MXPA99009690A

MXPA99009690A - Substituted benzopyran derivatives for the treatment of inflammation

Info

Publication number: MXPA99009690A
Application number: MXPA/A/1999/009690A
Authority: MX
Inventors: J Talley John; S Carter Jeffrey; R Bertenshaw Stephen; G Obukowicz Mark; Devadas Balekudru; L Brown David; J Graneto Matthew; J Rogier Donald Jr; R Nagarajan Srinivasan; J Hartmann Susan; L Ludwig Cindy; Metz Suzanne; E Hanau Cathleen
Original assignee: Gd Searle&Ampco
Priority date: 1997-04-21
Filing date: 1999-10-21
Publication date: 2001-09-07

Abstract

Se describe una clase de derivados benzopirano para uso en el tratamiento de los desórdenes mediada por la ciclooxigenasa-2. Los compuestos de particularinterés se definen por la Fórmula (I'), en donde X, Al, A2, A3, A4, R, R", R1 y R2 son como se describieron en la especificación. (Ver Fórmula)

Description

_-l BENZOPIRAN DERIVATIVES REPLACED FOR TREATMENT OF INFLAMMATIONS FIELD OF THE INVENTION This invention pertains to the field of anti-inflammatory pharmaceutical agents and relates specifically to compounds, compositions and methods for treating disorders mediated by cyclooxygenase-2, such as inflammatory disorders and disorders related to inflammations.

BACKGROUND OF THE INVENTION Prostaglandins play an important role in the process of inflammation and the inhibition of prostaglandin production, especially the production of PGG2, PGH2 and PGE2 has been the common target of the discovery of anti-inflammatory drugs. However, common non-steroidal anti-inflammatory drugs (NSAIDs), which are actively involved in the reduction of pain and swelling induced by the pros taglandins associated with the inflammation process, are also REF .: 31700 active in other processes regulated by prostaglandins that are not associated with the inflammatory process. Thus, the use of high doses of the most common NSAIDs can produce severe side effects, including life-threatening ulcers, which limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which present even more drastic side effects, especially when considering long-term therapy. It has been found that previous NSAIDs prevent the production of prostaglandins by inhibiting enzymes of the arachidonic acid / pros taglandin human pathway, including the enzyme cycloxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (termed "cycloxygenase-2 (COX-2)" or "prostaglandin G / H synthetase II") provides a target for viable inhibition that reduces inflammation more effectively and produces fewer effects secondary, which are also less drastic. The references described later on the anti-inflammatory activity show the continuous efforts to find a safe and effective anti-inflammatory agent.

The novel benzopyran, dihydroquinoline, benzothiopyran and dihydronaphthalene derivatives described herein constitute safe and also effective anti-inflammatory agents, thus responding to such efforts. The substituted benzopyran, dihydroquinoline, benzothiopyran and dihydronaphthalene derivatives described herein inhibit, preferably selectively, cycloxygenase-2 before cyclooxygenase-1. In U.S. Pat. No. 5,618,843, filed by Fisher et al., Substituted bicyclic groups are generically described as the Ilb / IIIA antagonists. In WO 94/13659, published on June 23, 1994, benzo fused compounds are described for the treatment of CNS disorders.

Manrao et al. (J. Indian, Counc. Chem., 12: 38-41 (1996)) describe carboxy coumarinimide derivatives and their antifungal activity. In U.S. Pat. No. 5,348,976, filed by Shibata et al., Substituted benzopyranamides are described as antifungal agents. In WO 96/40110, published on December 19, 1996, benzopyran derivatives are described as tyrosine kinase modulators. Loiodice et al. (Tetrahedron, 6: 1001-11 (1995)) describe the preparation of 6-chloro-2,3-dihydro-4H-1-benzopyrancarboxylic acids. Clemence et al. (J. Med. Chem., 31: 1453-62, (1988)) describe 4-hydroxy-3-quinolinecarboxylic acids as starting material in the preparation of anti-inflammatories. Lazer, et al. (J. Med. Chem., 40: 980-89 (1997)) describe benzothiopyran carboxylates as starting material in the preparation of anti-inflammatories. The benzopyran-3-carboxylic acids are described. Gupta et al. (Indian J. Chem., 21B, 344-347 (1982)) describe chromen-3-carboxylic acid as an intermediate in the preparation of centrally acting muscle relaxants. Rene and Royer (Eur. J. Med. Chem. - Chim. Ther., 10, 72-78 (1975)) describe the preparation of chromen-3-carboxylic acid. In U.S. Pat. No. 4,665,202, filed by Rimbault et al., Describe 2-phenyl substituted thioflavans and thiolavines as inhibitors of 5-lipoxygenase. In U.S. Pat. No. 5,250,547, filed by Lochead et al., Describe benzopyran derivatives as inhibitors of 5-lipoxygenase. Satoh et al. [J. Med. Chem., 36, 3580-94 (1993)] describe substituted chromosomes as inhibitors of 5-lipoxygenase. In U.S. Pat. No. 5,155,130, filed by Stanton et al., Substituted chromosomes are described as inhibitors of 5-lipoxygenase and, specifically, 6-benzyloxy-2H-benzopyran-3-carboxylic acid as an intermediate. However, the compounds of the present invention have not been described as cyclooxygenase inhibitors.

DESCRIPTION OF THE INVENTION A class of compounds that are useful in the treatment of disorders mediated by cyclooxygenase-2 is defined by Formula I ': where X is selected from O, S, CRCR and NRa; where Ra is selected from hydride, alkyl-Ca-C3 / (optionally substituted phenyl) - _- € C 1 -C 3 alkyl, alkylsulfonyl, phenylsulfonyl, benzylsul fonyl, acyl and carboxy-C 1 -C 6 alkyl; wherein each of the radicals Rb and Rc is independently selected from hydride, C alquilo-C3 alkyl / phenyl-C?-C3 alkyl, C perf-C3 perfluoroalkyl, chloro-alkylthio-Ci-Cß, C alco-alkoxy Cg, nitro, cyano and cyano-C 1 -C 3 alkyl; or where CRcRb form a cyclopropyl ring; where R is selected from carboxyl, amincarbonyl, C? -C6-alkylsul phonylamincarbonyl and C? -C6 alkoxycarbonyl; where R "is selected from hydride, phenyl, thienyl, alkynyl-Ca-Ce and C2-C6 alkenyl, where R1 is selected from perfluoroalkyl-C? -C3, chloro, alkyl thio-C? -C6, alkoxy-C? -C6, nitro, cyano and cyanoalkyl-C! -C3, where R2 is one or more radicals independently selected from hydride, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, haloalkynyl -C2-C6, arylalkyl-C? -C3, arylalkynyl-C2-C6, arylalkenyl-C2-C6 alkoxy-C? -C6, methylenedioxy, alkyl-C? -e-thio, alkyl-Ci-C6-sulfinyl, - 0 (CF2) 20-, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C6-alkoxy-C6-C6-alkyl, aryl-C-C6-oxy, hetero-C6-C6-oxy, arylalkoxy -C? -C6-C-C6-alkyl, C-C6 haloalkyl, haloalkoxy-Cx-C? / Haloalkylthio-Ci-C?, C? ~ C? -haloalkylsulfyl, C? -C6-haloalkylsul fonyl, C1 -C3- (haloalkyl-C? -C3-hydroxyalkyl, Ci-Cg-hydroxyalkyl, hydroxyiminoalkyl-C? -C6, alkyl-C? -C6-amine, arylamine, arylalkyl-Ci-Co-amine, heteroarylamine, heteroarylalkyl-C) ? -C3-amine, nitro, cyano, amine, aminsulf onyl, alkyl-Ci-Ce-aminsulfonyl, arylaminsul fonyl, heteroarylaminsul fonyl, arylalkyl-C? -C6-aminsulf onyl, heteroarylalkyl-Ci-C6-aminsul fonyl, heterocyclylsulphonyl, C? -C6-alkylsulf onyl, aryl-C? -C6-alkylsul fonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C? -C6-alkylcarbonyl, heteroaryl-C? -C6-alkylcarbon, heteroarylcarbonyl, arylcarbonyl, amincarbonyl, C? C6-alkoxycarbonyl, formyl, C? -Ce-haloalkylcarbonyl and C? -C6alkylcarbonyl; and wherein the ring atoms A, A1, A2, A3 and A4 are independently selected from carbon and nitrogen with the proviso that at least two of the atoms A1, A2, A3 and A4 are carbon; or wherein R2 together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; _-H.H or an isomer or an acceptable salt for pharmaceutical use thereof. A class of compounds that are useful in the treatment of disorders mediated by cyA-oxygenase-2 is defined by Formula I where X is selected from 0 or S or NRS; where Ra is alkyl; where R is selected from carboxyl, amincarbonyl, alkylsul fonilamincarbonyl and aleoxycarbonyl; wherein R1 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R 2 is one or more radicals selected from hydride, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkyloxy, haloalkyl, haloalkoxy, alkylamine, arylamine, aralkylamine, heteroarylamine, heteroarylalkylamine, nitro, amine, aminsul fonyl, alkylaminosulfonyl, arylaminsulfonyl, heteroarylaminsul fonyl, aralkyl-aminsul fonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, amincarbonyl and alkylcarbonyl; or where R2, together with ring A, forms a naphthyl radical; or an isomer or salt acceptable for pharmaceutical use thereof. The compounds of the present invention will be useful for, without limitations, the treatment of inflammation in a subject and for the treatment of other disorders mediated by c-cloxygenase-2, as an analgesic in the treatment of pain and headaches or as an antipyretic for the treatment of fever. For example, the compounds of the invention will be useful for treating arthritis, including, without limitation, rheumatoid arthritis, spondyloarthropathies, gout arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Said compounds of the invention will be useful in the treatment of asthma, bronchitis, menstrual cramps, labor, tendinitis, bursitis, liver diseases including hepatitis, skin-related conditions such as psoriasis, eczema, burns and dermatitis and post-inflammatory inflammations. surgical procedures, including ophthalmic surgery, such as cataract surgery and refractory surgery. The compounds of the invention will also be useful for treating gastrointestinal conditions, such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds of the invention will be useful in the treatment of inflammations in diseases such as migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction diseases including myasthenia. gravis, white matter diseases including multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet syndrome, polymyositis, gingivitis, nephritis, hypersensitivity, swelling after injury, including cerebral edema, myocardial ischemia and the like. The compounds will also be useful in the treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia and acute ocular tissue injuries.

The compounds will also be useful in the treatment of pulmonary inflammations, such as those associated with viral infections and cystic fibrosis. The compounds will also be useful for the treatment of certain disorders of the central nervous system, such as cortical dementias, including Alzheimer's disease, and lesions in the central nervous system resulting from stroke, ischemia and trauma. The compounds of the invention are useful as anti-inflammatory agents, as in the treatment of arthritis, with the additional advantage of having significantly less harmful side effects. These compounds will also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome and liver diseases. The compounds will also be useful in the treatment of pain, without limitations to post-fetal pain, toothaches, muscle aches and pains due to cancer. The compounds will be useful for the treatment of dementias. The term "treatment" includes the partial or total inhibition of dementia, including Alzheimer's disease, vascular dementia, multi-infarct dementia, presenile dementia, alcoholic dementia, and senile dementia. The above method will be useful, but without limitation, for the treatment and prevention of cardiovascular disorders related to inflammation in a subject. The method will be useful for the treatment and prevention of vascular diseases, arteriocoronary diseases, aneurysms, arteriosclerosis, atherosclerosis including atherosclerosis by heart transplantation, myocardial infarction, embolisms, stroke, thrombosis, including venous thrombosis, angina including unstable angina, inflammation by coronary plaques, bacterial-induced inflammation including Chl amydi a-induced inflammation, virus-induced inflammation and inflammations associated with surgical practices such as vascular grafts including coronary artery bypass surgery, revascularization practices including angioplasty, stent placement [stent] , endarterectomy and other invasive practices involving arteries, veins and capillaries. The compounds will be useful for, without limitation, the treatment of disorders related to angiogenesis in a subject. From i3 In accordance with the present invention, the compounds are administered to a subject in need of inhibition of angiogenesis. The method will be useful for the treatment of neoplasia, including metastasis; ophthalmological conditions such as rejection of corneal transplantation, ocular neovascularization, retinal neovascularization including neovascularization after injury or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological conditions, but not malignant, such as hemangiomas, including infantile hemangiomas, nasopharyngeal angiofibroma and vascular bone necrosis; and disorders of the female reproductive system such as endometriosis. The compounds of the invention will be useful for the prevention or • treatment of neoplasms including cancer, such as colorectal cancer, brain cancer, bone cancer, neoplasms derived from epithelial cells (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, .4 colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as basal cell and squamous cell cancers, prostate cancer, carcinoma of kidney cells and other known cancers that affect epithelial cells throughout the body. The neoplasm is selected, preferably, between gastrointestinal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as basal cell cancers and squamous cells. The compounds can also be used to treat the fibrosis that appears with radiation therapies. The method can be used to treat subjects suffering from adenomatous polyps, including those with familial adenomatous polyposis (FAP). In addition, the method can be used to prevent the formation of polyps in patients at risk of PAF. The administration of the compounds of the present invention can be employed alone or together with other therapies known to those skilled in the art for the prevention or treatment of neoplasms. Alternatively, the compounds described in the present documentation can be used in joint therapies. By way of example, the compounds may be administered alone or together with other antineoplastic agents or other growth inhibitory agents or other drugs or nutrients. There is a large number of commercially available antineoplastic agents in the development of clinical and preclinical evaluations that could be selected for the treatment of neoplasms by combined drug chemotherapy. Said antineoplastic agents can be grouped into several large categories, namely antibiotic-type agents, alkylating agents, antimetabolic agents, hormonal agents, immunological agents, interferon-like agents and a category of various agents. Alternatively, other antineoplastic agents may be employed, such as metal matrix proteases (MMPs), SOD mimetics or avß3 inhibitors. A first family of antineoplastic agents that can be used in combination with the compounds of the present invention is formed by anti-metabolic antineoplastic agents. Suitable antimetabolic antineoplastic agents can be selected from the group consisting of 5-FU-fibrinogen, acantholic acid, amint iadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxicit idina, dideoxyguanosine, didox, Yoshitomi DMDC, doxy fluridine, Wellcome EHNA, Merck &; Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate , Wellcome MZPES, norespermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentos tat ina, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, thiazofurine, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein inhibitors, Taiho UFT and uricitin. A second family of antineoplastic agents that can be used in combination with the compounds of the present invention is formed by the alkylating agent antineoplastic agents. Suitable alkylating agent type antineoplastic agents can be selected from the group consisting of Shionogi 254-S, analogs of aldo-phosphamide, altretamine, anaxirone, Boeringher Mannheim BBR-2207, bestrabucil, budotitan, Wakunaga CA-102, carboplatin, carmustine, Chinoin -139, Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cisplatate, • Degussa D-19-384, Sumimoto DACHP (Myr) 2, diphenylspiromustine, cytostatic diplatin, derivatives of distamycin Erba , Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine sodium phosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxalplatin, Upjohn PCNU, prednimus tina, Proter PTT-119, ranimustine, semustine, SmithKine SK &F-101772, Yakult Honsha SN-22, Spiromus tina, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and trimelamol. A third family of antineoplastic agents that can be used in combination with the compounds of the present invention is formed by antibiotic-type antineoplastic agents. The antibiotic-type antineoplastic agents can be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, act inoplanone, Erbamont ADR-456, derivative of aeroplisinin, Ajinomoto AN-201-II, Ajinomoto AN-3, anisomycins Nippon Soda , anthracycline, azinomycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY-27557, Bristol-Myers BMY-28438 , bleomycin sulfate, brios tatina-1, Taiho C-1027, calichemycin, chromoximicin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-AA Kyowa Hakko DC92- B, di trisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamycin-Al, esperamycin-Alb, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR- 900482, gl idobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudin, kazusamycin, kesari rhodina, Kyowa Hakko KM-5539, Kirin BrewKAN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, my toxantrone, SmithKIine M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRl International NSC-357704, oxalisin, oxaunomycin, peplomycin, pilatin, pirarubicin, porotramycin, pirindamicin A, Tobishi RA-I, rapamycin, rhizoxin, rodorubicin , sibanomycin, siwenmicin, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-73138, SS Pharmaceutical SS-98168, steffimine B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, trazine, tricrozarine A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin. A fourth family of antineoplastic agents that can be used in combination with the compounds of the present invention is formed by a miscellaneous family of antineoplastic agents selected from the group consisting of alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphetamine, amsacrine, Angiostat, anquinomycin, antineoplason A10, antineoplasic ton A2, antineoplasic ton A3, antineoplaston A5, ant ineplastone AS2-1, Henkel APD, afidicolin glycinate, asparaginase, Avarol, baccharin, batraciloin, benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromophosfamide, Wellcome BW-502 , Wellcome BW-773, Caracemide, Carmetizol Hydrochloride, Ajinomoto CDAF, Chlorosulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100, Warner-Lambert Cl-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner- Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, ci tochalasin B, cytarabine, cytocytin, Merz D-609, maleate DABIS, dacarbazine, dateliptinium, didemnin -B, dihaematoporphyrin ether, dihydrolenperone, dinalin, distamycin, Toyo Pharmar DM- 341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, eliprabine, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadafnin, Chugai GLA-43, Glaxo GR- 63178, grifolan NMF-5Ñ, hexadecylphosphocholine, Green Cross HO-221, homoharanillotonin, hydroxyurea; BTG ICRF-187, ilmofosin, isoglutamine, isotret inoin, Otsuka JI-36, Ramot K-477, Otsuka K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leucoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, maricine, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanin derivatives, methylanilinecridine, Molecular Genetics MGI-136, minactivine, mitonafide, mitochidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N- (retinoil) amino acids, Nisshin Flour Milling N-021, N-acylated dehydroalanines, nafazatrom, Taisho NCU-190, nocodazole derivative, NormoSang , NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono ONO-112, oquizanocin, Akzo Org-10172, pancratistatin, pazelliptin, Warner-Lambert PD-111707, Warner-Lambert PD -115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, peptide D ICRT, piroxantrone, polhaematoporphyrin, polyprotein acid, porphyrin Efamol, probimano, procarbazine, proglumide, protease nexin I Invitron, Tobishi RA-700, razoxane, Sapporo Breweries RBS, res trictina-P, retellipt ina, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKine SK &F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, derivatives Spirocyclopropane, Spirogermanium, Unimed, SS Pharmaceutical SS-554, Strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teñiposide, taliblastin, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01 , Kyowa Hakko UCN-1028, Ukraina, Eastman Kodak USB-006, vinblastine sulfate, vincris tub, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, witanolides and Yamanouchi YM-534.

Examples of radioprotective agents that can be used in combination with the compounds of the present invention are AD-5, adchnon, analogues of amifostine, detox, dimesna, 1-102, MM-159, N-acylated dehydroalanines, TGF-Genentech, tiprotimod, amifostine, WR-151327, FUT-187, transdermal ketoprofen, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon. In addition to being useful for the treatment of humans, these compounds are also useful for the veterinary treatment of domestic animals, exotic animals and farm animals, including mammalian rodents and the like. The most preferred animals include horses, dogs and cats. The present compounds can also be used in cotherapies, partially or completely, in place of other conventional anti-inflammatories, such as, for example, together with steroids, NSAIDs, iNOS inhibitors, 5-lipoxygenase inhibitors, LTB4 receptor antagonists and LTA4 hydrolase inhibitors. . Suitable inhibitors of hydrolase LTA4 include the following: RP-64966, benzylester of (S, S) -3-amin-4- (-benzyloxyphenyl) -2-hydroxybutyric acid (Scripps Res Inst.), N- (2 (R) - (cyclohexylmethyl -3- (hydroxycarbamoyl) propionyl) -L-alanine (Searle), 7- (4- (4-ureidobenzyl) phenyl) heptanoic acid (Rhone-Poulenc Rorer) and lithium salt of 3- (3- (1E, 3E-tetradecadienyl) -2-oxiranyl) benzoic acid (Searle). Suitable LTB4 receptor antagonists include, among others, ebselen, linazolast, ontazolast, Bayer Bay-x-1005, compound CGS-25019C Ciba Geigy, compound ETH-615 Leo Denmark, compound MAFP Merck, compound TMK-688 Terumo, compound T-0757 Tanabe, compounds LY-213024, LY-210073, LY223982, LY233469 and LY255283, LY-293111, 264086 and 292728 Lilly, compounds ONO-LB457, ONO-4057 and ONO-LB-448 ONO, compound S-2474 Shionogi, calcitrol, compounds Lilly compounds SC-53228, SC-41930, SC-50605 and SC-51146 Searle, composite BAC 15 Warner Lambert, compound SB-209247 SmithKIine Beecham and compound SKF-104493 SK &F. The LTB4 receptor antagonists are preferably selected from calcitrol, ebselen, Bayer Bay-x-1005, compounds CGS-25019C Ciba Geigy, compound ETH-615 Leo Denmark, compound LY-293111 Lilly, compound ONO-4057 Ono and compound TMK -688 Terumo. Suitable 5-LO inhibitors include, among others, compounds A-76745, 78773 and ABT761 Abbott, Bay-X-1005 Bayer, CMI-392 Cytomed, E-3040 Eisai, EF-40 Scotia Pharmaceutical, F-1322 Fujirebio, ML-3000 Merckle, PF-5901 Frederick Purdue, R-8403M Pharmaceuticals, rilopirox, flobufen, linasolast, lonapoleno, masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxaline, rilopirox, tub flezelas hydrochloride, enazadrem phosphate and bunaprolast. The present compounds can also be used in combination therapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (ie non-addictive) analgesics, monoamine uptake inhibitors, regulatory agents. of adenosine, cannabinoid derivatives, Substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, among others. More preferred are combinations with compounds selected from morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocin, meptazinol, hydrocodone, oxycodone, methadone, Tramadol [(+) enantiomer], DUP 747, Dynorphine A, Enadoline, RP -60180, HN-11608, E-2078, ICI-204448, acetaminophen (paracetamol), propoxyphene, nalbuphine, E-4018, filnadol, mirfentanil, amitriptyline, DuP631, Tramadol [(-) enantiomer], GP-531, acadesin, AKI-1, AKI-2, GP-1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AxC3742, SNX-III, ADL2-1294, ICI-204448, CT-3, CP-99 , 994 and CP-99, 994. The compounds can be used in combination with one or more antihistaminic agents, decongestants, diuretics, antifusives or with other agents previously known to be effective in combination with anti-inflammatory agents. The term "prevention" comprises either preventing the onset of clinically evident cardiovascular disorders as a whole or preventing the onset of an obvious preclinical stage of cardiovascular disorder in individuals. This includes the prophylactic treatment of those at risk of developing a cardiovascular disorder. The phrase "effective for therapeutic use" is intended to qualify the amount of each agent capable of achieving an improvement in the severity of the disorder and the frequency of incidence with the treatment with each agent by itself, while avoiding the adverse side effects typically associated with it. with alternative therapies.

The present invention preferably includes compounds that selectively inhibit cycloxygenase-2 before cyclooxygenase-1. The compounds preferably have an IC 50 of cycloxygenase-2 less than approximately 0.5 μM and also have a selectivity ratio of inhibition of cyclooxygenase-2 with respect to inhibition of cyclooxygenase-1 of at least 50 and with higher preference of at least 100. It is further preferred that the compounds possess a CI = or cyclooxygenase-1 greater than about 5 μM. Said preferred selectivity may indicate an ability to reduce the incidence of common side effects induced by NSAIDs. A preferred class of compounds is formed by those compounds of Formula I wherein X is oxygen or sulfur; where R is selected from carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; where R1 is selected from lower haloalkyl, cycloalkyl and lower phenyl; and wherein R 2 is one or more radicals selected from hydride, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamine, nitro, amine, aminsulfonyl, lower alkyl fonyl, 5- or 6-membered heteroarylalkylaminsulfonyl, lower aralkylamine sulfonyl, heterocyclesul fonilo containing 5 or 6 membered nitrogen, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl and lower alkylcarbonyl; or where R2, together with ring A, forms a naphthyl radical; or an isomer or an acceptable salt for pharmaceutical use thereof. A more preferred class of compounds consists of those compounds of Formula I wherein X is oxygen or sulfur; where R is selected from carboxyl; wherein R1 is selected from lower haloalkyl; and wherein R 2 is one or more radicals selected from hydride, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamine, amine, aminsulfonyl, lower alkylaminosulfonyl, 5 or 6 membered heteroarylalkylsulfoyl, lower aralkylaminsulfonyl, lower alkylsulfonyl, heterocyclic fonyl containing 6-membered nitrogen, optionally substituted phenyl, lower aralkylcarbonyl and lower alkylcarbonyl; or where R2, together with ring A, forms a naphthyl radical; or an isomer or an acceptable salt for pharmaceutical use thereof.

An even more preferred class of compounds consists of those compounds of Formula I wherein R is carboxyl; where R1 is selected from fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl and trifluoromethyl; and wherein R 2 is one or more radicals selected from hydride, chlorine, fluorine, bromine, iodine, methyl, ethyl, isopropyl, ter¬ butyl, butyl, isobutyl, pentyl, hexyl, methoxy, • ethoxy, isopyloxy, tert-butyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amine, N, N-dimethylamine, N, N-diethylamine, N-phenylmethylaminsulfonyl, N-phenylethyl insulyl, N- (2-furylmethyl) aminsulfonyl, Nitro, N, N-dimethylaminsulfonyl, aminsulfonyl, N-methylaminsulfonyl, N-ethylsulfonyl, 2,2-dimethylaminylsulfonyl, N, N-dimethylaminsulfonyl, N- (2-methylpropyl) aminsulfonyl, N-morpholine sulfonyl, • methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or where R2, together with ring A, forms a naphthyl radical; or an isomer or an acceptable salt for pharmaceutical use thereof. An even more preferred class of compounds consists of those compounds of Formula I wherein R is carboxyl; wherein R1 is trifluoromethyl or pentafluoroethyl; and wherein R 2 is selected from one or more hydride, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethyl-aminsulfonyl, N-phenylethylaminsulfonyl, N- (2) radicals -furyl ethyl) aminsulfonyl, N, N-dimethylaminsulfonyl, N-methylaminsulfonyl, N- (2,2-dimethylethyl) aminsulfonyl, dimethylamine sulphonyl, 2-methylpropylaminsulfonyl, N-morphinsulfonyl, methylsulfonyl, benzylcarbonyl and phenyl; or where R2, together with ring A, forms a naphthyl radical; or an isomer or an acceptable salt for pharmaceutical use thereof. A preferred class of compounds consists of those compounds of Formula I 'wherein X is selected from 0, S, CRcRb and NRa; where Ra is selected from hydrido, C-C3-alkyl, (optionally substituted phenyl) -alkyl-Cj-Cs, acyl and carboxy-C-C6-alkyl; wherein each of the radicals Rb and Rc is independently selected from hydride, C alquilo-C alquilo alkyl, phenylalkyl-Ci-Cj, perfluoroalkyl-C?-C3, chloro, alkylthio-C?-C6-alkoxy-C?-C6, nitro, cyano and cyanoalkyl-C? -C3; where R is selected from carboxyl, amincarbonyl, C6-C6-alkylsul phonylamin-carbonyl and C6-C-alkoxycarbonyl; where R 'is selected from hydride, phenyl, thienyl and C2-C6 alkenyl; wherein R1 is selected from perfluoroalkyl-C? -C3, chloro, alkylthio-C? -C6, alkoxy-Cx-Ce / nitro, cyano and cyanoalkyl-C? -C3; wherein R 2 is one or more radicals independently selected from hydride, halo, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 4 alkynyl / C 2 -C 2 haloalkynyl, C 1 -C 1 arylalkyl, C 2 -C 2 arylalkyl , C2-C6-arylalkenyl, C6-C6 alkoxy, methylenedioxy, C3-C3 alkyl-alkyl, Ci-Cb-sulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, alkoxy-Ci-Cb-alkyl-C ? -C6, arylalkyloxy-c ± -. heteroarylalkyloxy-Ci-Cb, arylalkoxy-Ci-Ce-alkyl-Ci-Cc, haloalkyl-C? -Cc, haloalkoxy-C? -Cc, haloalkyl-Cx-Cb, haloalkylsulfinyl-d-Cb, haloalkylsulfonyl -Ci-Ce, C? -C3- (haloalkyl-Ci-Cj-hydroxyalkyl, hydroxyalkyl-C? -Cb, hydroxyiminoalkyl-Ci-C? Alkyl-Ci-Cc-amine, arylamine, arylalkyl-C? -C3-amine , heteroarylamino, heteroarylalkyl-Ci-Ce-amine, nitro, cyano, amine, aminsulf onyl, alkyl-C? -C6-aminsulf onyl, arylaminsulf onyl, heteroarylamin-sulfonyl, arylalkyl-C? -Cc-aminsul fonyl, hetero -alkylalkyl-C? -C-aminsul fonyl, heterocyclylsulfonyl, alkylsulfonyl-Ci-Cb, arylalkyl-C? -C6-sulfonyl, optionally substituted aryl, optionally substituted heteroaryl, arylalkyl-C? -Cc-carbonyl, heteroarylalkyl-C? -C- carbohydrate, heteroarylcarbonyl, arylcarbonyl, amincarbonyl, C 1 -C 4 -carbonyl, formyl, C 1 -C 6 -haloalkylcarbonyl and C 1 -C 6 alkylcarbonyl, and where the ring atoms A, A1, A2, A3 and A4 , are independently selected between carbon and nitrogen with the proviso that at least three of A1, A2, A3 and A4 are carbon; or wherein R2, together with ring A, forms a naphthyl or quinolyl radical; or an isomer or an acceptable salt for pharmaceutical use thereof. A more preferred class of compounds consists of those compounds of Formula I 'wherein X is selected from 0, S and NRa; where Ra is selected from hydride, C-C3-alkyl and (optionally substituted phenyl) methyl; where R 'is selected from hydride and C-Cb alkenyl; where R is carboxyl; wherein R1 is selected from perfluoroalkyl-C? -C3; where R 2 is one or more radicals independently selected from hydride, halo, C 1 -C 6 alkyl, C-C alkenyl, C 2 -C 8 alkynyl, C 2 -C 2 haloalkynyl, phenylalkyl-Cj-Cb, phenylalkyl-C 2 -C, phenylalkyne lo-C2-Cb, alkoxy-Ci-Cj, methylenedioxy, C? -C-alkoxyalkyl-C? -C3, alkylthio-C? -C3, alkyl-C? -C3-sulfinyl, phenyloxy, phenylthio , phenylsulfinyl, haloalkyl-C? -C3-hydroxyalkyl-C? -C ?, phenyl-alkyloxy-CrCj-alkyl-Ci-Cj, haloalkyl-Cn-Co, haloalkoxy-C? -C3, haloalkyl thio-C? -C , hydroxy alkylo-d-Cj, alkoxy-Cj.-C3-alkyl-Cj.-C3, hydroxyiminoalkyl-Ci-Cs, alkyl-C? -Cb-amine, nitro, cyano, amine, aminsulfonyl, N-alkylaminsulfonyl, N-arylaminsulfonyl, N-heteroarylaminsulfonyl, N- (phenylalkyl-C? -Cb) aminsul fonyl, N- (heteroaryl-alky1-Ci-Ce) aminsulfonyl, phenylalkyl-C ± -C3-sulphonyl, heterocyclylsulfonyl from 5 to 8 members alkylsul fonilo-C? -C6y phenyl optionally substituted, 5- to 9-membered heteroaryl optionally substituted, phenylalkyl-C? -Cb-carbonyl, feni lcarbonyl, 4-chlorophenylcarbonyl, 4-hydroxyphenylcarbonyl, 4-trifluoromethylphenylcarbonyl, 4-methoxy phenylcarbonyl, amincarbonyl, formyl and alkylcarbonyl-C? -C; where the ring atoms A, A, A ~, A and A are independently selected from carbon and nitrogen, with the proviso that at least three atoms A1, A2, A3 and A4 are carbon; or wherein R2, together with ring A, forms a naphthyl, benzofurylphenyl or quinolyl radical; or an isomer or an acceptable salt for pharmaceutical use thereof. An even more preferred class of compounds consists of those compounds of Formula I 'wherein X is selected from 0, S and NRa; wherein PJ is selected from hydride, methyl, ethyl, (4-trifluoromethyl) benzyl, (-chloromethyl) benzyl, (4-methoxy) benzyl and (4-cyano) benzyl, (4-nitro) benzyl; where R is carboxyl; where R 'is selected from hydride and ethenyl; wherein R1 is selected from trifluoromethyl and pentafluoroethyl; where R 2 is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, tertbutyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl, 3, 3-dimethyl-1-butynyl, benzyl, phenylethyl, phenylethynyl, 4-chlorophenylethynyl, 4-methoxy phenylethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, tri fluoromethylthio, hydroxymethyl, hydroxy tri fluoroethyl, methoxymethyl, hydroxyiminmethyl, N-methylamine, nitro, cyano, amine, aminsulfonyl, N-methylaminsul fonyl, N-phenylaminsul fonyl, N-furyl insulfonyl, N- (benzyl) aminsul fonyl, N- (furylmethyl) aminsulfonyl, benzylsulfonyl, phenylethylaminsulfonyl, furylsulfonyl, methylsul fonyl, phenyl, phenyl substituted with one or more radicals selected from chlorine, fluorine, bromine, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted with n chlorine, furyl, furyl substituted with chlorine, benzylcarbonyl, optionally substituted phenylcarbonyl, amincarbonyl, formyl and methylcarbonyl; where the ring atoms A, A1, A2, A3 and A4 are independently selected from carbon and nitrogen with the proviso that at least three of the atoms A1, A2, A3 and A4 are carbon; or wherein R2, together with ring A, forms a naphthyl or quinolyl radical; or an isomer or an acceptable salt for pharmaceutical use thereof. There is a subclass of chromene compounds within Formula I 'wherein X is O; where R is carboxyl; where R "is selected from hydrido and C2-C6 alkenyl, where R1 is selected from perfluoroalkyl-C? -C3, where R2 is one or more radicals independently selected from hydride, halo, Ci-C6 alkyl, phenylalkyl-C? -Cb, phenylalkynyl-C2-Cb, phenylalkenyl-C2-Cß, alkoxy-C? -Cb, phenyloxy, 5- or 6-membered heteroaryloxy, phenylalkyloxy-C? -Cb, heteroarylalkyloxy-C? -C6 of 5 or 6 members, haloalkyl-C? -Cb, haloalkoxy-C? -Cb, N- (alkyl-C? -Cb) amine, N, N-di- (alkyl-C? -C6) amine, N-phenylamine, N- (phenylalkyl) -C? -C6) amine, N-hetero-arylamine, N- (heteroarylalkyl-C? -C6) amine, nitro, amine, aminsulfonyl, N- (C? -C6 alkyl) aminsulfonyl, N, N-di-? (C 1 -C 6 alkyl) minsulfonyl, N-arylamin sulfonyl, N-heteroarylaminsulfonyl, N- (phenyl-alkyl-Ci-Ce) aminsulfonyl, N- (heteroarylalkyl-Ci- Ce) amlnsulfonyl, heterocyclylsulfonyl from 5 to 8 members , C 1 -C 6 alkylsulfonyl, optionally substituted phenyl 5, optionally substituted 5 or 6 membered heteroaryl, phenyl-alkylated quil-C? -C6carbonyl, heteroarylcarbonyl, phenylcarbonyl, amincarbonyl and C 1 -C 6 alkylcarbonyl; where the atoms of ring A, A1, A2, A3 and A4, are selected independently between carbon and nitrogen, with • condition that at least three of the atoms A1, A2, A3 and A4 be carbon; or an isomer or an acceptable salt for pharmaceutical use thereof. An even more preferred class of compounds consists of those compounds of Formula I 'wherein X is O; where R is carboxyl; where R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, where R2 is one or • more radicals selected independently between hydride, chlorine, bromine, fluorine, iodine, methyl, terbutyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl, 3, 3-dimethyl-1-butynyl, benzyl, phenylethyl, phenylethynyl, 4-chlorophenylethynyl , 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, Phenyloxy, phenylthio, phenylsulfinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl thio, hydroxymethyl, hydroxytrifluoroethyl, methoxymethyl, hydroxyiminmethyl, N-methylamine, N-phenylamine, N- (benzyl) amine, nitro, cyano, amine, aminsulfonilo, N-metilaminsulfonilo, N-fenilaminsulfonilo, N-furilaminsulfonilo, N- (benzyl) aminsulfonilo, N- (furylmethyl) aminsulfonilo, benzylsulfonyl, phenylethyl aminsulfonilo, furylsulfonyl, methylsulfonyl, phenyl , f eniJL or substituted with one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and metilsul fonilo, benzimidazolyl, thienyl, tieneLlo substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, amincarbonilo, formyl and methylcarbonyl; and where one of the atoms of ring A, A1, A2, A3 and A4 is nitrogen and the other three are carbon; or an isomer or an acceptable salt for pharmaceutical use thereof. Another yet more preferred class of compound consists of those compounds of Formula I 'wherein X is O; where R is carboxyl; where R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, where R2 is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, tertbutyl, ethenyl, ethynyl, 5-chloro -l-pentynyl, 1-pentynyl, 3, 3-dimethyl-l-butynyl, benzyl, phenylethyl, phenylethynyl, 4-clorofeniletinilo, 4-methoxy phenylethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, tri fluoromethyl thio, hydroxymethyl, hydroxy-trifluoroethyl, methoxymethyl, hidroxiiminmetilo, N-methylamine, N-phenylamino, N- (benzyl) amine, nitro, cyano, amine, aminsulfonilo, N-metilaminsul fonilo, N-fenilaminsulfonilo, N-furilaminsulfonilo, N- (benzyl) aminsulfonilo, N- (furylmethyl) aminsulfonilo, benzylsulfonyl, phenylethyl aminsulfonilo, furylsulfonyl, meth ylsulfonyl, phenyl, phenyl substituted by one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, amincarbonilo, formyl and methylcarbonyl; where the atoms of ring A, A1, A2, A3 and A4, are carbon; or an isomer or an acceptable salt for pharmaceutical use thereof. There is another subclass of the benzothiopyran compound within Formula I 'where X is S; where R is carboxyl; wherein R1 is selected from perfluoroalkyl-C? -C3; where R 2 is one or more radicals independently selected from hydride, halo, C 1 -C 6 alkyl, phenylalkyl-C 1 -Cb, phenylalkyl-C 2 -C 6, phenylalkenyl-C 2 -Cb, C 1 -C 6 alkoxy, phenyloxy, heteroaryloxy of 5 or 6 members, phenylalkyloxy-Ci-Ce, heteroarylalkyloxy-C? -C6 of 5 or 6 members, haloalkyl-Ci-Cß, haloalkoxy-C? -C6, alkyl-Ci-Ce-amine, N-phenylamine, N - (phenylalkyl-Ci-C6) amine, N-heteroarylamine, N- (heteroarylalkyl-Ci-C6) amine, nitro, amine, aminsul fonyl, N-alkyl-aminsulfonyl, N-arylaminsulfonyl, N-hetero-arylaminsulfonyl, N- (phenylalkyl-C? -C6) amin-sulfonyl, N- (heteroarylalkyl-C? -C6) aminsulfonyl, heterocyclylsulfonyl 5- to 8-membered, alkylsulfonyl-C? -Cb, optionally substituted phenyl, 5- or 6-membered heteroaryl optionally substituted , phenylalkyl-C? -Cb-carbonyl, heteroarylcarbonyl, phenylcarbonyl, amincarbonyl and C-alkyl-C-carbonyl; where the ring atoms A, A2, A3 and A4 are independently selected from carbon and nitrogen, with the proviso that at least three atoms A1, A2, A3 and A4 are carbon; or an isomer or an acceptable salt for use • Pharmacist of the same. An even more preferred class of compound consists of those compounds of Formula I 'wherein X is S; where R is carboxyl; where R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, where R2 is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, tertbutyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl, 3, 3-dimethyl-1-butynyl, benzyl, phenylethyl, phenylethynyl, 4-chlorophenylethynyl, 4-methoxyphenyl-15-ethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, • pentafluoroethyl, trifluoromethoxy, tri fluoromethylthio, hydroxymethyl, hydroxytrifluoroethyl, methoxymethyl, hydroxyiminometyl, N-methylamine, N-phenylamine, N- (benzyl) amine, nitro, cyano, amine, aminsulfonyl, N-methylaminsul fonyl, N-phenylaminsulfonyl, N-furylaminsul fonyl , N- (benzyl) aminsul fonyl, N-25 (furylmethyl) aminsul fonyl, benzylsulfonyl, phenylethyl-aminsulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one or more radicals selected from chlorine, fluorine, bromine, methoxy, methylthio and methylsulfonyl , benzimidazolyl, thienyl, thiazolyl substituted with chlorine, furyl, furyl substituted with chlorine, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, amincarbonyl, formyl and methylcarbonyl; where the atoms of ring A, A1, A2, A3 and A4 are carbon; or an isomer or an acceptable salt for pharmaceutical use thereof. There is a third subclass of dihydroquinoline compounds of Formula I 'wherein X is NRa; where Ra is selected from hydrido, C 1 -C 3 alkyl, C 1 -C 3 phenylalkyl, C 1 -C 3 acyl and carboxyalkyl; where R is carboxyl; wherein R1 is selected from perfluoroalkyl-C? -C3; where R 2 is one or more radicals independently selected from hydride, halo, C 1 -C 4 alkyl, C 1 -C 4 phenylalkyl, C 2 -C 6 phenylalkynyl, C 2 -C 8 phenylalkenyl, C 1 -C 6 alkoxy, f 5xl, heteroaryloxy 5 or 6 members, phenylalkyloxy-C? -C6, heteroarylalkyloxy-Ci-C? Of 5 or 6 members, haloalkyl-C? -Cb, haloalkoxy-C? -Cb, alkyl-C? -Cb-amine, N-phenylamine , N- (phenylalkyl-Ci-Ce) amine, N-heteroarylamine, N- (heteroarylalkyl-Ci-C6) amine, nitro, amine, aminsulfonyl, N- A l alkylaminesulfonyl, N-arylaminsulfonyl, N-heteroarylamine sulfonyl, N- (phenylalkyl-C? -C6) amin-sulfonyl, N- (heteroarylalkyl-C? -C6) aminsulfonyl, heterocyclylsulfonyl of 5 to 8 members, alkylsulfonyl-C? -C6, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, phenyl-C1-C6-carbonyl, heteroarylcarbonyl, phenylcarbonyl, amincarbonyl, and C-C-carbonylcarbonyl; where the ring atoms A, A1, A2, A3 and A4 are independently selected from carbon and nitrogen, with the proviso that at least three atoms A1, A2, A3 and A4 are carbon; or an isomer or an acceptable salt for pharmaceutical use thereof. An even more preferred class of compounds consists of those compounds of Formula I 'wherein X is NRa; wherein Ra is selected from hydrido, methyl, ethyl, (4-trifluoromethyl) benzyl, (4-chloromethyl) benzyl, (4-methoxy) benzyl, (4-cyano) benzyl and (4-nitro) benzyl; where R is carboxyl; where R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, where R2 is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, tertbutyl, ethenyl, ethynyl, 5-chloro -l-pentynyl, 1-pentynyl, 3, 3-dimethyl-l-butynyl, benzyl, phenylethyl,? 2 phenylethynyl, 4-chlorophenylethynyl, 4-methoxy phenylethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulphinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl thio., hydroxymethyl, hydroxytrifluoroethylene, methoxymethyl, hydroxyiminmethyl, N-methylamine, N-phenylamine, N- (benzyl) amine, nitro, cyano, amine, aminsulfonyl, N-methylaminsul fonyl, N-phenylaminsulfonyl, N-furylaminsul fonyl, N- ( benzyl) aminsulfonyl, N- (furylmethyl) aminsulfonyl, benzylsulfonyl, phenylethylaminsulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one or more radicals selected from chlorine, fluorine, bromine, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted with chlorine, furyl, furyl substituted with chlorine, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, amincarbonyl, formyl and methylcarbonyl; where the atoms of the ring A, J, A2, A3 and A4, are carbon; or an isomer or an acceptable salt for pharmaceutical use thereof. There is a fourth subclass of compounds within Formula I ', wherein X is selected from 0, S and NRa; where Ra is selected from hydrido, C 1 -C 3 alkyl, phenylalkyl-Ci-Cs, C 1 -C 3 acyl and carboxyalkyl; wherein R is selected from carboxyl; wherein R1 is selected from perfluoroalkyl of C? -C3; where the atoms in ring A, A1, A2, A3 and. A4 are independently selected from carbon and nitrogen, with the proviso that at least three of A1, A2, A3 and A4 are carbon; and wherein R2 together with the ring A forms a naphthyl or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof. An even more preferred class of compounds consists of those compounds of Formula I ', wherein X is selected from O, S and NRa; wherein Ra is selected from hydride, methyl, ethyl, (4-trifluoromethyl) benzyl, (-chloromethyl) benzyl, (4-methoxy) benzyl, and (4-cyano) benzyl, (4-nit) benzyl; wherein R is carboxyl; wherein R 'is selected from hydride and ethenyl; wherein R1 is selected from trifluoromethyl and pentafluoroethyl; wherein the rings in ring A, A1, A2, A3 and A4 are independently selected from carbon and nitrogen, with the proviso that at least three of A1, A2, A3 and A4 are carbon; or wherein R2 together with the ring A forms a naphthyl or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.

? TO Within Formula I there is a subclass of compounds of high interest represented by Formula II: wherein X is selected from 0, NRa and S; wherein Ra is lower haloalkyl; wherein R3 is selected from hydride, -and halo; where R 4 is selected from hydride, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, dialkylaminosulfonyl lower, lower alkylaminsulfonyl, lower aralkylaminsulfonyl, heteroaralkylaminosulfonyl sulfonyl and heterocyclosulfonyl containing 5 or 6 membered nitrogen; wherein R5 is selected from hydrido, lower alkyl, halo, alkoxy and lower aryl; and wherein R6 is selected from hydride, halo, lower alkyl, lower alkoxy and aryl; or an isomer or an acceptable salt for pharmaceutical use thereof.

A class of compounds of particular interest consists of those compounds of Formula II wherein R 2 is trifluoromethyl or pentafluoroethyl; where R3 is selected from hydride, chlorine and fluorine; where R 4 is selected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminul sulphon, isopropylamine sulphonyl, methylaminsulfonyl, benzylaminsulfonyl, phenylethylaminsul fonyl, methylpropi 1 aminsul fonyl, methylsulphonyl and morpholinesulfonyl; wherein R5 is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamine and phenyl; and wherein R6 is selected from hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl; or an isomer or an acceptable salt for pharmaceutical use thereof. There is a subclass of compounds of Formula I of great interest, represented by the Formula lia: l to 6 wherein R is selected from hydride, lower alkyl, lower hydroxyalkyl, lower alkoxy and halo; wherein R 4 is selected from hydride, halo, lower alkyl, lower alkylthio, lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl, cyano, lower haloalkylthio, substituted or unsubstituted phenylcarbonyl, lower haloalkoxy lower alkoxy, lower aralkylcarbonyl, lower dialkylaryl fonyl, lower alkylaminosul fonyl, lower aralkyl-aminosulfonyl, lower heteroaralkylaminosul fonyl, 5- or 6-membered heteroaryl, lower hydroxyalkyl, optionally substituted phenyl, and 5 or 6 membered nitrogen-containing heterocyclic sulfonyl; wherein R5 is selected from hydride, lower alkyl, halo, lower haloalkyl, lower alkoxy, and phenyl; and wherein R * is selected from hydride, halo, cyano, hydroxyiminomethyl, hydroxy-lower alkyl, lower alkynyl, phenylalkynyl, lower alkyl, lower alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof. A class of compounds of particular interest consists of those compounds of Formula Ia, wherein R 3 is selected from hydride, and chloro; wherein R 4 is selected from chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethyl sulfur, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R5 is selected from hydride, methyl, tert-butyl, chloro; and wherein R6 is selected from hydride, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, and substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof. Within Formula I there is a subclass of high interest compounds represented by Formula I Ib: IIb wherein R3 is selected from hydride, lower alkyl, lower hydroxyalkyl, lower alkoxy and halo; wherein R 4 is selected from hydride, halo, lower alkyl, lower alkylthio, lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl, cyano, lower haloalkyl thio, substituted or unsubstituted phenylcarbonyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaryl fonyl, lower alkylaminosulfonyl, lower aralkyl-aminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6-membered heteroaryl, lower hydroxyalkyl, optionally substituted phenyl, and 5- or 6-membered nitrogen-containing heterocyclesul fonyl; wherein R5 is selected from hydride, lower alkyl, halo, lower haloalkyl, lower alkoxy, and phenyl; and wherein R6 is selected from hydride, halo, cyano, hydroxyiminomethyl, hydroxy-lower alkyl, lower alkynyl, phenylalkynyl, lower alkyl, lower alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof. A class of compounds of particular interest consists of those compounds of Formula Ilb, wherein R3 is selected from hydride, and chlorine; wherein R 4 is selected from chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R5 is selected from hydride, methyl, tert-butyl, chloro; and wherein R ° is selected from hydride, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, and substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof. Within Formula I there is a subclass of high interest compounds represented by the Formula lie: íe 30 wherein Ra is selected from hydride and lower aralkyl; wherein R3 is selected from hydride, lower alkyl, lower hydroxyalkyl, lower alkoxy and halo; wherein R 4 is selected from hydride, halo, lower alkyl, lower alkylthio, lower haloalkyl, amino, aminosulfonyl, lower alkylsulfonyl, lower alkylsulfinyl, lower alkoxyalkyl, lower alkylcarbonyl, formyl, cyano, lower haloalkylthio, substituted or unsubstituted phenylcarbonyl, lower haloalkoxy , lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkyl-aminosulfonyl, lower heteroaralkylaminosulfonyl, 5- or 6-membered heteroaryl, lower hydroxyalkyl, optionally substituted phenyl, and 5- or 6-membered nitrogen-containing heterocyclic sulfonyl; wherein R5 is selected from hydride, lower alkyl, halo, lower haloalkyl, lower alkoxy, and phenyl; and wherein R6 is selected from hydride, halo, cyano, hydroxyiminomethyl, hydroxy-lower alkyl, lower alkynyl, phenylalkynyl, lower alkyl, lower alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof. A class of compounds of particular interest consists of those compounds of Formula Lie, wherein R 3 is selected from hydride, and chlorine; wherein R 4 is selected from chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R: is selected from hydride, methyl, tert-butyl, chloro; and wherein R ° is selected from hydride, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, and substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof. A family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically acceptable salts thereof as follows: 6-chloro-2-tri fluorometho1-2H-1-benzopyran-3-carboxylic acid; 7-ethyl-2-tri fluoromethyl-2H-l-benzopy-3-carboxylic acid; 7-methyl-2-tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid; 2, 7-bis (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 7-bromo-2-trifluoromethyl-2H-l- • benzopyran-3-carboxylic acid; 5-chloro-7-methyl-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; 8- (1-methylethyl) -2-tri fluoromethyl-2H-l-benzopy-3-carboxylic acid; 6-chloro-7- (1,1-dimethylethyl) -2-10-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-Chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 15-8-Ethoxy-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 7- (1, 1-dimethylethyl) -2-tri fluoromethyl-2H-1 -benzopyran-3-carboxy 1 i co; • 6-Bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; 8-bromo-6-chloro-2-tri fluoromethyl-1H-1-benzopyran-3-carboxylic acid; 6-trifluoromethoxy-2-trifluoromethoxy-1-2H-1-benzopyran-3-carboxylic acid; 8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 5, 7-dichloro-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; 7, 8-dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 7-isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-phenyl-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; 7, 8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-bi (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 7- (1-methylethyl) -2-tri fluorometH-2H-1-benzopyran-3-carboxylic acid; 7-phenyl-2-tri fluoromethoxy-1-2H-1-benzopyran-3-carboxylic acid; 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-ethyl-2-trifluoromethyl-2JH-l- -benzopyran-3-carboxylic acid; 6-chloro-8-ethyl-2-trifluoromethyl-2H-l- • benzopy-3-carboxylic acid; 5-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 6,7-dichloro-2-tri fluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6, 8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; • 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 15 6-nitro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-amin-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; • ethyl 6-amin-2-tri fluoromethyl-2H-1 -benzopyran-3-carboxylate; 6-Chloro-8-methyl-1-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 25-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-difluoro-2-tri fluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-bromo-8-chloro-2-trifluoromethyl-1H-1-benzopyran-3-carboxylic acid; 8-bromo-d-fluoro-2-tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-bromo-6-methyl-2-triforomethyl-2H-1-benzopyran-3-carboxylic acid; 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 7- (N, N-diethylamine) -2- trifluoromethyl 1-2H-1-benzopyran-3-carboxylic acid; 6- [[(phenylmethyl) amine] sulfonyl] -2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; 6- [(dimethylamin) sulfonyl] -2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6-aminsulfoni1-2- trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6- (methylamin) sulfonyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [(4-morpholin) sulfonyl] -2- ^ trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6 - [(1, 1-dimethylethyl) aminsulfonyl] -2- trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6- [(2-methylpropyl) aminsulfonyl] -2- trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-6- [[phenylmethyl] amine] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-N, N-diethylaminsulfonyl-2-trifluoromethyl acid 1-2H-1-enzopyran-3-carboxylic acid; 6-phenylacetyl-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; 6- (2, 2-dimethyl-1-propylcarbonyl) -2- tri fluoromethyl-1-2H-1-benzopy-3-carboxylic acid; 6, 8-dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; 6-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [[(2-furanylmethyl) amin] sulfonyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 25 51 6- [(phenylmethyl) sulfonyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- [[(phenylethyl) a in] sulfonyl] -2- (trifluoromethyl) -2H-l -benzopyran-3-carboxylic acid; 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-iodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8-bromo-β-chloro-2-tri fluoromethyl-1H-1-benzopy-3-carboxylic acid; 6-formyl-2- (trifluoromethyl) -2H-1-ben-opyran-3-carboxylic acid; 6-chloro-8-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-bromo-7- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5,6-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-hydroxymethyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (di fluoromethyl) -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid; 2, 6-bi (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5, 6, 7-trichloro-2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6, 7, 8-trichloro-2- (trifluoromethyl) -2H-1-ben-opyran-3-c-carboxylic acid; 6- (methylthio) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (Methylsulfinyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5, 8-dichloro-2- (trifluoromethyl) -2H-l-benzopyr-n-3-carboxylic acid; 6- (pentafluoroethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (1,1-dimethylethyl) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 2- (Trifluoromethyl-6- [((trifluoromethyl) thio] -2H-1-benzopyran-3-carboxylic acid, 6, 8 -di-chloro-7-methyl-2 - (trifluoromethyl) -2H-1 -benzopyran-3-carboxylic acid, 6-chloro-2,7-bi (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid, 5-methoxy-2- (trifluoromethyl) -2H-1- benzopyran-3-carboxylic acid; 6-benzoyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorobenzoyl) -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid; 5 6- (4-hydroxybenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-phenoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8-chloro-6- (4-chlorophenoxy) -2-10-trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; • 2- (trifluoromethyl) -6- [4- (trifluoromethyl) -phenoxy) -2H-1-benzopyran-3-carboxylic acid; 6- (4-methoxyphenoxy) -2- (trifluoromethyl) 2H-1, -benzopyran-3-carboxylic acid; 6- (3-Chloro-4-methoxyphenoxy) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; • 8-Chloro-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenoxy] -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- [(hydroxyimin) methyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; JSO 6-chloro-8- (hydroxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8- (lH-benzimidazol-2-yl) -6-chloro-2- (tri fluoromet i 1) -2H-1-benzopyran-3-carboxylic acid; 7- (1, 1-dimethylethyl) -2- (pentafluoroethyl-1-benzopyran-3-carboxylic acid; * 6-chloro-8- (methoxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3 acid -carboxylic acid 6-chloro-8- (benzyloxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 6-chloro-8-ethenyl-2- (trifluoromethyl) -Hl-benzopyran -3-carboxylic acid 6-chloro-8-ethynyl-2- (trifluoromethyl) -Hl-benzopyran-3-carboxylic acid 6-chloro-8- (2-thienyl) -2- (trifluoromethyl) -2H -l-benzopyran-3-carboxylic acid 6-chloro-8- (2-furanyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid d-chloro-8- (5- chloro-l-pentynyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid d-chloro-8- (1-pentynyl) -2- (trifluoromethyl) -2H-l-benzopyran-3 -carboxylic acid 6-chloro-8- (phenylethynyl) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; d-chloro-8- (3, 3-dimethyl-1-butynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-chloro-indoyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-methoxyphenyl) ethynyl] -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (phenylethynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (4-chlorofeniJL) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; d-chloro-8 - [(4-methylthio) phenyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-d- [(-methylsulfonyl) phenyl] -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-bromo-8-fluoro-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxy 1 i co; 6- (4-fluorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; £ 2 8-chloro-6-fluoro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6, 8-diiodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (5-chloro-2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboalic acid; 6- (4-bromophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (ethynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-met il-2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (4-methoxy phenyl) -2-tri fluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6-chloro-2- (trifluoromethyl) -4-ethenyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-2- (trifluoromethyl) -4-phenyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-4- (2-thienyl) -2- (trifluoromethyl) • 2H-1-benzopyran-3-carboxylic acid; 6- (2, 2, 2-trifluoror- 1 -hydroxyethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-Methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-c-oxylic acid; 6, 8-dimethyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxy liic acid; 6,7-dimethyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 8-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6-chloro-7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 7-chloro-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6,7-dichloro-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 2- (trifluoromethyl) -6- [(trifluoromethyl) thio] -2H-1-benzo thiopyran-3-carb oxylic acid; J4 6, 8-dichloro-2-trif luoromethyl-2H-l-benzothiopyran-3-carboxylic acid; 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3- • quinolinecarboxylic acid; 6, 8-dichloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6,7-dichloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-iodo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-bromo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 1,2-dihydro-6- (tri-fluoromethyl) -2- (trifluoromethyl) -3-quinol-carbohydric acid; 6- (trifluoromethyl) -l, 2-dihydro-2- (trifluoromethyl) -3 -quinol, arboxylic acid; 6-cyano-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; • 6-chloro-l, 2-dihydro-l -me t -yl-2-20 (tri-fluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -1 - [[4- (trifluoromethyl) phenyl] methyl] -3-quinolinecarboxylic acid; 6-chloro-l- [(4-chlorofenyl) ethyl] -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; £ 5 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -1- [[4- (methoxy) phenyl] methyl] -3-quinolinecarboxylic acid; 6-chloro-l- [(4-cyanofenyl) methyl] -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-l- [(4-nitrophenyl) methyl] -2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-l-ethyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-2- (tri-fluoromethyl) -1,2-dihydro [1,8] naphthyridine-3-carboxylic acid; 2-trifluoromethyl-2H-naph to [1, 2-b] pyran-3-c to oxyl acid; 2-tri f luoromet-3 H-napht [2, 1-b] pyran-3-carboxylic acid; 2-trifluoromethyl-2H-naphtho [2,3-b] pyran-3-carboxylic acid; 5- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-pyran [2, 3-c] pi r idin-3-carboxy 1 acid; 6- (trifluoromethyl) -6h-1, 3-dioxolo [4,5-g] [1] benzopyran-7-carboxylic acid; and 3- (trifluoromethyl) -3H-benzofuro [3,2- f] [1] benzopyran-2-carboxylic acid. A preferred family of specific compounds that are of particular interest within Formulas 1 and 1 'is formed by the following compounds: (S) -6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -7-ethyl-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; (S) -7-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -2,7-bi (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -7-bromo-2-tri fluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-Chloro-7-methyl-2-trifluoromethyl-2H-1-benzo-3-carboxylic acid; (S) -8- (1-Methylethyl) -2- trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (1-methylethyl) -2-t-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -2- trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 4 (S) -8-ethoxy-2-trifluoromethyl-2H.-1-benzopyran-3-carboxylic acid; (S) -7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-bromo-2-tri fluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -8-chloro-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; (S) -8-bromo-6-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-tri fluoromethoxy-2-trifluoromethyl-2H-A-benzopyran-3-carboxylic acid; (S) -8-Fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -5,7-dichloro-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -7,8-Dichloro-2-trifluoromethyl-2H-l-enzopyran-3-carboxylic acid; (S) -7-isopropyloxy-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -8-phenyl-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; (S) -7,8-Dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6,8-Bi (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -7-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -7- (1-Methylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -7-phenyl-2-tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6-Chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -8-ethyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-Chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6-Chloro-7-phenyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; - (S) -6,8-Dichloro-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -6, 8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6,8-dimethoxy-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -6-nitro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-amin-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; £ 9 6-amin-2-tri-fluororneti 1-2H-1-benzopy-ran-3-carboxylate of (S) -ethyl; (S) -6-Chloro-8-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -8-chloro-6-methyl-2-trifluoro-ethyl-2H-1-benzopyran-3-carboxylic acid; (S) -8-chloro-6-methoxy-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6, 8-di-fluoro-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; (S) -6-Bromo-8-chloro-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; (S) -8-bromo-6-fluoro-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; (S) -8-Bromo-6-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8-fluoro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-Bromo-8-methoxy-2-trifluoromethyl-2H-l-enzopyran-3-carboyl acid; (S) - (N, N-Diethylamine) -2- trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6 - [[(phenylmethyl) amin] sulfonyl] -2- trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; (S) -6- [(dimethyl lamine) sulfonyl] -2- • trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; - (S) -6-aminsulfonyl-2-trifluoromethyl-2H-l-benzopyran-3-carboyl acid; (S) -6- (methylamin) sulfonyl-2-trifluoromethyl-1-2H-l-benzopyran-3-carboxylic acid; (S) -6- [(4-Morpholine) sulfonyl] -2- * 10-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -6 - [(1,1-dimethylethyl) aminsulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6 - [(2-methylapropyl) aminosulfonyl] 2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 15 (S) -6-methylsulfonyl-2-trifluoromethyl-2H-l-h > 3-carboxylic enzyme opiran; (S) -8-chloro-6- [[(phenylmethyl) amin] sulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6-N, N-diethylaminsul fonyl-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6- (2, 2-dimethylpropi-learbonyl) -2- trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6,8-Dichloro-7-methoxy-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-2-trifluoromethyl-2H-l-benzothiopyran-3-carboxylic acid; (S) -6- [[(2-furanylmethyl) amin] sulfonyl] acid] 2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- [(phenylmethyl) sulfonyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- [[(phenylethyl) amin] sulfonyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-iodo-2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid; (S) -6-Chloro-8-iodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -8-bromo-6-chloro-2-rifluoromethyl-2H-1-benzopy-3-carboxylic acid; (S) -6-formyl-2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid; (S) -6-chloro-8-formyl-2- (trifluoromethyl) 2H-1-benzopy-3-carboxylic acid; (S) -6-Bromo-7- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -5,6-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-Cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-hydroxymethyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (Difluoromethyl) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -2,6-bi (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -5,6,7-Trichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6,7,8-Trichloro-2- (trifluoromethyl) -2H-1 -be zopi-3-carboxylic acid; (S) -6- (Methylthio) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (Methylsulfinyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -5,8-Dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (pentafluoroethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid; (S) -2- (trifluoromethyl) -6- [(trifluoromethyl) -thio] -2H-1-benzothiopyran-3-carboxylic acid; (S) -6,8-Dichloro-7-methyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-2,7-b (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -5-methoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-Benzoyl-2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid; (S) -6- (4-Chlorobenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (4-hydroxybenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-phenoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -8-chloro-6- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -2- (trifluoromethyl) -6- [4-trifluoromethyl) phenoxy) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (4-methoxyphenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (3-Chloro-4-methoxyphenoxy) -2- (t -fluoromethyl) -2H-1-benzopy-3-carboxylic acid; (S) -6- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -8-Chloro-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenoxy) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8-cyano-2- (trifluoromethyl) -2H-1-benzo-3-carboxylic acid; (S) -6-Chloro-8- [(hydroxyimino) methyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (hydroxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -8- (1H-Benzimidazol-2-yl) -6-chloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -7- (1,1-dimethylethyl) -2- (pentafluoroethyl) -2H-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (methoxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (benzyloxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8-ethenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8-ethynyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (2-furanyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (5-chloro-l-pentynyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid: (S) -6-chloro-8- (1) acid -pentinyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid (S) -6-chloro-8- (phenylethynyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid (S) -6-chloro-8- (3, 3-dimethyl-l-butynyl) 2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid; (S) -6-chloro-8 acid - [(4-chlorophenyl) ethynyl] 2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid (S) -6-chloro-8 - [(-methoxyphenyl) ethynyl] 2- (trifluoromethyl) - 2H-l-benzopyran-3-carboxylic acid (S) -6- (phenylethynyl) -2- (tri fluoromethyl) -2H-l-benzopyran-3-carboxylic acid; - (S) -6-chloro- 8- (4-chlorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid (S) -d-chloro-8- (3-methoxyphenyl) -2- (trifluoromethyl) -2H- 1-benzopyran-3-carboxylic acid (S) -6-chloro-8 - [(-methylthio) phenyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8 - [(4-methylsulfonyl) phenyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8-phenyl-2- (trifluoromethyl) -2H-1-benzo-3-carboxylic acid; 1 6 (S) -6-Bromo-8-fluoro-2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid; (S) -6- (4-fluorophenyl) -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid; (S) -6-phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -8-chloro-6-fluoro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6,8-Diiodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (5-Chloro-2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (4-chlorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (4-Bromophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3 -carboyl acid; (S) -6- (Ethinyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-Methyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8- (4-methoxyphenyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-chloro-2- (trifluoromethyl) -4- ethenyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-chloro-2- (trifluoromethyl) -4- • phenyl-2H-1-benzopy-3-carboxylic acid; 5 (S) -6-Chloro-4- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6- (2,2,2-Trifluoro-l-hydroxyethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-Methyl-2- (trifluoromethyl) -2H-1- benzothiopyran-3-carboxylic acid; • (S) -6,8-dimethyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; (S) -6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 15 (S) -7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; (S) -6,7-Dimethyl-2- (tri fluoromethyl) -2H-1-benzothiopi-3-carboxylic acid; • (S) -8-Methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; (S) -2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; (S) -6-chloro-7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; (S) -7-chloro-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; (S) -6,7-Dichloro-2- (trifluoromethyl) -2H-1-benzothiopi-3-carboxylic acid; (S) -2- (trifluoromethyl) -6- [(trifluoromethyl) -thio] -2H-1-benzopyran-3-carboxylic acid; (S) -6, 8-dichloro-2-trifluoromethyl-2H-l-benzothiopi-3-carboxylic acid; (S) -6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6, 8-dichloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6,7-difluoro-l, 2-dihydro-2- (tri fluoromethyl) -3-quinolinecarboxylic acid; (S) -6-iodo-l, 2-dihydro-2- (trifluoromethyl) acid • 3-quinolinecarboxylic; (S) -6-bromo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -1,2-dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6- (trifluoromethyl) -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6-Cyano-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6-chloro-l, 2-dihydro-l-methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6-chloro-l, 2-dihydro-2- (trifluoromethyl) - • 1- [[4- (trifluoromethyl) phenyl] methyl] -3,5-quinolinecarboxylic acid; (S) -6-chloro-l- [(4-chlorophenyl) methyl] -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6-chloro-l, 2-dihydro-2- (trifluoromethyl) -1- [[4- (methoxy) phenyl] methyl] -3-quinolinecarboxylic acid; (S) -6-Chloro-l- [(4-cyanophenyl) methyl] - • l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6-chloro-l, 2-dihydro-l- [(-nitrophenyl) -methyl] -2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6-chloro-l, 2-dihydro-l-ethyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid; (S) -6-chloro-2- (trifluoromethyl) -1,2-dihyd or [1,8] naphthyridin-3-carboxylic acid; (S) -2-trifluoromethyl-2H-naphtho [1,2- b] pyran-3-carboxylic acid; 20 (S) -2-trifluoromethyl-3H-naphtho [2, 1-b] pyran-3-carboxylic acid; (S) -2-trifluoromethyl l-2H-naphtho [2,3-b] pyran-3-carboxylic acid; and (S) -5- (Hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-pyran [2, 3-c] pyridine-3-carboxylic acid.

The term "hydride" denotes a single hydrogen atom (H). This hydride radical can be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydride radicals can adhere to a carbon atom to form a methylene radical (-CH2-). Where the term "alkyl" is used, either alone or together with other terms such as "haloalkyl" and "alkylsulfonyl", it embraces linear or branched radicals having from one to about twenty carbon atoms or preferably between one and about twelve atoms. of carbon. The most preferred alkyl radicals are "lower alkyl" radicals having from one to about six carbon atoms. Examples of these radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, and the like. The most preferred are lower alkyl radicals having from one to three carbon atoms. The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms, or preferably two to about twelve carbon atoms. More preferably the radicals 31 alkenyl are "minor alkenyl" radicals having between two and about six carbon atoms. Examples of alkenyl radicals include ethylene, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term "alkynyl" denotes linear or branched radicals having between two and about twenty carbon atoms, or preferably, between two and twelve carbon atoms. More preferably alkynyl radicals F 10 are "minor alkynyl" having from two to about ten carbon atoms. The most preferred minor alkynyl radicals are those having two to about six carbon atoms. Examples of these radicals include propargyl, butynyl and the like. The terms "alkenyl" and "minor alkenyl" embrace the radicals having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. The term "halo" means F halogens such as, for example, fluorine atoms, chlorine, bromine or iodine. The term "haloalkyl" embraces radicals where one or more alkyl carbon atoms are replaced with halo, as defined above. The monohaloalkyl, dihaloalkyl and polyhaloalkyl. A monohaloalkyl radical may contain, for example, either an iodine, bromine, chlorine, or fluorine atom within the radical. The dihalo and polyalkyl radicals can have two or more F of the same halo atoms, or a combination of 5 different halo radicals. The "lower haloalkyl" comprise radicals having from 1 to 6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, F 10 trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dihlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all of their hydrogen atoms replaced with fluorine atoms. Examples include trifluoromethyl and pentafluoroethyl. The term "hydrosalkyl" embraces linear or branched alkyl radicals having from one to about F ten carbon atoms, any of which may be replaced with one or more hydroxyl radicals. More preferably, the hydroxyalkyl radicals are "minor hydroxyalkyl" having one to six carbon atoms and one or more hydroxyl radicals. Examples of these radicals are include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The term "cyanoalkyl" embraces linear or branched alkyl radicals having from one to F about ten carbon atoms any of which can be replaced with a cyano radical. More preferably radical cyanoalkyl radicals are "minor cyanoalkyl radicals" having from one to six carbon atoms and one cyano radical. Examples of these radicals are includes cyathyl. The term "alkoxy" embraces linear or branched oxy radicals each containing alkyl portions of one to about ten carbon atoms. More preferably the radical alkoxy radicals are are "lower alkoxy" radicals having from one to six carbon atoms. Examples of these radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The "alkoxy" radicals can F to be replaced in addition with one or more halo atoms as fluorine, chlorine, or bromine to obtain "haloalkoxy" radicals. Examples of these radicals are fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or combined, means a aromatic carbocyclic system containing one or two BA rings that can be linked together in a descending manner or can be fused. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and diphenyl. The said "aryl" group may have one to three substituents, such as minor alkyl, hydroxy, halo, haloalkyl, nitro, cyano, lower alkoxy and alkyloxy. The term "heterocyclic" comprises saturated, partially saturated and unsaturated heteroatoms containing ring-shaped radicals, wherein the heteroatoms may be chosen from nitrogen, sulfur and oxygen. Examples of the saturated heterocyclic radicals include the saturated 3 to 6 membered heteromonocyclic group containing one to four nitrogen atoms [eg, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; the saturated 3 to 6 membered hetrimonocitic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [eg, morpholinyl]; the saturated 3 to 6 membered heteromonocyclic group containing between 1 and 2 sulfur atoms and 1 and 3 nitrogen atoms [eg, thiazolidinyl]. Examples of partially saturated heterocyclic radicals include dihydrothiophene, 8b dihydropyran, dihydrofuran and dihydrothiazole. Examples of unsaturated heterocyclic radicals, also called "heteroaryl" radicals, are F include the 5 to 6-membered saturated 5 to 6-membered heteromonocyclic group containing from 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl , triazolyl [for example, 4H-1,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H-1,2,3-triazolyl]; the group of unsaturated condensed heterocyclics containing from 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indole and zinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, Tetrazolopyridazinyl [for example, tetrazole [1,5- b] pyridiazinyl]; the 3 to 6 membered unsaturated heteromonocyclic group containing one oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, F etc. To the unsaturated heteromonocyclic group from 3 to 6 members containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc .; the 5 to 6 membered unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1, 3, 36 4-oxadiazolyl, 1, 2, 5-oxadiazolyl]: the unsaturated condensed hetrocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [for example benzoxazolyl, benzoxadiazolyl]; the unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [eg, 1,2,4-thiadiazolyl, 1, 3, 4- thiadiazolyl, 1, 2, 5-thiadiazolyl]; the group unsaturated condensed heterocyclic having 1 to • 2 sulfur atoms and 1 to 3 nitrogen atoms [eg, benzothiazolyl, benzothiadiazolyl] and the like. The term also covers radicals where The heterocyclic radicals are fused with aryl radicals. Examples of these bicyclic fused radicals include benzofuran, benzothiophene and the like. The mentioned group • "heterocyclic" can have from 1 to 3 substituents For example, lower alkyl, hydroxy, oxo, amino and lower alkylamino. Preferred hetrocyclic radicals include radicals of five to ten members, fused or not. More preferred examples of heteroaryl radicals include Benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thioxxomanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl. The term "sulfonyl", whether used alone or associated with other terms such as alkylsulfonyl, denotes, respectively, bivalent radicals -S02-. "Alkylsulfonyl" embraces alkyl radicals adhered to a sulfonyl radical, where alkyl is as defined above. More preferably the alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having from 1 to 6 carbon atoms. Examples of these alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsul fonyl. "Haloalkylsul fonyl" comprises haloalkyl radicals adhered to a sulfonyl radical where the haloalkyl is as defined above. More preferably the haloalkylsul fonyl radicals are "lower haloalkylsul fonyl" radicals having between 1 and 6 carbon atoms. Examples of these minor haloalkylsul fonyl radicals include trifluoromethylsulfonyl. The term "arylalkylsulfonyl" comprises aryl radicals, according to the above definition, adhered to an alkylsulfinyl radical. Among the examples of these J38 radicals include benzylsulfonyl and phenylethylsulfonyl. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl", whether used alone or with terms such as "N-alkylaminosulfonyl", "N-arylaminosulfonyl", "N, N-dialkylaminosulfonyl" and "N-alkyl- N" -aril-aminosul fonilo ", denotes a sulphonyl radical replaced with an amino radical, to form a sulfonamide (-S02NH2). The term "alkylaminosulfonyl" includes "N-alkylaminosul fonyl" and - "N, N-dialkylaminosulfonyl" wherein the sulfamyl radicals are respectively replaced with an alkyl radical, or two alkyl radicals. More preferably the alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having from 1 to 6 carbon atoms. Examples of these minor alkylaminosulfoni radicals include N-methylaminosul fonyl, N-ethylaminosul fonyl and N-methyl-N-ethylaminosulfonyl . The terms "N-arylaminosulfonyl" and "N-alkyl-N-arylaminosulfonyl" denote sulphamyl radicals substituted respectively with an aryl radical or with an alkyl radical and an aryl radical. More preferably the N-alkyl-N-arylaminosulfonyl radicals are "N-alkyl-N-arylsulfonyl" radicals having alkyl radicals of 1 to 6 carbon atoms. Examples of these minor N-alkyl-N-arylaminosulfonyl radicals include N-methyl-N-F phenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl. Examples of these N-aryl-aminosulfonyl radicals include N-phenylaminosulfonyl. The term "arylalkylaminosul fonyl" embraces arylalkyl radicals, as described above, adhered to an aminosulfonyl radical.

The term "heterocyclylaminosulfonyl" comprises heterocyclic radicals described above adhered to an aminosulfonyl radical. The terms "carboxy" or "carboxyl" whether they are used alone or together with other terms such as "carboxyalkyl", denotes -C02H. The term "carboxyalkyl" embraces radicals having a carboxy radical, as defined above, adhered to an alkyl radical. The term "carbonyl" used alone or with others F terms such as "alkylcarbonyl", denotes - (C = 0) -. He The term "acyl" denotes a radical that remains after having removed a hydroxyl to an organic acid. Examples of these minor alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, Hexanoyl, trifluoroacetyl. The term "aroyl" comprises aroyl radicals comprising aryl radicals with carbonyl radicals, as defined above. Examples of aroyl include benzoyl, naphthoyl and the like, and the aryl in that aroyl radical may be further substituted. The term "alkylcarbonyl" comprises radicals having a carbonyl radical substituted with an alkyl radical. More preferably the alkylcarbonyl radicals are "lower alkylcarbonyl" radicals having from one to six carbon atoms. Examples of these radicals include methylcarbonyl and ethylcarbonyl. The term "haloalkylcarbonyl" comprises radicals having a carbonyl radical substituted with a haloalkyl radical. More preferably the haloalkylcarbonyl radicals are "lower haloalkylcarbonyl radicals" having from one to six carbon atoms. Examples of these radicals include trifluoromethylcarbonyl. The term "arylcarbonyl" comprised radicals having a carbonyl radical substituted with an aryl radical. More preferably the arylcarbonyl radicals include phenylcarbonyl. The term "hearoarylcarbonyl" comprises radicals having a carbonyl radical substituted with a heteroaryl radical. The term "aryalkylcarbonyl" comprises radicals having a carbonyl radical substituted with an arylalkyl radical. More preferably the arylcarbonyl radicals include benzylcarbonyl. The term "heteroalkylcarbonyl" comprises radicals having a carbonyl radical substituted with a heteroarylalkyl radical. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, adhered by an oxygen atom to a carbonyl radical. Preferably, the "lower alkoxycarbonyl" comprise alkoxy radicals having from one to six carbon atoms. Examples of these "lower alkoxycarbonyl ester" radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term "aminocarbonyl", used alone or with other terms such as "aminocarbonylalkyl", "N-alkylaminocarbonyl", "N-arylaminocarbonyl", "N, N-dialkylaminocarbonyl", "N-alkyl-N-arylaminocarbonyl", "N- alkyl-N-hydroxy-aminocarbonyl ", and" N-alkyl-N-hydroxyaminocarbonyl-alkyl ", denotes an amido group of formula -C (0) NH2. The terms "N-alkylaminocarbonyl and" N, N-dialkylaminocarbonyl "denote aminocarbonyl radicals, substituted with an alkyl radical and with two alkyl radicals respectively. More preferably they are "minor alkylaminocarbonyl" having minor alkyl radicals, as F described above, adhered to a 5-amidocarbonyl radical. The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl" denote aminocarbonyl radicals substituted, respectively, with an aryl radical, or with an alkyl radical and an aryl radical. The term "N-cycloalkylaminocarbonyl" F 10 denotes substituted ammocarboni radicals with at least one cycloalkyl radical. More preferably they are "minor cycloalkylaminocarbonyl" having cycloalkyl radicals of less than three to seven carbon atoms, adhered to an aminocarbonyl radical. 1 The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. The term "alkylaminoalkyl" comprises aminoalkyl radicals having the nitrogen atom substituted with a F alkyl radical. The term "heterocyclic alkyl" comprises alkyl radicals substituted with heterocyclic radicals. More preferably the heterocycloalkyl radicals are 5-6-membered heteroarylalkyl radicals having alkyl portions of one to six carbon atoms and a 5- or 6-membered heteroaryl radical. Examples include radicals such as pyridylmethyl and thienylmethyl. The term "aralkyl" comprises aryl-substituted alkyl radicals. Preferably the aralkyl radicals are "minor aralkyl" radicals having aryl radicals attached to alkyl radicals having from one to six carbon atoms. Examples of these radicals include benzyl, diphenylmethyl and phenylethyl. The aril in the aforementioned Aralkyl can be further substituted with • halo, alkyl, alkoxy, halcoalkyl and haloalkoxy. The term "arylalkenyl" embraces aryl-substituted alkenyl radicals. Preferably the arylalkenyl radicals are "minor arylalkenyl" radicals having aryl radicals adhered to alkenyl radicals having from two to six carbon atoms. Examples of these radicals include phenylethenyl. The aryl in said arylkenyl may be substituted • additionally with halo, alkyl, alkoxy, Haloalkyl, halcoalkoxy and haloalkoxy. The term "arylalkynyl" embraces aryl-substituted alkynyl radicals. Preferably arylalkynyl radicals are "minor arylalkynyl" radicals with aryl radicals adhered to the radicals Alkynyl having from two to six carbon atoms. 9 A Examples of these radicals include phenylethynyl. The aryl in said aralkyl can also be substituted with halo, alkyl, alkoxy, halcoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term "alkylthio" comprises radicals containing a linear or branched alkyl radical of one to ten carbon atoms, attached to a bivalent sulfur atom. An example of "alkylthio" is methylthio, (CH3-S-). The term "haloalkyl thio" comprises radicals having a haloalkyl radical of one to ten carbon atoms adhered to a bivalent sulfur atom. An example of "haloalkyl thio" is trifluoromet il thio. The term "alkylsul finyl" comprises radicals having a linear or branched alkyl radical of one to ten carbon atoms, adhered to a bivalent atom -S (= 0) -. The term "arylsul fonyl" comprises radicals having an aryl radical attached to a bivalent atom -S (= 0) -. The term "haloalkylsulfinyl" comprises radicals having a haloalkyl radical of one to ten carbon atoms attached to a bivalent atom S (= 0) -. The terms "N-alkylamino" and "N, N-dialkylamino" denote amino groups substituted with an alkyl radical and with two alkyl radicals. respectively. More preferably, the alkylamino radicals are "lower alkylamino" radicals having one to two alkyl radicals of one to six carbon atoms, adhered to a nitrogen atom. Suitable "alkylamino" can be mono or dialkylamino, such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino or the like. The term "arylamino" denotes amino groups substituted with one or two aryl radicals, such as N-phenylamino. The "arylamino" radicals can also be substituted in the aryl part of the radical ring. The term "heteroarylamino" denotes amino groups that have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals can also be substituted in the heteroaryl part of the radical ring. The term "aralkylamino" denotes amino groups that have been substituted with one or two aralkyl radicals, such as, for example, N-benzylamino. The "aralkylamino" radicals can also be substituted in the aryl part of the radical ring. The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" denote amino groups that have been substituted with an aralkyl radical and an alkyl radical, or an aryl radical -and- an alkyl radical, respectively, to an amino group. The term "arylthio" embraces aryl radicals of six to ten carbon atoms, attached to a bivalent sulfur atom. An example of "arylthio" is phenylthio. The term "aralkylthio" embraces the aralkyl radicals described above, adhered to a bivalent sulfur atom. An example of "aralkylthio" is benzylthio. The term "aralkylsul fonyl" embraces the aralkyl radicals described above, adhered to a bivalent sulfonyl radical. The term "heterocyclylsul fonyl" embraces the heterocyclic radicals described above, adhered to a bivalent sulfonyl radical. The term "aryloxy" embraces the aryl radicals defined above, adhered to an oxygen atom. Examples of these radicals include phenoxy. The term "aralkoxy" embraces aralkyl radicals containing oxy-adhered to other radicals by an oxygen atom. The most preferred alalkoxy radicals are the "minor aralkoxy" radicals having phenyl radicals adhered to a minor alkoxy radical as described above. The present invention comprises a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula 91 I associated with at least one pharmaceutically acceptable carrier, adjuvant or diluent. The present invention also comprises a method for treating disorders caused by cyclooxygenase-2, such as, for example, inflammation, in a subject, said method comprising treating the subject having or being susceptible to that disorder with a therapeutically effective amount of a compound of Formula I. In the family of compounds of Formula I their stereoisomers are also included. The compounds of the present invention may have one or more asymmetric carbon atoms and thus are capable of existing as optical isomers in the form of racemic and non-racemic mixtures thereof. Accordingly, some of the compounds of this invention may be present in racemic mixtures which are also included in this invention.The optical isomers may be obtained by resolution of the racemic mixtures according to conventional processes, for example, by formation of salts Tereoisomeric days by treatment with an optically active base and then by separation of the mixture of diastereomers by crystallization, followed by the release of the optically active bases of these salts Examples of suitable bases include brucine, strychnine, dehydroabietylamine , quinine, cinchonidine, ephedrine, a-methylbenzylamine, amphetamine, deoxyphedrine, chloramphenyl intermediates, 2-amino-1-butanol, and 1- (1-naphthyl) ethylamine Another different process for separation of optical isomers involves the use of a chiral chromatography column chosen optimally to maximize the separation of enantiomers. Another method also available involves the synthesis of covalent diastereomeric molecules. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, then hydrolyzed to obtain the enantiomerically pure compound. The optically active compounds of Formula I can also be obtained using optically active raw material. These isomers may be in the form of a free acid, a free base, an ester or a salt. Other methods for solving optical isomers may be employed, known to those skilled in the art, for example, those discussed by J. Jaques et al. In 'Enantiomers, Racemates and Resolutions' (Enantiomers, Racemates and Resolutions), (John Wiley and Sons, New York (1981) .In the family of the compounds of the Formula I and I 'are also included their acids protected by amides. In this way, the primary and secondary amines can be reacted with the chromene-3-carboxy acid acids of Formula I and I 'to form amides which can be useful as prodrugs. The amines are preferred heterocyclic amines, including the optionally substituted inot-azoles, and the optionally substituted amino-isoxazoles, and optionally substituted aminopyridines; the aniline derivatives; the sulfonamides; aminocarboxylic acids; and similar. In addition, the 1-acyldihydroquinolines can behave as pro-drugs for the 1H-dihydroquinolines. In the family of the compounds of the Formula I and I 'also include pharmaceutically acceptable salts thereof. The term pharmaceutically acceptable salts encompasses the salts commonly used to form alkali metal salts and to form acid salts 1.-00 free or free bases. The nature of the salt is not critical, as long as it is pharmaceutically acceptable. Pharmaceutically acceptable acid addition salts of the compounds of Formula I can be prepared from an inorganic acid or an organic acid. Examples of these inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Acids can be selected organic appropriate between the classes of acids • organic aliphatic, cycloaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulphonic, of which formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, -hydroxybenzoic, phenylactic, mandelic, embonic • (pamoic), methanesulfonic, ethanesulonic, benzene-sulphonic, pantothenic, 2-hydroxyethanesulfonic, tolunenosulfonic, sulphanilic, cyclohexylaminosulfonic, stearic, algenic, ß-hydroxybutyric, salicylic, galac- tartaric and galacturonic. The pharmaceutically acceptable addition base salts of the compounds of Formula I or I 'include the metal salts, such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary and tertiary amines , substituted amines including cyclic amines, such as caffeine, arginine, diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, the triethylamine, trimethylamine. All these salts are • they can be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formula I or I '. 15 GENERAL SYNTHESIS PROCEDURES The compounds of the invention can be • synthesize according to the procedures of the following Schemes 1-16, where the substituents Rl-R6 are as defined for Formulas I-II above, except where otherwise stated.

SCHEME 1 OH " Synthesis Scheme 1 illustrates the general method for the preparation of a wide variety of substituted 3 and 4 2H-1-benzopyran derivatives. In step 1, a representative ortho-hydroxybenzaldehyde derivative (salicialdehyde) 1 is condensed with an acrylate derivative 2 in the presence of a base, such as a potassium carbonate in a solvent, such as dimethylformamide, in order to obtain the 2H-1 ester -benzopyran 3 desired. An alternative base-solvent combination for this condensation includes an organic base, such as triethylamine and a solvent, such as dimethylsulfoxide. In step 2, the ester is hydrolyzed in the corresponding acid, such as by treatment with an aqueous base (sodium hydroxide) in a suitable solvent, such as ethanol, in order to obtain, after acidification, 2H-1- acid substituted benzopyran-3-carboxylic acid 4.

E SQUEMA 2 E, E '= halogen, acyl, sulfonyl • Synthesis Scheme 2 shows a general method for functionalizing selected 2H-1-benzopyrans. The treatment of 2H-1-10-benzopyran carboxylic acid 4 or ester 3 with an electrophilic agent results in 2H-1-benzopyran 6- substituted. A wide variety of electrophilic agents react selectively with the 2H-1-benzopyrans 4 in position 6 giving analogues new with great performance. The reagents • Electrophilic, such as a halogen (chlorine or bromine) allow to obtain the 6-halo derivatives. The chlorosulfonic acid reacts giving the sulfonyl chloride in position 6 which can then be convert to a sulfonamide or a sulfone. The Friedel-Crafts acylation of compound 4 gives 6-acylated 2H-1-benzopyrans in good to excellent yield. A number of other electrophiles may be employed to selectively react with these 2H-1-benzopyrans in a similar manner. The substituted 2H-1-benzopyran in the 6-position can react with an electrophilic reagent in the 8-position using a chemistry similar to that described for the electrophilic substitution of the 6-position. This makes it possible to obtain a 2H-1-benzopyran which is substituted in the positions 6 and 8.

SCHEME 3 Synthesis Scheme 3 illustrates a second general synthesis of substituted 2H-1-benzopyran-3-carboxylic acids that allow a substitution at the 4-position of 2H-1-benzopyran. In this case, commercially or synthetically available ortho-hydroxy acetophenone-6 substituted with two or more equivalents of a strong base, such as lithium bi (trimethylsilyl) amide, in a solvent such as tetrahydrofuran (THF), is treated, followed by reaction with diethyl carbonate to give the beta-keto ester 7. The ester 7 is condensed with a chloride or acid anhydride in the presence of a base, such as potassium carbonate, in a solvent, such as toluene, with heat to give the -oxo-4H -l-benzopyran 8. The reduction of olefin can be carried out by a variety of agents, including sodium borohydride (NaBH4), in solvent mixtures, such as ethanol and tetrahydrofuran (THF), or by the use of triethylsilane in a solvent such as trifluoroacetic acid, or by catalytic reduction using palladium on carbon and hydrogen gas in a solvent, such as ethanol, to give the new beta-potent ester 9 (two tautomeric structures are shown). The acylation of the oxygen of cetsna enolate in the presence of a base, such as 2,6-di-tr-butyl-4-methylpyridine, an acylating agent, such as trifluoromethanesulfonic anhydride, and using a solvent such as methylene chloride allows to obtain enol triflate 10. Triflate 10 can be reduced with reagents such as tri-n-butyltin hydride, lithium chloride and a palladium (0) catalyst, such as tetrakis (triphenylphosphine) palladium (0), in a solvent , such as tetrahydrofuran, to give the ester 2H-1-benzopyran wherein R "is hydrogen The ester 11 can be saponified with a base, such as 2.5 N sodium hydroxide, in a mixed solvent, such as the tetrahydrofuran- ethanol-water (7: 2: 1) to give the desired substituted 2H-l-benzopyran-3-carboxylic acid. In order to incorporate a carbon fragment R3, triflate 10 can be treated with reagents known to undergo "cross-coupling" chemicals, such as tributyltiniums, lithium chloride and a palladium (0) catalyst, such as tetrakis (triphenylphosphine) palladium (0), a solvent, such as tetrahydrofuran, to give the ester 2H-1-benzopyran 11, where R 3 is a vinyl group. The ester 6 can be saponified with a base, such as sodium hydroxide, 2.5 N, in a mixed solvent, such as the tetrahydrofuran-ethanol-water mixture (7: 2: 1), to give the acid 4-vinyl-2H-1 desired benzopyran-3-carboxylic acid (12, R "= CH2CH-) Similarly, triflate 10 can be converted under similar conditions using tri-n-butylphenylphenols at 2H-1-benzopyran, where R3 = phenyl and by hydrolysis of the ester can be converted to the carboxylic acid 12, where R3 = phenyl Using a similar strategy, the substituents that are incorporated as substituent R3 can be substituted olefins, substituted aromatics, substituted heteroaryl, acetylenes and substituted acetylenes.

E JEMPLO 4 Synthesis Scheme 4 shows an alternative general procedure for the preparation of 4-oxo-4H-l-benzopyran 8. The treatment of ortho-fluorobenzoyl chloride with the beta-keto ester 14 appropriately substituted with a base, such as carbonate of potassium, in a solvent, such as toluene, provides the 4-oxo-4H-l-benzopyran 8. The 4-oxo-4H-l-benzopyran 8 can be converted to the 2H-1-benzopyran 12 as described in Scheme 3 SCHEME 5 Synthesis Scheme 5 shows a general method for the substitution of the aromatic ring of 2H-1-benzopyran. This can be accomplished by "palladium-mediated" cross-coupling "cross-coupling" chemicals, using a palladium (0) catalyst to couple the benzopyran 15 to the Y-position, where Y is iodide, bromide or triflate, with a acetylene, olefin, nitrile or aryl coupling agent. The substituted acetylenes as coupling agent will provide the corresponding substituted acetylene. The substituted aryl groups can be incorporated using arylboronic acids or esters; the nitriles can be incorporated using zinc (II) cyanide. The resulting ester 16 can be converted to the carboxylic acid 17 as described in Scheme 1.

Another approach for the substitution of the aryl group of the benzopyran 15 is the conversion of Y, where Y is iodide or bromide, into a perfluoroalkyl group. Examples of this transformation is the conversion of 15 (Y = iodide) to 16 (R2 = pentafluoroethyl) using potassium pentafluoropropionate and copper (I) iodide in hexamethylphosphoramide (HMPA). The resulting ester 16 can be converted to the carboxylic acid 15 as described in Scheme 1. A similar method adds the substitution of the aromatic ring to dihydroquinoline-3-carboxylates. This can be carried out through couplings with organopalladium, with iodides, bromides or aryl triflates and various coupling agents (R.F. Heck, Pall dium Reagents in Organic Synthesis, Academic Press 1985). When a suitable palladium catalyst is used, such as tetrakis (triphenyl phosphin) -palladium (0), in this reaction, coupling agents, such as alkynes provide disubstituted alkynes, phenylboronic acids give biphenyl compounds and cyanides produce aryl cyano compounds. Other palladium catalysts and coupling reagents may be employed to selectively react with appropriately substituted dihydroquinol ina-3-carboxylates in a similar manner.

E SQUEMA 6 Synthesis Scheme 6 shows a general synthetic route for the conversion of a commercially available substituted phenol or synthetically into a substituted salylaldehyde. A number of different methods using formaldehyde or a chemically equivalent reagent are described in detail below. Reaction of an appropriately substituted phenol in a basic medium with formaldehyde (or a chemical equivalent) will result in the corresponding salicialdehyde 1. The intermediate, ortho-hydroxymethyl phenol 19, will be oxidized under the appropriate reaction conditions in the saline dehyde 1 in if you . The reaction commonly employs ethylmagnesium bromide or magnesium methoxide (one equivalent) as a base, toluene as a solvent, paraformaldehyde (two or more equivalents) as a formaldehyde source and uses hexamethylformamide (HMPA) or N, N, N ', N '- t-methylethylenediamine (TMEDA). (See: Casiraghi, G. et al., J.C.S. Perkins, 1978, 318-321). Alternatively, a phenol 18 can be reacted appropriately • substituted with formaldehyde under basic aqueous conditions to form the substituted ortho-hydroxybenzyl alcohol 19 (See: a) J. Leroy and C. Wakselman, J. Fluorine Chem., 40, 23-32 (1988). b) A. A. Moshfegh, et al., Helv. Chim. Acta., 65, 1229-1232 (1982)). The bases commonly used comprise potassium hydroxide or aqueous sodium hydroxide. Formalin (38% formaldehyde in water) is commonly used as a source of formaldehyde. The resulting ortho-hydroxybenzyl alcohol 19 can be converted to salithicdehyde 1 by means of an oxidizing agent, as manganese dioxide (IV) in a solvent, such as methylene chloride or chloroform (See: R-G Xie, et al., Synthetic Commun., 24, 53-58 (1994)). Appropriately substituted phenol 18 can be treated under acidic conditions with Hexamethylenetetramine (HMTA) to prepare salicylaldehyde 1 (Duff reaction; See: Y. Suzuki, and H. Takahashi, Chem. Pharm. Bull., 31,1751-1753 (1983)). This reaction commonly employs acids such as acetic acid, boric acid, acid methanesulfonic acid or trifluoromethanesulfonic acid. The formaldehyde source commonly used is hexamethylenetetramine.

• SCHEME 7 • Synthesis Scheme 7 shows the Reimer-Tiemann reaction in which a commercially available or appropriately substituted phenol 18 will synthetically react, under alkaline conditions, with chloroform to give the substituted 1-salitydehyde (See: Cragoe, EJ; S chul t ZJ EM; U.S. Patent No. 3,794,734, 1974).

E SQUEMA 8 21 19 Synthesis Scheme 8 shows the conversion of salicylic acid 21 appropriately 1Ü.3 substituted commercially or synthetically available in its respective salicialdehyde 1, through the intermediary alcohol 2-hydroxybenzyl 19. The reduction of salicylic acid 21 can be carried out with a hydride reducing agent, such as borane, in a solvent such as tetrahydrofuran. The treatment of the intermediate 2-hydroxybenzyl alcohol 19 with an oxidizing agent, such as manganese (IV) oxide in a solvent such as methylene chloride or chloroform, makes it possible to obtain salicylaldehyde 1.

SCHEME 9 Synthesis Scheme 9 illustrates a general synthesis method for the preparation of a wide variety of substituted 2- (tri fluoromethyl) -2H-1-benzothiopyran-3-carboxy acid acids (25). In step 1, ortho-metalla is appropriately substituted thiophenol 22 commercially or synthetically available with a base, such as n-butyllithium, employing TMEDA (N, N, N ', N' -tetramethylethylenediamine) followed by treatment with dimethylformamide to give the 2-mercaptobenzaldehyde 23. The condensation of the 2-mercaptobenzaldehyde 23 with the acrylate 2 in the presence of a base makes it possible to obtain the ester 24 which can be saponified in the presence of an aqueous base to give the 2H-1-benzothiopyran acids. 3-carboxylic substituted 25.

SCHEME 10 26 Synthesis Scheme 10 shows a method for the preparation of a substituted 2-mercaptobenzaldehyde from an appropriately available commercially available or synthetically available salicylaldehyde. In step 1, the phenolic salicialdehyde hydroxyl 1 is converted to the corresponding 0-aryl thiocarbamate 26 by acylation with an appropriately substituted thiocarbamoyl chloride, such as N, N-dimethyl thiocarbamoyl chloride, in a solvent such as dimethylformamide using a base like triethylamine. In step 2, the O-arylthiocarbamate 26 is rearranged in the S-aryl thiocarbamate 27 when it is subjected to sufficient heat, at 200 ° C, either without solvent or with a solvent such as N, N-dimethylaniline (See: A. Levai, and P. Sebok, Synth. Commun., 221735-1750 (1992)). The hydrolysis of S-aryl thiocarbamate 27 with a base, such as 2.5 N sodium hydroxide, in a mixture of solvents, such as a mixture of tetrahydrofuran and ethanol makes it possible to obtain the substituted 2-mercaptobenzaldehyde 23 which can be converted to the 2H-1 acids. -benzopyran-3-carboxylic acid substituted as described in Scheme 9.

E SQUEMA 11 Synthesis Scheme 11 illustrates a genexal method for the preparation of a wide variety of derivatives of dihydroquinoline-3-carboxylic acids 30. R2 represents the aromatic substitution of commercially and synthetically available 2-aminbenzaldehydes. The 2-amino-benzaldehyde derivative 28, where R2 represents several substitutions, is condensed with an acrylate derivative 2 in the presence of a base, such as a potassium carbonate, triethylamine or diazabicyclo [2.2.2] undec-7-ene in a solvent , such as dimethylformamide, to give the esters of dihydroquinoline-3-carboxylate 29. The ester 29 may be saponified in the corresponding acid, such as by treatment with an aqueous inorganic base, such as 2.5 N sodium hydroxide, in a suitable solvent, such as ethanol, to give, after acidification, the desired dihydroquinoline-3-carboxylic acid 30.

SCHEME 12 Synthesis Scheme 12 illustrates the preparation of dihydroquinoline-3-carboxylic acid 30 from 2-aminebenzoic acids 31. R2 represents the aromatic substitution of commercially available and synthetically available 2-aminobenzoic acids 31. The reduction of a representative 2-aminobenzoic acid 31 in the desired 2-aminabenzyl alcohol 32 was carried out with a hydride reducing agent, such as borane, in a solvent such as tetrahydrofuran. The treatment of the desired 2-aminobenzyl alcohol 32 with an oxidizing agent, such as manganese (IV) oxide in a solvent, such as methylene chloride, makes it possible to obtain the representative 2-aminobenzaldehydes 28. (C.T. Alabaster, et al., J. Med. Chem. 31, 2048-2056 (1988)). The 2-aminobenzaldehydes were converted to the desired dihydroquinoline-3-carboxylic acid 30 as described in Scheme 11.

SCHEME 13 33 31 30 Synthesis Scheme 13 illustrates a general method for the preparation of a wide variety of dihydroquinoline-3-carboxylic acid derivatives from the isatins 33. R2 represents the aromatic substitution of commercially available and synthetically available isatins. A representative isatin 33 was treated with alkaline peroxide generated from hydrogen peroxide and a base, such as sodium hydroxide, to yield the desired 2-aminobenzoic acids 31 representative. (M. S. Newman and M. W. Lougue, J. Org. Chem., 36, 1398-1401 (1971)). The 2-aminobenzoic acids 31 are subsequently converted to the desired dihydroquinoline-3-carboxylic acid derivatives as described in synthesis scheme 12.

E SQUEMA 14 Synthesis Scheme 14 is another method for the preparation of dihydroquinoline-3-carboxylic acid derivatives 30. In step 1, an appropriate commercially or synthetically substituted substituted aniline 34 can be treated with an acylating reagent, such as sodium chloride. pyroloyl, resulting in the amide 35. The ortho-dianion of amide 35 is prepared by treating the amide with organo lithium bases, such as n-butyllithium or tert-butyllithium in tetrahydrofuran at low temperature. The • reaction with the dianion is stopped with dimethylformamide to give the acylated 2-amin-benzaldehydes 36 (J. Turner, J. Org. Chem., 48, 3401-3408 (1983)). The reaction of these aldehydes in the presence of bases, such as lithium hydride, with an acrylate followed by reaction with aqueous inorganic bases and hydrolysis, as by treatment with an aqueous base • (sodium hydroxide) in a suitable solvent, such as ethanol, allows to obtain, after acidification, dihydroquinoline-3-carboxylic acid 30.

SCHEME 15 Synthesis Scheme 15 shows a genexal method for the nitrogen alkylation of the dihydroquinoline-3-carboxylate ester derivatives 29. The step comprises the treatment of the dihydroquinoline-3-carboxylate ester derivatives with alkyl halides, such as iodoethane, in the presence of phase transfer catalysts, such as tetrabutylammonium iodide, and a base such as caustic soda (50% aqueous sodium hydroxide) in a solvent such as dichloromethane. These conditions make it possible to obtain the N-alkylated dihydroquinoline-3-carboxylate esters 37. The saponification of compound 37 with an aqueous base provides the N-alkylated derivative of the N-alkylated dihydroquinoline-3-carboxylic acid 38. The following examples contain detailed descriptions of the methods of preparing the compounds of Formula I-II. These detailed descriptions are within the scope, and serve as an example, of the general synthesis procedures described above which constitute a part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended to restrict the scope of the invention. All parts are by weight and temperatures are degrees centigrade unless otherwise indicated. All the compounds showed NMR spectra coherent with the structures assigned to them. The following abbreviations are used: HCl - hydrochloric acid MgS04 - magnesium sulfate Na2S04 - sodium sulfate DMF - dimethylformamide THF - tetrahydrofuran NaOH - sodium hydroxide EtOH - ethansl K2C03 - potassium carbonate CDC13 - deuterated chloroform CD3OD - deuterated methanol Et20 - diethylether EtOAC - ethyl acetate NaHC03 - sodium bicarbonate KHSO4 - potassium sulfate NaBH4 - sodium borohydride TMEDA - tetrametilet ilendiamine HMTA - hexamethylenetetraine DMSO - dimethylsulphoxide HMPA - hexamethyl phosphoric triamide EXAMPLE 1 6-Chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid Step 1. Preparation of ethyl 6-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylate. A mixture of 5-chlorosalicylaldehyde (20.02 g, 0.128 mol) and 4 was dissolved., Ethyl 4,4-trifluorocrotonate (23.68 g, 0.14 mol) in anhydrous DMF, warmed to 60 ° C and treated with anhydrous K2CO3 (17.75 g, 0.128 mol). The solution was maintained at 60 ° C for 20 hours, cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with saline, dried with anhydrous MgSO4, filtered and concentrated in vacuo to obtain 54.32 g of an oil. The oil was dissolved in 250 ml of methanol and 100 ml of water, whereupon a white solid formed which was isolated by filtration, washed with water and dried in vacuo, to obtain the ester in the form of a solid. yellow (24.31 g, 62%): melting point 62-64 ° C. 1 H NMR (CDC13 / 90 MHz) 7.64 (s H), 7.30-7.21 (m, 2 H), 6.96 (d, 1 H, J = Hz), 5.70 (q, 1 H, J = Hz), 4.30 (q, 2 H , J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz).

Step_ 2. Preparation of 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid. A solution of the ester from Step 1 (13.02 g, 42 mmol) was dissolved in 200 ml of methanol and 20 ml of water, treated with lithium hydroxide (5.36 g, 0.128 mol) and stirred at room temperature for 16 hours. hours. The reaction mixture was acidified with 1.2 N HCl, whereupon a solid formed which was isolated by filtration. The solid was washed with 200 ml of water and 200 ml of hexanes and dried in vacuo to afford the title compound as a yellow solid (10.00 g, 85%): melting point 181-184 ° C: EXAMPLE 2 6- (Methylthio) -2- (trifluoromethyl) -2H-1 benzopyran-3-carboxylic acid Step 1. Preparation of 5- (methylthio) salicylaldehyde. Ethyl magnesium bromide (38 ml of a 3.0 M solution in diethyl ether, 113.8 mmol) was cooled with a freezing water bath. To the cold solution was added a solution of 4- (methylthio) phenol (15.95 g, 113.8 mmol) in diethyl ether (30 ml) for 0.15 hours, during which time gas was emitted. The reaction was maintained at 0 ° C for 0.5 hours, at room temperature for 0.5 hours and the funnel was replaced of aggregate with a distillation head. Toluene • (250 ml) and the diethyl ether were distilled outside the reactor. The reaction cooled, toluene was added (250 ml) and hexamethylphosphoramide (HMPA) (19.8 ml, . 4 g, 113.8 mmol) and the resulting mixture was stirred for 0.25 hours. The distillation head was replaced with a condenser and paraformaldehyde (8.5 g, 284.4 mmol) was added The reaction was heated at 90 ° C for 3 hours. • cooled to room temperature, acidified with IN HCl and the layers were separated. The organic phase was washed with water and with saline, dried with MgSO, filtered and concentrated in vacuo to yield a solid. This solid was purified by silica chromatography (hexanes-ethyl acetate, 5: 1) producing the salicylaldehyde as a yellow crystalline solid (6.01 g) of a purity suitable for use in the next reaction without further purification.

Step 2. Preparation of ethyl 6- (methylthio) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. 5-Methylthiosalicylaldehyde (Step 1) (2.516 g, 14.96 mmol) was added to dimethylformamide (3.5 ml), potassium carbonate (2.27 g, 16.45 mmol) and ethyl 4,4,4-trifluorocrotonate (3.3 ml, 3.8 g, 22.4 mmol). The mixture was heated at 65 ° C for 3 hours. The reaction was cooled to room temperature, poured into H20 (50 mL), and extracted with diethyl ether (2 X 75 mL). The combined ether phases were washed with aqueous NaHCO3 solution (3 X 50 ml), with 2 N HCl aqueous solution (3 X 50 ml), and with saline. (3 X 50 ml), dried MgSO4, filtered, diluted with isooctane and partially concentrated in va cuo causing the ethyl ester precipitation (2.863 g, 60%) as a yellow powder: mp 87.8-89.6 ° C. This ester was of a suitable purity to be used without further purification.

Step Preparation of 6- (methyl thio) -2- (trifluoromethyl-2H-1-benzopyran-3-carboxylic acid) The ester (Step 2) was hydrolysed to form the carboxylic acid by a method similar to that described in Example 1, Step 2: melting point 166.3-167.9 ° C. XE NMR (acetone-dd / 300 MHz) 7.87 (s, 1H, 7.43 (d, 1H, J = 2.2 Hz), 7.33 (dd, 1H, J = 8.5, 2.4 Hz), 6.98 (d, ÍH, J = 8.5 Hz), 5.79 (q, ÍH, J = 7.0 Hz), 2.48 (s, 3H), FABLRMS m / z 291 (M + H). ESHRMS m / z 289.0152 (MH, Calculated 289.0146) Anal.Calcd for C? 2H9F3? 3S ?: C, 49.66, H, 3.13; S, 11.05 Found: C, 49.57; H, 3.02; S, 11.37.

EXAMPLE 3 7-methi1-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 3-methylphenol was converted into the title compound by a procedure similar to that described in Example 2: mp 202.1- 203.1 ° C. ! H NMR (CDCl3 / 300 MHz) 7.84 (s, ÍH), 7.12 Id, IH, J = 8.3 Hz), 6.82 (m, 2H), 5.65 (q, ÍH, J = 6.8 Hz), 2.35 (s, 3H), FABLRMS m / z 259 (M + H). FABHRMS m / z 259.0576 (M + H), Calculated 259.0582). Anal. Calculated for C? 2H9F303: C, 55.82; H, 3.51 Found: C, 55.93; H, 3.59.

EXAMPLE 4 2, 7-bis (tri-uoromethyl) -2H-1-benzopyran-3-carboxylic acid The 3- (trifluoromethyl) phenol was converted to the title compound by a procedure similar to that described in Example 2: melting point: 190. 3-193.5 ° C. 2H NMR (acetone ~ d6 / 300 MHz), 7.91 s, ÍH), 7.73 (d, ÍH, J = 7.9 Hz), 7.46 (d, ÍH, J = 7.9 Hz); 7.36 (s, 2H), 5.93 (q, 1H, J = 7.1 Hz). FABLRMS m / z 313 (M + H). FABHRMS m / z 313.0267 (M + H, Calculated 313.0299). Anal. Calculated for C12H6Fb03: C, 46.17; H, 1.94. Found: C, 46.25; H, 2.00.

EXAMPLE 5 7-b-As-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 3-Bromophenol was converted to the title compound by a procedure similar to that described in Example 2: melting point: 198.4-199.5 ° C. X H NMR (acetone-d 6/300 MHz), 7.89 (s, H H), 7.43 (d, H H, J = 8.1 Hz), 7.31 (s, 1 H), 7.30 (d, H H, J = 8.1 Hz); 5.84 (q, ÍH; J = 7.1 Hz). FABLRM? m / z 323 (M + H). Anal. Calculated for CpHtlBrF;) 0J: C, 40.90; H, 1.87. Found: C, 41.00; H, 1.85.

E JEMPLO 6 6-Chloro-7-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid 4-Chloro-3-methylphenol was converted to the title compound by a procedure similar to that described in Example 2: melting point : 207-5-209.3 ° C. aH NMR (CDCl3 / 300 MHz) 7.77 (s, ÍH), 7.23 (s, 1H), 6.90 (s, 1H), 5.65 (q, ÍH; J = 6.8 Hz), 2.37 (s, 3h) FABLRMS m / z 292 (M + H). FABHRMS m / z 299.0287 (M + Li, Calculated 299.0274). Anal. Calculated for C? 2H8CIF303: C, 49.25; H, 2.76; Cl, 12.11 Found: C, 49.37; H, 2.82; Cl, 12.17. EXAMPLE 7 6- (methoxy-enoxi) -2- (tri-loromethyl) -2H-1-benzopyran-3-carboxylic acid 4- (4-methoxyphenyl) phenol was converted to the title compound by a procedure similar to that described in Example 2: melting point: 181 = 7-182.9 ° C. 1K NMR (acetone-d6 / 300 MHz), 7.87 (s, HH), 7.11 (m, HH), 7.02 (m, 2H), 6.98 (m, 4H), 5.81 (q, HH, J = 7.0 Hz) 3.80 (s, 3H). FABLRMS m / z 365 (M-H). FABHRMS m / z 367.0809 (M + H, Calculated 367.0793). Anal. Calculated for ClbH? 3F305: C, 59.02; H, 3.58. Found: C, 69.10; H, 3.61.

EXAMPLE 8 6-Chloro-7 (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid Step 1. Preparation of 4-tert-butylsalicylaldehyde. A five-liter, round-bottom, three-neck flask was equipped with a mechanical condenser and stirrer and charged with trifluoroacetic acid (2.4 1). A mixture of 3-tert-butylphenol (412 g, 2.8 mol) was added and HMTA (424 g, 3.0 mol) was added in portions producing an exotherm. By cooling, the temperature was kept below 80 ° C. The reaction was heated at 80 ° C for one hour, then cooled and water (2 1) was added. After 0.5 hours, additional water (4 1) was added and the mixture was extracted with ethyl acetate (6 1). The organic extract was washed with water and saline. The organic phase was divided into 2 volumes of 2 1 and each was diluted with water (11), and solid NaHCOO was added until the mixture was neutralized. The organic phases were isolated and combined, dried with MgSO 4, filtered and concentrated in vacuo to yield an oil. This oil was distilled at 95 ° C (0.8 mm) producing the desired salicylaldehyde as an oil (272.9 g, 56%) which was of sufficient purity to be used without further purification.

Step Preparation of 7- (1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid ethyl ester. F A one liter bottle of three nozzles 5 was charged with 4-tert-butylsalicylaldehyde (Step 1) (100.0 g, 0.56 mol) dimethylarformamide (110 ml) and potassium carbonate (79.9 g, 0.58 mol) raising the temperature of the mixture up to 40 ° C. 4, 4, 4 ethyl trifluorocrotonate (118.0 g, 0.70 mol) was added in dimethylformamide (110 ml) and the mixture was heated to 60 ° C, during which time the reaction temperature was raised to 70 ° C. The reaction was cooled to 60 ° C, maintained at 60 ° C (with added heat) for 8.5 hours and cooled to room temperature. HE added ethyl acetate (600 ml) and 3 N HCl (600 ml), mixed, and separated the layers. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The combined organic phases are F washed with saline-water solution (1: 1), with solution saline, dried with MgSO 4, filtered and concentrated in vacuo, yielding a semi-solid. Hexane (600 ml) was added by mixing and the mixture was filtered. The filtrate was washed with saline, dried with MgSO 4, filtered and concentrated in vacuo. producing a solid. This solid dissolved in 1-3: hot ethanol (600 ml). Water (190 ml) was added with induced crystallization. Filtration of the mixture and drying of the product gave the desired ester as a crystalline solid (131.3 g, 71%): melting point: 91.0-94.9 ° C. This material was of adequate purity to be used in subsequent steps without further purification.

Step 3. Preparation of 6-chloro-7- (1, 1, -dimethylethyl) - • 2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid ethyl ester. A one-liter, three-neck flask equipped with a mechanical stirrer and an inlet tube The gas was charged with the ester (Step 2) (100 g, 0.3 mol) and with acetic acid (300 ml). While cooling (water bath) the reaction mixture was added chlorine gas, (37.6 g, 0.53 mol) which caused a • Temperature rise up to 48 ° C. After After stirring for two hours, the reaction was cooled in an ice bath to 15 ° C. Zinc powder was added (19.5 g, 0.3 mol) in a portion that caused an increase in temperature to 72 ° C. After cooling to room temperature, more powder was added of zinc (5.0 g, 0.08 mol) and the mixture was stirred for 0.5 hour more. The crude mixture was filtered with diatomaceous earth and concentrated in va cuo producing an oil. The oil was dissolved in ethyl acetate • (700 ml), washed with saline-water (1: 1, 11) and with saline (0.5 1). The resulting aqueous phase was extracted with ethyl acetate (700 ml). This ethyl acetate phase was washed with saline-water (1: 1, 11) and with saline (0.5 1). The combined organic phases were dried with MgSO4, were filtered and concentrated in va cuo producing • the title compound in the form of a yellow oil (116 g, 106%). This material, which contained some of the retained ethyl acetate, was of sufficient purity to be used in subsequent steps without further purification.

Step_ 4. Preparation of 6-chloro-7- (1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. 20 To a solution of the ester (Step 3) (116 g, 0. 3 mol) in methanol (500 ml) and tetrahydrofuran (500 ml) in a one liter flask was added aqueous sodium hydroxide (2.5 N, 240 ml, 0.6 mol). After stirring overnight, the pH of the The solution was adjusted to 1 with concentrated hydrochloric acid and the solution was extracted with ethyl acetate. The ethyl acetate phase was dried with MgSO 4, filtered and concentrated in vacuo to yield a solid. This solid was dissolved in hot ethanol (500 ml). Water (500 ml) was added and upon cooling to room temperature crystals were formed, which were collected by vacuum filtration. The crystals were washed with ethanol-water (3: 7, 3 X 200 ml) and dried to give the title in the form of a crystalline solid (91.6 g, 91%): melting point: 194.9-196.5 ° C. lE NMR (acetone-d6 / 300 MHz) 7.86 (s, ÍH), 7.52 (s, ÍH), 7.12 (s, ÍH), 5.83 (q, ÍH; J = 7.1 Hz), 1.48 (s, 9H). Anal. Calculated for Cl bE1 4 Cl F 0j: C, 53.83; H, 4.22; Cl, 10.59. Found: C, 53.92; H, 4.24; Cl, 10.50.

EXAMPLE 9 Acid 6- (3-Chloro-4-methoxy-enoxy) -2- (tri-luomomethyl) -2H-1-benzopy-3-carboxylic acid.

To a stirred solution of chlorine in acetic acid (3.5 ml, 0.24 M solution, 0.84 mmol) was added 6- (4-methoxyphenoxy) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid ( 0.31 g, 0.85 mmol). (Example 7). After 1 hour more chlorine was added in acetic acid (1.5 ml of 0.24 M solution, 0.36 mmol). After another three hours, chlorine was added in acetic acid (0.25 ml of 0.25 M solution, 0.06 mmol). After 2.5 hours, the reaction was quenched with 10% aqueous sodium bisulfite solution and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, with saline solution, dried with MgSO 4, filtered and concentrated in vacuo resulting in a brown oil. The oil dissolved in a minimum of hexanes that induced crystallization. Filtration in vacuo of the mixture gave the title compound as yellow crystals (0.18 g, 53%): melting point: 205-207 ° C. 1E NMR (acetone-d6 / 300 MHz) 7.89 (s, ÍH), 6.97-7.18 (, 6H), 5.83 (q, ÍH, J = 7.0 Hz), 3.90 (s, 3H). FABLRMS m / z 400 (M +). FABHRMS m / z 399.02349 (M-H, Calculated 399.0247). Anal. Calculated for Ci6H? 2CIF30r ,: C, 53.95; H, 3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl, 8.98.

EXAMPLE 10 2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid Step 1. Preparation of ethyl 2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate. The ester was prepared from salicylaldehyde by a procedure similar to the method described in Example 1, Step 1: boiling point 107 ° C 2 mm. aHNMR (acetone-db / 300 MHz) 7.89 (s, 1H), 7.52-7.38 (m, 2H), 7.09 (dt, 1J = 1.0, 7.7 Hz), 7.03 (d, ÍH; J = 8.3 Hz); 5.84 (q, 1H, J = 7.3 Hz), 4.39-4.23 (m, 2H), 1.33 (t, 3H, J = 7.0 Hz). FABLRMS m / z 273 (M + H). ESHRMS (m / z 273.0720 (M + H Calculated 273.0739) Step 2. Preparation of 2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. , .- _-. The acid was prepared from ethyl ester (Step 1) by a procedure similar to the method described in Example 1, Step 2: melting point: 152.2-153.3 ° C. SH NMR (acetone-of / 300 MHz) 7.89 (s, ÍH), 7.39-7.49 (m, 2H), 7.11-7.01 (m, 2H), 5.81 (q H-F, ÍH, J = 7.2 Hz). FABHRMS m / z 245.0422 (M + H, Calculated 245.0426). Anal. Calculated for C? H FJOJ: C, 54.11; Hy 2.89. Found: C, 54.22; H, 2.97.

EXAMPLE 11 6,8-Dialoro-7-methyl-2- (tri-loromethyl) -2H-1- benzopyran-3-carboxylic acid Step 1. Preparation of 3,5-dichloro-4-methyl salicydehyde. 2-Dichloro-3-methylphenol (25.0 g, 141.2 mmol) was added to methanesulfonic acid (100 mL). With the • 15 shaking, hexamethylenetetramine (HMTA) was added (39.8 g, 282.4 mmol) and additional methanesulfonic acid (100 ml) was added in portions, and during that time the reaction started foaming and exotherm. The resulting mixture was heated to 100 ° C for 3 hours. The crude ocher suspension was cooled to 50 ° C and poured into a mixture of ice water (2 1) stirred mechanically. A yellow precipitate formed which was collected by vacuum filtration. This solid was purified by flash chromatography (silica, hexanes-methylene chloride, 9:10) producing the salicialdehyde as a pale yellow powder (6.17 g, 21%; melting point: 94.0-95.1 ° C) of a purity adequate to use it without further purification.

Step 2. Preparation of ethyl 6,8-di-chloro-7-methyl-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. A mixture of 3,5-dichloro-4-methyl-salicydehyde (Step 1) (5.94 g, 29.0 mmol) and ethyl 4,4,4-trifluorocrotonate (7.67 g, 45.6 mmol) dissolved in anhydrous DMSO (10 mL) was treated. with triethylamine (5.88 g, 58.1 mmol). The reaction was stirred at 85 ° C for 49 hours then cooled on ice and filtered to give an orange solid. The solid was dissolved in ethyl acetate (100 ml), washed with 3 N HCl (2 x 50 ml), with saturated NaHCO 3, washed with saline, dried with MgSO 4, and concentrated in vacuo to give an yellow solid (8.63 g, 84%): melting point: 117.1-119.5 ° C. JU NMR (CDCl3 / 300 MHz), 7.63 (s, ÍH), 7.17 (s, ÍH), 5.80 (q, 1H, J = 6.6 Hz), 4.33 (m, 2H), 2.48 (s, 3H), 1.35 (t, 3H, J = 7.1 Hz) .

Step 3. Preparation of 6,8-dichloro-7-methyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. The ester from Step 2 (8.39 g, 23.6 mmol) was dissolved in THF (30 mL) and ethanol (20 mL), treated with 2.5 N sodium hydroxide (20 mL, 50 mmol), and stirred at room temperature for 3.5 hours The reaction mixture was concentrated in vacuo, acidified with 3N HCl, filtered and recrystallized from ethanol / water to yield a yellow solid (6.0 g, 78%): melting point: 229.9-230.9 ° C . ? E NMR (acetone-d6 / 300 MHz), 7.90 (s,? H),? 58 (s, 2H), 6.00 (q, 1H, J = 6.8 Hz), 2.50 (s, 3H). FABLRMS m / z 325 (M-H). FABHRMS m / z 324.9636 (M-H, Calculated: 324.9646). Anal. Calculated for C2H7Cl2F303: C, 44.07; H, 2.16; Cl, 21.68. Found: C, 44.06; H, 2.21; Cl, 21.74.

EXAMPLE 12 Acidq_ 1 - (1,1-dimethylethyl) -2-trifluoromethyl-2H-J. ' benzo iran-3-carboxylic acid. 7 - (1, 1-Dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid ethyl ester (Example 8, Step 2) was hydrolyzed with the carboxylic acid • by a procedure similar to that described in Example 1, Step 2: melting point: 165.6-166.8 ° C. 1H NMR (acetone-d5 / 300 MHz) 7.86 (s, HH), 7.38 (d, HH, J = 8.1 Hz), 7.15 (dd ", HH, J = 1.8 Hz, and J = 7.8 Hz), 7.05 (bs, ÍH), 5.79 (q HF, ÍH, J = 7.2 Hz), 1.32 (s, 9H), FABHRMS m / z 301.1033 (M + H, Calculated 301.1051).

Anal. Calculated for Ci5H15F3? 3: C, 60.00; H, 5.04.

• Found: C, 59.80; H, 5.10.

E JEMPLO 13 6-Bromo-2-tri-loromethyl-2H-l-benzopyran-3-carboxylic acid 5-Bromosalidedanide was converted to the title of the compound by a procedure similar to that described in Example 1: melting point: 20 189.6-190.9 ° C. 2H NMR (acetone-dß / 300 MHz) 7.89 (s, HH), 7.70 (d, HH, J = 2.1 Hz) 7.55 (dd, HH, J = 2.4 Hz, and J = 8.7), 7.02 (d, HH; J - 8.7 Hz), 5.86 (q HF, ÍH, J = 7.2 Hz). FABHRMS m / z 322.9519 (M + H, Calculated 322.9531). Anal. Calculated for CnHbBrFJ0 ,: C, 40.90; H, 1.87; Br, 24.73. Found: C, 40.87; H, 1.92; Br, 24.80.

EXAMPLE 14 • 8-Chloro-2-tri luoromethyl 2H-1-benzopyran-3-carboxylic acid 2-chlorophenol was converted to the title compound 10 by a procedure similar to that described in Example 2: melting point: 224.5-225.6 ° C. lE NMR (acetone-dc / 300 MHz) 7.91 (s, ÍH), 7.49 (m, 2H), 7.11 (t, ÍH, J = 7.8 Hz), 5.96 (q, H-F, 1H, J = 7.2 Hz). FABHRMS m / z 279.0027 (M + H, Calculated 15 279.0036). Anal. Calculated for CnHeClF30J: C, 47.42; • H, 2.17. Found: C, 47.33; H, 2.17. 8-Bromo-6-chloro-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 2-Bromo-4-chlorosalicylic acid was converted to the title compound by a procedure similar to that described in Example 1: fusion: 227, 8-228.9 ° C. 2H NMR (acetone-d6 / 300 MHz) 7.90 (s, ÍH), 7.65 (dd, 2H, J = 2.4 and J = 28.8 Hz), 6.00 (q H- F, ÍH, J = 7.2 Hz). FABHRMS m / z 356.9134 (M + H, Calculated 356.9141). Anal. Calculated for C1? Hi) BrClF300: C, 36.96; H, 1.41. Found: C, 37.05; H, 1.33 • EXAMPLE 16 6-Trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 5- (tri-fluoromethoxy) -salicylaldehyde was converted into the title compound by a procedure similar to that described in Example 1: melting point: 118.4- 119.5 ° C. aH NMR (acetone-db / 300 MHz), 7.95 (s, 20 HH), 7.54 (d, HH; J = 2.1 Hz), 7.39 (dd, HH, J = 2.4 Hz and J = 9.0 Hz), 7.02 ( d, ÍH; J = 9.0 Hz), 5.88 (q hF, ÍH, J = 7.2 Hz). FABHRMS m / z 329.0228 (M + H, Calculated 329.0249). Anal. Calculated for C? HbFβ04 C, 43.92; H, 1.84. Found: C, 43.84; H, 1.87.

EXAMPLE 17 8-Luoro-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 3-Fluorosalicialdehyde was converted to the title compound by a procedure similar to that described in Example 1: melting point: 197.7-210. c. H NMR (acetone-d6 / 300 MHz), 7.94 (s, ÍH), 7.30 (m, 2H), 7.11 (m, ÍH), 5.93 (q H-FH, J = 7.2 Hz). FBHRMS m / z 263.0341 (M + H, CnH6F403 Calculated 263.0331). Anal. Calculated for CiiH6F403: C, 50.40; H, 2.31. Found: C, 50.48; H, 2.25.

EXAMPLE 18 , 7-Dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid 14. 4,6-Dichlorosalicialdehyde was converted to the title compound by a procedure similar to that described in Example 1: melting point: • 190.1-191.2 ° C. -1H NMR (acetone-d 6/300 MHz) 8.01 (s, ÍH), 7.3 (bs, 1H), 7.16 (bs, ÍH), 5.94 (q H_F 1H, J = 78.2 Hz). FABHRMS m / z 312.9636 (M + H, Calculated 312.9646). Anal. Calculated for CnH5Cl2F303: C, 42.20; H, 1.61. Found: C, 42.27; H, 1.56.

EXAMPLE 19 • 7, 8-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 3,4-dichlorophenol was converted into composed of the title by a procedure • similar to that described in Example 2: melting point: 219.5-220.9 ° C. : H NMR (acetone-db / 300 MHz), 7.94 (s, 1H), 7.51 Id, ÍH, J = 8.4 Hz) 7.34 (d, 1H, J = 8.4 Hz), 6.02 (qM-F ÍH; J = 7.2 Hz). FABHRMS m / z 318.9709 (M + Li, CÜH5C12F303 Calculated 318.9728). Anal. Calculated for CnH5C12F303: C, 42.20; H, 1.61. Found: C, 42.15; H, 1.68.

EXAMPLE 20 7-Isopropyloxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 2,4-Dihydroxybenzaldehyde was alkylated to prepare 4- (l-methylethyloxy) salicylaldehyde. This salicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: melting point: 161-163 ° C. aH NMR (CD3OD / 300 MHz) -7.73 (s, ÍH), 7.21 (d, 1H, J = 8.5 Hz), 6.57 (dd, ÍH, J = 8.5, 2.2 Hz). FABHRMS m / z 301.0688 (M-H +, C? Hi2F30 needs 301.0687). Anal. Calculated for CnH13F304: C, 55.63; H, 4.34. Found: C, 55.72; H, 434.

EXAMPLE 21 8-enyl -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 2-Phenylphenol was converted to the title compound by a procedure similar to that described in Example 2: melting point: 171.6- • 175-.0 ° C. 1E NMR iacetone-dd / 300 MHz) 7.95 (s, ÍH), 7.46 (m, 7H), 7.18 (t, 1H, J = 7.5 Hz), 5.81 (q H-FH, J = 7.2 Hz). FABHRMS m / z 327.0816 (M + Li, Calculated 327.0820). Anal. Calculated for C?, HnFjOj: C, 63.76; H, 3.46. Found: C, 63.52; H, 3.55.

EXAMPLE 22 7,8-Dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 2,3-dimethylphenol was converted to • compound of the titer by a procedure similar to that described in Example 2: melting point: 245.2-247.3 ° C. lE NMR (acetone-d6 / 300 MSz), 7.83 (s, ÍH), 7.17 (d, ÍH; J = 7.8 Hz), 6.89 (d, ÍH, J = 7.8 Hz), 5.82 (q HF ÍH, J = 7.2 Hz), 2.30 (s, 3H), 2.17 20 (s, 3H). Anal. Calculated for C? 3 HnF303 + 1.56% H20: C, 56.46; H, 4.18. Found: C, 56.46; H, 4.15. 6,8-Bis (1,1-dimethyl) -2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid 3,5-di-tert-butylsalicylaldehyde was converted into the title compound by a procedure similar to that described in Example 1: melting point: 171.6-175.0 ° C. XH NMR (acetone-dd / 300 MHz) 7.65 (s, 1H), 7.34 (d, HH; J = 2.4 Hz), 7.15 (d, HH; J = 2.4 Hz), 6.02 (H HF H H; J = 7.2 Hz). FABHRMS m / z 363.1743 (M + Li, Calculated 363.1759). Anal. Calculated for C? TíH2jBrF303: C, 64.03; H, 6.50. Found: C, 64.13; H, 6.39.

EXAMPLE 24 36-Iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid Step 1: Preparation of 2-hydroxy-5-iodobenzyl alcohol A solution of 5-iodosalicylic acid (25.0 g) was cooled to 0 ° C. , 94.6 mmol) in tetrahydrofuran (500 ml). A borane-methyl sulfide complex (15.1 ml of 10 M solution, 151.0 mmol) was added dropwise over 0.25 hours by means of a vigorous mixture. The solution was warmed to room temperature and then heated to reflux for 4 hours. During the reflux, a white precipitate formed. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (100 ml) was added over 15 minutes and stirred at room temperature for 2 hours. The precipitate was dissolved and the solvent was concentrated to a volume of about 200 ml. The solution was poured into ethyl acetate (300 ml) and washed with water (2 x 200 ml), with saturated sodium bicarbonate (2 x 200 ml), and with saturated ammonium chloride (2 x 200 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The 2-hydroxy-5-iodobenzyl alcohol was isolated as a white solid (21.3 g, 85.2 mmol) from hexanes (90% yield): melting point: 105-110 ° C. 1E NMR (CDCl 3/300 MHz) 8.21 (s, ÍH), 7.30-7.33 (M, 2H), 6.57 (d, ÍH, J = 8.3 Hz), 4.97 (bs, 1H), 4.62 (s, 2H), EIHRMS m / z = 249.9492 (M +, Calculated 249.9491).

Step 2: Preparation of 2-hydroxy-5-iodobenzaldehyde To a stirred solution of 2-hydroxy-5-iodobenzyl alcohol (43.5 g, 174.0 mmol) in acetone (700 mL) was added 85% activated manganese oxide (IV) (5 microns, 50 g, 494.0 mmol) and stirred at room temperature for 16 hours. The manganese oxide was removed by filtration with diatomaceous earth and the filtrate was concentrated in vacuo. The product was purified by flash silica chromatography (0-20% ethyl acetate in hexanes). The 2-hydroxy-5-iodobenzaldehyde was obtained in the form of a greenish-yellowish solid 124.3 g, 58%). A small amount of 2-hydroxy-5-iodobenzaldehyde was recrystallized from methanol / water to obtain an analytical sample and the rest of the compound was used without further purification: melting point: 99-100 ° C. 1HNMR (CDCl3 / 300 MHz), 9.83 (s, ÍH), 7.79 (d, ÍH, J = 2. 2 Hz), 7.77 (dd, ÍH, J = 8.7 Hz, J = 2.2 Hz), 6.81 (Id, 1H, J = 8.7 Hz). ESHRMS 236.9229 (M-H Calculated 246.9256).

Step 3: Preparation of ethyl d-iodo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylate. Combine in a mixture of 5- iodoalicylaldehyde (16.2 g, 65.3 mmol), ethyl 4,4,4-trifluorocrotonate (22.4 g, 133 mmol) and triethylamine (50 mL, 395 mmol) were stirred at 70 ° C for 8 hours. hours and then heated to reflux for 48 hours. The solution was poured into ethyl acetate (300 ml) and washed with IN hydrochloric acid (3 x 200 ml). The aqueous layers were combined and extracted with ethyl acetate (1 x 100 ml). The combined ethyl acetate extracts were washed with saturated ammonium chloride (2 x 200 ml), dried with magnesium sulfate and concentrated in vacuo to yield a dark red oil. This oil was purified by flash chromatography using ethyl acetate-hexanes (3: 7) yielding a red oil. Crystallization of this oil from hexanes afforded the title compound as clear red crystals (8.3 g, 31%): melting point: 105-106 ° C. _1H NMR (CDC13 / 30Q MHz) 7.63 (s, ÍH), 7.58 (dd, 2H, J = 8.6, J = 2.1 Hz, 7.54 (d, 1H, J = 2.1 Hz), 6.77 (d, ÍH, J = 8.6 Hz), 5.70 (q, ÍH, J = 6.7 Hz), 4.20-4.38 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz) ESHRMS 415.9926 (M + NH4"Calculated 396-9746).

Step 4: Preparation of 6-iodo-2- ___ (tri fluorometyl) -2H-1-benzopyran-3-carboxylic acid. Ester hydrolysis (Step 3), using a procedure similar to Example 1, Step 2, yielded the carboxylic acid: melting point: 168-170 ° C. 1E NMR (CD3OD / 300 MHz) 7.57 (s, ÍH), 7.70 (d, 1H, J = 2.2 Hz) 7.64 (dd, ÍH, J = 8.5, 2.2 Hz), 6.79 (d, 1H, J = 8.5 Hz ), 5.78 (q, 1H, J = 7.0 Hz). ESHRMS m / z 368.9222 (Calculated for M-H 368.9235). Anal. Calculated for CpH J O,: C, 35.70; H, 1.63. Found C, 35.67; H, 1.63.

EXAMPLE 25 7- (1-Methylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid 3- (1-Methylethyl) phenol was converted to the title compound by a procedure similar to that described in Example 2: fusion: 158 J3-159. 7 ° C. aH NMR (acetone-d6 / 300 MHz) 7.86 (s, ÍH), 7.37 (d, ÍH; J = 7.8 Hz), 7.00 J d, ÍH, J = 7.8 Hz), 6.91 (s, ÍH), 5.78 ( q, ÍH, j = 6.9 Hz), 2.93 (m, ÍH), 1.24 (d, 6H, j = 6.9 Hz). FABLRMS m / z 287 (M + H). Anal. Calculated for C? 4H13F303: C, 58.74; H, 4.58. Found: C, 57.37; H, 4.49.

EXAMPLE 26 7-pheny1-2-tri-luoromethyl-2H-l-benzopyran-3-carboxylic acid 3-phenylphenol was converted into the compound • of the titer by a procedure similar to that described in Example 2: melting point: 209.4-211.7 ° C. 1E NMR (acetone-db / 300 MHz) 7.94 (s, ÍH), 7.74 (m, 2H), 7.47 (, 5H), 7.33 (s, ÍH), 5.86 (q, ÍH; J = 7.2 Hz). FABLRMS m / z 321 (M + H). Anal. Calculated for HUFJOJ. C, 63.76; H, 3.46. Found: C, 64.17; H, 3.61.

EXAMPLE 27 • 15 6-Chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopy-3-carboxylic acid 4-Chloro-3-ethylphenol was converted into the title compound by a procedure similar to that described in Example 2: fusion: • 170.7-172.1 ° C. ? E NMR (CDCl3 / 300 MHz), 7.78 (s, ÍH), 7.26 (s, ÍH), 6.90 (s, ÍH), 5.67 (q, ÍH; J = 6.9 Hz), 2.73 (q, 2H, J = 7.8 Hz), 1.24 (t, 3H, J = 7.8 Hz). FABLRMS m / z 307 (M + H). Anal. Calculated for C, 50.92; H, 3.29. Found: C, 51.00; H, 3.33.

EXAMPLE 28 • 8-Ether-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid. 2-Ethylphenol was converted to the title compound by a procedure similar to that described in Example 2: melting point: 185.4-186.8 ° C . XH NMR (acetone-d6 / 300 MHz) 7.85 (s, ÍH), 7.28 (d, 2H, J = 7.5 Hz), 7.00 (t, 1H, J = 7.5 Hz), 5.84 (q, 1H, J = 7.2 JHz), 2.65 (m, 2H), 1.18 (t, 3H, j = 7.5 Hz). FABLRMS m / z 273 (M + H) Anal. Calculated for C, 57.36; H, 4.07. Found: C, 57.15; H, 4.11.

EXAMPLE 29 6-Chloro-8-ethyl-2-tri-chloromethyl-2H-1-benzopyran-3-carboxylic acid. 8-Ethyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid was dissolved (Example 28) (0.68 g, 2.5 • mmol) in trimethyl-phosphate (5 ml) and treated with sulfuryl chloride (0.35 g, 2.62 mmol) at 0 ° C. After stirring at 0 ° C for 45 minutes and 1 hour at At room temperature, the reaction was diluted with cold water (15 ml). The resulting oily mixture was extracted with hexanes-ethyl acetate. The organic phase was washed with saline, dried and concentrated in vacuo to yield the title compound as a solid (0.9 g, 117%): melting point: 197.2- 199.1 ° C. : H NMR (acetone -dJ 300 MHz) 7.86 (s, 1H), 7.38 (d, 1H, J = 2.7 Hz), 7.30 (d, ÍH, J = 2.4 Hz), 5.88 (q, ÍH, J = 7.2 Hz), 2.65 (m, 2H), 1.19 (t, 3H, J = 7.5 Hz). FABLRMS m / z 307 (M + H). Anal. Calculated for Ci3HiüCIF303: C, 50.92; H, 3.29. Found: C, 51.00; H, 3.23.

EXAMPLE 30 6-Chloro-7-pheny1-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 7-Phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid (Example 26) was converted to the title compound by a procedure similar to that described in Example 29: melting point: 185.3-187.8 ° C. 1E NMR (acetone-dd / 300 MHz) 7.94 (s, ÍH), 7.68 (s, ÍH), 7.47 (m, 5H), 7.06 (s, ÍH), 5.87 (q, 1H, J = 6.9 Hz). FABLRMS m / z 355 (M + H). Anal. Calculated for Ci, H ?? CIFj03: C, 57.56; H, 2.84. Found: C, 58.27; H, 3.11.

EXAMPLE 31 6, 7-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 3,4-dichlorophenol was converted into the title compound by a procedure similar to that described in Example 2: melting point: 196.1-198.3 ° C. 1K NMR (acetone-d6 / 300 MHz) 7.90 (s, ÍH), 7.74 (s, ÍH), 7.30 (s, ÍH), 5.88 (q, 1H, J = 6.9 Hz). FABLRMS m / z 314 (M H). Anal. Calculated for CUHÓCI ^ OS * C, 42.20; H; 1.61. Found: C, 42.31; H, 1.65.

EXAMPLE 32 6, 8-Dichloro-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 3,5-dichlorosalicylaldehyde was converted to the title compound by a "procedure similar to that described in Example 11, Steps 2 and 3: melting point: 212.8-216.8 ° C. XH NMR (CDC13 / 300 MHz) 7.77 (s, ÍH), 7.41 Id, ÍH, J = 2.4 Hz), 7.18 Id, ÍH, J = 2.2 Hz), 5.82 (q , H, J = 6.7 Hz) FABLRMS m / z 311 (MH) FABHRMS m / z 312.9644 (M + H, Calculated 31279646) Anal Calculated for CnHbF3CA03: C, 42.50; H; 1.71 Found: C, 42.50; H, 1.71.

EXAMPLE 33 6,8-Dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 3,5-Dibromosalicylic acid was converted into the title compound by a procedure similar to that described in Example 1: melting point: 225-226 ° C. H NMR (CD3OD / 300 MHz) 7.76 (s, 1H), 7.74 (d, ÍH, J = 2.2 Hz), 7.55 (d, ÍH, J = 2.2 Hz), 5.91 (qH-F, 1H, J = 7.2 Hz). FABHRMS m / z 400.8648 (M + H +, Calculated 400.8636) Anal. Calculated for CnH5br2F303: C, 32.87; H, 1.25. Found: C, 33.47 H, 1.38.

EXAMPLE 34 • Acid 6, 8 -Dime oxy-2-trifluoromethyl-2H-1-benzopy an-3-carboxylic acid 4,6-Dimethoxysalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: of fusion: 215-217 ° C. 1E NMR (CD3OD / 300 MHz) 7.95 (s, ÍH), 6.18-6.20 (m, 2H), 5.65 (qH-F, ÍH, J = 7.2 Hz), 3.87 (s, ÍH), 3.81 (s, ÍH) ). FABHRMS m / z 303.0497 (M-H +, Calculated 303.0380). Anal. Calculated for C? 3HnF30: 51.33; H, 3.64. Found: C, 51.19; H, 3.71.

EXAMPLE 35 6-Amino-2-tri l orometi1-2H-l-benzopyran-3-carboxylic acid ethyl ester Step 1: Preparation of ethyl 6-nitro-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. A mixture of n-trosalicialdehyde (4.80, 7 mmol, 4, 4, 4, ethyl tri-fluorocrotonate (6.6 g, 39.4 mol) in anhydrous DMF was heated to a temperature of 60 ° C and treated with anhydrous K2C03 (3.90 g, 38.9 g). mol).

The solution was maintained at a temperature of 60 ° C for 20 hours, cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extracts were washed with saline, dried with anhydrous MgSO4, filtered and concentrated in vacuo to obtain oil. The oil was dissolved in diethyl ether (5 ml). Hexanes were added until the solution became turbid. After remaining at room temperature, the ester was obtained in the form of yellow crystals (0.856 g, 7% yield). This material was of sufficient purity to be used in subsequent steps without further purification. 1H NMR (CDCl 3/300 MHZ) 8.15-8.19 (m, 2H), 7.74 (s, ÍH), 7.09 (d, ÍH; J = 8.9 Hz), 5.81 (q, ÍH, J = 5.8 Hz), 4.29- 4.39 (m, 2H), 1.35 (t, 3H, J = 6.0 Hz).

Step 2: Preparation of methyl 6-amino-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. The ester (Step 1) (0.345 g, 1.08 mmol) was stirred in ethanol (10.0 mL) with palladium on 10% carbon (15 mg) with hydrogen at 1 atmosphere for 1 hour. The catalyst was removed by filtration and the solvent was removed in vacuo to obtain the title compound as an orange-yellow solid (0.298 g, 95%): melting point: 111-115 ° C. (CD3OD / 300 MHz) 7.69 (s, ÍH), 6.69-6.74 (m, 3H), 5.65 (qH-F, ÍH, J = 7.2 Hz), 4.26-4.37 (m, 2H), 1.34 (t, 3H , J = 1 Hz). FABHRMS m / z 288.0860 (M + H +, C1 H13F3N03 requires 288.0847). Anal. Calculated for C? 3H F3N0j; C, 54.36; H, 4.21 N, 4.88. Found: C, 54.46; H, 4.27; N, 4.83.

EXAMPLE 36 10 • 6-Amino-2-tri luoromethyl 2H-1-benzopyran-3-carboxylic acid 6-amino-2- (trifluoromethyl) -2H-15 ethyl-l-benzopyran-3-carboxylate was hydrolysed (Example 35, Step • 2) with the carboxylic acid (title compound) by a procedure similar to that described in Example 1, Step 2: melting point: 126-133 ° C. 1E NMR (CDJOD / 300 MHz) 6.81-6.90 (m, 3H), 5.66 (qH-F, ÍH, J = 7.2 Hz). FABHRMS m / z 260.0535 (M + H +, CnH9F3N04 requires 260, 0534).

EXAMPLE 37 6-Nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 6-Nitro-2- (trifluoromethyl) -2H- • l-benzopyran-3-carboxylic acid ethyl ester (Example 35, Step 1) was hydrolyzed to the carboxylic acid (title compound) by a procedure similar to that described in Example 1, Step 2: melting point: 187-189 ° C. 1E NMR (CD3OD / 300 MHz) 8.34 (d, ÍH; J = 2.6 Hz), 8.27 (dd, 1H, J = 8.7, 2.6 Hz), 7.90 (s, 1H), 7.09 (s, ÍH, J = 8.7 Hz ), 5.81 (qH-F, ÍH, J = 7.2 Hz). EIHRMS m / z 289.0177 (Calculated 289.0198). Anal. Calculated for • CnHßFaNOs: C, 45.69; H, 2.09; N 4.84 Found: C, 45.71; H, 2.08; N, 4.75.

EXAMPLE 38 6-Chloro-8-methyl-2-trifluoro-2H-l-benzopyran-3-carboxylic acid 4-Chloro-2-methylphenol was converted into the title compound by a procedure similar to that described in Example 2: melting point : 231-9-233.2 ° C. X H NMR (CDCl 3/300 MHz) 7.76 (s, 1 H), 7.19 (d, ÍH, J = 1.8 Hz), 7.09 (d, ÍH, J = 2.4 Hz), 5.72 (q, ÍH, J = 6.9 Hz) , 2.23 (s, 3H), 19 F NMR (CDCl 3/282 MHz) -79.2 (d, J = 6.5 Hz). FABLRMS m / z 299 (M + Li). FABHRMS m / z 293.0196 (M + H, Calculated 293.0192). Anal. Calculated for C12HBCIF303: C, 49.25; H, 2.76. Found: C, 49.37; H, 2.86.

EXAMPLE 39 Acid 8-chloro-6-m ti 1-2 -tri luoromethyl-2H-1-benzopy-3-carboxylic acid 2-Chloro-4-methylphenol was converted to the title compound by a procedure similar to that described in Example 2 : melting point: 226.4-227.4 ° C. H NMR (CDCl3 / 300 MHz) 7.79 (s, ÍH), ÚJ64 7. 2:; d, ÍH, J = 1.4 Hz), 6.97 (d, ÍH; J = 1.4 Hz), 5.77 (q, ÍH, J = 6.8 Hz), 2.29 (s, 3H) 19F NMR (CDCl3 / 282 (MHz) - 79.1 (d, J = 7.3 Hz). FABLRMS m / z 291 (M-H).

EIHRMS m / z 292.0118 (M +, C? 2H8ClF303 Calculated 292, 0114).

EXAMPLE 40 8-Chloro-6-ethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 2-Chloro-4-methoxyphenol was converted to the title compound by a procedure similar to that described in Example 2: melting point : 204.5-206.9 ° C. XH NMR (CDCl3 / 300 MHz) 7.78 (s, 1H), 6.98 (d, ÍH, J = 2.8 Hz), 6.71 (d, 1H, J = 2.8 Hz), 5.74 (q, 1H, JJ = 6.9 Hz) 3.79 (s, 3H). FABLRMS m / z 326 (M + NH 4): EIHRMS m / z 308.0053 (M + Calculated 308.0063). Anal. Calculated for C? 2H8CIF304; C, 46.70; H, 2.61. Found: c, 46.60; H, 2.68.

EXAMPLE 41 6, 8-Di luoro-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 2,4-difluorophenol was converted into the title compound by a procedure similar to that described in Example 2: melting point: 207 -211 ° C. XH NMR (CDC13) 7.63 (s, 1H), 6.89-6.72 (m, 2H), 5.69 (q, 1H, J = 6.7 Hz). Anal. Calculated for CnH¿03F5; C, 47.16; H, 1.80. Found: C, 47.28; H, 1.87.

EXAMPLE 42 15 6-Bromo-8-chloro-2-tri-loromethyl-2H-1-benzopyran-3-carboxylic acid 4-bromo-2-chlorophenol was converted into composed of the title by a procedure similar to that described in Example 2: melting point: 220.7-221.7 ° C. tE NMR (CDC13) 7.58 (s, 1H), 7.44 (d, ÍH, J = 2.2 Hz), 7.22 (d, 1H, J = 2.2 Hz) 5.74 (q, 1H, < J = 6.8 Hz). Anal. Calculated for CnHsOjFjBrCl: C, 36.96; H, 1.41. Found: C, 37.03; H, 1.44.

EXAMPLE 43 8-Bromo-6-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 2-Bromo-4-fluorophenol was converted into the title compound by a procedure similar to that described in Example 2: melting point : > 300 ° C. X NMR (CDC13) 7.58 (s, ÍH), 7.22 (dd, ÍH, J = 6.3, 3 Hz), 6.88 (dd, 1H, J = 6.1, 3.1 Hz), 5.72 (q, ÍH, Ji5 = 6.7 Hz ). Anal. Calculated for CnH5? 3F Br: C, 38.74; H, 1.48. Found: C, 38.82; H, 1.56.

EXAMPLE 44 8-Bromo-6-methyl-1-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 2-Bromo-4-methylphenol was converted to the title compound by a procedure similar to that described in Example 2: melting point : 237-238 ° C. 2H NMR (CDC13) 7.59 (s, 1H), 7.27 (m, 1H), 6.91 (d, ÍH, J = 1. A Hz), 5.69 (q, ÍH, J = 6.9 Hz), 2.20 (s) , 3H). Anal. Calculated for C2H803F3Br: C, 42.76; H, 2.39. Found: C, 43.34; H, 2.56.

EXAMPLE 45 8-Bromo-5-luoro-2-tri luoromethyl-2H-1-benzopran-3-carboxylic acid 2-Bromo-5-fluorophenol was converted into the title compound by a procedure similar to that described in Example 2: melting point: 221.7-223.3 ° C. 1E NMR (CDC13) 7.81 (s, ÍH), 7.38 (dd, 1H, J = 7.3, 5.8 Hz), 6.58 (t, ÍH, J = 8.9 Hz), 5.71 (q, 1H, J = 6.7 Hz). Anal. Calculated for C?: LHb03FBr: C, 38.74; H, 1.48. Found: C, 38.70; H, 1.54.

EXAMPLE 46 6-Chloro-8-fluo or-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 4-Chloro-2-fluorophenol was converted into the title compound by a procedure similar to that described in Example 2: melting point: 190.8-193.0 ° C. aH NMR (CDCl 3/300 MHz), 7.77 (s, ÍH), 7.19 (d of d, ÍH, J = 2.2 and 9.7 Hz), 7.07 (t, ÍH, J = 1.8 Hz), 5.76 (q, 1H, J = 6.7 Hz). FABLRMS m / z 295 (M-H). EIHRMS m / z 295.9876 (M + Calculative 295.9863). Anal. Calculated for C 11 H 5 ClF 4 O 3: C, 44.54; H, 1.70. Found: C, 44.36; H, 1.85.

EXAMPLE 47 6-Bromo-8-m-toxy-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid 4-Bromo-2-methoxysalicylaldehyde was converted into the title compound by a procedure similar to that described in Example 1: fusion: dec. at a temperature of 244 ° C. ? E NMR (CD3OD / 300 MHz) 7.71 (s, 1H), 7.18 (d, ÍH, J = 2.2 Hz) 7.11 (d, ÍH, J = 2.2 Hz), 5.77 (qH_F 1H, J = 7.2 Hz), 3.84 (s, 3H). FABLRMS m / z 351 (M-H). anal. Calculated for C? 2H8BrF305: C, 40.82; H, 2.28. Found: C, 40.83; H, 2.30.

EXAMPLE 48 7- (N, N-diethylamino) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid. 4- (N, N-diethylamino) salicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: melting point: 214.4-215.4 ° C. 2E NMR (CD3OD / 300 MHz) 7.67 (s, ÍH), 7.06 (d, ÍH, J = 8.6 Hz), 6.34 (dd, ÍH; J = 8.6, 2.3 Hz), 3.60 (qH-F 1H, J = 7.2 Hz), 3.38 (q, 4H, J = 7.1 Hz), 1.16 (t, 6H, J = 7.1 Hz). ESLRMS m / z 316 (M + H). FABHRMS m / z 316.1145 (M + H +, Calculated 316.1161). Anal. Calculated for C? BH16FjN03: C, 57.14; H, 5.11; N, • 4.44. Found: C, 57.14; H, 5.08; N, 4.44.

EXAMPLE 49 6- [[(Phenylmethyl) amino] sulfonyl] -2- trifluoromethyl-2H-1-benzopyran-3-sarboxylyl acid Step 1: Preparation of ethyl 6-chlorosulfonyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylate Chlorosulfonic acid (50.0 ml) was cooled to a temperature of 15 ° C and ethyl 2-trifluoromethyl-2H-l-benzopyran-3-carboxylate was added (Example 10, F 15 Step 2) (6.21 g, 22.83 mmol). After stirring at -15 ° C for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The solution was added dropwise on ice (500 ml) with vigorous shaking and extracted with diethyl ether (2 x 250 ml). The ether layers were combined, washed with water (2 x 250 ml), saturated sodium bicarbonate (2 x 250 ml), and saline (2 x 250 ml). Hexanes were added (50 ml) and the solution was dried in sodium sulfate. The solvent was removed in vacuo to obtain the ester as a yellow solid (7.41 g, 87%): melting point: 97.2-98.4 ° C. 1H NMR (CDC13, 300 MHz), 7.97 (dd, ÍH, J = 8.6, 2.2 Hz), 7.92 (d, ÍH, J = 2.2 Hz), 7.73 (s, ÍH), 7.17 (d, 1H, J = 2.2 Hz), 5.82 (qH_F ÍH, J = 7.2 Hz), 4.28-4.39 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz). FABLRMS m / z 376 (M + LÍ +).

Step 2. Preparation of ethyl 6- [[(phenylmethyl) aminojsulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylate. The sodium chloride from Step 1 (451.0 mg, 1.22 mmol) and benzylamine (600 mg, 5.62 mmol) in diethyl ether (25 ml) were mixed for 1 hour at room temperature. The solution was washed with IN HCl (2 x 25 ml), saturated sodium bicarbonate (2 x 25 ml), and saline (2 x 25 ml). The solution was dried in sodium sulfate and dried in vacuo. Aminosulfonyl was obtained by crystallization from hexanes (431 mg, 84%): melting point: 128.2-131.9 ° C. X NMR (CDC13, 300 MHz) 7.76 (dd, ÍH, J = S.A, 2.2 Hz), 7.70 (d, 1H, J = 2.2 Hz), 7.67 (s, ÍH,), 7.12-7.30 (m, 5H), 7.05 (d, ÍH, J = 8.4 Hz), 5.78 (qH-FHI, J = 7.2 Hz), 4.68 (m, 2H), 4.19-4.32 (m, 2H), 1.37 (t, 3H, J = 7. O Hz). FABLRMS m / z 442 (M + H +). FABHRMS m / z 442.0936 (M + H +, C20H19F3NO5S • Calculated 442, 0916).

Step 3. Preparation of 6- [[((phenylmethyl) -amino] sulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid. The acid was converted from the ester (Step 2) by the method similar to that described in Example 1, Step 2: melting point: 223.3-224.4 ° C. X NMR (CD3OD / 300 MHz) 7.31-7.80 (m, 3H), 7.15-7.25 (m, 5H), 7.06 (d, 1H, J = 8.3, Hz), 5.87 (qH-FH, J = 7.2 Hz ), 4.11 (s, 2H). FABLRMS m / z 420 (M + Li +). FABHRMS m / z 414.0589 (M + H + Calculated 414.0623). Anal. Calculated for C1BH? 4F3NOsS: C, 52.30; H, 3.41; N, 3.39. Found: C, 5.16; H, 3.44; N, 3.32.

• EXAMPLE 50 6- [(Dimethylamino) sullyl] -2-tri-loromethyl-2H-1-benzopyran-3-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 49: melting point: 201.2-202.5 or C. 1R NMR (CD3OD / 300 • MHz) 7.90 (s, 1H), 7.82 (d, 1H, J = 2.2 Hz), 7.76 (dd, ÍH, J = 8.6, 2.2 Hz), 7.19 (d, ÍH, J = 8.6 Hz), 5.91 ( qH-FHH, J = 7.2 Hz), 2.70 (s, 6H). FABLRMS m / z 352 (M + H +). FABHRMS m / z 352.0466 (M + H + calculated 352.0467). Anal. Calculated for Ci3H? 2F3N05S: C, 44.45; H, 3.44 N, 3.99. Found: C, 4.42; H, 3.45; N, 3.96. 10 • EXAMPLE 51 6-Ami-osulfoni-1-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 39: melting point: 187.9-189.9 ° C. XH NMR (CD3OD / 300 MHz) 7.58-7.88 (m, 3H), 7.12 (d, J = 8.3 Hz), 5.87 (qH-F ÍH, J = 7.2 Hz). FABLRMS m / z 324 (M + H +).

FABHRMS m / z 324, 0156 (M + H + calculated 324.0154). Anal. Calculated for CpH8F3N05S * 0.74, H20: C, 39.26; H, 2.84; N, 4.16. Found: C, 39.33; H, 2.82; N, 4.11.

EXAMPLE 52 6- (Methylamino) sulfonyl-2-trifluoromethyl-2H-l-benzopyran-3-sarboxylyl acid The title compound was prepared by a procedure similar to that described in Example 49: melting point: 207.6-208.6 ° C. H NMR (CD3OD / 300 MHz) 7.83-7.97 (m, 3H), 7.19 (d, ÍH; J = 8.5 Hz), 5.91 (q h_F, H = 7.2 Hz), 3.11 (s, 3H). FABLRMS m / z 338 (M + H +). FABHRMS m / z 338.0331 (M + H + calculated 338.0310). Anal. Calculated for C? 2 HnF3N05S: C, 42.73; H, 2.99; N, 4.15. Found: C, 42.91; H, 3.06; N, 4.04.

E JEMPLO 53 6 - [(4-Morino) sulfonyl] -2-tri luoromethyl-2H-1-benzopyran-3-sarboxylic acid.

The title compound was prepared by a procedure similar to that described in Example 49: melting point: 215.2-219.3 ° C. E NMR (~ CD3OD / 300 MHz) 7.88 (s, ÍH), 7.81 (d, ÍH, J = 2.2 Hz), 7.74 118 (dd, HH; J = 8.6, 2.2 Hz), 5.90 (qH-F, HH, J = 7.2 Hz), 3.54-3.70 (m, 4H), 2.94-2.97 (m, 4H). FABLRMS m / z 394 (M + H +). FABHRMS 394.0567 (M + H +, C? 5H? 5F3N06S Calculated 394.0572).

EXAMPLE 54 6- [(1, 1-Dimethylethyl) aminosulfonyl] -2-trifluoromethyl-2H-1-benzopy-3-sarboxylic acid The title compound was prepared by a procedure similar to that described in Example 49: melting point: 229.3 -233.5 ° C. 2H NMR (CD3OD / 300 MHz), 7.82-7.87 (m, 3H), 7.12 (d, 1H, J = 8.6 Hz), 5.87 (q HF, 1H, J = 7.2 Hz), 1.18 (s, 9H) , FABLRMS m / z 380 (M + HA - Anal, Calculated for Ci5HibFN05S: C, 47.49; H, 4.25; N, 3.69, Found C, 47.95; H, 4.48; N, 3.55.

EXAMPLE 55 Asido 6- [(2-methylpropyl) minosul onyl] -2- trifluoromethyl-2H-1-benzopy an-3-carboxylic acid The title compound was prepared by a procedure similar to that described in Example • 49: melting point: 190.6- 192.4 ° C. 1H NMR (CD3OD / 300 MHz) 7.77-7.84 (, 3H), 7.13 (d, ÍH, J = 8.4 Hz), 5.86 (qH-FHI, J = 7.2 Hz), 2.64 (d, 2H, J = 6.8 Hz), 1.66 (Sept.IH, J = 6.6 Hz), 0.84 (d, 6H, J = 6.6 Hz). FABLRMS m / z 380 (M + H +). Anal. Calculated for C? 5H16F3N05S: C, 47.49; H, 4.25; N, 3.69. Found: C, 47.61; H, 3.34; N, 3.55. 15 • EXAMPLE 56 Acid 6 -methyl sul oni 1 -2-tri fluor ome ti 1 -2 H- l - benzopy-3-carboxy li Step 1. Preparation of 6-chlorosulfonyl-2- (trifluoromethyl) -2H-1 - benzopyran-3-carboxylic acid To chlorosulfonic acid (50.0 ml) cooled to a temperature of -15 ° C was added 2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid (Example 10) (4.0 g, 16.7 mmol). After stirring at -15 ° C for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The resulting solution was added dropwise on ice (100 ml) with two extractions of diethylether (2 x 75 ml). The diethyl ether layers were combined, washed with water (2 x 75 ml), and with saline (2 x 75 ml), dried over sodium sulfate and concentrated in vacuo. The resulting solids were triturated with hexane-ethyl acetate (9: 1, 100 ml). The 6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid was isolated as a white solid: melting point: 169-174. 1 HOUR NMR (CD3OD / 300 MHz) 8.18 (d, ÍH, J = 2.7 Hz), 8.06 (dd, ÍH, J = 8.7, 2.7 Hz), 7.93 (s, ÍH), 7.28 (d, ÍH, J = 8.7 Hz ), 6.00 (q, ÍH, J = 6.6 Hz). EIHRMS m / z 324.9977 (M +, Calculated 324.9994).

Step Preparation of 6-methylsulfonyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid one intermediate chlorosulfonyl slurry (Example 49, Step 1) (493 mg, 1.44 mmol), sodium carbonate (362 mg, 4.32 mmol), and sodium bisulfite (181 mg, 1.44 mmol) in water (1.5 ml) was heated at a temperature of 60 ° C for 1.5 h, followed by the addition of bromoacetic acid (212 mg, 1.55 mmol) . The resulting suspension was heated to reflux, then sodium hydroxide solution (50% soln. NaOH, 0.10 ml) and water (3.0 ml) was added. The solution was refluxed for 8 hours, cooled to room temperature, and acidified to pH 1 with IN aqueous hydrochloric acid. The solution was extracted with ethyl acetate (2 x 25 ml) The combined ethyl acetate layers were washed with IN aqueous hydrochloric acid (2 x 25 ml), water (2 x 25 ml), and saline (2 ml). x 25 ml), dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as an off-white solid as a product (231 mg, 50% product): m.f. 212.4 ° C. 1H NMR (CD30D, 300 MHZ) 7.97 (d, ÍH, 2.2 Hz), 7.91 (ÍH, dd, J = 8.7, 2.2 Hz), 7.19 (d, ÍH, J = 8.7 Hz), 5.91 (qH-F, ÍH, J = 7.2 Hz), 3.11 (Yes H) . HRLRMS m / z 321 (M-H). FABLRMS m / z 321 (M-H). Anal. Calculated for C12H9F305S * 0.61 H20: C, 43.26; H, 3.09. Found: C, 43.24; H, 3.09.

EXAMPLE 57 8-Chloro-6- [[(phenylmethyl) aminojsulfonyl] -2- trifluoromethyl-2H-1-benzopyran-3-aarboxylyl acid The title compound was prepared by a procedure similar to that described in Example 49: melting point: 167.0 -173.8 ° C. 2H NMR (CD3OD / 300 MHz) 7.78 (s, ÍH), 7.72 (d, 1H J = 2.0 Hz), 7.64 (d, ÍH; J = 2.0 Hz), 7.44 (s, ÍH), 7.15-7.23 (m , 5H), 6.01 (qH-FHH; J = 1. 2 Hz), 4.08-4.15 (m 2H). FABLRMS m / z 454 (M + Li +). Anal. Calculated for C? 6H? 3CIF3N05S: C, 48.28; H, 2.93; N, 3.13. Found: C, xx; H, xx; N, xx.

EXAMPLE 58 UBO Acid 6-N, N-diethylaminosulfoni1-2-tri-loromethyl-2H-1-benzopyran-3-carboxylic acid. The title compound was prepared by a procedure similar to that described in Example 49: melting point: 238-240 ° C. XH NMR (CD3OD / 300 MHz) 7.88 (s, ÍH), 7.85 (d, ÍH, J = 2.2 Hz), 7.79 (dd, ÍH, J = 8.5, 2.2 Hz), 7.14 (d, ÍH, J = 8.5 Hz), 5.88 (qH-F, 1H, J = 7.2 Hz), 3.24 (q, 2H, J = 7.3 Hz) , 1.1 (t, 3H, J = 7.3 Hz). FABHRMS m / z 380.0763 (M + H +, Calculated 380.0780). Anal. Calculated for Cii, H16F3N04S: • C, 47.49; H, 4.25; H, 3.69. Found: C, 47.62; H, 4.30; N, 3 72.

EXAMPLE 59 15 6-Phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid Step 1. Preparation of ethyl 6-phenylacetyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylate 2-trifluoromethyl acid was cooled -2H-1-benzopyran-3-carboxylic acid (Example 10) (1.32 g, 4.85 mmol) at a temperature of 0 ° C in dichloromethane (50 ml). Aluminum chloride (2.58 g, 19.5 mmol) was added and resulted in a dark red solution.

A solution of phenylacetyl chloride (1.8 g, 12.1 mmol) in dichloromethane was added dropwise. (10.0 ml) for 40 minutes. The solution was warmed to room temperature and stirred for 16 hours.

The solution was poured onto ice (200 ml) and extracted with diethyl ether (2 x 100 ml). The diethyl ether layers were combined, extracted with water (1 x 100 ml), 1 N HCl (2 x 100 ml), and saturated with sodium bicarbonate (3 x 100 ml). Hexanes (20 ml) were added and the solution was extracted with saline (1 x 100 ml). The solution was dried over sodium sulfate and the solvent was removed in vacuo. The crude ester was purified by flash chromatography on silica gel (with ethyl acetate as diluent) to obtain the ester which was crystallized from diethylether / hexanes (830 mg, 44%): melting point: 136.2-138.0 ° C . XH NMR (CDCl3 / 300 MHz) 7.98 (dd, 2H, J = 8.4, 2.0 Hz), 7.90 (d, ÍH, J = 2.0 Hz), 7.29 (s, ÍH), 7.22-7.38 (m, 5H), 7.02 (d, 1H, J = 8.4 Hz), . 75 (qH-F ÍH, J = 7.2 Hz), 4.25-4.40 (, 2H), 4.21 (s, 2H), 1.34 (t, 3H, J = 7.0 Hz). FABLRMS m / z 391 (M + HA.

Step 2. Preparation of 6-phenylacetyl-2-txifluoromethyl l-2H-1-benzopyran-3-carboxylic acid The acid was converted from the ester (Step 1) by a method similar to that described in Example 1, Step 2: melting point: 159.0-164.0 ° C. XH NMR (CD3OD / 300 MHz) 8.04-8.16 (m, 3H), 7.87 (s, 1H), 7.05-7.30 (m, 5H), 5.86 (qH-FH, J = 7.2 Hz), 1 4.31 (s) , 2H), FABLRMS m / z 363 (M + HA - Anal, Calculated for C? 9H? 3F3o4 * 0.29 H20: C, 62.08; H, 3.73, Found: C, 62.04; H, 4.03.

EXAMPLE 60 6- (2, 2-dimethylpropylcarbonyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 59: melting point: 198-200 ° C . XH NMR (CD3OD / 300 MHz), 7.98-8.06 (m, 2H), 7.88 (s, HH), 7.07 (d, 1H, J = 8.9 Hz), 5.86 (qp-F, HH, J = 7.2 Hz) , 2.88 (s, 2H), 1.05 (s, 9H). FABHRMS m / z 343.175 (M + HA C? 7H18F304 requires 343.1157). Anal. Calculated for C? H? 7F3? 4: C, 59.65; H, 5.01. Found: C, 59.70; H, 4.97.

EXAMPLE 61 6, 8-Dichloro-7-methoxy-2-tri luoromethyl-2H-1-benzopyral-3-sarboxylic acid Step 1: Preparation of ethyl 7-methoxy-2-trifluoromethyl-benzopyran-2H-3-carboxylate. 4-methoxysalicylaldehyde (2.38 g) was dissolved, 15.64 mmol), K2CO3 (2.16 g, 15.64 mmol) and ethyl 4,4,4-trifluorocrotonate (2.8 mL, 3.16 g, 18.77 mmol) in DMF (10 mL). The reaction was stirred at room temperature for 24 hours, diluted with water and extracted with Et20. The combined Et20 phases were washed with water, dried over MgSO4, filtered and concentrated in vacuo resulting in an oil. Trituration with hexane induced crystallization. Collection of the solid by vacuum filtration resulted in the ester in the form of a light brown crystalline solid (1.80 g, 38%): melting point: 78-80 ° C. X H NMR (CDCl 3/300 MHz) d 7.69 (s, 1 H), 7.14 (d, 1 H, J = 8.1 Hz); 6.59-6.50 (m, 2H), 5.68 (q, ÍH, J = 7.1 Hz), 4.39-4.24 (m, ^? * 2H), 3.82 (s, 3H), 1.34 (t, 3H, J = 7.3 Hz). FABLRMS m / z 303 (M + H) FABHRMS m / z 303.0849 '(M + H Calculated 303.0844). Anal. Calculated for C? 4H? 3F3.04: C, 55.63; H, 4.34. Found: C, 55.47; H, 4.31.

Step 2. Preparation of 6,8-dichloro-7-methoxy-2-10 trifluoromethyl-benzopyran-2H-3-carboxylic acid ethyl ester. Chlorine gas (excess) was added to a stirred solution of the ester (Step 1) (1.35 g, 4.47 mmol) in HOAc (30 mL) until the yellow color persisted. After 20 minutes, the reaction will dew with - nitrogen causing the reaction to take a straw color. Zinc (0.86 g, 13.40 mmol) was added to this solution by vigorous stirring. After 45 minutes, additional zinc was added (0.86 g, 13.40 • mmol) and the reaction was stirred overnight.

The crude mixture was diluted with EtOH and filtered through diatomaceous earth. The filtrate was concentrated in va c uo resulting in a crystalline mass. This solid was dissolved in EtOAC, washed with 2NHC1, saline, dried with MgSO4, filtered and was concentrated in va c uo resulting in an oil.

The oil dissolved in a minimum of isooctane, inducing crystallization. Vacuum filtration resulted in caramel colored needles (1.078 g) that were recrised from isooctane resulting in the dichloro ester in the form of tan crystals (0.71 g, 43%) of an adequate purity to use it in the next step: melting point: 113.3-115.1 ° C. 1H NMR (acetone-d6 / 300 MHz) 7.88 (s, ÍH), 7.63 (s, ÍH), 6.02 (q, ÍH, J = 6.8 Hz), 4.38-4.22 (, 2H), 3.93 (s, 3H) , 1.31 (t, 3H, J) 7.1 Hz), 19 F NMR (acetone-d6 / 282 MHz) -80.00 (d, J "= 7.2 Hz).

Step 3: Preparation of 6,8-dichloro-7-methoxy-2-tri fluoromethybenzopyran-2H-3-carboxylic acid To a stirred solution of dichloro ester from Step 2 (0.686 g, 1848 mmol) in THF (10 mL). ml) and EtOH (3 ml) was added NaOH (0.81 ml of 2.5 M aqueous solution, 2.03 mmol) in one portion. After stirring overnight, the reaction was partially concentrated, diluted with H20 and washed with diethyl ether. The resulting aqueous phase was sprayed with nitrogen and acidified with a 2N HCl solution causing turbidity of the solution. Filtration of this suspension resulted in compound 136 of the title in the form of a white powder (0.559 g, 88%): melting point: 195.6-199.1 ° C. XH NMR (CDCl 3/300 MHz) 7.90 (s, ÍH), 7.64 (s, ÍH), 6.01 (q, • H, J = 6.8 Hz), 3.94 (s, 3H). 19 F NMR (CDCl 3/282 MHz) -79.63 (d, J = 7.1 Hz). FABLRMS m / z 349 (M + Li). EIHRMS m / z 341.9681 (M +, Calculated 341.9673). Anal. Calculated for C 2 H 7 Cl 2 F 304: C, 42.01; H, 2.06. Found: C, 41.76; H, 2.14.

EXAMPLE 62 2-trifluoromethyl-2H-naphtha [1, 2-b] pi an -3-carboxylic acid Step 1_. Preparation of ethyl 2-trifluoromethyl-1-3H- • naphthopyran carboxylate. A mixture of 2-hydroxy-1-naphthaldehyde (8.6 g, 0.050 mol) and ethyl 4,4,4-trifluorocrotonate (9.2 g, 0.055 mol) was dissolved in anhydrous dimethylformamide (DMF) and treated with anhydrous K2CO3 (13.8 g, 0.100 mol). The solution was kept at room temperature for 50 hours and diluted with water. The solution was extracted with ethyl acetate and the combined extracts were washed with saline, dried with MgSO4.

• Anhydrous, filtered and concentrated in vacuo to obtain 4.8 g of an oil. The oil was purified by HPLC, solvent with hexanes ethyl acetate (30: 1). The appropriate fractions were concentrated to obtain 1.6 g (10%) of the naphthopyran ester as a yellow solid. Step 2. Preparation of 2-trifluoromethyl-3H-naphthopyrancarboxylic acid. A solution of the ester from Step 1 (0.8 g, 2.5 mmol) was dissolved in 40 ml of ethanol and 10 ml of Tetrahydrofuran, treated with sodium hydroxide (2.5 N, 10 ml, 25 mmol) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.0 N HCl, after which a solid formed • that was isolated by filtration. The solid was washed with 20 ml of water to obtain 0.7 g (95%) of the title compound as a yellow solid: melting point: 245.9-248.6 ° C. 1E NMR (acetone-d6 / 300 MHz) 8.57 (s, HH), 8.28 (d, HH; J = 8.7 Hz), 8.03 (d, HH, J = 9.0 Hz), 7.93 (d, HH, J = 8.7 ), 7167 (, ÍH), 7.50 (m, 1H), 7.28 (d, ÍH, J = 9.0), 5.96 (q H-F, ÍH, J = 7.2 Hz). FABHRMS m / z 295.0561 (M + H, Calculated 295.0582). Anal. Calculated for ClbH903F3 + 3.31% H0: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.

EXAMPLE 63 2-trifluoromethyl-3H-naphtha [2, lb] pyran-3-sarboxylic acid 2-Hidoxy-naphtha-1-aldehyde was converted into the title compound by a procedure similar to that described in Example 1: melting point: 244.7 -249.8 ° C. 1 H NMR (CDCl 3/300 MHz) 8.61 (s, HH), 8.09 (d, HH = 8.3 Hz), 7.90 (d H H, J = 8.9 Hz), 7.82 (d, HH, J = 8.3 Hz), 7.63 (t, ÍH, J = 8.1 Hz), 4.74 (t, ÍH, J = 8.1 Hz), 7.23 (d, ÍH, J = 9.1 Hz), 5.84 (q, 1H, J = 6.8 Hz). 19 F NMR (CDCl 3/282 MHz) -79.56 (d, J = 7.3 Hz). FABLRMS m / z 295 (M + H). FABHRMS m / z 295.0515 (M + H, Calculated 295.0582). Anal. Calculated for C? F9F303: C, 61.23; H, 3.08. Found: C, 60.85; H, 3.12.

EXAMPLE 64 Acid 2-trifluoromethyl-2H-naphtha [2,3-b] pyran-3-sarboxylyl 3-hydroxynaphthalene-2-carboxylic acid was converted to 3-hydroxynaphthalene-2-carboxaldehyde by a procedure similar to that described in Example 24, Steps 1 and 2. The 3-hydroxynaphthalene-2-carboxaldehyde was converted to the title compound by a procedure similar to that described in Example 1: melting point: decompose > 300 ° C. XH NMR (CD3OD / 300 MHz) 7.99 (s, ÍH), 7.99 (s, ÍH), 7.90 (s, ÍH), 7.84 (d, ÍH, J = 8.2 Hz), 7.74 (d, ÍH, J = 8.2 Hz), 78.50 (t, ÍH, J = 8.2 Hz), 7.39 (t, 1H, J - 8.2 Hz), 7.34 (s, 1H), 5.77 (q, ÍH, J = 6.6 Hz). EIHRMS m / z 294.0474 (M +, Calculated 294.0504).

EXAMPLE 65 6-sloro-2-tri luoromethyl-2H-1-benzothiopyran-3-carboxylic acid • 5 Step 1: Synthesis of 5-chloro-thiosalicylaldehyde. Tetramethylethylenediamine (TMEDA) was added (10.44 ml, 8.035 g, 69.15 mmol) syringe n-BuLi (43.22 ml of 1.6 M in hexanes, 69.15 mmol) and the solution cooled to 0 ° C. A solution of 4-10 chlorothiophenol (5.00 g, 34.57 mmol) in cyclohexane (25 ml) was added while stirring for 1 hour. The resulting caramel colored slurry was stirred overnight • room temperature, cooled to 0 ° C, and DMF (2.94 ml, 2.78 g, 38.03 mmol) was added through a syringe for 2 minutes. The resulting rubbery slurry was stirred at room temperature for 30 hours and converted into a powder slurry. A mixture of 2 N HCl was added and ice was added to the reaction mixture until the pH became acidic. (pH = 1). During this addition, the mixture heated up and first became red and then light yellow. The mixture was extracted with ethyl acetate. The combined organic layers were washed with saline in MgSO 4, filtered and concentrated in vacuo resulting in a red-brown chlorine oil. I This oil was crushed with hexanes resulting in a red-brown semi-solid. This semisolid was purified by flash chromatography on silica gel, diluting with 1: 1, hexanes: dichloromethane to obtain 5-chloro-thiosalicylaldehyde (0.858 g, 14%) eating an intensely yellow solid suitable for use without further purification.

Step 2: Preparation of ethyl 6-chloro-2-trifluoromethyl-benzo-l-thiopyran-2-H-3-carboxylate 5-chloro-thiosalicylaldehyde (Step 1) (0.84 g, 4.86 mmol) was added to DMF (3 ml) and ethyl 4,4,4-trifluorocrotonate (1.10 ml, 1.22 g). K C03 (0.67 g, 4.86 mmol) was added by stirring causing the reaction to turn dark red. After stirring overnight at room temperature, the reaction was diluted with diethyl ether and washed with water, with saturated NaHCO 3 solution, with aqueous KHS04 solution (0.25 M) and with saline, dried with MgSO 4, filtered and concentrated to vacuum 152 resulting in an oil. The oil was purified by flash chromatography (5: 1, hexanes: ethyl acetate) yielding with 6-chloro-2-trifluoromethyl-benzo-l-thiopyran-2H-3-carboxylic acid ethyl ester as a bright orange solid. (0.492 g, 31 melting point: 94.6-97.4 ° C? NMR (acetone d6 / 300 MHz) d 8.01 (s, ÍH), 7.71 (d, ÍH, J = 2.2 Hz), 7.50 (d, ÍH, J = 8.5 Hz), 7.44 (d of d, ÍH, J = 2.3 8.3 Hz), 5.07 (q, ÍH J = 8.5 Hz), 4.42-4.23 (, 2H), 1.35 (t, 3H, J = 7.1 Hz). FABLRMS m / z 329 (M + Li).

Step Preparation of 6-chloro-2-txifluoromethyl l-benzo-l-thiopyran-2-H-3-carboxylic acid. To a stirred solution of the ester of Step 2 (0.413 g, 1.280 mmol) in THF: EtOH: H20 (7: 2: 1, ml) was added by stirring a solution of NaOH (0.56 ml of 2.5 N solution, 1.408 mmol). After stirring overnight, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H20 and washed with several portions of diethyl ether. Acidification of the stirred aqueous phase with concentrated HCl caused the precipitation of a flocculent yellow precipitate. Vacuum filtration of the suspension gave 6-chloro-2-trif luoromethyl-benzo-l-thiopyran-2H-3-carboxylic acid in the form of a yellow powder (0.25 g, 66%): melting point: 188.8 -198-7 ° C. XH NMR (acetone-d6 / 300 MHz) d • 8.02 (s, 1H), 7.71 (d, 1H, J = 2.22 Hz), 7.50 (d, 1H, J = 8.4 Hz), 7.44 (d of d, 1H, J = 2.2 8.5 Hz), 5.05 (q , ÍH, J = 8.6 Hz). 19 F NMR (Acetone d6 / 282 MHz) d- 75.22, (d, J = 8.7 Hz). FABLRMS m / z 301 (M + Li); ESLRMS (negative ion) m / z 293 (M-H).

EXAMPLE 66 • Acid (S) -6-Chloro-2-tri luoromethyl-2H-l-benzopyran-3-carboxylic acid 15 To an acid solution. 6-Chloro-2-trifluoromethyl 1-2H-1-benzopyran-3-carboxylic acid (Example 1, Step 2) (12.00 g, 43.07 mmol) and (S) (-) - a-methylbenzylamine (2.61 g, 21.54 g) mmol) in methyl-tert-butyl ether (30 ml) was slowly added n-heptane (200 ml) until the mixture became turbid. The mixture was heated (steam bath) to boiling and separated for 24 hours, during which time crystals formed. Filtration of the suspension gave a crystalline product (5.5 g) which was recrystallized from methyl tert-butyl ether (30 ml) and n-heptane (200 ml) giving a white solid (3.1 g) by filtration. This solid was dissolved with EtOAC (100 ml) and washed with 1 N hydrochloric acid (50 ml) and saline (2 x 50 ml), dried with MgSO 4 and concentrated in vacuo to give a white solid. The recrystallization of this solid from methyl-t-butyl ether / n-heptane gave the title compound in the form of the highly enriched isomer, a white solid (2.7 g, 45%): melting point: 126.7-128.9 ° C. X H NMR (CDCl 3/300 MHz) 7.78 (s, 1 H), 7.3-7.1 (m, 3 H), 6.94 (d, 1 H, J = 8.7 Hz); 5.66 (q, ÍH, J) 6.9 Hz), 7.78 (s, ÍH), 7.3-7.1 (, 3H), 6.94 (d, ÍH, J = 8.7 Hz), 5.66 (q, ÍH, J = 6.9 Hz) . Anal. Calculated for CnHg03F3Cl: C, 47.42; H, 21.7; N, 0.0. Found: C, 47.53; H, 2.14; N, 0.0. It was determined that this compound had optical purity greater than 90% ee.

Procedure for determining optical purity To a solution of free acid (liquid compound) (0.005 g, 0.017 mmol) in ethyl acetate (1.5 ml) in a test tube was added (trimethylsilyl) diazomethane (30 ml of 2.0 N) hexanes solution, 60 mmol). The resulting yellow solution 155 it was heated until the solution started to boil slowly and then it was left to cool to room temperature and to stand for 0.08 hours. Mixing in • Energetically, the solution was soaked with aqueous 1 N HCl (1.5 ml). The layers were separated and a sample of the ethyl acetate fraction (0.3 ml) was transferred to a flask, concentrated under a stream of nitrogen, diluted with hexane (total of 1 ml) and a sample of (10 ml) was analyzed. ml) by chiral chromatography. HPLC used a Daicel Chiral Pak AD column diluted with 10% isopropanol-hexane at 0.5 ml / min using a UV detector equipment at 254 nm.

EXAMPLE 67 Acid (S) -6-tri-loromethoxy-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid To a solution of 6- trifluoromethoxy-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid ( Example 16) (17.72 g, 54.00 mmol) and (-) -cinchonidine (7.95 g, 27.04 mmol) in met-il-tert-butyl ether (100 ml) 156 heated in a steam bath, n-heptane (200 ml) was added. The mixture was heated in a steam bath until boiling and allowed to cool for 4 hours, during which time crystals formed. Filtration of the suspension gave a crystalline solid (18.7 g). This solid was dissolved in 2-butanone (30 ml) followed by the addition of n-heptane (500 ml). After standing for 16 hours, the resulting suspension gave a white solid (10.3 g). This solid was dissolved in ethyl acetate (150 ml), washed with 1N hydrochloric acid (100 ml) and saline (2 x 50 ml), dried with MgSO 4, filtered, and concentrated in vacuo to give a yellow viscous oil (52 g, 59%): 1B. NMR (acetone-d6 / 300 MHz) 7.16 (s, ÍH), 6.77 (d, ÍH, J = 2.7 Hz), 6.94 (d, 1H, «7 = 8.7 Hz), 6.64 (m, ÍH), 6.39 ( d, 1H, J = 8.7 Hz), 5.13 (q, ÍH, J = 7.2 Hz). Anal. Calculated for C12Hs04F6: C, 43.92; H, 1.84; N, 0.0. Found: C, 43.79; H, 1.83; N, 0.0. It was determined that this compound had optical purity greater than 90% ee. The chiral purity was determined as described in Example 66. 157 EXAMPLE 68 (S) -6-Chloro-7- (1,1-dimethylethyl) -2- 5 acid. { trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid To a solution of 6-chloro-7- (1, 1- • dimethyl-ethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 8) (11.4 g, 34.1 mmol) and (S) - (-) -2-amino-3-phenyl-1-propanol (2.57 g, 17.00 mmol) were added n-heptane (200 ml) and the mixture was left aside for 16 hours. The resulting suspension was filtered giving a solid (3.8 g). This solid was recrystallized from 2-butanone (20 ml) and n-heptane (200 ml), giving a white solid (3.0 g) with filtration.

This solid was dissolved in ethyl acetate (100 ml) • and washed with 1 N hydrochloric acid (50 ml) and saline (2 x 50 ml), dried with MgSO0 and concentrated in vacuo to give a white solid. This solid was recrystallized from n-heptane giving the composed of the title of high optical purity in the form of a crystalline solid (1.7 g, 30%): melting point: 175.4-176.9 ° C. 1U NMR (acetone-d6 / 300 MHz), 158 7. 86 (s, ÍH), 7.52 (s, 1H), 7.12 (s, ÍH), 5.83 (q, ÍH, J = 7.1 Hz), 1.48 (s, 9H). Anal. Calculated for C15H14O3F3CI: C, 53.83; H, 4.22; N, 0.0; Cl, 10.59. Found: C, 53.78; H, 4.20; N, 0.0; Cl, 10.65. It was determined that this compound had an optical purity greater than 90% ee. The chiral purity was determined as described in Example 66.

EXAMPLE 69 6- [[(2-furanylmethyl) amino] sulfonyl] -2- acid. { tri luoromethyl) -2H-1-benzopyran-3-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 49: melting point: 170-173 ° C. 1E NMR (CD3OD / 300 MHz) 7.78 (s, ÍH), 7.66-7.76 (m 2H), 7.18-7.22 (m, ÍH), 7.00-7.08 (m, ÍH), 6.12-6.18 (m, ÍH), 6.02-6.06 (m, ÍH), 5.85 (q, ÍH, J = 7.0 Hz), 4.13 (s, 2H). EIHRMS m / z 403.0332 (M +, Calculated 403.0337). 159 EXAMPLE 70 6 - [(Phenylmethyl) sulfonyl] -2- (tri-loromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-1-benzopyran-3-carboxylic acid was prepared analogously to the procedure described in Example 56: mp 172-176 ° C. H NMR (CD3OD / 300 MHz) 7.73 (s, 1H), 7.43-7.46 (m, 2H), 7.21-7.33 (m, 3H), 7.20-7.21 (, 3H), 5.88 (q, ÍH, J = 7.0 Hz), 4.83 (s, 2H), EIHRMS m / z 398.0399 (M +, calculated 398.0436).

EXAMPLE 71 6- [[(Phenylethyl) aminojsulfonyl] -2- acid. { trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-l-benzopyran-3-carboxylic acid was prepared in a manner similar to the procedure described in Example 49: mp 187-190 ° C LH NMR (CD3OD / 300 MHz) 7.82 (s, ÍH), 7.74-7.90 (m, 2H), 7.08-7.29 (m, 6H), 5.89 (q, ÍH, J = 6.8), 3.12 (t, 2H, J = 7.3 Hz), 2.72 (t, J = 7.3 Hz). EIHRMS m / z 427-0675 (M +, calculated 427.0701).

EXAMPLE 72 Asido 7-chloro-2-tri luoromethyl-2H-1-benzopyran-3-carboxylic acid. 4-Chlorosalicylic acid was converted to 3-chlorosalicylaldehyde by a procedure similar to that described in Example 24, Steps 1 and 2. 3-Chlorosalicylaldehyde was converted into the title compound by a procedure similar to Example 1: mp 175.2-177.6 ° C. t NMR (acetone-db / 300 MHz) 7.90 (s, ÍH), 7.51 (d, 1H, J = 7.8 Hz), 7.12 (m, 2H), 5.86 (q "_F / ÍH, J = 7.2 Hz). FABHRMS m / z 285.0114 (M + Li, 2JD1 calculated 285.0118). Anal. Calculated CnH6ClF303: C 47.42; H, 2.17; Cl, 12.72. Verified: C, 47.54; H, 2.37; Cl, 12.85.

EXAMPLE 73 6-Chloro-8-iodo-2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylyl acid. Step 1. Preparation of 3-iodo-5-chlorosalicylaldehyde N-Iodosuccinimide (144.0 g, 0. 641 mol) to a solution of 5-chlorosalicialdehyde (100 g, 0.638 mol) in dimethylformamide (400 ml). The reaction mixture was stirred for two days at room temperature. N-iodosuccinimide was added (20 g, 0.089 mol) additional and stirring was continued for another two days. The reaction mixture was diluted with ethyl acetate (1 liter), washed with hydrochloric acid (300 ml, 0.1 N), water (300 ml), sodium thiosulfate (300 ml, 5%) and brine (300 ml). . It was then dried in MgSO4, and concentrated to dryness, to give the desired aldehyde as a pale yellow solid (162 g, 90%): mp 84.8-86.7 ° C. 1E NMR 2.02 (CDCl3 / 300 MHz) 11.67 (s, 1H), 9.71 (s, 1H), 7.92 (d, ÍH, J = 2.5 Hz), 7.54 (d, ÍH, J = 2.6 Hz). FABLRMS m / z 281. 0 (M-H). ESHRMS m / z 280.8851 (M-H, calculated • 280.88630).

Step 2. Preparation of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. It was dissolved with 5-chloro-3-yodosalicylaldehyde (20 g, 70.8 mmol), 4, 4, 4-trifluorocrotonate of ethyl (17.85 g, 106 mmol), and triethylamine (14.33 g, 142 • mmol) in DMSO (200 ml). The reaction mixture was stirred at 90 ° C for three days. The reaction mixture was poured into ethyl acetate (800 ml). Then, it was extracted with 10% HCl (2 x 200 ml), NaHCO 3 aqueous saturated (2 x 200 ml), and water (2 x 200 ml). The ethyl acetate phase was dried over MgSO, filtered and evaporated to give a brown solid. Then, it was passed through a plug of silica with ethyl acetate - hexane (1:20). The Solvent to give a yellow solid that was recrystallized from hexane to give the ester as a white solid (19.61 g, 64%): mp 92.1-93.9 ° C. XH NMR (CDCl3 / 300 MHz) 7.71 (d, ÍH, J = 2.2 Hz), 7.56 (s, ÍH), 7.20 (d, ÍH, J = 2.2 Hz), 5.81 ~ (q, ÍH, J = 6.7 Hz), 4.37-4.29 (m, 2H), 1.35 (t, 3H, J = 7.2 Hz).

FABLRMS m / z 431.9 (M-H). EIHRMS m / z 431-9269 (M-H, calculated 431-9237).

• Step 3. Preparation of 6-chloro-8-iodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. The ester (Step 2) was converted to the acid by a procedure similar to the method described in Example 1, Step 2: mp 220-223 ° C. XH NMR (CD3OD / 300 MHz) 7.77 (d, 1H, J = 2.2 Hz), 7.71 (s, ÍH), 7.41 (d, H H, J = 2.2 Hz), 5.87 (q, H H, J = 7.0 Hz). EIHRMS m / z • 403.8893 (M-H, calculated 403.8924). Anal. Calculated CnH5CIF3103: C, 32.66; H, 1.25. Verified: C, 33.13; H, 1.29.

EXAMPLE 74 Acid 8-Bromo-6-chloro-2-tri luoromethyl-2H-1-benzopyran-3-sarboxylyl Step 1. Preparation of 8-bromo-6-chloro-2-trifluoromethyl-2H-l-benzopyran-3 ethyl-carboxylate. 2. 04 A mixture of 3-bromo-5-chlorosalicylaldehyde (1.9 g, 4.2 mmol), potassium carbonate (0.58 g, 4.2 mmol), and ethyl 4,4,4-trifluorocrotonate (0.79 g, 4.7 mmol) in N was stirred. , N-dimet ilformamide (5 ml) at 95 ° C for 18 hours. Water (100 ml) was added and the mixture was extracted with ether (3 x 50 ml). The combined organic extracts were washed with sodium hydroxide (10 ml) and water (2 x 50 ml). After being dried on MgSO4 and concentrated, the reaction mixture was filtered through a pad of silica and eluted with ethyl acetate-hexane (1: 4). The eluent was concentrated, and a light yellow solid was crystallized from cold hexane (0.43 g, 26%): mp 101.0-102.2 ° C XH NMR (acetone-dß / 300 MHz) 7.90 (s, 1H), 7.65 ( d, H, J = 2.4 Hz), 7.61 (d, HJ = 2.4 Hz), 6.03 (q, HF, ÍH, J = 6.9 Hz), 4.34 (m, 2H), 1.33 (t, 3H, J = 7.5 Hz). ESHRMS m / z 3 84.9435 (M-H, Calculated 384-9454). Anal. Calculated C? 3H9 BrClF303: C, 40.50; H, 2.35. Verified: C, 40.61; H, 2.40.

Step Preparation of acid-bromo-6-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxyl ico 2.05 Ethyl 8-bromo-6-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylate (0.3 g), ethanol (15 ml), tetrahydrofuran (10 ml), and a sodium hydroxide solution ( 10 ml, 2.5 N) at room temperature for 16 hours. Hydrochloric acid (IN) was added until the mixture was acidic on pH paper. Addition of water (50 ml) caused the formation of a precipitate which was collected by filtration and gave the title compound as a white solid (0.2 g, 72%): mp 227.8-228.9 ° C. X H NMR (acetone-d 6/300 MHz) 7.90 (s, 1 H), 7.65 (dd, 2 H, J = 2.4 and J = 28.8 Hz), 6.00 (q H-F, IH, J = 7.2 Hz). FABHRMS m / z 356.9134 (M + H, Calculated 356.9141). Anal. Calculated C H H5 BrClF303: C, 6.96; H, 1.41. Verified: C, 37.05; H, 1.33.

EXAMPLE 75 6-Formyl-2- (trifluoromethyl) -2H-l-benzopyran-3-sarboxylic acid Step 1. Preparation of ethyl 6-formyl-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate A vial was filled 50 ml round bottom with 5-formylsalicylaldehyde (3.21 g, 21.39 mmol), ethyl 4,4,4-trifluorocrotonate (3.50 ml, 3.96 g, 23.53 mmol), dimethylformamide (15 ml) and potassium carbonate (2.95 g) , 21.39 mmol), and heated at 60 ° C for 12 hours. Additional 4,, 4-trifluorocrotonate of ethyl (3.50 ml, 3.96 g, 23.53 mmol) was added and the reaction was re-heated for 16 hours at 75 ° C. After being cooled to room temperature, the reaction was divided between H20 and diethyl ether. The organic phase was washed with a solution of saturated NaHCO3, a solution of KHSO4 (0.25 M), and brine, and treated with decolorizing carbon (and heated gently). The resulting black suspension was dried in MgSO4. It was filtered under vacuum with diatomaceous earth, and concentrated in vacuo, to give an orange crystalline mass. This material was recrystallized from hot hexanes to give the ester (1.51 g, 24%) as orange crystals: mp 84.3-86.2 ° C. XHRMN (acetone-d6 / 300 MHz) 9.96 (s, ÍH), 8.06 (d, ÍH; J = 2Hz), 8.02 (s, ÍH), 7.99 (dd, ÍH, J = 8.5 2.0 Hz), 7.24 (d , 1H, J = 8.5 Hz), 5.99 (q, 1H, J = 7.1 Hz), 4.43-4.25 (m, 2H), 1.34 (t, 3H, J = 7.3 Hz). FABLRMS m / z 301 Z-07 (M + H). EIHRMS m / z 300.0605 (M +, Calculated 300.0609) Anal. calculated C? 4 HnF304: C, 56.01; H; 3.69 Verified: C, 56.11; H, 3.73.

Step Preparation of 6-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid The ester (Step 1) was converted to the acid by a method similar to that described in Example 1, Step 2: mp 211.3-215.7 ° C. 1H NMR (acetone-d 6/300 MHz) 9.97 (s, 1 H), 8.07 (d, ÍH, J = 2.0 Hz), 8.03 (s, 1H), 8. 00 (dd, ÍH, J = 8.3, 2.0 Hz), 7.25 (d, ÍH, J = 8.3 Hz), . 98 (q, ÍH, J = 6.9 Hz). FABLRMS m / z 273 (M + H).

EIHRMS m / z 272.0266 (M +, Calculated 272.0296). Anal. calculated C? 2H7F304: C, 52.95; H, 2.59. Verified: C, 52.62; H, 2.58.

EXAMPLE 76 6-Chloro-8-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2.08 Step 1. Preparation of 4-chloro-2,6-bis (hydroxymethyl) phenol. Potassium hydroxide was dissolved (84.82 g, • 1.30 mol) in H20 (200 ml) in a two-liter 5-round 3-nozzle flask fitted with a thermocouple, a mechanical beater, and a stopper. While mixing, 4-chlorophenol (128.56 g, 1.0 mol) was added with a cooling (ice bath), the temperature rose to 26 ° C. Formalin was added (230 ml of 37% aqueous solution, 2.83 mol) per • portions to keep the temperature below ° C. The reaction was heated at 35 ° C for 48 hours. Aqueous acetic acid was added to this solution (80.0 ml, 84.1 g, 1.40 mol in 800 ml H20) and in Consequently, the solution became cloudy. Vacuum filtration of the suspension gave a tan solid color. The solid was stirred in acetone (100 ml) and the insoluble product was collected in vacuo. • by vacuum filtration. The solution was diluted with hexane to give several diol groups as fine as needles (35.0 g, 19%) mp 160.6-163.3 ° C. XH NMR (acetone-NaOD, D2O / 300 MHz) 6.69 (s, 2H), 4.48 (s, 4H), 7.88 (d, 1H, J = 2.6 Hz), 7.75 (d, ÍH, J = 2.6 Hz), 6.08 (q, ÍH, J = 6.9 Hz). ESLRMS m / z 206 (M + NHA) • ESHRMS m / z 187.0131 (M-H, Calculated 187.0162).

Step 2. Preparation of 5-chloro-3-formyl-salicylaldehyde. To a stirred solution of diol (Step 1) (33.0 g, 0.18 mol) in chloroform (1.5 1) in a 2 1 round bottom flask was added manganese dioxide (139 g, 1.60 mol), and the suspension was heated resulting in reflux gently for 10 hours. The reaction was allowed to cool to room temperature, filtered with diatomaceous earth, concentrated in vacuo, preabsorbed in silica gel and purified by flash chromatography (hexane / ethyl acetate) to give the dialdehyde as a mustard-colored powder. (22.42 g, 67%): mp 120.7-122.8 ° C. This solid had a purity suitable for use in the next step without further purification.

Step Preparation of ethyl 6-chloro-8-formyl-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. A stirred solution of dialdehyde (Step 2) (1.13 g, 6.14 mmol) dimethyl sulfoxide (6 ml), ethyl 4, 4, 4 = - tri-fluorocrotonate (1.37 ml, 1.55 g, 9.21 mmol) and triethylamine (1.17 ml) was heated. , 1.24 g, 12.28 mmol) in a round bottom flask fitted with a condenser at 80 ° C for 8 h. When refixing at room temperature, the • reaction with diethyl ether (100 ml) and the resulting mixture was washed with a solution of aqueous sodium bicarbonate (3 x 75 ml), a solution of 1 N HCl (3 x 70 ml), and brine (1 x 75 ml). ); it was dried in MgSO, filtered and concentrated in vacuo to give a tan colored powder. This powder was added to hot hexane-ethyl acetate, and filtered to remove the insoluble material. After cooling the filtrate, crystallization followed by vacuum filtration gave the expected ester in the form of tan crystals (0.726 g, 35%): mp 118-1-119.7 ° C.

This material had an appropriate purity to be used without further purification.

Step 4. Preparation of 6-chloro-8-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid To a stirred solution of the ester (Step 3) (0.284 g, 0.849 mmol) in THF: EtOH:. H20 (7: 2: 1.5 ml) was added a solution of aqueous NaOH (0.41 ml of 2. 5 M, 1.02 mmol). After being stirred for 40 hours, the reaction was partially concentrated under vacuum to remove the organic solvents, then 2.11 it was diluted with H20, washed with diethyl ether, dewd with nitrogen to remove traces of diethyl ether, and acidified with concentrated HCl, to give a suspension. Vacuum filtration of the suspension gave the title compound as a light yellow powder (0.160 g, 23%). mp 243.3-252.4 ° C. aH NMR (acetone-of / 300 MHz) 10.39 (s, 1H), 7.98 (s, ÍH), 7.88 (d, 1H, J = 2.6 Hz), 7.75 (d, ÍH, J = 2.6 Hz), 6.08 ( q, ÍH, J = 6.9 Hz). FABLRMS m / z 307 (M + H). ESHRMS m / z 304.9839 (M-H, Calculated 304.9828). Anal, calculated for C? 2H6CI? F304: C, 47.01; H, 1.97. Verified: C, 46.64; H, 1.86.

EXAMPLE 77 6-Bromo-7- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. 7- (1,1-Dimethylethyl-2- (trifluoromethyl) -2H- acid was stirred. 1-benzopy-3-carboxylic acid (Example 12) (0.6 g, 2 mmol), chloroform (50 ml), iron filings (0.01 g, 0.2 mmol) and bromide (0.48 g, 3.00 mmol) at reflux for 16 h. h) 2J.2 was left Cool the mixture and wash with brine (2 x 50 ml). After being dried in MgSO4, the mixture was filtered and concentrated in vacuo, and the residue was crystallized from ether-hexane to give the title compound as a white solid (0.5 g, 66%): mp 198.6- 199.9 ° C. 1 H NMR (acetone-d 6/300 MHz), 7.85 (s, 1 H), 7.72 (s, H H), 7.13 (s, 1 H), 5.83 (q, H H, J = 7.2 Hz), 1.5 (s, 9 H) . Anal. calculated d5H? 403F3Br: C, 47.52; H, 3.72; N, 21.07. Verified: C, 47.42; H, 3.68; N, 21.15.

EXAMPLE 78 ,6-Dichloro-2- (trifluoromethyl) -2H-l-benzopyran-3-sarboxyliao acid. 5,6-Dichlorosalicylaldehyde was prepared according to the procedure described in Cragoe, E.J.; Schultz, E.M., US Pat. No. 3,794,734, 1974. This salicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 211 -5-213.5 ° C. E N3IR (acetone-d6 / 300 MHz) 8.09 (s, 1H), 7.63 (d, ÍH, J = 8.9 Hz), 7.12 (d, ÍH, J = 8.9 Hz), 5.94 (q, ÍH, J = 7.0 Hz). ESLRMS m / z 311 (M-H) EIHRMS m / z 311.9583 (M +, Calculated for 311.9568) Anal, calculated for C ?? H5Cl2F3? 3: C, 42.20; H, 1.61 Verified: C, 42.33; H, 1.67.

EXAMPLE 79 6-Cyano-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid Step 1. Preparation of 6- [(hydroxyimino) methyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate of ethyl. A 50 ml round bottom flask was filled with hydroxylamine HCl (0.255 g, 3.67 mmol), ethyl 6-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate (Example 75, Step 1) (1.00 g, 3.34 mmol), sodium acetate (0.301 g, 3.67 mmol), ethanol (10 ml), and H20 (2 ml). The reaction was stirred at room temperature for 18 hours, and then diluted with H20 and diethyl ether. The layers were separated and the organic phase was washed with H20 and brine, dried over MgSO4, filtered and concentrated in vacuo to give an orange semicrystalline mass. Recrystallization of this solid from hot ethyl acetate and isooctane gave the oxime (0.578 g, 55%): mp 113.0-116.2 ° C. E NMR (acetone- of / 300 MHz) 10.46 (s, ca.I exch.) 8.11 (s, 2H), 7.92 (s, ÍH), 7.72 (d, ÍH, J = 2Hz)), 7.68 (dd, ÍH, J = 8.5, 2.0 Hz), 7.07 (d, 1H, J = 8.5 Hz), 5.89 (q, ÍH, J = 7.1 Hz), 4.43-422 (m, 2H), 1.34 9t, 3H, J = 7.3 Hz). FABLRMS m / z 316 (M + H). EIHRMS m / z 315.0719 (M +, Calculated 315.0733). Anal, calculated C? H? 2F3N? 04: C, 53.34; H, 3.84; N, 4.44. Verified: C, 53.85; H, 3.90; N, 4.19. • Step 2. Preparation of ethyl 6-cyano-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. To a stirred solution of oxime (Step 1) (0.264 g, 0.840 mmol) in dioxane (4.5 ml) in a 25 ml flask in the form of pra was added trifluoroacetic anhydride (0.130 ml, 0.194 g 0.924 mmol) and triethylamine (0.140 ml, 0.102 g, 1,008 mmol).

• The reaction was stirred at room temperature for 12 hours and then heated to 85 ° C for 4 hours. After being cooled to room temperature, aqueous HCl (50 ml, 1NHC1) was added, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with aqueous HCl cooled (1 N), and brine, and dried over Na 2 SO 4, filtered and concentrated in vacuo to give a pale yellow oil. This oil was again subjected to similar reaction conditions. After dissolving • the yellow oil in dioxane (4.5 ml), then 5 trifluoroacetic anhydride (0.130 ml, 0.194 g, 0.924 mmol) and triethylamine (0.140 ml, 0.102 g, 1,008 mmol) were added. After stirring for 3 hours at room temperature, more triethylamine (0.50 ml, 0.36 g, 3.6 mmol) was added and heated at 85 ° C for 3 hours. hours. After cooling to room temperature, • added HCl (50 ml, 1 N HCl) and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was washed with cooled aqueous HCl (1 N), and brine, and dried over Na 2 SO, filtered and concentrated vacuum to give a pale yellow oil. The addition of hexanes induced a crystallization, followed by vacuum filtration, gave the title compound (0.101 g, 40%) as a yellow powder: • mp 101.6-106.1 ° C. aH NMR (acetone-d6 / 300 MHz) 7.97 (d, ÍH, J = 2.2 Hz), 7.95 (s, ÍH), 7.82 (dd, 1H, J = 8.5 2.0 Hz), 7.24 (d, 1H, J = 8.5 Hz), 6.01 (q, ÍH, J = 7.1 Hz), 4.38-4.24 (m, 2H), 1.34 (t, 3H, J = 7.3 Hz). FABLRMS m / z 298 (M + H). EIHRMS m / z 297.0575 (M +, Calculated 297.0613). Step Preparation of 6-cyano-2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid. To a stirred solution of the ester (Step 2) (0.077 g, 0.259 mmol) in THF-EtOH-H20 (7: 2: 1, 2 ml) in a 5 ml flask in the form of a pear, aqueous NaOH (solution 0.13 ml, 2.5 N) in one portion. After stirring for 6 hours at room temperature, the solution was partially concentrated in vacuo to remove the majority of THF and EtOH. The resulting solution was diluted with H20 and washed with diethyl ether. The resulting aqueous phase was sprayed with nitrogen to remove traces of diethyl ether and acidified with concentrated HCl to give a sticky suspension. The suspension was extracted with diethyl ether and the ether was dried in MgSO 4, filtered and concentrated in vacuo, and gave a pale yellow oil.

This oil was crystallized from methylene chloride-hexanes to give the title compound (0.041 g, 59%) in the form of a tan colored powder: mp 185.1-186.1 ° C. H NMR (acetone-d6 / 300 MHz) 7.99-7.94 (m, 2H), 7.83 (dd, 1H, J = 8.5, 2.0 Hz), 7.25 (d, 1H, J = 8.5 Hz) 5.99 (q, 1H, J = 7.0 Hz). FABLRMS m / z 270 (M + H). EIHRMS m / z 269.0316. (M +, Calculated 269. JX3 0 0).

EXAMPLE 80 6-Hydroxymethyl-2- (tri-loromethyl) -2H-1-benzopyran-3-sarboxylic acid To a cooled (ice bath), stirred solution of 6-formyl-2- (trifluoromethyl) -2H- 1- benzopyran-3-carboxylic acid (Example 75, Step 2) (0.133 g, 0.489 mmol) in THF (1 ml) and ethanol (1 ml) in a 10 ml round bottom flask was added NaBH4 (0.020 g, 0.528 mmol ) in two portions. The reaction was allowed to warm to room temperature and more NaBH 4 (0.050 g, 1322 mmol) was added. The total reaction time was 3 hours. The reaction was treated with aqueous HCl (1 N solution) and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a foam. This crude product was purified by flash chromatography (silica gel 60, eluent 1: 1, hexane-ethyl acetate with 2% acetic acid). The product collected from chromatography was recrystallized from hexanes and ethyl acetate, and collected by vacuum filtration to give the title compound 2r18. (0.042 g, 31%) in the form of a very pale yellow powder: mp 177.5-180.8 ° C. X H NMR (acetone-d 6/300 MHz) 7.89 (s, ÍH), 7.44 (s, ÍH), 7.41 (d, ÍH, J = 8.3 Hz), • 6.99 (d, ÍH, J "8.3 Hz), 5.80 (q, 1H, J = 7.3 Hz), 4.59 (s, 2H), FABLRMS m / z 275 (M + H), EIHRMS m / z 274.0417 (M + , calculated 274.0453) Anal calculated for C? 2H9F304: C, 52.57; H, 3.31 Verified: C, 52.43; H, 3.34.

EXAMPLE 81 • 6- (Difluoromethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid Step A. Preparation of 6- (difluoromethyl) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylate of ethyl. Ethyl 6-formyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylate (Example 75, Step 1) (1672 g, 5,569 mmol) in methylene chloride was added. (1.5 mL) to methylene chloride (1.5 mL) and diethylaminosulfur trifluoride (DAST) (0.74 mL, 0.898 g, 5.569 mmol) for 0.07 hours with a syringe. After stirring for 20 hours, the reaction was poured into HCl 2 ?. 9 aqueous (2.0 N) and the mixture was extracted with diethyl ether. The ether phase was washed with dilute aqueous HCl (2.0 N), a saturated NaHCO3 solution, and brine, and dried over MgSO4, filtered and concentrated in vacuo to give a clear colorless oil. This oil was purified by flash chromatography (silica gel 60, eluting (5: 1; Hexanes: ethyl acetate) to give ethyl 6-difluoromethyl-2-trifluoromethyl-1-2H-1-benzopy an-3-carboxylate (0.96 g, 54%) as an oil that solidified upon standing The product was of sufficient purity to be used in the next step without further purification: XHRMN (acetone-dß / 300 MHz) 7.97 (s, 1H), 7.74 (s, ÍH) *, 7.65 (d, ÍH, J = 8.5 Hz), 7.18 (d, 1H, J = 8.5 Hz), 6.90 (t, ÍH, J = 56.0Hz), 5.94 (q, ÍH, J = 7.0 Hz ), 4.40-4.25 (m, 2H), 1.34 (t, 3H, J = 7.0 Hz).

Step 2: Preparation of 6- (difluoromethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. Aqueous NaOH (solution 1.31 ml, 3. 277 mmol, 2.5 M) in one portion to the ester (Step 1) (0.880 g, 2.731 mmol) in THF: EtOH: H20 (7: 2: 1, 10 mL). The resulting solution was stirred for 60 hours. The reaction mixture was partially concentrated in vacuo to remove the organic solvents and diluted with H20. The resulting aqueous solution was washed with diethyl ether, sprayed with nitrogen to remove debris, and acidified with concentrated HCl. The resulting oily suspension was extracted with diethyl ether. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo to give the title compound (= .483 g, 60%) as oil which solidified as a white crystalline mass: mp 134.7-136.2 ° C. NMR (acetone-dß / 300 MHz) 7.97 (s, 1H), 7.73 (s, ÍH), 7.67 (dd, ÍH, J = 8.5, 1.0 Hz), 7.17 (d, ÍH, J = 8.5 Hz), 6.89 (t, ÍH, J = 56.2 Hz), 5.90 (q, ÍH, J = 7.1 Hz). FAB-ESLRMS m / z 293 (M-H). EIHRMS m / z 293.0235 (M-H, Calculated 293.0237). Anal. calculated for C? 2 H7F503: C, 49.00; H, 2.40. Verified: C, 48.78; H, 2.21.

EXAMPLE 82 Acid 2, 6-bis (tri luoromethyl) -2H-l-benzopyran-3-sarboxylase Step 1: Preparation of Ethyl 2, -bis (trifluoromethyl) -4-oxo-4H-l-benzopyran-3-carboxylate. To a stirred solution of ethyl 4,4,4- • trifluoroacetoacetate (3.22 ml, 4.06 g, 22.07 mmol) in toluene (100 ml) was added portionwise sodium hydride (0.971 g, 60% dispersion reagent). of oil, 22.07 mmol), which caused the evolution of the gas. After the evolution of the gas was finished, chloride was added 2-Fluoro-5- (trifluoromethyl) benzoyl (5.00 g, 22.07 • mmol). The reaction was stirred at room temperature for 24 hours, then heated at 105 ° C for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether, and the The resulting solution was washed with H20 and brine, dried over MgSO4, filtered and concentrated in vacuo to give a slightly sticky white solid. This solid was triturated with hexanes and gave the expected ester (3.05 g, 39%) as a white powder: mp 116-120 ° C LH NMR (CDCl 3/300 MHz) 8.52 (d, 2H, J = 1.6 Hz), 8.03 (dd, ÍH, J = 8.9, 2.2 Hz), 7.71 (d, ÍH, J = 8.9 Hz), 4.48 (q, 2H, J = 7.3 Hz), 1.39 (t, 3H, J = 7.3 Hz). FABLRMS m / z 355 (M + H). Anal. calculated for C? 4H8F604: C, 47.45; H, 2.28. 25 Verified: C, 47.59; H, 2.43.

Step 2: Preparation of ethyl 2,6-bis (trifluoromethyl) -4-oxo-dihydrobenzopyran-3-carboxylate A 250 ml bottle was filled in the bottom F round 2,6-bis (trifluoromethyl) -benzopyran-4-on-3-carboxylic acid ethyl ester (Step 1) (2.307 g, 6.513 mmol) and THF (20 mL), to give a clear yellow solution. Ethanol (20 ml) was added, and the reaction was cooled in a salt and ice bath. While the reaction temperature was maintained below 9 ° C, F 10 added NaBH (0.246 g, 6.513 mmol) in two portions and the mixture was stirred for 1 h. The crude reaction mixture was poured into a vigorously stirred mixture of ice (200 ml) and concentrated HCl (12 N, 5 ml) to give a precipitate. He vacuum filtration of the resulting suspension gave the expected ketoester (2,204 g, 87%) as a pale pink powder of sufficient purity to be used in the next step without further purification: mp 71.8-76.9 ° C. aH NMR (acetone-d6 / 300 MHz) 12.71 (br s, ÍH exch), 8.01 (d, 1H, J = 2.0 Hz) 8.01 (d, ÍH, J = 2.0 Hz), 7.88 (dd, ÍH, J = 8.7, 1.8 Hz), 7.31 (d, ÍH, J = 8.7 Hz), 5.98 (q, ÍH, J = 6.6 Hz), 4.51-4.28 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz). FABLRMS m / z 355 (M-H). ESHRMS m / z 355.0394 (M-H, Calculated 355.0405). Anal. calculated for: C, 47.21; H, 2.83 Verified: C, 47.31; H, 2.97.

Step 3: Preparation of 2, 6-bis (trifluoromethyl) -4-trifluoromethanesulfonate-2H-1-benzopyran-3-ethylcarboxylate A 50 ml three-well Morton flask filled with a funnel and 2 additional stoppers was filled. with 2,6-di-tert-butylpyridine (1576 g, 1.50 mmol), methylene chloride (12 ml), then, with a syringe, trifluoromethanesulfonic anhydride (1.08 ml, 1.80 g, 1.25 mmol) was added. To this solution was added dropwise a solution of the ketoester (Step 2) (1822 g, 5.115 mmol) in methylene chloride (10 mL) for 0.33 h, and the reaction was stirred for 48 h. The resulting bone-colored suspension was transferred to a 100 ml round bottom flask and concentrated in vacuo. The residue was suspended in diethyl ether (50 ml) and filtered under vacuum to remove the salts. The filtrate was diluted with diethyl ether (50 ml) and washed with an ice-cold HCl solution (2 N), brine, and dried over Na 2 CO 3, filtered and concentrated in vacuo to give the expected triflate (1.64 g, 66%). ) in the form of a tan-colored powder of color 2:24 enough purity to be used in the next step without further purification.

Step 4. Preparation of ethyl 2,6-bis (trifluoromethyl) -2H-1-benzopyran-3-carboxylate A pear-shaped 25 ml bottle was filled with LiCl (0.136 g, 3.219 mmol) and fixed to a vacuum pipe and heated with a heat ejector that removed the surface water. The flask was allowed to cool to room temperature, and tetrakis was added (triphenylphosphine) palladium (0) (0.124 g, 0.107 mmol) and THF (2 ml). A reflux condenser was attached to the flask and the apparatus was purged with nitrogen. A solution of triflate (Step 3) (0.524 g, 1.073 mmol) in THF (2 ml) and tri-n-butyl tin hydride (0.32 ml, 0.34 g, 1.18 mmol) was added sequentially with a syringe. The light orange solution was heated to 50 ° C, and stirred for 1 h, at 60 ° C for one hour, and at 65 ° C for one hour. The reaction was allowed to cool to room temperature and poured into 2 N HCl, stirred, and extracted with hexanes. The hexane phase was dried over MgSO4, filtered and concentrated to give a light brown oil. The oil was dissolved in hexane and lav with an aqueous solution of ammonium fluoride. The resulting hexane layer was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow oily solid that solidified as a • scales (0.443 g). This solid was purified by flash silica chromatography (eluent: hexanes-methylene chloride, 14: 1), to give ethyl 2,6-di-trifluoromethyl-2H-1-benzopyran-3-carboxylate (0.069 g, 19%) as a white crystalline solid of sufficient purity to proceed with the next step. 10 • Step 5: Preparation of 2,6-bis (trifluoromethyl) -2H-1-ben-opyran-3-carboxylic acid. To a stirred solution of the ester (Step 4) (0.065 g, 0.191 mmol) in THF-EtOH-H20 (7: 2: 1, 1 ml) A solution of NaOH (0.084 ml, 0.210 mmol) was added in one portion at room temperature and allowed to stir overnight. The reaction was partially concentrated under vacuum and gave a clear colored syrup • pale yellow. The syrup was diluted with water (5 ml) and brine (1 ml) and washing with diethyl ether (3 x 5 ml). The resulting aqueous phase is sprayed with nitrogen to remove traces of ether. While mixing, concentrated HCl was added to the aqueous phase, which caused the formation of a white precipitate very thin. This suspension was extracted with diethyl 22. 6 ether and dried in Na S0, filtered and concentrated by slow evaporation at atmospheric pressure. The resulting product was recrystallized from hexanes and ethyl acetate, to give the title compound (0.038 g, 64%) as a fine tan colored powder: mp 143.5-145.2 ° C. X H NMR (acetone-d 6/300 MHz) 11.97-11.67 (br s, ÍH), 8.03 (s, ÍH), 7.92 (s, ÍH), 7.77 (d, 1H, J = 8.5 Hz), 7.26 (d, 1H, J = 8.7 Hz), 5.96 (q, 1H, J = 7.0 Hz). FABLRMS m / z 311 (M-H). ESHRMS m / z 311.0107 (M-H, Calculated 311.0143).

EXAMPLE 83 , 6, 7-Trichloro-2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid. 3, 4, 5-Trichlorophenol was converted to 3-ethoxysalicylaldehyde by a procedure similar to that described in Example 11, Step 1. 4,5-d-Trichlorosalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 236.2-239.3 ° C. 2H NMR (acetone-d 6/300 MHz) 8.05 (s, ÍH), 7.40 (s, 1H), 5.99 (q, ÍH, J = 7.0 Hz). ESLRMS m / z 345 (M-H). ESHRMS m / z 344.9113 (M-H, Calculated 344.9100). Anal, calculated for CnH4Cl3F30 • + 0.89 weight% H20: C, 37.68; H, 1.25; Cl, 30.33. Verified: C, 37.48; H, 1.25; Cl, 30.33.

EXAMPLE 84 Acid 6, 7, 8-Trichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. 2, 3, 4-Trichlorophenol was converted to 3-ethoxysalicylaldehyde by a procedure similar to that described in Example 11, Step 1. It became 3, 4, 5-trichlorosalicylaldehyde in the compound of ^^ P "title by a procedure similar to that described in Example 1: mp 222.0-225.3 ° C. aH NMR (acetone-d6 / 300 MHz) 7.94 (s, ÍH), 7.78 (s, ÍH), 6.07 (q , HH, J = 7.0 Hz) ESLRMS m / z 345 (M-H) EIHRMS m / z 344.9117 (MH, Calculated 344.9100). Anal, calculated for C ??H4C ?3F3 ?3 + 1.56 weight% H20: C, 37.43; H, 1.32; Cl, 30.13. Verified: C, 37.79; H, 0.93; Cl, 29.55. 2:28 EXAMPLE 85 7-Eti1-2-trifluoromethyl-2H-1-benzopy an -3-carboxylic acid 3-Ethylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 167.0-168.6 ° C. 2 H NMR (CDCl 3/300 MHz) 7.84 (s, ÍH), 7.15 (d, ÍH, J = 7.5 Hz), 6.84 (m, 2H), 5.66 (q, ÍH, J = 6.8 Hz), 2.63 (q, 2H, J = 7.7 Hz, J = 7.7 Hz), 1.24 (t, 3H, J = 7.7 Hz). Anal. Calculated for C 13 H 11 F 3 O 3: C, 57.36; H, 4.07. Verified: c, 57.25; H, 4.10J EXAMPLE 86 6- (Methylsulfinyl) -2- (tri luoromethyl) -2H-1- benzopyran-3-sarboxyl acid Step 1 Preparation of 6- (methylsul fonyl) -2- (trifluoromethyl) -2H-l-benzopyral-3 ethyl carboxylate Cool 6- (methyl thio) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid ethyl ester (Example 2, Step 2) (1014 g, 3.18 mmol) in methylene chloride at 2 = 29 50 ° C (acetone on dry ice). While stirring, meta-chloroperbenzoic acid (0.91 g, 60% reactive, 3.18 mmol) was added, and the reaction took place for 3 hours. An aqueous NaHS03 solution (40 ml 0.25 M) was poured into the reaction. More methylene chloride was added and the layers were mixed and then separated. The organic phase was washed with an aqueous NaHS03 solution, a saturated NaHCO3 solution, and brine, and dried over MgSO4, filtered and concentrated, to give an oil. The oil was diluted with isooctane (2 ml) and concentrated, and gave an oil which crystallized upon standing. Hexanes were added, the solution was heated, and methylene chloride was added until a partial dissolution took place. After cooling and standing overnight, the suspension was filtered in vacuo to give the ethyl ester substituted by a sulfoxide (0.753 g, 71%) as white needles: mp 92.2-98.4 ° C. This ester had a sufficient purity to be used without further purification.

Step 2. Preparation of 6- (Methylsulfinyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2:30 To a stirred solution of the ester (Step 1) (0.683 g, 2.043 mmol) in THF: EtOH: H20 (7: 2: 1, 4 mL) was added an aqueous NaOH solution (0.98 mL of 2.5 M, 2.45 mmol) . After stirring for 12 hours, the reaction was partially concentrated in vacuo to remove the organic solvents. The residue was diluted with H20, washed with diethyl ether, flushed with nitrogen to remove the residues of the diethyl ether, and acidified with concentrated HCl, to give an oily suspension. The suspension was extracted with diethyl ether, and the resulting organic phase was dried over MgSO4, filtered, and diluted with hexanes. Upon being concentrated in vacuo, the title acid was obtained in the form of a white sticky powder (0.425 g, 68%): mp 148.3-151.0 ° C. 2E NMR (acetone-d6 / 300 MHz), 7.99 (s, ÍH), 7.82 (s, 1H), 7.78-7.68 (m, 1H), 7.24 (d, ÍH, J = 8. 3 Hz), 5.92 (q, ÍH, J = 7.1 Hz), 2.73 (s, 3H). FABLRMS m / z 307 (M + H). ESHRMS m / z 305. 0098 (M-H, Calculated 305. 0095).

Anal Calculated for C? 2HsF304S? : C, 47 06; H, 2 96; S, 10. 47. Verified: C, 46. 69; H, 2 86; S, 10.45. 231 , 8-Dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylic acid. 2,5-Dichlorophenol in 3,6-dichlorosalicylaldehyde was converted by a procedure similar to that described in Example 2, Step 1. converted 3, 6-dichlorosalicylaldehyde to the title compound by a procedure similar to that described in Example 11, Steps 2 and 3: mp 205.7-207.1 ° C. X H NMR (acetone-d 6/300 MHz) 8.02 (s, 1 H) / .53 (d, 1 H, J = 8.7 Hz), 7.22 (d, ÍH, J = 8.7 Hz), 6.04 (q, 1 H, J = 7.1 Hz). FABLRMS m / z 311 (M-H). ESHRMS m / z 310.9506 (M-H, Calculated 310.9490). Anal. Calculated for CnH5C? 2F303 + 0.63 weight% H20: C, 41.94; H, 1.67. Verified: C, 41.54; H, 1.27.

EXAMPLE 88 6- (Penta luoroethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-aarboxylyl acid. Step 1 Preparation of ethyl 6- (pentafluoroethyl) -2 - (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. Potassium pentafluoropropionate (0.476 g, 2.35 mmol) was dissolved in toluene (6 ml) and DMF (6 ml). 2. -32 The vessel was provided with a distillation nozzle, and Cul (0.471 g, 2.474 mmol) was added while stirring. The reaction was heated to 120 ° C and the toluene was removed by distillation. Ethyl 6-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate (Example 72, Step 3) (0.469 g, 1178 mmol) was added, and the reaction was heated at 150 ° C for 2 hours . The reaction was allowed to cool to room temperature and separated into diethyl ether and H20. The organic phase was dried in MgSO4, filtered and concentrated in vacuum. The resulting residue was purified by flash chromatography (silica gel 60, eluent: hexanes-ethyl acetate, 8: 1), and upon concentration of the solution, the expected ester (0.096 g, 21%) was formed as a solid, colored mass. Havana of sufficient purity to be used without further purification: XH NMR (acetone-d6 / 300 MHz) 8.04 (s, ÍH), 7.91 (d, ÍH, J = 2.2 Hz), 7.74 (dd, ÍH, J = 8.7, 2.2 Hz), 6.00 (q, ÍH J = 7.1 Hz), 4.42-4.24 (m, 2H), 1.34 (t, 3H, J = 7.3 Hz).

Step 2. Preparation of 6- (Pentafluoroethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. To a stirred solution of the ethyl ester (Step 1) (0.090 g, 0.231 mmol) in THF: EtOH: H20 (7: 2: 1) (4 mL) was added a solution of aqueous NaOH (0.11 mL, 2.5 M). After being stirred for 16 hours, the reaction was partially concentrated in vacuo to remove organic solvents, and then diluted with H20 and washed with diethyl ether. The resulting aqueous phase was acidified with concentrated HCl, extracted with diethyl ether, dried on MgSO 4, filtered and concentrated in vacuo to give an oil. This oil was purified by flash chromatography (silica, hexanes-ethyl acetate, 3: 1 with 5% acetic acid). This procedure gave the title compound (0.020 g, 24%) as a white powder: mp 162.3-164.7 ° C. X H NMR (acetone-ds / 100 MHz) 8.05 (s, 1 H), 7.90 (s, H), 7.74 (d, 1 H, J = 8.7 Hz), 7.29 (d, 1 H, J = 8.7 Hz), 5.97 ( q, ÍH, J = 6.8 Hz). FABLRMS m / z 361 (M-H). ESHRMS m / z 361.011 (M-H, Calculated 361.0094).

EXAMPLE 89: 6- (1,1-Dimethylethyl) -2- (tri-loromethyl) -2H-1-benzopyran-3-sarboxylic acid. 4-tert-Butylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 170.6-173.2 ° C LH NMR (acetone-ds / 300 MHz) 7.89 (s, 1H), 7.5-7.4 (m, 2H), 6.93 (d, 1H, J = 8.4 Hz), 5.76 (q, ÍH, J = 7.2 Hz), 1.3 (s, 9H). Anal. Calculated for dsHisOjF ,. : C, 60.00; H, 5.04. Verified: C, 59.93; H, 5.12.

EXAMPLE 90 - (Hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-pyrano [2,3-s] pyridine-3-sarboxylyl acid. 3-Hydroxylmethyl-5-methyl-4-ylpyridine was converted to the title compound by a procedure similar to that described in Example 1: mp 76.1-80.1 ° C. 2 H NMR (acetone-d 6/300 MHz) 8.14 (s, 2H), 5.93 (q, 1H, J = 7.2 Hz), 1.3 (s, 9H), 5.30 (br s, HI), 4.79 (br s, HI) ), 2.41 (s, 3H). ESHRMS m / z 288.0485 (M + H, Calculated 288.0483).

EXAMPLE 91: "ACC CF," 2 ^ 5 2- (Tri-luomomethyl) -6- [(tri-loromethyl) thio] -2H-l = benzopyran = -3'-carboxylic acid. 4- (Trifluoromethoxy) phenol was converted into 5- (trifluoromethoxy) salicylaldehyde by a procedure similar to that described in Example 2, Step 1. 5- (Trifluoromethoxy) salicylaldehyde was converted to the title compound by a procedure similar to that described in Example 11, Steps 2 and 3: mp 139.1- 143.2 ° C. 1 H NMR (acetone-d 6/300 MHz) 7.95 (s, 1 H), 7.88 (d, 2H, J = 2.4 Hz), 7.71-7.75 (m, ÍH), 6.93 (d, ÍH, J = 8.7 Hz), 5.91 (q, 1H, J = 6.9 Hz). Anal. Calculated for C1 H6? 3F3S: C, 41.87; H, 1.76. Verified: C, 41.94; H, 1.84.

E JEMPLO 92 ^ 6- (Trifluoromethyl) -6H-1r, 3-dioxolo [4,5- g] [l] benzopy-ran-7-carboxylyl acid. 4- Tert-butylphenol was converted to the title compound by a procedure similar to that described. in Example 2: mp 245.8-247.8 ° C. HRMN (acetone-d6 / 300 MHz) 7.77 (s, ÍH); 6.95 (s, 1H), 6.12 2:36 ("s, 1H), 6.05 (d, 2H, J = 0.90 Hz), 5.91 (q, 1H, J = 7.2 Hz), Anal, calculated for C? 2H, ObF3: C, 50.01, H, 2.45. they obtained C, 50.02, H, 2.50.

EXAMPLE 93 8-Ethoxy-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid The 2-ethoxyphenol was converted to 3-ethoxysalylaldehyde by a procedure similar to that described in Example 11, Step 1. The 3 = - Etoxysalicylaldehyde was converted into the title compound by a procedure similar to that described in Example 1: p.f. 159.4-160.9 ° C) 1 H NMR (acetone- • d6 / 300 MHz) 7.86 (s, ÍH), 6.97-7.14 (m, 3H), 5.83 (qH- F 1H, J = 7.2 Hz), 4.12 (q, 2H, J = 7.2 Hz), 1.38 (t, 3H, J = 7.2 Hz). FABHRMS m / z 289.0656 (M + H, Calculated 289.0686). Anal. Calculated for C? 3 HnF304: C, 54.17; H, 3.85. C, 54.06; H, 3.83. 2. -37 EXAMPLE 94 D-chloro-2,7-bis (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid The 4-chloro-3- (trifluoromethyl) phenol was converted to the title compound by a • procedure similar to that described in Example 11: p.f. 180.9-182.4 ° C. H NMR (acetone-d6 / 300 MHz) 7.96 (s, 1H), 7.84 (s, ÍH), 7.47 (s, ÍH), 5.96 (q, ÍH, J = 6. 8 Hz), 2.50 (s, 3H). FABLRMS m / z 3 45 (M-H). FABHRMS m / z 344.9767 (M-H, Calculated 344.9753). Anal. Calculated for C12H5C1F603: C, 41.58; H, 1.45; Cl, . 23. Obtained: C, 41.57; H, 1.50; Cl, 10.33. 15 F EXAMPLE 95 oo? CF3- -38 -Methoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 6-methoxysalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 11, Steps 2 and 3: p.f. 204.5-206.7 ° C. 2H NMR (acetone-d6 / 300 MHz) 8.08 (s, ÍH), 7.38 (dd, ÍH, J = 8.5 Hz 8.3 Hz), 6.74 (d, ÍH, J = 8.5 Hz), 6.65 (d, ÍH, J = 8.3 Hz), 5.80 (q, ÍH, J = 7.2 Hz), 3.94 (s, 3H). FABLRMS m / z 273 (M-H). EIHRMS m / z 274.0444 (M +, Calculated 274.0453). Anal. Calculated for C? 2H9F304: C, 52.57; H, 3.31. The following were obtained: C, 52.47; H, 3.34.

EXAMPLE 96 6-Benzoyl-2- (trifluoromethyl) -2H-l-benzopyran-3-sarboxylic acid Step 1. Preparation of ethyl 6-benzoyl-2 ^ j_trifluoromethyl) -2H-l-benzopyran-3-carboxylate 2- ( trifluoromethyl) -2H-1-benzopyran-3 = ethyl carboxylate (Example 10, Step 1) (1.59 g, 5.8 mmol) in 1,2-dichloroethane (3 mL) and added to a suspension at 0 ° C of chloride of aluminum (2.59 g, 19.4 mmol) in 1,2-dichloroethane (3 ml). A solution of benzoyl chloride (1.01 g, 7.2 mmol) in 1,2-dichloroethane (3 ml) was added and the reaction was heated to 80 ° C and stirred for 4 hours. The solution was poured onto 3 N HCl and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCl, saturated with sodium bicarbonate, brine, dried over MgSO, • and concentrated in vacuo- The crude ester was purified by flash chromatography on silica gel (with 1: 9 ethylacetate / hexane as eluent) to give the ester as a white crystalline solid (0.26 g, 12%): p.f. 114.7-116.1 ° C. 1 H NMR (CDCl 3/300 MHz) 7.82 (dd, ÍH, J = 8.5 Hz 2.0 Hz), 7.76 (m, H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, ÍH, J = 8.7 Hz), 5.79 (q, ÍH, J = 6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, • J = 7.2 Hz). Step 2. Preparation of 6-benzoyl-2'-trifluoromethyl 1-2H-1-benzopyran-3-carboxylic acid. The ester from Step 1 (0.24 g, 0.64 mmol) was dissolved in THF (2 ml) and ethanol (2 ml), treated with Sodium hydroxide 2.5 N (1.5 ml, 3.8 mmol), and stirred at room temperature for 4.3 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl HCl to give a solid. The solid was collected by filtration and was recrystallized with ethanol-water to give a white solid (0.14 g, 64%): m.p. 269.8-270.8 ° C. 1H NMR (acetone = d6 / 300 MHz) 8.04 (s, ÍH), 7.99 (d, ÍH, J = 2.0 Hz), 7.88 (dd, 1H, J = 8.4 Hz 2.0 Hz), 7.79 (m, 2H), 7.68 (m, HH), 7.57 (m, HH), 7.23 (d, HH, J = 8.6 Hz), 5.98 (q, HH, J = 7.0 Hz). FABLRMS m / z 347 (M-H). ESHRMS m / z 347.0560 (M-H, Calculated 347.0531). Anal. Calculated for C? BHnF304: C, 62.08; H, 3.18. The following were obtained: C, 61.48; H, 3.22.

EXAMPLE 97 6- (4-Chlorobenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylic acid The 2H-1-benzopyran-3-carboxylic acid was prepared by an analogous procedure to that described in Example 96: p.p. 268.3-269.4 ° C. H NMR (acetone- 2.-41 of / 300 MHz) 8.03 (s, 1H), 7.99 (d, ÍH, J = 2.0 Hz), 7.89 (d, IH, J = 8.5 Hz, 2.0 Hz), 7.81 (d, 2H, J = 8.5 Hz) , 7.62 (d, 2H, J = 8.5 Hz) 7.23 (d, ÍH, J = 8.5 Hz), 5.98 (q, ÍH, J = 7.1 Hz) FABLRMS m / z 381 (MH). ESHRMS m / z 381.0135 (M-H, Calculated 381.0141). Anal. Calculated for C? 8H10CI F304. C, 56.49; H; 2.63; Cl, 9.26. Obtained: C, 56.35; H, 2.66; Cl, 9.34.

EXAMPLE 98 6- (4-Hydroxybenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-l-benzopyran-3-carboxylic acid was prepared analogously to that described in Example 96: p.p. 234.0-239.5 ° C. XH NMR (acetone-d6 / 300 MHz) 8.03 (s, 1H), 7.92 (d, ÍH, J = 2.0 Hz), 7.83 (dd, ÍH, J = 8.5 Hz 2.0 Hz), 7.74 (d, 2H, J = 8.7 Hz), 7.20 (d, ÍH, J = 8.5 Hz) 7.00 (d, ÍH, J = 8.7 Hz), 5.94 (q, ÍH, J = 7.1 Hz) ESHRMS m / z 363.0471 (MH, Calculated 363.0480) . 6-Phenoxy-2- (trifluoromethyl) -2H-l-benzopyran-3-sarboxylyl acid The 4 = phenoxyphenol was converted to 5 = - phenoxysalicylic acid by a procedure similar to that described in Example 2, Step 1. 5- Phenoxysalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 11, Steps 2 and 3: p.f. 184.9-186.4 ° C. 1E NMR (acetone-de / 300 MHz) 7.90 (s, ÍH), 7.39 (m, 2H), 7.20 (d, 1H, J = 2.0 Hz), 7.08 (m, 3H), 7.02 (m, 2H), 5.98 (q, ÍH, J = 7.2 Hz). FABLRMS m / z 335 (M-H). FABHRMS m / z 337.0663 (M + H, Calculated 337.0687). Anal.

Calculated for C? 7HnF304; C, 60.72; H, 3.30. The following were obtained: C, 60.62; H, 3.29.

EXAMPLE 100 8-Aloro-6- (4-Aloro-enoxy) -2-tri-loromethyl) -2H-l = benzopyran = 3 = carboxylic acid Step 1. Preparation of 5-phenoxysalicylaldehyde. Ethylmagnesium bromide (67.5 ml of a 3.0 M solution in diethyl ether, 202.5 mmol) was added to toluene (50 ml). A solution of 4-phenoxyphenol (25.00 g, 134.26 mmol) in diethylether was added. (35 ml) which resulted in gas formation. The reaction was heated to 80 ° C causing the distillation of the diethyl ether. Toluene (300 ml), HMPA (23.4 ml, 24,059 g, 134.26 mmol) was added, and paraformaldehyde (10.07 g, 335.65 mmol) was added and the reaction was heated at 85 ° C for 4 hours. The reaction was cooled to room temperature and acidified with 2N HCl. The resulting layers were separated and the organic phase was collected. The organic phase was washed with brine. The combined aqueous phases were extracted with methylene chloride. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography on silica gel (hexanes-ethyl acetate, 95: 5). Vacuum concentration of the desired fractions gave the salicylaldehyde in Z44 form of pale yellow powder (12.0 g, 42%) of appropriate purity for use in the following steps.

Step 2. Preparation of 3-chloro-5- (4-chlorophenoxy) -salicylaldehyde To a stirred solution of salicylaldehyde (Step 1) (0.981 g, 4.58 mmol) in acetic acid (20 ml) was added chlorine gas by means of a tube while the yellow color of the chlorine persisted.

After stirring for four hours at temperature The reaction was sprinkled with nitrogen and diluted with water (50 ml). The resulting oily suspension was extracted with methylene chloride. The methylene chloride phase was washed with solution of sodium bisulfite, dried over MgSO4, filtered and concentrated in vacuo to give the dichlorinated salicylaldehyde as a yellow oil (0.66 g, 51%), of adequate purity to be used in the steps • following without further purification. Step 3. Preparation of 8-chloro-6- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-ethylcarboxylate. A mixture of dichlorinated salicylaldehyde 25 (Step 2) (0.66 g, 2.3 mmol), triethylamine (0.49 g, 2:45 p.m. 4. 8 mmol), ethyl 4, 4, 4-trifluorocrotonate (0.59 g, 3. 5 mmol) in dimethyl sulfoxide (5 ml) was heated to 85 ° C for 3.5 hours. The reaction was allowed to cool to room temperature and was diluted with ethyl acetate (50 ml). The resulting mixture was washed with NC1 3 N (50), aqueous potassium carbonate solution (10% by weight, 2 X 30 ml), and brine. The organic phase was dried over MgSO < Filtered and concentrated in vacuo, giving a brown oil. This oil was purified by flash chromatography on silica gel (hexanes-ethyl acetate, 9: 1) giving the substituted 2H-l-benzopyran (0.39 g, 39%) of suitable purity for use in the following steps without further purification.

Step Preparation of α-chloro-6- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid. To a solution of the substituted 2H-l-benzopyran ethyl ester (Step 3) (0.37 g, 0.85 mmol) in ethanol-THF (4 mL, 1: 1) was added sodium hydroxide solution (2 mL of 2.5 N, 5 mmol ). After stirring for six hours the mixture was concentrated in vacuo. Acidification of the mixture with 3 N HCl gave a solid which was collected by vacuum filtration. This solid was recrystallized with ethanol-water to give the title compound as yellow crystals (0.134 g., 38%): p.f. 227.8-228.9 ° C. ? E NMR (acetone-d6 / 300 MHz) 7.93 (s, ÍH), 7.42 (d, 2H, J = 8.9 Hz) 7.24 (s, 2H), 7.12 (d, 2H, J = 8.9 Hz), 5.97 ( q, ÍH, J = 7.1 Hz). FABLRMS m / z 403 (M-H). FABHRMS m / z 405.9790 (M-H, Calculated 405.9801). Anal. Calculated for C1, H9C12F204 + 2.33% H20: C, 49.22; H, 2.45. The following were obtained: C, 49.19; H, 2.27.

EXAMPLE 101 2- (Tri-loromethyl-6- [4 - (tri-loromethyl) -xxixy) -2H-1-benzopyran-3-carboxylic acid 4- (4-trifluoromethyl-phenyl) -phenol was converted to 5- (4-trifluoromethyl-phenyl) -salicylaldehyde by a procedure similar to that described in Example 2, Step 1. The 5- (4-trifluoromethylphenyl) -salicylaldehyde was converted to the title compound by a procedure similar to that described in Example 11, Steps 2 and 3: pf 153.5-154.4 ° C. ? E NMR (acetone-d6 / 300 MHz), 7.91 (s, ÍH) 7.71 (d, 2H, J = 2.47 8. 9 Hz), 7.33 (s, 1H, J = 2.8 Hz), 7.15 (m, 4H), 5.86 (q, 1H, J = 7.1 Hz). FABLRMS m / z 403 (M-H). ESHRMS m / z 403.0399 (M-H, Calculated 403.0405). Anal. Calculated • for C? 8H10F6? 4: C, 53.48; H, 2.49. C, 53.52 were obtained. H, 2.55.

EXAMPLE 102 8- (1-Methylethyl) -2-trifluoromethyl-2H-l-benzopy-3-carboxylic acid 4- (4-methoxyphenyl) phenol was converted to the title compound by a procedure similar to that described in Example 2: pf 210.5-211. ° C. XH NMR (acetone-of / 300 MHz), 7.86 (s, ÍH), 7.35 (d, ÍH, J = 7.7 Hz), 7.28 (s, ÍH, J = 7.5 Hz), 7.04 (t, ÍH, J = 7.7 Hz), 5.85 (q, ÍH, J = 7.2 Hz), 3.33 (sept. ÍH, J = 7.1 Hz), 1.25 (d, 6H, J = 7.1 Hz). Anal. Calculated for C1 H13F303: C, 58.74; H, 4.58. We obtained: C, 58.64; H, 4.60. 2. 4 EXAMPLE 103 6-Chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-sarboxylyl acid 8- (1-Methylethyl) -2- (trifluoromethyl) -2H-1-benzopyran- 3 acid was converted -carboxylic acid (Example 6) in the title compound by a procedure similar to that described in Example 9: p.f. 185.4-189.2 ° C. 2E NMR (acetone-d6 / 300 MHz) 7.87 (s, 1H), 7.38 (d, 1H, J = 2.4 Hz), 7.34 (d, 1H, J = 2. 4 Hz), 5.90 (q, ÍH, J = 7.3 Hz), 3.31 (, ÍH), 1.24 (d, 6H, J = 6.8 Hz). Anal. Calculated for C15H14CIF3O3: C, 52.43; H, 3.77; Cl, 11.05. We obtained: C, 52.58; H, 3.79; Cl, 10.96.

EXAMPLE 104 Asido 6- (4-slorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-l-benzopyran-3-WF carboxylic acid was prepared from 6-phenoxy-2 acid (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid (Example 99) as a starting material by a procedure similar to that described in Example 9: p.p. 140.5-142.5 ° C. aH NMR (acetone-d6 / 300 MHz) 7.90 (s, 1H), 7.39 (d, 2H, J = 9.1 Hz), 7.25 (d, 1H, J = 2.6 Hz), 7.01-7.15 (m, 4H), 5.85 (q, 1H, J = 7.2 Hz). FABLRMS m / z 370 (M +). ESHRMS m / z 369.0130 (M-H, Calculated 369.0141). Anal. Calculated for Ci7H10CIF3O4 + 0.96% H20: C, 54.55; H, 2.80. We obtained: C, 54. 38; H, 2.90. 15 EXAMPLE 105 Asido 8-chloro-2- (tri luoromethyl) -6- [4- (trifluoromethyl) -phenoxyJ-2H-1-benzopyran-3-sarboxylyl benzopyran-3-carboxylic acid was prepared using 2- (trifluoromethyl) -6 acid [4- (trifluoromethyl) -phenoxy-2H-1-benzopyran-3-carboxylic acid (Example 101) as a starting material, by a procedure similar to that described in Example 100: mp. 223.7- • 226.0 ° C. XH NMR (acetone-d6 / 300 MHz) 7.94 (s, ÍH), 7.74 (d, 2H, J = 8.5 Hz), 7.35 (m, 2H), 7.25 (d, 2H, J = 8.5 Hz), 6.00 (m, q, ÍH, J = 7.0 Hz). FABLRMS m / z 437 (M-H). ESHRMS m / z 437.0000 (M-H, Calculated 437.0015). Anal. Calculated for C? 8H9CIF604: C, 49.28; H, 2.07; Cl, 8.08. Were obtained: C, 49.42; H, 2.12; Cl, 8.17.

• EXAMPLE 106 3- (Trifluoromethyl) -3H-benzoyl [3, 2-f] [1] benzopyran-2-sarboxylyl acid. 2-Hydroxydibenzofuran was converted to the title compound by a procedure similar to that described in Example 2: p.p. 253.2-254.6 ° C. XH NMR (acetone-d6 / 300 MHz) 8.54 (s, HH), 8.23 (d, HH, J = 7.5 Hz) 7.71 (s, HH), 7.62 (m, HH), 7.50 (1H), 7.23 (d, ÍH, J = 8.9 Hz), 5.95 (q, 1H, J = 7.3 Hz). FABLRMS m / z 333 (M-H). ESHRMS m / z 333.0401 (M-H, Calculated 333.0375). Anal. Calculated for Ci7H9: F304: C, 61.09; H, 2.71. The following were obtained: C, 60.95; H, 2.80.

EXAMPLE 107 • Asido 6-Chloro-8-siane-2- (tri luoromethyl) -2H-1-benzopi an-3-sarboxylyl Step 1. Preparation 6-Chloro-8- (hydroxyiminomethyl) -2-10 (trifluoromethyl) -2H- 1-benzopyran-3-carboxy ethyl ester. Hydroxylamine hydrochloride was mixed (1.30 g, 18.7 mmol), sodium acetate (1.50 g, 19.4 mmol), and an ethanol-water mixture (80:20, 15 mL) stirring at room temperature for 0.4 • hours. The aldehyde (Example 76, Step 3) (3.07 g, 9.0 mmol) was dissolved in an ethanol-water solution (4: 1, 25 ml) and added to this mixture and stirred 100 ° C for 1 hour. The reaction was filtered in The mixture was heated and the filtrate was allowed to cool to room temperature. An orange solid crystallized in the filtrate and was collected by filtration in 2r52. empty. The solid was dissolved in ethyl acetate and the solution was washed with water, brine and dried over MgSO4, and concentrated in vacuo. The resulting solid was recrystallized from ethylacetate-hexane to give the oxime as a powder (1.50 g, 47%): m.p. 186.6-187.6 ° C. 1HNMR (acetone-d6 / 300 MHz) 10.87 (s, ÍH), 8. 34 (s, ÍH), 7.90 (s, ÍH), 7.77 (d, ÍH, J = 2.6 Hz), 7.60 (d, ÍH, J = 2.6 Hz), 6.02 (q, ÍH, J = 7.1Hz), 4. 35 (m, 2H), 1.34 (t, 3H, J = 7.0 Hz).

Step Preparation of ethyl 6-chloro-8-cyano-2-trifluoromethyl-2H-l-benzopyran-3-carboxylate The oxime from Step 1 (0.61 g, 1.7 mmol) and acetic anhydride (6 ml) were stirred at 140 °. C for 6.3 hours. The reaction was poured into water, extracted with acetylacetate, washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (1.09 g). The oil was purified by flash chromatography (10: 1; hexanes: ethyl acetate), giving a concentration similar to that of the title compound as a white solid (0.51 g, 88%): m.p. 114.6-115.6 ° C. HNMR (CDCl3 / 300 MHz) 7.65 (s, 1H), 7.53 (d, ÍH, J = 2.4 Hz), 7.44 (d, ÍH, J = 2.4 Hz), 5.87 (q, ÍH, J = 6.4 Hz), 4.36 (m, 2H), 1.37 (t, 3H, J = 6.5 Hz). 53 Step Preparation of 6-chloro-8-cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid The ester from Step 2 (0.51 g, 1.5 mmol) was dissolved in THF (5 ml) and ethanol ( 5 ml), treated with 2.5 N sodium hydroxide (1.2 ml, 3.0 mmol), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl, extracted with ethyl acetate, washed with water, brine, dried over MgSO0, concentrated in vacuo, and recrystallized with diethyl ether / hexane to give a white powder (0.10 g, 21% ): pf 238.1-239.7 ° C. XHNMR (acetone-d6 / 300 MHz) 7.97 (s, ÍH), 7.92 (d, 1H, J = 2.4 Hz) 7.89 (d, ÍH, J = 2.4 Hz), 6.14 (q, ÍH, J = 6. Hz). FABLRMS m / z 302 (M-H). ESHRMS m / z 301.9819 (M-H, Calculated 301.9832). Anal. Calculated for C12H5CIF3N03: C, 47.47; H, 1.66; N, 4.61. Were obtained: C, 47.41; H, 1.70; N, 4.55.

EXAMPLE 108 £ 54 6-Sloro-8- [(hydroxyimino) methyl] -2- (ri luoromethyl) -2H-1-benzopyran-3-sarboxylic acid 2H-1-benzopyran-3-carboxylic acid was prepared from the ethyl ester (Example 107) , Step 2) by a method similar to the procedure described in Example 1, Step 2: pf 246.9-247.9 ° C. XH NMR (acetone-d6 / 300 MHz) 10.90 (brs, 1H), 8.35 (s, ÍH), 7.92 (s, ÍH), 7.78 (d, ÍH, J = 2.6 Hz), 7.61 (d, 1H, J = 2.6 Hz), 5.98 (q, ÍH, J = 7.0 Hz). FABLRMS m / z 3 2 0 (M-H). ESHRMS m / z 319.9959 (M-H, Calculated • 319,997). Anal. Calculated for C? 2H7CIF3N04: C, 44.81; H, 2.19; N, 4.35. Obtained: C, 44.92; H, 2.25; N, 4.26.

EXAMPLE 109 6-Sloro-8- (hydroxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-aarboxylyl acid The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to that described in Example 80 using the carboxylic acid of Example 76, Step 4) as starting material: m.p. 174.6-178.9 ° C. 2H NMR (acetone-d6 / 3 OO MHz) 7.90 (s, ÍH) 7.57 (d, 1H, J = 2.6 Hz), 7.47 (d, ÍH, J = 2.6 Hz), 5.87 (q, ÍH, J = 7.0 Hz), 4.70 (s, 2H). FABLRMS m / z 308 (M + H). ESHRMS m / z 306.9981 (M-H, Calculated 306.9985). Anal. Calculated for C? H8CIF303 (3.81% by weight H20); C, 47.37; H, 3.08. Obtained: C, 47.33; H, 2.82.

EXAMPLE 110 8- (lH-Benzimidazol-2-yl) -6-sloro-2- (trifluoromethyl) -2H-l-benzopyran-3-sarboxylic acid Step 1. Preparation of 8- (lH-benzimidazol-2-yl) -6 -chloro-2- (trifluoromethyl) -2H-l-benzopyran-3-ethyl carbopylate. ,. _ A solution of the aldehyde was heated (Example 76, Step 3) (0.33 g, 0.99 mmol) and 1,2-phenylenediamine (0.11 g, 1.02 mmol) in nitrobenzene (20 ml) at 150 ° C for 1.8 hours. The mixture of 2.-56 The reaction was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo and purified by flash chromatography on silica gel (with 1: 9 ethylacetate / hexane as eluent) to give the ester as a brown solid ( 0.18 g, 43%) that was used in the next step without further purification.

Step 2. Preparation of 8- (1H-benzimidazol-2-yl) -6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid. The ester from Step 1 (0.18 g, 1.5 mmol) was dissolved in THF (5 ml) and ethanol (5 ml), treated with 2.5 N sodium hydroxide (2.6 ml, 6.5 mmol), and stirred at room temperature for 1.7 hours. . The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, filtered and recrystallized with ethanol-water to give a solid (0.09 g, 52%): m.p. > 300 ° C IHNMR (acetone-d6 / 300 MHz) 8.59 (d, ÍH, J = 2.6 Hz), 8.03 (s, ÍH), 7.73 (d, ÍH, J = 2.6 Hz), 7. 67 (brs, 2H), 7.28 (m, 2H), 6.13 (q, ÍH, J = 6.8 Hz). FABLRMS m / z 395 (M- { 37C1.}.). ESHRMS m / z 393.0262 (M-H, Calculated 393.0254). Anal. Calculated for C? 6H2oCIF3N2? 3 (2.8 8% and weight H20): C, 58.19; H, 2.80; N, 6.89. Were obtained: C, 53.22; H, 2.90; N, 6.80. £ 57 EXAMPLE 111 7- (1, 1-dimethylethyl) -2- (penta luoroethyl) -2H-1-benzopyran-carboxylic acid Step 1. Preparation of ethyl-3-hydroxy-4, 4, 5, 5, 5-pentafluorope tannate A solution of 4, 4, 5, 5, 5-pentafluoro-3-oxo-pentanoate ethyl (41.32 g, 0.18 mol) in diethyl ether (70 ml) was cooled to 0 ° C and treated with NaBH4 (7.09 g, 0.19 mol ). The reaction was allowed to warm to room temperature and was stirred for 2 hours before quenching with 1 N HCl (200 ml). The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with IN HCl, brine, dried over MgSO 4, and concentrated in vacuo to give the hydroxyester as a clear oil (46.40 g) which was used in the next Step without further purification. £ -58 Step 2. Preparation of ethyl 4, 4, 5, 5, 5-pentafluoro-2-pentenoate The hydroxyester from Step 1 (46.40 g, 0.18 mol) was stirred at 120 ° C with P20P5 (25.59 g, 0.09 mol) during 2.6 hours, then it was distilled under vacuum (95 torr, 45-64 ° C) to give the ester as clear oil (13.70 g, 35%):? E NMR (CDCl3 / 300 MHz) 6.78 (m, 1H9, 6.57 ( dt, ÍH, J = 15.9 Hz 2.0 Hz), 4.30 (q, 2H, J = 7.3 Hz), 1.34 (t, 3H, J = 7.1 Hz).

Step 3. Preparation of 7- (1,1-dimethylethyl) -2- (pentafluoroethyl) -2H-1-benzopyran-3-ethylcarboxylate. A mixture of 4-tert-butylsalicylaldehyde from Example 8, Step 1 (1.15 g, 6.4 mmol) and the ethyl ester from Step 2 (1.59 g, 7.3 mmol) was dissolved in anhydrous DMF (4 mL). While stirring, K2C03 (1.10 g, 9.0 mmol) was added, which caused the reaction to become deep red. The reaction was stirred at room temperature for 100 hours, acidified with 3 N HCl, diluted with ethyl acetate and washed with saturated NaHCO 3 solution, with brine and dried over MgSO 4, filtered and concentrated in vacuo to give a brown oil. This oil was purified by flash chromatography £ 59 on silica gel, eluted with 10% ethyl acetate / hexanes to give a yellow oil (1.72 g, 70%): 2 H NMR (CDCl 3/300 MHz) 7.76 (s, 1H), 7.14 (d, 1H, J = 8.1 Hz), 7.04 (dd, 1H, J = 8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, ÍH, J = 22.4 Hz 3.0 Hz) 4.32 (, 2H), 1.35 (t, 3H , J = 7.2 Hz), 1.30 (s, 9H).

Step Preparation of 7- (1,1-dimethyl) -2- (pentafluoroethyl) -2H-1-benzopyran-3-carboxylic acid. The ester of Step 3 was dissolved (1.58 g, 4. 20 mmol) in THF (3 ml) and ethanol (3 ml), treated with 2.5 N sodium hydroxide (2 ml, 5 mmol), and stirred at room temperature for 23.3 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, giving a suspension. The solid was collected by filtration and recrystallized with ethanol-water to give a yellow solid (0.76 g, 52%): m.p. 171.0-173.5 ° C LH NMR (acetone-d6 / 300 MHz) 7.93 (s, ÍH) 7.39 (d, ÍH, J = 8.1 Hz), 7.18 (dd, ÍH, J = 8.1 Hz, 1.8 Hz), 7.02 (s, ÍH), 6.01 ( dd, ÍH, J = 23.1Hz, 3.2 Hz), 1.32 (s, 9 H). FABLRMS m / z 351 (M + H). EIHRMS m / z 350.0945 (M +, Calculated 350. 0941). Anal. Calculated for C 16 H 15 F 5 O 3: C, 54.86; H, 4.32. The following were obtained: C, 54.88; H, 4.32. = 60 EXAMPLE 112 6-Sloro-8- (methoxymethyl) -2- (trifluoromethyl) -5 2H-l-benzopyran-3-sarboxylic acid Step 1. Preparation of 6-chloro-8- (hydroxymethyl) -2- • (trifluoromethyl) -2H ethyl-l-benzopyran-3-carboxylate A suspension of the aldehyde (Example 75, Step 1) (4.78 g, 14.3 mmol) was cooled to 0 ° C and treated with NaBH 4 (0.33 g, 4.8 mmol). The solution was stirred for 10 minutes, then it was quenched with 3 N HCl, extracted with ethyl acetate, washed with NaHCO3"brine, dried over MgSO 4 and concentrated in vacuo to give a brown solid which was filtered through a plug of silica gel to give the alcohol as a brown solid (3.60 g, 75%). 1 H NMR (CDCl 3/300 MHz) 7.66 (s, ÍH), 7.42 (d, ÍH, J = 2.4 Hz), 7.17 (d, ÍH, J = 2.4 Hz), 5.75 (q, ÍH, J = 6.8 Hz), 4.71 (s, 2H), 4.33 (m, 2H), 1.85 (brs, ÍH, 1.36 (t, 3H, J = 7.1). - 1 solid was used in the next step without further purification.

Step 2. Preparation of ethyl 6-chloro-8- (methoxymethyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate The alcohol from Step 1 (0.44 g, 1.3 mmol), silver triflate (0.36 g) g, 1.4 mmol) and 2,6-di-tert-butylpyridine (0.37 g, 1.9 mmol) were dissolved in methylene chloride (3 ml), cooled to 0 ° C and treated with methyloduro (0.40 g, 2.8 mmol). The reaction was allowed to warm and stirred at room temperature for 4.6 hours. The reaction was filtered through diatomaceous earth and the filtrate was washed with 3N HCl, saturated NaHCO3, brine and dried over MgSO4, and concentrated in vacuo to give a brown oil. This oil was purified by flash chromatography on silica gel, eluted with 10% ethyl acetate-hexanes to give the substituted 2H-1-benzopyran (0.19 g, 41%) as a white oily solid suitable for use without further purification. . 1 H NMR (CDCl 3/300 MHz) 7.63 (s, ÍH), 7.39 (d, H, J = 2.6 Hz), 7.13 (d, 1H, J = 2.6 Hz), 5.72 (q, ÍH, J = 6. Hz), 4.44 (m, 2H), 4.30 (m, 2H), 3.41 (s, 3H), 1.85 (brs, ÍH), 1.33 (t, 3H, J = 7.1). 2- ££ "-.

Step 3. Preparation of 6-chloro-8- (methoxymethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid The ester of Step 2 was hydrolyzed by a procedure similar to that described in Ex emp1o Step 2, p.f 166.7-168.0 ° C H NMR (acetone-dβ / 300 MHz) 7.90 (s, 1H), 7.50 (HH, J = 2.6), 7.46 (d, HH, J = 2.4 Hz), 5.92 (q, HH, J = 7.1 Hz), 4.49 ( s, 2H9, 3.42 (s, 3H), FABLRMS m / z 321 (MH), ESHRMS m / z 321.0141 (MH, Calculated 321.0141) Anal.For C13H? 0CIF3O4: C, 48.39; H, 312. C were obtained. , 48.45; H, 3.11.

EXAMPLE 113 6-Chloro-8- (bensyloxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylyl acid 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to that described in Example 112 : pf 133.8-135.4 ° C. XH NMR (acetone-dg / 300 MHz) 7.90 (s, 1H), 7.54 (d, ÍH, J = 2.6), 7.51 2.-63 (d, ÍH, J = 2.4 Hz), 7.42 (m, 5H), 5.91 (q, ÍH, J = 7.1 Hz), 4.68 (s, 2H), 4.63 (s, 2H). FBLRMS m / z 399 (M + H). ESHRMS m / z 397.0454 (M-H, Calculated 397.0461).

• Anal. Calculated for C? 9H13CIF304: C, 57.23; H, 3.54; Cl, 8.89. The following were obtained: C, 57.34; H, 3.63; Cl, 8.77.

EXAMPLE 114 6-Chloro-8-ethenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid Step 1. Preparation of ethenyl-6-chloro-8-ethenyl-2- (trifluoromethyl) -2H-1 - benzopyran-3-carboxylate In a 100 ml round bottom flask N2 atmosphere, ethyl 8-bromo-6-chloro-2- • trifluoromethyl-2H-benzopyran-3-carboxylate was dissolved (Example 74, Step 1) (2.21 g, 5.73 mmol) in toluene (30 ml of anhydrous reagent). Tetrakis added (triphenylphosphine) palladium (0) (0.132 g, 0.115 mmol) followed by tributylenedylstannane (2.0 g, 6.31 mmol). The resulting solution was heated to reflux for 5 hours. The reaction mixture was left £ 64 Cool to room temperature, pour into 50 ml of 20% ammonium fluoride solution and stir for one hour. Diethyl ether (100 ml) was added and the mixture was washed with water (2 x 50 ml). The organic phase was dried over MgSO4, filtered, and evaporated to give a yellow oil. The crude material was purified by flash chromatography (0.5% ethyl acetate in hexanes) to give the ester as a yellow solid (0.86 g, 45%): m.p. 75.9-77.2 ° C. XH NMR (CDCl 3/300 MHz) 7.64 (s, ÍH), 7.45 (d, ÍH, J = 2.5 Hz), 7.12 (d, ÍH, J = 2.6 Hz), 6.92 (dd, ÍH, = 17.7 Hz, 11.3 Hz) 5.81 (d, ÍH, J = 17.7 Hz), 5.76 (q, ÍH, J = 6.8 Hz), 5.41 (d, 2H, J = 11.1 Hz), 4.36-4.29 (m, 2H), 1.36 (t , 3H, J = 7.3 Hz). FABLRMS m / z 350.1 (M + NHA). ESHRMS m / z 350.0796 (M + NH 4A Calculated, 350.0771). Anal. Calculated for C? 9H? 3CIF304 + 4.07% H20: C, 51.96; H, 3.94. The following were obtained: C, 51.67; H, 3.69.

Step 2. Preparation of 6-chloro-8-ethenyl-2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid The ester (Step 1) (0.350 g, 1.05 mmol) was dissolved in a solution of THF: ethanol: water (7: 2: 1, 10 ml), treated with sodium hydroxide (0.46 ml, 1.05 mmol of a 2.5 N solution), and stirred at 2.65-55 room temperature 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 ml). Diethyl ether (10 ml) was added and the • mixture was acidified with concentrated HCl. The layers were separated and the aqueous phase was extracted with diethyl ether (2 x 10 ml). The organic phases were combined, dried over MgSO4, filtered, and evaporated to give a yellow solid which was recrystallized with diethyl ether-hexane to give the composed of the title as a yellow solid. (0.288 g, 90%): p.f. 183.2- 185.8 ° C. NMR (CDCl 3/300 MHz) 7.77 (s, 1 H), 7.49 (d, 1 H, J = 2.2 Hz), 7.16 (d 1 H, J = 2.4 Hz), 6.93 (dd, ÍH, J = 11.3, 17.7 Hz), 5.82 (d, ÍH, J = 17.7 Hz), 5.74 (q, ÍH, J = 6.9 Hz), 5.43 (d, ÍH, J = 11.1 Hz). FABLRMS m / z 303 (M-H). ESHRMS m / z 303.0014 (M-H, Calculated 303.003582). Anal. Calculated, for C? 3H8CIF303 + 1.58% _ H20: C, 50.44; H, 2.78. Obtained: C, 50.42; H, 2.65. • 20 EXAMPLE 115 2J66 ' 6-Chloro-8-ethynyl-2- (tri-luomomethyl) -2H-1-benzopyran-3-aarboxyliac acid 2H-l-benzopyran-3-carboxylic acid • prepared by a procedure similar to the method described in Example 114: p.f. 186.2-189.0 ° C. XR NMR (acetone-dl / 300 MHz) 7.87 (s, HH), 7.60 (d, HH, J = 2.4 Hz), 7.51 (d, 1H, J = 2.4 Hz), 5.95 (q, HH, J = 7.0) Hz), 4.02 (s, ÍH). FABLRMS m / z 301 (M-H). ESHRMS m / z 300.9875 (M-H, Calculated 300.9879). Anal.

Calculated for C? 3H6CIF303: C, 51.59; H, 2.00; Cl, 11.71. Obtained: C, 51.26; H, 2.06; Cl, 11.40.

EXAMPLE 116 6-Sloro-8- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 114: p.f. 257.5-258.8 ° C. XH NMR (acetone-dg / 300 MHz) 7.91 (s, ÍH), 7.79 (d, 2.-67 ÍH, J = 2.4 Hz), 7.74-7.72 (m, ÍH), 7.62-7.61 (m, ÍH), 7.51 (d, ÍH, J = 2.4 Hz), 7.19-7.16 (m, ÍH), 6.04 (q , ÍH, J = 7.1 Hz). FBLRMS m / z 359 (M-H). ESHRMS m / z 358.9747 (M-H, Calculated: 358.9756). Anal. Calculated for C? 5H8CIF303S: C, 49.94 H, 2.24; Cl, 9.83; S, 8.80. Obtained: C, 50.26; H, 2.45; Cl, 9.72; S, 9.00.

EXAMPLE 117 Asido 6-chloro-8- (2-furanyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 114: pf 171-5-173.3 ° C LH NMR (acetone-of / 300 MHz) 7.93 (s, ÍH), 7.82 (d, ÍH, J = 2.6 Hz), 7.72-7.71 (, 1H), 7.50 (d, ÍH, J = 2.6 Hz), 7.16 ( d, HH, J = 2.4 Hz), 6.65-6.63 (m H H), 6.11 (q, HH, J = 7.1 Hz). FABLRMS m / z 343 (M-H). ESHRMS m / z; 342.9995 (M-H, Calculated: 342.9985). Anal. Calculated: For C? 5H8CIF304 + 1.31% H20: C, 51.59; H, 2.46; Cl, 10.15. Obtained: C, 51.57; H, 2.33; Cl, 10.14. 2d68 EXAMPLE 118 6-Chloro-8- (5-chloro-l-pentynyl) -2- • (trifluoromethyl) -2H-1-benzopyran-3-aarboxylic acid Step A. Preparation of 6-chloro-8- (5-chloro-l) pentinyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-ethyl carboxylate 6-Chloro-8-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid ethyl ester was dissolved (Example 73, Step 2) (1.50 g, 3.47 mmol), tetrakis- (triphenylphosphine) palladium (0) (0.2 g, 0.174 mmol), • copper iodide (I) (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4 mmol) in toluene (50 mL). 5-Chloro-1-pentyne (0.53 g, 5.20 mmol) was added with a syringe and the mixture was stirred for 18 hours at room temperature. The reaction was diluted with diethyl ether (50 ml), extracted with 0.5 N HCl (2 x 25 ml), and water (2 x 25 ml). The organic phase was dried over MgSO4, filtered, and evaporated to give a £ 9 orange oil The crude material was purified by flash chromatography in 2% ethyl acetate in hexane. Recrystallization from hexane gave the ester as a white solid (0.96 g, 68%): m.p. 84-8-85.9 ° C. XH NMR (CDCl3 / 300 MHz), 7.61 (s, ÍH), 7.33 (d, 1H, J = 2.6 Hz), 7.14 (d, IH, J = 2.6 Hz), 5.79 (q, ÍH, J = 6.7 Hz ), 4.27-4.29 (m, 2H), 3.75 (t, 2H), J = 6.7 Hz), 2.67 (t, 2H, J = 6.7 Hz), 2.11-2.03 (m, 2H), 1.35 (t, 3H) , J = 7.2 Hz). FABLRMS m / z 424.1 (M + NH 4 +). ESHRMS m / z 424.0694 (M + NHA Calculated 424.0694). Anal. Calculated for C 8 8 H 15 Cl 2 F 3 3 3: C, 53.09; H, 3.71; Cl, 17.41. The following were obtained: C, 53.02; H, 3.90; Cl, 17.63.

Step 2. Preparation of 6-chloro-8- (5-chloro-l-pentynyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid The ester (Step 1) (0.500 g, 1.23 mmol) was dissolved in THF-ethanol-water (7: 2: 1, 10 ml). It was treated with sodium hydroxide (0.49 ml, 1.23 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 ml). Diethyl ether (10 ml) was added and the mixture was acidified with concentrated HCl. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2 x 10 ml). 2. -70 The combined extracts were dried over MgSO, filtered and evaporated to give a yellow solid, which was recrystallized from diethyl ether-hexane to give the title compound as a yellow solid (0.371 g, 80%): m.p. 154.4-156.4 ° C. tE NMR (acetone-of / 300 MHz) 7.88 (s, ÍH), 7.53 (d, ÍH, J = 2.4 Hz), 7.44 (d, ÍH, J = 2.4 Hz) 5.94 (q, 1H, J = 7.1 Hz ), 3.83 (t, 2H, J = 6.5 Hz), 2.68 (t, 2H, J = 6.8 Hz), 2.12-2.04 (m, 2H). ESLRMS m / z 377 (M-H). ESHRMS m / z 376.9930 (M-H, Calculated 376-9959). Anal. Calculated, for C? 6H1: LCl2F3? 3 + 1.18% H20: C, 50.% 08; H, 3.02; Cl, 18.48. The following were obtained: C, 50.11; H, 2.73; Cl, 18.28.

EXAMPLE 119 6-Chloro-8- (1-pentynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-aarboxylyl acid 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to that described in the Example 118: pf 168.1-171.2 ° C. aH NMR (CDCl 3/300 MHz) 7.75 (s, 1 H), 7.37 (d H, J = 2.6 Hz), 7.15 (d, ÍH, J = 2.4 Hz), 5.77 (1, ÍH, J = 6.7 Hz), 2.44 (t, 2H, J = 6.9 Hz), 1.68-1.61 (m, 2H), 1.07 (t, 3H, J = 7.25 Hz. FABLRMS m / z 345 (M + H) ESHRMS m / z 343.0373 (MH , Calculated 343.0349) Anal.Calculated, for C? 6H12CIF303 + 0.69% H20: C, 55.36; H, 3.56.The following were obtained: c, 55.21; H, 3.62.

EXAMPLE 120 6-Chloro-8- (f-enylethynyl) -2- (tri-loromethyl) -2H-1-benzopy-3-sarboxyl acid acid 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118: pf 190.1-192.1 ° C. XH NMR (CDCl 3/300 MHz) 7.92 (s, ÍH), 7.61-7.57 (m, 4H), 7.47-7.44 (m, 3H), 6.01 (q, 1H, J = 7.0 Hz). ESLRMS m / z 377 (M-H). ESHRMS m / z 377.0167 (M-H, Calculated, 377.0192). Anal. Calculated for C13H10CIF303: C, 60.26; H, 2.66; Cl, 9.36. The following were obtained: C, 60.09; H, 2.73; Cl, 9.09. £ -72 ' EXAMPLE 121 Asido 6 -aloro-8- (3, 3-dimethyl-l-butynyl) -2-. { tri luoromethyl) -2H-1-benzopy ran-3-carboxy lyso 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118: p.f. 218.3-222.4 ° C. XH NMR (acetone-d6 / 300 MHz) 7.87 (s, 1H), 7.51 (d, HH; J = 2.4 Hz), 7.38 (d, HH, J = 2.6 Hz), 5.92 (q, HH, J = 6.9 Hz), 1.32 (s, 9H). FABLRMS10 m / z 359 (M-H). ESHRMS m / z 357.0490 (M-H, Calculated 357.0505). Anal. Calculated for C? 7H14CIF303: C, 56.92; H, 3.93; Cl, 9.88. Obtained: C, 56.63; H, 3.94; Cl, 10.03.

• EXAMPLE 122 2r73 6-Sloro-8- [(-sil-enyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopy-3-sarboxyl acid The 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118: pf 210.4-211.4 ° C. XH NMR (CDCl 3/300 Mz), 7.75 (s, ÍH), 7.48-7.43 (m, 3H), 7.36 (s, 1H), 7.33 (s, ÍH), 7.22 (d, ÍH, J = 2.6 Hz) , 5.82 (q, ÍH, J = 6.6 Hz). FABLRMS m / z 411 (M-H) .. ESHRMS m / z 410.9802 (M-H, Calculated 410.980259). Anal. Calculated for C2oH12C? 2F3? 3. : C, 55.23; H, 2.20; Cl, 17.16. Obtained: C, 55.22; H, 2.07; Cl, 17.39.

EXAMPLE 123 Asido 6-sloro-8- [(4-methoxy-enyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopy-3 -carboxy-smooth acid 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118: pf 217.7-218.7 ° C. 1E NMR (CDCI3 / 3OO MHz) 7.75 (s, 1H), 7.51-7.47 (m, 3H), £ 74 7. 18 (d, ÍH, J = 2.4 Hz), 6.91-6.88 (m, 2H), 5.82 (1, ÍH, J = 6.7 Hz). ESLRMS m / z 407 (M-H). ESHRMS m / z 407-0293 (M-H, Calculated 407.0298). Anal. Calculated for C20H? 2CIF3O4: C, 58.77; H, 2.96; Cl, 8.67. Were obtained: C, 58.68; H, 2.85; Cl, 9.15.

EXAMPLE 124 6- (Phenylethynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118 using ethyl 6-benzopyran-3-carboxylic acid. -Iodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate (Example 24, Step 3) as starting material, mp 240.1-241.3 ° C. 1E NMR (acetone-d6 / 300 MHz) 7.94 (s, ÍH), 7.70-7.69 (m, ÍH), 7.61-7.53 (m, 3H), 7.44-7.41 (m, 3H), 7.10 (d, ÍH, J = 7.1 Hz). ESHRMS m / z 343.0550 (M-H, Calculated 343.0582). Anal. Calculated for C19H ?? F3? 3: C, 66.29; H, 3.22. Obtained: C, 66.26; H, 3.29. EXAMPLE 125 6-Chloro-8- (4-chlorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid Step 1. Preparation of 6-chloro-8- (4-chlorophenyl) -2- (trifluoromethyl) ) -2H-l-benzopyran-3-carboxylic acid ethyl ester. Ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate was added (Example 73, Step 2) (1.3 g, 3.02 mmol), potassium carbonate (1.25 g, 9.06 mmol), 4-chlorophenylboronic acid (0.52 g, 3.33 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.174 g, 0.151 mmol) to toluene (30 mL) and the resulting solution was heated to reflux for 18 hours.

After cooling to room temperature the reaction mixture was poured into ethyl acetate (50 ml). It was 236 washed with 1N HCl (2 x 25 ml), saturated aqueous sodium bicarbonate (2 x 25 ml), and water (2 x 25 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The crude material was purified by flash chromatography using 1% ethyl acetate in hexane, which gave a white solid. Recrystallization with hexane gave the ester as a white solid (0.79 g, 64%): m.p. 114.2- 115.9 ° C. XH NMR (CDCl3 / 300 MHz) 7.69 (s, HH) (s, 4H), 7.30 (d, 1H, J = 2.4 Hz), 7.22 (d, HH, J = 2.6 Hz), 5.70 (q, HH, J = 6.9 Hz), 4.37 - 4.29 (m, 2H), 1.35 (t, 3H, J = 7".1 Hz) ESLRMS m / z 434 (M + NH4 +) FABHRMS m / z 434.0574 (M + NH4A Calculated 434.053 8) Anal.Calcd for C? 9H? 3Cl2F303: C, 54.70; H, 3.14; Cl, 17.00 C, 54.79, H, 3.18, Cl, 16.65 were obtained.

Step 2. Preparation of 6-chloro-8- (4-chlorophenyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid The ester from Step 1 (0.500 g, 1.20 mmol) was dissolved in a solution of THF: ethanol: water (7: 2: 1; 10 ml), treated with sodium hydroxide (0.48 ml, 1.20 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent £ -77 it was removed in vacuo and the residue was dissolved in water (10 ml). Diethyl ether (10 ml) was added and the mixture was acidified with concentrated HCl HCl. The • organic layer was separated and the aqueous phase was extracted with diethyl ether (2 x 10 ml). The combined extracts were dried over MgSO4, filtered and evaporated to give a white solid which was recrystallized from diethyl ether-hexane to give the title compound as a white solid. (0.40 g, 86%): p.f. 205.5-207.3 ° C. NMR (CDC13 / 300 MHz) 7.81 (s, ÍH), 7.42 (s, 4H), 7.34 (d, 1H, J = 2.4 Hz), 7.25 (s, 1H), 5.69 (q, ÍH, J = 6.8 Hz ). FABLRMS m / z 387 (M-H). ESHRMS m / z 386.9788 (M-H, Calculated 386-980259). Anal. Calculated for C? 7H9Cl2F303: C, 52.47; H, 2.33; Cl, 18.22. We obtained: C, 52.38; H, 2.47; Cl, 18.20.

EXAMPLE 126 • £ 20 6-Chloro-8- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid Step 1. Preparation of 6-chloro-8- (3-methoxyphenyl) -2-; ethyl trifluoromethyl) -2H-l-benzopyran-3-carboxylate In a 100 ml round bottom flask under nitrogen, ethyl-chloro-8-iodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxy was dissolved. lato (Ex emp.> 73, Step 2) (1.00 g, 2.31 mmol) and 3- 10-methoxyphenylboronic acid (0.369 g, 2.43 mmol) in 1-propanol •; 50 ml). The mixture was stirred at room temperature for 0.5 hours, allowing the solids to dissolve. The resulting solution was treated with palladium (II) acetate (0.016 g, 0.0693 mmol), triphenylphosphine (0.055 g, 0.208 mmol), sodium carbonate (0.294 g, 2. 77 mmol), and deionized water (10 mmll)) .. LLaa mmeezzccllaa d < The reaction was heated to reflux for 3 hours After cooling to room temperature and mmeezzcc.l'a • was extracted with ethyl acetate (1 x 150 ml, 2 x 25 ml). The combined organic phases were washed with saturated aqueous NaHC03 (50 ml) and brine (2 x 50 ml), dried over MgSO4, filtered and concentrated in vacuo to give yellow oil. The crude material was purified by flash chromatography in ethyl acetate at 0.5% in hexane, giving a solid £ 79 White. The solid was recrystallized with hexane, giving the desired ester as a white solid (0.60 g, 63%): p.f. 93.7-95.1 ° C. aH NMR (CDCl 3/300 MHz) 7.69 (s, ÍH), 7.35-7.32 (, 2H), 7.22 (d, ÍH, J = 2.6 Hz), 7.05-7.03 (m, 2H), 6.96-6.93 (m, ÍH), 5.72 (q, ÍH, J = 6.7 Hz), 4.34-4.31 (2H), 1.35 (t, 3H, J = 7.1 Hz). FABLRMS m / z 413 (M + H). ESHRMS m / z 413.0765 (M + H, Calculated 413.076747). Anal. Calculated for C20H16CIF304: C, 58.19; H, 3.91; Cl, 8.59. Were obtained: C, 58.33; H, 4.10; Cl, 8.61.

Step Preparation of 6-chloro-8- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid The ester of Step 1 (0.300 g, 0.727 mmol) was dissolved in THF-ethanol -water (7: 2: 1, 10 ml). It was treated with sodium hydroxide (0.29 ml of a 2.5 N 0.727 mmol solution), and stirred at room temperature for 18 hours. The solvent was evaporated and the residue was dissolved in water (10 ml). Ether (10 ml) was added, followed by a few drops of concentrated HCl. The ether layer was separated and the aqueous phase was extracted with ether (2 x 10 ml). The ether extracts were combined, dried over MgSO.sub.j-filtered and concentrated in vacuo to give a 2? 0 white solid that was recrystallized from diethyl ether-hexane to give the title compound as a white solid (0.23 g, 81%): m.p. 173.1-177.4 ° C. H F NMR (CDCl 3/300 MHz), 7.81 (s, ÍH), 7.39-7.37 (m, 2H), 7.05-7.04 (m, 2H), 6.97-6.94 (m, ÍH), 5.71 (q, 1H, J = 6.7 Hz), 3.85 (s, 3H). ESHRMS m / z 383.0278 (M-H, Calculated 383.029796). Anal. Calculated for C? 8H12CIF304: C, 56.20; H, 3.14; Cl, 9.21. C, 55.90; H, 3.11; Cl, 9.48. 10 EXAMPLE 127 6-Chloro-8 - [(4-methylthio) phenyl] -2- 15 (trifluoromethyl) -2H-1-benzopyran-3-sarboxylic acid 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to method described in Example 126: pf 211.4-212.5 ° C. 1E NMR (acetone-d6 / 300 MHz) 7.94 (s, ÍH), 7.57 (d, ÍH, J = 2.6 Hz), 7.53-7.50 (m, 2H), 7.45 (d, 1H, J = 2.6 2.81 Hz), 7.39-7.36 (m, 2H), 5.87 (q, ÍH, J = 7.1 Hz), 2.55 (s, 3H). ESHRMS m / z 399.0051 (M-H, Calculated 399.0069). Anal. Calculated for C18H? CIF303 S: C, 53.94; H, 3.02, Cl, 8.84, S, 8.00. The following were obtained: C, 53.86; H, 2.82; Cl, 8.91; S, 8.12.

EXAMPLE 128 Asido 6-chloro-8- [(4-methylsulfonyl) phenyl] -2- (tri-loromethyl) -2H-1-benzopyran-3-carboxylic acid Step 1. Preparation of et-6-chloro-8 [(4-) methyl-sulfonyl) phenyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate. Oxone ™ (1.44 g, 2.34 mmol) was dissolved in H20 (10 ml) and then cooled to 5 ° C. A solution of ethyl 6-chloro-8 - [(4-methylthio) phenyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate (Example 127, ethyl ester) (0.5 g, 1.17 g. mmol) in methanol (20 ml) to the reaction mixture, and £ -82 The solution was stirred at room temperature for 5 hours. The methanol was then removed in vacuo. The remaining solution was extracted with methylene chloride (2 x 50 ml). The combined organic layers were dried over MgSO4, filtered and evaporated to a yellow solid. This solid was recrystallized from ether-hexane to present the sulfone as a white solid (0.46 g, 84%): m.p. 139.2-146.2 ° C. * H NMR (CDCl3 / 300 MHz) 8.03 (s, ÍH), 8.00 (s, 1H) 7. 70 (d, 2H J = 2.4 Hz), 7.28 (d, ÍH, J = 2.6 Hz), . 71 (q, ÍH, J = 6.9 Hz), 4.35-4.32 (m, 2H), 3.11 (s, 3H), 1.35 (t, 3H, J = 7.2 Hz). FABLRMS m / z 467 (M + Li), ESHRMS m / z A l 8, 01 1 (M + NH 4, Calculated 478.070281). Analysis calculated for C oH16CIF305S: C, 52.12; H, 3.50; Cl, 7.69; Found: C, 52.17; H, 3.36; Cl, 7.77.

Step Preparation of 6-chloro-8 - [(4-methylsulfo-nyl) phenyl] -2- (tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid) The sulfone of Step 1 (0.300 g, 0.651 mmol) dissolved in a THF solution: ethanol: water (7: 2: 1, 10 ml). It was treated with sodium hydroxide (0.26 ml, 0.651 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent is £ 83 eliminated in vacuum and the residue dissolved in water (10 ml). Diethyl ether (10 ml) was added and the mixture was acidified with concentrated HCl. The organic layer was separated and the aqueous phase was extracted with diethylether (2 x 10 ml). The combined organic extracts were dried over MgSO4. They were filtered and evaporated to yield a white solid. Recrystallization of this solid from ether-hexane gave the title compound as a white solid 10.20 g, 73%): mp 286.5-287.8 ° C. 1H NMR (acetone-d6 / 300 MHz) 8.07 (d, 2H, J = 6.7 Hz), 7.97 (s, ÍH), 7.83 (d, 2H, J = 6.7 Hz), 7.67 (d, ÍH J = 2.6 Hz) 7.55 (d, 1H, J = 2.6 Hz), 5.92 (q, ÍH, J = 7.1 Hz), 3.20 (s, ÍH). ESHRMS m / z 430.9947 (M-H, Calculated 430,996782). Analysis calculated for C? 8H? 2CIF305S: C, 49.95; H, 2.80; Cl, 8.19; Found: C, 50.04; H, 2.80; Cl, 8.25.

EXAMPLE 129 284 Acid 6-Chloro-8-f nyl-2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylyl Step 1_. Preparation of ethyl 6-chloro-8-phenyl-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. A mixture of ethyl 6-chloro-8-bromo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate (Example 74, Step 1) (2.0 g, 5.2 mmol), tetrakis (triphenylphosphine) palladium ( ) (2.15 g, 1.7 mmol), triphenylphosphine (0.013 g, 0.05 mmol), and tributyl phenyltin (1.9 ml, 5.7 mmol) in toluene (60 ml) was heated at 110 ° C for 3 days. The reaction mixture was allowed to cool to room temperature and was filtered through a plug of silica gel, eluent gel with 25% ethyl acetate in hexanes. The filtrate was concentrated in vacuo and then purified by flash chromatography (silica gel, ethyl acetate-hexanes, 1: 9). The fractions containing the desired product were combined and concentrated in vacuo. To remove the remaining tin impurities, the mixture was converted into THF (10 ml) and aqueous solution of ammonium fluoride (10% w / w, 20 ml) and stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate. The "extracts were combined, dried over MgSO, £ 85 they were filtered and concentrated in vacuo to present the ester as an oil (1.30 g, 65%). 1H NMR (CDC13 / 300 MHz) 7.67 (s, ÍH), 7.47-7.36 (, 5H), 7.31 (d, ÍH, J = 2.6 Hz), 7.18 (d, ÍH, J = 2.4 Hz), 5.69 (q , ÍH, J = 6.8 Hz), 4.30 (, 2H), 1.33 (t, 3H, J = 7. 1Hz 'FNMR (CDCl3 / 282 MHZ) d -78.27 (d, J = 7.2 Hz). FABLRMS m / z 383 (M + H). ESHRMS m / z 400.0937 (M + NH 4, Calculated 400.0927).

Step 2. Preparation of 6-chloro-8-phenyl-2- • trifluoromethyl-2H-1-benzopyran-3-carboxylic acid A solution of the ester from Step 1 (1.0 g, 2.6 mmol) was dissolved in THF (5 ml. ) and methanol (5 ml), treated with a 2.5 N NaOH solution (4.0 ml, 10.4 mmol). The resulting mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue was taken up in ethyl acetate and acidified with 3 N HCl. The solution was extracted with • ethyl acetate. The extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. Recrystallization from ethyl acetate-hexanes presented the title compound as a pale yellow solid (0.42 g, 46%); mp 196.3-197.7 ° C. 1 H NMR (CDCl 3/300 MHz) d 7.65 (s, ÍH), 7.40-7.23 (m, 6H), 7.15 (s, 1H), 5.63 (q, £ 86) ÍH, J = 6.5 Hz), 3.35 (broad s, 1H). 19F NMR (CDCl3 / 282 MHz) d -78.71 (d, J = 5.8 Hz). FABLRMS m / z (M + H). ESHRMS m / z 353.0198 (M-H, Calculated 353, 0192).

EXAMPLE 130 6-Bromo-8-fluoro-2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylic acid. 4-Bromo-2-fluorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 206 -208 ° C. X NMR (CD3OD / 300 MHz) 7.78 (s, ÍH), 7.36-7.48 (m, 2H), 5.87 (q, ÍH, J = 6.8 Hz). EIHRMS m / z 339.9349 (Calculated 339.9358). Analysis Calculated for CnH5BrF403: C 38.74; H1.48; Found C 38.97; H, 1.60.

EXAMPLE 131 twenty-one 6- (4-Fluorophenyl) -2- (tri-loromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 125, using ethyl 6-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate (Example 24, Step 3) as the starting material: mp 207-210 ° C. XH NMR (CD3OD / 300 MHz) 7.87 (s, ÍH), 7.54-7.64 (, 4H), 7.10-7.20 (, 2H), 7.03 (d, 1H, J = 9.4 Hz), 5.77 (q, ÍH, J = 7.0 Hz). EIHRMS m / z 338.0573 (Calculated 338.0566). Analysis calculated for CnH6F3I03 + 1, 2.5% H20: C, 59.62; H, 3.08. Found C, 59.61; H, 3.09.

EXAMPLE 132 6-Phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 125, using 6-iodo- 2- 2.-88 - (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid ethyl ester (Example 24, Step 3) as the starting material: mp 197-198 ° C. aH NMR (CD3OD / 300 MHz) 7.87 (s, ÍH), • 7.28-7.64 (m, 7H), 7.03 (d, 1H, J = 6.8 Hz), 5.76 (q, ÍH, J = 7.0 Hz). EIHRMS m / z 320.0604 (M +, Calculated 320.0660). Analysis calculated for C17, HuF303: C, 63.7 5; H, 3, 4. 6. Found C, 63.56; H, 3.46.

EXAMPLE 133 10 • 8-Chloro-6-fluoro-2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylic acid 2-Chloro-4-fluorophenol was converted to composed of the title by a procedure similar to that described in Example 2: mp 240-241 ° C lH NMR (CD3OD / 300 MHz) 7.77 (s, 1H), 7.26 (dd, ÍH, J = 8.3, 2.9), 7.14 (dd, ÍH, J = 8.1, 2.9) 5.87 (q, 1H, J = 6.8 Hz) . EIHRMS m / z 295.9836 (Calculated 295.9863).

Analysis calculated for C?.? H5CIF403: C, 44.54; H, 1.70. Found C, 44.70; H, 1.73. 2J39 EXAMPLE 134 Acid 6, 8-Diiodo-2- (tri luoromethyl) -2H-l-benzopyran-3-sarboxylyl The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 1. mp 243 -244 ° C? NMR (CD3OD / 300 MHz) 7.07 (d, ÍH J = 2.0 Hz), 7.71 (s, ÍH), 7.70 (d, ÍH, J = 2.0 Hz), 5.89 (q, ÍH, J = 6.8 Hz). ESHRMS m / z 494.8174 (Calculated for M-H 494. 8202). Analysis calculated for CnH5F3I2? 3: C, 26.64 H, 1.02. Found C, 26.75; H, 1.06.

EXAMPLE 135 6- (5-Chloro-2-) -2- (trifluoromethyl) -2H-1 benzopyran-3-sarboxylic acid £ 50 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 125, using ethyl 6-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate ( Example 72, Step 3) as the starting material: mp 205-206 ° C. XH NMR (CD3OD / 300 MHz) 7.83 (s, ÍH), 7.50-7.58 (m, 2H), 7.14 (d, ÍH, J = 4.0 Hz), 7.00 (d, 1H, J = 8.86 Hz), 6.93 ( d, ÍH, J = 4.0 Hz), 5.77 (q, ÍH, J = 7.0 Hz). EIHRMS m / z 359.9810 (M +, Calculated 359.9835). Analysis calculated for C? 5H8CIF303S: C, 49.94; H, 2.24. Found C, 50.14; H, 2.29.

EXAMPLE 136 6- (2-thienyl) -2- (tri-loromethyl) -2H-1-benzopyran-3-sarboxylyl acid 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 125, using ethyl 6-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate (Example 24, Step 3) as the starting material: £ -91 mp 209-212 ° C. XH NMR (CD3OD / 300 MHz) 7.83 (s, ÍH), 7.58-7.62 (m, 2H), 7.30-7.38 (m, 2H), 6.80-7.09 (, 2H), 5.76 (q, ÍH, J = 7.0 Hz). FABHRMS m / z 325.0153 • (Calculated for M-H 325.0146).

EXAMPLE 137 6- (4-Chlorophenyl) -2- (trifluoromethyl) -2H-1-10 benzopyran-3-carboxylic acid The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 125, using 6-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate Ethyl (Example 24, Step 3) as the starting material: mp 212-213 ° C. XH NMR (CD3OD / 300 MHz) 7.89 (s, ÍH), 7. 56-7.66 (m, 4H), 7.40-7.48 (m, 2H), 7.04-7.10 (m, ÍH), 5.77 (q, ÍH, J = 7.0 Hz). ESHRMS m / z 353.0190 (Calculated for M-H 3.53, 0192). Calculated analysis for C17H10CIF3O3: C, 57.56; H, 2.84. Found C, 57.41; H, 2.82. 252 EXAMPLE 138 6- (4-Bromophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylyl acid 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 126, using Ethyl 6-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate (Example 24, Step 3) as the starting material: mp 215-216 ° C. XH NMR (CD3OD / 300 MHz) 7.89 (s, 1H), 7.06-7.71 (m, 6H), 7.04-7.06 (m, ÍH), 5.78 (q, ÍH, J = 6.8 Hz). ESHRMS m / z 396.9681 (Calculated for M-H 396, 9687).

EXAMPLE 139 £ 53- Asido 6- (ethynyl) -2- (tri luoromethyl) -2H-l-benzopyran-3-sarboxylyl 2H-l-benzopyran-3-carboxylic acid • prepared by a procedure similar to the method described in Example 118, using ethyl 6-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate (Example 24, Step 3) as the starting material: mp 198 -200 ° C. XH NMR (CD3OD / 300 MHz) 7.80 (s, ÍH), 7.47 (dd, 1H, J = 8.5 2.0 Hz), 7.41 (d, ÍH, J = 2.0 Hz), 6.97 (d, ÍH, J = 8.5 Hz), 5.71 (q, 1H, J = 6.8 • Hz), 3.06 (s, 1H). ESHRMS m / z 267.0271 (Calculated for M-H 267.0269). Analysis calculated for C 13 H 7 F 303 + 1, 0.6% H20: C, 57.60; H, 2.72. Found C, 57.59; H, 2.62. 15 E JEMPLO 14 0 6-Methyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 4-Me-tylosalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 191.8-254 193. 0 ° C. XH NMR (acetone-d6 / 3 O O MHz) 7.80 (s, ÍH) 7.72-7.73 (m, 2H), 6.90 (d, ÍH, J = 8.4 Hz), 5.91 (q, ÍH, J = 7.2 Hz). Analysis calculated for C? 2Hg03F3: C, • 55.82; H, 3.51. Found: C, 55.89; H, 3.49.

EXAMPLE 141 6-Chloro-8- (4-methoxy-nyl) -2-trifluoromethyl-2H-l-l-benzopyran-3-sarboxylyl acid 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 126: mp 194.0-1 6.0 ° C. H NMR (CDCl3 / 300 MHz) 7.81 (s, 1H), 7.44 (s, ÍH), 7.41 (s, ÍH), 7.34 (d, ÍH, J = 2.4 Hz) 7.21 (d, ÍH J = 2.4 Hz), 6.99 (s, ÍH), 6.96 (s, ÍH), 5.69 (q, 1H, J = 6.7 Hz), 3.86 (s, 3H). FABLRMS m / z 402.2 (M + NH,). ESHRMS m / z 383.0267 (M-H, calculated 383.029796). Analysis calculated for C? 8H? 2CIF304: C, 56. ¿0; H, 3.14; Cl, 9.21. Found: C, 56.08; H, 3.11; Cl, 9.13. 255 EXAMPLE 142 Asido 6-Chloro-2- (tri-loromethyl) -4-ethenyl-2H-l-benzopyran-3-carboxylic acid Step 1: Preparation of ethyl 3- (3-chloro-2-hydroxyphenyl) -3-oxo-propionate • A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution in THF, 800.0 mmol) was cooled to -78 ° C under an atmosphere of hydrogen. HE added a solution of 5-chloro-2-hydroxyacetophenone (45.493 g, 266.67 mmol) in THF (130 mL) dropwise to the stirred solution for 0.5 hour. The reaction was maintained at -78 ° C for 1 hour, warmed at 10 ° C for 2 hours, warmed at 0 ° C for 1 hour, then cooled to -78 ° C. Diethylcarbonate added (35.54 ml, 34.65 g, 29.34 mmol) via syringe in one portion. The temperature was maintained at -78 ° C during 0. 5 hours, it was warmed to room temperature during 0. 5 hours and stirred for 3 hours. The mixture of The crude reaction was carefully poured onto a rapidly stirred ice mixture (1200 ml) / conc HCl (222 ml). The layers were separated and the aqueous phase 256 it was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give an oil that began to crystallize. Hexanes (150 ml) were added and the crystallization proceeded. The crystalline product was collected by vacuum filtration to present the title compound (29.04 g, 45%) as crystalline tin needles: mp 71.8-73.1 ° C. E NMR (CDCl 3/300 MHz) 7.63 (d, ÍH, J = 2.4 Hz), 7.45 (dd, ÍH, J = 8.9, 2.6), 6.98 (d, ÍH, J = 8.9 Hz), 4.25 (q, 2H , J = 7.3 Hz), 3.98 (s, 2H), 1.29 (t, 3H, 7.3 HZ). FABLRMS m / z 249 (M + Li). EIHRMS m / z242.0346. (M +, Calculated 242.0346). Analysis calculated for CnH ?? CI04: C, 54.45; H, 4.57. Found: c, 54.48; H, 4.62.

Step 2. Preparation of ethyl 2- (trifluoromethyl) -6-chloro-4-oxo-4H-l-benzopyran-3-carboxylate. The ketoester (Step 1) (19.2 g, 79.1 mmol) was added with trifluoroacetic anhydride (67.2 mL, 49.9 g, 475.8 mmol), potassium carbonate (44 g, 318 mmol) and toluene (400 mL). This suspension was stirred at room temperature for 36 hours, then heated to reflux for 4 hours. After cooling to room temperature, the suspension was £ 97 poured onto rapidly stirred ice (mechanical stirrer) (300 ml) and aqueous HCl (12 N, 50 ml). The resulting organic phase was separated from the clear mixture, washed with water (5 x 500 ml), brine (1 x 500 ml), dried over MgSO, filtered and concentrated in vacuo, giving solid tin which was dried under vacuum high. This sample was partially dissolved in heptane (100 ml) and ethyl acetate (12 ml) with heating in a steam bath to remove the insoluble material. The filtrate was allowed to cool to room temperature to give desired 4-oxo-4H-l-benzopyran as a fluffy tin solid (14.17 g, 56%): mp 106.7-108.6 ° C. This material was of adequate purity to be used in the next step without further purification.

Step 3. Preparation of ethyl 2- (trifluoromethyl) -4-oxo-dihydro-l-benzopyran-3-carboxylate. A solution of the ketone (Step 2) (6.92 g, 21.58 mmol) stirred and cooled (0 ° C) in tetrahydrofuran (40 ml) and ethanol (50 ml) was treated portionwise with sodium borohydride (NaBH 4, 0.41 g, 10.79 mmol). After 3 hours additional sodium borohydride (0.30 g, 7.93 mmol) was added per portion for 1 hour. The reaction was poured 258 in cold, rapidly stirred aqueous HCl (15 ml of 12 N HCl diluted in 300 ml). During the addition a precipitate formed, which was collected by vacuum filtration and dried under high vacuum to give the desired 4-oxo-dihydro-1-benzopyran substituted as a white powder (6.92 g, 99%): mp 80.2- 84.9 ° C. ? E NMR (CDCl3 / 300 MHz) 12.60 (broad s, ÍH), 7.69 (d, ÍH, J = 2.6 Hz), 7.34 (dd, ÍH, J = 2.6, 8.7 Hz), 6.93 (d, ÍH, J = 8.7 Hz) 5.59 (q, ÍH, 6.6 Hz), 4.46-4.23 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz). FABLRMS / z 329 (M + Li). EIHRMS m / z 322.0213 (M +, Calculated 322.0220). Analysis calculated for CI3H10CI1F3O ..}. with 3.57% water: C, 46.67; H, 3.41. Found: C, 46.62; H, 3.14.

Step Preparation of ethyl 6-chloro-4-trifluoro-methanesulfonoxy) -2-ltrifluoromethyl) -2H-l-benzopyran-3-carboxylate. A 50 ml Hartan flask equipped with partitions and additional funnel was charged with 2,6-di-tert-butylpyridine (1.782 g, 8.679 mmol), methylene chloride (15 ml) and trifluoromethanesulphonic anhydride. (1.22 ml, 2.04 g, 7.23 mmol) followed by dropwise addition of chroman-4-one (Step 3) (2.145 g, ,786 mmol) in methylene chloride (12 ml) for 0.33 hours. After stirring for 16 hours at 259- room temperature, the reaction was concentrated in vacuo and diluted with diethyl ether (50 ml), giving a suspension. The suspension was filtered under vacuum and the filtrate was washed with cold 2N HCl and brine, dried over MgSO, filtered and concentrated in vacuo to give the desired triflate as a mild yellow powder (1.45 g, 55%) of adequate purity. to use without further purification: mp 79.2-80.4 ° C. XH NMR (CDCl3 / 300 MHz) 7.40 9s HH), 7.37 (d, HH, J = 2.4 Hz), 7.02-6.99 (m, HH), 5.92 (q, HH, J = 6.6 Hz), 4.47-4.32 ( , 2H), 1.39 (t, 3H, J = 7.2 Hz).

Step 5_. Preparation of ethyl 6-chloro-4-ethenyl-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate. 6-Chloro-4-trifluoromethanesulfoxy-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid ethyl ester (Step 4) (1.50 g, 3.30 mmol) in anhydrous THF was dissolved. (40 ml) in a 100 ml round bottom flask under nitrogen. Tetrakis (triphenylphosphine) palladium (0) (0.267 g, 0.231 mmol) and lithium chloride were added (0.140 g, 3.3 mmol), followed by tributyleteniles tannano (1.15 g, 3.6 mmol). The resulting solution was heated to reflux for 18 hours. The GCMS analysis indicated that the initial material had been consumed. The reaction mixture was allowed to cool to room temperature and poured into a 20% ammonium fluoride solution (50 ml). After stirring for 1 hour, diethyl ether (100 ml) was added and the mixture was washed with water (2 x 50 ml). The organic phase was dried over MgSO, filtered and concentrated in vacuo to give a brown oil. The crude material was purified by flash column chromatography (hexane) to present the ester as a yellow oil, which crystallized on standing (0.760 g, 69%): mp 51.9-53.2 ° C. XH NMR? . 10 (CDCl 3/300 MHz) 7.46 (d, ÍH, J = 2.4 Hz), 7.28-7.14 (M, 2H), 6.96 (d, ÍH, J = 8.7 Hz), 5.77-5.71 (, 2H), 5.38 ( dd, J = 1.2, 17.9 Hz), 4.32-4.26 (m, 2H), 1.33 (t, 2H, J = 7.1 Hz). FABLRMS m / z 333.2 (M + H). ESHRMS m / z 333.0550 (M + H, Calculated 333.050532). Analysis calculated for Ci5H? 2CIF303 (1.14% w / w H20): C, 53.53; H, 3.72; Cl, 10.53. Found: C, 53.46; H, 3.42; Cl, 10.70.

Step 6. Preparation of 6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid. Step 5 The ester from Step 5 (0.300 g, 0.902 mmol) was dissolved in a mixture of THF-EtOH-H20 (10 mL, 7: 2: 1) and treated with sodium hydroxide (0.360 mL, 0.902 mmol of a solution 2.5 N). This solution was stirred at room temperature for 18 hours. He The solvent was evaporated and the residue was dissolved in water (10 ml). Diethyl ether (10 ml) was added and the mixture was acidified by the addition of concentrated HCl. The organic layer was separated and the aqueous phase was extracted with diethylether (2 x 10 ml). The ether extracts were combined, dried over MgSO, filtered and concentrated in vacuo to give a yellow solid, which was recrystallized from diethyl ether-hexane to present the title compound as a white solid. (0.163 g, 59%): mp 143.0-145.0 ° C. H NMR (CDCl3 / 300 MHz 7.49 (d, 1H, J = 2.6 Hz), 7.33-7.17 (m, 2H), 6.99. (d, ÍH J = 8.5 Hz), 5.82-5.72 (M, 2H), 5.42 (d, ÍH, "= 17.9 Hz) ESHRMS m / z 303.00207 (MH, Calculated 303.003582) Analysis calculated for C? 3H8CIF303 (1.10% w / w H20): C, 50.69; H, 2.74; Cl, 11.51. Found: C, 50.57; H, 2.37; Cl, 11.75.

EXAMPLE 143 Asido 6-chloro-2- (trifluoromethyl) -4-enyl-2H-l-benzopyran-3-sarboxylyl 3r02 - 2H-l-benzopyran-3-carboxylic acid was prepared from ethyl 6-chloro-4- (trifluorome tanosul fonoxi) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate (Example 142, Step 4), using a procedure similar to that described in Example 142, Steps 5-6: mp 225.5-226.6 ° C. 2H NMR (DMSO-d6 / 300 MHz) 7.46-7.39 (m, 4H), 7.20-7.13 (m, 3H), 6.52 (d, ÍH, J = 2.42 Hz) 6.12 (q, 1H, J = 7.1 Hz). FABLRMS m / z 355.1 (M + H). ESHRMS m / z 353.0215 (M-H, Calculated 33.019232). Analysis calculated for C17H? 0CIF3O3: C, 57.56; H, 2.84; Cl, 10.17. Found: C, 57.18; H, 2.66; Cl 10.17.

EXAMPLE 144 6-Chloro-4- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-aarboxyl acid 2H-1-benzopyran-3-carboxylic acid was prepared from 6-chloro- 4- (trif luor ome tansul fonoxi) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate from 3.-03 ethyl (Example 142, Step 4), using a procedure similar to that described in Example 142, Steps 5-6: mp: 200.8-206.7 ° C. aH NMR (CDCl3 / 300 MHz) 7.52 (dd, 1H, J • = 1.21, 5.04 Hz), 7.28 (dd, ÍH, J = 2.42, 8.67 Hz), 7.15 (dd, ÍH, J = 1.21, 3.42 Hz), 6.98-6.93 (m, 2H), 5.83 (q, ÍH) , J = 6.9 Hz). FABLRMS m / z 378 (M + NH 4). Analysis calculated for C15H8CIF303S: C, 49.94; H, 2.24; Cl, 9.83; S, 8.89. Found: C, 50.02; H; 1.98; Cl, 9.34; S, 8.89. 10 • E JEMPLO 145 6-Methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-sarboxylyl acid Step 1. Preparation of 5-methyl-2-mercaptobenzaldehyde.

• Tetarmethyl ethylenediamine was added via syringe (TMEDA) (12.6 ml, 83.5 mmol) to n-BuLi (33 ml of 1.6 M in hexanes, 82.5 mmol) in cyclohexane (40 ml) was added with stirring for 5 minutes. Pasta The resulting tin wash was stirred overnight at room temperature, cooled to 0 ° C, and DMF syringe (4.0 ml, 3.77 g, 51.6 mmol) was added via syringe for 2 minutes. The resulting rubbery gummy paste was stirred at room temperature for 1.3 hours. The reaction mixture was added to 3 N HCl (150 ml). This mixture • it was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated in vacuo to give a brown oil. This oil was purified by flash chromatography on silica gel, eluent with 10% ethyl acetate-hexanes for present 5-methyl-2-mercaptobenzaldehyde (4.47 g, • 69%) as an intensely yellow solid, suitable for use without further purification.

Step 2. Preparation of ethyl 6-methyl-2- (trifluoromethyl) -l 2H-l-benzothiopyran-3-carboxylate. 5-methyl-2-mercaptobenzaldehyde was added (Step 1) (3.25 g, 21.3 mmol) to the DMF (5 ml) and the 4, 4, 4-ethyl trifluorocrotonate (4.32 g, 25.7 mmol). With stirring, K2C03 (3.78 g, 27.3 mmol), causing the reaction to turn deep red. The reaction was stirred at room temperature for 20 hours, acidified with 3N HCl, diluted with ethyl acetate and washed with water, saturated NaHCO 3 solution, brine, dried over MgSO4, filtered and concentrated in vacuo to give an oil. The oil was crystallized from diethyl ether-petroleum ether to give 6-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylate. • ethyl as a mild yellow solid (4.47 g, 69%); mp 93.1-94.7 ° C. tE NMR (acetone-d6 / 300 MHz), 7.94 (s, 1H), 7.41 (s, ÍH), 7.31 (d, ÍH, J = 7.9 Hz), 7.25 (d, 1H, J = 7.9 Hz), 4.96 (q, ÍH, J = 8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H, 1.35 (t, 3H, J = 7.0 Hz), FABLRMS m / z309 (m + Li).

Step 10 Preparation of 6-methyl-2- (trifluoromethyl) -2H-1-benzothiopi-3-carboxylic acid The ester from Step 2 (0.55 g, 1.8 mmol) was dissolved in THF (1.5 mL) and ethanol (1.5 ml), treated with 2.5 N sodium hydroxide (1.5 ml, 3.8 mmol) and stirred at room temperature for 88 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, filtered and recrystallized from diethyl ether / petroleum ether to yield the title compound as a yellow solid (0.14 g, 28%): mp 180.8-184.2 ° C. H NMR (acetone-d6 / 300 MHz) 7.95 (s, ÍH), 7.42 (s, ÍH), 7.31 (d, 1H, J = 8.1 Hz), 7.25 (d, ÍH, J = 8.1 Hz), 4.94 ( q, ÍH, J = 8.7 Hz), 2.34 (s, 3H). FABLRMS m / z 281 (M + Li). EIHRMS / z 274.0250 (M +, Calculated 274.0275). Analysis Calculated for C? 2H9F302S: C, 52.55; H, 3.31. Found: C, 52.54; H, 3.35. 3. 06 6, 8-Dimethyl-2- (tri luroomethyl) -2H-1-benzothiopyran-3-aarboxylyl acid 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: p.p. 220-225 ° C (dec.). tE NMR (acetone-ff / 300 MHz) 11.5 (brs, ÍH), 7.94 (s, 1H), 7.26 (s, ÍH), 7.14 (s, ÍH), 4.98 (q, ÍH, J = 8.7 Hz), 2.34 (s, 3H), 2.31 (s, 3H). FABLRMS m / z 295 (M + Li). EIHRMS m / s 288.0431 (M +, Calculated 288.0432). Analysis Calculated for Ci3HnF302S: C, 54.16; H, 3.85. Found: C, 54.10; H, 3.91.

EXAMPLE 147 6- (1,1-Dimethylethyl) -2- (tri-loromethyl) -2H-1-benzothiopyran-3-sarboxylyl acid. 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: pf 183.8-184.6 ° C. XH NMR (acetone-df5 / 300 MHz) 8.04 (s, ÍH), 7.68 (d, ÍH, J = 2.2 Hz), 7.46 (dd, ÍH, J = 8.3 Hz 2.2 Hz), 7.37 (d, ÍH, J = 8.3 Hz, 4.94 (q, ÍH, J = 8.7 Hz), 1.34 (s, 9H), FABLRMS m / z 334 (M + NH4), ESHRMS m / z 334.1087 300 MHz) 7.52 (dd, ÍH, J = 1.21, 5.04 Hz), 7.28 (dd, 1H, J = 2.42, 8.67 Hz), 7.15 (dd, 1H, J = 1.21, 3.42 Hz), 6.98-6.93 (m, 2H), 5.83 (q, 1H, J = 6.9 Hz). FABLRMS m / z 378 (M + NH 4). Analysis Calculated for C? 5H8ClF303S: C, 49.94; H, 2.24; Cl, 9.83; S, 8.89. Found: C, 50.02; H, 1.98; Cl, 9.34; S, 8.89. (M + NH 4, Calculated 334.1089). Analysis Calculated for C? 5H? 5F302S: C, 56.95; H, 4.78. Found: C, 57.03; H, 4.83.

EXAMPLE 148 7-Methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-sarboxyliase acid 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: p.p. 186.6- 191.9 ° C. aH NMR (acetone-di5 / 300 MHz) 7.96 (s, 1H), 7.49 (dd, 1H, J = 7.6 Hz 2.82 Hz), 7.27 (s, ÍH), 7.14 (d, ÍH, J = 7.6 Hz), 4.96 (q, ÍH, J = 5.3 Hz), 2.36 (s, 3H). ESHRMS m / z 273.0204 (M-H, Calculated 273.0197). Analysis Calculated for C? 2H9F302S (3.32% by weight of H20): C, 50.81; H, 3.57. Found: C, 50.79; H, 3.44. 10 • EXAMPLE 149 6, 7-dimethyl-2- (tri-loromethyl) -2H-1- 15 benzothiopyran-3-carboxy-smooth acid. The 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: pf 235-237 ° C. H NMR (acetone-d / 300 MHz) 7.90 (s, ÍH), 7.33 (s, 20 ÍH), 7.19 (s, ÍH), 4.91 (q, ÍH, J = 8.7 Hz), 2.28 (s, 3H) , 2.26 (s, 3H). FABLRMS m / z 295 (M + Li). EIHRMS m / z 288.0439 (M +, Calculated 288.0432). Analysis Calculated for C? 3H ?? F302S: C, 54.16; H, 3.85. Found: C, 54.13; H, 3.85.

Asido 8-methyl-2- (tri luoromethyl) -2H-1-benzothiopyran-3-sarboxylyl 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: p.p. 224-225 ° C. XH NMR (acetone-d / 300 MHz) 11.60 (br s, 1H), 8.00 (s, 1H), 7.44 (d, ÍH, J = 6.7 Hz), 7.31 (d, 1H, J = 6.8 Hz), 7.21 (m, ÍH), 5.05 (q, ÍH, J = 8.5 Hz), 2.38 (s, 3H). FABLRMS m / z 292 (M + NH4). ESHRMS m / z 292.0591 (M + NH4, Calculated 292.0619). Calculated Analysis for C? 2H9F302S: C, 52.55; H, 3.31. Found: C, 52.63; H, 3.38. 15 EXAMPLE 151 Asido 2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: p.p. 187-190 ° C. 1H NMR (acetone-dg / 300 MHz), 8.01 (s, ÍH), 7.60 (d, ÍH, J = 7.5 Hz), 7.45 (m, 2H), 7.31 (m, ÍH), ~ 4.98 (q, ÍH , J = 8.7 Hz). ESHRMS m / z259.0070 (M-H, Calculated 259.0041). Analysis calculated for CnH7F302S: C, 50.77; H, 2.71. Found: C, 50.75; H, 2.78.

EXAMPLE 152 Asido 6-sloro-7- Jmetsil-2- (trirfluoromethyl) -2H-1-benzothiopyran-3-aarboxylyl Step 1. Preparation of N, N-dimethyl-0- (4-chloro-2-formyl-5-methyl phenyl) thiocarbamate. A mixture of 5-chloro-4-methylsalicylaldehyde (12.96 g, 76.0 mmol) and triethyloamine (11.58 g, 114.4 mmol) was dissolved in anhydrous-DMF (15 mL), treated with N, N-dimethyl thiocarbamoyl chloride (11.25 g, 91.0 mmol) and stirred at room temperature. environment for 16 hours. The reaction was treated with 3 N HCl (50 mL), and filtered to give an orange solid. The solid was dissolved in ethyl acetate, washed with 3 N HCl, water, brine, dried over MgSO4, filtered and concentrated in vacuo to present a brown solid. • (16.79 g) which was recrystallized from diethylether / hexane to give the O-aryl thiocarbamate as a tan solid (4.92 g, 25%). 1U NMR (acetone-of / 300 MHz), 9.96 (s, ÍH) 7.80 (s, ÍH), 7.19 (s, ÍH), 3.46 (s, 3H), 3.42 (s, 3H), 2.43 (s, 3H ).

Step 2. Preparation of N, N-dimethyl-S- (-chloro-2-formyl-5-methylphenyl) thiocarbamate. The O-aryl thiocarbamate was dissolved (Step 1) (4.92 g, 19.1 mmol) in N, N-dimethylaniline (25 mL) and immersed and stirred at 200 ° C for 1.5 hours. The The reaction mixture was cooled to room temperature and poured into a mixture of 3 N HCl (200 ml) and ice. The filtrate gave a brown semisolid which was dissolved in ethyl acetate, washed with 3 N HCl, brine, • dried over anhydrous MgSO4, filtered and concentrated in vacuum to present the S-aryl thiocarbamate as a brown oil (3.80 g, 77%) which was used in the next step without further purification.

Step 3. Preparation of ethyl 6-chloro-7-methyl-2- (trifluoromethyl) -25 2H-l-benzothiopyran-3-carboxylate.

The S-arylthiocarbamate (Step 2) (3.80 g, 14.7 mmol) was dissolved in THF (10 ml) and ethanol (10 ml), treated with 2.5 N sodium hydroxide (16.5 ml, 34.2 mmol), and stirred at room temperature for 0.9 hours. The reaction was diluted with diethyl ether and washed with 3 N HCl, brine, dried over MgSO 4, filtered and concentrated in vacuo to yield the crude substituted 2-mercaptobenzaldehyde as a brown oil (2.82 g). This oil was added to DMF (10 ml) and ethyl 4,4,4-trifluorocrotonate (3.89 g, 23.1 mmol). With stirring K2C03 (3.23_g, 23.4 mmol) was added causing the reaction to become deep red. The reaction was stirred at room temperature for 14.5 hours, acidified with 3 N HCl, extracted with ethyl acetate. The resulting organic phase was washed with brine, dried over MgSO, filtered and concentrated in vacuo to give a yellow solid (6.36 g) which was used in the next step without further purification. - Step 4. Preparation of 6-chloro-7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid The ester from Step 3 (2.02 g, 6.0 mmol) was dissolved in THF (10 mL) and ethanol (10 Ail), treated with 2.5 N sodium hydroxide (5.5 ml, 13.8 mmol) and stirred at room temperature for 4.8 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCl, giving a suspension. The solid was collected by filtration and recrystallized from ethanol-r to yield the title compound as a yellow solid (0.20 g, 11%): mp 240.5-241-7 ° C. ? E NMR (acetone-d6 / 300 MHz) 7.99 (s, ÍH), 7.67 (s, ÍH), 7.43 (s, ÍH), 4.99 (q, ÍH, J = 8.5 Hz), 2.39 (s, 3H) . FABLRMS m / z 307 (M-H). FABHRMS m / z 306.9831 (M-H, Calculated 306.9807). Analysis Calculated for C? 2H8CIF302S: C, 46.69; H, 2.61; Cl, 11.48. Found: C, 46.78; H, 2.61; Cl, 11.41.

EXAMPLE 153 7-Chloro-2- (trifluoromethyl) -2H-1-benzothiopyran-3-sarboxyliase acid 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 152: mp 225.7-227.3 ° C. ? E NMR (acetone-of / 300 MHz) 8.02 (s, 1H), 7.63 (d, ÍH, J = .3: 14 8. 3 Hz), 7.54 (d, 1H, J = 2.0 Hz), 7.36 (dd, 1H, J = 8.3 Hz, 2.0 Hz), 5.04 (q, 1H, J = 8.5 Hz). ESHRMS / z 292.9646 (M-H, Calculated 292.9651).

EXAMPLE 154 Acid 6, 7 -Dichloro-2- (trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 152: mp 262.5- 263.5 ° C. TE NMR (acetone-dg / 300 MHz) 8.04 (s, 1H) 7.90 (s, ÍH), 7.74 (s, ÍH), 5.09 (q, ÍH, J = 8.5 Hz). ESHRMS m / z 326.9242 (M-H, Calculated 326.9261).

E JEMPLO 155 2- (Trifluoromethyl) -6- [(trifluoromethyl) thio] -2H-1-benzothiopyran-3-carboxylic acid 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 152 : mp 129.3-132.4 ° C. aH NMR (acetone-of / 300 MHz), 8.10 (s, 2H), 8.00 (s, 2H), 7.71 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.1 Hz), 5.09 (q, ÍH, J = 8.5 Hz). ESHRMS m / z # 358, 9630 (M-H, Calculated 358.9635).

EXAMPLE 156 6,8-Dichloro-2-tri luoromethyl-2H-1-benzothiopi-3-carboxylic acid 2H-1-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 152: mp 217.9 -220.3 ° C. XE NMR (acetone-d6 / 300 MHz) 12.50-11.20 (broad s, 1H intrc), 8.06 (s, 1H) 7.75 (d, ÍH, J = 2.0 Hz), 7.64 (d, ÍH, J = 2.2 Hz), 5.23 (q, 1H, J = 8.5 Hz). ESLRMS m / z 327 (M-H). ESHRMS m / z 326.9272 (M-H, Calculated 326.9261). .316 EXAMPLE 157 6-Chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinesarboxyl acid. Step 1. Preparation of 2-amino-5-chlorobenzaldehyde. 2-Amino-5-chlorobenzyl alcohol (4.8 g, 30 mmol) and activated manganese (IV) oxide (21 g, 240 mmol) were refluxed in chloroform (100 ml) for 1 hour. The contents were allowed to cool, filtered through diatomaceous earth and concentrated in vacuo to present the 2-amino-5-chlorobenzaldehyde as a dark solid (4.14 g, 81%): mp 74-76 ° C. H NMR (CDC13, 300 MHz) 9.80 (s, ÍH), 7.42 (s, ÍH), 7.23 (d, ÍH, J = 7.0 Hz), 6.06 (d, 1H, J = 7.0 Hz).

Step 2_. Preparation of ethyl 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate. The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol), anhydrous potassium carbonate (27.6 g, 200 mmol) and ethyl 4,4,4-trifluorocrotonate (34 ml, 200 mol) were mixed in anhydrous dimethylformamide and heated at 100 ° C for 7 hours. hours. The contents were allowed to cool and were partitioned between ethyl acetate (200 ml) and • water (200 ml). The aqueous layer was extracted with ethyl acetate (1 x 100 ml). The ethyl acetate extracts were combined and washed with brine (1 x 200 ml), dried over MgSO, and concentrated in vacuo, leaving a dark oil which solidified upon standing. The solid was purified by Flash chromatography (silica gel; ethyl acetate-hexanes, 1: 9). The fractions containing the desired product were combined, concentrated in vacuo and the residue recrystallized from ethyl acetate-hexanes to present ethyl 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate as a yellow solid (16.36 g, 56%): mp 132.6- 134.2 ° C. XH NMR (CDC13, 300 MHz), 7.61 (s, ÍH), 7.10 (m, 2H), 6.55 (d, ÍH, J = 8.0 Hz), 5.10 (q, ÍH, J = • 6 0 Hz), 4.55 (broad s, ÍH), 4.23 (m, 2H), 1.32 (t, 3H, J "= 7.0 Hz) FABHRMS m / z 306.04648 (M + H +, Calculated 306.0509) Analysis Calculated for C13H11NO2F3CI: C, 51.08; H, 3.63; N, 4.58. Found: C, 50.81; H, 3.49; N, 4.72.

Step 3. Preparation of 6-chloro-l, 2-dihydro-2-l trifluoro-methyl) -3-quinoline incarboxylic acid. The ester of Step 2 (1.7 g, 5.6 mmol) and • 5 N sodium hydroxide (4.4 ml, 11 mmol) were mixed in tetrahydrofuran (25 ml), methanol (10 ml) and water (25 ml). After stirring overnight, the contents were concentrated in vacuo to remove THF and methanol. The remaining aqueous solution was extracted with diethyl ether (2 x 100 ml). The aqueous layer The resultant was acidified with 2 N HCl causing the precipitation of an oil. The oil was purified by flash chromatography on silica gel, eluent with ethyl acetate-hexanes (1: 1). The fractions containing the desired product were combined and concentrated in vacuum. The residue was triturated with dichloromethane and filtered to give 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid as a yellow solid (0.645 g, • 41%): mp 187.8-188.8 ° C. H NMR (acetone-d6, 300 MHz) 7,, 69 (s, 1H9, 7.36 (s, ÍH), 7.15 (d, ÍH, J = 8.0 Hz), 6.83 (d, ÍH, J = 8.0 Hz), 6.60 (broad s, ÍH), 5.20 (m, 1H) ESHRMS m / z 276.0040 (MH, Calculated 276.0039) Analysis calculated for CpH7N02F3Cl + 2.6% H20: C, 46.39; H, 2.98; N, 4.92 Found: C, 45.99; H, 2.54; N, 4.85.

EXAMPLE 158 Asid 6, 8-Dichloro-l, 2-dihydro-2- (tri-luomomethyl) -3-quinolinesarboxylyl The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 157: mp 223.4 -225.7 ° C. t E NMR (acetone-dg / 300 MHz) 7.82 (s, ÍH), 7.40 (m, 2H), 6.53 (broad s, ÍH), 5.40 (m, ÍH). ESHRMS m / z 309.9657 (M-H, Calculated 309.9649). Analysis calculated for CnH6N02F3Cl2: C, 42.34; H, 1.94; N, 4.49. Found: C, 42.20; H, 1.74; N, 4.52.

EXAMPLE 159 6, 7-Difluoro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinesarboxylic acid The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 157: mp 186.6- 188.9 ° C. X H NMR (acetone-d 6, 300 MHz), 7.79 (s, 1 H), 7.32 (m, 1 H), 6.71 (m, 1 H), 6.64 (broad s, 1 H), 5.21 (m, 1 H). ESHRMS m / z 278.0262 (M-H, Calculated 278.0240). Analysis calculated for CpHeNO? Fs + 1.58% H20: C, 46.58; H, 2.31; N, 4.94. Found: C, 46.20; H, 2.07; N, 4.54.

EXAMPLE 160 6-Iodo-l, 2-dihydro-2- (tri-luomomethyl) -3-quinolinesarboxyl acid Step 1. Preparation of ethyl 6-iodo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate. A mixture of 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol), diazabicyclo [2, 2, 2] -undec-7-ene (32.2 g, 212.0 mmol) and ethyl 4, 4, 4-trifluorocrotonate ( 35.7 g, 212.0 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1H) -pyridiminone (48 ml) was heated at 60 ° C for 8 hours. The solution was brought to room temperature and the solution was poured into ethyl acetate-hexanes (1: 1, 500 ml). The solution was extracted with 2.5 N aqueous hydrochloric acid (2 x a-21 200 ml), saturated aqueous ammonium chloride (2 x 200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexanes (100 ml) and fine yellow crystals formed on standing. Vacuum filtration of this suspension afforded ethyl 6-iodo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate as fine yellow crystals (19.3 g, 50% product): mp 137-138 ° C . XH NMR (CDC13, 300 MHz) 7.62 (s, ÍH), 7.36-7.48 (m, 2H), 6.43 (d, J = 8.2 Hz), 5.36 (broad s, ÍH), 5.11 (q, ÍH, J = 7.1 HzJ, 4.25-4.35 (m, 2H), 1.34 (t, 3H, J = 7.0 Hz) ESHRMS m / z 395.9716 (MH, Calculated 395, 9708).

Step 2. Preparation of 6-iodo-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid. The hydrolysis of the ester was carried out (Step 1) by a procedure similar to that described in Example 157, Step 3, yielding the carboxylic acid: mp 188-192 ° C. XH NMR (CD3OD / 300 MHz) 7.668 (s, HH), 7.46 (d, HH, J = 2.2 Hz), 7.39 (dd, 1H, J = 84.22 Hz), 6.52 (d, HH, J = 8.4 Hz) , 5.01 (q, ÍH, J = 7.5 Hz). ESHRMS m / z 367.9401 (M, Calculated 367, 9395).

EXAMPLE 161 6-Bromo-1,2-dihydro-2- (trifluoromethyl) -3-quinolinesarboxyl acid The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 160: mp 185-186 ° C. ? E NMR (CD3OD / 300 MHz) 7.68 (s, ÍH), 7.31 (d, ÍH, J = 2.2 Hz) 7.23 (dd, 1H, J = 8.7, 2.2 Hz), 6.64 (d, ÍH, J = 8.7 Hz), 5.01 (q, 1H, J = 7.5 Hz). EIHRMS m / z 319.9519 (M, Calculated 319.9534). Analysis Calculated for CnH7BrF3N02: C, 41.02; H, 2.19; N, 4.35; Found: C, 41.27, H, 2.23, N, 4.26.

EXAMPLE 162 Asido 1, 2-Dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinesarboxylyl Step 1. Preparation of 2-amino-5- (trifluoromethoxy) benzoic acid. _ Pellets of (trifluoromethoxy) isatin (15.0 g, 65 mmol) and potassium hydroxide (4 g) in water (35 ml) were mixed and cooled to 0 ° C. With vigorous stirring, a solution of 30% aqueous hydrogen peroxide (11.7 g), potassium hydroxide pellets (5.8 g) and water (80 ml) was added drop by drop, keeping the temperature below 10 ° C. r stirring 1 hour at 0 ° C, glacial acetic acid (22 ml) was added drop by drop, causing the formation of foam and a precipitate. The contents were stirred overnight and filtered to present 2-amino-5-trifluoromethoxy-benzoic acid as an amber solid (12.5 g, 87%). A small amount was recrystallized from ethyl acetate-hexanes to present amber needles for an analytical sample and the remaining compound was used without further purification: mp 142.5-144.2 ° C. H NMR (CDC13, 300 MHz) 7.98 (s, ÍH), 7.18 (d, ÍH, J 0 8.0 Hz), 6.62 (d, ÍH, J = 8.0 Hz), 6.40 (broad s, 2H). Analysis calculated for C8H6N03F3: C, 43.35; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35.

Step 2. Preparation of alcohol 2-amino-5- (trifluoromethoxy) benzyl. 2-Amino-5-trifluoromethoxybenzoic acid (2.0 g, 9.0 mmol) in tetrahydrofuran (20 ml) was added dropwise to the borane methyl sulfide complex (1.5 mL, 15.0 mmol) in tetrahydrofuran (5 mL). The reaction was refluxed overnight and allowed to cool.

A solution of 30% aqueous hydrogen peroxide (0.5 ml), 2.5 N sodium hydroxide (0.5 ml) and water (10 ml) were added drop by drop and the reaction was stirred 0.5 hours. After diluting with diethyl ether (50 ml), the organic layer was washed with 0.1 M aqueous sodium metabisulfite (2 x 10 ml) and 2.5 N aqueous sodium hydroxide (2 x 10 ml). The organic layer was further diluted with hexanes (50 ml) and washed with brine. (2 x 20 ml), dried over anhydrous Na 2 SO 4 and concentrated in vacuo, leaving an amber oil (1.9 g) which solidified. The solid was recrystallized from ethyl acetate-hexanes to present the alcohol 2-amino-5-trifluoromethoxybenzyl as a mild amber solid (1.44 g, 77%): mp 75.9-77.6 ° C. ? E NMR (CDC13, 300 MHz), 7.00 (m, 2H), 6.65 (d, 1H, J = 8.0 Hz), 4. 05 (s, 2H), 3.25 (broad s, 3H). ESHRMS m / z 208.0592 (M + HA Calculated 208.0585). Analysis Calculated for C8H (N02F3 C, 46.39; H, 3.89; N, 6.76) Found: C, 46.61; H, 3.79; N, 6.71.

Step 3. Preparation of 2-amino-5- (trifluoromethoxy) -benzaldehyde. The 2-amino-5-trifluoromethoxybenzyl alcohol from Step 2 (9.7 g, 47 mmol) and manganese (IV) oxide (21 g, 240 mmol) in chloroform (200 mL) were refluxed for 1 hour. The contents were allowed to cool and filtered. The filtrate was concentrated in vacuo, leaving an amber oil (8.2 g) which solidified. The oil was distilled (bulb to bulb or apparatus) at 50 ° C (0.1 m) to present a yellow solid. The solid was recrystallized from hexanes to present the desired 2-amino-5- (trifluoromethoxy) -benzaldehyde as yellow crystals 14.4 g 46%): mp. 42-44 ° C. XH NMR (CDC13, 300 MHz), 9.81 (s, ÍH), 7.36 (s, 1H), 7.20 (d, 1H, J = 9.0 Hz), 6.64 (d, ÍH, J = 9.0 Hz). EIHRMS m / z 205.0328 (M ~, Calculated 205, 0350).

Step 4. Preparation of ethyl 1,2-dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinecarboxylate.

The 2-amino-5- (trifluoromethoxy) benzaldehyde from Step 3 (5.3 g, 26 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol) and ethyl 4,4,4-trifluorocrotonate (7.7 mL, 50 mmol) they were mixed in anhydrous dimethylformamide (50 ml) and heated at 90 ° C for 6 hours. The reaction was allowed to cool to room temperature and was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was extracted with more ethyl acetate (100 ml). The F 10 ethyl acetate extracts were combined and washed with brine (200 ml), dried over MgSO 4 and concentrated in vacuo to give an oil (9.6 g). The oil was purified by flash chromatography on silica gel, eluent with ethyl acetate-hexanes (1: 1). The fractions containing the desired product were combined, concentrated in vacuo, and the residue recrystallized from ethyl acetate-hexanes to present 1,2-dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3- quinolinecarboxylate of ethyl as a yellow solid (4.05 g, 32%): mp 123-135 ° C. ? E NMR (CDC13, 300 MHz) 7.65 (s, ÍH), 7.02 (m, 2H), 6.06 (m, ÍH), 5.10 (m, ÍH), 4.60 (broad s, ÍH), 4.28 (m, 2H), 1.32 (t, 3H, J = 7.0 Hz) at ESHRMS m / z 356.0698 (M-H, Calculated 356.0721). Analysis 3 £ 7 calculated for C14HpN03F6: C, 47.34; H; 3.12; N, 3.94 Found: C, 47.37; H, 3.04; N, 3.93.

Step Preparation of 1,2-dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinecarboxylic acid 1,2-Dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinecarboxylate ethyl of Step 4 (880 mg, 2.5 mmol) and aqueous sodium hydroxide 2.5 N (2 ml) were mixed in methanol (15 ml) and water • (15 ml). The solution was heated in a steam bath for 2 hours. The reaction was allowed to cool to room temperature and extracted with diethylether (50 ml). The aqueous layer was acidified (pH = 1) with HCl N and was extracted with ethyl acetate (2 x 50 ml). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo, leaving an oil. The oil crystallized from • cold dichloromethane-hexanes to present the acid 1, 2-dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinecarboxylic acid as yellow needles (0.727 g, 89%): mp 127.7-128.9 ° C. XH NMR (CDC13, 300 MHz) 7.80 (s, ÍH), 7.05 (m, 2H), 6.62 (d, ÍH, J 8.0 Hz), 5.13 (m, 1H), 4.62 (broad s, ÍH). ESHRMS m / z 326.0252 (M-25 H), Calculated 326.0252). Analysis calculated for C? 2H7N03F6: C, 44.05; H, 2.16; N, 4.28. Found: C, 43.89; H, 2.04; N, 4.24.

• EXAMPLE 163 Asido 6- (tri-loromethyl) -1,2-dihydro-2 - (trifluoromethyl) -3-quinolinesarboxylyl • Step 1. Preparation of N- (4-tri luoromethylphenyl) -2,2-dimethylpropanamide. 10 A solution of dichloromethane (200 ml), 4-aminobenzotrifluoride (32.0 g, 199 mmol) and triethyloamine (40 g, 396 mmol) was coded at 0 ° C under an atmosphere of dry nitrogen. Trimethyloacetylchloride (32.9 g, 273 mmol) was added dropwise drop for 2 hours, keeping the temperature below 10 ° C. After addition, the contents were allowed to warm to room temperature for 2 hours. The reaction was washed with water (2 x 200 ml), saturated ammonium chloride solution (2 x 200 ml), dried over sodium sulfate and filtered. The solvent was removed in vacuo to give a white solid, N- (4-trifluoromethylphenyl) -2,2-dimethylpropanamide (48.0 g, 98%): mp 157-159 ° C. ? E NMR (CDCl3 / 300 MHz) 7.61 (ab, 4H, J = 8.7 (? V = 28.6 Hz), 7.47 (broad s, 1H), 1.33 (s, 9H). ESHRMS m / z 246.1123 (M + HJ Calculated 246.1106) Analysis Calculated for C? 2H14F3NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.

Step 2. Preparation of N-12-formyl-4- (trifluoromethyl) -phenyl-2,2-dimethylpropanamide. A three-necked round bottom flask equipped with equalization addition funnel, magnetic stirrer and temperature monitoring device was charged with N- (4- trifluoromethylphenyl) -2,2-dimethylpropropane ida (10.13 g, 41.4 mmol) and anhydrous tetrahydrofuran (150 ml). The reaction was cooled to -78 ° C under nitrogen followed by the slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) for 0.5 hour, so that the reaction temperature did not rise to more than -65 ° C. The contents were stored at -78 ° C for one hour, 0 ° C for two hours, and cooled again to -78 ° C. Excess N, N-dimethylformamide (100 mL, 1.37 mol) was added. The contents were warmed to room temperature and stirred for two hours. INN HCl was added to the reaction until the pH reached 1. The reaction was washed with water (2 x 200 ml), saturated ammonium chloride solution (2 x 200 ml), dried over sodium sulfate and filtered . The filtrate was concentrated in vacuo to present a yellow solid. The product was purified by flash chromatography (silica gel, 10% ethyl acetate, 90% hexanes) to yield, upon concentration of the appropriate fractions, N- (2-formyl-4-txifluoromethylphenyl) -2, 2-dimet Ipropanamide as a solid (7.36 g, 65%): mp 69-73 ° C. aH NMR (CDCl3 / 300 MHz) 11.5 (broad s, 1H) 9.99 (s, HH), 8.67 (d, HH, J = 8.8 Hz) 7.94 (d, HH, J = 1.6 Hz), 7.83 (m, HH) ), 1.37 (s, 9H). ESHRMS m / z 274.1060 (M + H +, Calculated 274.1055). Analysis Calculated for C? 3H? 4F3N02: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15H, H, 5.43; N, 5.01.

Step 3. Preparation of ethyl 6- (trifluoromethyl) -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate. To a suspension of N- (2-formyl-4- (trifluoro-methyl-phenyl) -2,2-dimethylpropanamide (Step 2) (921 mg, 3.7 mol) and lithium hydride (115 mg, 14.5 mmol) in dimethyl sulfoxide (10 mL) was added 4, 4, 4-trifluorocrotonate of ethyl (2.83 g, 16.8 mmol) and the contents were warmed at 30 ° C for 4 hours. After the addition of ethyl acetate (50 ml), the reaction was washed with water (2 x 30 ml), saturated ammonium chloride solution (2 x 30 ml), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to present a yellow solid. The product was purified by flash chromatography (silica gel, eluent: ethyl acetate-hexanes, 1: 9) to produce, at Concentrate the appropriate fractions, 6- • trifluoromethyl 1-1, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate ethyl as a yellow solid (65 mg, 5%): mp 138-139 ° C. ? E NMR (CDCl3 / 300 MHz), 7.67 (s, ÍH), 7.26 (s, ÍH), 7.04 (d, ÍH, J = 6.6 Hz), 6. 62 (M, 1H), 5.14 (m, ÍH), 4.60 (broad s, ÍH), 4.32 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz). ESHRMS m / z 338.0592 (M-H, Calculated 338.0616). Analysis Calculated for C? 3 HnF3N02: C, 49.57; H, 3.27; N, 4.13; • Found. C, 49.23; H, 2.81; N, 3.93. Step 4. Preparation of ethyl-6-trifluoromethyl-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid 6-trifluoromethyl-1,2-dihydro-2- (trifluoromethyl) -3- was suspended quinolinecarboxylate Ethyl from Step 3 (45 mg, 0.13 mmol) in methanol-tetrahydrofuran-water (10 mL, 7: 2: 1). Lithium hydroxide (24 mg, 0.52 mmol) was added and the mixture was heated gently to reflux for two hours. The reaction was coded at room temperature and 1N HCl was added until the pH = 1. The organic solvent was removed under vacuum to present a suspension of a crude yellow solid. Diethyl ether (20 ml) was added and the solution was washed with water (2 x 20 ml), saturated ammonium sulfate (2 x 20 ml), dried over sodium sulfate and filtered. He • filtrate was concentrated in vacuo to yield 6-trifluoromethyl-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid as a yellow solid, (0.041 g, 0.132 mmol, 99%): microprocessor 150-15 15 ° C. aH NMR (CD3OD / 300 MHz) 7.78 (s, ÍH), 7.48 (s, ÍH), 7.40 (m, ÍH), 6.81 (m, ÍH), 5.17 (m, ÍH). ESHRMS m / z 310.0307 (M-H, Calculated 310.0303).

• EXAMPLE 164 6-Cyano-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinearboxyl acid Step 1. Preparation of ethyl 6-cyano-l, 2-dihydro-2- (tri fluoromethyl) -3-quinolinecarboxylate. N, N-Dimethylformamide (5 ml) was degassed with nitrogen for thirty minutes in a three-necked round bottom flask, equipped with a temperature control, nitrogen purification and heat mantle condenser. Ethyl 6-iodo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added at N, N dimethylformamide and stirred vigorously for ten minutes. Tetrakis (triphenylphosphine) palladium (0) (0.068 g, 0.53 mmol) was added and the contents were gently warmed at 80 ° C for 2 hours under a hydrogen atmosphere. Ethyl acetate (20 ml) was added, followed by extraction with 2N aqueous ammonium hydroxide (2 x 10 ml), water (2 x 10 ml), saturated ammonium chloride (2 x 10 ml), dried over Sodium sulfate and the solvent was removed in vacuo to yield a yellow solid. The product was purified by flash chromatography (silica gel, ethyl acetate-hexanes, 3: 1) to yield, upon concentration of the appropriate fractions, 6-cyano-l, 2-dihydro-2- (trifluoromethyl) -3- ethyl quinolinecarboxylate as a yellow solid (188 mg, 48%): mp 211-212 ° C. 3. -3. 4 tE NMR (CDCl 3 / 3OO MHz) 7.68 (s, ÍH), 7.43 (m, 2H), 6.60 (d, 1H, J = 8.3 Hz), 5.22 (m, ÍH), 4.98 (broad s, 1H), 1.30 (m, 2H), 1.36 (t, 3H, J = 7.1 Hz).

• EIHRMS m / z 314.1147 (M + NHA Calculated 314.1116). Analysis Calculated for C? 4 HnF3N 02: C, 56.76; H, 3.74; N, 9.46. Found: C, 56.44; H, 4.03, N, 9.29.

Step 2. Preparation of 6-cyano-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid 10 To a suspension of 6-cyano-1,2-dihydro-2- • (trifluoromethyl) -3- ethyl quinolinecarboxylate (140 mg, 0.45 mmol) in methanol-tetrahydrofuran-water (10 mL, 7: 2: 1) was added lithium hydroxide (76 mg, 0.91 mmol) and the mixture was heated gently to reflux for two hours. The contents were cooled to room temperature and 1N aqueous hydrochloric acid was added until pH = 1. The organic solvent was removed under vacuum to present a suspension of crude yellow solid. Added diethyl ether (20 ml) and the solution was washed with water (2 x 20 ml), saturated ammonium sulfate (2 x 20 ml), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 6-cyano-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid. as a yellow solid, (116 mg, 95%): mp 238-240 ° C.

XH NMR (CD3OD / 3OO MHz) 7.75 (s, ÍH), 7.56 (m, 1H), 7.43 (m, 1H), 6.79 (d, ÍH, J = 8.5 Hz), 5.19 (q, 1H, J = 7.1 Hz). EIHRMS m / z 267.0405 (M-H, Calculated 267.0381). Analysis Calculated for C? HnF3N202: C, 53.74; H, 2.63; N, 10.45. Found: C, 53.99; H, 2.89; N, 10.19.

EXAMPLE 165 Asido 6-Chloro-l, 2-dihydro-l-methyl-2- (trifluoromethyl) -3-quinolinecarboxylyl Step 1. Preparation of 6-chloro-1,2-dihydro-l-methyl-2- (trifluoromethyl) - Ethyl 3-quinolinecarboxylate. Ethyl 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-15 quinolinecarboxylate (Example 157, Step 2) (1.28 g, 4.21 mmol), tetrabutylammonium iodide (0.36 g, 0.92 mmol) and NaOH aqueous (50%, 2 ml) were stirred vigorously in methylene chloride (40 ml). Dimethyl sulfate (2.12 g, 16.84 mmol) was added to the dark orange mixture via syringe for 2 hours. Hexane (5 ml) was added and the solution was washed with water (2 x 20 ml), saturated ammonium chloride solution (2 x 20 ml), dried over 3.36.

Sodium sulfate and filtered. The filtrate was concentrated in vacuo to present the crude ester as a yellow solid. The solid was purified by F flash chromatography (silica gel, 50 g; 5 ethyl acetate-hexanes, 1:19) to produce, upon concentration of the appropriate fractions, 6-chloro-l, 2-dihydro-l-methyl-2- (trifluoromethyl) Ethyl) -3-quinolinecarboxylate (1.2 g, 90% product): mp 118-120 ° C. 1E NMR (CD3OD / 300 MHz) 7.71 (s, ÍH), 7.30.7.26 (m, 2H), F 10 6.77-6.74 (m, ÍH), 5.12 (q, ÍH, J = 6.8 Hz), 4.44- 4.22 (m, 2H), 3.18 (s, 3H), 1.35 (t, 3H, J = 7.0 Hz) . EIHRMS m / z 320.0701 (M-H, Calculated 320.0665) '. Analysis calculated for C? H? 3F3N02CI: C, 52.60; H; 4.10; N, 4.38. Found: C, 52.57; H, 4.14; N, 4.32. Step 2. Preparation of 6-cyclo-l, 2-dihydro-1-methyl-2- (trifluoromethyl) -3-quinol incarboxylic acid. Ethyl 6-chloro-l, 2-dihydro-l-methyl-2- (trifluoromethyl) -3-quinolinecarboxylate was suspended (1.21 g, 3.78 mmol) in methanol-tetrahydrofuran-water (20 mL, 7: 2: 1). Lithium hydroxide (0.262 g, 6.24 mmol) was added and the mixture was heated gently to reflux for two hours. The reaction was coded at room temperature and HCl was added 1 N until the pH = 1. The organic solvent was ved under vacuum to present a suspension of crude yellow solid. Diethyl ether (20 ml) was added and the resulting solution was washed with water 12 x 20 ml), saturated ammonium chloride (2 x 20 ml), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to present the product as a yellow solid, 6-chloro-l, 2-dihydro-l-methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid (1.08 g, 98% of the product): mp 208-209 ° C. XH NMR (CD3OD / 300 MHz) 7.69"(d, ÍH, J = 2.5 Hz), 7.28-7.24 (m, 2H), 6.73 • (dd, ÍH J = 9.5, 2.5 Hz) 5.13 (q, ÍH, J = 7.0), 3.16 (s, 3H). Analysis Calculated for d2H9F3N02Cl: C, 49. 42; H, 3.11; N, 4.80; Cl, 12.16. Found: 49.88; H, 3.29; N, 4.59; Cl, 12.42. 15 EXAMPLE 166 6-Chloro-l, 2-dihydro-2- (trifluoromethyl) -1- [[4- (tri-loromethyl) enyl] methyl] -3-quinolinecarboxylase 3.38 ' The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a similar procedure in Example 165: mp 229-231 ° C. aH NMR (CD3OD / 300 MHz) 7.7 (s, ÍH), 7.58 (d, 2H, J = 8.0 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.30 (d, ÍH, J = 2.4), 7.13 (dd, ÍH, J = 8.0, 2.4 Hz), 6.75 (d, 1H, J = 8.9 Hz), 5.27 (q, ÍH, J = 7.0 Hz), 4.90 (ab, 2H, J = 16.7 Hz,? v = 95.2 Hz). EIHRMS m / z 434.0401 (Calculated for M-H 434.0383). Analysis calculated for C? 9H? 4F6N02Cl: C, 52.13; H, 3.22; N, 3.22; Found: C, 52.36; H, 2.91; N, 3.21. • EXAMPLE 167 6-Chloro-l- [(4-chloro-enyl) methyl] -1,2-dihydro-2- (trifluoromethyl) -3-quinolinesarboxylyl acid. The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a similar procedure in the Example 165: mp 250-253 ° C. H NMR (CD3OD / 300 MHz) 7. 74 (s, 1H), 7.2-7.3 (m, 6H), 6.76 (d, ÍH, J = 8.7 ? Z), 5.22 (q, ÍH, J = 7.0 Hz), 4.81 (ab, 2H, J = 3.-39 16. 3 Hz,? V = 54.7, Hz). ESHRMS m / z 400.0105 (M-H, Calculated 400, 0119).

EXAMPLE 168 Asido 6-Chloro-l, 2-dihydro-2- (trifluoromethyl) -1- [[4- (methoxy) phenyl] methyl] -3-quinolinesarboxylyl 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a process similar to that described in Example 165: mp 196-197 ° C lH NMR (CD3OD / 300 MHz) 7.71 (s, 1H), 7.27-7.26 (m, ÍH), 7.18-7.12 (m, 3H), 6.85-6.81 (m, 3H), 5.16 (q, ÍH, J = 7.1 Hz ), 4.69 (ab, 2H, J = 15.3 Hz,? V = 111.8 Hz), 3.73 (s, 3H). ESHRMS m / z 396.0625 (M-H, Calculated 396, 0614). Analysis Calculated for C? 9H? 4F6N02Cl: C, 52.13; H, 3.22; N, 3.22. Found: C, 52.36; H, 2.91; N, 3.21.

EXAMPLE 169 • 5 Acid 6 Chloro-1- [(4-cyano-enyl) methyl-1,2-dihydro-2- (trifluoromethyl) -3-quinolinesarboxylyl 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a similar procedure to that described in Example 165: mp 258-260 ° C. 2H NMR (CD3OD / 300 MHz) 7.78 (s, ÍH), 7.66 (d, 2H, J = 8.2 Hz), 7.41 (d, 2H, J = 8.2 Hz), 7.33 (d, 1H, J = 2.7 • Hz), 7.15 (dd, 1H, J = 8.7, 2.7Hz), 6.71 (d, ÍH, J = 8.7) 5.31 (q, ÍH, J = 7.0 Hz), 4.94 (ab, 2H, J = 17.1? v = 91.8 Hz). ESHRMS m / z 391.0443 (M-H, Calculated 391.0461). Analysis Calculated for C? 9H? 2F3N202Cl + 0.53% H20: C, 57.79; H, 3.55; N, 7.09; Found: C, 57.26; H, 3.17; N, 6.78. 3. 1 EXAMPLE 170 Asido 6-Chloro-l, 2-dihydro-l- [(4-nitro-enyl) methyl] -2- (trifluoromethyl) -3-quinolinesarboxylyl 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a similar procedure to that described in Example 165: mp 225-228 ° C LH NMR (CD30D - 3% TFA / 300 MHz) 8.14 (d, 2H, J = 8.8 Hz), 7.77 (s, 1H), 7.42 (d, 2H J = 8.8 Hz), 7.29 (d, ÍH, J = 2.4 Hz ), 7.11 (dd, ÍH, J = 8.9, 2.4 Hz), 6.67 (d, 1H, J = 8.9 Hz), 5.27 (q, 1H, J = 6.8 Hz) 4.93 (ab, 2H, J = 17.2 Hz, ? v = 95.0 Hz). ESHRMS m / z 411, 0327 (M-H, Calculated 411, 0359).

EXAMPLE 171 Aoir Asido 6-Chloro-l, 2-dihydro-l-ethyl-2- (tri-luomomethyl) -3-quinolinesarboxylyl The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a similar procedure in Example 165: mp 201-202 ° C. 1K NMR (CD3OD / 300 MHz) 7.67 (s, ÍH), 7.25-7.22 (m, 2H), 6.86 (d, 1H, J = 8.7 Hz) 5.21 (q, ÍH, J = 7.0 Hz), 3.81-3.71 (m, ÍH), 3.47-3.39 (m, ÍH), 1.20 (t, 3H, J = 7.2 Hz). ESHRMS m / z 304.0360 (M-H, Calculated 304.0352).

EXAMPLE 172 (S) -6-Chloro-l, 2-dihydro-2- (tri-luomomethyl) -3-quinolinecarboxylic acid To a solution of 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid (Example 157) (6.75 g, 24.3 mmol) in ethyl acetate (25 ml), (S) - (-) -a-methylbenzylamine (1.50 g, 12.2 mmol) was added. To the resulting solution was added hexanes (50 ml) with mixture. Agitation was discontinued and the reaction remained static at room temperature for 16 hours, at which time yellow crystals formed. The crystals were collected and washed with ethyl acetate-hexanes (100 mL, 1: 2). The resulting yellow solid (932 mg) was dissolved in ethyl acetate (20 ml) and extracted with IN HCl (3 x 10 ml). The organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. The acid (s) -6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid was obtained as a yellow solid (648 mg, 10% product). mp 173-176 ° C. XH NMR (acetone-300 MHz) 7.80 (s, ÍH), 7.35 (d, 1H, J = 2.2 Hz), 7.18 (d, ÍH, J = 8.0, J = 2.2 Hz), 6.86 (d, ÍH, J = 8.0 Hz) 6.60 (broad s, ÍH), 5.20 (m, ÍH). Analysis calculated for CnH7N02F3Cl C, 47.40, H, 2.54; N, 5.40. Found C, 47.49; H, 2.60; N, 4.98. It was determined that the compound has an optical purity greater than 90% ee. The optical purity was determined by HPLC as described in Example 66.

EXAMPLE 173 6- (2,2,2-Trifluoro-oxyethyl) -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid Step A. Preparation of 6- (l-hydroxy-2), 2,2-trifluoroethyl) -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid ethyl ester. The aldehyde (Example 75, Step 1) (0.89 g, 3.0 mmol) was coded at 0 ° C and treated with a solution of 0.5 M trimethyl- (trifluoromethyl) -silane (8.4 ml, 4.2 mmol) four drops of water were added. a solution of 1.0 M ammonium tetrabutyl fluoride. The reaction was allowed to warm to room temperature and stirred for 21.1 hours. The reaction was cut with 3N HCl, extracted with ethyl acetate, washed with water, brine, dried over MgSO0 and concentrated in vacuo to give a brown oil (1.02 g). This oil was purified by flash chromatography on silica gel, eluent with 10% ethyl acetate / hexanes to present a brown oil. (0.77 g, 58%): NMR (CDCl3 / 300 MHz) 7.72 (d, ÍH, J = 3.4 Hz), 7.34 (m, 2H), 6.99 (d, 1H, J = 8.5 Hz), . 71 (q, ÍH, J 0 6.8 Hz), 4.83 (q, 1H, J = 6.4 Hz), 4.33 (m, 2H), 1.35 (t, 3H, J = 7.1 Hz), 0J 11 (s, 9H) . FABLRMS m / z (M + H).

Step 2. Preparation of 6- (1-hydroxy-2,2,2-trifluoroethyl) -2-trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid: The ester from Step 1 (0.15 g, 0.34 mmol) was dissolved in THF (2 ml) and ethanol (2 ml), treated with 2.5 N NaOH (1 ml, 2.5 mmol) and stirred at room temperature for 18.6 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl, extracted with ethyl acetate, washed with 3 N HCl, brine, dried over MgSO 4 and concentrated in vacuo to give a yellow oil which was recrystallized from from ethyl acetate / hexane to give a white solid (0.03 g, 25%): mp 114-120 ° C. XH NMR (acetone-of / 300 MHz), 7.94 (s, HH), 7.65 (s, 1H), 7.60 (d, ÍH, J = 8.2 Hz, 2.0 Hz), 7.11 (d, HH, J = 8.3 ~ Hz) 5.87 (q, ÍH, J '7.0 Hz), 5.24 (q, ÍH, J "= 7.0 Hz) FABLRMS m / z 341 (MH) ESHRMS / z 341.0241 (MH, Calculated 341.0249) .

EXAMPLE 174 6-Chloro-2- (trifluoromethyl) -1,2-dihydro [1, 8-naphthyridin-3-sarboxyliac acid Step 1. Preparation of N- [5-chloropyridin-2-yl] -2,2-dimethylpropanamide. 3. 46 - To a 2-amino-5-chloropyridine (10.0 g, 0.078 mol) (Aldrich) and triethylamine (12 ml, 0.086 mol) in methylene chloride (200 ml), at 0 ° C, trimethylacetyl chloride in chloride was added dropwise. of methylene (15 ml). The reaction was allowed to warm to room temperature while stirring at night. The resulting mixture was washed with water, brine, dried over MgSO, and filtered. Concentration of the filtrate in vacuo gave a colorless oil (19.2 g). The oil was dissolved in hexanes and cooled causing the precipitation of a solid. The solid was collected by filtration, presenting the amide as a white solid (14.96 g, 90%): mp 51.4-53.4 ° C. 1 H NMR (CDCl 3/300 MHz), 8.25-8.15 (m, 2H), 8.00 (broad s, 1H), 7.68-7.60 (m, ÍH), 1.28 (s, 9H). Analysis calculated for C 10 H 13 N 2 OC 1: C, 56.47; H, 6.16; N, 13.17. Found: C, 56.72; H, 6.34; N, 12.88.

Step 2. Preparation of N- [5-chloro-3-formylpyridin-2-yl] -2, 2 -dimethylpropanamide. To a cooled (-78 ° C) and stirred solution of the amide (Step 1) (5.0 g, 0.024 mol) in tetrahydrofuran (100 ml) was added t-butyl-thio (1.7 M in pentane, 32.4 ml, 0.055). mol) drop depletes. Dimethylformamide (2.3 ml, 0.03 mol) was added dropwise at -78 ° C for 3 hours and the mixture was allowed to warm to room temperature. The reaction was cut with ice water (200 ml) and extracted with ethyl acetate. The resulting organic phase was dried over MgSO4 and concentrated in vacuo to a volume of 20 ml. A white solid was precipitated which was collected by filtration, yielding the formulated product (3.24 g, 56%): mp 168.7-170.8 ° C. XH NMR (CDCl3 / 300 MHz) 10.60 (broad s, ÍH), 9.88 (s, ÍH), 8.57 (s, ÍH), 8.00 (s, ÍH), 1.28 (s, 9H). Calculated Analysis • for CnH? 3N202Cl: C, 54.89; H, 5.44; N, 11.64. Found: C, 54.87; H, 5.42; N, 11.40.

Step Preparation of 2-amino-5-chloro-3-formylpyridine. The product of Step 2 (2.7 g, 11 mmol) and 3 N HCl (50 mL) were heated to reflux for 2 hours. The reaction was allowed to cool to room temperature • environment and concentrated in vacuum, producing a soft yellow solid (2.1 g). The solid was partitioned between ethyl acetate and 2.5 N NaOH solution. The ethyl acetate layer was dried over MgSO4 and concentrated in vacuo to give a solid (1.7 g). The solid was recrystallized from ethyl acetate Ethyl to give the desired substituted pyridine as yellow needles (1.2 g, 68%): mp 176.1-177.3 ° C. X H NMR (CDCl 3/300 MHz) 9.80 (s, 1 H), 8.21 (s, 1 H), 7.75 (s, 1 H), 6.75 (broad s, 2 H). Analysis calculated for C6H5N20C1: C, 46.03; H, 3.22; N, 17.89. Found: C, 45.90; H, 3.24; N, 17.80.

Step 4. Preparation of 6-chloro-2- (trifluoromethyl) -1,2-dihydro [1, 8] -naphyridine-3-carboxylic acid ethyl ester. The substituted pyridine from Step 3 (1.7 g, 11 mmol), anhydrous potassium carbonate (3.0 g, 22 mmol) and ethyl 4,4,4-tri-fluorocrotonate (3.3 mL, 22 mmol) were mixed in anhydrous dimethylformamide. ml) and heated at 80 ° C for 2 hours. The reaction was allowed to cool to room temperature and was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with more ethyl acetate (100 ml). The combined organic extracts were washed with brine (100 ml), dried over MgSO4 and concentrated in vacuo to yield a waxy amber solid. The solid was triturated with diethylether providing the ester as a yellow solid (613 mg, 18%). A small amount was recrystallized from ethyl acetate for the analytical data: mp 180.1-181.9 ° C. XH NMR (CDCl3 / 300 MHz) 7.99 (s, 1H), 7.61 (s, ÍH), 7.39 (s, ÍH), 6.00 (broad s, ÍH), 5.33-5.20 (m, ÍH), 4.04-4.23 ( m, 2H), 1.40-1.30 (m, 3H). Analysis Calculated for C? 2H? 0N2O2F3Cl: C, 47.00; H, 3.29; N, 9.13. Found: C, 46.83; H, 3.03; N, F 9.18.

Step Preparation of 6-chloro-2- (trifluoromethyl) -1,2-dihydro [1,8] naphthyridin-3-carboxylic acid. The ester of Step 4 (1.3 g, 4.4 mmol) and Sodium hydroxide solution 2.5 N (3.5 ml, 9 mmol) was mixed in tetrahydrofuran (25 ml), methanol (10 ml) and water (25 ml). The mixture was heated at 50 ° C for 4 hours, allowed to cool to room temperature and concentrated in vacuo to remove the tetrahydrofuran and methanol. The resulting aqueous solution was washed with diethyl ether (2 x 100 ml). The aqueous phase was acidified with 3 N HCl, causing the precipitation of a yellow solid (1.1 g). He • solid was triturated with ethanol-acetone and collected by vacuum filtering. Providing the title compound as a yellow solid (276 mg, 23%): mp 287-4-288. ° C. XH NMR (acetone-d6 / 300 MHz) 11.50 (broad s, 1H), 8.03 (s, ÍH), 7.83 (s, ÍH), 7.75 (s, ÍH), 7.28 (broad s, ÍH), 5.42-5.30 (my h) . Analysis 3.-50 Calculated for C 2 H 10 N 2 O 2 F 3 Cl: C, 43.11; H, 2.17; N, 10.05. Found: C, 42.88; H, 2.03; N, 10.06.

EXAMPLE 175 Acid (S) -6,8-Dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-sarboxylyl 6,8-Dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid ( Example 32) (300g, 1.04 mol) was added to ethyl acetate (750 ml). The mixture was stirred for 5 minutes, warmed to 70 ° C and kept at this temperature for 5 minutes.

The resulting solution was coded at 50 ° C and (s) - (-) -a-methylbenzylamine (58 g, 0.48 mol) was added. Heptane (1880 ml) was added and the mixture was stirred for 0. 5 hours, then the agitation was interrupted. The reaction was allowed to cool to 22 ° C and was allowed to stand for 8 hours. The salt crystallized in that period of time and was collected by vacuum filtration. The solid was washed with ethyl acetate-heptane (1: 3, 2 x 50 ml). The solid obtained was dried at 40 ° C under vacuum (20 m) for 24 hours to give the salt (35 g, 16%).

A three neck, round bottom flask was deburred with nitrogen and charged with deionized water (750 ml) and salt (103 g, 0.24 mol). This material was obtained using a procedure similar to that described above). To the resulting stirred suspension was added concentrated HCl (37 ml) drop by drop during 0.5 hours with good agitation at less than 20 ° C, precipitating the free carboxylic acid. After stirring for 2 hours, the suspension was filtered under vacuum and the solid was washed with deionized water (5 x 50 ml) until the washings were neutral. The solid was dried at 40 ° C under vacuum (20 mm) for 12 hours, yielding the title compound as a solid (74 g, 100%): mp 166.0-168.4 ° C. 2 NMR (acetone-d6 / 300 MHz), 7.94 (s, 1H), 7.60 (s, 2H), 6.04 (q, ÍH, J = 6.8 Hz). ESHRMS m / z 310.9489 (M-H, Calculated 310.9450). It was determined that this compound has an optical purity greater than 90% ee. The optical purity was determined by the method described in Example 66.

BIOLOGICAL EVALUATION Carrageenan edema test in the rat leg plant The edema test in the rat leg plant with carrageenan was carried out essentially with the materials, reagents and procedures described by Winter, et al., (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats were selected in each group in such a way that the average body weight was as close as possible. The rats were left fasting with free access to water for more than sixteen hours before the test. Rats received oral doses (1 ml) of compounds suspended in a vehicle containing 0.5% methylcellulose and 0.025% surfactant, or, only with vehicle. One hour later, a subplant injection of 0.1 ml of a 1% saline 0.9% solution was teril / carrageenan and the volume of the foot injected was measured with a displacement plethysmograph connected to a pressure transducer with digital indicator. Three hours after the injection of carrageenan, the volume of the foot was measured again. The average swelling of the foot in a group of animals treated with drug was compared with that of the group of animals treated with placebo and the percentage of inhibition of edema was determined (Otterness and Bliven, Labora tory Model s for Tes ting NSAID, in Non- steroidal Anti- Inflammatory Drugs, (J. Lombardino, de. 1985)). The% inhibition shows the% decrease compared to the volume control of the foot determined with this procedure and the data for the selected compounds are summarized in Table I. TABLE I.

Evaluation of COX-1 and COX-2 activity in vi tro The compounds of this invention exhibited inhibition in vitro of COX-2. The COX-2 inhibitory activity of the compounds of this invention illustrated in the Examples was determined by the following methods. to. Preparation of recombinant COX baculoviruses The recombinant COX-1 and COX-2 were prepared according to the description of Gierse et al, [J. Biochem, 305, 479-84 (1995). A 2.0 kb fragment containing the human or murine COX-1 or human or murine COX-2 coding region was cloned into a BamHI site of the baculovirus transfer vector pVL1393 (Invitrogen) in order to generate the baculovirus transfer vectors for COX-1. and COX-2 in a manner similar to the method used by D.R. O. Reilly et al. { Bacul ovi rus Expressi on Vectors: A Labora tory Manual (1992)). Recombinant baculoviruses were isolated by transfection of 4 μg of baculovirus transfer vector DNA into SF9 insect cells (2 x 108) together with 200 ng of baculovirus plasmid DNA aligned by the calcium phosphate method. See, M.D. Summers and G.E. Smith, A Manual of Methods for Bacul ovirus Vectors and Insect Cell Cul t ure Procedures, Texas Agrie. Exp. Station Bull. 1555 (1987). The recombinant viruses were purified by three rounds of plaque purification and high titre virus stock solutions were prepared (107- 108 pfu / ml). For large scale production, SF9 insect cells were infected in 10 liter fermenters (0.5 x 10 6 / ml) with the recombinant baculovirus stock solution in such a way that the multiplicity of infection factor was 0.1. After 72 hours, the cells were centrifuged and the cell pellet was homogenized in Tris / sucrose (50 mM: 25%, pH 3.0) containing 3- [(3-colamidopropyl) dimethylammonium] -1-propane 1% sulfonate. (CHAPS). The homogenate was centrifuged at 10,000 x G for 30 minutes and the resulting supernatant was stored at -20 ° C before evaluating the COX activity. b) Evaluation of COX-1 and COX-2 activity COX activity was evaluated as PGE2 formed / μg protein / time using an ELISA to detect prostaglandin released. Membranes of insect cells solubilized in CHAPS containing the appropriate COX enzyme were incubated in potassium phosphate buffer (50 mM, pH 3.9) containing epinephrine, phenol and heme with the addition of arachidonic acid (10 μM). The compounds were pre-incubated with the enzyme for 10-20 minutes before the addition of the arachidonic acid. The reaction between the arachidonic acid and the enzyme was stopped after ten minutes at 37 ° C / room temperature by transferring 40 μl of reaction mixture into 160 μl ELISA buffer and 25 μM indomethacin. The formed PGE2 was measured by standard ELISA technology (Cayman Chemical). The results are shown in Table II. c. Rapid assessment of COX-1 activity and COX-2 The COX activity was evaluated as PGE2 formed / μg protein / time using an elisa to detect prostaglandin released. Membranes of insect cells solubilized in CHAPS containing the appropriate COX enzyme were incubated in potassium phosphate buffer (0.05 M potassium phosphate, pH 7.5, 2 μM phenol, 1 μM heme, 300 μM epinephrine) with the addition of 20 μM. μl of 100 μM arachidonic acid (10 μM). The compounds were pre-incubated with the enzyme for 10 minutes at 25 ° C before the addition of the arachidonic acid. The reaction between the arachidonic acid and the enzyme was stopped after two minutes at 37 ° C room temperature by transferring 40 μl of reaction mixture to 160 μl of ELISA buffer and 25 μM indomethacin. The PGE formed was measured by standard ELISA technology (Cayman Chemical). The results are shown in Table II.

TABLE II. Example COX-2 * COX-1 * COX-2 COX-1 1 0.3 45 2 < 0.1 78 < 0.1 5.0 6 < 0.1 > 100 7 0.1 16 < 0.1 1.0 8 < 0.1 61 < 0.1 21 9 < 0.1 1.4 < 0.1 < 0.1 12 7 55 13 .3 >; 100 14 • > 100 > 100 15 > 0.1 11 133.6 44 16 < 0.1 24 1.4 51 18 12 > 100 21 11 3.5 22 > 100 > 100 23 7 > 100 24 > 100 25 > 100 78 26 > 100 20 27 67 > 100 29 < 0.1 > 100 • 30 < 0.1 1.2 16 3.8 31 < 0.1 94 32 0.3 31 0.3 0.7 33 < 0.1 5.7 8.2 28 35 2.2 8.9 1.7 11 38 0.2 6.2 25.7 57 39 0.2 45 1.3 > 100 40 < 0.1 24 74 43 Example COX-2"COX-l" COX-2 COX-l IC "UM IC? uM 15M_μM IC ^ .. μM 42 < 0.1 2.3 < 0.1 11 43 99 85 • 44 0.3 72 21 > 100 45 0.2 47 46 > 100 46 0.2 24 74 43 47 1.9 31 1.7 > 100 49 24 > 100 31 > 100 50 79 > 100 52 20 > 100 53 8 13 6 > 100 54 19 > 100 55 46 > 100 53 > 100 56 12 > 100 29 > 100 57 21 10 21 > 100 59 43 > 100 63 1.4 > 100 65 < 0.1 1.0 66 82 38 < 0.1 16.9 67 < 0.1 30 < 0.1 6.7 81 < 0.1 10.5 < 0.1 1.6 82 < 0.1 16 < 0.1 5.6 83 < 0.1 9.6 < 0.1 1.4 84 0.1 25 < 0.1 2.8 • 88 < 0.1 12.4 < 0.1 6.4 91 < 0.1 23 0.2 36 96 0.2 > 100 0.3 100 97 0.2 78 0.1 25 98 2.0 > 100 1.5 19 99 0.2 36 < 0.1 23 101 < 0.1 18 < 0.1 16 103 36 61 104 < 0.1 24 < 0.1 8.2 105 0.3 4.5 0.2 0.1 Example COX-2 COX-l COX-2 COX-l 106 0.2 21 < 0.1 5.7 114 • < 0.1 < 0.1 < 0.1 < 0.1 115 < 0.1 < 0.1 < 0.1 < 0.1 116 < 0.1 < 0.1 < 0.1 < 0.1 120 < 0.1 98 < 0.1 33 125 < 0.1 0.2 < 0.1 < 0.1 129 0.2 2.6 < 0.1 0.3 138 0.3 42.5 < 0.1 11.1 152 < 0.1 74 < 0.1 10 154 0.5 68.5 < 0.1 37 155 < 0.1 1.6 < 0.1 < 0.1 156 < 0.1 0.8 < 0.1 0.1 * rapid test This invention also encompasses a class of pharmaceutical compositions containing the active compounds of Formula I in association with one or more carriers and / or diluents and / or adjuvants • non-toxic, acceptable for pharmaceutical use (collectively referred to as "transport materials") in this documentation) and, if conveniently, other active ingredients. The active compounds of the present invention can be administered by any convenient route, preferably in the form of a pharmaceutical composition adapted to said route and at an effective dose for the intended treatment. Active compounds and composition can be • administered, for example, orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or by topications. The phrase "therapy" (or "combination therapy"), to define the use of a cyclooxygenase-2 inhibitory agent and other agents pharmacists, aims to cover the administration of • each agent sequentially in a regimen that will provide the beneficial effects of the drug combination and also aims to encompass the co-administration of these agents in a manner Substantially simultaneous, as for example in a single capsule having a fixed ratio of these active agents or in multiple separate capsules for each agent. A • The phrase "therapeutically effective" aims to qualify the amount of each agent that will achieve the goal of improvement in the severity of the disease and the frequency of incidence with respect to the treatment of each agent alone, while avoiding associated side effects typically with alternative therapies.

For oral administration, the pharmaceutical composition can be found in the form of, for example, a tablet, a capsule, a • suspension or a liquid. The pharmaceutical composition 5 is preferably made in the form of a dosage unit containing a particular amount of active ingredient. Examples of said dosage units are tablets or capsules. The active ingredient can also be administered by injection a composition in which you can • use, for example, saline, dextrose or water as a suitable transporter. The quantity of therapeutically active compounds that is administered and the regimen of Dosage for the treatment of the disease with the compounds and / or the compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the The route and frequency of administration and the particular compound employed and therefore can vary widely. The pharmaceutical compositions may contain active ingredients in the range of 0.1 to 2000 mg, preferably in the range of 0.5 to 500 mg and more preferably between 1 and 100 mg. A daily dose of 0.01 to 100 mg / kg body weight, preferably between about 0.5 and 20 mg / kg body weight and more preferably from about 0.1 to 10 mg / kg body weight is appropriate. The daily dose can be administered in one to four doses per day. In the case of psoriasis and other skin conditions, it may be preferable to apply a topical preparation of the compounds of the invention four times per day. For eye inflammations or other external tissues, for example, in the mouth and skin, the formulations are preferably applied in an ointment or cream or as a suppository containing the "active ingredients in a total amount of, for example, 0.075 to 30% w / w, preferably 0.2 to 20% w / w and more preferably 0.4 to 15% w / w When formulated as an ointment, the active ingredients can be used with a paraffinic or water-miscible base, Alternatively, the active ingredients are they can be formulated as a cream with a base for oil-in-water cream If convenient, the aqueous phase of the cream base can include, for example, at least 30% by weight of a polyhydric alcohol, such as propylene glycol , butan-, 1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof The topical formulation may conveniently include • a compound that improves the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of said dermal penetration enhancers include dimethyl sulfoxide and related analogues. The compounds of this invention can be administered in a transdermal device. Topical administration is • will be carried out, preferably, using a patch either of the reservoir type or of the porous membrane type or of the solid matrix variety. In any case, the active agent is distributed from continuously from the reservoir or microcapsules through a membrane to the adhesive permeable to the active agent, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, it administers a controlled and predetermined flow of active agent to the recipient. In the case of the microcapsules the encapsulating agent can also function as a membrane. The oil phase of the emulsions of this The invention can be constituted from the known ingredients in a manner also known. While the phase may merely comprise an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with a fat and an oil. The hydrophilic emulsifier is preferably included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier (s) with or without one or more stabilizers, constitute the so-called emulsifying wax, and the wax together with the oil and the fat constitute the so-called emulsifying ointment base which forms the oily dispersed phase of the creamy formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate, among others. The choice of fats or oils suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most of the oils that can be used in the formulations of pharmaceutical emulsions is very low. By 3.65 consequently, the cream will preferably be a non-greasy, non-colored and washable product with a suitable consistency to avoid loss of the • tubes or other containers. Alkyl, straight-chain or branched, mono- or dibasic esters, such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a mixture of esters of • branched chain. These can be used alone or in combination, depending on the required properties. Alternatively, high-melting lipids, such as paraffin, can be used soft white and (or liquid paraffin or other mineral oils.) Formulations suitable for ocular topical administration also include ophthalmic drops in which the active ingredients are dissolve or suspend in a suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in a concentration of 0.5 to 20%, more preferably 0.5 to 10% and with particular preference to 1.5% w / w.

For therapeutic purposes, the active compounds of this invention of combinations are usually combined with one or more adjuvants appropriate for the indicated route of administration. If administered per os, the compounds can be mixed with lactose, sucrose, powdered starch, cellulose esters of alkane acids, cellulosic alkylesters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol and are then formed into tablets or encapsulated for convenient administration. Said capsules or tablets may contain a controlled release formulation, which may be provided in a dispersion of active compound in hydroxypropylmethylcellulose. Formulations for parenteral administration can be found in the form of sterile, isotonic, aqueous or non-aqueous solutions or suspensions for injection. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for the oral administration formulations. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. other adjuvants and modes of administration are well and widely known in the art of pharmaceutical. All references mentioned are incorporated by reference as if they were transcribed in this documentation. The priority document, USSN 60 / 044,485, is also incorporated herein by reference. While this invention was described with respect to specific embodiments, the details of such embodiments should not be considered as limitations.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1 . A compound of Formula I '• characterized in that X is selected from O, S, CR "Rt and wherein Ra is selected from hydrido, C1-C3 alkyl, phenyl-C1-C3 alkyl, (substituted phenyl) -10-C3 alkyl wherein the phenyl ring is substituted with 1 to 3 substituents selected from C-alkyl? -C6, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and C? -C6 alkylamino / acyl and carboxyC? -C6 alkyl; 15 where each of Rb and Rc is independently • selected from hydride, d-C3 alkyl, phenylalkyl of C? -C3, perfluoroalkyl of C1-C3, chloro, alkylthio of C? -C6, alkoxy of Cx-C6, nitro, cyano and cyano-C1-C3 alkyl; Wherein R is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and C6-C6 alkoxycarbonyl; wherein R "is selected from C2-C6 hydride, phenyl, thienyl and alkenyl, wherein R1 is selected from C: -C3 perfluoroalkyl, chloro, C? -C6 alkylthio, C? -C6 alkoxy, nitro, cyano and cyano-C 1 -C 3 alkyl, wherein R 2 is one or more radicals independently selected from hydride, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl , aryl-C de-C3 alkyl, C2-C6 arylalkynyl, C2-C¿ ary1-alkenyl, C?-C6 alkoxy, methylenedioxy, C?-C alqu alkylthio, C?-C6 alkylsulfinyl, aryloxy , arylthio, arylsulfinyl, heteroaryloxy, C? -C? alkoxy of C? -C6alkyl, arylalkyloxy of C? -CD, heteroaryl-C? -C6alkyloxy, arylalkoxy of C? -Ct- alkyl of C? -C6, C? -C6 haloalkyl, Ci-C? haloalkoxy, C? C6 haloalkylthio, C? -C6 haloalkylsulfin, Ci-C haloalkylsulphonyl, C? -C3 haloalkyl hydroxyalkyl ? -C3, hydroxyalkyl of C? -C6, hydroxyimino-alkyl of Ci-C?, Alkylamino of C? ~ C6, arylamino, arylalkyl C 1 -C 6, heteroarylamino, heteroaryl C 1 -C 6 alkylamino, nitro, cyano, amino, aminosulfonyl, C 1 -C 0 alkylaminosul fonyl, arylaminosulfonyl, heteroarylaminosul fonyl, aryl alkylaminosulfonyl of Ci-Ce, heteroaryl C 1 -C 6 -alkylsulfonyl, heterocyclylsulfonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 arylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, C 1 -C 5 aryl alkylcarbonyl, C 6 heteroarylcarbonyl C ", heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C? -C6 alkoxycarbonyl, formyl, C? -C6 haloalkylcarbonyl and C? -C6 alkylcarbonyl; and wherein the ring atoms A, A1, A2, A3 and A "are independently selected from carbon and nitrogen, with the proviso that at least two of A1, A2, A3 and A4 are carbon, or where R2 together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinol and zinyl, quinoxalinyl and dibenzofuryl, or an isomer or pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, characterized in that X is selected from CReRl NRa; wherein R "is selected from hydride, Cx-C3 alkyl, phenylalkyl of C? ~ C3, (phenyl its tituids) -Ci-C3 alkyl where the phenyl ring is substituted with 1 to 3 selected C-alkyl substituents Cr, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and C 1 -C 6 alkylamino, acyl and C 1 -C 4 carboxy alkyl, wherein each is independently selected from hydride, dC alkyl, phenyl, -C1-C3 alkyl, C: -C- perfluoroalkyl, chloro, C? -C6 alkylthio, C? -C6 alkoxy, nitro, cyano and cyanoC? -C3 alkyl, wherein R is selected of carboxyl, aminocarbonyl, C 1 -C 6 alkylsulfonylaminocarbonyl and alkoxycarbonyl F of C? -C6; wherein R "is selected from C2-Ce hydride, phenyl, thienyl and alkenyl, wherein R1 is selected from C1-C3 perfluoroalkyl, chloro, C? -C6 alkylthio, d-C6 alkoxy, nitro, cyano and 15 cyano-C alquilo-C3 alkyl; wherein R 2 is one or more radicals independently selected from hydride, halo, C 1 -C 6 alkyl, C 1 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, or aryl F C 1 -C 3 alkyl, C 1 -C aryl alkynyl, C 2 -C 6 aryl alkenyl, C 1 -C 6 alkoxy, methylenedioxy, Ci-Ce alkylthio, C 1 -C 6 alkylsulfinyl, aryloxy, arylthio, arylsul finyl, heteroaryloxy, C alco-C alco alkoxy, C?-C6 alkyl, C?-C6 alkyloxy, C hetero-C6 heteroaryl-alkyloxy, C?-C alco-alkylaryl-alkyloxy from 25 Ca-Ce, haloalkyl of C? ~ C6, haloalkoxy of C-? -C0, haloalkylthio of d-C6, haloalkylsulfinyl of C? -C6, haloalkylsulfonyl of C? -C6, haloalkyl of C1-C3-hydroxyalkyl of C? -C3, Ci-Cβ hydroxyalkyl, d-C6 hydroxyiminoalkyl, C? -Cu alkylamino, arylamino, C? -C6 arylalkylamino, heteroarylamino, C? -C6 heteroaryl-alkylamino, nitro, cyano, amino, aminosulfonyl, C 1 -C 4 alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, C 1 -C 6 alkylaminosulfonyl, C 1 -C 6 heteroaryl alkylaminosulfonyl, heterocyclylsulfonyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfonyl C6, optionally substituted aryl, optionally substituted heteroaryl, C 1 -C 6 aryl alkylcarbonyl, C 6 -C 6 heteroarylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C 1 -C 0 alkoxycarbonyl, formyl, C 1 -C 6 haloalkylcarbonyl, and alkylcarbonyl of C? -C6; and wherein the atoms in ring A, A1, A2, A3 and A4 are independently selected from carbon and nitrogen, with the proviso that at least three of A1, A2, A3 and A4 are carbon; or wherein R2 together with the ring A forms a naphthyl or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.
3. A compound according to claim 2, characterized in that X is selected from O, S and NRa; wherein Ra is selected from hydride, C? ~ C3 alkyl, (phenyl) ethyl and (optionally phenyl) thiol) methyl where the phenyl ring is substituted with 1 to 3 substituents selected from C? -C6 alkyl, hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and C? -C6 alkylamino; wherein R is carboxyl; wherein R "is selected from hydride and alkenyl of -Ce, wherein R1 is selected from perfluoroalkyl of Ci-d, wherein R2 is one or more radicals independently selected from hydride, halo, dd alkyl, C2-C6 alkenyl , C2-C6 alkynyl, C2-C6 haloalkynyl, phenyl-C6-C6 alkyl, d-C6 phenyl-alkynyl, C-Ce phenyl-alkenyl, d-C3 alkoxy, methylenedioxy, Ci-d-C de-C3 alkyl, C?-C3 alkylthio, at the end of dC, phenyloxy, phenylthio, phenylsulfinyl, Ci-d-hydroxyalkyl haloalkyl of C ?C3, phenylalkyloxy Ci-d-C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 haloalkylthio, C 1 -C 3 hydroxyalkyl, C 3 -C 3 alkoxy, C 1 -C 3 alkyl, hydroxyimino-C 1 -C 3 alkyl, C 1 -C 6 alkylamino, nitro, cyano, amino, aminosulfonyl, N-alkylaminosul fonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl, N- (phenyl-dC 6 alkyl) aminosulfonyl, N - (heteroaryl-d-C6 alkyl) aminosulfonyl, phenyl-alkylsulfonyl of Ca-C3, 5- to 8-membered heterocyclylsulfonyl, C?-C6 alkylsulfonyl, optionally substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, phenyl-Cil-C6-alkylcarbonyl, phenylcarbonyl, 4-chlorophenylcarbonyl, 4- hydroxy phenylcarbonyl, 4-trifluoromethylphenylcarbonyl, 4-methoxyphenylcarbonyl, aminocarbonyl, formyl and C 1 -C 6 alkylcarbonyl; wherein the atoms in ring A, A1, A2, A3 and A4 are independently selected from carbon and nitrogen, with the proviso that at least three of A1, A2, A3 and A4 are carbon; or wherein R2 together with ring A forms a naphthyl, benzofurylphenyl, or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.
4. A compound according to claim 3, characterized in that X is selected from 0, S, and NRa; wherein Ra is selected from hydride, methyl, ethyl, (4-trifluoromethyl) benzyl, (4-chloromethyl) benzyl, (4-methoxy) benzyl, and (4-cyano) benzyl, (4-nit) benzyl; wherein R is carboxyl; wherein R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, wherein R2 is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, tertbutyl, ethenyl, ethynyl, 5-Chloro-1-pentynyl, 1-pentynyl, 3, 3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl, 4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, methylsulphinyl, phenyloxy, phenylthio, phenylsulfinyl, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxytrifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, nitro, cyano, amino, aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl, N- (benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzylsulfonyl, phenyl-ethylaminosulfonyl, furylsulfonyl, methylsul fonyl, phenyl, phenyl substituted with one or more selected radicals chlorine, fluoro, bromo, methoxy, methylthio and methylsul fonyl, benzimidazolyl, thienyl, thienyl substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, optionally substituted phenylcarbonyl, aminocarbonyl, formyl and methylcarbonyl; wherein the atoms of the ring A, AA A2, A3 and A4 are independently selected from carbon and nitrogen with the proviso that at least three of A1, A2, A3 and A4 are carbon; or wherein R2 together with ring A form a naphthyl, or quinolyl radical; or an isomer or its pharmaceutically acceptable salt.
5. A compound according to claim 4, characterized in that it is selected from compounds, and their isomers and pharmaceutically acceptable salts, from the group consisting of: 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7-ethyl-2-tri fluoromethyl 1-2H-1-benzopyran-3-carboxylic acid; 7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 2, 7-bis (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 7-bromo-2-trifluorometho1-2H-1-benzopy-3-carboxylic acid; 6-chloro-7-methyl-1-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-7- (1,1-dimethylethyl) -2- • trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 5-chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 2-trifluoromethyl 1-2H-1-benzopyran-3-carboxylic acid; 8-Ethoxy-2-trifluoromethyl-1-2H-1-10-benzopyran-3-carboxylic acid; • 7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-bromo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 15-Chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 8-bromo-6-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; • 6-trifluoromethoxy-2-trifluoromethyl 1-2H-20 l-benzopyran-3-carboxylic acid; 8-Fluoro-2-tri fluorometho1-2H-1-benzopyran-3-carboxylic acid; 5, 7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 373- 7,8-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7-isopropyloxy-2-tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7, 8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,8-bis (l, 1-dimethylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 7-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7- (1-methylethyl) -2-trifluoromethyl-2H-benzopyran-3-carboxylic acid; 7-phenyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-Chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-Chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6, 8-dibromo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6, 8-dimethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-Nitro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-amino-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-amino-2-trifluoromethyl 1-2H-1 -benzopyran-3-carboxylic acid ethyl ester; 6-chloro-8-methyl-2-trifluoromethyl-2H-A benzopyran-3-carboxylic acid; 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-6-methoxy-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6, 8-difluoro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-bromo-6-fluoro-2-trifluorometH1-2H-1-benzopyran-3-carboxylic acid; 8-bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-bromo-5-fluoro-2-trifluoromethyl-2H-l-benzoyran-3-carboxylic acid; 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7- (N, N-diethylamino) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [[(phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [(dimethylamino) sulfonyl] -2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6-aminosulfoni-2- (2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6- (methylamino) sulfonyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [(-morpholino) sulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [(1,1-dimethylethyl) -minosulfonyl] -2-trifluoromethyl-1-2H-1-benzopyran-3-carboalic acid; 6- [(2-methylpropyl) aminosul-fonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-6- [[(phenylmethyl) aminojsulfonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-N, N-diethylaminosulfonyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-phenylacetyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- (2, 2-dimethylpropylcarbonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid 6,8-dichloro-7-methoxy-2-tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid: 6- [[(2-furanylmethyl) aminojsul-fonyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid 6- [(phenylmethyl) sulfonyl] -2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid, 6- [[(phenylethyl) aminojsul fonyl] -2- (trifluoromethyl) -2H-l- acid benzopyran-3-carboxylic acid 6-iodo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-chloro-8-iodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8-bromo-6-chloro-2-trifluoromet i 1-2H-1 - • benzopyran-3-carboxylic acid; 5 6-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-bromo-7- (1,1-dimethylethyl) -2- 10- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5,6-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 15 6-hydroxymethyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (difluoromethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 2, 6-bis (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5, 6, 7-trichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6,7,8-trichloro-2- (trifluoromethyl) -2H-1-benzopy-3-carboxylic acid; 6- (methylthio) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (methylsulfonyl) -2- (trifluoromethyl) • 2H-l-benzopyran-3-carboxylic acid; 5, 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (pentafluoroethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 2- (trifluoromethyl) -6- [(trifluoromethyl) thio] -2H-1-benzopyran-3-carboxylic acid; 6, 8-dichloro-7-methyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-2,7-bis (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5-methoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-benzoyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorobenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-hydroxybenzoyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-phenoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8-chloro-6- (4-chlorophenoxy) -2-trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 2- (trifluoromethyl) -6- [4- (trifluoromethyl) -phenoxy) -2H-1-benzopy-3-carboxylic acid; 6- (4-methoxyphenoxy) -2- (trifluoromethyl) -2H-l-benzopyr-n-3-carboxylic acid; 6- (3-Chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8-chloro-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenoxy] -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- [(hydroxyimino) methyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (hydroxymethyl) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8- (1H-Benzimidazol-2-yl) -6-chloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 7- (1,1-dimethylethyl) -2- (pentafluoroethyl) -2H-1-benzopyran-3-carboxylic acid; 335 6-chloro-8- (methoxymethyl) -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (benzyloxymethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-ethenyl-2- (trifluoromethyl) acid • 2H-l-benzopyran-3-carboxylic acid; 6-chloro-8-ethynyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (2-furanyl) -2- (trifluoromethyl) -2H-1-benzopyrn-3-carboxylic acid; 6-chloro-8- (5-chloro-l-pentynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-Chloro-8- (1-pentynyl) -2- (trifluoromethyl) -H-1-benzopy-3-carboxylic acid; 6-chloro-8- (phenylethynyl) -2- (trifluoromethyl) -H-l-enz-opiran-3-carboxylic acid; 6-chloro-8- (3, 3-dimethyl-1-butynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-chlorophenyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-methoxy phenyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (phenylethynyl) -2- (trifluoromethyl) -2H-l-b nzopyran-3-carboxylic acid; 6-chloro-8- (4-chlorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5-chloro-8- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-methyl thio) phenyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-methylsulfonyl) phenyl] -2-10 (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; • 6-chloro-8-phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-bromo-8-fluoro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-fluorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; • 8-chloro-6-fluoro-2- (trifluoromethyl) -20 2H-1-benzopyran-3-carboxylic acid; 6, 8-diiodo-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (5-chloro-2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorophenyl) -2- (trifluoromethyl) - • 2H-1-benzopyran-3-carboxylic acid; 6- (4-bromo-phenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, 6- (ethynyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-methyl-2- (trifluoromethyl) -2H-1- • 10 benzopyran-3-carboxylic acid; 6-chloro-8- (4-methoxy phenyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-2- (trifluoromethyl) -4-ethenyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-2- (trifluoromethyl) -4-phenyl-2H-1-benzopy-3-carboxylic acid; 6-chloro-4- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (2,2,2-trifluoro-l-hydroxyethyl) -2-20 (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-methyl-2- (trifluoromethyl) -2H-1-benzothiopi-3-carboxylic acid; 6, 8-dimethyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6,7,7-dimethyl-2- (trifluoromethyl) -2H-1-bromozole opiran-3-carboxylic acid; 8-methyl-2-trifluoromethyl) -2H-1-benzothi opiran-3-carboxylic acid; 2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; • 6-Chloro-7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 7-chloro-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 15,6,7-dichloro-2- (tri fluorometyl) -2H-1-benzothiopyran-3-carboxylic acid; 2- (trifluoromethyl) -6- [(trifluoromethyl) thio] -2H-1-benzopyran-3-carboxylic acid; • 6,8-dichloro-2-trifluoromethyl-2H-1-benzo-thiopyran-3-carboxylic acid; 6-chloro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6, 8-dichloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6,7-difluoro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-iodo-l, 2-dihydro-2- (trifluoromethyl) acid • • 3-quinolinecarboxylic; 5 6-bromo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 1, 2-dihydro-6- (trifluoromethoxy) -2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6- (trifluoromethyl) -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarbo-xylic acid; • 6-cyano-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-l-methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -1- [[4- (trifluoromethyl) phenyl] methyl] -3-quinolinecarboxylic acid; 6-chloro-l- [(-chlorophenyl) methylj-1, 2- dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; • 6-Chloro-1,2-dihydro-2- (trifluoromethyl) -1-20 [[4- (methoxy) phenyl] methyl] -3-quinolinecarboxylic acid; 6-chloro-l- [(4-cyanophenyl) methylj-1, 2- dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-l- [(4-nitrophenyl) methyl] -2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-l-ethyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-2- (trifluoromethyl) -1,2- • dihydro [1,8] naphthyridine-3-carboxylic acid; 2-trifluoromethyl-2H-naphtho [1,2-bjpyran-3-carboxylic acid; 2-trifluoromethyl-3H-naphtho [2, 1-b] pyran-3-carboxylic acid; 2-trifluoromethyl-2H-naphtho [2,3-b] pyran- & 3-carboxylic acid; 5- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-pyrano [2,3-c] pyridine-3-carboxylic acid; 6- (trifluoromethyl) -6H-1, 3-dioxolo [4,5- g] [l-benzopyran-7-carboxylic acid; and 3- (trifluoromethyl) -3H-benzofuro [3, 2-f] [l] benzopyran-2-carboxylic acid.
6. A compound according to claim 2, characterized in that X is 0; in Wherein R is carboxyl; wherein R "is selected from C2-C6 hydride and alkenyl, wherein R1 is selected from perfluoroalkyl of d-d, wherein R ~ is one or more radicals independently selected from hydride, halo, C-C alkyl, P-C6 phenylalkyl, C_-C phenylalkynyl, C2-C6 phenylalkenyl, d-C6 alkoxy, phenyloxy, 5- or 6-membered heteroaryloxy, Ci-Ce phenylalkyloxy, C6-C6 heteroaryl-alkyloxy; or 6 • members, haloalkyl of C? ~ C6, haloalkoxy of Ci-C. , 5 N- (C? -C6 alkyl) amino, N, N-di- (C-d alkyl) amino, N-phenylamino, N- (phenyl-dCS) amino, N-heteroarylamino, N- (heteroaryl-C 1 -C 6 -alkylamino), nitro, amino aminosulfonyl, N- (C 1 -C 6 alkyl) aminosulfonyl, N, N-di- (alkyl) 10 C? -C6) aminosulfonyl N-arylaminosul fonyl, N-heteroarylaminosulfonyl, N- (phenyl-dC6 alkyl) aminosulfonyl, N- (heteroaryl-Ct-C6 alkyl) aminosulfonyl, 5- to 8-membered heterocyclisulfonyl, C? -C6 alkylsulfonyl, phenyl Optionally substituted, optionally substituted 5 or 6 membered heteroaryl, C 1 -C 6 phenylalkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl, aminocarbonyl, and alkylcarbonyl • C? -C6; where the ring atoms A, A1, A2, A3 and A4 20 are independently selected from carbon and nitrogen with the proviso that at least three of A1, A2, A3 and A4 are carbon; or an isomer or pharmaceutically acceptable salt thereof.
7. A compound according to claim 6, characterized in that X is 0; wherein R is carboxyl; where R "is selected from F hydride and ethenyl; wherein R1 is selected from trifluoromethyl and pentafluoroethyl; wherein R: is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, terbutyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1- pentynyl, 3, 3-dimethyl-1- Butynyl, benzyl, ** phenylethyl, phenylethynyl, 4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, 15 difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl thio, hydroxymethyl, hydroxytrifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, N-phenylamino, N- (benzyl) amino, nitro, cyano, amino, aminosulfonyl, N-methylaminosul fonyl, N-phenylaminosulfonyl, N-furylaminosul fonyl, N- (benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzylsulphonyl, phenylethylaminosulfonyl, furylsulfonyl, methylsul fonyl, phenyl, phenyl substituted with one or more radicals selected from chlorine, fluoro, bromo, Methoxy, methylthio and methylsul fonyl, benzimidazolyl, thienyl, thienyl substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl and methylcarbonyl; and wherein one of the ring atoms A, A1, A2, A3 and A4 is nitrogen and the other three are carbon; or an isomer or pharmaceutically acceptable salt thereof.
8. A compound according to claim 7, characterized in that X is O; wherein R is carboxyl; wherein R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl; wherein R 2 is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, tertbutyl, ethenyl, ethynyl, 5-chloro-1-pentynyl, 1-pentynyl, 3, 3-dimethyl-1-butynyl , benzyl, phenylethyl, phenyl-ethynyl, 4-chloropheni-1-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, methylsulphinyl, phenyloxy, phenylthio, phenylsulphinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl thio, hydroxymethyl, hydroxytrifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, N-phenylamino, N-35 AAA (benzyl) amino, nitro, cyano, amino, aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl, N- (benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzylsulfonyl, phenylethyl aminosulfonyl, furylsulfonyl, methylsul fonyl, phenyl, phenyl substituted with one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted with. chlorine, furyl, furyl & 10 substituted with chloro, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl and methylcarbonyl; wherein the atoms of ring A, AA A2, A3 and A4 are carbon; or an isomer or pharmaceutically acceptable salt thereof.
9. A compound according to claim 8, characterized in that it is selected from compounds, and their isomers and pharmaceutically acceptable salts, of the group consisting of 20 of: 6-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; (S) -6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-Chloro-7-methyl-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6-chloro-7- (1, 1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-chloro-8- (1-methylethyl) -2-tri fluorome-t-2H-1-benzopyran-3-carboxylic acid; 7- (1,1-dimethylethyl) -2-tri fluorometylH-1-benzopyran-3-carboxylic acid; 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6-trifluoromethoxy-2-tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; (S) -6,8-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-dichloro-7-methoxy-2-trifluoromethyl-2H-1-benzopyran-3 -carboyl acid; 6-Chloro-2-trifluoromethyl-2H-1-benzoyl-3-carboxylic acid; (S) -6-chloro-2-trifluoromethyl-2H-l-benzothiopyran-3-carboxylic acid; 6-cyano-2- (trifluoromethyl) -2H-1- • benzopyran-3-carboxylic acid; 5 (S) -6-Cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-hydroxymethyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (difluoromethyl) -2- (trifluoromethyl) -10 2H-1-benzopyran-3-carboxylic acid; 2,6-bis (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 5, 6, 7-trichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6, 7, 8-trichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (methylthio) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; • 6- (pentafluoroethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 2- (trifluoromethyl) -6- [(trifluoromethyl) thio] -2H-1-benzopyran-3-carboxylic acid; 6, 8-dichloro-7-methyl-2- (trifluoromethyl) -2H-1 -benzopyran-3-carboxylic acid; 6-benzoyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorobenzoyl) -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid; 6- (4-hydroxybenzoyl) -2- (trifluoromethyl) acid 2H-1-benzopyran-3-carboxylic acid; 6-phenoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 2- (trifluoromethyl) -6- [4- (trifluoromethyl) -phenoxy) -2H-1-benzopyran-3-carboxylic acid; (S) -2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenoxy) -2H-1-benzopyran-3-carboxylic acid; 6- (4-methoxyphenoxy) -2- (trifluoromethyl) • 2H-1-benzopyran-3-carboxylic acid; 6- (3-chloro-4-methoxyphenoxy) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 8-chloro-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenoxy] -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-cyano-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (2-thienyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (phenylethynyl) -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-chlorophenyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8 - [(4-methoxyphenyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; (S) -6-chloro-8 - [(4-methoxy phenyl) ethynyl] -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (phenylethynyl) -2- (tri fluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (4-chlorophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-phenyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- (4-bromophenyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6-chloro-8- (4-methoxyphenyl) -2-trifluoromethyl-2H-1-benzspyran-3-carboxylic acid; and 6- (2,2,2-trifluoro-l-hydroxyethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid.
10. A compound according to claim 2, characterized in that X is S; wherein R is carboxyl; wherein R1 is selected from perfluoroalkyl of d-C3; wherein R 2 is one or more radicals independently selected from hydride, halo, C 1 -C 6 alkyl, C 1 -C 6 phenylalkyl, C 2 -C 6 phenylalkyl, C 2 -C 6 phenylalkenyl, C 6 -C 6 alkoxy, phenyloxy, 5 or 6 membered heteroaryloxy, dd phenylalkyloxy, 5 or 6 membered C? -C6 heteroarylalkyloxy, C? -C6 haloalkyl, C? -C6 haloalkoxy, C? -C6 alkylamino, N-phenylamino, N-? (phenyl-C: -Ce) amino, N-heteroarylamino, N- (C 1 -C 3 heteroaryl-alkylamino, nitro, amino, aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosul fonyl, N-heteroarylaminosulfonyl, N- ( phenyl-C?-C6 alkyl) aminosulfonyl, N- (heteroaryl-C?-C6 alkyl) aminosulfonyl, 5- to 8-membered heterocyclylsulfonyl, optionally substituted C?-C¿-phenyl alkylsulfonyl, 5- or 6-membered heteroaryl optionally substituted, phenyl-C 1 -C 6 -alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl, aminocarbonyl and alkylcarbonyl -Ce; wherein the ring atoms A, A1 A 'A4 are sele independently of carbon and nitrogen with the proviso that at least three of A1, A2, A3 and A4 are carbon; or an isomer or pharmaceutically acceptable salt thereof.
11. A compound according to claim 10, characterized in that X is S; wherein R is carboxyl; wherein R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, wherein R" is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, terbutyl, ethenyl, ethynyl , 5-chloro-1-pentynyl, 1-pentynyl, 3, 3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl, 4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, met ilsulfinyl, phenyloxy, phenylthio, phenylsulfonyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxy-tri-fluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, N-phenylamino, N - (benzyl) mino, nitro, cyano, amino, aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosul fonyl, N- (benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzylsulphonyl, phenylethylaminosul fonyl, furilsulf onyl, methylsulfonyl, phenyl, phenyl substituted with one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and methylsul fonyl, benzimidazolyl, thienyl, thienyl substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, furylcarbonyl, phenylcarbonyl, aminocarbonyl, formyl and methylcarbonyl; wherein the atoms of ring A, AA A2, A3 and A4 are carbon; or an isomer or pharmaceutically acceptable salt thereof.
12. A compound according to claim 11, characterized in that it is selected from compounds, and their isomers and pharmaceutically acceptable salts, from the group consisting of: 6-chloro-2-trifluoromethyl-2H-l-benzothiopyran-3-carboxylic acid; 6-methyl-2- (tri fluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6, 8-dimethyl-2- (trifluoromethyl) 2-H-benzothiopi-3-carboxylic acid; 6- (1, 1-dimethylethyl) -2- tri fluorome thi 1) -2H-1-benzothiopyran-3-carboxylic acid 7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6,7-dimethyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 8-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6-chloro-7-methyl-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 7-chloro-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 6,7-dichloro-2- (trifluoromethyl) -2H-1-benzothiopyran-3-carboxylic acid; 2- (trifluoromethyl) -6- [(trifluoromethyl) -thio] -2H-1-benzopyran-3-carboxylic acid; and 6,8-dichloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.
13. A compound according to claim 2, characterized in that X is NRa; wherein Ra is selected from hydride, C?-C3 alkyl, phenyl-C de-C3 alkyl, acyl and carboxy-alkyl C? ~ D; wherein R is carboxyl; wherein R1 is selected from perfluoroalkyl of d.-C3; wherein R ^ is one or more radicals independently selected from hydride, halo, C1-6 alkyl, phenyl-C1-6 alkyl, phenyl-C1-Cr alkynyl, p-C6 phenyl-alkenyl, C-alkoxy? -C6, phenyloxy, 5- or 6-membered heteroaryloxy, phenylalkyloxy of Ci-Ce, heteroaryl-alkyloxy of 5- or 6-membered, haloalkyl of C? -C6, haloalkoxy of C? -C6, alkylamino of Ci-Ce, N phenylamino, N- (phenylalkyl of C? -C6) amino, N-heteroarylamino, N- (heteroaryl-C 1-4 alkylamino), nitro, amino, aminosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, N-heteroarylaminosulfonyl, N- (phenyl-C?-C6 alkyl) aminosulfonyl, N- (heteroaryl-C?-C6 alkyl) aminosulfonyl, 5- to 8-membered heterocyclisulfonyl, Ci-Cß alkylsulfonyl, substituted phenyl Optionally, optionally substituted heteroaryl • of 5 or 6 members, d-C6 phenyl-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl, aminocarbonyl, and d-C6 alkylcarbonyl; where the ring atoms A, A2, A3 and A4 are selected 15 independently of carbon and nitrogen with the proviso that at least three of A1, A2, A3 and A "1 are carbon, or an isomer or pharmaceutically acceptable salt thereof • 20
14. A compound according to the claim 13, characterized in that X is NRa, wherein Ra is selected from hydride, methyl, ethyl, (4- 'tri fluoromethyl) benzyl, (4-chloromethyl) benzyl, (4-methoxy) benzyl, (-cyano) benzyl and ( 4-nitro) benzyl; Wherein R is carboxyl; wherein R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, wherein R" is one or more radicals independently selected from hydride, chlorine, bromine, fluorine, iodine, methyl, tert-butyl, ethenyl , ethynyl, 5-chloro-1-pentynyl, 1-pentynyl, 3, 3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl, 4-chlorophenyl-ethynyl, 4-methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio , methylsulfinyl, phenyloxy, phenylthio, phenylsulfonyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxytrifluoroethyl, methoxy ethyl, hydroxyiminomethyl, N-methylamino, N-phenylamino, N - (benzyl) amino, nitro, cyano, amino, aminosulfonyl, N-methylaminosul fonyl, N-phenylaminosulfonyl, N-furylaminosul fonyl, N- (benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzylsulfonyl, phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one or more radicals selected from chloro, fluoro, bromo, methoxy, methylthio and methylsul fonyl, benzimidazolyl, thienyl, thienyl substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, furylcarbonylp, phenylcarbonyl, aminocarbonyl, formyl and methylcarbonyl; wherein the atoms of ring A, AA A2, A3 and A4 are carbon; or an isomer or pharmaceutically acceptable salt thereof. •
15. A compound in accordance with ia 5 claim 14, characterized in that it is selected from compounds, and their isomers and pharmaceutically acceptable salts, from the group consisting of: 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -F 10 3-quinolinecarboxylic acid; 6, 8-dichloro-l, 2-dihydro-2 - (trifluoromethyl) -3-quinolinecarboxylic acid 6,7-di-fluoro-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 15 6-iodo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-bromo-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; F 1,2-dihydro-6- (trifluoromethoxy) -2-20 (trifluoromethyl) -3-quinolinecarboxylic acid; 6- (trifluoromethyl) -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid: 6-cyano-1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-l-methyl-2 - (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -1 - [[4- (trifluoromethyl) phenyl] methyl] -3-quinolinecarboxylic acid; 6-chloro-l- [(4-chlorophenyl) methyl] -1,2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-2- (trifluoromethyl) -1- [[4- (methoxy) phenyl] methyl] -3-quinolinecarboxylic acid; 10 6-Chloro-l- [(4-cyanophenyl) methylj-1, 2- • dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-l- [(4-nitrophenyl) methyl-2- (trifluoromethyl) -3-quinolinecarboxylic acid; 6-chloro-l, 2-dihydro-1-ethyl-2-15- (trifluoromethyl) -3-quinolinecarboxylic acid; and (S) -6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylic acid.
16. A compound according to claim 2, characterized in that X is selected from 0, S and NRa; wherein Ra is selected from hydride, C?-C3 alkyl, phenyl-C de-d alkyl, acyl and carboxy-C?-C3 alkyl; wherein R is selected from carboxyl; wherein R1 is selected from perfluoroalkyl of C? -C3; wherein the atoms of ring A, A1, A2, A3 and A4 are independently selected from carbon and nitrogen with the proviso that at least three of A1, A2, A "and A4 are carbon, and wherein R2 together with Ring A forms a naphthyl or quinolyl radical, or an isomer or pharmaceutically acceptable salt thereof.
17. A compound according to claim 16, characterized in that X is selected from 0, S, and NRa; wherein Ra is selected from hydride, methyl, ethyl, (4-trifluoromethyl) benzyl, (4-chloromethyl) benzyl, (4-methoxy) benzyl and (4-cyano) benzyl, (4-nitro) benzyl; wherein R is carboxyl; wherein R "is selected from hydride and ethenyl, wherein R1 is selected from trifluoromethyl and pentafluoroethyl, wherein the ring atoms A, AA A2, A3 and A4 are independently selected from carbon and nitrogen with the proviso that at least three of A1, A2, A3 and A4 are carbon, or where R2 together with ring A form a naphthyl radical, or quinolyl, or an isomer or pharmaceutically acceptable salt thereof.
18. A compound according to claim 19, characterized in that it is selected from compounds, and their isomers and pharmaceutically acceptable salts, from the group consisting of: 2-trifluoromethyl-2H-naphtho [1,2-b] pyran-3-carboxylic acid lico 2-trifluoromethyl-3H-naphtho [2, 1-b] pyran-3-carboxylic acid; 2-trifluoromethyl-2H-naphtho [2,3-b] pyran-3-carboxylic acid; 10-5- (Hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-pyrano [2,3-c] pyridine-3-carboxylic acid; 6- (trifluoromethyl) -6h-1, 3-dioxolo [4,5- g] [l-benzopyran-7-carboxylic acid; and 3- (trifluoromethyl) -3H-benzofuro [3, 2- 15 f] [l] benzoyran-2-carboxylic acid.
19. A compound of Formula I Characterized in that X is selected from O or S or NRA wherein Ra is alkyl; wherein R is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl; wherein R1 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R 2 is one or more radicals selected from hydride, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl , arylalkylsulfonyl, heteroaryl aminosulfonyl, aral qui laminosulphyl, heteroaralkylaminosilonyl, heterocyclosul fonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroarylalkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or where R2 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
20. A compound according to claim 19, characterized in that X is oxygen or sulfur; wherein R is selected from carboxyl, d-C6 alkyl, arylalkyl of C? -Cr and alkoxycarbonyl of d-C6; wherein R 1 is selected from C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl and phenyl; and wherein R 2 is one or more radicals selected from hydride, halo, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 6 haloalkyl, d-, C 1 -C 6 alkylamino, nitro, amino, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, 5- or 6-membered heteroarylalkyl-fonyl, aryl-C 1-6 -alkylaminosulfonyl, 5- or 6-membered nitrogen containing heterocyclosulfonyl, C 1 -C 6 alkylsulfonyl, optionally substituted phenyl, arylalkylcarbonyl of C? -C6, and C? -C6 alkylcarbonyl; or wherein R2 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
21. A compound according to claim 20, characterized in that X is oxygen or sulfur; wherein R is carboxyl; wherein R-1 is C6-C6 haloalkyl; and wherein R 2 is one or more radicals selected from hydride, halo, C 1-6 alkyl, C? -C 6 haloalkyl, C 1-6 haloalkoxy, C? -C6 alkylamino, amino, aminosulfonyl, C? -C6 alkylaminosulfonyl, 5- or 6-membered heteroarylalkyl-aminosulfonyl, C 1 -C 6 arylalkyl-aminosulfonyl, C: -d alkylsulfonyl, 6-membered nitrogen containing heterocyclosulfonyl, optionally substituted phenyl, C 1 -arylalkylcarbonyl, and Ca-C 6 alkylcarbonyl; or wherein R2 together with the ring A form a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
22. A compound according to claim 21, characterized in that R is carboxyl; wherein R 1 is selected from fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; and wherein R 2 is one or more radicals selected from hydride, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tertbutyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy amino, N, N-dimethylamino, N, N-diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N- (2-furylmethyl) aminosulfonyl, nitro, N, N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosul fonyl , N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N, N-dimethylaminosulfonyl, N- (2-methylpropyl) aminosulfonyl, N-morpholinesulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or where R2 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
23. A compound according to claim 22, characterized in that R is carboxyl; wherein R 1 is trifluoromethyl or pentafluoroethyl; and wherein R 2 is one or more radicals selected from hydride, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N- (2- furylmethyl) aminosulfonyl, N, N-dimethylamino-sulfonyl, N-methylaminosulfonyl, N- (2,2-dimethylethyl) aminosulfonyl, dimethylaminosulfonyl, 2-methypropylaminosul fonyl, N-morpholino sulphonyl, methylsulfonyl, benzylcarbonyl and phenyl; or wherein R2 together with the ring A form a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.
24. A compound according to claim 23, characterized in that it is selected from compounds, and their isomers and pharmaceutically acceptable salts, from the group consisting of: 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid lico 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8- (1-methylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-chloro-7- (1,1-dimethylethyl) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-chloro-8- (1-methylethyl) -2-trifluoromethyl-1-2H-1-benzopy-3-carboxylic acid; 2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 7- (1,1-dimethylethyl) -2-tri fluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-bromo-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 8-Chloro-2-trifluoromethyl-1H-1-benzopyran-3-carboxylic acid; 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 5, 7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7, 8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-bis (1,1-dimethylethyl) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 7- (1-methylethyl) -2-trifluoromethyl-2H-benzopyran-3-carboxylic acid; 7-pheny1-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-Chloro-7-ethyl-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-7-phenyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6,7-dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6, 8-dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 2-trifluoromethyl-3H-naphtho [2, 1-bjpyran-3-carboxylic acid; 6-Chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-6-methoxy-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6-bromo-8-chloro-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 8-bromo-6-fluoro-2-trifluorometho1-2H-1-benzopyran-3-carboxylic acid; 8-bromo-6-methyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-bromo-8-methoxy-2-trifluoromethyl-1-2H-1-benzopyran-3-carboxylic acid; 6- [[(phenylmethyl) aminojsulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [(dimethylamino) sulfonylj-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [(methylamino) sulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; [(4-morpholino) sulfonyl] -2-tri fluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6- [(1, 1-dimethylethyl) aminosulfonyl] -2-trifluoromethyl-2H-l-enzopyran-3-carboalic acid; 6- [(2-methylpropyl) aminosulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-methylsulfoni-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 8-chloro-6- [[(phenylmethyl) aminojsulfoni 1] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-phenyl acetyl-2-trifluoromethyl-1H-1-benzopyran-3-carboxylic acid; 6, 8-dibromo-2-trifluorometho1-2H-1-benzopyran-3-carboxylic acid; 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6, 8-dichloro- (S) -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6-benzylsulfoni-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid; 6- [[N- (2-furylmethyl) aminojsul-fonyl] -2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; 6- [[N- (2-phenylethyl) aminojsulfonyl] -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-iodo-2-trifluoromethyl-2H-1-benzo-3-carboxylic acid; 7- (1,1-dimethylethyl) -2- entafluoroethyl-2H-1-benzopyran-3-carboxylic acid; and 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid.
25. A compound according to claim 19, characterized in that it has Formula II where X is O or S; wherein R1 is C6-C6 haloalkyl; wherein R3 is selected from hydride, and halo; wherein R 4 is selected from hydride, halo, C 1 -C 6 alkyl, Ci-d haloalkoxy, C -C alkoxy, Ci-d arylalkylcarbonyl, dialkylaminosulfonyl Ci-Ce, C?-C6 alkylaminosulfonyl, Ci-Ce arylalkyl-aminosulfonyl, C?-C6 heteroarylalkyl-aminosulfonyl, and 5 or 6 nitrogen • members containing heterocyclosulfonyl; wherein R5 is selected from hydride, C? -C6 alkyl, halo, C? -C6 alkoxy, and aryl; and wherein R 6 is selected from hydride, halo, C 1 -C 6 alkyl, Ci-Ce alkoxy, and aryl; or an isomer or pharmaceutically salt 10 acceptable of them. •
26. A compound according to claim 1, characterized in that it has the formula lia: wherein R3 is selected from hydride, C? -C6 alkyl, hydroxyalkyl of C? -C0, alkoxy of 20 d-C6 and halo; wherein R 4 is selected from hydride, halo, C 1 -C 6 alkyl, d-alkylthio, d-C 6 haloalkyl, amino, aminosulfonyl, 43L 3 1A C 1 -C 6 alkylsulfonyl, dC alkylsulfinyl, C 1 -C 6 alkoxyalkyl, dd alkylcarbonyl, formyl, cyano, dd haloalkylthio, substituted or unsubstituted phenylcarbonyl, C 1 -C 6 haloalkoxy, C 6 -C 6 alkoxy, arylalkylcarbonyl C? -Cb, dialkylaminosulfonyl of d-C6, alkylaminosulfonyl of C? -C6, arylalkylaminosul fonyl of C: -C < , C? -C6 heteroarylalkylsulfonyl, 5- or 6-membered heteroaryl, d.-Ce hydroxyalkyl, optionally substituted phenyl and 5- or 6-membered nitrogen containing heterocyclosulfonyl; wherein R5 is selected from hydride, d-C6 alkyl, halo, C? -C6 haloalkyl, C? -C6 alkoxy and phenyl; and wherein R6 is selected from hydride, halo, cyano, hydroxyiminomethyl, hydroxyalkyl of Ci-, C2-C6 alkynyl, phenylalkynyl, d-d alkyl, C? -C6 alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof.
27. A compound according to claim 28, characterized in that R3 is selected from hydride, and chlorine; wherein R 4 is selected from chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenylc; wherein R5 is selected from hydride, methyl, tert-butyl, chloro; and wherein R "is selected from hydride, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, and substituted or unsubstituted phenyl, or a pharmaceutically acceptable isomer or salt thereof.
28. A compound according to claim 1, characterized in that it has the Formula Ilb: wherein R 3 is selected from hydride, C 1 -C 6 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce alkoxy and halo; wherein R 4 is selected from hydride, halo, C 1 -C 6 alkyl, C 1 -C 4 alkylthio, C 1 -C 6 haloalkyl, amino, aminosulfonyl, C 1 -C 6 alkylsulfonyl, d-CD alkylsulfin, alkoxyalkyl of d-C6, alkylcarbonyl of d-Ce, formyl, cyano, haloalkylthio of d-d, substituted or unsubstituted phenylcarbonyl, haloalkoxy of C? -C6, alkoxy of d-C6, arylalkylcarbonyl of C-C6, dialkylaminosulfonyl of -C6 , C 1 -C 6 alkylaminosulfonyl, C 1 -C 6 arylalkylaminosulfonyl, Ci-Cβ heteroarylaminosulphonyl, 5 or 6 membered heteroaryl, C-C6 hydroxyalkyl, optionally substituted phenyl and 5 or 6 membered nitrogen containing heterocyclosulfonyl; wherein R5 is selected from hydride, d-C6 alkyl, halo, C? -C6 haloalkyl, C? -C6 alkoxy and phenyl; and wherein R6 is selected from hydride, halo, cyano, hydroxyiminomethyl, hydroxyalkyl of d-C ", C2-C6 alkynyl, phenylalkynyl, Ci-d alkyl, C? ~ Ce alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof.
29. A compound according to claim 28, characterized in that R3 is selected from hydride, and chlorine; wherein R is selected from chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R5 is selected from hydride, methyl, tert-butyl, chloro; and wherein R6 is selected from hydride, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl • replace, and substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof.
30. A compound according to claim 1, characterized in that it has the wherein Ra is selected from C? ~ C6 hydride and arylalkyl; wherein R 3 is selected from hydride, C 1 -C 6 alkyl, C 1 hydroxyalkyl, C 1 -C 6 alkoxy and halo; wherein R4 is selected from hydride, halo, Ci-Ce alkyl, Ca-C6 alkylthio, Ci-, amino, aminosulfonyl haloalkyl, d-C6 alkylsulfonyl, Ci-alkylsulfinyl, C? -C6 alkoxyalkyl, alkylcarbonyl from Ci-, Formyl, cyano, haloalkyl thio of dd, substituted or unsubstituted phenylcarbonyl, haloalkoxy of C? -C3, alkoxy of C? -C6, arylalkylcarbonyl of Ci-Ce, di-alkylaminosulfonyl of Ci-Ce, alkylaminosulfonyl of C? -C6, Ci-C arylalkylaminosulfonyl, C? -C6 heteroarylalkylsulfonyl, 5- or 6-membered heteroaryl, C? -C6 hydroxyalkyl, optionally substituted phenyl and 5- or 6-membered nitrogen containing heterocyclosulfonyl; wherein R 5 is selected from hydrido, d-d alkyl, halo, C 1 -C 6 haloalkyl, Ci- and phenyl alkoxy; and wherein R6 is selected from hydride, halo, cyano, hydroxyiminomethyl, hydroxyalkyl of Ci-d, C2-C6 alkynyl, phenylalkynyl, C? -C alkyl, C? -C6 alkoxy, formyl and phenyl; or an isomer or pharmaceutically acceptable salt thereof.
31. A compound according to claim 30, characterized in that Ra is hydride; wherein R3 is selected from hydride, and chlorine; wherein R 4 is selected from chloro, methyl, tert-butyl, methylthio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl; wherein R ~ is selected from hydride, methyl, tert-butyl, chloro; and wherein R6 is selected from hydride, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethynyl, and substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof.
32. The use of a compound according to claims 1-30; or pharmaceutically acceptable salt thereof for preparing a medicament for treating a cyclooxygenase-2 mediated disorder in a subject.
33. The use according to claim 32, wherein the disorder mediated by cyclo-oxygenase-2 is inflammation.
34. The use according to claim 32, wherein the disorder mediated by cyclooxygenase-2 is arthritis.
35. The use according to claim 32, wherein the cyclooxygenase-2 mediated disorder is pain.
36. The use according to claim 32, wherein the cyclooxygenase-2 mediated disorder is fever. ^ 25_
37. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound, the compound is selected from a family of compounds according to claims 1-30; or pharmaceutically acceptable salt thereof.
38. A process for preparing compounds according to claim 26, the process is characterized in that it comprises (a) condensing an ortho-hydroxybenzaldehyde derivative with an acrylate derivative in the presence of a base to produce a substituted 2H-1-benzopyran ester; e (b) hydrolyzing the ester to the corresponding acid.
39. The process according to claim 38, characterized in that the base is selected from potassium carbonate or an organic base.
40. The process according to claim 39, characterized in that the base is selected from potassium carbonate and triethylamine.
41. A process for preparing compounds according to claim 26, the process is characterized in that it comprises: (a) treating an ortho-hydroxy substituted acetophenone with two or more equivalents of a strong base followed by a reaction with diethyl carbonate to produce an ester beta-keto; (b) condensing the beta-keto ester with an acid chloride or anhydride in the presence of a base with heat to produce a substituted 4-oxo-4H-l-benzopyran; (c) reducing 4-oxo-4H-l-benzopyran to produce a beta-keto ester; (d) acylation of the beta-keto ester in base to produce an enol triflate; (e) the triflate is reduced to produce a substituted 2H-l-benzopyran ester; and (f) saponifying the ester to produce a substituted 2H-l-benzopyran-3-carboxylic acid.
42. The process according to claim 41, characterized in that the strong base is lithium bis (trimethylsilyl) amide.
43. The process according to claim 41, characterized in that the reduction is achieved by reducing an agent selected from sodium borohydride (NaBH4), triethylsilane, and catalytic reduction.
44. The process according to claim 41, characterized in that the acylating agent is trifluoromethanesulfonic anhydride.
45. The process according to claim 41, characterized in that the triflate is reduced with a reagent selected from tri-n-butyltin hydride, lithium chloride and a palladium (0) catalyst.
46. A process for preparing compounds according to claim 28, the process is characterized in that it comprises: (a) treating a thiophenol substituted with a base followed by a treatment with dimethylformamide to produce a substituted 2-mercaptobenzaldehyde; (b) condensing the 2-mercaptobenzaldehyde with an acrylate in the presence of a base to provide a 2H-1-benzothiopyran ester; and (c) saponifying the ester to produce a substituted 2H-l-benzothiopyran-3-carboxylic acid. •
47. The process according to claim 46, characterized in that thiophenol is treated with n-butyl lithium, using TMEDA (N, N, N ', N' -tetramethylethylenediamine).
48. A process for preparing compounds according to claim 30, the process is • characterized in that it comprises: (a) condensing a 2-amino-benzaldehyde derivative with an acrylate derivative to produce a dihydroquinoline-3-carboxylate ester; and (b) saponifying the ester to the corresponding dihydro quinoline-3-carboxylic acid.
49. A process for preparing compounds according to claim 30, the process is characterized in that it comprises: (a) acylating a substituted aniline to produce an amide; (b) treating the amide with an organolithium base, then with dimethylformamide to produce acylated 2-25-aminobenzaldehyde; (c) reacting the benzaldehyde in the presence of a base with an acrylate to form an ester; and (d) treating the ester with an aqueous base to produce a dihydroquinoline-3-carboxylic acid.