solution of [3- (4-chlorobenzyl) -4-difluoromethoxy- methyl ester 8-fluoro-2-methylquinolin-5-yloxy] acetic acid (0.18 g), methanol (3.5 mL), water (2.0 mL), tetrahydrofuran (3.5 mL) and lithium hydroxide solution (0.036 g) was stirred at room temperature for 30 minutes. The solution was acidified by the addition of aqueous l.O M hydrochloric acid, extracted with ethyl acetate and the combined extracts were dried over sodium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse phase HPLC, using a gradient for 30 minutes of acetonitrile in water, gave the title compound as a yellow solid, 0.088 g. XH NMR (DMSO-d6): d 2.50 (s, 3H), 4.30 (s, 2H), 4.90 (s, 2H), 7.00 (dd, J = 3.7, 8.8 Hz, ÍH), 7.10 (d, J = 8.5 Hz, 2H), 7.25 (t, J = 75 Hz, ÍH), 7.35 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 8.8, 10.2 Hz, ÍH), 13.35 (br s, ÍH ). MS: ESI (tve) (Method A): 425 (M + H) +, Retention time 11.2 min. Example 28: [8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinolin-5-yl] acetic acid Preparation 28a: 8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinolin-5-ol A mixture of 3-amino-4-chlorophenol (1.0 g), 3- (4-methanesulfonylbenzyl) pentane-2, 4-dione (0.53 g), methanesulfonic acid (3 drops) and toluene (20 mL) was heated to reflux for 3 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. 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 methanol (1: 0 to 99: 1 by volume) gave the title compound as a yellow solid. pale, 0.32 g. MS: ESI (+ ve) (Method B): 376 (M + H) 0 Retention time 2.5 min. Preparation 28b: 8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinoline-5-yl ester of trifluoromethanesulfonic acid A mixture of 8-chloro-3- (4-methanesulfonylbenzyl) -2, 4-dimethylquinolin-5-ol (0.10 g), N-phenyltrifluoromethanesulfonimide (0.11 g), potassium carbonate (0.11 g) and tetrahydrofuran (3.0 mL) was heated by microwave irradiation at 130 ° C for 5 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave the title compound as a cream solid, 0.11 g. MS: ESI (+ ve) (Method B): 508 (M + H) +, Retention time 4.1 min. Preparation 28c: [8-chloro-3- (4-methanesulfonylbenzyl) -2,4-dimethylquinol.in-5-yl] acetic acid methyl ester A mixture of 8-chloro-3- (4-methanesulfonylbenzyl) -2 ester , 4-dimethylquinolin-5-yl of trifluoromethanesulfonic acid (0.11 g), l- (tert-butyldimethylsilyloxy) -1-methoxyethene (0.22 mL), sodium acetate (0.019 g), bis (dibenzylidene ketone) palladium (0.006 g) and 1, 1 '-bis (diphenylphosphino) ferrocene (0) (0.006 g) in N, N-dimethylformamide (1.0 mL) was heated by microwave irradiation at 120 ° C for 20 minutes. The mixture was diluted with ethyl acetate and this solution was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed at reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1: 0 to 99: 1 by volume) gave the title compound as an oil. coffee, 0.050 g MS: ESI (+ ve) (Method B): 431 (M + H) 0 Retention time 3.3 min. Preparation 28d: [8-chloro-3- (4-methanesulfonylbenzyl) -2,4-d? Met? Lmolmol-5? L] acetic acid A solution of methyl ester of acid [8-chloro-3- (4 -methanesulfon? lbenc? l) -2,4-d? met? l? nolm-5? l acetic acid (0.050 g), methanol (3.0 mL) and aqueous sodium hydro solution 0.1 M (0.63 mL) it was stirred at room temperature for 18 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitop in water (30% to 70% organic modifier) gave the title compound as a white solid, 0.0060 g. ? H NMR (CD3OD): d 2.65 (s, 3H), 2.70 (s, 3H), 3.10 (s, 3H), 4.25 (s, 2H), 4.45 (s, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 7.7 Hz, ÍH), 7.75 (d, J = 7.7 Hz, ÍH), 7.85 (d, J = 8.6 Hz, 2H). MS: ESI (+ ve) (Method B): 418 (M + H) +, Retention time 8.1 min. Example 29: [8-chloro-4-difluoromethoxy-2-ethyl-3- (4-methanesulfonylbenzyl) -quinolin-5-yloxy] acetic acid Preparation 29a: 2- (4-methanesulfonylbenzyl) -3-oxopentanoic acid ethyl ester A suspension of potassium tert-butoxide (3.9 g) in anhydrous tetrahydrofuran (60 mL) at 0 ° C was treated with a mixture of tert-butanol (0.15 mL) and 3-oxopentanoic acid ethyl ester (5.0 g). The mixture was warmed to room temperature and after 30 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (8.6 g) in tetrahydrofuran (20 mL) was added and the resulting mixture was heated at 70 ° C for 17 hours. The mixture was cooled to room temperature and diluted with water (20 mL) and this mixture was extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 4: 1 by volume) to give the title compound as a white solid, 3.6 g. MS: ESI (+ ve) (Method B): 313 (M + H) 0 Retention time 3.2 min. Preparation 29b: [8-chloro-2-et? L-3- (4-methanesulfonylbenzyl) -4-oxo-l, 4-d? -hydroquinoline? -5? Lox?] -acetic acid methyl ester A mixture of (3-ammo-4-chlorophenoxy) acetic acid methyl ester (0.54 g), 2- (4-methanesulfonylbenzyl) -3-oxopentane-co-ethyl ester (0.78 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130 ° C for 17 hours. The mixture was diluted with water (100 mL) and the pH of this solution was adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound as a honey-colored solid, 1.2 g. MS: ESI (+ ve) (Method B): 462 (M + H) 0 Retention time 2.9 min. Preparation 29c: [8-chloro-4-difluoromethoxy] -2-et? L-3- (4-methanesulfonylbenzyl) qumolm-5-yloxy] acetic acid methyl ester A mixture of [8-chloro-2] methyl ester -et? l-3- (4-methanesulfonylbenzyl) -4-oxo-l, 4-d? -hydroquinoline-5-yloxy] acetic acid (1.2 g), N, Nd? met? lformamide (15 mL) and potassium carbonate (1.1 g) was cooled to -80 ° C and chlorodifluoromethane was bubbled through this solution for 30 minutes. The flask was sealed and the resulting mixture was heated at room temperature for 30 minutes and then heated at 50 ° C for 17 hours. Excess chlorodifluoromethane was allowed to evaporate and the residue was diluted with ethyl acetate and this mixture was washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 4: 1 by volume) to give the title compound as a clear gum, 0.27 g. MS: ESI (+ ve) (Method B): 514 (MiH) 0 Retention time 3.9 min. Preparation 29d: [8-chloro-4-d? Fluoromethoxy? -2-et? L-3- (4-methanesulfonylbenzyl) qumolm-5-? Lox] acetic acid A solution of methyl ester of acid [8-chloro- 4-difluoromethoxy? -2-et? L -3- (4-methanesulfonylbenzyl) qumolm-5-yloxy] acetic acid (0.10 g), methanol (5.0 mL), water (1.0 mL) and saturated aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 45 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol was removed under reduced pressure. The residue was diluted with water (2.0 mL) and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a white solid, 0.075 g. XH NMR (DMSO-d6): d 1.25 (t, J = 7.2 Hz, 3H), 2.85 (q, J = 7. 2 Hz, 2H), 3.15 (s, 3H), 4.40 (s, 2H), 4.45 (s, 2H), 6.90 (d, J = 8.4 Hz, ÍH), 7.35 (d, J = 8.4 Hz, 2H) 7.80 (d, J = 8. 4 Hz, ÍH), 7.85 (d, J = 8.4 Hz, 2H), 8.10 (t, J = 75 Hz, ÍH). MS: ESI (+ ve) (Method A): 500 (M + H) +, Retention time . 7 min. MS: ESI (+ ve) (Method B): 500 (M + H) +, Retention time 3.6 min. Example 30: [3- (4-Chlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] -acetic acid Preparation 30a: 2- (4-chlorobenzyl) -3-oxothiobutyric acid S-er-butyl ester The title compound was prepared by the method of Preparation 34a using 1-bromomet l-4-chlorobenzene and S-tert-butyl ester of 3-oxot? obutí rico acid. ? H NMR (CDCI3): d 1.40 (s, 9H), 2.20 (s, 3H), 3.05-3.20 (m, 2H), 3.80 (m, ÍH), 7.10 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H). Preparation 30b: 2- (4-chlorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyl-ram The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and S-tert-butyl ester of 2- (4-chlorobenzyl) -3-oxotoputyl alcohol. TH NMR (DMSO-d6): d 2.20 (s, 3H), 3.05 (m, 2H), 4.15 (mH), 6. 50 (m H H), 7.00 (dd, J = 9.0, 10.6 Hz, HH), 7.25 (m, 3H), 7. 35 (d, J = 8.3 Hz, 2H), 9.40 (s, ÍH), 9.95 (s, ÍH). MS: ESI (+ ve) (Method B): 336 (M + H) +, Retention time 3.2 min. Preparation 30c: 3- (4-chlorobenzyl) -8-fluoro-5-hydroxyl-4-methyl-1H-quinol-2-one The title compound was prepared by the method of Preparation 34c using 2- (-chlorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyl-ram. XH NMR (DMSO-d6): d 2.60 (s, 3H), 4.00 (s, 2H), 6.50 (dd, J = 4. 4, 8.9 Hz, ÍH), 7.15-7.25 (m, 3H), 7.30 (m, 2H), 10.15 (s, ÍH), 11.40 (s, ÍH). MS: ESI (i-ve) (Method B): 318 (MiH) 0 Retention time 3.3 min.

Preparation 30d: [3- (-chlorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-d? H? Droqumolm-5-? Lox?] Acetic acid methyl ester] acetic acid compound The title was prepared by the method of Preparation 34d using 3- (4-chlorobenzyl) -8-fluoro-5-hydroxyl-4-methyl-lH-qumolm-2-one. Preparation 30e: [3- (4-chlorobenzyl) -2-d? Fluorometox? -8-fluoro-4-met? Lmolm-5? -oxid] -acetic acid methyl ester A mixture of acid methyl ester [ 3- (4-chlorobenzyl) -8-f1-uoro-4-methyl-2-oxo-l, 2-d-hydroquinol-5-yloxy] acetic acid (1.0 g), N, Nd? Met? L formamide (15 mL), potassium carbonate (0.89 g) and chlorodifluoromethyl acetic acid ester (1.1 mL) was stirred at 70 ° C for 18 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (4: 1 by volume) gave the title compound as a white solid, 0.49 g. XH? MR (DMSO-d6): d 2.85 (s, 3H), 3.70 (s, 3H), 4.2 (s, 2H), 5.0 (s, 2H), 6.95 (dd, J = 4.1, 8.8 Hz, ), 7.15 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.8, 9.8 Hz, ÍH), 7.85 (t, J = 72 Hz, ÍH) ). MS: ESI (tve) (Method B): 440 (Mi-H) 0 Retention time 4.5 min.

Preparation 30f: [3- (4-chlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] -acetic acid A solution of [3- (4-chlorobenzyl) -2-difluoromethoxy] methyl ester -8- fluoro-4-methylquinolin-5-yloxy] acetic acid (0.45 g), tetrahydrofuran (5.0 mL), methanol (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.3 mL) was stirred at room temperature for 18 hours. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Crystallization of the residue of a mixture of water and propan-2-ol gave the title compound as a white solid, 0.33 g.

XH NMR (DMSO-d6): d 2.95 (s, 3H), 4.25 (s, 2H), 4.75 (s, 2H), 6.85 (dd, J = 4.0, 9.0 Hz, ÍH), 7.10 (d, J = 8.6 Hz, 2H), 7. 25 (d, J = 8.6 Hz, 2H), 7.30 (m, ÍH), 7.80 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 426 (M-C3H6) +, Retention time 12. 6 min Example 31: [8-chloro-3- (4-fluorobenzyl) -2-isopropoxy-4-methylquinolin-5-yloxy] acetic acid Preparation 31a: [8-chloro-3- (4-fluorobenzyl) -4-methyl-2-oxo-l, 2-dh? -hydroquinol-5? -oxid] -acetic acid methyl ester and methyl ester of acid [8-chloro-3- (4-fluorobenzyl) -2-methyl-4-oxo-l, 4-d? h? -ducqumol? n-5-? lox?] -acetic A mixture of methyl (3-ammo-4-chlorophenoxy) -acetic acid ester (1.5 g), 2- (4-fluorobenzyl) -3-oxobutypic acid ethyl ester (1.7 g) and polyphosphoric acid (15 g) was heated to 100 g. ° C for 3 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3: 7 by volume) to provide [8-chloro] methyl ester. 3- (4-fluorobenzyl) -4-met? L-2-oxo-l, 2-d? H? Droqu? Nolm-5-ylox?] -acetic acid as a yellow-brown solid, 0.13 g and methyl acid ester [8-Chloro-3- (4-fluorobenzyl) -2-meth? L-4-oxo-l, 4-d? H? Droqu? Nol? N-5-? Lox] acetic acid as a brown oil, 0.21 g. Methyl ester of acid [8-chloro-3- (4-fluorobenzyl) -4-met? L-2-oxo-l, 2-d? H? Ducmol? N-5? Lox?] Acetic XH NMR (CDC13 ): d 2.75 (s, 3H), 3.80 (s, 3H), 4.15 (s, 2H), 4.70 (s, 2H), 6.50 (d, J = 8.8 Hz, ÍH), 6.95 (m, 2H), 7.20 (m, 2H), 7.70 (d, J = 8.8 Hz, ÍH), 9.2 (br s, ÍH). MS: ESI (-tve) (Method B): 390 (Mi-H) +, Retention time 3.7 in. Methyl ester of acid [8-chloro-3- (4-fluorobenzyl) -2-met? L-4-oxo-l, 4-d? H? Droqumolm-5-? Lox] acetic XH NMR (CDC13): d 2.50 (s, 3H), 3.85 (s, 3H), 4.05 (s, 2H), 4.80 (s, 2H), 6.60 (d, J = 8.5 Hz, ÍH), 6.90 (m, 2H), 7.20 (s) m, 2H), 7.55 (d, J = 8.5 Hz, ÍH). MS: ESI (+ ve) (Method B): 390 (M + H) +, Retention time 3.2 min. Preparation 31b: [8-chloro-3- (4-fluorobenzyl) -2-? Sopropox? -4-met? Lqumolm-5-? Lox?] Acetic acid methyl ester A mixture of [8-chloro] methyl ester -3- (4-fluorobenzyl) -4-met? L-2-oxo-l, 2-d? H? Droqu? Nolm-5-? Lox?] -acetic (0.020 g), N, Nd? Met? lformamide (1.0 mL), potassium carbonate (0.020 g) and 2-iodopropane (0.050 g) was stirred at room temperature for 4 hours. The mixture was diluted with water (20 mL), extracted with ethyl acetate and the combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 9 by volume) to give the title compound as a cream solid, 0.023 g.

XH NMR (CDCl 3): d 1.35 (d, J = 6.2 Hz, 6H), 2.85 (s, 3H), 3.80 (s, 3H), 4.15 (s, 2H), 4.70 (s, 2H), 5.60 (m , HH), 6.50 (d, J = 8.4 Hz, HH), 6.90 (m, 2H), 7.10 (m 2H), 7.55 (d, J = 8.4 Hz, HH). MS: ESI (+ ve) (Method B): 432 (M + H) 0 Retention time 5.0 min. Preparation 31c: [8-chloro-3- (4-fluorobenzyl) -2-isopropoxy-4-methylquinolin-5-yloxy] acetic acid A solution of [8-chloro-3- (4-fluorobenzyl) - methyl acid ester 2-isopropoxy-4-methylquinolin-5-yloxy] acetic acid (0.020 g), methanol (1.0 mL) and 0.1 M aqueous sodium hydroxide solution (0.25 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water (30% to 90% organic modifier) gave the title compound as a white solid, 0.0085 g. H NMR (CDCl 3): d 1.35 (d, J = 6.4 Hz, 6H), 2.85 (s, 3H), 4.15 (s, 2H), 4.75 (s, 2H), 5.60 (m, ÍH), 6.55 (d , J = 8.3 Hz, HH), 6.90 (m, 2H), 7.10 (m, 2H), 7.55 (d, J = 8.3 Hz, HH). MS: ESI (+ ve) (Method A): 376 (M-C3H6) +, Retention time 14.3 min. Example 32: [8-chloro-3- (4-fluorobenzyl) -4-isopropoxy-2- n acid: methylquinolin-5-yloxy] acetic acid Preparation 32a: [8-chloro-3- (4-fluorobenzyl) -4-isopropoxy-2-methylquinolin-5-yloxy] acetic acid methyl ester A mixture of [8-chloro-3- (4- fluorobenzyl) -2-methyl-4-oxo-l, 4-dihydroquinolin-5-yloxy] -acetic (0.020 g), N, N-di ethyl formamide (1.0 mL), potassium carbonate (0.020 g) and 2- Iodopropane (0.050 g) was stirred at room temperature for 2 days. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 9 by volume) to give the title compound as a light brown oil. , 0.024 g. XH? MR (CDC13): d 1.25 (d, J = 6.8 Hz, 6H), 2.60 (s, 3H), 3.80 (s, 3H), 4.25 (s, 2H), 4.60 (m, ÍH), 4.80 ( s, 2H), 6.70 (d, J = 8.4 Hz, ÍH), 6.90 (m, 2H), 7.05 (m, 2H), 7.65 (d, J = 8.4 Hz, ÍH). MS: ESI (+ ve) (Method B): 432 (M -? - H) +, Retention time 4.2 min. Preparation 32b: Acid [8-chloro-3- (4-fluorobenzyl) -4-? Sopropox? -2-met? Lmolm-5-? Lox?] Acetic acid A solution of methyl ester of acid [8-chloro- 3- (4-Fluorobenzyl) -4-? Sopropox? -2-met? Lol? Nolm-5-? Lox] acetic acid (0.020 g), methanol (1.0 mL) and 0.1 M aqueous sodium hydroxide solution (0.25 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitop in water (30% to 90% organic modifier) gave the title compound as a pale yellow solid, 0.012 g. ? H NMR (CDC13): d 1.30 (d, J = 6.2 Hz, 6H), 2.60 (s, 3H), 4.25 (s, 2H), 4.45 (m, ÍH), 4.80 (s, 2H), 6.85 ( d, J = 8.3 Hz, HH), 6.95 (m, 2H), 7.00 (m, 2H), 7.70 (d, J = 8.3 Hz, HH). MS: ESI (i-ve) (Method A): 376 (M-C3H6) +, Retention time 10.3 m. Example 33: 2- [8-chloro-3- (4-chlorobenzyl) -2,4-dimethylquinolin-5-yloxy] propionic acid Preparation 33a: 2- [8-chloro-3- (4-chlorobenzyl) -2,4-d? Met? Lqumolm-5-? Lox?] Methyl ester] propionic A mixture of 8-chloro-3- (4 -chlorobenzyl) -2,4-d? met? lmol? n-5-ol (0.18 g), N, Nd? met? lformamide (2.0 mL), potassium carbonate (0.092 g) and methyl ester of acid 2-bromopropionic acid (0.11 g) was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 9 to 1: 4 by volume) to give the title compound, 0.092 g. XH? MR (CDC13): d 1.70 (d, J = 6.8 Hz, 3H), 2.70 (s, 3H), 2.85 (s, 3H), 3.75 (s, 3H), 4.25 (s, 2H), 4.90 ( q, J = 6.8 Hz, HH), 6.60 (d, J = 8.4 Hz, ÍH), 6.95 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, ÍH). MS: ESI (+ ve) (Method B): 418 (M + H) 0 Retention time 4.5 min. Preparation 33b: 2- [8-Chloro-3- (4-chlorobenzyl) -2,4-d? Met? Lmol? N-5-? Lox?] Propionic acid A solution of methyl ester of acid 2- [ 8-chloro-3- (4-chlorobenzyl) -2,4-d? Met? L? Nolm-5-? Lox?] Propionic (0.092 g), tetrahydrofuran (2.0 mL) and aqueous lithium hydroxide solution 1.0 M (0.25 mL) was stirred at room temperature for 30 minutes. The tetrahydrofuran was removed at reduced pressure and the pH of the residue was adjusted to 2 by the addition of 1.0 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution. and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting solid was washed with pentane to provide the title compound, 0.080 g. XH NMR (CDC13): d 1.75 (d, J = 6.7 Hz, 3H), 2.75 (s, 3H), 2.85 (s, 3H), 4.25 (s, 2H), 4.95 (q, J = 6.7 Hz, ), 6.65 (d, J = 8.6 Hz, ÍH), 6.90 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.6 Hz, ÍH). MS: ESI (+ ve) (Method A): 404 (M-C3H6) +, Retention time 11.4 mm. Example 34: [8-chloro-2-d? Fluoromethoxy-3- (4-methanesulfonylbenzyl) -4-methylquinol? N-5-? Loxy] acetic acid Preparation 34a: 2- (4-methanesulfonylbenzyl) -3-oxot? -butyl S-tertiary-butyl ester A solution of S-er-butyl 3-oxothiobutyric acid ester (7.5 g) in 1,2-dimethoxy? Ethane (10 mL) was added to a stirred suspension of sodium hydride (60% in oil, 1.9 g) in 1,2-dimethoxyethane (100 mL) at -20 ° C. The mixture was heated at 0 ° C for 10 minutes and then a solution of l-bromomethyl-4-methanesulfonylbenzene (12.9 g) in 1,2-dimethoxyethane (30 mL) was added dropwise over a period of 10 minutes. The resulting mixture was warmed to room temperature for 30 minutes and then stirred at this temperature for 17 hours. The mixture was diluted with saturated aqueous ammonium chloride solution (70 mL) and the phases were separated. The aqueous phase was extracted with diethyl ether and the combined organic phases were dried over magnesium sulfate. 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 4: 1 by volume) gave the title compound, 7.1 g. XH NMR (CDC13): d 1.40 (s, 9H), 2.25 (s, 3H), 3.05 (s, 3H), 3.20-3.30 (m, 2H), 3.85 (m, ÍH), 7.40 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H). Preparation 34b: N- (2-Chloro-5-hydroxyphenyl) -2- (4-methanesulfonylbenzyl) -3-oxo-butyramide Silver trifluoroacetate (1.3 g) was added in two portions over 20 minutes to a stirred solution of 3- amino-4-chlorophenol (0.5 g) and 2- (4-methanesulfonylbenzene) -3-oxoxy-3-oxoyl ester (0.8 g) in 1,2-dimethoxyethane (10 mL) ) at room temperature. The mixture was stirred at room temperature for 15 hours and then filtered through hyflo, washed with 1,2-d-methoxetane. 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 0: 1 by volume) gave the title compound as a Pale peach solid, 0.75 g. MS: ESI (+ ve) (Method B): 396 (M-IH) 0 Retention time 2.7 min. Preparation 34c: 8-Chloro-5-hydroxyl-3- (4-methanesulfonylbenzyl) -4-methylene-lH-qumol-n-2-one A mixture of N- (2-chloro-5-h) ? drox? phenyl) -2- (4-methanesulfonylbenzyl) -3-oxo-but? NaH (0.25 g) and methanesulfonic acid (1.1 g) was heated at 100 ° C for 10 minutes. The mixture was cooled to room temperature and emptied into an aqueous solution, saturated with sodium acetate (20 mL). The resulting precipitate was collected by filtration, washed with water and dried to provide the title compound as a pale pink solid, 0.21 g. MS: ESI (+ ve) (Method B): 378 (M + H) 0 Retention time 2.8 min. Preparation 34d: [8-Chloro-3- (4-methanesulfonylbenzyl) -4-met? L-2-oxo-l, 2-d? hydroquinone-5-yloxy] acetic acid A mixture of 8-chloro-5-hydroxyl-3- (4-methanesulfonylbenzyl) -4-methy1-lH-qumolm-2-one (0.20 g) , N, Nd? Met formamide (4.0 mL), potassium carbonate (0.091 g) and methyl bromoacetic acid ester (0.079 g) was stirred at room temperature for 1 hour. The mixture was diluted with water (20 L) and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 1: 1 by volume) to give the title compound as a solid. white, 0.14 g. XH? MR (CDC13): d 2.65 (s, 3H), 3.15 (s, 3H), 3.70 (s, 3H), 4.20 (s, 2H), 4.95 (s, 2H), 6.80 (d, J = 8.9 Hz, ÍH), 7.45 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 8.9 Hz, 2H), 10.70 (br s, ÍH). Preparation 34e: [8-chloro-2-difluoromethoxy] -3- (4-methanesulfonylbenzyl) -4-methoquinol-n-5-yloxy] acetic acid methyl ester A stirred mixture of methyl acid ester [8] -chloro-3- (4-methanesulfon? lbenc? l) -4-met? l-2-oxo-l, 2-d? h? droqumolm-5-? lox?] acetic (0.13 g), N, N-dimethylformamide (5.0 mL) and potassium carbonate (0.12 g) was cooled to -80 ° C and then chlorodi fluoromethane was bubbled through this solution for 30 minutes. The flask was sealed and the resulting mixture was heated at room temperature for 30 minutes and then heated at 40 ° C for 15 hours. Excess chlorodifluoromethane was allowed to evaporate and the residue was diluted with water. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a white solid, 0.15 g. XH NMR (DMSO-d6): d 2.90 (s, 3H), 3.20 (s, 3H), 3.70 (s, 3H), 4.35 (s, 2H), 5.00 (s, 2H), 7.05 (d, J = 8.7 Hz, ÍH), 7.40 (d, J = 8.7 Hz, 2H), 7.80 (m, 3H), 7.90 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method B): 400 (M + H) +, Retention time 4.0 min. Preparation 34f: [8-chloro-2-difluoromethoxy-3- (4-methanesulfonylbenzyl) -4-methylquinolin-5-yloxy] acetic acid A solution of [8-chloro-2-difluoromethoxy-3- (4-methyl) -ethyl ester -methanesulfonylbenzyl) -4-methylquinolin-5-yloxy] acetic acid (0.14 g), methanol (5.0 mL), saturated aqueous lithium hydroxide solution (0.5 mL) and water (0.4 mL) was stirred at room temperature for 35 minutes . The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the methanol was removed under reduced pressure. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a white solid 0.13 g.

XH NMR (DMS0-d6): d 2.90 (s, 3H), 3.15 (s, 3H), 4.30 (s, 2H), 4. 35 (s, 2H), 6.80 (d, J = 8.6 Hz, ÍH), 7.40 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.6 Hz, ÍH), 7.85 (d, J = 8.0 Hz, 2H), 7.90 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 486 (M + H) +, Retention time . 9 min. MS: ESI (+ ve) (Method B): 486 (M -? - H) 0 Retention time 3.7 min. Example 35: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -4-difluoro-methoxy-2-methylquinolin-5-yloxy] acetic acid Preparation 35a: (4-chloro-3-nitrophenoxy) -acetic acid methyl ester A mixture of 4-chloro-3-nitrophenol (25 g), N, N-dimethylformamide (200 mL), potassium carbonate (60 g) and Bromoacetic acid methyl ester (15.5 mL) was stirred at room temperature for 2.5 hours. The mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was washed with diethyl ether to give the title compound as a white solid, g. X H NMR (CDCl 3): d 3.85 (s, 3 H), 4.70 (s, 2 H), 7.10 (dd, J = 3. 0, 8.9 Hz, HH), 7.40 (dd, J = 3.0 Hz, HH), 7.45 (d, J = 8.9 Hz, HH). Preparation 35b: (3-amino-4-chlorophenoxy) acetic acid methyl ester A solution of (4-chloro-3-nitrophenoxy) acetic acid methyl ester (30 g) in methanol (100 mL) was added to a mixture of iron (26 g), ammonium chloride (33 g) and water (400 mL) at room temperature. The resulting mixture was heated in an ultrasonic bath at 60 ° C for 4 hours. The mixture was basified by the addition of sodium hydroxide and extracted with ethyl acetate. The combined extracts were washed with 1.0 M aqueous hydrochloric acid and the pH of the combined aqueous phases were adjusted to 7-8 by the addition of sodium hydroxide. The resulting precipitate was collected by filtration and dried to provide the title compound, 14 g. XH NMR (DMSO-d6): d 3.70 (s, 3H), 4.60 (s, 2H), 5.35 (br s, 2H), 6.10 (dd, J = 3.0, 8.8 Hz, 1H), 6.35 (d, J = 3.0 Hz, ÍH), 7.05 (d, J = 8.8 Hz, ÍH). Preparation 35c: 2- (2-chloro-4-methanesulfonylbenzyl) -3-oxobutyric acid ethyl ester The title compound was prepared by the method of Preparation 34a using l-bromomet-l-2-chloro-4-methanesulfonylbenzene and ester Ethyl acid 3-oxobutyr? co. XH NMR (CDCl 3): d 1.25 (t, J = 7.1 Hz, 3H), 2.30 (s, 3H), 3.05 (s, 3H), 3.25-3.40 (m, 2H), 3.95 (dd, J = 6.4, 8.3 Hz, HH), 4.10-4.25 (m, 2H), 7.50 (d, J = 8.2 Hz, HH), 7.75 (d, J = 1.9, 8.2 Hz, HH), 7.95 (d, J = 1.9 Hz, ÍH). Preparation 35d: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -2-metho-4-oxo-l, 4-d? H? Droqu? Nolm-5-yloxy] methyl ester] acetic acid A mixture of (3-amino-4-chlorophenoxy) acetic acid methyl ester (0.85 g), 2- (2-chloro-4-methanesulfonylbenzyl) -3-oxobutyric acid ethyl ester (2.1 g) and polyphosphoric acid (10 g) was heated at 130 ° 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 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound, 0.35 g. MS: ESI (+ ve) (Method B): 484 (MiH) +, Retention time 3.1 min. Preparation 35e: [8-Chloro-3- (2-chloro-4-methanesulfonylbenzyl) -4-difluoromethoxy-2-methoquinol-5-yloxy] acetic acid methyl ester A mixture of methyl ester [8-chloro-3- (2-chloro-4-methanesulfon-lbenc?) -2-met? l-4-oxo-l, 4-d? h? dro-qu? nolm-5-? lox acid ?] acetic (0.34 g), N, Nd? methylformamide (15 mL), potassium carbonate (0.58 g) and chlorodifluoromethyl acetic acid ester (0.4 mL) was stirred at 70 ° C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were dried over sodium sulfate and then the solvent was removed under reduced pressure. The purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (7: 3 by volume) gave the title compound, 0.37 g. MS: ESI (+ ve) (Method B): 534 (M + H) +, Retention time 4.0 min. Preparation 35f: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -4-d? Fluoromethoxy? -2-met? Lm? N-5-yloxy] acetic acid A mixture of methyl ester of acid [8] -chloro-3- (2-chloro-4-methanesulfonylbenzyl) -4-d? fluorometox? -2-met? lqu? n-5-? lox?] acetic acid (0.034 g), methanol (8.0 mL), tetrahydrofuran ( 8.0 mL), water (5.0 mL) and lithium hydroxide (0.027 g) was stirred at room temperature for 1 hour. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient of acetonitrile in water gave the title compound as a yellow solid, 0.09 g. 1H NMR (DMSO-d6): d 2.55 (s, 3H), 3.15 (s, 3H), 4.55 (s, 2H), 4.90 (s, 2H), 6.95 (d, J = 7.9 Hz, ÍH), 7.00 (d, J = 8.7 Hz, HH), 7.15 (t, J = 75 Hz, ÍH), 7.70 (d, J = 1.9, 8.2 Hz, HH), 7.80 (d, J = 8.7 Hz, HH), 8.05 (d, J = 1.9 Hz, ÍH). MS: ESI (+ ve) (Method A): 520 (M + H) 0 Retention time 10.5 min. Example 36: [8-chloro-2-d? Fluorometox? -3- (4-methanesulfonylbenzyl) -4-met? L? Nol? N-5? L] acetic acid Preparation 36a: 8-Chloro-3- (4-methanesulphylbenzyl) -4-methyl-2-oxo-l, 2-d? -hydroquinol-5-yl ester of trifluoromethanesulfonic acid A mixture of 8 -chloro-5-hydroxy? -3- (4-methanesulfonylbenzyl) -4-met l-lH-qumol? n-2-one (0.67 g), N-phenyltrifluoromethanesulfonimide (0.63 g), potassium carbonate (0.49 g) g) and tetrahydrofuran (10 mL) was heated by microwave irradiation at 130 ° C for 20 minutes. The mixture was filtered and the filtrate was 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 2: 1 by volume) gave the title compound as an off-white solid, 0.64 g. XH NMR (DMSO-d6): d 2.55 (s, 3H), 3.15 (s, 3H), 4.25 (s, 2H), 7.30 (d, J = 8.8 Hz, ÍH), 7.45 (d, J = 8.3 Hz , 2H), 7.80-7.85 (m, 3H), 11.35 (br s, ÍH). MS: ESI (+ ve) (Method B): 510 (M-IH) +, Retention time 3.6 min. Preparation 36b: [8-Chloro-3- (4-methanesulfonylbenzyl) -4-methyl-2-oxo-l, 2-d? -hydroquinoline-5-yl] acetic acid methyl ester A mixture of 8-Chloro-3- (4-methanesulfonylbenzyl) -4-methyl-2-oxo-l, 2-d? -hydroquinol-5-yl ester of tpfluoromethanesulfonic acid (0.042 g), l- (ter -butyldimethylsi li loxi) -1-methoxethene (0.10 mL), sodium acetate (0.008 g), bis (dibenzylidene ketone) palladium (0.002 g) and 1,1 '-bis (diphenylphosphmo) ferrocene (0) (0.002 g) ) in N, N-dimethylformamide (0.8 mL) was heated by microwave irradiation at 120 ° C for 15 minutes. The mixture was diluted with ethyl acetate and this solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. 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 1: 1 by volume) gave the title compound as a whitish solid, 0.053 g. MS: ESI (+ ve) (Method B): 434 (M + H) 0 Retention time 3.0 min. Preparation 36c: [8-Chloro-2-difluoromethoxy] -3- (4-methanesulfonylbenzyl) -4-met? Lmolm-5-yl] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [8-Chloro-3- (4-methanesulfonylbenzyl) -4-methyl-2-oxo-l, 2-d? -hydroquinoline-5-yl] acetic acid methyl ester. MS: ESI (+ ve) (Method B): 484 (M + H) +, Retention time 3.9 min. Preparation 36d: [8-chloro-2-d? Fluorometox? -3- (4-methanesulfonylbenzyl) -4-met? L? Nol acid? n-5? l] acetic acid A solution of [8-chloro-2-difluoromethoxy? -3- (4-methanesulfonylbenzyl) -4-met? l? nolm-5-? l] acetic acid methyl ester ( 0.030 g), methanol (2.0 mL), saturated aqueous lithium hydroxide solution (0.20 mL) and water (0.40 mL) was stirred at room temperature for 2.5 hours and then at 40 ° C for 2 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected by filtration, washed with water and methanol and then dried to give the title compound as a white solid, 0.016 g. XH NMR (DMSO-d6): d 2.75 (s, 3H), 3.15 (s, 3H), 4.00 (s, 2H), 4. 35 (s, 2H), 7.30 (d, J = 8.0 Hz, ÍH), 7.40 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.0 Hz, ÍH), 7.85 (d, J = 8.5 Hz, 2H), 7.90 (t, J = 73 Hz, ÍH). MS: ESI (+ ve) (Method A): 470 (M + H) 0 Retention time . 5 min MS: ESI (+ ve) (Method B): 470 (M + H) 0 Retention time 3.5 min. Example 37: [8-chloro-4-difluoromethoxy-2-ethyl-3- (4-fluorobenzyl) quinolin-5-yloxy] acetic acid Preparation 37a: 2- (4-fluorobenzyl) -3-oxopentanoic acid methyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-4-fluorobenzene and 3-oxopentanoic acid ethyl ester. XH NMR (CDC13): d 1.00 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H), 2.35 (m, 1H), 2.60 (m, ÍH), 3.15 (m, 2H), 3.75 (t, J = 7.7 Hz, 1H), 4.15 (m, 2H), 6.95 (m, 2H), 7.15 (m, 2H). Preparation 37b: [8-Chloro-2-ethyl-3- (4-fluprobenzyl) -4-hydroxy-1,4-dihydroquinolin-5-yloxy] -acetic acid methyl ester A mixture of methyl 3- (3-hydroxy) amino-4-chlorophenoxy) acetic acid (1.0 g), 2- (4-fluorobenzyl) -3-oxopentanoic acid ethyl ester (2.1 g) and polyphosphoric acid (10 g) was heated at 130 ° C for 4 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1: 0 to 19: 1 by volume) to give the title compound, 0.25 g. MS: ESI (+ ve) (Method B): 404 (M -? - H) +, Retention time 3.6 min. Preparation 37c: [8-chloro-4-difluoromethoxy-2-ethyl-3- (4-fluorobenzyl) quinolin-5-yloxy] -acetic acid methyl ester A mixture of [8-chloro-2-ethyl] methyl ester -3- (4-Fluorobenzyl) -4-hydroxy-l, 4-dihydroquinolin-5-yloxy] acetic acid (0.25 g), N, N-dimethylformamide (11 mL), potassium carbonate (0.51 g) and chlorodifluoromethyl ester of Acetic acid (0.33 mL) was stirred at 70 ° C for 16 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were dried over sodium sulfate and then the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave the title compound, 0.06 g. MS: ESI (+ ve) (Method B): 454 (M-iH) +, Retention time 4.6 min. Preparation 37d: [8-chloro-4-d? Fluoromethoxy? -2-et? L-3- (4-fluorobenzyl) qu? Nol? N-5-? Lox?] Acetic acid A solution of methyl acid ester [ 8-Chloro-4-difluoromethoxy-2-ethyl-3- (4-fluorobenzyl) qumolm-5-? Lox?] - acetic acid (0.060 g), methanol (1.5 mL), tetrahydrofuran (1.5 mL), water (1.0 mL) and lithium hydroxide (0.01 g) was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid, extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse phase HPLC using a gradient of acetonitop in water gave the title compound as a yellow solid, 0.022 g. * H NMR (CD3OD): d 1.25 (t, J = 7.5 Hz, 3H), 2.90 (q, J = 7.5 Hz, 2H), 4.35 (s, 2H), 4.90 (s, 2H), 6.95-7.00 ( m, 3H), 7.10 (m, 2H), 7.15 (t, J = 75 Hz, ÍH), 7.75 (d, J = 8.6 Hz, ÍH). MS: ESI (+ ve) (Method A): 440 (M + H) +, Retention time 12.6 min.

• Example 38: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -2,4-dimethylquinolin-5-yloxy] acetic acid Preparation 38a: 3- (2-chloro-4-methanesulfonylbenzyl) pentane-2,4-dione Sodium hydride (60% oil, 0.30 g) portion in portion was added to a stirred solution of pentane-2,4- dione (0.92 g) in N, N-dimethyl formamide (8.0 mL) at 0-10 ° C. The resulting mixture was stirred at 0-10 ° C for 20 minutes and then a solution of l-bromomethyl-2-chloro-4-methanesulfonylbenzene (2.0 g) in N, N-dimethylformamide (3.0 mL) was added dropwise. . The resulting mixture was stirred at room temperature for 5 hours and then diluted with water and this mixture was extracted with ethyl acetate. The combined extracts were washed with water and solution of Aqueous sodium chloride, saturated and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 4 to 3: 7 in Volume) gave the title compound as a white solid, 1.2 g. MS: ESI (+ ve) (Method B): 303 (M + H) 0 Retention time 2.9 min. Preparation 38b: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -2,4-d? Met? Lqumol? N-5-? Lox methyl ester. ] acetic acid A mixture of (3-ammo-4-chlorophenoxy) acetic acid methyl ester (0.35 g), 3- (2-chloro-4-methanesulfonylbenzyl) pentane-2,4-dione (0.5 g) and acid Polyphosphoric (5.0 g) was heated at 100 ° C for 3.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (2: 8 to 3: 7 by volume) to give the title compound as a pale yellow waxy solid, 0.36 g. MS: ESI (tve) (Method B): 482 (M + H) +, Retention time 3.9 mm. Preparation 38c: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -2,4-dimethyl-1 -quinol acid! -5-? Lox?] Acetic A solution of methyl ester of acid [8-chloro-3- (2-chloro-4-methanesulfon? Lbenc? L) -2,4-d? Met? L? Nol? n-5-yloxy] acetic acid (0.36 g), methanol (10 mL) and 0.1 M aqueous sodium hydroxide solution (4.0 mL) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the pH of the residue was adjusted to 5. by the addition of formic acid. Purification by preparative reverse phase HPLC using a gradient of acetonitrile in water (50% to 65% organic modifier) gave the title compound as a white solid, 0.035 g. 10? Ti NMR (DMSO-d6): d 2.55 (s, 3H), 2.75 (s, 3H), 3.25 (s, 3H), 4.35 (s, 2H), 4.80 (s, 2H), 6.85 (d, J = 8.2 Hz, HH), 6.95 (d, J = 8.5 Hz, ÍH), 7.70 (d, J = 1.9, 8.2 Hz, HH), 7.75 (d, J = 8.5 Hz, HH), 8.10 (d, J = 1.9 Hz, ÍH). MS: ESI (+ ve) (Method A): 468 (M + H) +, Retention time 9.6 min. Example 39: [8-chloro-3- (4-chlorobenzyl) -4-difluoromethoxy-2-ethylquinolin-5-yloxy] acetic acid Preparation 39a: 2- (4-chlorobenzyl) -3-oxopentanoic acid ethyl ester A suspension of potassium tert-butoxide (2.8 g) in anhydrous tetrahydrofuran (400 mL) at 0 ° C was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid ethyl ester (3.0 g). After stirring at room temperature for 45 minutes a solution of l-bromomet? L-4-chlorobenzene (4.3 g) in tetrahydrofuran (100 mL) was added and the resulting mixture was heated at 70 ° C for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and tert-butyl methyl ester (4: 1 by volume) to provide the title compound. 4.8 g. MS: ESI (+ ve) (Method B): 269 (Mi-H) +, Retention time 4.0 min. Preparation 39b: [8-chloro-3- (4-chlorobenzyl) -2-et? L-4-oxo-l, 4-d? H? Droqu? Nolm-5? -oxid?] Acid methyl ester acét? co A mixture of (3-amino-4-chlorophenoxy) acetic acid methyl ester (0.53 g), 2- (4-chlorobenzyl) -3-oxopentane-co-ethyl ester (0.66 g), methanesulfonic acid ( 0.032 mL) and toluene (20 mL) was heated to reflux 20 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with water, extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (9: 1 by volume) to give the title compound, 0.034 g MS: ESI (+ ve) (Method B): 420 (MiH) +, Retention time 3.8 min. Preparation 39c: [8-Cl-oro-3- (4-chlorobenzyl) -4-d? -fluoromethoxy-2-ethyl-quino-n-5? -oxid] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using methyl ester of acid [8-chloro-3- (4-chlorobenzyl) -2-et? l-4-oxo-l, 4-d? -hydroquinoline-5-yloxy ] acetic MS: ESI (+ ve) (Method B): 470 (MlH) +, Retention time 4.8 min. Preparation 39d: [8-chloro-3- (4-chlorobenzyl) -4-difluoromethoxy? -2-et? Lmolm-5-? Lox?] Acetic acid A solution of methyl ester of acid [8-chloro-3] - (4-chlorobenzyl) -4-d? Fluorometox? -2-et? L? Nolm-5-? Lox?] -acetic (0.017 g), tetrahydrofuran (3.0 mL) and aqueous lithium hydroxide solution 1.0 M (0.20 mL) was stirred at room temperature 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of the resulting mixture was adjusted to 5 by the addition of sodium dihydrogenphosphate and extracted with ethyl acetate.

The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient of acetonitrile in water (30% to 95% organic modifier) gave the title compound, 0.010 g. XH NMR (DMSO-d6): d 1.35 (t, J = 7.4 Hz, 3H), 2.90 (q, J = 7. 4 Hz, 2H), 4.35 (s, 2H), 4.90 (s, 2H), 6.75 (d, J = 8.6 Hz, ÍH), 6.85 (t, J = 75 Hz, ÍH), 7.00 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.6 Hz, ÍH). MS: ESI (+ ve) (Method A): 456 (M + H) 0 Retention time 13. 4 min. Example 40: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -2-difluoro-methoxy-4-methylquinolin-5-yloxy] acetic acid Preparation 40a: 2- (2-Chloro-4-methanesulfonylbenzyl) -3-oxothiobutyric acid S-er-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-2-chloro-4-methanesulfonylbenzene and S-er-butyl 3-oxothiobutyric acid ester. : H NMR (CDCl 3): d 1.45 (s, 9H), 1.75 (s, 3H), 3.10 (s, 3H), 3. 80 (s, 2H), 7.40 (d, J = 8.1 Hz, ÍH), 7.75 (dd, J = 1.9, 8. 1 Hz, HH), 7.95 (d, J = 1.9 Hz, HH). MS: ESI (-ve) (Method B): 375 (M-HV, Retention time 3.7 min Preparation 40b: N- (2-chloro-5-hydroxyphenyl) -2- (2-chloro-4-methanesulfonylbenzyl) 3-Oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-amino-4-chlorophenol and 2- (2-chloro-4-methanesulfonylbenzyl) -3-oxothiobutyric acid S-tert-butyl ester. : ESI (+ ve) (Method B): 430 (M -? - H) +, Retention time 2. 97 min. Preparation 40c: 8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -5-hydroxy-4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 34c using N- (2-chloro-5-hydroxyphenyl) -2- (2-chloro-4-methanesulfonylbenzyl) -3-oxobutyramide. X H NMR (DMSO-d 6): d 2.55 (s, 3 H), 3.25 (s, 3 H), 4.15 (s, 2 H), 6. 65 (d, J = 8.8 Hz, ÍH), 7.15 (d, J = 8.2 Hz, ÍH), 7.45 (d, J = 8.8 Hz, ÍH), 7.75 (dd, J = 1.9, 8.2 Hz, ÍH), 8.00 (d, J = 1. 9 Hz, ÍH), 10.50 (br s, ÍH). MS: ESI (+ ve) (Method B): 412 (M + H) +, Retention time 3.1 min.

Preparation 40d: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34d using 8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -5-hydroxy-4-methyl-1H-quinolin-2-one.

XH NMR (DMS0-d6): d 2.60, (s, 3H), 3.25 (s, 3H), 3.70 (s, 3H), 4.20 (s, 2H), 4.95 (s, 2H), 6.80 (d, J = 8.9 Hz, ÍH), 7. 15 (d, J = 8.2 Hz, HH), 7.60 (d, J = 8.9 Hz, HH), 7.75 (d, J = 1.9, 8.2 Hz, HH), 8.05 (d, J = 1.9 Hz, HH), 10.75 (br s, ÍH). MS: ESI (+ ve) (Method B): 484 (M + H) +, Retention time 3.4 min. Preparation 40e: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -4-methyl-2-oxo-l, 2-dihydro-quinolin-5-yloxy] -acetic acid methyl ester. MS: ESI (+ ve) (Method B): 534 (M + H) +, Retention time 4.3 min. Preparation 40f: [8-chloro-3- (2-chloro-4-methanesulfonylbenzyl) -2-difluoromethoxy-4-methyl-Iquinolin-5-yloxy] acetic acid A solution of methyl ester of acid [8-chloro-3-] (2-Chloro-4-methanesulfonylbenzyl) -2-difluoromethoxy-4-methyl-quinolin-5-yloxy] acetic acid (0.50 g), methanol (10 mL), aqueous lithium hydroxide solution, saturated (0.5 mL) and stir water (1.0 mL) at 40 ° C for 3 hours. The methanol was removed under reduced pressure and the pH of the residue was adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water, methanol and diethyl ether and then dried to give the title compound as a white solid, 0.15 g. XH NMR (DMSO-d6): d 2.85 (s, 3H), 3.25 (s, 3H), 4.30 (s, 2H), 4.35 (s, 2H), 6.80 (d, J = 8.6 Hz, ÍH), 7.00 (d, J = 8.4 Hz, HH), 7.70 (d, J = 1.8, 8.4 Hz, HH), 7.75 (d, J = 8.6 Hz, HH), 7.85 (t, J = 72 Hz, HH), 8.05 (d, J = 1.8 Hz, ÍH). MS: ESI (+ ve) (Method A): 520 (M + H) +, Retention time 11. 7 min. MS: ESI (+ ve) (Method B): 520 (M + H) 0 Retention time 3.9 min. Example 41: [8-chloro-2,4-diethyl-3- (4-methanesulfonylbenzyl) quinolin-5-yloxy] acetic acid Preparation 41a: 4- (4-methanesulfonylbenzyl) heptane-3,5-dione. Sodium hydride (60% in oil, 0.17 g) was added portion by portion to a stirred solution of heptane-3,5-dione (0.54 g). mL) in N, Nd? met? lformamide (4.0 mL) at 0-10 ° C. The resulting mixture was stirred at 0-10 ° C for 10 minutes and then a solution of l-bromomet? L-4-methanesulfonylbenzene (1.2 g) in N, N-d? Meth? Lformamide (2.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 4 by volume) gave the title compound as a white solid, 0.61. g. MS: EST (+ ve) (Method B): 297 (M + H) +, Retention time 3.0 and 3.4 mm. Preparation 41b: [8-chloro-2,4-d? Et? L-3- (4-methanesulfonylbenzyl) qu? Nolm-5-? Lox?] Acetic acid methyl ester A mixture of methyl 3- (3-methyl) acid ammo-4-chlorophenoxy) acetic (0.35 g), 4- (4-methanesulfonylbenzyl) heptane-3,5-dione (0.49 g) and polyphosphatic acid (5.0 g) was heated at 100 ° 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 and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (99.5: 0.5 by volume) to provide the title compound, 0.20g. MS: ESI (+ ve) (Method B): 476 (M + H) +, Retention time 4.1 min. Preparation 41c: [8-chloro-2,4-diethyl-3- (4-methanesulfonylbenzyl) quinolin-5-yloxy] acetic acid A mixture of [8-chloro-2,4-diethyl-3- ( 4-methanesulfonylbenzyl) quinolin-5-yloxy] acetic acid (0.20 g), methanol (4.0 mL) and 0.1M aqueous sodium hydroxide solution (2.0 mL) was stirred at room temperature for 5 hours. The pH of the solution was adjusted to 5 by the addition of formic acid and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient of acetonitrile in water (40% to 85% organic modifier) gave the title compound as a pale yellow solid, 0.034 g-: H NMR (DMSO-d6) : d 1.15 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7. 2 Hz, 3H), 2.50 (q, J = 7.2 Hz, 2H), 2.85 (q, J = 7.2 Hz, 2H), 3.15 (s, 3H), 4.45 (s, 2H), 4.85 (s, 2H), 6.95 (d, J = 8.7 Hz, ÍH), 7.30 (d, J = 8.5 Hz, 2H), 7.75 ( d, J = 8.7 Hz, ÍH), 7.85 (d, J = 8.5 Hz, 2H). MS: ESI (+ ve) (Method A): 462 (Mt-H) 0 Retention time 10.4 min. Example 42: 8-chloro-3- (4-chlorobenzyl) -2,4-d? Met? L-5- (1H-tetrazol-5? L) quinoline Preparation 42a: 8-chloro-3- (4-chlorobenzyl) -2,4-d? Met? Lmol? Ne-5-carbon? Tp lo A mixture of ester 8-chloro-3- (4-chlorobenz? l) -2, 4-d? met? l-qumolm-5-íl? of trifluoromethanesulfonic acid (0.29 g), zinc cyanide (0.036 g), tetrakis (tp phenylphosphine) pal adio (0), (0.071 g) ) in N, N-dimethylformamide (8.0 mL) was heated by microwave irradiation at 125 ° C for 10 minutes. The mixture was diluted with water and the resulting precipitate was collected by filtration and then purified by column chromatography on silica gel, eluting with a mixture of cyclohexane, dichloromethane and ethyl acetate (1: 1: 0 to 0: 1). : 0 to 0: 20: 1 by volume) to provide the title compound as a white solid, 0.17 g. XH? MR (CDC13): d 2.75 (s, 3H), 3.00 (s, 3H), 4.30 (s, 2H), 6.90 (m, 2H), 7.25 (m, 2H), 7.80-7.90 (m, 2H) ). Í43 MS: ESI (-tve) (Method B): 341 (Mi-H) +, Retention time 4.6 min. Preparation 42b: 8-chloro-3- (4-chlorobenzyl) -2,4-d? Met? L-5- (1H-tetrazol-5? L) quinoline A mixture of 8-chloro-3- ( 4-chlorobenzyl) -2,4-d? Met? L? Nol? N-5-carbon? Tlo (0.048 g), toluene (1.5 mL), trimethylsilyl azide (0.081 g) and dibutyltin oxide (0.007 g) were sealed in a flask and heated at 100 ° C for 66 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution and the pH of the aqueous phase was adjusted to 5 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with dilute aqueous acetic acid solution and dried to give the title compound as a white solid, 0.017 g. XH NMR (DMSO-d6): d 1.75 (s, 3H), 2.65 (s, 3H), 4.25 (s, 2H), 7.00 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz , 2H), 7.65 (d, J = 7.8 Hz, ÍH), 8.05 (d, J = 7.8 Hz, ÍH). MS: ESI (+ ve) (Method A): 384 (M + H) 0 Retention time 11.2 min. MS: ESI (+ ve) (Method B): 384 (M + H) 0 Retention time 3.8 mm. Example 43: [8-Chloro-4-difluoromethoxy-2-isopropyl-3- (4-methanesulfonylbenzyl) quinolin-5-loxethacrylic acid] Preparation 43a: 2- (4-methanesulfonylbenzyl) ethyl ester - 4-3-oxopentanoic A suspension of potassium tert-butoxide (0.54 g) in anhydrous tetrahydrofuran (200 mL) at 0 ° C was treated with a mixture of tert-butanol (0.1 mL) and ethyl 4-methyl-4-methyl ester. 3-oxopentanoic acid (0.65 mL). After stirring at room temperature for 45 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (1.0 g) in tetrahydrofuran (50 mL) was added and the resulting mixture was heated at 70 ° C for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and then the solvent was removed under reduced pressure to provide the title compound, 1.4 g. MS: ESI (+ ve) (Method B): 327 (M + H) 0 Retention time 3.3 min. Preparation 43b: [8-Chloro-2-isopropyl-3- (4-methanesulfonylbenzyl) -4-oxo-1,4-dihydro-quinolin-5-yloxy] -acetic acid methyl ester A mixture of methyl ester of -ammo-4-chlorophenoxy) acetic acid (0.70 g), ethyl 2- (4-methanesulfonylbenzyl) -4-methyl-3-oxopentane? co (1.4 g), polyphosphoic acid (3.5 g) and dioxane ( 50 mL) was heated at 120 ° C for 2 days. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 1 by volume) to give the title compound. 0.79 g. MS: ESI (+ ve) (Method B): 478 (M + H) +, Retention time 3.4 min. Preparation 43c: [8-Chloro-4-difluoromethoxy-2-β-propyl] -3- (4-methanesulfonylbenzyl) -quinol-5-ylox] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using methyl ester of acid [8-chloro-2-? sopropyl-3- (4-methanesulfoylbenzyl) -4-oxo-l, 4-d? h? droqu? -nolm-5- ? lox?] acetic. XH NMR (CDC13): d 1.25 (d, J = 6.7 Hz, 6H), 3.00 (s, 3H), 3.20 (m, ÍH), 3.80 (s, 3H), 4.50 (s, 2H), 4.85 (s) , 2H), 6.70 (d, J = 8.5 Hz, HH), 6.95 (t, J = 75 Hz, HH), 7.25 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, HH ), 7.85 (d, J = 8.5 Hz, 2H).

MS: ESI (+ ve) (Method B): 528 (M + H) +, Retention 4.2 min. Preparation 43d: [8-chloro-4-d? Fluorometox? -2-? Soprop? L-3- (4-methanesulfonylbenzyl) quinolm-5-? Lox?] Acetic acid A mixture of methyl ester of acid [8-chloro] -4-difluoromethoxy? -2-? Soprop? L-3- (4-methanesulfonyl-benzyl) qu? Nolm-5-? Lox?] Acetic (0.040 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.10 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water and then the pH was adjusted to 5 by the addition of sodium dihydrogenphosphate. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and then the solvent was removed under reduced pressure to provide the title compound., 0.025 g. XH NMR (DMSO-d6): d 1.15 (d, J = 6.4 Hz, 6H), 2.50 (m, ÍH), 3.15 (s, 3H), 4.50 (s, 2H), 4.80 (s, 2H), 7.00 (d, J = 8.7 Hz, HH), 7.35 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 75 Hz, HH), 7.80-7.85 (m, 3H). MS: ESI (+ ve) (Method A): 514 (Mi-H) +, Retention time 11.7 min. Example 44: [8-chloro-2-c? Ano-3- (4-methanesulfonylbenzyl) -4-met? Lquinolin-5-yloxy] acetic acid Preparation 44a: [8-chloro-3- (4-methyl) acid methyl ester -methanesulfonylbenzyl) -4 -met? l-2-tr? fluoromethanesulfonyl-ox? qumolm-5-? lox?] acetic acid A mixture of [8-chloro-3- (4-methanesulfonylbenzyl) -4-met) methyl ester L-2-oxo-l, 2-d? -hydroquinol-5-yloxy] acetic acid (0.22 g), N-phenyltrifluoromethanesulfonimide (0.35 g), potassium carbonate (0.090 g) and N, N Dimethylformamide (5.0 mL) was stirred at room temperature for 17 hours. The mixture was partitioned between dichloromethane and water and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave the title compound, 0.080 g. MS: ESI (+ ve) (Method B): 582 (M + H) 0 Retention time 4.1 min. Preparation 44b: [8-Chloro-2-c? Ano-3- (4-methanesulfonylbenzyl) -4-met? Lqu? N-5-? Lox?] Acetic acid methyl ester A mixture of methyl acid ester [8] -chloro-3- (4-methanesulfon-lbencll) -4 -met? l-2-tpfluoromethanesulfonyl-ox? qu? nolm-5-? lox?] acetic acid (0.080 g), zinc cyanide (0.010 g) , tetraqui (triphenylphosphine) paladi or (0) (0.030 g) and lithium chloride (0.001 g) in N, Nd? met? lformamide (8.0 mL) was heated by microwave irradiation at 120 ° C for 15 minutes. The mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water and diethyl ether and then dried to give the title compound, 0.056 g. MS: ESI (+ ve) (Method B): 459 (M + H) 0 Retention time 3.7 min. Preparation 44c: [8-chloro-2-c? Ano-3- (4-methanesulfonylbenzyl) -4-met? Lmolm-5-lox?] Acetic acid A mixture of methyl ester of acid [8-chloro-2-c] ? ano-3- (4-methanesulfonylbenzyl) -4-met? lmol? n-5-? lox?] -acetic (0.056 g), methanol (1.5 mL), tetrahydrofuran (1.5 mL), water (2.0 mL) and Lithium hydroxide (0.60 g) was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and l.O M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water gave the title compound as a white solid, 0.015 g- XH NMR (DMSO-d6): d 2.90 (s, 3H), 3.20 (s, 3H), 4.60 (s, 2H), 4. 90 (s, 2H), 7.20 (d, J = 8.5 Hz, ÍH), 7.40 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 8.00 (d, J = 8.5 Hz, ÍH). MS: ESI (+ ve) (Method A): 445 (M + H) +, Retention time 9.8 min. MS: ESI (+ ve) (Method B): 445 (M + H) +, Retention time 3.3 min. Example 45: [4-difluoromethoxy-2-ethyl-8-fluoro-3- (4-methanesulfonylbenzyl) -quinolin-5-yloxy] acetic acid Preparation 45a: 2- (4-methanesulfonylbenzyl) -3-oxopentanoic acid methyl ester A suspension of potassium tert-butoxide (2.7 g) in anhydrous tetrahydrofuran (35 mL) at 0 ° C was treated with a mixture of tert-butanol (0.1 mL) and 3-oxopentanoic acid methyl ester (3.2 g). After stirring at room temperature for 15 minutes a solution of l-chloromethyl-4-methanesulfonylbenzene (5.0 g) in tetrahydrofuran (15 mL) was added and the resulting mixture was heated at 70 ° C for 16 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran was removed under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous ammonium chloride solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1: 1: 0 to 0: 1: 0 to 0: 4). : 1 in volume) to provide the title compound as a waxy white solid, 3.0 g. MS: ESI (+ ve) (Method B): 299 (M + H) +, Retention time 3.0 min. Preparation 45b: [2-et? L-8-fluoro-3- (4-methanesulfonylbenzyl) -4-oxo-l, 4-d? H? Droqumolm-5-yloxy] acetic acid methyl ester A mixture of methyl ester of (3-ammo-4-fluorophenoxy) acetic acid (1.0 g), 2- (4-methanesulfonylbenzyl) -3-oxopentane-1-methyl acid ester (1-4 g), polyphosphoric acid (5 mL) and heated dioxane (20 mL) at 130 ° C for 17 hours. The mixture was cooled to room temperature, diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound as a honey-colored gum, 2.3 g. MS: ESI (+ ve) (Method B): 448 (M + H) +, Retention time 2.6 min. Preparation 45c: [4-difluoromethoxy-2-ethyl-8-fluoro-3- (4-methanesulfonylbenzyl) quinolin-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using methyl ester of acid [2-ethyl-8-fluoro-3- (4-methanesulfonylbenzyl) -4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid. MS: ESI (+ ve) (Method B): 498 (M + H) 0 Retention time 3.6 min. Preparation 45d: [4-difluoromethoxy-2-ethyl-8-fluoro-3- (4-methanesulfonylbenzyl] quinolin-5-yloxy (acetic acid) A mixture of [4-difluoromethoxy-2-ethyl-8-fluoro] methyl ester -3- (4-Methanesulfonylbenzyl) quinolin-5-yloxy] acetic acid (0.82 g), methanol (33 mL), 5.0M aqueous lithium hydroxide solution (0.7 mL) and water (1.4 mL) were stirred at room temperature for 35 minutes The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent was removed under reduced pressure The residue was diluted with water (4.0 mL) and the solid was collected by filtration, washed with water and dried to provide the title compound as a pale cream solid, 0.60 g XH NMR (DMS0-d6): d 1.20 (t, J = 7.3 Hz, 3H), 2.80 (q, J = 7.3 Hz, 2H) , 3.15 (s, 3H), 4.40 (s, 2H), 4.45 (s, 2H), 6.80 (dd, J = 3.6, 8.9 Hz, ÍH), 7.35 (d, J = 8.2 Hz, 2H), 7.45 ( dd, J = 8.9, 10.2 Hz, HH), 7.85 (d, J = 8.2 Hz, 2H), 8.20 (t, J = 75 Hz, HH MS: ESI (+ ve) (Method A): 484 (M + H) +, Retention time 9.6 min. MS: ESI (+ ve) (Method B): 484 (M + H) +, Retention time 3.2 min. Example 46: [3- (2-Chloro-4-methanesulfonylbenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid Preparation 46a: 2- (2-Chloro-4-methanesulfonylbenzyl) -3-oxothiobutyric acid S-er-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-2-chloro-4-methanesulfonylbenzene and S-tert-butyl ester of 3-oxothiobutyric acid MS: ESI (+ ve) (Method B): 377 (M + H) +, Retention time 3.8 min. Preparation 46b: 2- (2-chloro-4-methanesulfonylbenzyl) -N- (2- 133 fluoro-5-hydroxyphenyl) -3-oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-ammo-4-fluorophenol and 2- (2-chloro-4-methanesulfonylbenzyl) -3-oxothiobutyric acid S-tert-butyl ester. XH NMR (CD3OD): d 2.30 (s, 3H), 3.10 (s, 3H), 3.50 (m, ÍH), 4. 15 (m, ÍH), 6.55 (m, ÍH), 6.90 (dd, J = 8.9, 10.5 Hz, ÍH), 7. 20 (m, ÍH), 7.55 (d, J = 8.0 Hz, ÍH), 7.80 (dd, J = 1.9, 8. 0 Hz, ÍH), 8.00 (d, J = 1.9 Hz, ÍH). MS: ESI (+ ve) (Method B): 378 (M + H) +, Retention time 2.8 min. Preparation 46c: 3- (2-chloro-4-methanesulfonylbenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 34c using 2- ( 2-chloro-4-methanesulfonylbenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobuty-ramide. XH NMR (DMSO-d6): d 2.55 (s, 3H), 3.25 (s, 3H), 4.10 (s, 2H), 6. 55 (dd, J = 4.4, 8.9 Hz, ÍH), 7.10-7.20 (m, 2H), 7.75 (dd, J = 1.9, 8.1 Hz, ÍH), 8.00 (d, J = 1.9 Hz, ÍH), 11.35 (br s, ÍH). MS: ESI (+ ve) (Method B): 396 (M + H) +, Retention time 3.0 min. Preparation 46d: [3- (2-Chloro-4-methanesulfonylbenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydro-qumolm-5-? Lox]] acetic acid methyl ester title was prepared by the method of Preparation 34d using 3- (2-chloro-4-methanesulfonylbenzyl) -8-fluoro-5-hydrox-4-methyl-lH-qumol-n-2-one. MS: ESI (+ ve) (Method B): 468 (M + H) 0 Retention time 3.2 rain. Preparation 46e: [3- (2-Chloro-4-methanesulfonylbenzyl) -2-difluoromethoxy-8-fluoro-4-methyl-quinol-5-ylox] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (2-chloro-4-methanesulfonylbenzyl) -8-fluoro-4-met-l-2-oxo-l, 2-d? H? Droqu? Acid methyl ester - nolm-5-ylox?] acetic. XH NMR (DMS0-d6): d 2.80 (s, 3H), 3.25 (s, 3H), 3.70 (s, 3H)? 4. 35 (s, 2H), 5.00 (s, 2H), 7.00 (m, 2H), 7.55 (m, ÍH), 7.75 (dd, J = 1.8, 8.2 Hz, ÍH), 7.80 (t, J = 72 Hz, ÍH), 8.10 (d, J = 1.8 Hz, ÍH). MS: ESI (+ ve) (Method B): 518 (M + H) +, Retention time 4.1 min. Preparation 46f: [3- (2-Chloro-4-methanesulfonylbenzyl) -2-difluoromethoxy? -8-fluoro-4-met? Lmmolm-5-? Lox] acetic acid A solution of methyl ester of acid [3- ( 2-Chloro-4-methanesulfonylbenzyl) -2-d? Fluorometox? -8-fluoro-4-met? Lqumolm-5-? Lox?] Acetic acid (0.22 g), methanol (8.0 mL), aqueous lithium hydroxide solution 5.0 M (0.4 mL) and water (0.8 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 4 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid was collected by filtration, washed with water and methanol and dried to give the title compound as a white solid, 0.17 g. XH NMR (DMSO-d6): d 2.85 (s, 3H), 3.25 (s, 3H), 4.25 (s, 2H), 4.30 (s, 2H), 6.75 (dd, J = 4.1, 9.0 Hz, ÍH) , 7.00 (d, J = 8.2 Hz, ÍH), 7.45 (dd, J = 9.0, 9.9 Hz, ÍH), 7.75 (d, J = 1.9, 8.2 Hz, ÍH), 7.80 (t, J = 72 Hz, ÍH), 8.05 (d, J = 1.9 Hz, ÍH). MS: ESI (+ ve) (Method A): 504 (M + H) +, Retention time 11.3 min. MS: ESI (+ ve) (Method B): 504 (M + H) +, Retention time 3.7 min. Example 47: [3- (2-Chloro-4-methanesulfonylbenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid Preparation 47a: 3- (2-chloro-4-methanesul fonylbenzyl) -2-ethyl-fluoro-5-hydroxy-lH-quinolin-4-one A suspension of potassium tert-butoxide (1.2 g) in anhydrous tetrahydrofuran (200 mL) at 0 ° C was treated with a mixture of tert-butanol (1.0 mL) and methyl ester of 3-oxopentanoic acid (1.2 g). After stirring at room temperature for 45 minutes a solution of l-bromomethyl-2-chloro-4-methanesulfonylbenzene (2.5 g) in tetrahydrofuran (50 mL) was added and the resulting mixture was stirred at room temperature for 3 days. The mixture was diluted with water and the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel., eluting with a mixture of cyclohexane, diethyl ether, ethyl acetate and dichloromethane (1: 1: 0: 0 to 0: 0: 1: 9 by volume) to give the title compound, 3.0 g. MS: ESI (+ ve) (Method B): 333 (M + H) +, Retention time 3.2 min. Preparation 47b: [3- (2-Chloro-4-methanesulfonylbenzyl) -2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy] -acetic acid methyl ester A mixture of methyl ester of (3-amino-4-fluorophenoxy) acetic acid (1.0 g), 2- (2-chloro-4-methanesulfonylbenzyl) -3-oxopentanoic acid methyl ester (2.1 g), polyphosphoric acid (10 g) and dioxane ( 10 mL) was heated at 130 ° C for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (19: 1 by volume) to give the title compound, 1.6 g. MS: ESI (+ ve) (Method B): 482 (M + H) +, Retention time 3.0 min. Preparation 47c: [3- (2-chloro-4-methanesulfonylbenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (2-chloro-4-methanesulfonylbenzyl) -2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinoline-5-yloxy] acetic acid methyl ester. XH NMR (DMS0-d6): d 1.25 (t, J = 7.4 Hz, 3H), 2.80 (q, J = 7.4 Hz, 2H), 3.30 (s, 3H), 3.75 (s, 3H), 4.45 (s) , 2H), 5.00 (s, 2H), 6.90 (d, J = 8.2 Hz, ÍH), 7.05 (dd, J = 3.7, 8.8 Hz, ÍH), 7.20 (t, J = 75 Hz, ÍH), 7.55 (dd, J = 8.8, 10.1 Hz, HH), 7.70 (dd, 1.9, 8.2 Hz, HH), 8.05 (d, J = 1.9 Hz, HH). MS: ESI (+ ve) (Method B): 532 (M + H) +, Retention time 3.9 min.

Preparation 47d: [3- (2-chloro-4-methanesulfonylbenzyl) -4-difluoromethoxy? -2-et? L-8-fluoroquinoline? N-5-? Lox?] Acetic acid A mixture of methyl acid ester [3 - (2-Chloro-4-methanesulfonylbenzyl) -4-d? Fluoromethoxy? -2-et? L-8-fluoroquinol-5? -oxa] acetic acid (1.0 g), methanol (38 mL), 5.0 M aqueous lithium hydroxide (0.8 mL) and water (1.6 mL) was stirred at room temperature for 35 minutes. The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water (4.0 mL) and the solid was collected by filtration, washed with water and dried to give the title compound as a cream solid, 0.66 g. XH NMR (DMSO-d6): d 1.25 (t, J = 7.6 Hz, 3H), 2.80 (q, J = 7.6 Hz, 2H), 3.25 (s, 3H), 4.40 (s, 2H), 4.45 (s) , 2H), 6.85 (dd, J = 3.7, 8.9 Hz, ÍH), 6.90 (d, J = 8.1 Hz, ÍH), 7.50 (dd, J = 8.9, 10.3 Hz, ÍH), 7.70 (dd, J = 1.9, 8.1 Hz, HH), 8.00 (d, J = 1.9 Hz, HH), 8.05 (t, J = 75 Hz, HH). MS: ESI (+ ve) (Method A): 518 (M + H) 0 Retention time 10.6 mm. MS: ESI (+ ve) (Method B): 518 (M + H) +, Retention time 3.5 mm. Example 48: [2-difluoromethoxy-8-fluoro-3- (4-methanesulfonylbenzyl) -4-methyl-γ-n'-n-5-yloxy] -acetic acid Preparation 48a: N- (2-fluoro-5-hydroxyphenyl) - 2- (4-methanesulfonylbenzyl) -3-oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2- (4-methanesulfonylbenzyl) -3-oxothiobutyric acid S-tert-butyl ester. MS: ESI (+ ve) (Method B): 380 (M + H) +, Retention time 2.5 min. Preparation 48b: 8-Fluoro-5-hydroxy-3- (4-methanesulfonylbenzyl) -4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 36c using N- (2-fluoro-5-hydroxyphenyl) -2- (4-methanesulfonylbenzyl) -3-oxobutyramide. * H? MR (DMSO-d6): d 2.60 (s, 3H), 3.20 (s, 3H), 4.15 (s, 2H), 6.55 (J = 4.3, 8.8 Hz, ÍH), 7.20 (dd, J = 8.8, 10.1 Hz, ÍH), 7. 45 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 10.15 (s, ÍH), 11.45 (s, ÍH). MS: ESI (+ ve) (Method B): 362 (M + H) 0 Retention time 2.6 min. Preparation 48c: [8-fluoro-3- (4-methanesulfonyl-benzyl) -4-methyl-2-oxo-l, 2-d? -hydroquinol-5-yloxy] -acetic acid methyl ester The compound of title was prepared by the method of Preparation 34d using 8-fluoro-5-hydroxyl-3- (4-methanesulfonylbenzyl) -4-methyl-lH-qumol m-2-one. X H NMR (DMSO-d 6): d 2.65 (s, 3 H), 3.15 (s, 3 H), 3.70 (s, 3 H), 4. 20 (s, 2H), 4.90 (s, 2H), 6.70 (dd, J = 4.1, 9.1 Hz, ÍH), 7. 30 (m, ÍH), 7.45 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 11.65 (s, 1H). MS: ESI (+ ve) (Method B): 434 (MH-H) 0 Retention time 2. 9 min. Preparation 48d: [2-d? Fluorometox? -8-fluoro-3- (4-methanesulfon-l-benzyl) -4 -met-l-quinol-n-5-lox?] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [8-fluoro-3- (4-methanesulfonylbenzyl) -4-met? L-2-oxo-l, 2-d? H? Droqu? Nol? N-5-? Lox) methyl ester] acetic. XH NMR (DMSO-d6): d 2.90 (s, 3H), 3.20 (s, 3H), 3.70 (s, 3H), 4.35 (s, 2H), 5.00 (s, 2H), 6.95 (dd, J = 4.0, 8.9 Hz, ÍH), 7. 40 (d, J = 8.4 Hz, 2H), 7.50 (dd, J = 8.9, 9.8 Hz, ÍH), 7. 65-8.05 (m, 3H). MS: ESI (+ ve) (Method B): 484 (M + H) +, Retention time 3.8 min. Preparation 48e: [2-d? Fluoromethoxy -8-fluoro-3- (4-methanesulfonylbenzyl) -4-methylquinolin-5-yloxy] acetic acid A mixture of [2-difluoromethoxy-8-fluoro-3-] methyl ester (4-methanesulfonylbenzyl) -4-methyl-quinolin-5-yloxy] acetic acid (0.57 g), methanol (24 mL), 5.0M aqueous lithium hydroxide solution (0.5 mL) and water (1.0 mL) was stirred at room temperature for 90 minutes. The pH of the mixture was adjusted to 4 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected by filtration, washed with water and dried to give the title compound as a white solid, 0.53 g. H NMR (DMSO-d6): d 2.90 (s, 3H), 3.15 (s, 3H), 4.25 (s, 2H), 4.35 (s, 2H), 6.75 (dd, J = 4.1, 9.1 Hz, ), 7.35-7.45 (m, 3H), 7.80 (d, J = 8.1 Hz, 2H), 7.85 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 470 (MH-H) +, Retention time 10.4 min. MS: ESI (+ ve) (Method B): 470 (M + H) +, Retention time 3.5 min. Example 49: [3- (4-Chlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid Preparation 49a: 2- (4-chlorobenzyl) -3-oxopentanoic acid ethyl ester A suspension of potassium tert-butoxide (7.8 g) in anhydrous tetrahydrofuran (140 mL) at 0 ° C was treated with a mixture of tert-butanol (0.3 mL) and 3-oxopentanoic acid ethyl ester (10 g). After stirring at room temperature for 30 minutes a solution of l-bromomet? L-4-chlorobenzene (14 g) in tetrahydrofuran (20 mL) was added and the resulting mixture was stirred at room temperature for 6 days. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (1: 0 to 10: 1 by volume) to give the title compound as a yellow solid, 9.3 g. Preparation 49b: [3- (4-chlorobenzyl) -2-et? L-8-fluoro-4-oxo-l, 4-d? H? Droqu acid methyl ester nol? n-5-? lox?] acetic A mixture of (3-amino-4-fluorophenoxy) acetic acid methyl ester (1.9 g), 2- (4-chlorobenzyl) -3-oxopentane ethyl ester Co (0.95 g) and polyphosphoric acid (10 mL) was heated at 120 ° C for 5 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were washed with aqueous, saturated sodium chloride solution and aqueous sodium hydrogen carbonate solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 10: 1 by volume) to give the title compound as a solid coffee, 0.10 g. MS: ESI (+ ve) (Method B): 404 (M-) H) +, Retention time 3.3 min. Preparation 49c: [3- (4-chlorobenzyl) -4-d? Fluoromethoxy? -2-et? L-8-fluoroquinoline-5? -oxid] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (4-chlorobenzyl) -2-e? l-8-fluoro-oxo-1,4-dihydro-n-5-yloxy] acetic acid methyl ester. MS: ESI (+ ve) (Method B): 454 (M + H) 0 Retention time 4.4 min. Preparation 49d: acid [3- (4-chlorobenzyl) -4-d? Fluoromethoxy? -2-et? L-8-fluoroquinol? N-5-? Lox] acetic acid methyl ester solution [3 - (4-Chlorobenzyl) -4-d? Fluoromethoxy-2-ethyl-8-fluoroquinol-5-yloxy] acetic acid (0.11 g), methanol (10 mL) and 5.0 M aqueous sodium hydroxide solution (1.0 mL) were added. stirred at room temperature for 30 minutes. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid.

The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water (40% to 95% organic modifier) to provide the title compound as a white solid, 0.040 g. XH NMR (DMSO-dd): d 1.15 (t, J = 7.3 Hz, 3H), 2.80 (q, J = 7.3 Hz, 2H), 4.30 (s, 2H), 4.40 (s, 2H), 6.80 (dd) , J = 3.8, 8.9 Hz, ÍH), 7.10 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.45 (dd, J = 8.9, 10.4 Hz, ÍH), 8.20 (t, J = 75 Hz, ÍH). MS: ESI (+ ve) (Method A): 440 (M + H) 0 Retention time 12. 3 min. MS: ESI (+ ve) (Method B): 440 (M + H) +, Retention time 4.1 min. Example 50: [4-difluoromethoxy-2-ethyl-8-f luoro-3- (4-f luorobenzyl) quinolin-5-yloxy] acetic acid Preparation 50a: 2- (4-fluorobenzyl) -3-oxopentanoic acid methyl ester 3-Oxopentanoic acid methyl ester (7.5 g) was added to a stirred suspension of sodium hydride (60% in oil, 4.6 g) in N , N-dimethyl formamide (20 mL) and tetrahydrofuran (80 mL) at 0 ° C and the resulting mixture was stirred at 0 ° C for 30 minutes. A solution of 1-bromomethyl-4-fluorobenzene (7.0 mL) in tetrahydrofuran was added and the resulting mixture was warmed to room temperature and then stirred at this temperature for 17 hours. The mixture was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (19: 1 by volume) to give the title compound, 1.0 g. Preparation 50b: [2-ethyl-8-fluoro-3- (4-fluorobenzyl) -4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid methyl ester A mixture of 3-amino acid methyl ester -4-fluorophenoxy) acetic acid (0.80 g), 2- (4-fluorobenzyl) -3-oxopentanacid methyl ester (1.0 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 130 ° C for 17 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound, 1.5 g.

MS: ESI (+ ve) (Method B): 488 (M -? - H) 0 Retention time 3.1 min. Preparation 50c: [4-difluoromethoxy-2-ethyl-8-fluoro-3- (4-fluorobenzyl) quinolin-5-yloxy] acetic acid methyl ester A mixture of [2-ethyl-8-fluoro-] methyl ester 3- (4-Fluorobenzyl) -4-oxo-l, 4-dihydroquinolin-5-yloxy] -acetic acid (1.5 g), N, N-dimethyl formamide (30 mL), potassium carbonate (5.2 g) and chlorodifluoromethyl ester of acetic acid (5.5 mL) was stirred at 70 ° C for 4 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (3: 1 by volume) to give the title compound, 0.50 g. XH? MR (CDC13): d 1.25 (t, J = 7.5 Hz, 3H), 2.90 (q, J = 7.5 Hz, 2H), 3.85 (s, 3H), 4.35 (s, 2H), 4.80 (s, 2H), 6.70 (dd, J = 3.7, 8.7 Hz, ÍH), 6.90-7.00 (m, 2H), 7.00-7.10 (m, 2H), 7.20-7.30 (m, 2H). MS: ESI (+ ve) (Method B): 438 (MH-H) +, Retention time 4.2 min. 50d Preparation: [4-difluoromethoxy-2-ethyl-8-fluoro-3- (4-fluorobenzyl) quinolin-5-yloxy] acetic acid A mixture of [4-difluoromethoxy-2-ethyl-8-fluoro] methyl ester -3- (4-Fluorobenzyl) quinolin-5-yloxy] acetic acid (050 g), methanol (10 mL), tetrahydrofuran (10 mL), water (8 mL) and lithium hydroxide (0.050 g) were stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water, after washing with diethyl ether gave the title compound as a white solid, 0.090 g. XH NMR (DMSO-d6): d 1.16 (t, J = 7.3 Hz, 3H), 2.80 (q, J = 7.3 Hz, 2H), 4.35 (s, 2H), 4.90 (s, 2H), 7.00 (dd) , J = 3.7, 8.7 Hz, HH), 7.05-7.15 (m, 4H), 7.30 (t, J = 75 Hz, HH), 7.50 (dd, J = 8.8, 10.1 Hz, HH). MS: ESI (+ ve) (Method A): 424 (M + H) +, Retention time 11.5 min. Example 51: [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid Preparation 51a: 2- (2,4-dichlorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide A mixture of 2- (2,4-dichlorobenzyl) -3-oxobutyric acid methyl ester (4.6 g) and 3-amino-4-fluorophenol (1.0 g) was heated by microwave irradiation at 120 ° C for 20 minutes. The mixture was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:19 to 1: 1 by volume) to give the title compound, 0.67 g. Preparation 51b: 3- (2,4-dichlorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 34c using 2- (2,4-dichlorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide. MS: ESI (+ ve) (Method B): 352 (M-t-H) +, Retention time 3.6 min. Preparation 51c: [3- (2,4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydro-quinolin-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34d using 3- (2,4-dichlorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one. MS: ESI (+ ve) (Method B): 424 (M + H) +, Retention time 3.9 min. Preparation 51d: [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methoquinol-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (2, 4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-d? H? Dro-qumolm-5-yloxy] acetic acid methyl ester. MS: ESI (i-ve) (Method B): 474 (M + H) +, Retention time 4.8 min. Preparation 51e: [3- (2,4-d? Chlorobenzyl) -2-difluoromethoxy? -8-fluoro-4-met? Lmolm-5-? Lox] acetic acid A solution of methyl acid ester [3 - (2, 4-dichlorobenzyl) -2-difluoromethoxy? -8-fluoro-4-methoquinol? N-5-? Lox?] Acetic acid (0.071 g), methanol (10 mL) and sodium hydroxide solution aqueous 5.0 M (0.15 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the pH of the residue was adjusted to 4 by the addition of glacial acetic acid. The mixture was diluted in ethyl acetate, washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and methanol (1: 0 to 1: 1 by volume) to give the title compound as a white solid, 0.040 g. XH NMR (DMSO-d6): d 2.85 (s, 3H), 4.20 (s, 2H), 4.35 (s, 2H), 6.70 (d, J = 8.4 Hz, ÍH), 6.80 (dd, J = 2.1, 8.4 Hz, ÍH), 7. 25 (t, J = 2.1, 8.4 Hz, HH), 7.40 (t, J = 9.4 Hz, HH), 7.65 (d, J = 2.1 Hz, HH), 7.80 (t, J = 72 Hz, HH). MS: ESI (+ ve) (Method A): 460 (M + H) +, Retention time 13.4 min. MS: ESI (+ ve) (Method B): 460 (M + H) +, Retention time 4.4 min. Example 52: [2-difluoromethoxy-8-fluoro-3- (4-fluorobenzyl) -4-methylquinol? N-5-ylox?] Acetic acid Preparation 52a: 2- (4-Fluorobenzyl) -3-oxot? -superic acid S-er-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomet? L-4-fluorobenzene and 3-oxot? 3-tert-butyl ester obutíp co. XH NMR (CDC13): d 1.40 (s, 9H), 2.20 (s, 3H), 3.10 (m, 2H), 3.80 (t, J = 7.5 Hz, ÍH), 6.95 (m, 2H), 7.10 (m , 2H). Preparation 52b: 2- (4-fluorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyl-ram The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2- (4-fluorobenzyl) -3-oxot? Obutyric acid S-tert-butyl ester.

Preparation 52c: 8-Fluoro-3- (4-fluorobenzyl) -5-hydroxy-4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 34c using 2- (4-fluorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide. MS: ESI (+ ve) (Method B): 302 (M + H) +, Retention time 3.1 min. Preparation 52d: [8-fluoro-3- (4-fluorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34d using 8-fluoro-3- (4-fluorobenzyl) -5-hydroxy-4-methyl-lH-quinolin-2-one. XH? MR (DMSO-d6): d 2.65 (s, 3H), 3.70 (s, 3H), 4.05 (s, 2H), 4.90 (s, 2H), 6.65 (dd, J = 4.0, 9.1 Hz, ), 7.05 (m, 2H), 7. 20-7.35 (m, 3H), 11.60 (s, ÍH). MS: ESI (+ ve) (Method B): 374 (M + H) +, Retention time 3.5 min. Preparation 52e: [2-difluoromethoxy-8-fluoro-3- (4-fluorobenzyl) -4-methylquinolin-5-yloxy] acetic acid methyl ester A mixture of methyl ester of [8-fluoro-3- (4- fluorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] acetic acid (0.48 g), N, N-dimethylformamide (6.0 mL), potassium carbonate (0.72 g) and chlorodifluoromethyl acetic acid ester (1.7 mL) was stirred at 70 ° C for 5 days. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts were washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 6 by volume), after washing with diethyl ether gave the title as a white solid, 0.29 g. ? H NMR (CDC13): d 2.95 (s, 3H), 3.80 (s, 3H), 4.20 (s, 2H), 4.70 (s, 2H), 6.60 (dd, J = 4.0, 8.7 Hz, ÍH), 6.90-7.00 (m, 2H), 7.10 (m, 2H), 7.20 (t, J = 9.0 Hz, ÍH), 7.80 (t, J = 73 Hz, ÍH). Preparation 52f: [2-difluoromethoxy-8-fluoro-3- (4-fluorobenzyl) -4-methylquinolin-5-yloxy] acetic acid A mixture of [2-difluoromethoxy-8-fluoro-3- (4-methylester) methyl ester -fluorobenzyl) -4-methylquinolin-5-yloxy] acetic acid (0.20 g), tetrahydrofuran (4.0 mL), methanol (4.0 mL), water (3.0 mL) and lithium hydroxide (0.020 g) was stirred at room temperature for 40 minutes. minutes The mixture was partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water gave the title compound as a white solid, 0.10 g. X H NMR (DMSO-d 6): d 2.90 (s, 3 H), 4.20 (s, 2 H), 4.80 (s, 2 H), 6. 90 (dd, J = 4.0, 8.9 Hz, ÍH), 7.05-7.20 (m, 4H), 7.50 (m, ÍH), 7.85 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 410 (M + H) +, Retention time 12. 2 min. MS: ESI (+ ve) (Method B): 410 (M -? - H) 0 Retention time 3.9 min. Example 53: [3- (2,4-difluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid Preparation 53a: N- (2-fluoro-5-nitrophenyl) acetamide. Acetic anhydride (8.0 mL) was added dropwise over a period of 10 minutes to a mixture of 2-fluoro-5-nitrophenylamine (7.8 g) and acetic acid. (50 mL) at reflux. The resulting mixture was refluxed for 30 minutes and cooled to 40 ° C. The mixture was poured into cold water (800 mL) and the resulting precipitate was collected by filtration, washed with 1.0 M aqueous hydrochloric acid and water and dried to give the title compound as a light brown solid, 9.2 g. XH NMR (DMS0-d6): d 2.15 (s, 3H), 7.55 (dd, J = 9.1, 10.3 Hz, ÍH), 8.00-8.05 (ddd, J = 2.9, 4.2, 9.1 Hz, ÍH), 9.00 ( dd, J = 2.9, 6.8 Hz, ÍH), 10.20 (s, ÍH). Preparation 53b: N- (5-amino-2-fluorophenyl) acetamide A mixture of 2-fluoro-5-nitrophenylamine (2.0 g), palladium, 10% by weight on activated carbon (0.10 g) and ethanol (20 mL) were stirred at room temperature for 2 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washed with ethanol and the solvent was removed under reduced pressure to give the title compound as a white solid, 1.7 g. XH? MR (DMSO-d6): d 2.05 (s, 3H), 4.95 (s, 2H), 6.25 (m, ÍH), 6.85 (dd, J = 8.7, 10.9 Hz, ÍH), 7.15 (dd, J = 2.6, 6.7 Hz, ÍH), 9.90 (s, ÍH). Preparation 53c: 3-amino-4-fluorophenol A solution of sodium nitrite (17.3 g) in water (40 mL) was added dropwise to a mixture of N- (5-amino-2-fluorophenyl) acetamide (36.7 g ), sulfuric acid (50 mL) and water (270 mL) at 0-10 ° C. The mixture was stirred at 0-10 ° C for 20 minutes and then a solution of urea (2.0 g) in water (20 mL) was added and the resulting mixture was stirred at 0-10 ° C for 20 minutes. The mixture was added dropwise over a period of 75 minutes to a stirred solution of copper pentahydrate sulfate (131 g) in water (110 mL) at 130 ° C and the resulting mixture was heated at 130 ° C for 2.5 hours. The mixture was cooled in an ice bath and the pH of the solution was adjusted to 14 by the addition of 30% aqueous sodium hydroxide solution. The mixture was filtered through hyflo, washed with water. The pH of the filtrate was acidified by the addition of concentrated hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to give the title compound as a brown solid, 22.1 g. XH NMR (DMSO-d6): d 4.95 (br s, 2H), 5.8 (m, HH), 6.15 (dd, J = 2.9, 7.8 Hz, HH), 6.70 (dd, J = 8.7, 11.4 Hz, HH ), 8.85 (br s, ÍH). Preparation 53d: (3-amino-4-fluorophenoxy) acetic acid methyl ester 3-ammo-4-fluorophenol (3.0 g) was added to a stirred suspension of sodium hydride (60% in oil, 0.94 g) in N, Nd? Met? Lformamide (30 mL) at 0 ° C. The mixture was warmed to room temperature for 15 minutes and then cooled to 0 ° C and this mixture was treated with bromoacetic acid methyl ester (3.3 g). The resulting mixture was warmed to room temperature and then stirred at this temperature for 2 hours. The mixture was diluted with dilute aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate. (2: 1: 0 to 0: 1: 0 to 0: 20: 1 by volume) gave the title compound, 2.7 g. ? ti NMR (DMS0-d6): d 3.70 (s, 3H), 4.65 (s, 2H), 5.15 (br s, 2H), 6.00 (dt, J = 3.1, 8.8 Hz, ÍH), 6.30 (dd, J = 3.1, 7.6 Hz, ÍH), 6.85 (dd, J = 8.8, 11.2 Hz, ÍH). MS: ESI (+ ve) (Method B): 200 (M + H) +, Retention time 2.5 min. Preparation 53e: 2- (2,4-difluorobenzyl) -3-oxopentanoic acid methyl ester A suspension of potassium tert-butoxide (3.2 g) in anhydrous tetrahydrofuran (40 mL) at 0 ° C was treated with a mixture of tert. -butanol (0.15 mL) and 3-oxopentanoic acid methyl ester (3.8 g). The mixture was heated at room temperature for 30 minutes and then a solution of 1-bromomethyl-2, 4-difluorobenzene (6.0 g) in tetrahydrofuran (10 mL) was added and the resulting mixture was stirred at room temperature for 72 hours. The mixture was diluted with water (10 mL) and the tetrahydrofuran was removed under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous ammonium chloride solution and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (4: 1: 0 to 0: 1: 0 to 0: 25: 1 by volume) to provide the compound of the title as a colorless oil, 4.5 g. H NMR (DMSO-d6): d 0.9 (t, J = 7.2 Hz, 6H), 2.45-2.60 (m 4H), 3.05 (m, 2H), 3.30 (s, 2H), 3.60 (s, 6H), 4.00 (m, ÍH), 7.00 (m, 2H), 7.20 (m, 2H), 7.30 (, 2H). Preparation 53f: [3- (2,4-difluorobenzyl) -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid methyl ester A mixture of methyl acid ester (3 -amino-4-fluorophenoxy) acetic acid (0.5 g), 2- (2,4-difluorobenzyl) -3-oxopentanoic acid methyl ester (0.64 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated to 130 ° C for 17 hours. The mixture was diluted with water and the pH adjusted to 4 by the addition of sodium acetate. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a creamy solid, 0.84 g.

MS: ESI (+ ve) (Method B): 406 (M + H) 0 Retention time 3. 2. Preparation 53g: [3- (2,4-difluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (2, 4-difluorobenzyl) -2-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy] acetic acid methyl ester. 1 H NMR (DMSO-d 6): d 1.20 (t, J = 7.4 Hz, 3 H), 2.85 (q, J = 7.4 Hz, 2 H), 3.75 (s, 3 H), 4.30 (s, 2 H), 5.00 (s) , 2H), 6.85 (m, ÍH), 6.95 (m, ÍH), 7.05 (dd, J = 3.7, 9.0 Hz, ÍH), 7.20 (t, J = 75 Hz, ÍH), 7.25 (m, ÍH) , 7.55 (dd, J = 8.9, 10.1 Hz, ÍH). MS: ESI (+ ve) (Method B): 456 (M + H) +, Retention time 4.3 min. Preparation 53h: [3- (2, -difluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid A solution of [3- (2,4-difluorobenzyl) -4] methyl ester -difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid (0.54 g), methanol (20 mL), water (1.0 mL) and 5.0 M aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected by filtration, washed with water and dried to give the title compound as a cream solid, 0.089 g. XH NMR (DMSO-d6): d 1.2 (t, J = 7.4 Hz, 3H), 2.85 (q, J = 7.4 Hz, 2H), 4.25 (s, 2H), 4.50 (s, 2H), 6.80-6.85 (m, 2H), 6.95 (dt, J = 2.3, 8.5 Hz, ÍH), 7.25 (m, ÍH), 7.45 (dd, J = 8.9 Hz, 10.2 Hz, ÍH), 7.95 (t, J = 75 Hz, ÍH). MS: ESI (+ ve) (Method A): 442 (M + H) +, Retention time 18. 8 min. MS: ESI (+ ve) (Method B): 442 (M + H) 0 Retention time 3.9 min. Example 54: [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-ethyl-8-f-uoroquinolin-5-yloxy] acetic acid Preparation 54a: 2- (2,4-Dichlorobenzyl) -3-oxopentanoic acid methyl ester A suspension of potassium tert-butoxide (8.4 g) in anhydrous tetrahydrofuran (180 μL) at 0 ° C was treated with a mixture of tert-butanol (0.4 mL) and 3-oxopentanoic acid methyl ester (9.8 g). After stirring at room temperature for 30 minutes a solution of 2,4-dichloro-1-chloromethylbenzene (14.7 g) in tetrahydrofuran (20 mL) was added and the resulting mixture was warmed to room temperature and then stirred at this temperature for 6 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate and the combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (1: 0 to 1: 1 by volume) to give the title compound as a solid. white, 7.0 g. ? H NMR (CDC13): d 1.00 (t, J = 6.9 Hz, 3H), 2.40 (m, ÍH), 2.60 (m, ÍH), 3.25 (m, 2H), 3.70 (s, 3H), 3.95 ( t, J = 7.5 Hz, ÍH), 7.15-7.20 (m, 2H), 7.35 (m, ÍH). Preparation 54b: [3- (2,4-dichlorobenzyl) -2-et? L-8-fluoro-4-oxo-l, 4-d? Hydroquinol-5-yloxy] acetic acid methyl ester A mixture of methyl ester of (3-ammo-4-fluorophenoxy) acetic acid (0.75 g), methyl ester of 2- (2,4-d? chlorobenzyl) -3-oxopentane? co (1.3 g), polyphosphoric acid (5 mL) and dioxane (25 mL) was heated at 120 ° C for 17 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and this mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound as a brown oil, 1.7 g. MS: ESI (+ ve) (Method B): 438 (M-tH) 0 Retention time 3.6 min. Preparation 54c: [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-et? -1-8-fluoroquinol? N-5-yloxy] acetic acid methyl ester The title compound was prepared by the Preparation method 34e using methyl ester of acid [3- (2, 4-dichlorobenzyl) -2-et? L-8-fluoro-4-oxo-l, 4-d? H? -ducqumol? N-5-yloxy] acetic acid. XH NMR (DMSO-d6): d 1.20 (t, J = 7.4 Hz, 3H), 2.80 (q, J = 7.4 Hz, 2H), 3.75 (s, 3H), 4.35 (s, 2H), 5.00 (s) , 2H), 6.65 (d, J = 8.4 Hz, ÍH), 7.05 (dd, J = 3.7, 8.9 Hz, ÍH), 7.20 (t, J = 75 Hz, ÍH), 7.25 (dd, J = 2.2, 8.4 Hz, HH), 7.55 (dd, J = 8.9, 10.1 Hz, HH), 7.70 (d, J = 2.2 Hz, HH). Preparation 54d: [3- (2, 4-d? Chlorobenzyl) -4-difluoromethoxy? -2-et? L-8-fluoroquinol-5? Lox] acetic acid A solution of methyl acid ester [3 - (2,4-dichlorobenzyl) -4-d? Fluorometox? -2-et? L-8-fluoroquinol? N-5-yloxy] acetic acid (0.17 g), methanol (6 mL), water (0.3 mL) ) and 5.0 M aqueous sodium hydroxide solution (0.15 mL) was stirred at room temperature for 1 hour. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected by filtration. Purification by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (1: 0 to 3: 1 by volume) gave the title compound as a white solid, 0.030 g. XH NMR (DMSO-d6): d 1.20 (t, J = 7.4 Hz, 3H), 2.75 (t, J = 7.4 Hz, 2H), 4.30 (s, 2H), 4.50 (s, 2H), 6.60 (d , J = 8.5 Hz, HH), 6.85 (dd, J = 3.7, 8.9 Hz, 1H), 7.25 (dd, J = 2.1, 8.4 Hz, HH), 7.50 (dd, J = 8.9, 10.2 Hz, HH) , 7.70 (d, J = 2.1 Hz, ÍH), 8.00 (t, J = 75 Hz, ÍH). MS: ESI (+ ve) (Method A): 474 (M + H) +, Retention time 13.5 min. MS: ESI (+ ve) (Method B): 474 (M + H) +, Retention time 4.5 min. Example 55: [3- (2,4-difluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid Preparation 55a: 2- (2,4-difluorobenzyl) -3-oxothiobutyric acid S-tert-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-2, -difluorobenzene and S-er ester. -butyl 3-oxothiobutyric acid MS: ESI (-ve) (Method B): 323 (MH) ", Retention time 4.2 min Preparation 55b: 2- (2,4-difluorobenzyl) -N- (2-fluoro) -5-hydroxyphenyl) -3-oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol S-er-butyl ester and 2- (2,4-difluorobenzyl) -3-oxothiobutyric acid S-tert-butyl ester. ? H? MR (DMSO-d6): d 2.20 (s, 3H), 3.00 (m, 2H), 4.20 (dd, J = . 4, 9.4 Hz, ÍH), 6.50 (m, 1H), 7.00 (m, 2H), 7.15-7.30 (m, 3H), 9.40 (s, ÍH), 9.95 (s, 1H). MS: ESI (+ ve) (Method B): 338 (M + H) +, Retention time 3.1 min. Preparation 55c: 3- (2,4-difluorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 34c using 2- (2,4-difluorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide. XH? MR (DMSO-dd): d 2.55 (s, 3H), 4.00 (s, 2H), 6.50 (dd, J = 4. 4, 8.9 Hz, ÍH), 6.95 (m, ÍH), 7.00 (m, ÍH), 7.15-7.25 (m, 2H), 10.15 (s, ÍH), 11.40 (s, ÍH). MS: ESI (+ ve) (Method B): 320 (M + H) +, Retention time 3.2 min. Preparation 55d: [3- (2, 4-difluorobenzyl) -8-f-loro-4-methyl-2-oxo-l, 2-d? H? Droqumolm-5-? Lox? acetic acid The title compound was prepared by the method of Preparation 34d using 3- (2, 4-d? F luorobenzyl) -8-f luoro-5-h? Drox? -4-met? L-lH-qumolm-2-one. XH NMR (DMS0-d6): d 2.60 (s, 3H), 3.70 (s, 3H), 4.00 (s, 2H), 4. 90 (s, 2H), 6.65 (dd, J = 4.0, 9.1 Hz, ÍH), 6.95 (dt, J = 2. 5, 8.5 Hz, ÍH), 7.00 (m, ÍH), 7.20 (m, ÍH), 7.30 (m, ÍH), 11. 65 (br s, ÍH). MS: ESI (+ ve) (Method B): 392 (M + H) +, Retention time 3.5 min. Preparation 55e: [3- (2,4-difluorobenzyl) -2-difluoromethoxy-8-fluoro-4-met-l-molyl-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (2,4-difluorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-d-hydroquinol-5-yloxy] acetic acid methyl ester. XH NMR (DMSO-d6): d 2.60 (s, 3H), 3.70 (s, 3H), 4.00 (s, 2H), 4.90 (s, 2H), 6.65 (dd, J = 4.1, 9.0 Hz, ÍH) , 6.95 (dt, J = 2. 5, 8.6 Hz, ÍH), 7.00 (m, ÍH), 7.20 (m, ÍH), 7.30 (m, ÍH), 11. 65 (s, ÍH), MS: ESI (tve) (Method B): 442 (M-tH) +, Retention time 4.4 min. Preparation 55f: [3- (2,4-d? Fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid A solution of [3- (2,4-difluorobenzyl) methyl ester ) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid (0.20 g), methanol (10 mL), water (0.8 mL) and 5.0 M aqueous sodium hydroxide solution (0.4 mL) was stirred at room temperature for 2 hours. The pH of the mixture was adjusted to 5 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected by filtration, washed with water and dried to give the title compound as a white solid, 0.030 g. XH NMR (DMSO-d6): d 2.90 (s, 3H), 4.15 (s, 2H), 4.80 (s, 2H), 6.90-7.00 (m, 3H), 7.25 (m, ÍH), 7.500 (dd, J = 8.9, 9.7 Hz, ÍH), 7.85 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 428 (M + H) +, Retention time 12.3 min. MS: ESI (tve) (Method B): 428 (M + H) +, Retention time 4.0 min. Example 56: [3- (4-chloro-2-fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid Preparation 56a: 2- (4-chloro-2-fluorobenzyl) -3-oxothiobutyric acid S-er-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-4-chloro-2-fluorobenzene and S-er-butyl ester of 3-oxothiobutyric acid. xti NMR (CDC13): d 1.40 (s, 9H), 1.45 (s, 9H), 1.80 (s, 3H), 2.20 (s, 3H), 3.05 (dd, J = 8.4, 14.0 Hz, ÍH), 3.15 (dd, J = 6.6, 14.0 Hz, ÍH), 3.65 (s, 2H), 3.90 (dd, J = 6.6, 8.4 Hz, ÍH), 7.00-7.15 (m, 6H). Preparation 56b: 2- (4-chloro-2-fluorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2- (4-Chloro-2-fluorobenzyl) -3-oxothiobutyric acid S-tert-butyl ester. XH? MR (CDCI3): d 2.25 (s, '3H), 3.25 (m, 2H), 3.85 (t, J = 7.4 Hz, ÍH), 6.40 (br s, ÍH), 6.55 (m, ÍH), 6.95 (dd, J = 8.9, 10.4 Hz, ÍH), 7.05 (m, 2H), 7.10 (t, J = 8.1 Hz, ÍH), 7.90 (dd, J = 3.0, 6.3 Hz, ÍH), 8.55 (br Yes H) . MS: ESI (+ ve) (Method B): 354 (M + H) +, Retention time 3.2 min. Preparation 56c: 3- (4-chloro-2-fluorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 34c using 2- ( 4-chloro-2-fluorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide. XH NMR (CD3OD): d 2.65 (s, 3H), 4.10 (s, 2H), 6.55 (dd, J = 4. 2, 8.8 Hz, ÍH), 6.95- 7.15 (m, 4H). MS: ESI (+ ve) (Method B): 336 (M + H) 0 Retention time 3.4 min. Preparation 56d: [3- (4-Chloro-2-fluorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34d using 3- (4-chloro-2-fluorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one. MS: ESI ¡+ ve) (Method B): 408 (M + H) +, Retention time 3.7 min. Preparation 56e: [3- (4-chloro-2-fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (4-chloro-2-fluorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] acetic acid methyl ester. X H NMR (CDCl 3): d 2.9 (s, 3 H), 3.80 (s, 3 H), 4.20 (s, 2 H), 4. 70 (s, 2H), 6.60 (dd, J = 3.9, 8.8 Hz, ÍH), 6.80 (t, J = 8. 2 Hz, 1H), 6.90 (dd, J = 2.1, 8.8 Hz, ÍH), 7.10 (dd, J = 2. 1, 9.7 Hz, HH), 7.25 (m, HH), 7.80 (t, J = 73 Hz, HH). MS: ESI (+ ve) (Method B): 458 (M + H) 0 Retention time 4.6 min. Preparation 56f: [3- (4-Chloro-2-fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid A solution of methyl ester of [3- (4-chloro-2 -fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methyl-quinolin-5-yloxy] acetic acid (0.094 g), tetrahydrofuran (10 mL) and 1.0 M aqueous lithium hydroxide solution (0.22 mL) was stirred at room temperature environment for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of this mixture was adjusted to 4 by the addition of sodium dihydrogen phosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to provide the title compound, 0.090 g. XH NMR (CDC13): d 2.85 (s, 3H), 4.20 (s, 2H), 4.80 (s, 2H), 6.65 (d, J = 3.9, 8.7 Hz, ÍH), 6.80 (m, ÍH), 7.00 (m, ÍH), 7.10 (dd, J = 2.1, 9.8 Hz, ÍH), 7.25 (m, ll-l), 7.80 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 444 (M + H) 0 Retention time 13.1 min. Example 57: [8-chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] acetic acid Preparation 57a: 2- (4-chlorobenzyl) -3-oxothiobutyric acid S-tert-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-4-chlorobenzene and S-er-butyl 3-oxothiobutyric acid ester. XH NMR (CDC13): d 1.40 (s, 9H), 2.20 (s, 3H), 3.05-3.15 (m, 2H), 3.80 (t, J = 7.4 Hz, ÍH), 7.10 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H). Preparation 57b: 2- (4-chlorobenzyl) -N- (2-chloro-5-hydroxyphenyl) -3-oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-amino-4-chlorophenol and 2- (4-chlorobenzyl) -3-oxothiobutyric acid S-tert-butyl ester. MS: ESI (+ ve) (Method B): 352 (M + H) 0 Retention time 3.3 min. Preparation 57c: 8-chloro-3- (4-chlorobenzyl) -5-hydroxy-4-methyl-1H-quinolin-2-one The title compound was prepared by the method of Preparation 34c using 2- (4-chlorobenzyl) -N- (2-chloro-5-hydroxyphenyl) -3-oxobutyramide, XH? MR (DMSO-d6): d 2.75 (s, 3H), 4.05 (s, 2H) , 6.65 (d, J = 8. 7 Hz, ÍH), 7.20-7.35 (m, 4H), 7.40 (d, J = 8.7 Hz, ÍH), . 35 (br s, ÍH), 10.50 (br s, ÍH). MS: ESI (+ ve) (Method B): 334 (M + H) 0 Retention time 3.6 min.

Preparation 57d: [8-chloro-3- (4-chlorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34d using 8-chloro-3- (4-chlorobenzyl) -5-hydroxy-4-methyl-1H-quinolin-2-one. XH NMR (DMSO-d6): d 2.60 (s, 3H), 3.70 (s, 3H), 4.05 (s, 2H), 4. 95 (s, 2H), 6.75 (d, J = 8.9 Hz, ÍH), 7.20 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.9 Hz, ÍH), 10.65 (br s, ÍH). MS: ESI (+ ve) (Method B): 406 (M-t-H) 0 Retention time 3.9 min. Preparation 57e: [8-chloro-3- (4-chlorobenzyl) -difluoromethoxy-4-methylquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [8-chloro-3- (4-chlorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -acetic acid methyl ester. XH NMR (DMSO-d6): d 2.85 (s, 3H), 3.75 (s, 3H), 4.20 (s, 2H), 5.00 (s, 2H), 7.00 (d, J = 8.4 Hz, ÍH), 7.15 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.4 Hz, ÍH), 7.85 (t, J = 72 Hz, 1H). MS: ESI (+ ve) (Method B): 456 (M + H) +, Retention time 4.8 min. Preparation 57f: [8-chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] acetic acid A solution of [8-chloro-3- (4-chlorobenzyl) - methyl acid ester 2-difluoromethoxy-4-methylquinolin-5-yloxy] -acetic acid (0.52 g), methanol (20 mL), water (2.0 mL) and 5.0 M aqueous sodium hydroxide solution (1.0 mL) was stirred at room temperature for 1 hour. hour. The pH of the mixture was adjusted to 5 by the addition of glacial acetic acid and the solvent was removed under reduced pressure. The residue was diluted with water and the solid was collected by filtration, washed with water and acetonitrile and then dried to give the title compound as an off-white solid, 0.41 g. XH NMR (DMSO-d6): d 2.90 (s, 3H), 4.20 (s, 2H), 4.30 (s, 2H), 6.80 (d, J = 8.2 Hz, ÍH), 7.15 (d, J = 8.7 Hz , 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.2 Hz, ÍH), 7.85 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 442 (M + H) +, Retention time 13.5 min. MS: ESI (+ ve) (Method B): 442 (M + H) +, Retention time 4.4 min. Example 58: [3- (2-Chloro-4-fluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid Preparation 58a: 2- (2-Chloro-4-fluorobenzyl) -3-oxopentanoic acid methyl ester A suspension of potassium tert-butoxide (1.6 g) in anhydrous tetrahydrofuran (25 mL) at 0 ° C was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.5 g). After stirring at 0 ° C for 45 minutes a solution of l-bromomethyl-2-chloro-4-fluorobenzene (2.6 g) in tetrahydrofuran (5.0 mL) was added and the resulting mixture was stirred at room temperature for 3 days. The mixture was diluted with water and the tetrahydrofuran was removed under reduced pressure. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to give the title compound, 3.2 g. MS: ESI (+ ve) (Method B): 273 (MH-H) 0 Retention time 3.8 min. Preparation 58b: [3- (2-chloro-4-fluorobenzyl) -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid methyl ester A mixture of methyl acid ester (3-amino-4-fluorophenoxy) acetic acid (1.1 g), 2- (2-chloro-4-fluorobenzyl) -3-oxopentanoic acid methyl ester (2.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) ) was heated at 130 ° C for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the solid was washed with diethyl ether and dried to give the title compound, 1.5 g. MS: ESI (+ ve) (Method B): 422 (MH-H) +, Retention time 3.4 min. Preparation 58c: [3- (2-chloro-4-fluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (2-Chloro-4-fluorobenzyl) -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy] -acetic acid methyl ester. XH NMR (CDC13): d 1.25 (t, J = 7.5 Hz, 3H), 2.80 (q, J = 7.5 Hz, 2H), 3.85 (s, 3H), 4.40 (s, 2H), 4.80 (s, 2H) ), 6.55 (dd, J = 6.1, 8.5 Hz, ÍH), 6.70 (dd, J = 3.6, 8.9 Hz, ÍH), 6.80 (dt, J = 2.5, 8.4 Hz, ÍH), 6.96 (t, J = 75 Hz, ÍH), 7.20 (dd, J = 2.5, 8.4 Hz, ÍH), 7.30 (t, J = 8.9 Hz, 1H). MS: ESI (+ ve) (Method B): 472 (M -? - H) +, Retention time 4.5 min. Preparation 58d: [3- (2-chloro-4-fluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid A mixture of [3- (2-chloro-4 -fluorobenzyl) -4-difiuoromethoxy? -2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid (1.2 g), tetrahydrofuran (10 mL) and 1.0 M aqueous lithium hydroxide solution (3.0 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the pH of the residue was adjusted to 4 by the addition of sodium dihydrogen phosphate. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. . The solvent was removed under reduced pressure to provide the title compound, 1.1 g. XH NMR (DMSO-d6): d 1.20 (t, J = 7.4 Hz, 3H), 2.75 (q, J = 7.4 Hz, 2H), 4.30 (s, 2H), 4.90 (s, 2H), 6.65 (dd) , J = 6.2, 8.7 Hz, HH), 7.00-7.10 (m, 2H), 7.25 (t, J = 75 Hz, HH), 7.50-7.60 (m, 2H). MS: ESI (+ ve) (Method A): 458 (M + H) +, Retention time 12.5 min. Example 59: [3- (2-Chloro-4-fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid Preparation 59a: 2- (2-Chloro-4-fluorobenzyl) -3-oxothiobutyric acid S-tert-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-2-chloro-4-fluorobenzene and S-tert-butyl ester of 3-oxothiobutyric acid. Preparation 59b: 2- (2-chloro-4-fluorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and 2- (2-chloro-4-fiuorobenzyl) -3-oxothiobutyric acid S-tert-butyl ester. MS: ESI (+ ve) (Method B): 354 (M + H) +, Retention time 3.2 min: Preparation 59c: 3- (2-chloro-4-fluorobenzyl) -8-fluoro-5-hydroxy-4 methyl-lH-quinolin-2-one The title compound was prepared by the method of Preparation 34c using 2- (2-chloro-4-fluorobenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide . ? H? MR (DMSO-d6): d 2.50 (s, 3H), 4.00 (s, 2H), 6.55 (dd, J = 4. 3, 8.8 Hz, ÍH), 6.85 (dd, J = 6.4, 8.6 Hz, ÍH), 7.05 (dt, J = 2.7, 8.6 Hz, ÍH), 7.20 (dd, J = 8.8, 10.2 Hz, ÍH), 7.45 (dd, J = 2.7, 8.8 Hz, ÍH), 10.20 (s, ÍH), 11.45 (s, ÍH) . MS: ESI (+ ve) (Method B): 336 (M + H) 0 Retention time 3.3 min. Preparation 59d: [3- (2-Chloro-4-fluorobenzyl) -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 36d using 3- (2-chloro-4-fluorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one. ? H NMR (DMS0-d6): d 2.55 (s, 3H), 3.70 (s, 3H), 4.05 (s, 2H), 4.90 (s, 2H), 6.70 (dd, J = 4.0, 9.1 Hz, ), 6.90 (dd, J = 6. 2, 8.6 Hz, ÍH), 7.05 (dt, J = 2.7, 8.6 Hz, ÍH), 7.35 (dd, J = 9.1, 10.0 Hz, ÍH), 7.45 (dd, J = 2.7, 8.8 Hz, ÍH), 11.70 (Yes H) . MS: ESI (+ ve) (Method B): 408 (M -? - H) +, Retention time 3.7 min. Preparation 59e: [3- (2-Chloro-4-fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [3- (2-Chloro-4-fluorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -acetic acid methyl ester. XH NMR (CDC13): d 2.8 (s, 3H), 3.8 (s, 3H), 4.25 (s, 2H), 4.75 (s, 2H), 6.60-6.65 (m, 2H), 6.80 (m, ÍH), 7.20 (dd, J = 2.6, 8.5 Hz, ÍH), 7.25 (t, J = 9.1 Hz, ÍH), 7.80 ( t, J = 72.5 Hz, ÍH). MS: ESI (+ ve) (Method B): 458 (M + H) 0 Retention time 4.6 min. Preparation 59f: [3- (2-Chloro-4-fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid A mixture of methyl ester of [3- (2-chloro-4 -fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid (0.20 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.45 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of the mixture was adjusted to 4 by the addition of sodium dihydrogen phosphate and the resulting precipitate was collected by filtration and dried to give the title compound as a white solid, 0.18 g. XH NMR (DMS0-d6): d 2.80 (s, 3H), 4.20 (s, 2H), 4.65 (s, 2H), 6.75 (dd, J = 6.1, 8.8 Hz, ÍH), 6.85 (dd, J = 4.0, 8.8 Hz, HH), 7.05 (dt, J = 2.7, 8.5 Hz, HH), 7.45-7.55 (m, 2H), 7.80 (t, J = 72 Hz, HH). MS: ESI (tve) (Method A): 444 (M + H) +, Retention time 12.9 min. Example 60: [4-difluoromethoxy-3- (4-ethanesulfonylbenzyl) -2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid Preparation 60a: 2- (4-ethanesulfonylbenzyl) -3-oxopentanoic acid methyl ester The title compound was prepared by the method of Preparation 34a using l-bromomet-l-4-ethanesulfonylbenzene and 3-oxopentanoic acid methyl ester. XH NMR (CDC13): d 1.00 (t, J = 7.3 Hz, 3H), 1.25 (t, J = 7.3 Hz, 3H), 2.40 (m, ÍH), 2.60 (m, ÍH), 3.10 (q, J = 7.3 Hz, 2H), 3.25 (m, 2H), 3.80 (t, J = 7.5 Hz, ÍH), 3.70 (s, 3H), 7.40 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H). Preparation 60b: [3- (4-ethanesulfonylbenzyl) -2-et? L-8-fluoro-4-oxo-l acid methyl ester, 4-d? H? Droqu? -nolm-5-? Lox?] Acetic A mixture of methyl ester of (3-ammo-4-fluorophenoxy) acetic acid (0.90 g), methyl ester of 2- (4-) acid ethanesulfonylbenzyl) -3-oxopentane? co (1-4 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 120 ° C for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure to give the title compound, 1.9 g. MS: ESI (+ ve) (Method B): 462 (M + H) +, Retention time 2.7 mm. Preparation 60c: [4-d? Fluorometox? -3- (4-ethanesulfon? Lbenc? L) -2-et? L-8-fluoroquinol-5? Lox?] -acetic acid methyl ester A mixture of methyl ester of [3- (4-ethanesulfonylbenzyl) -2-et? l-8-fluoro-4-oxo-l, 4-d? h? droqu? -nolm-5-? lox?] acetic acid (1.9 g ), N, N-dimethylformamide (30 mL), potassium carbonate (1.7 g) and chlorodifluoromethyl acetic acid ester (2.2 mL) was stirred at 70 ° C for 3 days. The mixture was diluted with saturated aqueous ammonium chloride solution, extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by an Isoluto SCX2 column, eluting with methanol and then 2.0M ammonia in methanol gave the title compound, 0.090 g. XH? MR (CD3OD): d 1.20 (m, 6H), 2.90 (q, J = 7.4 Hz, 2H), 3.20 (q, J = 7.4 Hz, 2H), 3.80 (s, 3H), 4.55 (s, 2H), 4.95 (s, 2H), 6.95 (dd, J = 3.7, 8.8 Hz, ÍH), 7.10 (t, J = 75 Hz, ÍH), 7.35-7.50 (m, 3H), 7.80 (m, 2H ). Preparation 60d: [4-d? F1 uoromethoxy? -3- (4-ethanesulfon? Lbenc? L) -2-et? L-8-fluoroquinoline? -5? 0x1] acetic acid A mixture of methyl ester of [4-difluoromethoxy? -3- (4-ethanesulfonylbenzyl) -2-et? l-8-fluoro-qumolm-5-? lox?] acetic acid (0.080 g), methanol (2.0 mL), tetrahydrofuran (2.0 mL) , water (2.0 mL) and lithium hydroxide (0.006 mg) was stirred at room temperature for 45 minutes. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid and purified by preparative reverse phase HPLC using a gradient for 30 minutes of acetonitrile in water to give the title compound as an off white solid, 0.025 g. XH NMR (DMSO-d6): d 1.05 (t, J = 7.4 Hz, 3H), 1.45 (t, J = 7.4 Hz, 3H), 2.80 (q, J = 7.4 Hz, 2H), 3.25 (q, J) = 7.4 Hz, 2H), 4.45 (s, 2H), 4.90 (s, 2H), 7.00 (dd, J = 3.6, 8.8 Hz, ÍH), 7.30 (t, J = 75 Hz, ÍH), 7.35 (d , J = 8.3 Hz, 2H), 7.55 (dd, J = 8.8, 10.0 Hz, ÍH), 7.80 (d, J = 8.3 Hz, 2H). MS: ESI (+ ve) (Method A): 498 (M + H) +, Retention time 10.2 min. Example 61: [2-difluoromethoxy-3- (4-ethanesulfonylbenzyl) -8-fluoro-4-methylquininoin-5-yloxy] acetic acid Preparation 61a: 2- (4-Ethanesulfonylbenzyl) -3-oxothiobutyric acid S-er-butyl ester The title compound was prepared by the method of Preparation 34a using l-bromomethyl-4-ethanesulfonylbenzene and S-er-butyl ester of 3-oxothiobutyric acid. XH NMR (CDC13): d 1.30 (t, J = 7.4 Hz, 3H), 1.50 (s, 9H), 1.80 (s, 3H), 3.10 (q, J = 7.4 Hz, 2H), 3.80 (s, 2H) ), 7.40 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H). Preparation 61b: 2- (4-Ethanesulfonylbenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide The title compound was prepared by the method of Preparation 34b using 3-amino-4-fluorophenol and S-ester. 2- (4-ethanesul fonylbenzyl) -3-oxothiobutyric acid tert-butyl ester. Preparation 61c: 3- (4-Ethanesulfonylbenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2 -one The title compound was prepared by the method of Preparation 34c using 2- (4-ethanesulfonylbenzyl) -N- (2-fluoro-5-hydroxyphenyl) -3-oxobutyramide * H? MR (DMSO-d6): d 1.05 (t, J = 7.3 Hz, 3H), 2.60 (s, 3H), 3. 20 (q, J = 7.3 Hz, 2H), 4.15 (s, 2H), 6.50 (dd, J = 4.2, 8.7 Hz, ÍH), 7.20 (m, ÍH), 7.45 (d, J = 8.2 Hz, 2H ), 7.75 (d, J = 8.2 Hz, 2H), 10.20 (br s, ÍH), 11.45 (s ÍH). Preparation 61d: [3- (4-Ethanesulfonylbenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] acetic acid methyl ester The title compound was prepared by the method from Preparation 34d using 3- (4-ethanesulfonylbenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2 -one MS: ESI (+ ve) (Method B): 448 (M + H) +, Retention time 3.0 min. Preparation 61e: [2-difluoromethoxy-3- (4-ethanesulfonylbenzyl) -8-fluoro-4-met? L? Nol? N-5? Lox?] -acetic acid methyl ester A mixture of methyl acid ester [ 3- (4-Ethanesulfonylbenzyl) -8-fluoro-4-met? L-2-oxo-l, 2-d? H? Dro? -nolm-5-? Lox?] Acetic (0.33 g), N, Nd Methylformamide (5.0 mL), potassium carbonate (0.16 g) and chlorodifluoromethyl acetic acid ester (1.2 mL) was stirred at 70 ° C for 3 days. The mixture was diluted with saturated aqueous ammonium chloride solution, extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave the title as a white solid, 0.10 g.

XH? MR (CDC13): d 1.25 (t, J = 7.4 Hz, 3H), 2.90 (s, 3H), 3.10 (q, J = 7.4 Hz, 2H), 3.85 (s, 3H), 4.35 (s, 2H), 4.75 (s, 2H), 6.65 (dd, J = 3.9, 8.8 Hz, ÍH), 7.25 (m, ÍH), 7.35 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.80 (t, J = 73 Hz, ÍH). MS: ESI (+ ve) (Method B): 498 (M + H) 0 Retention time 3.9 min. Preparation 61f: [2-d? Fluorometox? -3- (4-ethanesulfonylbenzyl) -8-fluoro-4-met? L? Nol? N-5-? Lox?] Acetic acid A mixture of methyl ester of acid [2- difluoromethoxy-3- (4-ethanesulfonylbenzyl) -8-fluoro-4-methyl-quinolin-5-yloxy] acetic acid (0.10 g), methanol (2.0 mL), tetrahydrofuran (2.0 L), water (2.5 mL) and hydroxide of Lithium (0.017 mg) was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid and purified by preparative reverse phase HPLC., using a gradient for 30 minutes of acetonitrile in water to provide the title compound as a white solid, 0.070 g. XH NMR (DMSO-d6): d 1.05 (t, J = 7.3 Hz, 3H), 2.90 (s, 3H), 3.25 (q, J = 7.3 Hz, 2H), 4.35 (s, 2H), 4.80 (s) , 2H), 6.95 (dd, J = 4.0, 8.9 Hz, ÍH), 7.40 (d, J = 8.4 Hz, 2H), 7.50 (dd, J = 8.9, 9.7 Hz, ÍH), 7.80 (d, J = 8.4 Hz, 2H), 7.85 (t, J = 72 Hz, 1H). MS: ESI (+ ve) (Method A): 484 (M + H) 0 Retention time 10.8 min. Example 62: [8-chloro-3- (4-chloro-2-fluorobenzyl) -4-difluoromethoxy-2-ethylquinolin-5-yloxy] acetic acid Preparation 62a: 2- (4-Chloro-2-fluorobenzyl) -3-oxopentanoic acid methyl ester A suspension of potassium tert-butoxide (1.6 g) in anhydrous tetrahydrofuran (75 mL) at 0 ° C was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.5 g). After stirring at 0 ° C for 45 minutes a solution of l-bromomethyl-4-chloro-2-fluorobenzene (2.6 g) in tetrahydrofuran (25 mL) was added and the resulting mixture was stirred at room temperature for 17 hours. The mixture was diluted with water and the tetrahydrofuran was removed under reduced pressure. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:19 to 1: 9 by volume) to give the title compound, 1.4 g. MS: ESI (+ ve) (Method B): 273 (M + H) 0 Retention time 3.8 min. Preparation 62b: [8-Chloro-3- (4-chloro-2-fluorobenzyl) -2-ethyl-4-oxo-1,4-dihydroquinolin-5-yloxy] -acetic acid methyl ester A mixture of methyl ester of (3-amino-4-chlorophenoxy) acetic acid (0.37 g), 2- (4-chloro-2-fluorobenzyl) -3-oxopentanoic acid methyl ester (0.60 g), polyphosphoric acid (3 g) and dioxane (10 g) mL) was heated at 120 ° C for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane. (1: 4 to 1: 1 by volume) to provide the title compound, 0.082 g. 1H NMR (CD3OD): d 1.25 (t, J = 7.6 Hz, 3H), 2.85 (q, J = 7.6 Hz, 2H), 3.75 (s, 3H), 4.00 (s, 2H), 4.85 (s, 2H) ), 6.70 (d, J = 8.8 Hz, ÍH), 7.00-7.10 (m, 2H), 7.15 (dd, J = 1.8, 9.9 Hz, HH), 7.65 (d, J = 8.8 Hz, 1H). MS: ESI (+ ve) (Method B): 438 (M + H) +, Retention time 3.8 min. Preparation 62c: [8-chloro-3- (4-chloro-2-fluorobenzyl) -4-difluoromethoxy-2-ethyl-quinolin-5-yloxy] -acetic acid methyl ester The title compound was prepared by the method of Preparation 34e using [8-chloro-3- (4-chloro-2-fluorobenzyl) -2-ethyl-4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid methyl ester MS: ESI (+ ve) (Method B): 488 (M + H) 0 Retention time 4.8 min. Preparation 62d: [8-chloro-3- (4-chloro-2-fluorobenzyl) -4-difluoromethoxy-2-ethylquinolin-5-yloxy] acetic acid A mixture of [8-chloro-3- (4-methyl) -ethyl ester -chloro-2-fluorobenzyl) -4-difluoromethoxy-2-ethyl-quinolin-5-yloxy] acetic acid (0.075 g), tetrahydrofuran (2.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.20 mL) was stirred at room temperature environment for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of the mixture was adjusted to 4 by the addition of sodium dihydrogen phosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was crystallized from a mixture of acetonitrile and water to give the title compound, 0.057 g. XH NMR (CDC13): d 1.35 (t, J = 7.4 Hz, 3H), 2.90 (q, J = 7.4 Hz, 2H), 4.35 (s, 2H), 4.90 (s, 2H), 6.65 (d, J = 8.1 Hz, ÍH), 6.75 (d, J = 8.6 Hz, ÍH), 6.35 (t = J 75 Hz, ÍH), 6.95 (m, ÍH), 7.10 (m, ÍH), 7.75 (d, J = 8.6 Hz). MS: ESI (+ ve) (Method A): 474 (M + H) +, Retention time 13.8 min. Example 63: [3- (4-Chloro-2-fluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid Preparation 63a: [3- (4-Chloro-2-fluorobenzyl) -2-et? L-8-fluoro-4-oxo-l, 4-d? H? Droqu? Nolm-5-yloxy] methyl ester] acetic acid A mixture of (3-ammo-4-fluorophenoxy) acetic acid methyl ester (0.80 g), 2- (4-Chloro-2-fluorobenzyl) -3-oxopentane-co-methyl ester (1-4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 120 ° C for 23 hours . The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3: 7 to 7:10 by volume) to give the title compound, 0.20 g. XH NMR (CD3OD): d 1.20 (t, J = 7.1 Hz, 3H), 2.08 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 4.00 (s, 2H), 4.80 (s, 2H) ), 6.65 (mHH), 7.00-7.15 (m, 3H), 7.35 (t, J = 9.7 Hz, ÍH). MS: ESI (+ ve) (Method B): 424 (M + H) +, Retention time 3.4 min. Preparation 63b: [3- (4-chloro-2-fluorobenzyl) -4-d? Fluoromethoxy? -2-et? L-8-fluoroquinol? N-5-yloxy] acetic acid methyl ester An ester mixture [3- (4-chloro-2-fluorobenzyl) -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid methyl ester (0.20 g), N, N-dimethylformamide ( 3.0 mL), potassium carbonate (0.20 g) and chlorodifluoromethyl acetic acid ester (0.15 mL) was stirred at 80 ° C for 4 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1: 4 by volume) gave the title compound, 0.071 g. XH? MR (CDC13): d 1.30 (t, J = 7.4 Hz, 3H), 2.90 (q, J = 7.4 Hz, 2H), 3.80 (s, 3H), 4.35 (s, 2H), 4.80 ( s, 2H), 6.65-6.75 (m, 2H), 6.95 (m, HH), 7.10 (m, HH), 7.25-7.35 (m, 2H). Preparation 63: [3- (4-chloro-2-fluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid A mixture of [3- (4-chloro-2-methyl) methyl ester -fluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid (0.071 g), tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.30 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of the mixture was adjusted to 4 by the addition of sodium dihydrogen phosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to provide the title compound, 0.064 g. XH NMR (CDCl 3): d 1.3 (t, J = 7.5 Hz, 3H), 2.90 (q, J = 7.5 Hz, 2H), 4.35 (s, 2H), 4.85 (s, 2H), 6.70 (m, HI) ), 6.75 (dd, J = 3.6, 8.7, Hz, ÍH), 6.90 (t, J = 75 Hz, ÍH), 6.95 (m, ÍH), 7.10 (dd, J = 2.1, 9.7 Hz, ÍH), 7.30 (t, J = 9.3 Hz, ÍH). MS: ESI (+ ve) (Method A): 458 (M + H) +, Retention time 12.7 min. Example 64: acid. { 4-difluoromethoxy-2-ethyl-8-fluoro-3- [4- (morpholin-4-sulfonyl) benzyl] quinolin-5-yloxy} acetic Preparation 64a: 4- (4-bromomethylbenzenesulfonyl) morpholine A solution of 4-bromomethylbenzenesulfonyl chloride (0.81 g) in anhydrous diethyl ether (5.0 mL) at -10 ° C was treated with a solution of morpholine (0.26 mL) and triethylamine (0.46 mL) in anhydrous diethyl ether (5.0 mL). The resulting mixture was heated at room temperature for 1 hour and then stirred at this temperature for 17 hours. The mixture was diluted with water, extracted with dichloromethane and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3: 7 by volume) to give the title compound, 0.53 g. XH NMR (CD3OD): d 2.95 (m, 4H), 3.70 (m, 4H), 4.65 (s, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H ). Preparation 64b: 2- [4- (Morpholin-4-sulfonyl) benzyl] -3-oxopentanoic acid methyl ester A suspension of potassium tert-butoxide (0.26 g) in anhydrous tetrahydrofuran (40 mL) at 0 ° C was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (0.25 mL). The mixture was stirred at 0 ° C for 45 minutes and then a solution of 4- (4-bromomethylbenzenesulfonyl) morpholine (0.53 g) in tetrahydrofuran (10 mL) was added and the resulting mixture was heated at room temperature for 1 hour and then it was stirred at this temperature for 17 hours. The mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 1 by volume) to give the title compound, 0.41 g. MS: ESI (+ ve) (Method B): 370 (M + H) +, Retention time 3.2 min. Preparation 64c: methyl ester of acid. { 2-et? L-8-fluoro-3- [4- (morpholine-4-sulfonyl) benzyl] -4-oxo-l, 4-d? H? Droqumolm-5-yloxy} acetic acid A mixture of (3-amino-4-fluorophenoxy) acetic acid methyl ester (0.22 g), 2- [4- (morphol-4-sulfonyl) benzyl] -3-oxopentane-co-methyl acid methyl ester ( 0.41 g), polyphospho-acid (1 g) and dioxane (20 mL) was heated at 130 ° C for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate, dichloromethane and methanol (1: 4: 0 to 1: 1: 0 to 0: 9: 1 by volume) to provide the composed of the title, 0.14 g. XH NMR (DMSO-d6): d 1.00 (t, J = 7.3 Hz, 3H), 2.70 (q, J = 7.3 Hz, 2H), 2.80 (m, 4H), 3.60 (m, 4H), 3.70 (s) , 3H), 4.00 (s, 2H), 4.80 (s, 2H), 6.65 (m, ÍH), 7.40 (m, ÍH) 7.45 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 11.10 (br s, ÍH). Preparation 64d: methyl ester of acid. { 4-d? Fluorometox? -2-et? L-8-fluoro-3- [4- (morpholm-4-sulfonyl) benzyl] qumol? N-5-lloxy} acetic A mixture of methyl ester of acid. { 2-et? L-8-fluoro-3- [4- (morpholine-4-sulfonyl) benzyl] -4-oxo-l, 4-d? H? Dro-qumolm-5-? loxi } acetic acid (0.14 g), N, N-dimethylformamide (3.0 mL), potassium carbonate (0.12 g) and chlorodifluoromethyl ester of acetic acid (0.15 mL) was stirred at 80 ° C for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1: 1 by volume) gave the title compound, 0.092 g. XH? MR (CDC13): d 1.30 (t, J = 7.2 Hz, 3H), 2.90 (q, J = 7.2 Hz, 2H), 2.95 (m, 4H), 3.70 (m, 4H), 3.85 (s, 3H), 4.45 (s, 2H), 4.85 (s, 2H), 6.70 (dd, J = 3.7, 8.7 Hz, ÍH), 7.00 (t, J = 75 Hz, ÍH), 7.25 (d, J = 8.3 Hz, 2H), 7.30 (dd, J = 8.7, 9.6 Hz, ÍH), 7.65 (J = 8.3 Hz, 2H). Preparation 64e: acid. { 4 -d? F luoromethoxy? -2-et? L-8-f luoro-3- [4 - (morpholm-4-sulfonyl) benc? L] qumol? N-5-? loxi } acetic A mixture of methyl ester of acid. { 4 -dif luoromethoxy? -2-et? L-8-f luoro-3- [4 - (morph ol? N-4-sulfonyl) -benzyl] qumol? N-5-? Lox? } acetic acid (0.16 g), tetrahydrofuran (5.0 mL) and aqueous lithium hydroxide solution 1. 0 M (0.32 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of the mixture was adjusted to 4 by the addition of sodium dihydrogen phosphate and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was triturated with a mixture of acetonitrile and water to give the title compound, 0.083 g. XH NMR (DMSO-d6): d 1.15 (t, J = 7.4 Hz, 3H), 2.80 (m, 6H), 3.60 (m, 4H), 4.45 (s, 2H), 4.90 (s, 2H), 7.00 (dd, J = 3.7 Hz, 8.9 Hz, HH), 7.30 (t, J = 75 Hz, HH), 7.35 (d, J = 8.3 Hz, 2H), 7.55 (dd, J = 8.9, 10.1 Hz, HH ), 7.65 (d, J = 8.3 Hz, 2H). MS: ESI (+ ve) (Method A): 555 (M + H) 0 Retention time 10.0 min. MS: ESI (+ ve) (Method B): 555 (M + H) 0 Retention time 3.5 min. Example 65: acid. { 4-difluoromethoxy-2-ethyl-8-fluoro-3- [4- (pyrrolidin-1-carbonyl) benzyl] quinolin-5-yloxy} acetic Preparation 65a: (4-chloromethylphenyl) pyrrolidin-1-ylmetanone A solution of 4-chloromethylbenzoyl chloride (5.0 g) and pyrrolidine (2.2 mL) in dichloromethane (30 mL) at 0 ° C was treated with ethyldiisopropylamine (5.2 mL). The resulting mixture was heated at room temperature for 1 hour and then stirred at this temperature for 2 hours. The mixture was diluted with l.O M aqueous hydrochloric acid, extracted with dichloromethane and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound, 6.0 g. ? H NMR (CDC13): d 1.85-2.00 (m, 4H), 3.40 (t, J = 6.5 Hz, 2H), 3.60 (t, J = 6.8 Hz, 2H), 4.60 (s, 2H), 7.40 ( d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H). Preparation 65b: 3-oxo-2- [4- (pyrrolidin-1-carbonyl) benzyl] pentanoic acid methyl ester A suspension of potassium tert-butoxide (1.4 g) in anhydrous tetrahydrofuran (40 mL) at 0 ° C treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid methyl ester (1.3 mL). The mixture was stirred at 0 ° C for 45 minutes and then a solution of (4-chloromethylphenyl) pyrrolidin-1-ylmethanone (2.0 g) in tetrahydrofuran (10 mL) was added and the resulting mixture was heated at 70 ° C for 24 hours. hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3: 7 by volume) to give the title compound, 1.1 g. MS: ESI (+ ve) (Method B): 318 (M + H) +, Retention time 3.0 min. Preparation 65c: methyl ester of acid. { 2-et? L-8-fluoro-4-oxo-3- [4- (p? Rrol? D? N-1-carbon? L) benzyl] -1,4-d? H? Droqu? Nol? N -5-? Lox ?} acetic A mixture of methyl ester of (3-ammo-4-fluorophenoxy) acetic acid (0.39 g), methyl ester of 3-oxo-2- [4- (pyrrolidone-1-carbon? ) benzyl] pentanoic acid (1.0 g), polyphosphoric acid (2 g) and dioxane (20 mL) was heated at 120 ° C for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (9: 1 by volume) to give the title compound, 0.25 g. MS: ESI (+ ve) (Method B): 467 (M + H) 0 Retention time 2.7 min. Preparation 65d: methyl ester of acid. { 4-d? Fluorometox? -2-et? L-8-fluoro-3- [4- (p? Rrol? Dm-1-carbon? L) benc? L] qu? Nolm-5-yloxy} acetic A mixture of methyl ester of acid. { 2-et? L-8-fluoro-4-oxo-3- [4- (p? Rrol? Dm-1-carbon? L) benzyl] -1,4-d? H? -droqumolm-5-? Lox ? } acetic acid (0.25 g), N, N-d? met? lformamide (5.0 mL), potassium carbonate (0.22 g) and chlorodifluoromethyl acetic acid ester (0.28 mL) was stirred at 80 ° C for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1: 1 by volume) gave the title compound, 0.14 g. MS: ESI (-th) (Method B): 517 (M + H) +, Retention time 3.7 min. Preparation 65e: acid (4-d? Fluorometox? -2-et? L-8-fluoro-3- [4- (p? Rrol? D? N-1-carbon? L) benc? L] qu? Nol? n-5-? lox ?.} acetic A mixture of methyl ester of acid. {4-difluoromethoxy? -2-et? l-8-fluoro-3- [4- (p? rrol? dm-1- carbon? l) -benzyl] quinolin-5-yloxy} acetic acid (0.14 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.55 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of the mixture was adjusted to 4 by the addition of sodium dihydrogen phosphate and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound, 0.11 g. XH NMR (DMSO-d6): d 1.15 (t, J = 7.4 Hz, 3H), 1.75 (m, 4H), 2.85 (q, J = 7.4 Hz, 2H), 3.35 (t, J = 6.4 Hz, 2H ), 3.40 (t, J = 6.8 Hz, 2H), 4.40 (s, 2H), 4.85 (s, 2H), 7.00 (d, J = 3.8, 8.8 Hz, ÍH), 7.15 (d, J = 8.2 Hz , 2H), 7.35 (t, J = 75 Hz, ÍH), 7.45 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.8, 10.1 Hz, ÍH). MS: ESI (+ ve) (Method A): 503 (M + H) +, Retention time 9.4 min. Example 66: 2- [8-chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] -2-methylpropionic acid Preparation 66a: 2- [8-chloro-3- (4-chlorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -2-methylpropionic acid methyl ester A mixture of 8-chloro -3- (4-chlorobenzyl) -5-hydroxy-4-methyl-lH-quinolin-2-one (0.14 g), N, N-dimethylformamide (10 mL), sodium hydride (60% in oil, 0.020 g) ) and 2-bromo-2-methylpropionic acid methyl ester (0.11 g) was stirred at 100 ° C for 3 days. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3: 7 by volume) to give the title compound, 0.056 g. MS: ESI (-? - ve) (Method B): 434 (M + H) +, Retention time 4.3 min. Preparation 66b: 2- [8-chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] -2-methylpropionic acid methyl ester The title compound was prepared by the method of Preparation 65d using 2- [8-chloro-3- (4-chlorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -2-methylpropionic acid methyl ester. MS: ESI (+ ve) (Method B): 484 (M + H) 0 Retention time 5.0 min. Preparation 66c: 2- [8-chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] -2-methylpropionic acid A mixture of 2- [8-chloro-3] methyl ester - (4-Chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] -2-methylpropionic acid (0.030 g), tetrahydrofuran (2.0 mL) and 1.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature environment for 24 hours. The solvent was removed under reduced pressure, diluted with water and the pH adjusted to 4 by the addition of sodium dihydrogen phosphate. The mixture was extracted with ethyl acetate and the combined extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure to provide the title compound, 0.027 g. XH NMR (CDC13): d 1.75 (s, 6H), 2.85 (s, 3H), 4.20 (s, 2H), 6.60 (d, J = 8.4 Hz, ÍH), 7.05 (d, J = 8.5 Hz, 2H ), 7.25 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.4 Hz, ÍH), 7.85 (t, J = 73 Hz, ÍH). MS: ESI (+ ve) (Method A): 470 (M + H) +, Retention time 13.7 min. Example 67: 2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid Preparation 67a: 2- [3- (2,4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-1,2-dihydroquinolin-5-yloxy] propionic acid methyl ester The title compound was prepared by the method of Preparation 34d using 3- (2,4-dichlorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one and 2-bromopropionic acid methyl ester. MS: ESI (tve) (Method B): 438 (M + H) +, Retention time 4.2 min. Preparation 67b: 2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methy1quinolin-5-yloxypropionic acid methyl ester The title compound was prepared by the method of Preparation 65d using methyl ester of 2- [3- (2,4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-l acid, 2-dihydroquinolin-5-yloxy] propionic acid. MS: ESI (+ ve) (Method B): 488 (M + H) 0 Retention time 5.0 min. Preparation 67c: 2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid A mixture of 2- [3- (2,4- -dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid (0.15 g), methanol (5.0 mL), water (0.2 mL) and 5.0 M aqueous lithium hydroxide solution (0.090 mL) it was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was acidified by the addition of glacial acetic acid and the resulting precipitate was collected by filtration, washed with water and a mixture of water and methanol (1: 1 by volume) and then dried to provide the title compound as a solid white, 0.13 g. XH NMR (DMSO-d6): d 1.50 (d, J = 6.6 Hz, 3H), 2.75 (s, 3H), 4.15 (s, 2H), 4.95 (q, J = 6.6 Hz, ÍH), 6.70 (d , J = 8.4 Hz, HH), 6.80 (dd, J = 2.2, 8.4 Hz, HH), 7.20 (dd, J = 2.2, 8.4 Hz, HH), 7.40 (dd, J = 9.0, 10 Hz, HH) , 7.65 (d, J = 2.2 Hz, ÍH), 7.75 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 474 (M + H) 0 Retention time 14.0 min. Example 68: (S) -2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid Preparation 68a: (S) -2- [3- (2,4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] propionic acid methyl ester A mixture of 3- (2,4-dichlorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.40 g), N, N-dimethylformamide (5.0 mL), potassium carbonate (0.17 g) ) and (R) -2-chloropropionic acid methyl ester (0.15 g) was stirred at 40 ° C for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1: 1: 0 to 0: 1: 0 to 0: 10: 1 by volume) to provide the compound of the title as a cream solid, 0.21 g. MS: ESI (+ ve) (Method B): 438 (M + H) +, Retention time 4.2 min. Preparation 68b: (S) -2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid methyl ester The title compound was prepared by the method of Preparation 65d using (S) -2- [3- (2,4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinoline-5-yloxy] propionic acid methyl ester . MS: ESI (+ ve) (Method B): 488 (M + H) 0 Retention time 5.0 min. Preparation 68c: (S) -2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid A mixture of methyl ester of (S) -2 acid - [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methyl-quinolin-5-yloxy] propionic acid (0.070 g), methanol (3.0 mL), water (0.1 mL) and solution of 5.0 M aqueous lithium hydroxide (0.060 mL) was stirred at room temperature for 18 hours. The mixture was acidified by the addition of glacial acetic acid and concentrated under reduced pressure. The residue was triturated with water to give the title compound as a white solid, 0.067 g. XH NMR (DMSO-d6): d 1.45 (d, J = 6.6 Hz, 3H), 2.75 (s, 3H), 4.15 (s, 2H), 4.65 (q, J = 6.6 Hz, ÍH), 6.70 (d , J = 8.5 Hz, HH), 6.75 (dd, J = 4.2, 8.8 Hz, ÍH), 7.20 (dd, J = 2.2, 8.5 Hz, HH), 7.40 (dd, J = 8.8, 9.9 Hz, HH) , 7.65 (d, J = 2.2 Hz, ÍH), 7.75 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 474 (M + H) +, Retention time 14.0 min. Example 69: 2- [8-chloro-3- (4-chlorobenzyl) -2-di luoromethoxy-4-methylquinolin-5-yloxy] propionic acid Preparation 69a: 2- [8-chloro-3- (4-chlorobenzyl) -4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] -propionic acid methyl ester The title compound was prepared by the Preparation method 34d using 8-chloro-3- (4-chlorobenzyl) -5-hydroxy-4-methyl-1H-quinolin-2-one and 2-bromopropronic acid methyl ester. MS: ESI (i-ve) (Method B): 420 (M + H) +, Retention time 4.1 min. Preparation 69b: 2- [8-chloro-3- (4-chlorobenzyl) -2-d? Fluoromethoxy-4-methyl? -quino? -5? Lox?] -propionic acid methyl ester The title compound was prepared by the method of Preparation 65d using 2- [8-chloro-3- (4-chlorobenzyl) -4-met-l-2-oxo-l, 2-d? h? droqu? nolm- methyl ester. 5-Iloxy] propionic. MS: ESI (+ ve) (Method B): 470 (M + H) Retention time 4.8 min. Preparation 69c: 2- [8-Chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolol n-5-? Loxy] propionic acid A mixture of 2- [8-chloro-] methyl ester 3- (4-chlorobenzyl) -2-d? Fluorometox? -4-met? L? Nolm-5-? Lox?] -propionic (0.22 g), tetrahydrofuran (3.0 mL) and aqueous lithium hydroxide solution 1.0 M (1.0 mL) was stirred at room temperature for 3 hours. The mixture was acidified by the addition of sodium dihydrogen phosphate, concentrated low and the residue was extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure to provide the title compound, 0.20 g. XH NMR (DMSO-d6): d 1.60 (d, J = 6.8 Hz, 3H), 2.85 (s, 3H), 4.20 (s, 2H), 5.10 (q, J = 6.8 Hz, ÍH), 6.90 (d , J = 8.7 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.7 Hz, ÍH), 7.90 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 456 (M + H) +, Retention time 13.8 min. Example 70: (R) -2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] ropionic acid Preparation 70a: (R) -2- [3- (2,4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] propionic acid methyl ester A mixture of 3- (2,4-dichlorobenzyl) -8-fluoro-5-hydroxy-4-methyl-1H-quinolin-2-one (0.30 g), N, N-dimethylformamide (4.0 mL), potassium carbonate (0.13 g) ) and (S) -2-chloropropionic acid methyl ester (0.11 g) was stirred at 45 ° C for 3 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 6: 4 by volume) to give the title compound as a pale peach solid, 0.17. g. MS: ESI (+ ve) (Method B): 438 (M + H) +, Retention time 4.2 min. Preparation 70b: (R) -2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid methyl ester The title compound was prepared by the method of Preparation 65d using (R) -2- [3- (2,4-dichlorobenzyl) -8-fluoro-4-methyl-2-oxo-l, 2-dihydroquinolin-5-yloxy] propionic acid methyl ester . MS: ESI (+ ve) (Method B): 488 (M + H) 0 Retention time 4.9 min. Preparation 70c: (R) -2- [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid A mixture of methyl ester of acid (R) -2 - [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methyl-quinolin-5-yloxy] propionic acid (0.054 g), methanol (2.0 mL), water (0.1 mL) and solution of 5.0 M aqueous lithium hydroxide (0.044 mL) was stirred at room temperature for 15 hours. The mixture was acidified by the addition of glacial acetic acid, diluted with water and the resulting precipitate was collected by filtration to give the title compound as a white solid, 0.048 g. XH NMR (DMSO-dd): d 1.50 (d, J = 6.7 Hz, 3H), 2.75 (s, 3H), 4. 15 (s, 2H), 4.85 (q, J = 6.7 Hz, ÍH), 6.70 (d, J = 8. 4 Hz, ÍH), 6.75 (dd, J = 4.0, 9.0 Hz, ÍH), 7.20 (dd, J = 2.1, 8.4 Hz, ÍH), 7.40 (dd, J = 9.0, 9.7 Hz, ÍH), 7.65 (d, J = 2.1 Hz, ÍH), 7.75 (t, J = 72 Hz, ÍH). MS: ESI (+ ve) (Method A): 474 (M + H) 0 Retention time 14. 4 min. Example 71: acid. { 8-chloro-4-difluoromethoxy-2-ethyl-3- [4- (pyrrolidin-1-carbonyl) benzyl] quinolin-5-yloxy} acetic Preparation 70a: methyl ester of acid. { 8-Chloro-2-ethyl-4-oxo-3- [4- (pyrrolidin-1-carbonyl) benzyl] -1, -dihydroquinolin-5-yloxy} acetic acid A mixture of (3-amino-4-chlorophenoxy) acetic acid methyl ester (1.0 g), 3-oxo-2- [4- (pyrrolidin-1-carbonyl) benzyl] pentanoic acid methyl ester (1.9 g) , polyphosphoric acid (6.0 g) and dioxane (20 mL) was heated at 120 ° C for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and methanol (9: 1: 0 to 0: 9: 1 by volume) to give the title compound, 0.079 g . MS: ESI (+ ve) (Method B): 483 (M + H) +, Retention time 3.0 min. Preparation 70b: methyl ester of acid (8-chloro-4-difluoromethoxy? -2-et? L-3- [4- (p? Rrol? D? N-1-carbon? L) -benzyl] quinol? N- 5-? Lox ?.} acetic The title compounds were prepared by the method of Preparation 65d using methyl ester of acid. {8-chloro-2-et? L-4-oxo-3- [4-p? r? d? nl-carbon? l) benc? l] -ld? h? droqu? nolm-5-? lox?] acetic. MS: ESI (+ ve) (Method B): 533 (M + H) 0 Retention time 4.1 min. Preparation 70c: acid. { 8-chloro-4-d? Fluorometox? -2-et? L-3- [4- (p? Rrol? D? N-1-carbon? L) benc? L] qumolm-5-? Lox ?} acetic A mixture of methyl ester of acid. { 8-chloro-4-difluoromethoxy? -2-et? L-3- [4- (p? Rrol? Dm-1-carbonyl) benzyl) qumolm-5-? Lox?) Acetic (0.037 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.0 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, acidified by the addition of sodium dihydrogen phosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure to provide the title compound, 0.034 g. XH NMR (DMSO-d6): d 1.15 (t, J = 7.3 Hz, 3H), 1.70-1.80 (m, 4H), 2.80 (q, J = 7.3 Hz, 2H), 3.40 (m, 4H), 4.35 (s, 2H), 4.70 (s, 2H), 6.90 (d, J = 8.5 Hz, ÍH), 7.10 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.50 (m, ÍH), 7.80 (d, J = 8.5 Hz, ÍH). MS: ESI (+ ve) (Method A): 519 (M + H) 0 Retention time 11.1 min. Example 72: acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy} acetic Preparation 72a: 4-bromomethyl-3-chlorobenzonitrile A mixture of 3-chloro-4-methylbenzonitrile (4.8 g), N-bromosuccinimide (5.5 g), dibenzoyl peroxide (0.43 g) and carbon tetrachloride (30 mL) was heated to reflux for 2 hours. The mixture was cooled to room temperature, filtered and washed with dichloromethane. The filtrate was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1: 0 to 19: 1 by volume) gave the title compound, 4.1 g. XH NMR (CDC13): d 4.55 (s, 2H), 7.55 (m, 2H), 7.70 (m, ÍH). Preparation 72b: 4-bromomet? L-3-chlorobenzoic acid A mixture of 4-bromomet? L-3-chloro-3-benzonthyl (0.24 g) and hydrogen bromide solution (48% by weight) in water, 3.0 mL) was heated overnight in a sealed vial at 100 ° C. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were extracted with dilute aqueous potassium carbonate solution and the combined aqueous extracts were acidified by the addition of 1.0 M aqueous hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give the title compound as a white solid, 0.10 g. MS: ESI (+ ve) (Method B): 250 (M-1H) +, Retention time 3.2 mm. Preparation 72c: (-bromomet? L-3-chlorophenyl) p? Rrol? D? N-1-ylmetanone A mixture of 4-bromomet? L-3-chlorobenzoic acid (0.090 g) and thionyl chloride (3.0 mL. ) was heated at 85 ° C for 90 minutes. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the resulting solution was cooled to 0 ° C and then treated with N, N-diisopropylethylamine, followed by pyrrolidine (0.030 mL). The mixture was stirred at 0 ° C for 20 minutes, diluted with saturated aqueous hydrogen carbonate solution and extracted with dichloromethane. The combined extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4: 1 by volume) to give the title compound as a yellow solid, 0.070 g. XH? MR (CDC13): d 1.90 (m, 4H), 3.40 (m, 2H), 3.65 (m, 2H), 4.70 (s, 2H), 7.40 (dd, J = 1.6, 7.8 Hz, ÍH), 7.50 (d, J = 7.8 Hz, ÍH), 7.55 (d, J = 1.6 Hz, ÍH). Preparation 72d: 2- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -3-oxopentanoic acid methyl ester A solution of 3-oxopentanoic acid ethyl ester (14 mL) in 1,2-dimethoxyethane ( 25 mL) was added to a stirred suspension of sodium hydride (60% in oil, 3.7 g) in 1,2-dimethoxyethane (250 mL) and N, N-dimethylformamide (30 mL) at 0 ° C and the resulting mixture it was stirred at 0 ° C for 10 minutes. A solution of (4-bromomethyl-3-chlorophenyl) pyrrolidin-1-ylmethanone (9.7 g) in 1,2-dimethoxyethane (25 mL) was added and the resulting mixture was warmed to room temperature and then stirred at this temperature for 20 hours. The mixture was diluted with saturated aqueous ammonium chloride solution, extracted with diethyl ether and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9: 1 by volume) to give the title compound, 1.8 g. MS: ESI (+ ve) (Method B): 266 (M + H) +, Retention time 3.4 min. Preparation 72e: methyl ester of acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy} acetic acid The title compound was prepared by the method of Preparation 65c using 2- (2-chloro-4- (pyrrolidin-1 -carbonyl) benzyl] -3-oxopentanoic acid methyl ester and methyl ester of 3-amino acid 4-fluorophenoxy) acetic acid. MS: ESI (+ ve) (Method B): 501 (M + H) +, Retention time 2.9 min. Preparation 72f: methyl ester of acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy} acetic The title compounds were prepared by the 2JJ Preparation method 65d using methyl ester of acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) encyl] -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy] acetic acid. MS: ESI (+ ve) (Method B): 551 (M + H) +, Retention time 3.5 min. Preparation 72g: methyl ester of acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid A mixture of methyl ester of acid. { 3- [2-chloro-4-pyrrolidin-1-carbonol) benzyl] -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy} acetic acid (0.26 g), tetrahydrofuran (5.0 mL), water (5.0 mL) and lithium hydroxide (0.040 g) were stirred at room temperature for 20 minutes. The mixture was washed with ethyl acetate and the aqueous phase was acidified by the addition of 1.0 M aqueous hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by preparative reverse phase HPLC, using a gradient of acetonitrile in water gave the title compound as an off-white solid, 0.13 g. XH NMR (DMSO-d6): d 1.20 (t, J = 7.4 Hz, 3H), 1.80-1.95 (m, 4H), 2.80 (q, J = 7.4 Hz, 2H), 3.40 (t, J = 6.4 Hz , 2H), 3.50 (t, J = 7.0 Hz, 2H), 4.45 (s, 2H), 4.85 (s, 2H), 6.70 (d, J = 8.0 Hz, ÍH), 6.90 (dd, J = 3.7, 8.8 Hz, ÍH), 7.10 (t, J = 75 Hz, ÍH), 7.25 (dd, J = 1.7, 8. 0 Hz, ÍH), 7.40 (dd, J = 8.0, 10 Hz, ÍH), 7.60 (d, J = 1.7 Hz, ÍH). MS: ESI (+ ve) (Method A): 537 (M + H) +, Retention time . 1 min. MS: ESI (+ ve) (Method B): 537 (M + H) +, Retention time 3.6 min. Example 73: (S) -2- acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy} propionic Preparation 73a: methyl ester of (S) -2- acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy} propionic The title compound was prepared by the method of Preparation 65c using 2- (2-chloro-4- (pyrrolidin-1-carbonyl) -benzyl] -3-oxopentanoic acid methyl ester and (S) -2-methyl ester - (3-amino-4-fluorophenoxy) propionic. MS: ESI (+ ve) (Method B): 515 (M + H) +, Retention time 3.2 min.

Preparation 73b: methyl ester of (S) -2- acid. { 3- [2-chloro-4- (p? Rrol? Dm-1-carbon? L) benzyl] -4-d? Fluorometox? -2-et? 1-8-fluoroqumolm-5-? Lox? } propionic The title compounds were prepared by the method of Preparation 65d using methyl ester of (S) -2- acid. { 3- [2-chloro-4- (p? Rrol? Dm-1-carbon? L) benz? J-2-et? L-8-fluoro-4-oxo-l, 4-d? H? Droqu? nolm-5-? lox? } propionic MS: ESI (Fve) (Method B): 565 (M + H) 0 Retention time 3.7 min. Preparation 73c: (S) -2- acid. { 3- [2-chloro-4- (p? Rrol? Dm-1-carbonyl) benzyl] -4-d? Fluorometox? -2-et? L-8-fluoroquinol-5-yloxy} propionic A mixture of methyl ester of (S) -2- acid. { 3- [2-chloro-4- (p? Rrol? D? N-1-carbon? L) benzyl] -4-d? Fluorometox? -2-et? L-8-fluoroqumolm-5-? Lox? Jpropionic (0.75 g), tetrahydrofuran (20 mL), water (20 mL) and lithium hydroxide (0.11 g) was stirred at room temperature for 20 minutes. The mixture was washed with ethyl acetate and the aqueous phase was acidified by the addition of 1.0 M aqueous hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on a C-18 column, eluting with a mixture of water and methanol (4: 1 to 0: 1 by volume) gave the title compound as an off-white solid, 0.20 g. XH NMR (DMSO-d6): d 1.20 (t, J = 7.5 Hz, 3I-J 1.65 (d, J = 6.8 Hz, 3H), 1.85-1.95 (m, 4H), 2.80 (m, 2H, 3.40 ( t, J = 6.4 Hz, 2H), 3.50 (t, J = 6.9 Hz, 2H), 4.40 (d, J = 17 Hz, ÍH), 4.50 (d, J = 17 Hz, ÍH), 5.10 (q, J = 6.8 Hz, ÍH), 6.70 (d, J = 8.0 Hz, ÍH), 6.85 (dd, J = 3.6, Hz, IH: 7.15 (dd, J = 70, 81 Hz, ÍH), 7.25 (dd, J = 1.7, 8.0 Hz, HH), 7.35 (dd, J = 8.8, 10 Hz, HH), 7.60 (d, J = 1.7 Hz, HH) MS: ESI (+ ve) (Method A): 551 ( M + H) +, Retention time 10.6 min Example 74 and 75: (S) -2- [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy acid ] propionic acid and (S) -2- [3- (2,4-dichlorobenzyl) -2-ethyl-8-fluoro-4-methoxyquinolin-5-yloxy] propionic acid Preparation 74a and 75a: (S) -2- (3-amino-4-fluorophenoxy) propionic acid methyl ester A solution of 3-amino-4-fluorophenol (4.1 g) in N, N-dimethylformamide (15 mL) was added dropwise to a stirred suspension of sodium hydride (60% in oil, 1.3 g) in N, N-dimethyl formamide (35 mL) at 0 ° C. The mixture was stirred at room temperature for 30 minutes, cooled to 0 ° C and then (R) -2-chloropropionic acid methyl ester (4.0 g) was added in one portion. The resulting mixture was stirred at room temperature overnight and was treated with saturated, aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the purification of the residue by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 0 to 3: 2 by volume) to give the mixture of the compounds of the title as a golden oil, 2.5 g. XH NMR (CDC13): d 1.55 (d, J = 6.7 Hz, 3H), 3.75 (s, 3H), 4.65 (q, J = 6.7 Hz, ÍH), 6.15 (dt, J = 3.0, 8.8 Hz, ÍH ), 6.35 (dd, J = 3.0, 7.5 Hz, ÍH), 6.85 (dd, J = 8.8, 10.6 Hz, ÍH).

Preparation 74b and 75b: (S) -2- [3- (2,4-dichlorobenzyl) -2-ethyl-8-fluoro-4-oxo-l, 4-dihydroquinolin-5-yloxy] propionic acid methyl ester Title compounds were prepared by the method of Preparation 65c using (S) -2- (3-amino-4-fluorophenoxy) propionic acid methyl ester and 2- (2,4-dichlorobenzyl) -3-oxopentanoic acid methyl ester . MS: ESI (+ ve) (Method B): 452 (MH-H) +, Retention time 3.8 min. Preparation 74b and 75b: (S) -2- [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] propionic acid methyl ester and methyl ester of acid (S) ) -2- [3- (2,4-dichlorobenzyl) -2-ethyl-8-fluoro-4-methoxyquinolin-5-yloxy] -propionic The title compounds were prepared by the method of Preparation 65d using acid methyl ester (S) -2- [3- (2,4-dichlorobenzyl) -2-ethyl-8-fiuoro-4-oxo-l, 4-dihi-droquinolin-5-yloxy] propionic acid. Methyl ester of (S) -2- [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] propionic acid ester MS: ESI (+ ve) (Method B): 502 (M + H) +, Retention time 4.5 min. Methyl ester of (S) -2- [3- (2,4-dichlorobenzyl) -2-ethyl-8-fluoro-4-methoxyquinolin-5-yloxy] propionic acid MS: ESI (+ ve) (Method B): 466 (M + H) +, Retention time 4.3 min. Preparation 74c and 75c: (S) -2- [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] propionic acid and (S) -2- [3 - (2,4-dichlorobenzyl) -2-ethyl-8-fluoro-4-methoxyquinolin-5-yloxy] propionic acid A mixture of methyl ester of (S) -2- [3- (2,4-dichlorobenzyl) - 4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] propionic acid and (S) -2- [3- (2,4-dichlorobenzyl) -2-ethyl-8-fluoro-4-methoxyquinoline methyl ester -5-yl-xylpropionic acid (0.58 g), methanol (10 mL), water (0.8 mL) and 5.0 M aqueous lithium hydroxide solution (0.40 mL) were stirred at room temperature overnight. The mixture was acidified by the addition of glacial acetic acid and concentrated under reduced pressure. Purification of the residue by column chromatography on a C-18 column, eluting with a mixture of water and acetonitrile (4: 1 to 0: 1 by volume) gave (S) -2- [3- (2, 4) acid. -d? clorobenz?) -4-difluoromethoxy? -2-et? l-8-fluoroquinol-5? lox?] propionic as a white solid, 0.23 and acid (S) -2- [3- (2, 4-dichlorobenzyl) -2-et? L-8-fluoro-4-methox? Qumolm-5-? Lox?] -propionic as a white solid, 0.035 g. (S) -2- [3- (2, 4-d? Chlorobenzyl) -4-d? Fluoromethoxy? -2-et? L-8-fluoroquinolm-5-? Lox?] Propionic XH NMR (DMS0-d6): d 1.15 (t, J = 7.4 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H), 2.60-2.80 (m, 2H), 4.20 (d, J = 17 Hz, ), 4.35 (d, J = 17 Hz, ÍH), 4.60 (d, J = 6.7 Hz, ÍH), 6.55 (d, J = 8.4 Hz, ÍH), 6.75 (dd, J = 3.8, 9.1 Hz, HH), 7.20 (dd, J = 2.2, 8.4 Hz, HH), 7.40 (dd, J = 8.9, 10.4 Hz, ÍH), 7.65 (d, J = 2.2 Hz, HH), 8.25 (dd, J = 66, 86 Hz, ÍH). MS: ESI (+ ve) (Method A): 488 (MH-H) 0 Retention time 14.1 min. (S) -2- [3- (2, 4-d? Chlorobenzyl) -2-et? L-8-fluoro-4-methox? Qu? Nolm-5-? Lox?] Propionic XH NMR ( DMSO-d6): d 1.15 (t, J = 7.3 Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H), 2.65 (m, 2H), 3.80 (s, 3H), 4.10 (d, J = 17 Hz, ÍH), 4.20 (d, J = 17 Hz, 1H), 4.35 (q, J = 6.7 Hz, ÍH), 8.60 (m, 2H), 7.20 (dd, J = 2.2, 8.4 Hz, ÍH) , 7.30 (dd, J = 8.8, 11 Hz, ÍH), 7.60 (d, J = 2.2 Hz, ÍH). MS: ESI (+ ve) (Method A): 452 (M + H) +, Retention time 12.7 min. Example 76: [3- (2-chloro-74-cyclobutylcarbamoylbenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid Preparation 76a: 4-Bromomethyl-3-chloro-N-cyclobutylbenzamide A mixture of 4-bromomethyl-3-chlorobenzoic acid (1.4 g) and thionyl chloride (10 mL) was heated to reflux for 5 hours. The mixture was cooled to room temperature, diluted with toluene and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and the resulting solution was cooled to 0 ° C and then treated dropwise with a mixture of N, N-diisopropylethylamine (1.1 mL) and cyclobutylamine (0.48 mL). The resulting mixture was stirred at room temperature overnight, dichloromethane was diluted and washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1: 1 by volume) to give the title compound as an oil, 0.070. g. MS: ESI (+ ve) (Method B): 303 (M + H) +, Retention time 3.4 min. Preparation 76b: 2- (2-chloro-4-cyclobutylcarbamoylbenzyl) -3-oxopentanoic acid ethyl ester A suspension of potassium tert-butoxide (0.34 g) in anhydrous tetrahydrofuran (15 mL) at 0 ° C was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid ethyl ester (038 mL). The mixture was stirred at 0 ° C for 45 minutes and then a solution of 4-bromomethyl-3-chloro-N-cyclobutylbenzamide (0.67 g) in tetrahydrofuran (5.0 mL) was added and the resulting mixture was heated at 70 ° C for 24 hours. hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran was removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1: 5 by volume) to give the title compound, 0.44 g.

MS: ESI (+ ve) (Method B): 366 (MH-H) +, Retention time 3.7 min. Preparation 76c: [3- (2-Chloro-4-cyclobutylcarbamoylbenzyl) -2-ethyl-8-fluoro-4-oxo-1,4-dihydro-quinolin-5-yloxy] -acetic acid methyl ester The title compound is prepared by the method of Preparation 65c using 2- (2-chloro-4-cyclobutylcarbamoylbenzyl) -3-oxopentanoic acid methyl ester and (3-amino-4-fluorophenoxy) acetic acid methyl ester. MS: ESI (+ ve) (Method B): 501 (M + H) +, Retention time 2.9 min. Preparation 76d: [3- (2-chloro-4-cyclobutylcarbamoylbenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid methyl ester The title compounds were prepared by the method of Preparation 65d using [3- (2-Chloro-4-cyclobutylcarbamoylbenzyl) -4-ethyl-8-fluoro-4-oxo-1,4-dihydroquinolin-5-yloxy] acetic acid methyl ester. MS: ESI (+ ve) (Method B): 551 (M + H) +, Retention time 3.6 min. Preparation 76e: [3- (2-chloro-4-cyclobutylcarbamoylbenzyl) -4-difluoromethoxy-2-ethyl-8-fluoro-quinolin-5-yloxy] acetic acid A mixture of methyl ester of [3- (2-chloro) acid -4-cyclobutylcarbamoylbenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid (0.23 g), tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.2 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, acidified by the addition of sodium dihydrogen phosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on a C-18 column, eluting with a mixture of water and methanol gave the title compound as an off-white solid, 0.13 g. ? ti NMR (DMS0-d6): d 1.15 (t, J = 7.4 Hz, 3H), 1.60 (m, 2H), 2.00 (m, 2H), 2.15 (m, 2H), 2.70 (q, J = 7.4 Hz, 2H), 4.35 (m, 3H), 4.80 (s, 2H), 6.65 (d, J = 8.1 Hz, ÍH), 6.95 (dd, J = 3.8, 9.0 Hz, ÍH), 7.25 (t, J = 75 Hz, ÍH), 7.50 (dd, J = 9.0, 10 Hz, ÍH), 7.55 (dd, J = 1.7, 8.1 Hz, HH), 7.95 (d, J = 1.7 Hz, HH), 8.65 (d, J = 7.5 Hz, HH). MS: ESI (+ ve) (Method A): 537 (M + H) +, Retention time 10.9 min. Example 77: (S) -2- [3- (2-chloro-4-cyclobutylcarbamoylbenzyl) -4-difluoromethoxy-2-ethyl-8-fluoro-quinolin-5-yloxy] propionic acid Preparation 77a: (S) -2- [3- (2-chloro-4-cyclobutylcarbamoylbenzyl) -2-et? L-8-fluoro-4-oxo-l, 4-d? qumolm-5-? lox?] propionic The title compound was prepared by the method of Preparation 65c using 2- (2-chloro-4-c? clobut? lcarbamo? lbenc? l) -3-oxopentane methyl ester? co and (S) -2- (3-am? no-4-fluorophenoxy) propionic acid methyl ester.

MS: ESI (+ ve) (Method B): 515 (M + H) +, Retention time 2.9 min. Preparation 77b: (S) -2- [3- (2-chloro-4-cyclobutylcarbamoylbenzyl) -4-d? Fluoromethoxy? -2-et? L -8-fluoro-qumolm-5-? Lox methyl ester? ] propionic The title compounds were prepared by the method of Preparation 65d using (S) -2- [3- (2-chloro-4-c? clobut? lcarbamo? lbenc? l) -2-et? l-8-fluoro-4-oxo-l, 4-d? h? droqumolm-5-? lox?] propionic. MS: ESI (+ ve) (Method B): 565 (M + H) +, Retention time 3.8 min. Preparation 77c: (S) -2- [3- (2-Chloro-4-cyclobutylcarbamoylbenzyl) -4-d? Fluorometox? -2-et? L-8-fluoro-qumolm-5-? Lox?] Propionic A mixture of methyl ester of (S) -2- [3- (2-chloro-4-c? clobut? lcarbamo? lbenc? l) -4-difluoromethoxy? -2-et? l-8-fluoroquinol-5- ? lox?] propionic (0.18 g), tetrahydrofuran (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.0 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, acidified by the addition of sodium dihydrogen phosphate and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification of the residue by column chromatography on a C-18 column, eluting with a mixture of water and methanol (9: 1 to 0: 1 by volume) gave the title compound as a pale yellow solid, 0.13 g. * H NMR (DMSO-d6): d 1.20 (t, J = 7.6 Hz, 3H), 1.60 (d, J = 6.7 Hz, 3H), 1.65 (m, 2H), 2.05 (m, 2H), 2.20 ( m, 2H), 2.75 (m, 2H), 4.40 (m, 3H), 5.10 (q, J = 6.7 Hz, ÍH), 6.70 (d, J = 8.1 Hz, ÍH), 6.90 (dd, J = 3.4 , 9.0 Hz, ÍH), 7.35 (t, J = 75 Hz, ÍH), 7.55 (dd, J = 9.0, 10 Hz, 'ÍH), 7.60 (dd, J = 1.8, 8.1 Hz, ÍH), 8.00 ( d, J = 1.8 Hz, HH), 8.70 (d, J = 7.5 Hz, HH). MS: ESI (+ ve) (Method A): 551 (M + H) 0 Retention time 10.9 min. MS: ESI (+ ve) (Method B): 551 (M + H) +, Retention time 3.9 min. Example 78: [3- (4-chlorobenzyl) -, 7-dimethylquinolin-5-yloxy] acetic acid Preparation 78a: 2-chloro-3- (4-chlorobenzyl) -4,7-dimethylquinolin-5-ol A solution of 3- (4-chlorobenzyl) -5-hydroxy-4,7-dimethyl-lH-quinolin-2-one (1.8 g) in phosphorus oxychloride (9.0 mL) was heated at 180 ° C in a microwave reactor for 15 minutes. The solution was poured into a mixture of ice and water and the resulting precipitate was collected by filtration, washed with water and then dried to give the title compound, 2.3 g. Preparation 78b: [2-chloro-3- (4-chlorobenzyl) -4,7-dimethylquinolin-5-yloxy] acetic acid methyl ester A mixture of 2-chloro-3- (4-chlorobenzyl) -4, 7- dimethylquinolin-5-ol (1.7 g), N, N-dimethylformamide (25 mL), potassium carbonate (2.1 g) and bromoacetic acid methyl ester (1.1 g) was stirred at 60 ° C overnight. The mixture was cooled to room temperature, diluted with water and the resulting precipitate was collected by filtration, washed with water and then dried to provide the title compound, 0.53 g. MS: ESI (+ ve) (Method B): 404 (M + H) 0 Retention time 4.4 min. Preparation 78c: [3- (4-Chlorobenzyl) -4,4-dimethylquinolin-5-yloxy] acetic acid methyl ester A mixture of [2-chloro-3- (4-chlorobenzyl) -ethyl acid methyl ester -4-7 -dimethylquinolin-5-yloxy] acetic acid (0.20 g), palladium (10% by weight on activated carbon, 0.020 g), ethanol (7.0 mL) and 1.0 M aqueous hydrochloric acid (1.5 mL) was stirred at 40 ° C for 17 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washed with ethanol and the filtrate was concentrated under reduced pressure to provide the title compound0.18 g. MS: ESI (+ ve) (Method B): 370 (M + H) 0 Retention time 2.8 min. Preparation 78d: [3- (4-chlorobenzyl) -4,7-dimethylquinolin-5-yloxy] acetic acid A mixture of [3- (4-chlorobenzyl) -4,7-dimethylquinolin-5-yloxy] methyl ester] acetic acid (1.8 g), tetrahydrofuran and potassium trimethylsilanolate (0.19 g) was heated at 100 ° C in a microwave reactor for 5 minutes. The mixture was concentrated under reduced pressure, diluted with water and acidified by the addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration and purified by preparative reverse phase HPLC, using a gradient for 30 minutes of acetonitrile in water (35% to 95% organic modifier) to provide the title compound, 0.015 g.

X H NMR (DMSO-d 6): d 2.40 (s, 3 H), 2.75 (s, 3 H), 4.15 (s, 2 H), 4. 80 (s, 2H), 6.80 (s, ÍH), 7.10 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.35 (m, ÍH), 8.65 (s, ÍH), 13.00 (br s, ÍH). MS: ESI (+ ve) (Method A): 356 (M + H) 0 Retention time 7.3 min. MS: ESI (+ ve) (Method B): 356 (M + H) +, Retention time 2.3 min. Example 79: [3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid Preparation 79a: [3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid methyl ester A mixture of [4,8-dichloro-3- (4-chlorobenzyl) -2-methylquinoline] methyl ester -5-yloxy] acetic acid (0.13 g), palladium (5% by weight on activated carbon, 0.010 g), ethanol (5.0 mL) and 1.0 M aqueous hydrochloric acid (1.0 mL) was stirred at room temperature for 17 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washed with ethanol and water and the solvent was removed under reduced pressure to give the title compound, 0.11 g. Preparation 79b: [3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid A solution of [3- (4-chlorobenzyl) -2-methylquinolin-5-yloxy] acetic acid methyl ester (0.11 g) ), ethanol (6.0 mL), water (2.0 mL) and saturated, aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 5 hours. The ethanol was removed under reduced pressure and the pH of the residue was adjusted to 4 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with water and purification by preparative reverse phase HPLC using a gradient for 37 minutes of acetonitrile in water (20% to 95% organic modifier) gave the title compound as a gum yellow, 0.028 mg. XH NMR (DMSO-d6): d 2.70 (s, 3H), 4.30 (s, 2H), 5.00 (s, 2H), 7.10 (d, J = 8.1 Hz, ÍH), 7.25 (d, J = 8.5 Hz , 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, ÍH), 7.80 (t, J = 8.1 Hz, ÍH), 8.65 (s, ÍH). MS: ESI (+ ve) (Method A): 342 (M + H) +, Retention time 6.9 min. MS: ESI (+ ve) (Method B): 342 (M + H) +, Retention time 2.2 min. Biological Methods The compounds of the invention of the formula [1] were tested using the following biological test methods to determine their ability to displace PGD2 from the CRTH2 receptor and by their ability to antagonize the functional effects of PGD2 to the CRTH2 receptor in a system of complete cell. Radioligand Linkage Assay The receptor linkage assay is performed in a final volume of 200 μL of binding buffer solution [10 mM BES (pH 7.4), 1 mM EDTA, 10 mM manganese chloride, 0.01% BSA] and [3 H] -PGD2 1 nM (Amersham Biosciences UK Ltd). The ligands are added in assay buffer containing a constant amount of DMSO (1% by volume). The total binding is determined using 1% by volume of DMSO in assay buffer and the non-specific binding is determined using 10 μM of unlabeled PGD2 (Sigma). Human embryonic kidney (HEK) cell membranes (3.5 μg) expressing the CRTH2 receptor are incubated with 1.5 mg SPA beads of wheat germ agglutinin and 1 nM [3H] -PGD2 (Amersham Biosciences UK Ltd) and The mixture is incubated for 3 hours at room temperature. Bound [3H] -PGD2 is detected using a Microbeta TRILUX liquid scintillation counter (Perkin Elmer). The IC 50 value of the compound is determined using a 6-fold dose response curve in duplicate with a series of semi-log compound dilution. IC5o 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. The compounds of the invention that have been tested in the binding assay are illustrated below in the following Table. zsz Password: "+++" CRTH2 Ki < lOOnM; "++" Ki < IμM; "+" Ki < lOμM Functional Assay: Calcium Mobilization Stable CHO-K1 cells that co-express the CRTH2 receptor and Gal6 protein G are seeded (40, 000 cells per well in a plate extension volume of 75 μL in F-12 Hams supplemented with 1% fetal bovine serum) in 96 cavity plates coated with collagen 24 hours before the test. The cells are then loaded with a fluorescence imaging plate reader (FLIPR) of calcium equipment stain (Calcium 3 equipment, Molecular Devices Ltd) containing 5 mM final concentration of probenecid and incubated at 37 ° C for 1 min. hour in an atmosphere of C02 at 5%. The fluorescence emission caused by the mobilization of intracellular calcium produced by the PGD2 to the CRTH2 receptor is determined with a superior FLEXstation bank scan and integrated fluid transfer workstation (Molecular Devices Ltd). To detect antagonists and determine the IC50 of the compound, the compounds are pre-incubated at varying concentrations with the cells loaded for 15 minutes at 37 ° C, 5% C02, before the addition of the agonist at its ECso- value. and the agonist are added in Hanks balanced salt solution containing 20 mM HEPES and 0.1% BSA). The fractional response values for each cavity are calculated by subtracting the basal response from the peak response. The results are calculated as the mean of tripled cavities using Excel and XLfit (Microsoft). As an illustration, the following compounds were shown to have IC50S of <; 1 μM in this assay: 20, 42; and the following compounds had IC50s < 100 nM in this trial: 12, 18.

Claims

CLAIMS 1. Use of a compound of the formula [1] or a pharmaceutically acceptable salt, N-oxide, hydrate or solvate thereof:

[1] wherein: R1, R2, R3, R4 and R5 are independently hydrogen, Ci-Cd alkyl, Ci-Ce alkyl, fully or partially fluorinated, cyclopropyl, halo, -S (0) nR6, -S02NR7R8, -NR7R8, -NR7C (0) R6, -C02R7, -C (0) NR7R8, -C (0) R6, -N02, -CN or a group -OR9; wherein each R6 is independently Ci- Ce alkyl, C6-C6 alkyl completely or partially fluorinated, cycloalkyl, aryl or heteroaryl; R7, R8 with independently Ci-Cg alkyl, C6-C6 alkyl completely or partially fluorinated, cycloalkyl, cycloalkyl- (Ci- C? Alkyl), aryl, heteroaryl or hydrogen; R 9 is C 1 -C 6 alkyl, C 1 -C 6 alkyl completely or partially fluorinated, cycloalkyl, cycloalkyl- (C 6 -C 6 alkyl), or a -S02R6 group; A is -CHR10-, -C (0) -, -S (0) n-, -O- or -NR10- wherein n is an integer of 0-2 and R10 is hydrogen, C1-C3 alkyl or C1-C3 alkyl completely or partially fluorinated; B is a divalent radical selected from -CH2-, -CH2CH2-, -CHR11-, -CR ?: LR12-, -CH2CHRn- in any orientation, CH2CR R12- in any orientation, -CHRUCHR12- in any orientation and - (CR11R12) P-Z- where Z joins the ring bearing R1, R2 and R3; wherein R 11 is C 1 -C 3 alkyl, cyclopropyl or C 1 -C 3 alkyl completely or partially fluorinated; R12 is methyl or methyl completely or partially fluorinated; p is independently 1 or 2; and Z is -O-, -NH- or -S (0) n_, where n is an integer of 0-2; X is a carboxylic acid, tetrazole, 3-hydroxyisoxazole, hydroxamic acid, phosphinate, phosphonate, phosphonamide or sulfonic acid group, or a group of the formula C (= 0) NHS02R6 or S02NHC (= 0) R6; and Y is aryl, heteroaryl, heterocycloalkyl fused with aryl, cycloalkyl fused with heteroaryl, heterocycloalkyl fused with heteroaryl or cycloalkyl group fused with aryl; characterized in that it is for the manufacture of a medicament for use in the treatment of conditions responsive to the modulation of CRTH2 receptor activity. 2. Use according to claim 1, characterized in that R1 is fluoro or chloro. 3. Use according to claim 1 or claim 2, characterized in that R2 is hydrogen, chlorine or methyl. 4. Use according to any of the preceding claims, characterized in that R3 is hydrogen. 5. Use according to any of the preceding claims, characterized in that R4 is methyl, ethyl, methoxy or difluoromethoxy. 6. Use according to any of the preceding claims, characterized in that R5 is methyl, ethyl, ethoxy, isopropoxy, difluoromethoxy or cyano. 7. A use according to any of the preceding claims, characterized in that A is -CH2-, -O- or -S (0) n- where n is 0, 1 or 2. 8. A use in accordance with any of the preceding claims, characterized in that B is -CH2-, -0CH (CH3) - or -0CH2- wherein the oxygen is attached to the ring bearing R1, R2 and R3. 9. Use according to any of the preceding claims, characterized in that X is -C02H. 10. A use according to any of the preceding claims, characterized in that Y is 4-fluorophenyl, 4-chlorophenyl, 4-methanesulfonylphenyl, 4-ethanesulfonylphenyl, 4- (morpholin-4-sulfonyl) phenyl, 4- (pyrrolidine-1-carbonyl ) phenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methanesulfonylphenyl, 2-chloro-4- (pyrrolidin-1) carbonyl) phenyl or 2-chloro-4-cyclobutylcarbamoyl. 11. A compound as defined in any of the preceding claims, characterized in that R4 and R5 are not simultaneously hydrogen. 12. A compound according to claim 11, characterized in that R1 is fluoro or chloro; R2 and R3 are hydrogen; R4 is methyl, ethyl, methoxy or difluoromethoxy; R5 is methyl, ethyl, ethoxy, isopropoxy, difluoromethoxy or cyano; A is -CH2-, -O- or -S (0) n- wherein n is 0, 1 or 2; B is -CH2-, -OCH (CH3) - or -OCH2- wherein the oxygen is attached to the ring bearing R1, R2 and R3; X is -C02H; and Y is 4-fluorophenyl, 4-chlorophenyl, 4-methanesulfonylphenyl, 4-ethanesulfonylphenyl, 4- (morpholin-4-sulfonyl) phenyl, 4- (pyrrolidin-1-carbonyl) phenyl, 2,4-difluorophenyl, 2,4 -dichlorophenyl, 2-chloro-2-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methanesulfonylphenyl, 2-chloro-4- (pyrrolidin-1-carbonyl) phenyl and 2-chloro-4-cyclobutylcarbamoyl. 13. A compound, characterized in that it is selected from the group consisting of: [8-chloro-3- (4-chlorobenzyl) -4-difluoromethoxy-2-ethylquinolin-5-yloxy] acetic acid, [3- (4- chlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid [3- (2,4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid , [4-difluoromethoxy-2-ethyl-8-fluoro-3- (4-fluorobenzyl) quinolin-5-yloxy] acetic acid, [3- (2,4-difluorobenzyl) -4-difluoromethoxy-2-ethyl- acid] 8-Fluoroquinolin-5-yloxy] acetic acid [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid [3- (4-chloro-2-acid]] -fluorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] acetic acid, [8-chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] acetic acid, [3- (2-Chloro-4-fluorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid, [3- (2-chloro-4-fluorobenzyl) -2-difluoromethoxy- 8-fluoro-4-methylquinolin-5-ilox i] acetic, [8-chloro-3- (4-chloro-2-fluorobenzyl) -4-difluoromethoxy-2-ethylquinolin-5-yloxy] acetic acid, [3- (4-chloro-2-fluorobenzyl)] - 4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid. { 4-difluoromethoxy-2-ethyl-8-fluoro-3- [4- (morpholin-4-sulfonyl) benzyl] quinolin-5-yloxy} acetic, acid. { 4-difluoromethoxy-2-ethyl-8-fluoro-3- [4- (pyrrolidin-1-carbonyl) benzyl] quinolin-5-yloxy} acetic, 2- [3- (2, 4-dichlorobenzyl) -2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy] propionic acid, (S) -2- [3- (2,4-dichlorobenzyl) acid ) -2-difluoromethoxy-8-fluoro-4-methylquininoin-5-yloxy] propionic acid, 2- [8-chloro-3- (4-chlorobenzyl) -2-difluoromethoxy-4-methylquinolin-5-yloxy] propionic acid, acid { 8-Chloro-4-difluoromethoxy-2-ethyl-3- [4-pyrrolidin-1-carbonyl) -benzyl] -quinolin-5-yloxy} acetic, acid. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy} acetic, acid (S) -2-. { 3- [2-chloro-4- (pyrrolidin-1-carbonyl) benzyl] -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy} propionic, (S) -2- [3- (2,4-dichlorobenzyl) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] propionic acid, [3- (2-chloro-4-cyclobutylcarbamoylbenzyl) acid ) -4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy] acetic acid, (23) (S) -2- [3- (2-chloro-4-cyclobutylcarbamoylbenzyl) -4-difluoromethoxy-2-ethyl acid -8-fluoroquinolin-5-yloxy] propionic acid, and pharmaceutically acceptable salts, N-oxides, hydrates and solvates thereof. 14. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 11 to 13, together with a pharmaceutically acceptable carrier. 15. Use according to claim 1, characterized in that the compound is as claimed in any of claims 11 to 13. 16. A use according to any of claims 1 to 10 and 15, characterized in that the condition is selects for asthma, chronic obstructive pulmonary disease, allergic airway syndrome, bronchitis, cystic fibrosis, emphysema and rhinitis. 17. Use according to any of claims 1 to 10 and 15, characterized in that the condition is selected from psoriasis, atopic and non-atopic dermatitis, Crohn's disease, ulcerative colitis and irritable bowel disease. 18. A method of treating a condition responsive to the modulation of receptor activity CRTH2, characterized in that it comprises administering to a patient suffering from such a disease an effective amount of a compound as defined in claim 1. 19. A method according to claim 18, characterized in that the condition is selected from asthma, lung disease. chronic obstructive, allergic respiratory tract syndrome, bronchitis, cystic fibrosis, emphysema and rhinitis. 20. A method according to claim 18, characterized in that the condition is selected from psoriasis, atopic and non-atopic dermatitis, Crohn, ulcerative colitis and irritable bowel disease. SUMMARY OF THE INVENTION Compounds of the formula [1] are antagonists of CRTH2, useful in the treatment of conditions that have an inflammatory component; wherein: R1, R2, R3, R4 and R5 are independently hydrogen, C6-C6 alkyl, C6-C6 fluoroalkyl, cyclopropyl, halo, -S (0) nR6, -S02NR7R8, -NRR8, -NR7C (0) R6, -C02R7, -C (0) NR7R8, -C (0) R6, -N02, -CN or a group -OR9; wherein each R6 is independently Ci-Ce alkyl, Ci-Cß fluoroalkyl, cycloalkyl, aryl or heteroaryl; R7, R8 are independently C?-C5 alkyl, Ci-Ce fluoroalkyl, cycloalkyl, cycloalkyl- (Ci-Cß alkyl) -, aryl, heteroaryl or hydrogen; R9 is hydrogen, Ci-Cß alkyl, Ci-Cß fluoroalkyl, cycloalkyl, cycloalkyl- (C?-C6 alkyl) - or a -S02R6 group; A is -CHR10-, -C (O) -, -S (0) n-, -O- or -NR10- wherein n is an integer of 0-2 and R10 is hydrogen, C1-C3 alkyl or fluoroalkyl group of C? -C6; B is a direct bond, or a divalent radical selected from -CH2-, -CH2CH2-, -CHR11-, -CRnR12-, -CH2CHRn-, -CH2CR R12-, -CHR CHR12- and divalent radicals of the formula - (CR R12) PZ-wherein Z is attached to the ring bearing R1, R2 and R3; wherein R 11 is C 1 -C 3 alkyl, cyclopropyl, C 1 -C 6 fluoroalkyl; R 12 is methyl or fluoromethyl; p is independently 1 or 2; and Z is -O-, -NH- or -S (0) n-, where n is an integer of 0-2; X is a carboxylic acid, tetrazole, 3-hydroxyisoxazole, hydroxamic acid, phosphinate, phosphonate, phosphonamide or sulfonic acid group or a group of the formula C (= 0) NHS02R6 or S02NHC (= 0) R6; and Y is aryl, heteroaryl, heterocycloalkyl fused with aryl, cycloalkyl fused with heteroaryl, heterocycloalkyl fused with heteroaryl or cycloalkyl group fused with aryl.