Substituted benzopyran derivatives for the treatment of inflammation.

SUBSTITUTED BENZOPYRAN DERIVATIVES FOR THE TREATMENT OF INFLAMMATION

FIELD OF THE INVENTION

This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders, such as inflammation and inflammationrelated disorders .

BACKGROUND OF THE INVENTION

Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG₂, PGH₂ and PGE₂ has been a common target of antiinflammatory drug discovery. However, common non20 steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process.Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.

Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent co o

cr, □5 i .

CL discovery of an inducible enzyme associated with inflammation (named cyclooxygenase-2 (COX-2) or prostaglandin G/H synthase II) provides a viable target of inhibition which. more effectively reduces inflammation and produces fewer and less drastic side effects .

The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel benzopyran, dihydroquinoline, benzo thi opyr an and dihydronapthalene derivatives disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The substituted benzopyran, dihydroquinoline, benzothiopyran and dihydronapthalene derivatives disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.

US Patent No. 5,618,84 3, to Fisher et al. , generically describes acid substituted bicyclic moieties as Ilb/IIIA antagonists. WO 94/13659, published June 23, 1994, describes fused benzo compounds for the treatment of CNS disorders. Manrao et al. (J. Indian. Counc. Chem., 12, 38-41 (1996)) describes carboxy coumarininide derivatives and their antifungal activity. US Patent No. 5,348,976, to Shibata et al., describes amide substituted benzopyrans as anti fungals.

W096/40110, published December 19, 1996, describes benzopyran derivatives as tyrosine kinase modulators. Loiodice et al. (Tetrahedron, 6, 1001-11 (1995)) describe the preparation of 6-chloro-2,3dihydro-4H-l-benzopyran carboxylic acids.

Clemence et al. (J. Med. Chem., 31, 1453-62, (1988)) describe 4-hydroxy-3-quinoltnecarbooxylic acids as starting material in the preparation of antiinflammatories. Lazer, et al. (J. Med. Chem., 40, 980-89 (1997)) describe

APC0 1 149 benzothiopyran carboxylates as starting material in the preparation of antiinflammatories.

Benzopyran-3-carboxylic acids have been described.

Gupta et al. (Indian J. Chem., 21B, 344-347 (1982)) describe .chromene-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 chromene-3-carboxylic acid. US Patent No. 4,665,202, to Rimbault et al., describes 2-phenyl substituted flavenes and thioflavenes as 5-lipoxygenase inhibitors. U.S. Patent No. 5,250,547, to Lochead et al., describe benzopyran derivatives as 5-lipoxygenase inhibitors. Satoh et al. [J. Med. Chem., 36, 3580-94 (1993)] describe substituted chromenes as 5-lipoxygenase inhibitors. U.S. Patent No. 5,155,130, to Stanton et al. describes substituted chromenes as 5-lipoxygenase inhibitors, and specifically 6-benzyloxy-2H-benzopyran-3carboxylic acid as an intermediate.

However, compounds of the current invention have not been described as cyclooxygenase inhibitors.

DESCRIPTION OF THE INVENTION

A class of compounds useful in treating cyclooxygenase25 2 medicated disorders is defined by Formula I':

<img file="AP1149A_D0001.tif" />

AP/T' 9 9 '0 1 6 77 wherein X is selected from 0, S, CR^cR^b and NR^a;

wherein R* is selected from hydrido, C_x-C₃-alkyl, (optionally substituted phenyl)-C_x-C₃-alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-C_x-C₄-alkyl;

wherein each of R^b and R^c is independently selected from hydrido, C_x-C₃-alkyl, phenyl-C_x-C₃-alkyl, C_x-C₃-perf luoroalkyl, chloro, C_x-C₆-alkylthio, C_x-C₆-alkoxy, nitro, cyano and cyanoC_x-C₃-alkyl;

oe wherein CR^eR^b form a cyciopropyl ring,· wherein R is selected from carboxyl, aminocarbonyl, C._tC₆-alkylsulfonylam.inocarbonyl and C_x-C_£-alkoxycarbonyl;

wherein R is selected from hydrido, phenyl, thienyl,

C₂-C₆-alkynyl and C₂-C₆-alkenyl;

wherein R¹ is selected from C_x-C₃-perf luoroalkyl, chloro,

C_x-C_s-alkylthio, C_x-C_e-alkoxy, nitro, cyano and cyano-C_x-C₃alkyl;

wherein R² is one or m;ire radicals independently selected from hydrido, halo, C_x-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆alkynyl, halo-C₂-C_s-alkynyl, aryl-C_x-C₃-alkyl, aryl-C₂-C₆alkynyl, aryl-C₂-C₆-alkenyl, C_x-C_s-alkoxy, methylenedioxy, C_xC₆-alkylthio, C_x-C_e-alkylsulfinyl, -O(CF₂).O-, aryloxy, aryl thio, arylsulf inyl, heteroaryloxy, C_x-C₆-alkoxy-C_x-C₆alkyl, aryl-C_x-C₆-alkyl oxy, heteroaryl-C_x-C₆-alkyloxy, arylC_x-C₆-alkoxy-C_x-C₆-alkyl, C_x-C_e-haloalkyl, C_x-C₆-haloalkoxy, C,C₆-haloalkylthio, C₁-C₆-haloalkylsulfinyl, C₁-C_ihaloalkylsulfonyl, C_x-C₃- (haloalkyl-C_x-C₃-hydroxyalkyl, C_x-C₆hydroxyalkyl, hydroxyimino-C_x-C₆-alkyl, C_x-C₆-alkylamino, arylamino, aryl-C_x-C₆-alkyleimino, heteroarylamino, heteroaryl-C_x-C₆-alkylamino, nitro, cyano, amino, aminosulfonyl, C_x-C₆-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulf onyl, ax'yl-C_x-C_s-alkylaminosulfonyl, heteroaryl-C_x-C₆-alkylaminosulfonyl, heterocyclylsulfonyl, C_x-C₆-alkylsulfonyl, aryl-C_x -C₆-alkylsulf onyl, optionally substituted aryl, optionally substituted heteroaryl, arylC_x-C₆-alkylcarbonyl, heteroaryl-C_x-C₆-alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C_x-C₆ΑΡυΜ 149 alkoxycarbonyl, formyl, Ci-Cg-haloalkylcarbonyl and C₁-C_salkylcarbonyl; and wherein the A ring atoms A¹, A², A³ and A⁴ are independently selected from carbon and nitrogen with the proviso that at least two of A¹, A², A³ and A⁴ are carbon;

or wherein R* together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl;

or an isomer or pharmaceutically acceptable salt 10 thereof.

A related class of compounds useful in treating cyclooxygenase-2 medicated disorders is defined by Formula I:

<img file="AP1149A_D0002.tif" />

wherein X is selected from O or S or NR^a; wherein R^a 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 R² is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optional.ly substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl;

or wherein R^: together with ring A forms a naphthyl radical;

or an isomer or pharmaceutically acceptable salt thereof.

Compounds of the present invention would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other cyclooxygenase-2 mediated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis, liver disease including hepatitis, skin-related conditions such as psoriasis, eczema, burns and dermatitis, and from post-operative inflammation including from ophthalmic surgery such as cataract surgery and refractive surgery. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. Compounds of the invention would be useful in treating inflammation in such diseases as migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin s disease, sclerodoma, rheumatic fever, type I diabetes, neuromuscular junction disease including myasthenia gravis, white matter disease including multiple sclerosis, sarcoidosis, nephrotic syndrome,

Behcet’s syndrome, polymyositis, gingivitis, nephritis,

ΑΡο οιΐ49 hypersensitivity, swelling occurring after injury including brain edema, myocardial ischemia, and the like. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, conjunctivitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. The compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders, such as cortical dementias including Alzheimer’s disease, and central nervous system damage resulting from stroke, ischemia and trauma.

The compounds of the invention are useful as antiinflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, and liver disease. The compounds would also be useful in the treatment of pain, but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer. The compounds would be useful for the treatment of dementias. The term treatment includes partial or total inhibition of the dementia, including Alzheimer's disease, vascular dementia, multi25 infarct dementia, pre-senile dementia, alcoholic dementia, and senile dementia.

The method above would be useful for, but not limited to, treating and preventing inflammation-related cardiovascular disorders in a subject. The method would be useful for treatment and prevention of vascular diseases, coronary artery disease, aneurysm, arteriosclerosis, atherosclerosis including cardiac transplant atherosclerosis, myocardial infarction, embolism, stroke, thrombosis, including venous thrombosis, angina including unstable angina, coronary plague inflammation, bacterialAPT 99/01677 induced inflammation including Chiamydia-induced inflammation, viral induced inflammation, and inflammation associated with surgical procedures such as vascular graining including coronary artery bypass surgery, revascularization procedures including angioplasty, stent placement, endarterectomy, or other invasive procedures involving arteries, veins and capillaries.

The compounds would ba useful for, but not limited to, the treatment of angiogenesis-related disorders in a subject. According to the present invention, the compounds are administered to a subj act in need of angiogenesis inhibition. The method would be useful for treatment of neoplasia, including metastasis,- ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemangiomas, including invantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; and disorders of the female reproductive system such as endometriosis .

Compounds of the invention would be useful for the prevention or treatment of neoplasia including cancer, such as colorectal cancer, braii:. cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamus cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other ):nown cancers that effect epithelial cells throughout the body. Preferably, neoplasia

ΑΡ ο Ο 1 1 4 $ is selected from gastrointestinal cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as sguamus cell and basal cell cancers. The compounds can also be used to treat the fibrosis which occurs with radiation therapy. The method can be used to treat subjects having adenomatous polyps, including those with familial adenomatous polyposis (FAP). Additionally, the method can be used to prevent polyps from forming in patients at risk of FAP.

The administration of compounds of the present invention may be used alone or in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of neoplasia. Alternatively, the compounds described herein may be used in conjunctive therapy. By way of example, the compounds may be administered alone or in conjunction with other antineoplastic agents or other growth inhibiting agents or other drugs or nutrients.

There are large numbers of antineoplastic agents available in commercial use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of neoplasia by combination drug chemotherapy.

Such antineoplastic agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents. Alternatively, other antineoplastic agents , such as metallomatrix proteases (MMP),

SOD mimics or α_νβ₃ inhibitors may be used.

A first family of antineoplastic agents which may be used in combination with compounds of the present invention consists of antimetabolite-type antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from the group consisting of 5-FU-fibrinogen,

LL 9 t 0 a ⁶ ‘SdV acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba-Geigy CGP-3C694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATKF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, doxifluridine,

Wellcome EHNA, Merck &amp; Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N-(2’-furanidyl)-5fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612557, WarnerLambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase inhibitors, Taiho UFT and uricytin.

A second family of antineoplastic agents which may be used in combination with compounds of the present invention consists of alkylating-type; antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from the group consisting of Shionogi 254-S, aldo-phosphamiae analogues, altretamine, anoxirone, Boehringer Mannheim BBR2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, &gt; carmustine, Chinoin-139, Chinoin-153, chlorambucil, ' cisplatin, cyclophosphamide., American Cyanamid CL-286558,

Sanofi CY-233, cyplatate, begussa D-19-384, Sumimoto

DACH?(Mvr)2, diphenylspironustine, diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactol, Nippon Kayaku MK-121, NCI NSC-264395, NCI NSC342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT119, ranimustine, semustine, SmithKline SK&amp;F-101772, Yakult

Honsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, ceroxirone, tetraplatin and trimelamol.

A third family of antineoplastic agents which may he used in combination with compounds of the present invention consists of antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from the group consisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, BristolMyers BMY-25551, Bristol-Myers BMY-26605, Bristol-Myers BMY27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-l, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, Erbamont FCE20 21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid

LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I, rapamycin,

0 rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo SM5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko UCN10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and zorubicin..

A fourth family of antineoplastic agents which may be used in combination with compounds of the present invention consists of a miscellaneous family of antineoplastic agents selected from the group consisting of alpha-carotene, alphadifluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC52, alstonine, amonafide, amphethinile, amsacrine,

Angiostat, ankinomycin, anci-neoplaston A1C, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin, benfluron, benzotript, IpsenBeaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, bromofosfamide, Wellcome BW-502, Wellcome BW-773, caracemide, carmetiiizole hydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX100, Warner-Lambert CI-921.. Warner-Lambert CI-937, WarnerLambert CI-941, Warner-Lamoert CI-958, clanfenur, claviridenone, ICN compound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, elliprabin, elliptinium acetate, Tsumura EPMTC, ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-577 04, gallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, gr.i.folan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin. Otsuka JI-36, Ramot K-477,

Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641 NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine

AP υ ύ 1 1 4 9 derivatives, methylanilinoacridine, Molecular Genetics MGI136, minactivin, mitonafide, mitoguiaone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinoyl) 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 0N0-112, oguizanocine, Akzo Org-10172, pancratistatin, pazelliptine, Warner-Lambert PD111707, Warner-Lambert PD-115934, Warner-Lambert PD-131141,

Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP15 49532, Rhone-Poulenc RP-56976, SmithKline SK&amp;F-104864,

Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-I0094, spatol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypolaione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T20 506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29, tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides and Yamanouchi YM-534.

Examples of radioprotective agents which may be used in combination with compounds of the present invention are AD5, adchnon, amifostine analogues, detox, dimesna, 1-102, MM159, N-acylated-dehydroalanines, TGF- Genentech, tiprotimod,/ amifostine, WR-151327, FUT-187, ketoprofen transdermal, nabumetone, superoxide dismutase (Chiron) and superoxide dismutase Enzon.

Besides being useful for human treatment, these compounds are also useful for veterinary treatment.of companion animals, exotic animals and farm animals,

AP/?/ 9 9 / 0 1 6 77 including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

The present compounds may also be used in cotherapies, partially or ccmpletely, in place of other conventional antiinflammatories, such as together with steroids, NSAIDS, iNOS inhibitors, 5lipoxygenase inhibitors, LTB^ receptor antagonists and LTi hydrolase inhibitors.

Suitable LTA₄ hydrolase inhibitors include RP64956, (S, S) -3-amino-4-(4-benzyloxyphenyl) -2hydroxybutyric acid benzyl ester {Scripps Res.

Inst.), N-(2(R)-(cyclohexylmethyl)-3(hydroxycarbamoyl)propionyl)-L-alanine (Searle) , 7(4-(4-ureidobenzyl)phenyl)heptanoic acid [RhonePoulenc Rorer), and 3-(3-(IE, 3E-tetradecadienyl)-2oxiranyl)benzoic acid lithium salt (Searle).

Suitable LTB₄ receptor antagonists include, among others, ebselen, linazolast, ontazolast, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Merck compound MAFP,

Terumo compound TMK-688, T;inabe compound T-0757, Lilly compounds LY-213024, LY-210073, LY223982, LY233469, and LY255283, LY-293111, 264086 and 292728, ONO compounds ONO-LB457, ONO-4057, and ONOLB-448, Shionogi compound .-5-2474, calcitrol, Lilly compounds Searle compound,;; SC-53228, SC-41930, SC50605 and SC-51146, Warner Lambert compound BPC 15, SmithKline Beecham compound SB-209247 and SK&amp;F compound SKF-104493. Preferably, the LTB₄ receptor antagonists are selected from calcitrol, ebselen, Bayer Bay-x-1005, Ciba Geicry compound CGS-25019C,

Leo Denmark compound ETH-615, Lilly compound LY293111, Ono compound ONO-4057, and Terumo compound TMK-688.

Λ Π 0 π 1 14 9

Suitable 5-LO inhibitors include, among others, Abbott compounds A-76745, 78773 and ABT761, Bayer Bay-x-1005, Cytomed CMI-392, Eisai E-3040, Scotia Pharmaceutica EF-40, Fujirebio F-1322, Merckle ML3000, Purdue Frederick PF-5901, 3M Pharmaceuticals R-840, rilopirox, flobufen, linasolast, lonapolene, masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.

The present compounds may also be used in combination tnerapies with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e. non-addictive) analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin-1 receptor antagonists and sodium channel blockers, among others. More preferred would be combinations with compounds selected from morphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol, dezocine, meptazinol, hydrocodone, oxycodone, methadone, Tramadol [(+) enantiomer], DuP 747, Dynorphine A, Enadoline, RP60180, HN-11608, E-2078, ICI-204448, acetominophen (paracetamol) , propoxyphene, nalbuphine, E-4018, filenadol, mirfentanil, amitriptyline, DuP631, Tramadol [(-) enantiomer], GP-531, acadesine, AKI-1, AKI-2, GP1683, GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078, AXC3742, SNX-111, ADL2-1294, ICI-204448, CT3, CP-99,994, and CP-99,994.

The compounds can be used in combination with one or more antihistamines, decongestants, diuretics, antitussive agents or with other agents previously known to be effective in combination with antiinflammatory agents.

Γ*» ex» o&gt;

The term prevention includes either preventing the onset of clinically evident cardiovascular disorders altogether or preventing the onset of a preclinically evident stage of cardiovascular disorder in individuals.

This includes prophylactic treatment of those at risk of developing a cardiovascular disorder.

The phrase therapeutically-effective'¹ is intended to qualify the amount of each agent which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

The present invention preferably includes compounds which selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Preferably, the compounds have a cyclooxygenase-2 IC₅₀ of less than about 0.5 pM, and also have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase-1 IC_5Q of greater than about 5 μΜ. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.

A preferred class of compounds consists of those compounds of Formula I wherein X is oxygen or sulfur; wherein R is selected from carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl; wherein R¹ is selected from lower haloalkyl, lower cycloalkyi and phenyl; and wherein P? is one or more radicals selected from hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- or G- membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, 5or 6- membered nitrogen containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower

APO π ί 14$ aralkyicarbonyl, and lower alkylcarbonyl; or wherein R²together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.

A more preferred class of compounds consists of those compounds of Formula I wherein X is oxygen or sulfur;

wherein Ris selected from carboxyl; wherein R^xis selected from lower haioalkyl; and wherein R² is one or more radicals selected from hydrido, halo, lower alkyl, lower haioalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5- or 6- membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6- membered nitrogen containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkyicarbonyl, and lower alkylcarbonyl; or wherein R² together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds of Formula I wherein R is carboxyl; wherein R¹ is selected from fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyi; and wherein R² is one or more radicals selected from hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyi, difluoromethyl, trifluoromethoxy, amino,

N,N-dimethylamino, Ν,Ν-diethylamino, Nphenylme thy lamino sulfonyl, N-phenylethylaminosulf onyl, N-(230 furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2dimethylethylaminosulfonyl, N, N-dimethylaminosulf onyl, N-(2methylpropyl) aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl and phenyl; or wherein R² together with ring A

IL 9 L o ¹ θθ /J/dv forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds of Formula I wherein R is carboxyl; wherein R¹ is trifluoromethyl or pe/.itaf luor ethyl; and wherein R² is selected from one or more radicals hydriao, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, Nphenyimethylaminosulfonyl, N-phenylethylaminosulf onyl, N-(2furylmethyl) aminosulfonyl, N,N-dimethylaminosulfonyl, Nmethylaminosulfonyl, N-(2,2-dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2-methylpropylaminosulf onyl, Nmorpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or wherein R² together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof .

A preferred class of compounds consists of those compounds of Formula I' wherein X is selected from 0, S,

CR^cR^b and NR^a; wherein R^a is selected from hydrido, C\-C3alkyl, (optionally substituted phenyl) -C^-Cj-alkyl, acyl and carboxy-Cj-Cg-alkyl; whereix:. each of R^b and R^b is independently selected from hydrido, C^Cj-alkyl, phenyl-C2C₃-alkyl, C₃-C₃-perf luoroalkyl, chloro, C₃-C₆-alkylthio, C₂-C_£alkoxy, nitro, cyano and cyano-C,-C₃-alkyl; wherein Ris selected from carboxyl, aminocarbonyl, C₁-C₆alkylsulfonylaminocarbonyl and Cj-C_s-alkoxycarbonyl; wherein R' is selected from hydride:, phenyl, thienyl and C₂-C₆alkenyl; wherein R^l is selected from C3-C3-perfluoroalkyl, chloro, Cj-C^alkylthio, Cj-Ig-alkoxy, nitro, cyano and cyanoC3-C3-alkyl; wherein R² is one or more radicals independently selected from hydrido, hale:, C3-C_e-alkyl, C₂-C₆-alkenyl, C₂-C₆alkynyl, halo-C₂-C₆-alkynyl, aryl-C₃-C₃-alkyl, aryl-C₂-C₆alkynyl, aryl-C₂-C₆-alkenyl, C₂-C₆-alkoxy, methylenedioxy, C₂C_e-alkyl thio, C₁-C₆-alkylsul :;inyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C₁-C₆-alkoxy-C₁-C₆-alkyl, arylπ 1 14 g

Cj-C_e-alkyloxy, heteroaryl-C^-Cg-alkyloxy, aryl-C_x-C₆-alkoxyC₁-C₆-alkyl, C_x-C₆-haloalkyl, Cj-C^-haloalkoxy, C.-C₆haloalkylthio, C.-Cj-haloalkylsulfinyl, C₃-C₆haloalkylsulf onyl, C₃-C₃-(haloalkyl-C,-C₃-hydroxyalkyl, C^-Cj5 hydroxyalkyl, hydroxyimino-C₁-C₆-alkyl, Cj-Cg-alkvlamino, arylamino, aryl-C₁-C₆-alkylamino, heteroarylamino, heteroaryl-Cj-Cj-alkylamino, nitro, cyano, amino, aminosulfonyl, C,-C₆-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-Cj-Cg-alkylaminosulfonyl, heteroaryl-C^-Cj-alkylaminosulfonyl, heterocyclvlsulfonyl, C_x-C_s-alkylsulfonyl, aryl-C₁-C₆-alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, arylC₁-C₆-alkylcarbonyl, heteroaryl-C,-C_s-alkylcarbonyl, heteroaryicarbonyl, arylcarbonyl, aminocarbonyl, C_x-C₆15 alkoxycarbonyl, formyl, C₁-C₆-haloalkylcarbonyl and C_x-C₆alkylcarbonyl; and wherein the A ring atoms A', A², A³ and A⁴are 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 or 20 .quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.

A more preferred class of compounds consists of those compounds of Formula I' wherein X is selected from 0, S and NR*; wherein R* is selected from hydrido, C^-Cj-alkyl and (optionally substituted phenyl)methyl; wherein R' is selected from hydrido and C₂-C₆-alkenyl; wherein R is carboxyl; wherein R¹ is selected from C1-C3-perfluoroalkyl; wherein R² is one or more radicals independently selected from hydrido, halo, C1-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, .

0 halo-C₂-C₆-alkynyl, phenyl-C₁-C₆-alkyl, phenyl-C₂-C₆-alkynyl, phenyl-C,-C₆-alkenyl, C₁-C₃-alkoxy, methylenedioxy, C_x-C₃alkoxy-C,-C₃-alkyl, C^-Cj-alkylthio, C,-C₃-alkylsulfinyl, phenyloxy, phenyl thio, phenylsulf inyl, C₁-C₃-haloalkyl-C₁-C₃hydroxyalkyl, phenyl-C₁-C₃-alkyloxy-C₁-C₃-alkyl, C₁-C₃35 haloalkyl, C_x-C₃-haloalkoxy, C₁-C₃-haloalkylthio, C_x-C₃LL 9 i. 0 I 6 6 hydroxvalkyl, Cj-C-j-alkoxy-'^-Cj-alkyl, hydroxyimino-Cj-C₃alkyl, Cfi-Cfi-alkylamino, ni::ro, cyano, amino, aninosulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, Nheteroarylaminosulfonyl, N (phenyl-Cfi-Cg-alkyl) aminosulfonyl, N- (heteroaryl-Cj-Cg-alkyl) aminosulfonyl, phenyi-C,-C₃alkylsulfonyl, 5- to 8-membered heterocyclylsulfonyl, C.-C₆alkylsulfonyl, optionally substituted phenyl, optionally substituted 5- to 9-membere.d heteroaryl, phenyl-C₃-C₆alkylcarbonyl, phenylcarbor.yl, 4-chlorophenylcarbonyl, 4hydroxyphenylcarbonyl, 4-trif luoromethy lpheny 1 carbonyl, 4methoxyphenylcarbonyl, aminocarbonyl, formyl, and Cj-C_galkylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are independently selected from carbon and nitrogen with the proviso that at least three; of A', A², A³ and A⁴ are carbon; or wherein R² together with ring A forms a naphthyl, benzo fury lpheny 1, or quinolyl radical; or an isomer or pharmaceutically acceptable: salt thereof.

An even more preferred, class of compounds consists of those compounds of Formula 1' wherein X is selected from 0, S and NR^a; wherein R^s is selected from hydrido, methyl, ethyl, (4-tri fluoromethyl) benzyl, (4-chloromethyl) benzyl, (4-methoxy)benzyl, and (4-cyano)benzyl, (4-nitro)benzyl;

wherein R is carboxyl; wherein R' is selected from hydrido and ethenyl; wherein R¹ is selected from trifluoromethyl and pentafluoroethyl; wherein R'^! is one or more radicals independently selected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-lpentynyl, 1-pentynyl, 3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl, 4-chlorophenyl-ethynyl, 4methoxyphenyl-ethynyl, phenviethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, methylenedioxy, benzyloxymefhyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl thio, hydroxymethyl, hydroxy-trif luo.roethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, nitro,

ΛΓ*η π j 14 9 cyano, amino, aminosulfonyl, N-methylaminosulf onyl, Nphenylaminosulfonyl, N-furylaminosulfonyl, N(benzyl) aminosulfonyl, N- (furylmethyl) aminosulfonyl, benzyisulfonyl, phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with 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, optionally substituted phenylcarbonyl, aminocarbonyl, formyl and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are independently selected from carbon and nitrogen with the proviso that at least three of A.¹, A², A³ and A⁴ are carbon; or wherein R²together with ring A forms a naphthyl, or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I' there is a subclass of chromene compounds wherein X is 0,- wherein R is carboxyl; wherein R is selected from hydrido and C₂-C₆-alkenyl; wherein R¹ is selected from C1-C3-perf luoroalkyl; wherein R² is one or more radicals independently selected from hydrido, halo, C2-C₆alkyl, phenyl-C_x-C₆-alkyl, phenyl-C₂-C₆-alkynyl, phenyl-C₂-C₆alkenyl, C^-C^-alkoxy, phenyloxy, 5- or 6-membered heteroaryloxy, phenyl-C₁-C_s-alkyloxy, 5- or 6-membered heteroaryl-C^-Cj-alkyloxy, Cj-Cj-haloalkyl, C^-C^-haloalkoxy,

N-(C₁-C₆-alkyl) amino, N,N-di-(C₁-C_i-alkyl) amino, Nphenylamino, N- (phenyl-Cj-Cj-alkyl) amino, N-heteroarylamino, N- (heteroaryl-C₁-C₆-alkylamino, nitro, amino, aminosulfonyl, N- (Cj-Cj-alkyl) aminosulfonyl, N,N-di- (Cj-C₆alkyl)aminosulfonyl, N-arylaminosulfonyl, Nheteroarylaminosulf onyl, N- (phenyl-Cj-C₆-alkyl) aminosulfonyl, N- (heteroaryl-C^-Cg-alkyl) aminosulfonyl, 5- to 8-membered heterocyclylsulfonyl, Cj-C₆-alkylsulfonyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, phenyl-Cj-Cj-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl, aminocarbonyl, and C^-Cg-alkylcarbonyl;

I**&lt;© ΐΟ

Ch

Cb (· a

&lt;

wherein the A ring atoms 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 an isomer or pharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds of Formula I' wherein X is 0; wherein R is carboxyl; wherein R is selected from hydrido and ethenyl; wherein R¹ is selected from trifluoromethyl and pentafluoroethyl; wherein R²is one or more radicals independently selected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-l” pentynyl, 1-pentynyl, 3,3-dimethyl-l-butynyl, benzyl, phenylethyl, phenyl-ethynyl, 4-chlorophenyl-ethynyl, 4methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenylo;;cy, phenyl thio, phenylsulf inyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzylo:&lt;ymethy 1, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trif luoromethyl thio, hydroxymethyl, hydroxy-trifluoroethyl, methoxymethyl, hydroxyininomethyl, N-methvlamino, Nphenylamino, N-(benzyl) amino, nitro, cyano, amino, amino sulfonyl, N-methylc.minosulf onyl, N-phenylaminosulfonyl, N-furylaminosulfonyl, N-(benzyl)aminosulfonyl, N(furylmethyl) aminosulf or yl, benzylsulfonyl, phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with 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, furylcaroonyl, phenylcarbonyl, aminocarbonyl, formyl, and methylcarbonyl; and wherein one of the A ring atoms A¹, A², A³ and A⁴ is nitrogen and the other three are carbon; or an isomer or pharmaceutically acceptable salt thereof.

APO Ο 1 14 9

Another even more preferred class of compounds consists of those compounds of Formula 1' wherein X is 0; wherein R is carboxyl; wherein R is selected from hydride and ethenyl; wherein R¹is selected from trifluoromethyl and pentafluoroethyl; wherein R² is one or more radicals independently selected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-lpentynyl, 1-pentynyl, 3,3-dimethyl-l-butynyl, benzyl, phenylethyl, phenyl - ethynyl, 4-chlorophenyl-ethynyl, 410 methoxyphenyl-ethynyl, phenyl ethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluorometnylthio, hydroxymethyl, hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, Nphenylamino, N-(benzyl)amino, nitro, cyano, amino, aminosulfonyl, N-methylaminosulfonyl, N-phenylaminosulfonyl, N-furylaminosulfonyl, N-(benzyl)aminosulfonyl, N2 0 (fury lmethyl) aminosulfonyl, benzylsulf onyl, phenylethylaminosulfonyl, furylsulf onyl, methyl sulfonyl, phenyl, phenyl substituted with 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, aminocarbonyl, formyl, and methyl carbonyl; wherein the A ring atoms A*, A², A³ and A⁴ are carbon; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I' there is another subclass of benzothiopyran compounds wherein X is S; wherein R is carboxyl; wherein R¹ is selected from C2-C3-perfluoroalkyl; wherein R² is one or more radicals independently selected from hydrido, halo, C1-C₆-alkyl, phenyl-Cj-Cj-alkyl, phenyl35 C₂-C₆-alkynyl, phenyl-C₂-C₆-alkenyl, C^-Cj-alkoxy, phenyloxy,

44910/66 /J/dV

5- or 6-membered heteroaryloxy, phenyl-Cj-Cg-alkyl oxy, 5- or

6- membered heteroaryl-C^-C,-alkyloxy, C^-Cg-haloalkyl, C^-Cghaloalkoxy, Cj-C₆-alkylamiro, N-phenylamino, N-(phenyl-Cj-Cgalkyl)amino, N-heteroarylamino, N-(heteroaryl-C^-Cg5 alkylamino, nitro, amino, aminosulfonyl, Nalkylaminosulfonyl, N-ary 1 aminosulfonyl, Nheteroarylaminosulfonyl, N- (phenyl-C.-C₆-alkyl) aminosulfonyl, N-(heteroaryl-C^Cg-alkyl)aminosulfonyl, 5- to 8-membered heterocyclylsulfonyl, C_x-C₆-alkylsulfonyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, phenyl-C₁-C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl, aminocarbonyl, and Cj-Cg-alkylcarbonyl ; wherein the A ring atoms 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 an isomer or pharmaceutically acceptable salt thereof.

An even more preferred class of compounds consists of those compounds of Formula 1' wherein X is S; wherein R is carboxyl; wherein R is selected from hydrido and ethenyl;

wherein R¹is selected from trifluoromethyl and pentafluoroethyl; wherein R²is one or more radicals independently selected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-lpentynyl, 1-pentynyl, 3,3-dimethyl-l-butynyl, benzyl, phenylethyl, phenyl-ethynyl, 4-chlorophenyl-ethynyl, 4methoxyphenyl-ethynyl, phenylethenyl, methoxy, methylthio, methylsulfinyl, phenyloxy, phenylthio, phenylsulfinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, trifluoromethoxy, trifluoromethylthio, hydroxymethyl, hydroxy-trifluoroethyl, methoxymethyl, hydroxyiminomethyl, N-methylamino, Nphenylamino, N-(benzyl) amir.o, nitro, cyano, amino, aminosulfonyl, N-methylamiriosulfonyl, N-phenylaminosulfonyl,

N-furylaminosulfonyl, N-(beinzyl) aminosulfonyl, N10

ΛΠοπί149 ( furylmethyl) aminosulfonyl, benzylsulf onyl, phenylethylaminosulfonyl, furylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with 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, f urylcarbonyl, phenyl carbonyl, aminocarbonyl, formyl, and me thyl carbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I' there is a third subclass of dihydroquinoline compounds wherein X is NR°; wherein R“ is selected from hydrido, Cq-Cj-alkyl, phenyl-Cj-C₃-alkyl, acyl and carboxy-C₁-C₃-alkyl; wherein R is carboxyl; wherein R¹is selected from C1-C3-perfluoroalkyl; wherein R² is one or more radicals independently selected from hydrido, halo, CxC₆-alkyl, phenyl-C₁-C₆-alkyl, phenyl-C₂-C₆-alkynyl, phenyl-C₂C₆-alkenyl, C₁-C₆-alkoxy, phenyloxy, 5- or 6-membered heteroaryloxy, phenyl-C^C^alkyloxy, 5- or 6-membered heteroaryl-C₁-C₆-alkyloxy, C_l-C_s-haloalkyl, cq-Cg-haloalkoxy, C_x-C₆-alkylamino, N-phenylamino, N-(phenyl-C_x-C₆-alkyl) amino, N-heteroarylamino, N- (heteroaryl-Cj-Cj-alkylamino, nitro, amino, aminosulfonyl, N-alkylaminosulfonyl, Narylaminosulfonyl, N-heteroarylaminosulfonyl, N-(phenyl-C_xC₆-alkyl) aminosulfonyl, N- (heteroaryl-Cj-Cgalkyl) aminosulfonyl, 5- to 8-membered heterocyclylsulfonyl, C_x-C₆-alkylsulfonyl, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, phenylC₁-C₆-alkylcarbonyl, heteroarylcarbonyl, phenylcarbonyl, aminocarbonyl, and Cj-Cg-alkylcarbonyl; wherein the A ring atoms A , A , A and A are independently selected from carbon and nitrogen with the proviso that at least three of A¹, A²,

A and A are carbon; or an isomer or pharmaceutically acceptable salt thereof.

rv «ο

O) r

X c

An even more preferred class of compounds consists of those compounds of Formula 1' wherein X is NR^a; wherein R^ais selected from hydrido, methyl, ethyl, (4trifluorometnyl)benzyl, (4-chloromethyl)benzyl, (4methoxy)benzyl, (4-cyano)beazyl, and (4-nitro)benzyl; wherein R is carboxyl; wher ein R is selected from hydrido and ethenyl,· wherein R¹ is selected from trifluoromethyl and pentafluoroethyl; wherein R^! is one or more radicals independently selected from hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, ethenyl, ethynyl, 5-chloro-lpentynyl, 1-pentynyl, 3,3-dimethyl-1-butynyl, benzyl, phenylethyl, phenyl-ethynyl,. 4-chiorophenyl-ethyny1, 4methoxyphenyl-ethynyl, phenyl ethenyl, methoxy, methyl thio, methylsulfinyl, phenyloxy, phenyithio, phenylsulfinyl, pyridyloxy, thienyloxy, furyloxy, phenylmethoxy, methylenedioxy, benzyloxymethy 1, trifluoromethyl, difluorometnyl, pentafluoroethyl, trifluoromethoxy, trifluoromethyl thio, hydroxymethyl, hydroxy-trif luoroethyl, methoxymethyl, hydroxyiminomethyl, N-methyl amino, Nphenylamino, N-(benzyl) amino, nitro, cyano, amino, amino sulfonyl, N-methyl amino sulfonyl, N-phenylaminosulf onyl, N-furylaminosulfonyl, N-(beazyl)aminosulfonyl, N(fury lme thy 1) aminosulfonyl, benzyl sulfonyl, phenylethylaminosulfonyl, f arylsulfonyl, methylsulfonyl, phenyl, phenyl substituted with one or more radicals selected from chloro, fluoro, bromo, methoxy, methvlthio and methylsulfonyl, benzimidazolyl, thienyl, thienyl substituted with chloro, furyl, furyl substituted with chloro, benzylcarbonyl, furylcarbonyl, phenyl carbonyl, aminocarbonyl, formyl, and methylcarbonyl; wherein the A ring atoms A¹, A², A³ and A⁴ are carbon; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I' there is a fourth subclass of compounds wherein X is selected from 0, S and NR^a; wherein R“ is selected from hydrido, C^-Cj-alkyl, phenyl-C^-Cj-alkyl,

APO 0 114 Q AMENDED PAGES 27 AND 29-32 r-ki w ι ι *t a retyped acyl and carboxy-Ci-Ca-alkyl; wherein R is selectee from carboxyl; wherein R¹ is selected from Ci-C3~perflucroalkyl; wherein the A ring atoms 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 R²together with 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 0,

S and NR^a; wherein R^a is selected from hydrido, methyl, ethyl, (4-triflucromethyl)benzyl, (4-chloromethyl)benzyl, (4-methoxy)benzyl, and (4-cyano)benzyl, (4-nitro)benzyl; wherein R'is carboxyl; wherein R' is selected from hydrido and ethenyl; wherein R¹ is selected from trifluoromethyl and pentafluoroethyl; wherein the A ring atoms Ά¹, A², A³ and A⁴are 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, or quinolyl radical; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I there is a subclass of compounds of high interest represented by Formula II;

<img file="AP1149A_D0003.tif" />

CO₂H

R

II r&lt;o

O o&gt;

σ&gt;;

t.

&lt;

wherein X is selected from 0, NR^a and S;

wherein R¹ is lower haloalkyl;

wherein R³ is selected from hydrido, and halo;

wherein R⁴ is selected from hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulf onyl, and

5- or 6- membered nitrogen containing heterocyclosulfonyl;

wherein R⁵ is selected from hydriao, lower alkyl, halo, lower alkoxy, and aryl; and wherein R⁶ is selected from hydrido, halo, lower alkyl, lower alkoxy, and aryl;

or an isomer or pharmaceutically acceptable salt thereof.

A class of compounds of particular interest consists of those compounds of-Formula II wherein R² is trifiuoromethyl or pentafluoroethyl; wherein R³ is selected from hydrido, chloro, and fluoro; wherein R⁴ is selected from hydrido, chloro, bromo, fluoro, iodo,, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaninosulfonyl, isop copy 1 amino su If onyl, methylamino suit onyl, benzylaminosulfonyl, phenylethylaminosulfonyl, msthylpropylaminosulfonyl, methylsulfonyl, and morpholi.nosulfonyl; wherein R⁵ is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, di ethy lamino, and phenyl; and wherein R^s is __ selected from hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I there is a subclass of compounds of high interest represented by Formula Ila:

ΑΡ^υ 1 1 4 9

<img file="AP1149A_D0004.tif" />

wherein R³ is selected from hydrido, hydroxyalkyl, lower alkoxy and halo;

wherein R⁴ is selected from hydrido, lower alkylthio, lower haloalkyl, amino, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylcarbonyl, formyl, cyano, lower lower alkyl, lower halo, lower alkyl, aminosulfcnyl, lower alkoxyalkyl, haloalky.lbhio, substituted or unsubstituted phenylcarbonvl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower neteroaralkylaminosulfcnyl, 5or 6- membered heteroaryl, lower hydroxyalkyl, optionally substituted phenyl and 5- or 6- membered nitrogen containing heterocyclcsulfonyl;

wherein R⁵ is selected from hydrido, lower alkyl, halo, lower haloalkyl, lower alkoxy, and phenyl; and wherein R⁶ is selected from hydrido, halo, cyano, hydroxyiminomethyl, lower hydroxyalkyl, 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 Ila wherein R³ is selected from hydrido, and chloro; wherein R⁴ is selected from chloro, methyl, tert-butyl, methyltnio, trifluoromethyl, difluoromethyl, pentafluoromethyl, trifluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbor.yi, and substituted or unsubstituted phenyl;

L L 9 ί 0 ' S fi 'd.’dV 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 substitute:! or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I there is a subclass of compounds cf hich interest represented bv Formula rib

<img file="AP1149A_D0005.tif" />

lib wherein R³ is selected from hydride, lower alkyl, lower hydroxyalkyl, lower alkoxy and halo;

wherein R⁴ is selected from hydride, halo, lower alkyl, lower alkylthio, rower haloalkyl, amino, aminosulfonyl, lower alkylsulfcnyl, lower alkylsulfinvl, lower alkoxyaikyl, lower alkylcarbonvl, formyl, cyano, lower haloalkylthio, substituted or unsubstitutec. phenylcarbonyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonvl, 5or 6- membered heteroaryl, lower hydroxyalkyl, optionally substituted phenyl and 5- or 6- membered nitrogen containing heterocyclosulfonyl;

wherein R⁵ is selected from hydrico, lower alkyl, halo, lower haloalkyl, lower alkoxy, and phenyl; and wherein R⁶ is selected from hydrido, halo, cyano, hydroxyiminomethyl, lower h/droxyalkyl, lower alkynyl, phenylalkynyl, lower alkyl, lower alkoxy, formyl and phenyl;

APO 0 114 9 or an isomer or pharmaceutically acceptable sale thereof.

A class of compounds of particular interest consists of those compounds of Formula lib wherein F^J is selected from hydrido, and chloro; wherein R⁴ is selected from chloro·, * methyl, tert-butyl, methylthio, trifluoromethyi, diflucromethyl, pentafluoromethyl, trifluoromethylsulfide, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyl, and substituted or unsubstituted phenyl;

wherein R⁵ is selected from hydrido, methyl, tert-butyl, chloro; and wherein R⁶ is selected from hydrido, chloro, thienyl, hydroxyiminomethyl, substituted or unsubstituted phenylethy.nyl, and substituted or unsubstituted phenyl; or an isomer or pharmaceutically acceptable salt thereof.

Within Formula I there is a subclass of- compounds of high interest represented by Formula lie:

<img file="AP1149A_D0006.tif" />

ΑΡ/Γ 9 9 '01677 wherein R^s is selected from hydrido wherein R~ is selected from hydrido, hydroxyalkyl, lower alkoxy and halo;

wherein R⁴ is selected from hydrido, lower alkylthio, lower haioalkyl, amino, lower alkylsulfonyl, lower alkylsulfinyl lower alkylcarbonyl, formyl, cyano, lowe and lower aralkyl; lower alkyl, lower halo, lower alkyl, aminosulfonyl, , lower alkoxyalkyl, r haioalkylthio, substituted or unsubstituted phenylcarbonyl, lower haloalkoxy, lower alkoxy, lower aralkyicarbonyl, lower dialkylami.nosulf onyl, lower alkylaminosulfonyl, lower aralkylamincsulfonyl, lower hereroaraikylaminosulfonyl, 5or 6- membered heteroaryl, lower hydroxyalky.l, optionally substituted phenyl and 5- or 6- membered nitrogen containing heterocyclcsuifonyl ;

wherein ?? is selected from hydrido, lower alkyl, halo, lower haloalkyl, lower alkoxy, and phenyl; and wherein R^s is selected from hydrido, halo, cyano, hydrexyiminomethyl, lower hydroxyalkyl, lower alkynyl, phenylalkynyl, lower alkyl, lower alkoxy, formyl and phenyl;

or an isomer or pharmaceutically acceptable salt chereof.

A class cf compounds of particular interest consists of those compounds of Formula lie wherein R³ is selected from hydrido, and chloro; wherein R⁴ is .selected from chloro, methyl, tert-butyl, methylthio, trifluoromethyl, dif luoromethyl, pentaf luoromethyl, trifluoromethylsulfi.de, trifluoromethoxy, cyano, substituted or unsubstituted phenylcarbonyi, and substituted or unsubstituted phenyl; wherein R⁵ is selected from hydrido, methyl, tert-butyl, chloro; and wherein R⁶ is selected from hydrido, chloro, chienyl, hydrexyiminomethyl, substituted or unsubstituted phenyiethynyl, 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 pharmaceuticallyacceptable salts thereof as follows:

c-chlor0-2-trifluoromethy1-2n-1-benzopyran-3-carboxylic acid;

~-ethyl-2-trifluoromethyl-2K-l-benzopyran-3-carboxylic acid;

7-methyl-2-trifluoromethy1-2H-1-benzopyran-3-carboxylic a c i d ;

2,7-bis(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid;

7-brcmo-2-trifiuoromethyl-2H-l-benzopyran-3-carboxylic acid;

€-ohloro-7-methyl-2-trifluoromethyl-2H-l-benzopyran-335 carboxvlic acid;

ΑΡυ 0114 9

5- (1-methylethyl) -2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid;

6- chloro-7- (1,1-dime thy le thy 1) -2-trif luoromethyl-2H-lbenzopyran-3-carboxylic acid;

6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

8-ethoxy-2 - trif luoromethyl-2H-l-benzopyr an-3-carboxylic acid;

7- (1,1-dime thy lethyl) -2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid;

6-bromo-2 - trif luorome thyl-2H-l-benzopyran-3-carboxylic acid; 8-chloro-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid;

8-bromo-6-chloro-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid;

6- trif luoromethoxy-2-trif luor ome thy 1-2H-1-benz opyr an-3 carboxylic acid;

8-f luoro-2- trif luoromethyl-2H-l-benzopyran-3-carboxylic 20 acid;

5.7- dichloro-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid;

7.8- dichloro-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid;

7-isopropyloxy-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid;

8-phenyl-2-trif luorome thyl-2H-l-benzopyr an-3-carboxylic acid;

7.8- dimethyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

6.8- bis(1,1-dimethylethyl) -2-trif luoromethyl-2H-lbenzopyran-3-carboxylic acid;

7- chloro-2-trif luoromethyl-2H- l-benzopyran-3-carboxylic acid;

r·^ co o

an σ&gt;

i

CU

7- (1 -methy 1 ethyl) -2-triflucromethy 1-2H-1-benzopyran-3carboxylic acid;

-phenyl-2- trif luoromethyl - 2H-1-benzopyran-3 - carboxylic acid;

6-chloro-7-ethyl-2-trifluor omethyl-2H-l-benzopyran-3carboxylic acid;

8- ethyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

6-chloro-8-ethyl-2-trifluor omethyl-2H-l-benzopyr an-3 carboxylic acid;

6-chloro-7 -phenyl- 2 -trif luc romethyl-2H-l-benzopyran-3carboxylic acid;

6.7- dichloro-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid;

6.8- dichloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

6.8- dibromo-2-trif luoromethy 1-2H-1-benzopyran-3 - carboxylic acid;

6.8- dimethoxy-2-trifluorome thyl-2H-1-benz opyr an-3-carboxylic acid;

6-nitro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid; 6-amino-2-trif luor omethyl-2 H-l-benzopyran-3-carboxylic acid; ethyl 6-amino-2-trifluoromethyl-2H-l-benzopyran-3carboxylate;

6-chloro-8-methyl-2-triflucromethyl-2H-l-benzopyran-325 carboxylic acid;

8-chloro-6-methyl-2-trif luc romethyl-2H-l-benzopyran-3carboxylic acid;

8-chloro-6 -me thoxy-2-tr if lvoromethyl-2H-1 -benzopyran-3 carboxylic acid;

6,8-difluoro-2-trifluoromet.hyl-2H-l-benzopyran-3-carboxylic acid;

6-bromo-8-chloro-2-trif luoiomethyl-2H-l-benzopyran-3carboxylic acid;

8-bromo-6-f luoro-2-trif luoromethyl-2H-1-benzopyran-3 35 carboxylic acid;

ΑΡϋ01149

8-bromo-β -methyl-2-trif luorome thyl-2H-l-benzopyran-3carboxylic acid;

8-bromo-5-f luoro-2-trif luorome thyl-2H-l-benzopyran-3carboxylic acid;

6-chloro-8-f luoro-2- tri fluoromethyl-2H-l -benzopyran-3 carboxylic acid;

-br omo - 8 -methoxy -2-trif luorome thy 1 -2H-1-benz opyran - 3 carboxylic acid;

7- (N, N-diethylamino) -2-trif luoromethyl-2H-l-benzopyran-310 carboxylic acid;

6- [ [ (phenylmethyl) amino] sulfonyl] -2-trif luoromethyl-2H-lbenzopyran-3-carboxylic acid;

6- [ (dimethylamino) sulfonyl] -2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

6-aminosulf onyl-2-tr if luorome thyl-2K-l-benzopyran-3carboxylic acid;

6- (methylamino) sulfonyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-l20 benzopyran-3-carboxylic acid;

6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

6-methylsulfonyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

8- chloro-6-[[(phenylmethyl)amino]sulfonyl]-2trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

6-N, N-diethylaminosulfonyl-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

6-phenylacetyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

ΑΡ/Γ.’ 9 9 0 16 77

6,8-dichloro-7-methoxy-2-trifluoromethyl-2H-l-benzopyran-3 carboxylic acid;

6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid;

6-[[(2-furanylmethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H l-benzopyran-3-carboxylic acid;

6-[(phenylmethyl)sulfonyl]-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

6-[[(phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-110 benzopyran-3-carboxylic acid;

6-iodo-2-trifluoromethyl-2E-l-benzopyran-3-carboxylic acid; 6-chloro-8-iodo-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

8-bromo-6-chloro-2-trifluoromethyl-2H-l-benzopyran~315 carboxylic acid;

6-formyl-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid;

6-chloro-8-formyl-2- (trifItoromethy 1) -2H-1-benzopyran-3carboxylic acid;

6-bromo-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

5,6-dichloro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

λ 6-cyano-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic 25*· acid;

6-hydroxymethyl-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-(difluoromethyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

2,6-bis(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid;

5.6.7- trichloro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6.7.8- trichloro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

ΛΠο η ι 1 4 9

6-(methylthio)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-(methylsulfinyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

5.8- dichloro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-(pentafluoroethyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1benzopyran-3-carboxylic acid;

6.8- dichloro-7-methyl-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-chloro-2,7-bis(trifluoromethyl)-2H-l-benzopyran-3carboxylic 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-l-benzopyran-3carboxylic acid;

6-(4-hydroxybenzoyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-phenoxy-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid;

8-chloro-6-(4-chlorophenoxy)-2-trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

2-(trifluoromethyl)-6-[4-(trifluoromethyl)phenoxy)-2H-1benzopyran-3-carboxylic acid;

6- (4-methoxyphenoxy) -2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

6- (3-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-1benzopyran-3-carboxylic acid;

9 t. 0 / 6 6 /J/dV

6- (4-chlorophenoxy) - 2- (trif luoromethyl) -2H-l-benzopyram-3 carboxylic acid;

8-chloro-2-(trifluoromethyl i — 6 —[4 —(trifluoromethyl)phenoxy] 2H-l-benzopyran-3-carboxylic acid;

6-chloro-8-cyano-2- (trif luoromethyl) -2H-l-benzopyran-3 carboxylic acid;

6-chloro-8- [ (hydroxyimino)methyl] -2- (trifluoromethyl) -2H-1benzopyran-3-carboxylic acid;

6- chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxyli :: acid;

8- (lH-benzimidazol-2-yl) -6-::hloro-2- (trif luoromethyl) -2H-1benzopyran-3-carboxyli:: acid;

7- (1,1-dimethylethyl) -2- (peatafluoroethyl) -2H-l-benzopyran3-carboxylic acid;

6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

6-chloro-8-(benzyloxymethy 11-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

6-chloro-8-ethenyl-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-chloro-8-ethynyl-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

€-chloro-8-(2-furanyl)-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

6-chloro-8-(5-chloro-l-pentynyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

6-chloro-8-(1-pentynyl)-2-(trifluoromethyl)-2H-l-benzopyran-. 3-carboxylic acid;

6-chloro-8-(phenylethynyl) -2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

6-chloro-8-(3,3-dimethyl-l-butynyl)-2-(trifluoromethyl)-2H1-benzopyran-3-carboxylic acid;

APO01148

6-chloro-8-[ {4-chlorophenyl)ethynyl]-2-(trifluoromethyl)-2H1-benzopyran-3-carboxylic acid;

6-chloro-8-[{4-methoxyphenyl)ethynyl]-2-(trifluoromethyl)2H-l-benzopyran-3-carboxylic acid;

6-(phenylethynyl)-2-(trifluoromethyl)-2H-1-benzopyran-3carboxylic acid;

6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-110 benzopyran-3-carboxylic acid;

6-chloro-8-[(4-methylthio) phenyl]-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

6-chloro-8-[(4-methylsulfonyl)phenyl]-2-(trifluoromethyl)2H-l-benzopyran-3-carboxylic acid;

6-chloro-8-phenyl-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

6-bromo-8-fluoro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-(4-fluorophenyl)-2-(trifluoromethyl)-2H-1-benzopyran-320 carboxylic acid;

6-phenyl-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid;

8-chloro-6-fluoro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6,8-diiodo-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid;

6-(5-chloro-2-thienyl)-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

6- (2-thienyl)-2-(trifluoromethyl)-2H-l-benzopyran-330 carboxylic acid;

6-(4-chlorophenyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

6-(4-bromophenyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

ΑΡ/Γ7 9 9 /0 1 6 77

6- (ethynyl) -2- (trifiuoromethyl) -2H-l-benzopyran-3-carboxylic acid;

6-methyl-2- (trifiuoromethyl) -2H-l-benzopyran-3-carboxylic acid;

6-chloro-8- (4-methoxyphenyl) -2-trif luoromethyl-2H-lbenzopyran-3-carboxylic acidu.

6-chloro-2- (trifiuoromethyl) -4-ethenyl-2H-l-benzopyran-3carboxylic acidj.

6-chloro-2- (trifiuoromethyl) -4-phenyl-2H-l-benzopyran-3 carboxylic acid;

6-chloro-4- (2-thienyl) -2- (trifiuoromethyl) -2H-l-benzopyran3-carboxylic acid;

6-(2,2,2-trifluoro-l-hydrox’/ethyl) -2- (trifiuoromethyl) -2K-1benzopyran-3-carboxylic acid;

6-methyl-2- (trifiuoromethyl; -2H-l-benzothiopyran-3carboxylic acid;

6,8-dimethyl-2 - (trifiuoromethyl) -2H-l-benzothiopyran-3carboxylic acid;

6- (1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1benzothiopyran-3-carboxylic acid;

7- methyl-2- (trifiuoromethyl ι -2H-l-benzothiopyran-3carboxylic acid;

6.7- dimethyl-2 - (trifiuoromethyl) -2H-l-benzothiopyran-3carboxylic acid;

8- methyl-2- (trifiuoromethyl; -2H-l-benzothiopyran-3carboxylic acid;

2- (trifiuoromethyl) -2H-l-bei:.zothiopyran-3-carboxylic acid;

6- chloro-7-methyl-2- (trifiuoromethyl) -2H-l-benzothiopyran-3carboxylic acid;

7- chloro-2- (trifiuoromethyl) -2H-l-benzothiopyran-3carboxylic acid;

6.7- dichloro-2- (trifiuoromethyl) -2H-l-benzothiopyran-3carboxylic acid;

ΑΡΟ ο 1 1 4 9

2- (trifluoromethyi) -6- [ (trifluoromethyi) thio] -2H-1benzothiopyran-3-carboxylic acid;

6,8-dichloro-2-trifluoromethyl-2H-l-benzothiopyran-3carboxylic acid;

6-chloro-l,2-dihydro-2-(trifluoromethyi)-3quinolinecarboxylic acid;

6,8-dichloro-l,2-dihydro-2-(trifluoromethyi)-3quinolinecarboxylic acid;

6,7-difluoro-1,2-dihydro-2-(trifluoromethyi)-3quinolinecarboxylic acid;

6-iodo-l, 2-dihydro-2- (trifluoromethyi) -3-quinolinecarboxylic acid;

6-bromo-l,2-dihydro-2-(trifluoromethyi)-3quinolinecarboxylic acid;

1,2-dihydro-6- (trif luoromethoxy) -2- (trifluoromethyi) -3quinolinecarboxylic acidj.

6- (trifluoromethyi) -1,2-dihydro-2- (trifluoromethyi) -3quinolinecarboxylic acid;

6-cyano-l,2-dihydro-2-(trifluoromethyi)-3quinolinecarboxylic acidj.

6-chloro-l,2-dihydro-1-methyl-2-(trifluoromethyi)-3quinolinecarboxylic acid;

6-chloro-l,2-dihydro-2-(trifluoromethyi)-1-[[4(trifluoromethyi)phenyl]methyl] -3-quinolinecarboxylic acid;

6-chloro-l- [ (4-chlorophenyl)methyl] -1,2-dihydro-2(trifluoromethyi)-3-quinolinecarboxylic acid;

6-chloro-l,2-dihydro-2-(trifluoromethyi)-1- [ [4(methoxy)phenyl]methyl] -3-quinolinecarboxylic acid;

6-chloro-l-[(4-cyanophenyl)methyl]-1,2-dihydro-2(trifluoromethyi)-3-quinolinecarboxylic acid;

6-chloro-l,2-dihydro-l-[(4-nitrophenyl)methyl]-2’ (trifluoromethyi)-3-quinolinecarboxylic acid;

9 10/66 ,J/dV

6-chloro-l, 2-dihydro-I-ethyl-2- (trifluoromethyl) -3cruinolinecarboxylic acid;

6--chloro-2- (triflouromethyl) -1,2-dihydro[l, 8jnapthyridine-Ιο arboxylic acid;

2-trif luoromethyl-2H-naphtho [1,2-b] pyran-3-carboxylic acid; 2-trif luoromethyl-3K-napht;ho [2 , l-b]pyran-3-carboxylic acid;

2- trif luor ome thyl-2H-napht:ho [2,3-b]pyran-3-carboxylic acid;

5- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2Hpyrano [2,3-c] pyridine:-3-carboxylic acid;

6- (trif luoromethyl) -6h-l, 2 -dioxolo [4,5-g] [1]benzopyran-7carboxylic acid; and

3- (trif luorome thyl) -3K-ber..zofuro [3,2-f] [ l]benzopyran-2carboxylic acid.

A preferred family of specific compounds of particular interest within Formulas I and I' consists of compounds as follows:

(S) -6-chloro-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S) -7-ethyl-2-tr if luoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S) -7-methyl-2-trif luorome thyl-2H-l-benzopyran-3-carboxylic acid;

(S) -2,7-bis (trif luoromethy!) -2H-l-benzopyran-3-carboxylic acid;

(S) -7-bromo-2-trif luorome thyl-2H-l-benzopyran-3-carboxylic acid;

(S) - 6-chloro-7 -methyl-2-trifluorome thy1-2H-l-benzopyran-3carboxylic acid;

(S) - 8- (1-methyl ethyl) -2 -tr if luorome thyl-2H-l-benzopyran-3 carboxylic acid;

(S) -6-chloro-7 - (1,1-dime thyl ethyl) -2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

APC 0 114 3 (S) -6-chloro-8- (1-methylethyl) -2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

(S) -2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S) -8-ethoxy-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S) -Ί- ¢1,1-dime thyl ethyl) -2-trifluoromethyl-2H-l-benzopyran3-carboxylic acid;

{S) - 6 -bromo-2 - trif luorome thyl-2H-1 -benzopyran-3 - carboxylic acid;

(S) -8-chloro-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S) -8-bromo-G-chloro-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid;

(S) - 6-trif luoromethoxy-2-trif luoromethyl-2H-l-benzopyran-315 carboxylic acid;

(S) -8-f luoro-2- trif luorome thyl-2H-1-benzopyran-3-carboxylic acid;

' 3) -5,7-dichloro-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S)-7,8-dichloro-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid;

(S) -7-isopropyloxy-2-trifluorornethyl-2H-l-benzopyran-3carboxylic acid;

(S) -8-phenyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic 25 acid;

(S)-7,8-dimethyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

&lt; S)-6,8-bis(1,1-dimethylethyl)-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

(S)-7-chloro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S)-7-{1-methylethyl)-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid;

(S)-7-phenyl-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

9 4 0/ 66 ,d V (S)-6-chloro-7-ethyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S)-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

(S)-6-chloro-8-ethyl-2-tri fluoromethy1-2H-1-benzopyran-3carboxylic acid;

(S)-6-chloro-7-phenyl-2-tr ifluoromethy1-2H-1-benzopyran-3carboxylic acid;

(S)-6,7-dichloro-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(£)-6,8-dichloro-2-trifluoromethy1-2H-1-benzopyran-3carboxylic acid;

(£)-6,8-dibromo-2-trifluoromethy1-2H-1-benzopyran-3carboxylic acid;

(£)-6,8-dimethoxy-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(£) -6-nitro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid;

(£)-6-amino-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

(£)-ethyl 6-amino-2-trifluoromethyl-2H-l-benzopyran-3carboxylate ?

(£) -6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3~ carboxylic acid;

(S)-8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3~ carboxylic acid;

(£)-8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3 carboxylic acid;

(£)-6,8-difluoro-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S)-6-bromo-8-chloro-2-trifluoromethy1-2Η-I-benzopyran-3carboxylic acid;

(£)-8-bromo-6-fluoro-2-trifluoromethy1-2H-1-benzopyran-3carboxylic acid;

ΑΡ υ υ 1 14 9 (S) - 8-br omo-6-me thy 1-2-trif luorome thyl-2Η-1-benzopyran-3 carboxylic acid;

(S) -8-bromo-5-f luoro-2-tri fluoromethyl-2H-1-benzopyran-3 carboxylic acid;

(S) -6-chloro-8-fluoro-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S) -6-bromo-8-methoxy-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S) -7- (N, N-di ethyl amino) -2-trifluoromethyl-2K-l-benzopyran10 3-carboxylic acid;

(S)-6-[ [ (phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H1-benzopyran-3-carboxylic acid;

(S) -6- [ (dime thy lamino) sulfonyl] -2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

(S)-6-aminosulfonyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S) -6- (methylamino) sulfonyl-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

(S) -6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-l20 benzopyran-3-carboxylic acid;

(S) -6- [ (1,1-dimethylethyl) aminosulfonyl] -2-trifluoromethyl2H-1-benzopyran-3-carboxylic acid;

(S)-6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H1-benzopyran-3-carboxylic acid;

(S) -6-methylsulfonyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S) -8-chloro-6- [ [ (pheny Ime thyl) amino] sulfonyl] -2trifluoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S) -6-N,N-diethylaminosulfonyl-2-trif luorome thyl-2H-130 benzopyran-3-carboxylic acid;

(S)-6-phenylacetyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S)-6-(2,2-dimethylpropylcarbonyl)-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid;

ΑΡ/Γ.' 9 9 ' 0 1 6 77 (S) -6,8-aichloro-7-methoxy-2-trif luoromethyl-2H-lbenzopyran-3-carboxylic acid;

(S) -6-chloro-2-trif luoromethyl-2H-l-benzothiopyran-3carboxylic acid;

(S)-6-[[(2-furanylmethyl)amino]sulfonyl)-2(trif luorometnyl) -2H- l-benzopyran-3-carboxylic acid;

(S)-6-[(phenylmethyl)sulfcnyl] -2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S) -6- [ [ (phenylethyl)amine] sulfonyl] -2- (trifluoromethyl) -2H1-benzopyran-3-carboxylic acid;

(S) -6-iodo-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid;

(S)-6-chloro-8-iodo-2-(tricluoromethy1)-2H-l-benzopyran-3carboxylic acid;

(Ξ) -8-bromo-6-chloro-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid;

(S)-6-formyl-2-(trifluoromethyl)-2H-1-benzopyran-3carboxylic acid;

(S)-6-chloro-8-formyl-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

(S) -6-bromo-7- (1,1-dimethyLethyl) -2- (trifluoromethyl) -2H-1benzopyran-3-carboxyl:.c acid;

(S) -5,6-dichloro-2- (trifluoromethyl) -2H-l-benzopyran-3 carboxylic acid;

(S)-6-cyano-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid ;

(S)-6-hydroxymethyl-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

(S)-6-(difluoromethyl)-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

(S)-2,6-bis(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid;

(S)-5,6,7-trichloro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

ΑΡ ό ο 114 9 (S) - 6,7,8-trichloro-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

(S) - 6- (methylthio) - 2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

(S) -6 - (me thyl sulfinyl) -2- (trifluoromethyl) -2H-i-benzopyran3-carboxylic acid;

(S) -5,8-dichloro-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

(S) -6- (pentafluoroethyl) -2- (trifluoromethyl) -2H-110 benzopyran-3-carboxylic acid;

(S) -6- (1,1-dimethylethyl) -2- (trifluoromethyl) -2K-1benzopyran-3-carboxylic acid;

(S) -2- (trifluoromethyl) -6- [ (trifluoromethyl) thio] -2H-1benz o t hi opyran - 3 - c arboxy 1 i c acid;

(S) -6,8-dichloro-7-methyl-2- (trifluoromethyl) -2H-1benzopyran-3-carboxylic acid;

(S) -6-chloro-2,7-bis (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

(S) -5-methoxy-2- (trifluoromethyl) -2H-l-benzopyran-320 carboxylic acid;

(S) -6-benzoyl-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

(S) -6- (4-chlorobenzoyl) -2- (trifluoromethyl) -2H-l-benzopyran3-carboxylic acid;

(S)—6— (4-hydroxybenzoyl) -2- (trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S) -6-phenoxy-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

(S) -8-chloro-6- (4-chlorophenoxy) -2-trifluoromethyl)-2H-130 benzopyran-3-carboxylic acid;

(S) -2- (trifluoromethyl) -6- [4- (trifluoromethyl)phenoxy) -2H-1benzopyran-3-carboxylic acid;

(S) -6- (4-methoxyphenoxy) -2- (trifluoromethyl) -2H-1benzopyran-3-carboxylic acid;

ΑΡ/Γ 9 9 / 0 1 6 77 (S) - 6- (3 -chloro-4-methoxyphenoxy) -2-( trifluoromethyl) -2H-1benzopyran-3-carboxylic acid;

(S) — 6—(4-chlorophenoxy)-2- (trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

(S)-8-chloro-2-(trifluoromethyl)-6-[4(trifluoromethyl) phenoxy] - 2H-l-benzopyran-3-carboxylic acid;

(S) -6-chloro-8-cyano-2- (trif luoromethyl) -2H-1-benzopyran-3carboxylic acid;

(S) -6-chloro-8- [ (hydroxy imino) methyl] -2- (tri fluoromethyl) 2H-l-benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(hydroxymethyl) -2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S) -8- (lH-benzimidazol-2-yl)-6-chloro-2- (trif luoromethyl) 2H-l-benzopyran-3-carboxylic acid;

(S) -7- (1,1-dimethylethyl) -2- (pentafluoroethyl) -2H-1benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(methoxymethyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(benzyloxymethy 1) -2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S) -6-chloro-8-ethenyl-2- (trifluoromethyl) -2H-l-benzopyran3-carboxylic acid;

(S)-6-chloro-8-ethynyl-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

(S)-6-chloro-8-(2-thienyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(2-furanyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(5-chloro-l-pentynyl)-2-(trifluoromethyl)-2H1-benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(1-penfynyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(phenylethynyl)-2-(trifluoromethyl)-2H-1 benzopyran-3-carboxylic acid;

ΑΡιυ 1 1 4 9 (S)-6-chloro-8- (3,3-dimethyl-1-butynyl)-2-(trifluoromethyl)2H-1-benzopyran-3-carboxylic acid;

(S) -6-chloro-8- [ (4-chlorophenyl) ethynyl] -2(trifluoromethy1)-2H-1-benzopyran-3-carboxylic acid;

(S) -6-chloro-8-[(4-methoxyphenyl)ethynyl]-2(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid;

(S) -6- (phenylethynyl) -2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid;

(S)-6-chloro-8-(4-chlorophenyl)-2-(trifluoromethyl)-2H-110 benzopyran-3-carboxylic acid;

(S)-6-chloro-8-(3-methoxyphenyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid;

(S)-6-chloro-8-[(4-methylthio)phenyl]-2-(trifluoromethyl)2H-l-benzopyran-3-carboxylic acid;

(S)-6-chloro-8-[(4-methylsulfonyl)phenyl]-2(trifluoromethy1)-2H-l-benzopyran-3-carboxylic acid;

(S)-6-chloro-8-phenyl-2-(trifluoromethyl)-2H-1-benzopyran-3carboxylic acid;

(S)-6-bromo-8-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-320 . carboxylic acid;

(S)-6-(4-fluorophenyl)-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

(S)-6-phenyl-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

(S)-8-chloro-6-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3carboxylic acid;

(S)-6,8-diiodo-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

(S)-6-(5-chloro-2-thienyl)-2-(trifluoromethyl)-2H-130 benzopyran-3-carboxylic acid;

(S)-6-(2-thienyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid;

(S)-6-(4-chlorophenyl)-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid;

LL 9 I 0 I 6 6 '.”dV (S) - 6- (4-bromophenyl) -2- (trif luoromethyl) -2 H-l-benzopyran-3 carboxylic acid;

(S) - 6- (ethynyl) -2- (trif luocomethyl) - 2H-1-benzopyran-3carboxylic acid;

(S) -6-methyl-2- (trifluoromethyl) -2H-1-benzopyran-3carboxylic acid;

(S) -6-chloro-8- (4-methoxyphenyl) -2-trifluoromethyl-2H-1benzopyran-3-carboxylic acid;

(S) -6-chloro-2 - (trif luoromethyl) -4-ethenyl-2H-l-benzopyran3-carboxylic acid;

(S) -6-chloro-2- (trifluoromethyl) -4-phenyl-2H-l-benzopyran-3carboxylic acid;

(S) -6-chloro-4- (2-thienyl)-2-(trifluoromethyl)-2K-1benzopyran-3-carboxyl:.c acid;

(S) -6- (2,2,2-trifluoro-l-hydroxyethyl) -2- (trif luoromethyl) 2H-l-benzopyran-3-carboxylic acid;

(S) - 6-methyl-2 - (trif luoroms-thyl) -2H-1 -benzothiopyran-3carboxylic acid;

(S) -6,8-dimethyl-2- (trifluoromethyl) -2H-l-benzothiopyran-3carboxylic acid;

(S)-6- (1,1-dimethyl ethyl) -2- (trif luoromethyl) -2H-1benzothiopyran-3-carbcxylic acid;

(S)-7-methyl-2- (trifluoromethyl)-2H-l-benzothiopyran-3carboxylic acid;

(S) -6,7-dimethyl-2- {trif luc romethyl) -2H-1-benzothiopyran-3carboxylic acid;

(S) -8-methyl-2-(trifluoromethyl)-2H-l-benzothiopyran-3carboxylic acid;

(S) -2- (trifluoromethyl)-2K-l-benzothiopyran-3-carboxylic acid;

(S)-6-chloro-7-methyl-2-(trifluoromethyl)-2K-1benzothiopyran-3-carbo.cylic acid;

(S) -7-ohloro-2-(trifluoromethyl)-2H-l-benzothiopyran-3carboxylic acid;

AP 0 0 114 9 (S) -6,7-dichloro-2- (trifluoromethyl) -2H-l-benzothiopyran-3carboxylic acid;

(S)-2-(trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1benzopyran-3-carboxylic acid;

(S)-6, 8-dichloro-2-trifluoromethyl-2H-l-benzothiopyran-3carboxylic acid;

(S) -6-chloro-l, 2-dihydro-2- (trifluoromethyl) -3quinolinecarboxylic acid;

(S)-6,8-dichloro-l,2-dihydro-2-(trifluoromethyl)-3quinolinecarboxylic acid;

(S)-6,7-difluoro-1,2-dihydro-2-(trifluoromethyl)-3quinolinecarboxylic acid;

(S)-6-iodo-l,2-dihydro-2-(trifluoromethyl)-315 quinolinecarboxylic acid;

(S) -6-bromo-1,2-dihydro-2 - (trif luoromethyl) -3quinolinecarboxylic acid;

(S)-1,2-dihydro-6-(trifluoromethoxy)-2-(trifluoromethyl)-3quinolinecarboxylic acidj.

(S)-6-(trifluoromethyl)-1,2-dihydro-2-(trifluoromethyl)-3quinolinecarboxylic acid;

(S)-6-cyano-1,2-dihydro-2-(trifluoromethyl)-3quinolinecarboxylic acid;

(S)-6-chloro-l,2-dihydro-1-methyl-2-(trifluoromethyl)-325 quinolinecarboxylic acid;

(S)-6-chloro-l,2-dihydro-2-(trifluoromethyl)-1-[[4(trifluoromethyl) phenyl]methyl]-3-quinolinecarboxylic acid;

(S)-6-chloro-l-[(4-chlorophenyl)methyl]-1,2-dihydro-230 (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]-1,2-dihydro-2(trifluoromethyl)-3-quinolinecarboxylic acid;

(S) -6-chloro-1,2- dihydro-5- [ (4-nitrophenyl)methyl] -2(trif luoromethyl) -3-ciuinolinecarboxylic acid;

(S) -6-chloro-l, 2-dihydro-2 -ethyl-2- (trifluoromethyl) -3quinolinecarboxylic ccid;

(S) -6-chloro-2- (trif lour or ethyl) -1,2dihydro[l, 8]napthyrioine-3-carboxylic acid;

(S) -2-trif luoromethyl-2H-naphtho [1,2-b] pyran-3-carboxylic acid;

(S) -2-trif luoromethyl-3H-naptho[2, l-b]pyran-3-carboxylic acid;

(S) -2 - trif luoromethyl-2H-r±iphtho [2,3 -b] pyran-3-carboxylic acid; and (S) -5- (hydroxymethyl) -8-me ,:hyl-2- (trifluoromethyl) -2Hpyrano [2,3-c]pyridine-3-carboxylic acid.

The term hydrido dei:.otes a single hydrogen atom (H) . This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached tc a carbon atom to form a methylene (-C^-) radical. Where the term alkyl is used, either alone or within other terms such as haloalkyl and alkylsulfonyl, it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. Most preferred are lower alkyl radicals having 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 preferred alkenyl radicals are lower alkenyl radicals having two to about six carbon atoms.

AP 0 0 1 1 4 9

Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The term alkynyl denotes linear or branched radicals having two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are lower alkynyl radicals having two to about ten carbon atoms. Most preferred are lower alkynyl radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like. The terms alkenyl and lower alkenyl, embrace radicals having cis and trans orientations, or alternatively, E and Z orientations.

The term halo means halogens such as fluorine, chlorine, bromine or iodine atoms. The term haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Lower haloalkyl embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifiuoromethyl, chloromethyl, dichloromet'nyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, di chi or of luoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Perfluoroalkyl means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifiuoromethyl and pentafluoroethyl. The term hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals . More preferred hydroxyalkyl radicals are lower hydroxyalkyl radicals having one to six carbon atoms and' one or more hydroxyl radicals. Examples of such

ΑΡ/Γ.' 9 9/01877 radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The term cyanoalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one cyano radicals. More preferred cyanoalkyl radicals are lower cyanoalkyl radicals having one to six carbon atoms and one cyano radical. Examples of such radicals include cyanomethyl. The terms alkoxy embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are lower alkoxy radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chlcro or bromo, to provide haloalkoxy radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term aryl, alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a pendent manner or may be fused. The term aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Said aryl group may have 1 to 3 substituents such as lower alkyl, hydroxy, halo, haioalkyl, nitro, cyano, alkoxy and lower alkylamino. The term heterocyclyl embraces saturated, partially saturated and unsaturated heteroatomcontaining ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinvl] ; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered

APO 0 114 9 heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and 5 dihydrothiazole. Examples of unsaturated heterocyclic radicals, also termed heteroaryl radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 410 pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated 3 to 5-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to β-membered heteromonocyclic group containing a sulfur atom, 20 for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered 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, 1,3,4oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated condensed 25 heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,430 thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl];

unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl] and the like. The term also embraces radicals where heterocyclic radicals are fused 35 with aryl radicals. Examples of such fused bicyclic radicals ££910/66 ZJ/JV include benzofuran, benzotkiophene, and the like. Said heterocyclyl group may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include benzofuryl, 2,3dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyraz :.nyl. The term sulfonyl, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO₂-. Alkylsulfonyl embraces aikyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are lower alkylsulfonyl radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. Haloalkylsulfonyl embraces haloalkyl radical::; attached to a sulfonyl radical, where haloalkyl is defined as above. More preferred haloalkylsulfonyl radicals are lower haloalkylsulfonyl radicals having one to six carbon atoms. Examples of such lower haloalkylsulfonyl radicals include trifluoromethylsulfonyl. The term arylalkylsulfonyl embraces aryl radicals as defined above, attached to an alkylsulfonyl radical. Examples of such radicals include benzylsulf onyl and phenyl et:hylsulf onyl. The terms sulfamyl, aminosulfonyl' and sulfonamidyl, whether alone or used with terms such as N-alkylaminosulfonyl, Narylaminosulfonyl, Ν,Ν-dialkylaminosulfonyl and N-alkylN-arylaminosulfonyl, denotes a sulfonyl radical substituted with an amine radical, forting a sulfonamide (-SO2NH2). The term alkylaminosulfonyl includes N-alkylaminosulfonyl and Ν,Ν-dialkylaminosulforyl where sulfamyl radicals are substituted, respectively, with one alkyl radical, or two

ΑΡν 0 114 9 alkyl radicals. More preferred alkylaminosulf onyl radicals are lower alkylaminosulfonyl radicals having one to six carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl. The terms Narylaminosulfonyl and N-alkyl-N-arylaminosulf onyl denote sulfamyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. More preferred N-alkyl-N-arylaminosulfonyl radicals are lower N-alkyl-N10 arylsulfonyl radicals having alkyl radicals of one to six carbon atoms. Examples of such lower N-alkyl-N-arylaminosulf onyl radicals include N-methyl-Nphenylaminosulfonyl and N-ethyl-N-phenylaminosulfonyl. Examples of such N-aryl-aminosulfonyl radicals include N15 phenylaminosulf onyl. The term arylalkylaminosulfonyl embraces aralkyl radicals as described above, attached to an aminosulfonyl radical. The term heterocyclylaminosulfonyl embraces heterocyclyi radicals as described above, attached to an aminosulfonyl radical. The terms carboxy or carboxyl, whether used alone or with other terms, such as carboxyalkyl, denotes -CO₂H. The term carboxyalkyl embraces radicals having a carboxy radical as defined above, attached to an alkyl radical. The term carbonyl, whether used alone or with other terms, such as alkylcarbonyl, denotes -(C=O)-. The term acyl denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl.

The term aroyl embraces aryl radicals with a carbonyl radical as defined above. Examples of aroyl include benzoyl, naphthoyl, and the like and the aryl in said aroyl may be additionally substituted. The term alkylcarbonyl embraces radicals having a carbonyl radical substituted with

AP/?9 9 '0 1 6 77 an alkyl radical. More preferred alkylcarbonyl radicals are lower alkylcarbonyl radicals having one to six carbon atoms. Examples of such radicals include methylcarbonyl and ethylcarbonyl. The term haloalkylcarbonyl embraces radicals having a carbonyl, radical substituted with an haloalkyl radical. More preferred haloalkylcarbonyl radicals are lower haloalkylcarbonyl radicals having one to six carbon atoms. Examples of such radicals include trifluoromethylcarbonyl. The term arylcarbonyl embraces radicals having a carbonyl radical substituted with an aryl radical. More preferred arylcarbonyl radicals include phenylcarbonyl. The term heteroarylcarbonyl embraces radicals having a carbonyl radical substituted with a heteroaryl radical. The term arylalky1carbonyl embraces radicals having a carbonyl radical substituted with an arylalkyl radical. More preferred arylcarbonyl radicals include benzylcarbonyl. Tiie term heteroarylalkylcarbonyl embraces radicals having a carbonyl radical substituted with a heteroarylalkyl radical. The term alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical.

Preferably, lower alkoxycarbonyl embraces alkoxy radicals having one to six carbon atoms. Examples of such lower alkoxycarbonyl ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, butoxycarbonyl and hexyloxycarbonyl. The term aminocarbonyl when used by itself or with other terms such as aminocarbonylalkyl, N-alkyl aminocarbonyl, Narylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-Narylaminocarbonyl, N-alky 1-N-hydroxyaminocarbonyl and Nalkyl-N-hydroxyaminocarbonylalkyl, denotes an amide group of the formula -C(=O)NH₂. The terms N-alkylaminocarbonyl and Ν,Ν-dialkylaminocarbonyl denote aminocarbonyl radicals which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred are lower

ΑΡ υΟ 1 14 9 alkylaminocarbonyl having lower alkyl radicals as described above attached to an aminocarbonyl radical. The terms Narylaminocarbonyl and N-alkyl-N-arylaminocarbonyl denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. The term N-cycloalkylaminocarbonyl denoted aminocarbonyl radicals which have been substituted with at least one cycloalkyl radical. More preferred are lower cycloalkylaminocarbonyl having lower cycloalkyl radicals of three to seven carbon atoms, attached to an aminocarbonyl radical. The term aminoalkyl embraces alkyl radicals substituted with amino radicals. The term alkylaminoalkyl embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical. The term heterocyclylalkyl embraces heterocyclic15 substituted alkyl radicals. More preferred heterocyclylalkyl radicals are 5- or 6- membered heteroarylalkyl radicals having alkyl portions of one to six carbon atoms and a 5- or 6- membered heteroaryl radical. Examples include such radicals as pyridylmethyl and thienylmethyl. The term aralkyl embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are lower aralkyl radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl.

The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term arylalkenyl embraces aryl-substituted alkenyl radicals. Preferable arylalkenyl radicals are lower arylalkenyl radicals having aryl radicals attached to alkenyl radicals having two to six carbon atoms. Examples of such radicals include phenylethenyl. The aryl in said arylalkenyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term arylalkynyl embraces aryl-substituted alkynyl radicals.

Preferable arylalkynyl radicals are lower arylalkynyl

LL 9 I 0 i 6 6 /J'dV radicals having aryl radicals attached to alkynyl radicals having two to six carbon atoms. Examples of such radicals include phenyiethynyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of alkylthio is methylthio, (CH₃S—) . The term haloalkylthio embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of haloalkylthio is trifluoromethylthio. The term alkylsulfinyl embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent -S(=O)atom. The term arylsulfinyl embraces radicals containing an aryl radical, attached to a divalent -S(=0)- atom. The term haloalkylsulfinyl embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent -S(=O)- atom. The terms N-alkylamino and N,Ναι alkyl amino denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are lower alkylamino radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Suitable alkylamino may be mono or dialkylamino such as N-methylamino, N-echylamino, N, N-dimethylamino, N,Ndiethylamino or the like. The term arylamino denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The arylamino radicals may be further substituted on the aryl ring portion of the radical. The term heteroarylamino denotes amino groups which have been subs;tituted with one or two heteroaryl radicals, such as N-thienylamino. The heteroarylamino radicals may be further substituted on the

ΑΡϋ 01 1 4 9 heteroaryl ring portion of the radical. The term aralkylamino denotes amino groups which have been substituted with one or two aralkyl radicals, such as Nbenzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion of the radical. The terms N-alkyl-N-arylamino and N-aralkyl-N-alkylamino denote amino groups which have been substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group. The term arylthio embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of arylthio is phenylthio. The term aralkylthio embraces aralkyl radicals as described above, attached to a divalent sulfur atom. An example of aralkylthio is benzylthio.

The term aralkylsulfonyl embraces aralkyl radicals as described above, attached to a divalent sulfonyl radical.

The term heterocyclylsulfonyl embraces heterocyclyl radicals as described above, attached to a divalent sulfonyl radical. The term aryloxy embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The term aralkoxy embraces oxycontaining aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are lower aralkoxy radicals having phenyl radicals attached to lower alkoxy radical as described above.

The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.

The present invention also comprises a method of treating cyclooxygenase-2 mediated disorders, such as inflammation, in a subject, the method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound of Formula I.

Also included in the family of compounds of Formula I are the stereoisomers thereof. Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic 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 can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active base and then separation of the mixture of diastereoisomers by crystallization, followed by liberation of the optically active bases from these salts. Examples of appropriate bases are brucine, strychnine, dehydroabietylamine, quinine, cinchonidine, ephedrine, amethylbenzylamine, amphetamine, deoxyphedrine, chloramphenicol intermediate, 2-amino-1-butano1, and 1-(1napthyl)ethylamine. A different process for separation of optical isomers involves t.he use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of Formula I can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. Additional methods for resolving optical isomers, known to those skilled in the art may be used, for example, those discussed by J. Jaques et al in Enantiomers,

APO01149

Racemates, and Resolutions. John Wiley and Sons, New York (1981).

Also included in the family of compounds of Formula 1 and 1' are the amide protected acids thereof. Thus primary and secondary amines can be reacted with the chromene-3carboxylic acids of Formula 1 and I' to form amides which can be useful as pro drugs. Preferred amines heterocyclicamines, including optionally substituted aminothiazoles, optionally substituted amino-isoxazoles, and optionally substituted aminopyridines; aniline derivatives; sulfonamides; aminocarboxylic acids; and the like. Additionally, l-acyldihydroquinolines can behave as prodrugs for the lH-dihydroquinolines .

Also · included in the family of compounds of Formula I and I' are the pharmaceutically-acceptable salts thereof.

The term pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceuticallyacceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of 'such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, 4-hydroxybenzoic, phenvlacetic, mandelrc, embonic (pamoic), methanesulfonic, ethanesulSonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic,

AP/R 99/01677 stearic, algenic, P-hydro;&gt;cfbutyric, salicyclic, galactaric and galacturon:.c acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I or I' include metallic 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, Nethyl piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may 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'.

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be synthesized according to the following procedures of Schemes 1-15, wherein the R--R® substituents are as defined for Formulas Σ-ΙΙ, above, except where further noted.

SCHEME 1

<img file="AP1149A_D0007.tif" />

ΑΡΟο 1 149

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

SCHEME 2

<img file="AP1149A_D0008.tif" />

<img file="AP1149A_D0009.tif" />

E, E' = halogen, acyl, sulfonyl

Synthetic Scheme 2 shows the general method for functionalizing selected 2H-l-benzopyrans. Treatment of the

2H-l-benzopyran carboxylic acid 4 or ester 3 with an electrophilic· agent makes a 6-substituted 2H-l-benzopyran 5. A wide variety of electrophilic agents react selectively with 2H-1-benzopyrans 4 in the 6-position to provide new analogs in high yield. Electrophilic reagents such as halogen (chlorine or bromine) give the 6-halo derivatives. Chlorosulfonic acid reacts to afford the 6position sulfonyl chloride that can further be converted to a sulfonamide or sulfone. Friedel-Crafts acylation of 4 provides 6-acvlated 2H-l-benzopyrans in good to excellent yield. A number of other electrophiles can be used to selectively react with these 2H-l-benzopyrans in a similar

ΑΡ/Γ/ 9 9 / 0 1 6 77 manner. A 6-position substituted 2H-1-benzopyran can react with an electrophilic reagent at the 8-position, using similar chemistries substitution of the benzopyran which is oositions.

to that described for electrophilic 6-position. This yields an 2K-1subsc:ltuted at both the 6 and 8

SCHEME 3

<img file="AP1149A_D0010.tif" />

Synthetic Scheme 3 illustrates a second general synthesis of substituted BE-1-benzopyran-3-carboxylic acids which allows benzopyran. available sub substitution at position 4 of the 2H-1In this case a commercially or synthetically tituted ortho-hydroxy acetophenone 6 is treated wrth two or more equivalents of a strong base such as lithium bis (trimethylsilyl)amide in a solvent such·as tetrahydrofuran (THF), followed by reaction with diethyl

Ester 7 is

ARC 0 114 9 carbonate to afford the beta-keto ester 7.

condensed with an acid chloride or anhydride in the presence of a base such as potassium carbonate in a solvent such as toluene with heat to afford 4-oxo-4H-l-benzopyran 8.

Reduction of the olefin can be accomplished by a variety of agents including sodium borohydride (NaEHJ in solvent mixtures such as ethanol and tetrahydrofuran (THE), or by use of triethylsilane in a solvent such as trifluoroacetic acid, or by catalytic reduction using palladium on charcoal and hydrogen gas in a solvent such as ethanol to yield the new beta-keto ester 9 (two tautomeric structures shown). Acylation of the oxygen of the ketone enolate in the presence of a base such as 2,6-di-tert-butyl-4methylpyridine, an acylating agent such as trifluoromethanesulfonic anhydride, and using a solvent such as methylene chloride yields the 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 yield 2H-i-benzopyran ester 11 where 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 tetrahydrofuran-ethanol-water (7:2:1) to yield the desired substituted 2H-l-benzopyran-3-carboxylic acid.

To incorporate a carbon fragment R³ one can treat triflate 10 with reagents known to undergo cross-coupling chemistries such a tributyletlvenyltin , lithium chloride and a palladium(O) catalyst such as tetrakis (triphenylphosphine)palladium (0) in a solvent such , as tetrahydrofuran to yield 2K-l-benzopyran ester 11 where R³ is a vinyl moiety. The ester 6 can be saponified with a base such as 2.5 N sodium hydroxide in a mixed solvent such as tetrahydrofuran-ethanol-water (7:2:1) to yield the desired 4-vinyl-2H-l-benzopyran-3-carboxylic acid (12, R = CH,CH-) . Similarly triflate 10 can be converted under similar conditions using tri-n-butylphenyltin to 2H-1benzopyran where R³ = phenyl and by hydrolysis of the ester

AP/T.' 9 9 '01677 converted to the carboxylic acid 12 where R³ = phenyl.

Using a similar strategy, substituents which be incorporated as substitutent R³ can be substituted olefins, substituted aromatics, substuced heteroaryl, acetylenes and substituted acetylenes .

SCHEME 4

<img file="AP1149A_D0011.tif" />

Synthetic Scheme 4 slows an alternative general procedure for the preparation of 4-oxo-4H~l-benzopyran 8.

Treatment of an ortho-fluorobenzoyl chloride with an appropriately substituted beta-keto ester 14 with a base such as potassium carbonate in a solvent such as toluene provides 4-oxo-4H-l-benzogyran 8. 4.-oxo-4K-l-benzopyran 8 can be converted to 2H-l-oenzopyran 12 as described in Scheme 3.

SCHEME 5

<img file="AP1149A_D0012.tif" />

Y = Br, I, CF₃SO₃

<img file="AP1149A_D0013.tif" />

Synthetic Scheme 5 snows a general method for substitution of the aromatic ring of the 2H-l-benzopyran. This can be accomplished through organo-palladium mediated cross-coupling chemistries using a palladium (0) catalyst to couple benzopyran 15 at position Y, where Y is iodide, bromide or triflate, with an acetylene, olefin, nitrile, or aryl coupling agent. Substituted acetylenes as the coupling agent will provide the cotresponding substituted acetylene.

ΑΡϋ 0 114 9

Substituted aryl moieties can be incorporated using arylboronic acids or esters; nitriles can be incorporated by use of zinc (II) cyanide. The resulting ester 16 can be converted to carboxylic acid 17 as described in Scheme 1.

Another approach to substitution of the aryl moiety of the benzopyran 15 is to convert Y, where Y is iodide or bromide, to a perfluoroalkyl moiety. Exemplary of this transformation is the conversion of 15 (Y = iodide) to 16 (R² =pentafluoroethyl) using a potassium pentafluoropropionate and copper (I) iodide in hexamethylphosphoramide (HMPA) . The resulting ester 16 can be converted to carboxylic acid 15 as described in Scheme 1.

A similar method adds substitution of the aromatic ring in dihydroquinoline-3-carboxylates. This can be accomplished through organopalladium couplings with aryl iodides, bromides, or triflates and various coupling agents (R. F. Heck, Palladium Reagents in Organic Synthesis. Academic Press 1985). When using a suitable palladium catalyst such as tetrakis (triphenyl-phospine)palladium(0) in this reaction, coupling agents such as alkynes provide disubstituted alkynes, phenyl boronic acids afford biphenyl compounds, and cyanides produce arylcyano compounds. A number of other palladium catalysts and coupling reagents could be used to selectively react with appropriately substituted dihydroguinoline-3-carboxylates in a similar manner.

ΑΡ/Γ7 9 9 / 0 1 6 77

SCHEME 6

<img file="AP1149A_D0014.tif" />

· Synthetic Scheme 6 shows a general synthetic route for conversion of a commercially or synthetically available substituted, phenol· into a substituted salicylaldehyde. Several different methods which utilize formaldehyde or a chemically equivalent reagent are described in detail below.

Reaction of an appropriately substituted phenol 18 in basic media with formaldehyde (or chemical equivalent) will yield the corresponding salicylaldehyde 1. The intermediate, ortho-hydrox_;/methylphenol 19, will under appropriate reaction conditions be oxidized to the salicylaldehyde 1 in situ. The reaction commonly employs ethyl magnesium bromide or magnesium methoxide (one equivalent) as the base, toluene as the solvent, paraformaldehyde (two or more equivalents) as the source of formaldehyde, and employs liexame thy lphor amide (HMPA) or Ν, Ν, N', N'-tetramethylethylenediamine (TMEDA) . (See:

Casiraghi, G. et al. , J. C. S'. Perkin I, 1978, 318-321.)

Alternatively an appropriately substituted phenol 18 may react with formaldehyde under aqueous basic conditions to form the substituted ortho-hydroxybenzyl alcohol 19 (See: a) J. Leroy and C. Wakselma.n, J. Fluorine Chem., 40, 23-32 (1988). b) A. A. Moshfegh, et al. , Helv. Chim. Acta., 65,

1229-1232 (1982)). Commonly used bases include aqueous potassium hydroxide or sodium hydroxide. Formalin (38% formaldehyde in water) is commonly employed as the source of formaldehyde. The resulting ortho-hydroxybenzyl alcohol 19 '25 can be converted to the salicylaldehyde 1 by an oxidizing agent such as manganese (IV) dioxide in a solvent such as methylene chloride or chloroform (See: R-G. Xie, et al. , Synthetic Commun. 24, 53 — 58: (1994)).

An appropriately substituted phenol 18 can be treated under acidic conditions wit.h hexamethylenetetramine (HMTA) to prepare the salicylaldehyde 1 (Duff Reaction; See: Y. Suzuki, and H. Takahashi, C’.hem. Pharm. Bull., 31, 1751-1753 (1983)). This reaction commonly employs acids such as acetic acid, boric acid, methanesulfonic acid, or trifluoromethanesulfonic acid. The source of formaldehyde commonly used is hexamethylenetetramine.

APO01149

SCHEME 7

<img file="AP1149A_D0015.tif" />

Synthetic Scheme 7 shows the Reimer-Tiemann reaction in which an commercially or synthetically available appropriately substituted phenol 18 will under basic conditions react with chloroform to yield a substituted salicylaldehyde 1 (See: Cragoe, E.J.; Schultz, E.M., U.S. Patent 3 794 734, 1974).

<img file="AP1149A_D0016.tif" />

ΑΡ/Γ7..9 9 /0 1 6 77

21 ^{10 * * * * 15 * * * 19 20} 1

Synthetic Scheme 8 shows the conversion of a commercially or synthetically available appropriately substituted salicylic acid 21 to its respective salicylaldehyde 1 via an intermediate 2-hydroxybenzyl alcohol 19. Reduction of the salicylic acid 21 can be accomplished with a hydride reducing agent such as borane in a solvent such as tetrahydrofuran. 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 provides salicylaldehyde 1.

SCHEME 9

<img file="AP1149A_D0017.tif" />

Synthetic Scheme 9 illustrates a general synthetic method for preparation of a wide variety of substituted 25 (trifluoromethyl)-2H-l-berizothiopyran-3-carboxylic acids (25). In step 1, an appropriately commercially or synthetically available substituted thiophenol 22 is orthometallated with a base such as n-butyllithium employing TMEDA (27, N, N', 27'-tetramethylethylenediamine) followed by treatment with dimethylformamide to provide the 2mercaptobenzaldehyde 23. Condensation of the 2mercaptobenzaldehyde 23 with an acrylate 2 in the presence of base provides ester 24 which can be saponified in the presence of aqueous base to afford the substituted 2H-1'15 benzothiopyran-3-carboxylic acids 25.

AP Ο Ο 1 14 8

SCHEME 10

<img file="AP1149A_D0018.tif" />

Synthetic Scheme 10 shows a method for preparing a substituted 2-mercaptobenzaldehyde from an appropriate commercially or synthetically available substituted salicylaldehyde. In step 1, the phenolic hydroxyl of salicylaldehyde 1 is converted to the corresponding O-aryl thiocarbamate 26 by acylation with an appropriately substituted thiocarbamoyl chloride such as N,N10 dimethylthiocarbamoyl chloride in a solvent such as dimethylformamide using a base such as triethylamine. In Step 2, O-aryl thiocarbamate 26 rearranges to S-aryl thiocarbamate 27 when heated sufficiently such as to 200 °C using either no solvent or a solvent such as N, N15 dimethylaniline (See: A. Levai, and P. Sebok, Synth. Commun., 22 1735-1750 (1992)). Hydrolysis of S-aryl thiocarbamate 27 with a base such as 2.5 N sodium hydroxide in a solvent mixture such as tetrahydrofuran and ethanol yields the substituted 2-mercaptobenzaldehyde 23 which can be converted to the substituted 2H-l-benzothiopyran-3carboxylic acids 25 as described in Scheme 9.

ΑΡ/Γ'9 9 /0 1 6 77

SCHEME 11

<img file="AP1149A_D0019.tif" />

<img file="AP1149A_D0020.tif" />

Synthetic Scheme 11 illustrates the general method for the preparation of a wide variety of dihydroquinoline-35 carboxylic acid derivatives 30. R² represents the aromatic substitution of commercial!/ and synthetically available 2aminobenzaldeydes 28. The 2-amino-benzaldehyde derivative 28, where R² represents various substitutions, is condensed with a acrylate derivative ,',ί in the presence of base such as potassium carbonate, triethylamine, or aiazbicyclo[2.2.2]undec-7-ene in solvents such as y dimethylformamide to afford the dihydroquinoline-3 carboxylate esters 29. The ester 29 can be saponified to the corresponding acid, such as by treatment with aqueous inorganic base such as 2.5 U sodium hydroxide in a suitable solvent such as ethanol to afford after acidification the desired dihydroquinoline-3-carboxylic acid 30.

ΑΡΟ 0 114 9

SCHEME 12

<img file="AP1149A_D0021.tif" />

<img file="AP1149A_D0022.tif" />

<img file="AP1149A_D0023.tif" />

Synthetic Scheme 12 illustrates the preparation of dihydroquinoline-3-carboxylic acid 30 from 2-aminobenzoic acids 31. R² represents the aromatic substitution of commercially and synthetically available 2-aminobenzoic acids 31. Reduction of the representative 2-aminobenzoic acid 31 to the desired 2-aminobenzyl alcohol 32 was accomplished with a hydride reducing agent such as borane in a solvent such as tetrahydrofuran. Treatment of the desired 2-aminobenzyl alcohol 32 with an oxidizing agent such as manganese(IV)oxide in a solvent such as methylene chloride provides 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.

ΑΡ/Γ7 9 9 /0 1 6 77

SCHEME 13

<img file="AP1149A_D0024.tif" />

<img file="AP1149A_D0025.tif" />

<img file="AP1149A_D0026.tif" />

Synthetic Scheme 13 illustrates the general method for the preparation of a wide variety of dihydroquinoline-3carboxylic acid derivatives 30 from isatins 33. R²represents the aromatic subs;titution of commercially and synthetically available isatins 33. A representative isatin 33 was treated with basic pe;roxide generated from hydrogen peroxide and a base such as sodium hydroxide to afford the desired representative 2-aminobenzoic acids 31. (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 30 as described in synthetic Scheme 12.

SCHEME 14

<img file="AP1149A_D0027.tif" />

Synthetic Scheme 14 is another general method for the preparation of dihydroquinoline-3-carboxylic acid derivatives 30. In step 1, etn appropriate commercially or synthetically available substituted aniline 34 can 'be treated with an acylating reagent such as pivaloyl chloride

APO 0 114 9 yielding an amide 35. The ortho-dianion of amide 35 is prepared by treating amide 35 with organo-lithium bases such as n-butyllithium or tert-butyllithium in tetrahydrofuran at low temperature. The dianion is quenched with dimethylformamide to afford the acylated-2-aminobenzaldehydes 36. (J. Turner, J. Org. Chem., 48, 3401-3408 (1983)) Reaction of these aldehydes in the presence of bases such as lithium hydride with a acrylate followed by work up with aqueous inorganic bases and hydrolysis, such as by treatment with aqueous base (sodium hydroxide) in a suitable solvent such as ethanol affords, after acidification, a dihydroquinoline-3-carboxylic acid 30.

SCHEME 15

<img file="AP1149A_D0028.tif" />

<img file="AP1149A_D0029.tif" />

<img file="AP1149A_D0030.tif" />

L L 9 I 0 &gt; 6 6 0,'d V

Synthetic Scheme 15 shows a general method for alkylation of the nitrogen of dihydroquinoline-3-carboxylate ester derivatives 29. The step involves treatment of dihydroquinoline-3-carboxylate ester derivatives 29 with alkyl halides such as iodoethane in the presence of phase transfer catalysts such a tetrabutylammonium iodide, and a base such as caustic (50% aqueous sodium hydroxide) in a solvent such as dichloromethane. These conditions afford the N-alkylated dihyrdoquinoline-3-carboxylate esters 37.

Saponification of 37 with a:jueous base provides N-alkylateddihyroquinoline-3-carboxyli : acid derivatives 38.

The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas IZC. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention.

These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures cire in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures.

The following abbreviations are used:

HCl - hydrochloric acid MgSO4 ^- magnesium sulfate NajSO^ - sodium sulfate DM? - dimethylformamide THF - tetrahydrofuran NaOH - sodium hydroxide EtOH - ethanol

K2CO3 - potassium carbonate

CDCI3 - deuterated chloroform

CD3OD - deuterated methanol

Et2O - diethyl ether

EtOAc - ethyl acetate

NaHCO₃ sodium bicarbonate

KHSO4 ~ potassium sulfate

Na3H4 - sodium borohydride

TMEDA - tetrametylethylenedirmine

HMTA. - hexamethylenetetraamine

DMSO - dimethyl sulfoxide

HMPA hexamethyl phosphoric tiriamide

APO 0 114 9

EXAMPLE 1

<img file="AP1149A_D0031.tif" />

- Chloro- 2-trif luor omethyl - 2 Η-1 -her z opyran- 3 carboxylic acid

5teo 1. Preparation of ethvl 6-chloro-2crif luorome thvl-2K-l-ber.zoovr an-3-carboxvlate.

A mixture of 5-chlorosaiicylaldehyde (20.02 g,

0.128 mole) and ethyl 4,4,4-trifluorocrotonate (23.68 g, 0.14 mole) was dissolved in anhydrous DMF, warmed to SO ^CC and treated with anhydrous K₂CO, (17.75 g, 0.128 mole). 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 brine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo to afford 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 that was isolated by filtration, washed with water and dried in vacuo, to afford the ester as a yellow solid (24.31 g, 62%); mp 62-64 °C.

NMR (CDCl₃/90 MHz) 7.64 (s, IK), 7.30-7.21 (m, 2H) , f

* (X &lt;

6.96 (d, IK, J = Hz), 5.70 (q, 1H, 2H, J =7.2 Hz), 1.35 (t, 3K, J -Ί u = Hz), 4.30 (q 2 HZ) .

Steo 2. Preparation of 6-chloro-2trifluoromethvl-2H-l-benzoovran-3-carboxylic acid.

A solution of the ester from Step 1 (13.02 g, 42 mmole) was dissolved in 200 mL of methanol and 20 mL of water, treated with lithium hydroxide (5.3 6. g, 0.128 mole) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.2 N HCI, whereupon a solid formed that 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%); mp 181184 °C.

EXAMPLE 2

<img file="AP1149A_D0032.tif" />

6- (Methylthio) -2- (trif luoromethyi) -2H-l-benzopyran-3carboxylic acid

Steo 1. Preparation of 5-(methvlthlo)salicvlaldehvde.

Ethyl magnesium bromide (38 mL of a 3.0 M solution in diethyl ether, 113.8 mmole) was chilled with an ice-water bath. To the chilled solution was added a solution of 4(methylthio)phenol (15.95 g, 113.8 mmole) in diethyl ether (30 mL) over 0.15 hour during which time gas was evolved. The reaction was held at 0 °C for 0.5 hour, at room temperature for 0.5 hour, and the addition funnel replaced with a distillation head. Toluene (10C mL) was added and the diethyl ether was distilled out of the reactor. The reaction w^ras cooled, toluene (250 mL) and hexamethylphosphoramide (HMPA) (19.8 mL, 20 .4 g, 113.8 mmole) were added, and the resulting mixture was stirred for 0.25 hours. The distillation head was replaced with a condenser and paraformaldehyde (8.5 g, 234.4 mmole) was added. The reaction was heated to 90 ”C for 3 hours. The reaction mixture was cooled to room temperature, was acidified with IN HCI and the layers separated. The organic phase was washed with water, and with brine, dried over MgS0₄, filtered, and concentrated in vacuo to yield a solid. This solid was purified by silica chromatography (hexanes-ethyl acetate, 5:1) yielding the salicylaldehyde as a yellow

AP Ο Ο 1 1 4 9 crystalline solid (6.01 g) of suitable purity to be used in the next reaction without further purification.

Step 2. Preparation of ethyl 6-(methylthio)-25 (trif luoromethyl) -2H-l-benzopvran-3-carboxvlate .

5-Methylthiosalicylaldehyde (Step 1)(2.516 g, 14.96 mmole) was added to dimethylformamide (3.5 mL) , potassium carbonate (2.27 g, 16.45 mmole) and ethyl 4,4,4trifluorocrotonate (3.3 mL, 3.8 g, 22.4 mmole). The mixture was heated to 65 °C for 3 h. The reaction was cooled to room temperature, poured into H₂O (50 mL) , and extracted with diethyl ether (2 X 75 mL) . The combined ethereal phases were washed with aqueous NaHCO₃ solution (3 X 50 mL) , aqueous 2 N HCI solution (3 X 50 mL), and brine (3 X 50 mL), dried over MgSO₄, filtered, diluted with isooctane and partially concentrated in vacuo causing the precipitation of the ethyl ester (2.863 g, 60 %) as a yellow powder: mp 87.8-89.6 °C This ester was of suitable purity to use without further purification.

Step 3. Preparation of 6-(methylthio)-2-(trifluoromethyl)2H-l-benzopyran-3-carboxylic acid.

The ester (Step 2) was hydrolyzed to form the carboxylic acid via a method similar to that described in ^η5 Example 1, Step 2: mp 166.3-167.9 °C. NMR (acetoned^/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, 1H, J = 8.5 Hz), 5.79 (q, 1H, J = 7.0 Hz), 2.48 (s, 3H) . FABLRMS m/z 291 (M+H). ESHRMS m/z 289.0152 (M-H, Calc'd 289.0146). Anal. Calc'd for C₁₂H₉F₃O3S_1: C, 49.66; H, 3.13; S, 11.05. Found: C, 49.57; H,3.02; S, 11.37.

APT' 99*01677

EXAMPLE 3 ^^co₂h

H,C'

<img file="AP1149A_D0033.tif" />

7-Methyl-2-tri£luoromethyl-2H-l-benzopyran-3 carboxylic: acid

3-Methylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 202.1-203.'.. °C. NMR (CDCl₃/300 MHz) 7.84 (s, 1HI, 7.12 (d, IH, J= 8.3

Hz), 6.82 (m, 2H), 5.65 (q, IH, J= 6.8 Hz), 2.35 (s, 3H) . FABLRMS m/z 259 (I:i+H) . FABHRMS m/z 259.0576 (M+H, Calc'd 259.0582). Anal. Calc'd for Ci2^H9^F3⁰3^{: c}&gt; 55.82; H, 3.51. Found: C,

55.93; H, 3.59.

EXAMPLE 4

<img file="AP1149A_D0034.tif" />

.co₂h f₃ct o xf₃

2,7 -bis {Trifluoromethyl) - 2H-l-benzopyran-3 carboxylic acid

3-(Trifluoromethyl)phenol was converted to the title compound by a procedure similar to that described in Example 2: mp 150.3-193.5 °C. ^H NMR (acetone-d_d/300 MHz) 7.98 (s, IH), 7.73 (d, IH, J = 7.9 Hz), 7.46 (d, IH, J = 7.9 Hz), 7.36 (s, IH) , 5.93 (q, IH, J = 7.1 Hz). FABLRMS m/z 313 (M+H). FABHRMS m/z 313.0267 (M+H, Calc'd 313.0299). Anal. Calc'd for C-^HgFgC^ : C, 46.17; H, 1.94. Found: C, 46.25; H, 2.00.

APO 01149

EXAMPLE 5

Β

<img file="AP1149A_D0035.tif" />

7-Bromo-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid

3-Bromophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 198.4-199.5 °C. -^H NMR (acetonedg/300 MHz) 7.89 (s, 1H), 7.43 (d, 1H, J- 8.1

Hz), 7.31 (s, 1H), 7.30 (d, 1H, J =8.1 Hz), 5.84 (q, 1H, J = 7.1 Hz). FABLRMS m/z 323 (M+H).

Anal. Calc'd for C^iHgBrFjOj: C, 40.90; H, 1.87. Found: C, 41.00; H, 1.85.

EXAMPLE 6 ££910/66

6-Chloro-7-methyl-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid

4-Chloro-3-methyIphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 207.5-209.3 °C. ^H NMR (CDC1₃/300 MHz) 7.77 (s, 1H), 7.23 (s, 1H), 5.90 (s, 1H), 5.65 (q, 1H, J=6.8Hz), 2.37 (s, 3H). FABLRMS m/z 292 (M+H). FABHRMS m/z 299.0287 (M+Li, Calc'd 299.0274). Anal. Calc'd for ^C12^H8^C1F3°3^{: C}' 49.25; H, 2.76; Cl, 12.11. Found: C, 49.37; H, 2.82; Cl, 12,17.

EXAMPLE

<img file="AP1149A_D0036.tif" />

O Cf-3

OH

6- (4-Methoxyphenoxy) -2- (trifluoromethyl)-2H-l-benzopyran-3car.boxylic acid

4- (4-Methoxyphenyl)phenol was converted to the title compound by a procedure similar to that described in Example 2: mp 181.7-182.9 °C. ^XH EMR (acetone-d^/300 MHz) 7.87 (s,

IH) , 7.11 (m, IH) , 7.02 (m, 2H) , 6.98 (m, 4H) , 5.81 (q, IH,

J = 7.0 Hz), 3.80 (s, 3K) . FABLRMS m/z 365 (M-H) . FABHRMS m/z 367.0809 (M+H, Calc'd 367.0793). Anal. Calc'd for C₁₈H₁₃F₃O_S: C, 59.02; H, 3.58. Found: C, 59.10; H, 3.61.

EXAMPLE 8

6-Chloro-7-(1,1-dimethylethyl) -2-trif luoromethyl2H-l-benzopyran-3-carboxylic acid

Step 1. Preparation of 4-tert-butvlsalicvlaldehvde.

A five liter three-ne::k round bottom flask equipped with overhead mechanical s/.irrer and condenser was charged with trifluoroacetic acid (2.4 L). A mixture of 3-tertbutylphenol (412 g, 2.8 mole) and HMTA (424 g, 3.0 mole) was

APO Ο 1 1 4 9 added portion-wise causing an exotherm. With cooling, the temperature was maintained under 80 °C. The reaction was heated at 80 °C for one hour, then cooled, and water (2 L) added. After 0.5 hour additional water (4 L) was added and the mixture was extracted with ethyl acetate (6 L) . The organic extract was washed with water and brine. The resulting organic phase was divided into 2 L volumes and each diluted with water (1 L) , and solid NaHCO₃ added until the mixture was neutralized. The organic phases were isolated and combined, dried over MgSO₄, filtered and concentrated in vacuo yielding an oil. This oil was distilled at 95 °C (0.8 mm) yielding the desired salicylaldehyde as an oil (272.9 g, 56 %) which was of sufficient purity to be used without further purification.

Step 2. Preparation of ethyl 7-(1,1-dimethvlethvl)-2(trifluoromethyl) -2H-l-benzopvran-3-carboxylate.

A one liter three-neck flask was charged with 4-tertbutylsalicylaldehyde (Step 1)(100.0 g, 0.56 mole), dimethyiformamide (110 mL) , and potassium carbonate (79.9 g, 0.58 mole) causing the temperature of the mixture to rise to 40 °C. Ethyl 4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethyiformamide (110 mL) was added and the mixture heated to 60 °C at which time the reaction temperature rose to 70 °C. The reaction was cooled to 60 °C, maintained at 60 °C (with added heating) for 8.5 hours and cooled to room temperature. Ethyl acetate (600 mL) and 3 N HCI (600 mL) were added, mixed, and the layers separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The combined organic phases were washed with brine-water (1:1), brine, dried over MgSO₄, filtered and concentrated in vacuo, yielding a semi-solid. Hexane (600 mL) was added with mixing and the mixture was filtered. The filtrate was washed with brine, dried over

MgSO₄,' filtered and concentrated in vacuo yielding a solid.

This solid was dissolved in hot ethanol (600 mL) . Water (190 mL) was added which induced crystallization. Filtration of the mixture and drying of the product provided the desired ester as a crystalline solid (131.3 g, 71%) : mp 91.0-94.9 °C. This material was of suitable purity to be used in subsequent steps without further purification.

Steo 3. Preparation of ethvi 6-chloro-7-(1,1dimethvlethvl )-2-( trifluorornethyl) -2H-l-ber.zopvran-3carboxvlate.

A one liter three-neck flask equipped with mechanical stirrer and gas inlet tube was charged with the ester (Step 2) (100 g, 0.3 mole) and acetic acid (300 mL) . While cooling (water bath) the reaction mixture, chlorine gas (37.6 g, 0.53 mole) was added which caused the temperature to rise to 48 °C. After stirring for two hours, the reaction was cooled in an :..ce-water bath to 15 °C. Zinc powder (19.5 g, 0.3 mole) vas added in one portion which caused the temperature to arise to 72 °C. After cooling to room temperature additional zinc powder (5.0 g, 0.08 mole) was added and the mixture v;as stirred for 0.5 hour longer. The crude mixture was filtered through diatomaceous earth and was concentrated in vacuo yielding an oil. The oil was dissolved in ethyl acetate (700 mL) washed with brine-water {1:1, 1 L) and brine (0.5 1) . The resulting aqueous phase was extracted with ethyl acetate (700 mL) . This ethyl acetate phase was washed with brine-water (1:1, 1 L) and brine (0.5 L) . The combined organic phases were dried over MgSO_&lt;( filtered and concentrated in vacuo yielding the title compound as a yellow oil (116 g, 106 %) . This material, which contained some entrained ethyl acetate, was of suitable purity to be used in subsequent steps without further purification.

Step 4. Preparation of 6-c;iloro-7-(1,1-dimethvlethvl)-2_(trifluorornethyl ).-2H-l-benzopyran-3-carboxvlic acid.

To a solution of the erier (Step 3) (116 g,

0.3 mole) in methanol (500 niL) and tetrahydrofuran

ΑΡ Ο ο 1 U 9 (500 mL) in a one liter flask was added aqueous sodium hydroxide (2.5 N, 240 mL, 0.6 mole). After stirring overnight, the pH of the solution was adjusted to 1 with concentrated hydrochloric acid and the solution was extracted with ethyl acetate.

The ethyl acetate phase was dried over MgSO₄, filtered and concentrated in vacuo yielding a solid. This solid was dissolved in hot ethanol (500 mL). Water (500 mL) was added and upon cooling to room temperature crystals formed which were collected by vacuum filtration. The crystals were washed vjith ethanol-water (3:7, 3 X 200 mL) and dried providing the title acid as a crystalline solid (91.6 g, 91 %): mp 194.9-196.5 °C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (ε, 1H) ,

7.52 (s, 1H), 7.12 (s, 1H), 5.83 (q, 1H, J= 7.1 Hz), 1.48 (s, 9H) . Anal. Calc'd for C-L5K2.4CIF3O3:

C, 53.83; H, 4.22; Cl, 10.59. Found: C, 53.92; H, 4.24; Cl, 10.50.

EXAMPLE 9

<img file="AP1149A_D0037.tif" />

ART.' 9 9 /0 1 6 77

6- (3-Chloro-4-methoxyphenoxy)-2-(trifluoromethyl) -2H-1benzopyran-3-carboxylic acid

To a stirred solution of chlorine in acetic acid (3.5 mL of 0.24 M solution, 0.84 mmol) was added 6-(43 0 methoxyphenoxy) -2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid (0.31 g, 0.85 mmol) (Example 7). After 1 hour additional chlorine in acetic acid (1.5 mL of 0.24 M solution, 0.36 mmol) was added. After three additional hours additional chlorine in acetic acid (0.25 ml of 0.25 M solution, 0.06 mmol) was added. After 2.5 hours the reaction was quenched with aqueous 10% sodium bisulfite solution and the resulting mixture extracted with ethyl acetate. The organic phase was washed with water, brine, dried over MgSO_£, filtered, and concentrated in vacuo yielding a brown oil. The oil was dissolved in a minimum of hexanes which induced crystallization. Vacuum filtration of the mixture provided the title compound as yellow crystals (0.18 g, 53%) : mp 205-207 °C. ^XH NMR (acetone-d^/300 MHz)

7.89 (s, 1H), 6.97-7.18 (m, 6H), 5.83 (q, 1H, J = 7.0 Hz),

3.90 (ε, 3H) . FABLRMS m/z 400 (M+). FABHRMS m/z 399.0249 (M-H, Calc'd 399.0247). Aral. Calc'd for C_1SH_J2C1F₃O₅: C, 53.95; H, 3.02; Cl, 8.85. Found: C, 53.78; H, 3.08; Cl,

8.98.

<img file="AP1149A_D0038.tif" />

OH

O CF₃

- Tri f luorome thy 1 - 2H-1 -be nzopyr an- 3 - carboxylic acid

S_tep_l.......Preparation of ethyl 2-(trifluoromethvl)-2H-1benzoovran-3-carboxvlate.

The ester was prepared from salicylaldehyde by a procedure similar to the method described in Example 1, Step 1: bp 107 °C 2mm. ¹HNMR (acetone-d^/300 MHz) 7,.89 (s, 1H) ,

7.52-7.38 (m, 2H) , 7.09 (dt, 1 J = 1.0, 7.7 Hz), 7.03 (d,

1H, J - 8.3 Hz), 5.84 (q, IF, 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 CaLcd 273.0739)

ΑΡϋ Ο 1 14 9

Step 2. Preparation of 2-(trifluoromethvl)-2H-l-benzopyran3-carboxylic acid.

The acid was prepared from the ethyl ester (Step 1) by a procedure similar to the method described in Example 1,

Step 2: mp 152.2-153.3 °C. ^XH NMR (acetone-d^/300 MHz) 7.89 (s, 1H) , 7.39-7.49 (m, 2H), 7.11-7.01 (m, 2H) , 5.81 (q _H__F,

1H, J = 7.2 Hz). FABHRMS m/z 245.0422 (M+H, Calc'd 245.0426). Anal. Calc'd for C11H7F3O3: C, 54.11; H, 2.89. Found: C, 54.22; H, 2.97.

EXAMPLE 11

<img file="AP1149A_D0039.tif" />

6, 8-Dichloro-7-methyl-2- (trif luoromethyl) -2H-l-ben.zopyrajn.-3carboxylic acid

Step 1. Preparation of 3,5-dichloro-4methvlsalicylaldehvde.

2,4-Dichloro-3-methylphenol (25.0 g, 141.2 mmol) was added to methanesulfonic acid (100 mL). With stirring, hexamethylenetetramine (HMTA) (39.8g, 282.4 mmol) and additional methanesulfonic acid (100 mL) was added portionwise during which time the reaction began to froth and exotherm. The resulting mixture was heated to 100 °C for 3 hours. The crude ocher colored suspension was cooled to 50 °C and poured over a mechanically stirred mixture of icewater (2 L). A yellow precipitate was formed which was collected by vacuum filtration. This solid was purified by flash chromatography (silica, hexanes-methylene chloride,

9:10) -yielding the salicylaldehyde as a pale yellow powder

APT,' 99701677 (6.17 g, 21%; mp 94.0-95.1 °C) of suitable purity to use without further purification.

Steo 2. Preparation of ethvl 6,8-dichloro-7-methvl-2(trifluoromethyl)-2H-l-benz:;pyran-3-carboxy late .

A mixture of 3,5-dichloro-4-methylsalicylaldehyde (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 hours then cooled in ice and filtered to give an orange solid. The solid was dissolved in ethyl acetate (100 mL), washed with 3 N HCI (2 x 50 mL) , saturated NaHCO₃, washed with brine, dried over MgSO/, and concentrated in vacuo to give a yellow solid (8.63 g, 84%) : mp 117.1-119.5 °C. NMR (CDCl₃/300 MHz) 7.63 (s, 1H) , 7.17 (s, IK), 5.80 (q, IK, J = 6.6 Hz), 4.33 (m, 2H), 2.48 (s,

3H) , 1.3 5 (t, 3H, J = 7.1 Hz).

Step 3. Preparation of 6,8-dichloro-7-methvl-2(trifluoromethyl)-2H-l-benzoovran-3-carboxylic acid.

The ester from Step 2 (8.39 g 23.6 mmol) was dissolved in THF (30 mL) and ethanol (?.O 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 3 N HCI, filtered, and recrystallized from ethanol/ water to yield a yellow solid (6.0 c, 78%) : mp 229.9-230.9 °C. ^XH NMR (acetone-d^/300 MHz)

7.90 (s, 1H) , 7.58 (s, 1H), 6.00 (q, 1H, J = 6.8 Hz), 2.50 (s, 3K) . FABLRMS m/z 325 (M-H). FABHRMS m/z 324.9636 (M-H, Calc'd 324.9646). Anal. Calc'd for C₁₂H,C1₂F₃O₃; C, 44.07; H, 2.16; Cl, 21.68. Found: C, 44.06; H, 2.21; Ci, 21.74.

EXAMPLE 12 η 1 14 9

<img file="AP1149A_D0040.tif" />

7-(1, 1-Dimethylethyl) -2-trif luoromethyl-2Η-1benzopyran-3-carboxylic acid

Ethyl 7-(1,1-dime thyl ethyl) -2- (trifluoromethyl) -2H-1benzopyran-3-carboxylate (Example 8, Step 2) was hydrolyzed to the carboxylic acid via a procedure similar to that described in Example 1, Step 2: mp 165.6-166.8 °C. NMR (acetone-d^/300 MHz) 7.86 (s, IH), 7.38 (d, IH, J= 8.1 Hz),

7.15 (dd, IH, J = 1.8 Hz, and J = 7.8 Hz), 7.05 (bs, IH) , 5.79 (q _H__F, IH, J- 7.2 Hz), 1.32 (s, 9H). FABHRMS m/z 301.1033 (M+H, Calc'd 301.1051). Anal. Calc'd for ^C15^H15^F3°3^{: C}' ⁶⁰·⁰⁰'· ^H' 5.04. Found: C, 59.80; H, 5.10.

EXAMPLE 13

<img file="AP1149A_D0041.tif" />

6-Bromo-2-trifluoromethyl-2H-1-benzopyran-3carboxylic acid

5-Bromosalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 189.6-190.9 °C. NMR (acetone-d^/300 MHz) 7.89 (s, IH), 7.70 (d, IH, J = 2.1 Hz), 7.55 (dd, IH, J = 2.4 Hz, and J = 8.7 Hz) , 7.02 (d, IH, J = 8.7 Hz), 5.86 (q j|_f» = 7.2 Hz). FABHRMS m/z 322.9519 (M+H, Calc'd

322.9531)

40.90; Η, 1.92; Br,

Anal. Calc'd for : C,

1.87; Br, 24.73. Found: C, 40.87; H, 24.80.

EXAMPLE 14

<img file="AP1149A_D0042.tif" />

8-Chloro-2-trif luoromethyl-2K-l-benzopyran--3 carboxylic: acid

2-Chlorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 224.5-225.:5 °C. NMR (acetoned₅/300 MHz) 7.91 (s, IH), 7.49 (m, 2H), 7.11 (t, IH,' J = 7.8 Hz) , 5.96 (q _H__r, IH, J = 7.2 Hz).

FABHRMS m/z 279.0027 (M+H, Calc'd 279.0036).

Anal. Calc'd for C-QHgClFjO; : C, 47.42; H, 2.17. Found: C, 47.33; H, 2.17.

EXAMPLE 15 o

<img file="AP1149A_D0043.tif" />

Br

8-Bromo-6-chloro-2-tri£Xuorometb.yl-2H-lbenzopyran-3-carboxylic acid

APO 0 114 9

2-Bromo-4-chlorosalicylaldehyde was converted to the title compound by a similar procedure to that described in Example 1: mp 227.8-228.9 °C.

^ΤΗ NMR (acetone-dg/300 MHz) 7.90 (s, 1H), 7.65 (dd, 2H, J = 2.4 and J = 28.8 Hz), 6.00 (a _H__F,

1H, J = 7.2 Hz). FABHRMS m/z 356.9134 (M+H,

Calc'd 356.9141). Anal. Calc'd for C₁₁H₅BrClF₃O₃: C, 36.96; H, 1.41. Found: C,

37.0:

H, 1.33.

EXAMPLE 16

CF₃ o

o

OH

CF₃

6-Tri fluoromethoxy-2-trifluoromethy1-2H-1benzopyran-3-carboxylic acid

5-(Trifluoromethoxy)salicylaldehyde was converted to the title compound by a similar procedure to that described in Example 1: mp 118.4-119.5 °C. J-H NMR (acetone-dg/300 MHz) 7.95 (s, 1H), 7.54 (d, 1H, J = 2.1 Hz), 7.39 (dd, 1H, _t= 2.4 Hz, and J = 9.0 Hz) , 7.02 (d, 1H, J = 9.0 '99 '0 1 6 77 &lt; th

Hz), 5.88 (o _H__F, 1H, J = 7.2 Hz)

329.0228 (M+H, Calc'd 329.0249). for C₁₂HgF₆O₄: C, 43.92; H, 1.84. 43.84; H, 1.87.

FABHRMS m/z

Anal. Calc'd Found: C,

EXAMPLE 17

<img file="AP1149A_D0044.tif" />

8-Fluoro-2-trifluoromethy1-2H-1-benzopyran-3 carboxylic acid

3-Fluorosalicylaldehycie was converted to the title compound by a similar procedure to that described in Example 1: mp 197.7-210.1 °C. ~H NMR (acetone-d^/300 MHz) 7.94 (s, 1H) , 7.30 (m, 2H) , 7.11 (m 1H), 5.93 (q _H__F, 1H, J = 7.2 Hz).

FABHRMS m/z 263.0341 (M+H, 'qiH₅F₄O₃ Calc'd 263.0331). Anal. Calc'd for C^HgF^: C, 50.40; H, 2.31. Found: C, 50.48; ii, 2.25.

EXAMPLE 18

<img file="AP1149A_D0045.tif" />

5,7-Dichloro-2-trifluoromethyl-2H-1-benzopyran-3carboxylic acid

4,6-Dichlorosalicylaldehyde was converted to the title compound by a similar procedure to that described in Example 1: mp 190.1-191.2 °C. NMR (acetone-d^/300 MHz) 8.01 (s, 1H), 7.3 (bs, 1H), 7.16 (bs, 1H), 5.94 (q _H__F, 1H, J = 7.2 Hz).

FABHRMS m/z 312.9636 (M+H, Calc'd 312.9646).

Anal. Calc'd for C-qH₅C12F3O3: C, 42.20; H, 1.61. Found: C, 42.27; H, 1.56.

APO 0 1U9

EXAMPLE 19

<img file="AP1149A_D0046.tif" />

7, 8-Dichloro-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid

3,4-Dichlorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 219.5-220.9 °C. NMR (acetoned-/300 MHz) 7.94 (s, IH), 7.51 (d, IH, J = 8.4 Hz), 7.34 (d, IH, J = 8.4 Hz), 6.02 (q _H__F, IH, J = 7.2 Hz). FABHRMS m/z 318.9709 (M+Li, C11H5CI2F3O3 Calc'd 318.9728). Anal. Calc'd for ^C11^H5^C12^F3°3 ^{: C}' ⁴²-²⁰'' ^H' 1-61- Found: C, 42.15; H, 1.68.

EXAMPLE 20

LL 9 I 0 / 6 6 .-.dV

<img file="AP1149A_D0047.tif" />

7-Isopropyloxy-2-trif luorome thyl-2H-l-benzopyr an-3carboxylic acid

2,4-Dihydroxybenzaldehyde was alkylated to prepare 4(1-me thy lethyloxy) salicylaldehyde. This salicylaldehyde was κ converted to the title compound by a similar procedure to that described in Example 1: mp 161-163 °C. ^H NMR (CD3OD/3OO MHz) 7.73 (dd, 1H, J = 8.5, 2. Cit_Hi_2^f3°4 requires (s, lii) , 7.21 (d, 1H, J = 8

Hz). FABHRMS m/z 301.0688 301.06:37). Anal. Calc'd for

Hz), 6.57 (M-H⁺,

CHH13F3O4 :

C, 55.63; H, 4.34.

Found: C,

55.72; H, 4

EXAMPLE 21

<img file="AP1149A_D0048.tif" />

8-Phenyl-2- trif luoromethyl-2H-1-benzopyran-3 carboxylic: acid

2-Phenylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 171.6-175.3 °C. NMR (acetonedg/300 MHz) 7.95 (s, 1H), 7.46 (m, 7H), 7,18 (t, 1H, J = 7.5 Hz) , 5.81 (q _H__?, 1H, J - 7.2 Hz) .

FABHRMS m/z 327.0816 (M+Li, Calc'd 327.0820). Anal. Calc'd for ^^γΗ^^Ρ^Οβ C, 63.76; H, 3.46. Found: C, 63.52; H, 3.55.

EXAMPLE 22

<img file="AP1149A_D0049.tif" />

π 1 1 4 9

7,8-Dimethyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid

2,3-Dimethylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 245.2-247.3 °C. NMR (acetoned^/300 MHz) 7.83 (s, IH), 7.17 (d, IH, J =7.8 Hz), 6.89 (d, IH, J = 7.8 Hz), 5.82 (q _H__F, IH, J = 7.2 Hz), 2.30 (ε, 3H), 2.17 (s, 3H). Anal.

Calc'd for C₁₃H₁₁F₃O₃ + 1.56 % H₂^{0: c}- 56.46; H,

4.18. Found: C, 56.46; H, 4.15.

EXAMPLE 23

<img file="AP1149A_D0050.tif" />

6, 8-bis(1,1-Dimethylsthyl) -2-trif luoromethyl-2H-lbenzopyran-3-carboxylic acid

3,5-Di-tert-butylsalicylaldehyde was converted to the title compound by a similar procedure to that described in Example 1: mp 171.6-175.0 °C. ¹H NMR (acetone-d^/300 MHz) 7.65 (s, IH), 7.34 (d, IH, J= 2.4 Hz), 7.15 (d, IH, J = 2.4 Hz), 6.02 (q _H__F, ^1H' ^{J = 7}·^{2 Hz}) · FABHRMS m/z 363.1743 (M+Li, Calc'd 363.1759). Anal. Calc'd for C₁₉H₂₃BrF₃O₃: C, 64.03; H, 6.50.

Found: C, 64.13; H, 6.49.

/£910/66 /J.'dV

EXAMPLE 24

<img file="AP1149A_D0051.tif" />

6-Iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid

Step 1: Preparation of 2-h^.^rdroxv-5-iodobenzvl alcohol.

A solution of 5-iodosalicylic acid (25.0 g, 94.6 mmol) in tetrahydrofuran (500 mL) was cooled to 0°C. With vigorous mixing, borane-methyl sulfide complex (15.1 ml of 10 M solution, 151.0 mmol) was added drop-wise over 0.25 hours . The solution was warmed to room temperature and then heated at reflux for 4 n. A white precipitate formed during the reflux. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (100 mL) was added over 15 min and the solution stirred at room temperature for 2 h. The precipitate dissolved and the solvent was concentrated in vacuo to a volume of approximately 200 mL. The solution was poured into ethyl acetate (300 mL) and washed with water (2 x 200 mL), saturated sodium bicarbonate (2 x 200 mL), and 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 moDfrom hexanes. (90% yield): mp

105-110°C. ^-H NMR (CDCl_a/3C0 MHz) 8.21 (s, IH) , 7.30-7.33 (Μ, 2H), 6.57 (d, IH, J =8.3 Hz), 4.97 (bs, IH), 4.62 (s,

2H). EIHRMS m/z = 249.9492 IM+, Calc'd 249.9491).

Step 2: Preparation of 2-hvdroxv-5-iodobenzalaehvde

To a stirred solution cf 2-hydroxy-5-iodobenzyl alcohol (43.5 g, 174.0 mmol) in acetone (700 mL) was added 85% activated manganese (IV) oxide (5 micron, 50 g, 494.0 mmol) and the solution stirred at room temperature for 16 hours. The manganese oxide was removed by filtration through diatomaceous earth and the filtrate concentrated in vacuo. The product was purified by flash silica chromatography (0APO 0 114 9

20% ethyl acetate in hexanes) The 2-hydroxy-5iodobenzaldehyde was obtained as a greenish-yellow solid {24.3 c, 58%). A small amount of the 2-hydroxy-5iodobenzaldehyde was recrystallized from methanol/water to afford an analytical sample and the remainder of the compound was used without further purification: mp 99-101 °C. ¹H NMR (CDCl₃/300 MHz) 9.83 (s, 1H) , 7.79 (d, 1H, J = 2.2 Hz), 7.77 (dd, 1H, J = 8.7 Hz, J = 2.2 Hz), 6.81 (d, 1H, J= 8.1 Hz). ESHRMS 246.9229 (M-H Calc'd 246.9256).

Step 3: Preparation of ethyl 6-iodo-2-trifluoromethvl-2H-lbenzopvran-3-carboxvlate.

A mixture of 5-iodosalicylaldehyde (16.2 g, 65.3 mmol), ethyl 4,4,4-trifluorocrotonate (22.4 g, 13 3 mmol) and triethylamine (50 ml, 395 mmol)were combined, stirred at 70°C for 8 h and then heated at reflux for 48 h. The solution was poured into ethyl acetate (300 mL) and washed with IN hydrochloric acid (3 x 2 00 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 over magnesium sulfate and concentrated in vacuo yielding 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 yielded the title compound as light red crystals (8.3 g, 31%) : mp 105-106 °C. ^ΧΗ NMR (CDC1₃/300 MHz) 7.63 (s, 1H), 7.58 (dd, 2H, J = 8.6,

J = 2.1 Hz, 7.54 (d, 1H, J = 2.1 Hz), 6.77 (d, 1H, J = 8.6 Hz), 5.70 (q, 1H, J = 6.7 Hz), 4.20-4.38 (m 2H), 1.35 (t,

3H, J =7.2 Hz). ESHRMS 415.9926 (M+NH4* Calc'd 396.9746) ££910/66

Step 4: Preoartation of 6-iodo-2- (trifluoromethvl)-2H-1benzopyran-3-carboxylic acid.

Hydrolysis of the ester (Step 3), using a procedure similar to Example 1, Step 2, yielded the carboxylic acid: mp 168-170 °C. ¹H NMR (CD₃OD/300 MHz) 7.57 (s, 1H), 7.70 (d, 1H, J = 2.2 Hz), 7.64 (dd, 1H, J = 8.5, 2.2 Hz), 6.79

100 (d, 1H, J = 8.5 Hz) 5.78 )q, IK, J = 7.0 Hz). ESHRMS m/z

368.9222 (Calc'd for M-H 368.9235). Anal. Calc'd for

C, 35.70; H, 1.63. Found C, 35.67; H, 1.63.

EXAMPLE 25

<img file="AP1149A_D0052.tif" />

7- (1-Methylethyl) -2-t2.’if luoromethyl-2H-l10 benzopyran-3-carboxylic acid

3-(1-Methylethyl)phenol was converted to the title compound by a procedure similar to that described in Example 2; mp 158.3-159.7 °C. -^K NMR (acetone-d₀-/300 MHz) 7.86 )s, 1H) , 7.37 (d, 1H, J = 7.8 Hz) , 7.00 (d, 1H, J -- 7.8 Hz) , 6.91 (s, 1H) , 5.78 (q, 1H, J= 6.9 Hz), 2,93 (m, 1H), 1.24 (d, 6H, J = 6.9 Hz). FABLRMS m/z 287 (M+H). Anal. Calc'd for C₁₄H₁₃F₃O₃ : C, 58.74; H, 4.58. Found:

C, 57.37; H, 4.49.

EXAMPLE 26

<img file="AP1149A_D0053.tif" />

-Phenyl - 2 - tri f luorome thy 1-2H-1 -benzopyran- 3 carboxylic acid

APO 0 114 9

101

3-Phenylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 209.4-211.7 °C. ^FH NMR (acetoned^/3 00 MHz) 7.94 (s, 1H) , 7.74 (m, 2H) , 7.47 (m,

5H) , 7.33 (ε, 1H), 5.86 (q, 1H, J = 7.2 Hz). FABLRMS m/z 321 (M+H) . Anal. Calc'd for ^C17^H11^F3°3^{: c}' 63.76; H, 3.46. Found: C, 64.17; H, 3.61.

EXAMPLE 27

<img file="AP1149A_D0054.tif" />

6-Chloro-7-ethyl-2-trif luorome thyl-2H-lbenzopyran-3-carboxylic acid

4-Chloro-3-ethylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 170.7-172.1 °C. ~H NMR (CDCl₃/300 MHz) 7.78 .(s, 1H), 7.26 (s, 1H), 6.90 (s, 1H) , 5.67 (q, 1H, 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. Calc'd for C₁₃H₁₀F₃O3^{: C}' 50.92; H, 3.29. Found: C, 51.00; H, 3.33.

EXAMPLE 28

<img file="AP1149A_D0055.tif" />

1C 2

-Ethyl- 2 - trif luorooet layl -2E -1 -benzopyran-3 carboxy],ic acid

2-Ethylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 185.4-186.8 °C. NMR (acetonedg/3 00 MHz) 7.85 (s, 1H) , 7.28 (d, 2H, J =7.5

Hz) , 7.00 (t, 1H, J = 7.5 Hz) , 5.84 (q, IH, J =

7.2 Hz), 2.65 (m, 2H), 1.18 (t, 3H, J = 7.5 Hz). FABLRMS m/z 273 (M+H) . Anal. Calc'd for ^C13^H11^F3°3^{: C}' 57.36; H, 4.07. Found: C, 57.15; H, 4.11.

EXAMPLE 29

<img file="AP1149A_D0056.tif" />

6-Chloro-8-ethyl-2-tr ifluoromethyl-2H-lbenzopyran-3-carboxylic acid

8-Ethyl-2 - (trifluoromethyl) 2H-l-benzopyran-3carboxylic acid (Example 23) (0.68 g, 2.5 mmol) was dissolved in trimethylphosphate (5 mL) and was treated with sulfuryl chloride (0.35 g, 2.62 mmol) at 0 °C. After stirring ak. 0 °C for 45 minutes and 1 hour 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 brine, dried, and concentrated in vacuo yielding the title compound as a solid (0.9 g, 117 %):

*· π 0 0 114 9

103 mp 197.2-199.1 °C. ^Η NMR (acetone-d^/300 MHz)

7.86 (s, 1H), 7.38 (d, 1H, J = 2.7 Hz), 7.30 (d, 1H, J = 2.4 Hz), 5.88 (q, 1H, J = 7.2 Hz), 2.65 (m, 2H), 1.19 (t, 3H, J = 7.5 Hz). FABLRMS m/z 307 (M+H). Anal. Calc'd for C₁₃H₁₀ClF₃O₃: C, 50.92; H, 3.29. Found: C, 51.00; H, 3.23.

EXAMPLE 30 ‘OH

6-Chloro-7-pbenyl-2-trifluoromethyl-2H-l-benzopyran carboxylic acid

7-Phenyl-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid (Example 26) was converted to the title compound by a procedure similar to that described in Example 29: mp 185.3-187.8 °C. ^H NMR (acetone-c?g-/300 MHz) 7.94 (s, 1H) , 7.68 (s,

1H) , 7.47 (m, 5H) , 7.06 (s, 1H) , 5.87 (q, 1H, J = 6.9 Hz). FABLRMS m/z 355 (M+H). Anal. Calc'd for C₁₇H₁₀ClF₃O₃: c, 57.56; H, 2.84. Found: C, 58.27; H, 3.11.

AP,T/ 9 9 '01677

EXAMPLE 31

Cl

OH

104

6,7-Dichloro-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid

3, 4-Dichlorophenol was converted to the title compound by a procedure similar tc that described in Example 2: mp 196.1-198.3 °C. ¹H NMR ( acetone-d₅/300 MHz) 7.90 (s, IH) ,

7.74 (s, IH), 7.30 (s, IH), 5.88 (q, IH, J= 6.9 Hz). FABLRMS m/z 314 (M+H) . Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C,

42.20; H, 1.61. Found: C, 42.31; H, 1.65.

EXAMPLE 32

<img file="AP1149A_D0057.tif" />

6, 8-Dichloro-2-trif luoroi:iatbyl-2H-l-benzopyran-3-carbo3cylic acid

3,5-DichlorosalicylaIdehyde was converted to the title compound by a procedure similar to that described in Example 11, Steps 2 &amp; 3 : mp 212.8 -216.8 °C. NMR (CDCl₃/300 MHz)

7.77 (s, 1H), 7.41 (d, IH, J = 2.4 Hz), 7.18 (d, IH, J = 2.2 Hz), 5.82 (q, IH, J= 6.7 Hz). FABLRMS m/z 311 (M-H). FABHRMS m/z 312.9644 (M+H, Calc'd 312.9646). Anal. Calc'd for C]_]_H5F₃Cl₂O₃ : C, 42.2¹.); H, 1.61. Found: C, 42.50; H,

1.71.

EXAMPLE 33

APU 0 114 9

105

<img file="AP1149A_D0058.tif" />

6,8 -Dibromo - 2 - tri f luoromethy 1 - 2H-1 -benz opyr an- 3 - carboxylic acid

3,5-Dibromosalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 225-226 °C. ¹H NMR (CD₃OD/300 MHz) 7.76 (s, IH), 7.74 (d, 1H, J = 2.2 Hz), 7.55 (d, IH, J = 2.2 Hz), 5.91 (q h-F,

IH, J = 7.2 Hz). FABHRMS m/z 400.8648 (M+H+, Calc'd

400.8636). Anal. Calcd for CnH₅Br₂F3O3 : C, 32.87; H, 1.25. Found: C, 33.47; H, 1.38.

EXAMPLE 34

<img file="AP1149A_D0059.tif" />

APT/ 9 9 / 0 1 6 77

6,8-Dimethoxy-2-trif luoromethyl-2H-l-benzopyran-3-carboxylic acid

4,6-Dimethoxysalicylaldehyde was converted to the title compound by a procedure similar to that described in Example

<td colspan="2"> 1: mp 215-217</td><td> °C.</td>

<td> 6.18-6.20</td><td> (m,</td><td> 2H)</td>

<td> IH), 3.81</td><td> (s,</td><td> IH)</td>

^ΧΗ NMR (CD3OD/3OO MHz) 7.95 (s, IH), 5.65 (q _H__F/ IH, J = 7.2 Hz), 3.87 (s, FABHRMS m/z 303.0497 (M-H⁺, Calc'd

106

303.0380). Anal. Calc'd for 3Q5: C, 51.33; K, 3.64.

Found: C, 51.19; H, 3.71.

EXAMPLE 35

<img file="AP1149A_D0060.tif" />

Ethyl 6-amino-2-triflu oromethyl-2H-l-benzopyran-3 carboxylate

Step 1. Preparation of ethyl 6-nitro-2(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A mixture of 5-nitrosalicylaldehyde (4.80g, 28.7 mmol) and ethyl 4,4,4-trifluorocrotonate (6.6 g, 39.4 mol) in anhydrous DMF was warmed to 60 °C and treated with anhydrous K2CO3 (3.90 g, 28.9 mol). The solution was maintained at 60 °C for 20 hours, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous MgSO_4; filtered and concentrated in vacuo to afford an oil. The oil was dissolved in diethyl ether (5 mL). Hexanes was added until the solution became cLoudy. Upon standing at room temperature overnight the ester was obtained as yellow crystals (0.856 g, 7% yield). This material was of sufficient purity to be used in subsequent steps without further purification. ^H NMR (CDCI3/3OO MHz) 8.15-8.19 (m, 2H), 7.74 (s, 1H), 7.09 (d, 1H, J = 8.9 Hz), 5.81 (q, 1H, J = 5.8 Hz), 4.29-4.39 (m, 2H), 1.35 (t, 3H, J = 6.0 Hz),

Step 2. Preparation of ethyl 6-amino-2(trifluoromethvl)-2H-l-benzopyran-3-carboxylate.

AP U 0 1 1 4 9

107

The ester (Step 1)(0.345 g, 1.08 mmol) was stirred in ethanol (10.0 mL) with 10% palladium on charcoal (15 mg) with hydrogen at 1 atmosphere for 1 hour. The catalyst was removed by filtration and the solvent removed in vacuo to afford the title compound as an orange-yellow solid (0.298 g, 95 %) : mp 111-115 °C. (CD₃OD/300 MHz) 7.69 (s, 1H) , 6.696.74 (m, 3H), 5.65 (q _H__F/ 1H, J = 7.2 Hz), 4.26-4.37 (m,

2H) , 1.34 (t, 3H, J = 7 Hz). FABHRMS m/z 288.0860 (M+H⁺, C13H13F3NO3 requires 288.0847). Anal. Calc'd for C13H12F3NO3: C, 54.36; H, 4.21; N, 4.88. Found: C, 54.46;

H, 4.27; N, 4.83.

EXAMPLE 36

<img file="AP1149A_D0061.tif" />

6-Amino-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid

Ethyl 6-amino-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylate (Example 35, Step 2) was hydrolyzed to the carboxylic acid (title compound) by a procedure similar to that described in Example 1, Step 2: mp 126-133 °C. ^-H NMR (CD3OD/3OO MHz) 6.81-6.90 (m, 3H), 5.66 (q _H-F, ^1H' ·²

Hz). FABHRMS m/z 260.0535 (M+H⁺, C11H9F3NO5 requires 260.0534).

££910/66 -ZdV

EXAMPLE 37

108

6-Nitro-2-trifluoromethyl-2H-l-benzopyran-3-carboxylic acid

Ethyl 6-nitro-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylate (Example 35, Step 1) was hydrolyzed to the carboxylic acid (title compound) by a procedure similar to that described in Example 1, Step 2: mp 187-189 °C. NMR (CD3OD/3OO MHz) 8.34 (d, IH, J = 2.6 Hz), 8.27 (dd, IH, J = 8.7, 2.6 Hz), 7.90 (s, IH) , 7.09 (s, IH, J = 8.7 Hz), 5.81 (q _H__F&gt; IH, J = 7.2 Hz). E1HRMS m/z 289.0177 (Calc'd 289.0198). Anal. Calc'd for C11H6F3NO5: C, 45.69; H, 2.09; N 4.84 Found: C, 45.71; 8:, 2.08; N 4.75.

<img file="AP1149A_D0062.tif" />

-Chloro- 8 -methyl -2 - tri f luoromethyl - 2H-1 -benzopyran- 3 carboxylic acid

4-Chloro-2-methylphenol was converted to the title compound by a procedure similar to that described in Example

<td> 2: mp 231.9-233.2 °C,</td><td> . ¹H</td><td> I^MR</td><td> (CDC1;:</td><td> j/300</td><td> MHz) 7.76 (s,lH),</td>

<td> 7.19 (d, IH, J = 1.8</td><td> Hz) ,</td><td> 7.</td><td> 09 (d,</td><td> 1H,</td><td> J = 2.4 Hz), 5.72</td>

<td> (q, IH, J = 6.9 Hz),</td><td> 2.24</td><td> (s,</td><td> 3H) .</td><td> 19_f</td><td> NMR (CDCI3/282 MHz)</td>

-79.2 (d, J = 6.5 Hz). FA1LRMS m/z 299 (M+Li) . FABHRMS m/z

ΑΡ Μ ο 1 1 4 9

109

293.0196 (M+H, Calc'd 293.0192). Anal. Calc'd for ^c12^H8^c1f3°3^{: C}' ⁴9·25; H, 2.76. Found: C, 49.37; H, 2.86.

EXAMPLE 39

<img file="AP1149A_D0063.tif" />

-Chloro- 6 -methyl - 2 - trifluoromethyl - 2H-1 -benzopyran-3carboxylic acid

2-Chloro-4-methylphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 226.4-227.4 °C. ¹H NMR (CDCl₃/300 MHz) 7.79 (s, IH), 7.23 (d, IH, J = 1.4 Hz), 6.97 (d, 1H, J = 1.4 Hz), 5.77 (q,

IH, 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+, C₁₂H₈C1F₃O₃ Calc'd 292.0114).

EXAMPLE 40 rVP!P! 99/01677

<img file="AP1149A_D0064.tif" />

8-Chloro-6-methoxy-2-trif luoromethyl - 2H-1-benzopyran-3carboxylic acid

2-Chloro-4-methoxyphenol was converted to the title compound by a procedure similar to that described in Example 2: mp 204.5-206.9 °C. ¹H NMR (CDCl₃/300 MHz) 7.78 (s, IH), ¹ &amp; *

11;

, 6.71 (d, 1H, J = 2.8 Hz), 5.74 (q, , 5H) . FABLRMS m/z 326 (M+NH₄).

Calc'd 308.0063). Anal. Calc'd for H, 2.61. Found: C, 46.60; K, 2.68.

6.98 {d, 1H, J = 2.8 Hz) 1H, J = 6.9 Hz), 3.79 (s EIHRMS m/z 308.0053 (M+ ^C12^K8^C1F3°4^{: C}' ⁴⁶·⁷⁰'·

EXAMPLE 41

<img file="AP1149A_D0065.tif" />

6, 8-Dif luoro-2-1rif luoronethyl-2H- 1-benzopyran-3- carboxylic acid

2,4-Difluorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 207-211 °C. ¹H NMR (CDCI3) 7.63 (ε, 1H), 6.89-6.72 (m, 2H) , 5.69 (q, 1H, J =6.7 Hz). Anal. Calc'd for C,

47.16; H, 1.80. Found: C, 47.28; H, 1.87.

EXAMPLE 42

<img file="AP1149A_D0066.tif" />

6-Bromo-8-chloro-2-trif ?uoromefchyl-2H-l-benzopyran-3carbexylic acid

4-Bromo-2-chlorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 220.7-221.7 °C. ¹H NMR (CDCI3) 7.58 (s, 1H), 7.44 (d, 1H, J =2.2 Hz), 7.22 (d, 1H. J =2.2 Hz), 5.74 (q, 1H, J =6.8

APu Ο 1 14 9

111

Hz). Anal. Calc'd for C₁₁H₅O₃F₃BrCl: C, 36.96; H, 1.41. Found: C, 37.03; H, 1.44.

EXAMPLE 43

<img file="AP1149A_D0067.tif" />

8-Bromo-6-f luoro-2 -trif luorome thyl-2H-1-benzopyr an-3 carboxylic acid

2-Bromo-4-fluorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp &gt;300 °C. ^-H NMR (CDC1₃) 7.58 (s, 1H) , 7.22 (dd, 1H, J =6.3, 3 Hz), 6.88 (dd, 1H, J =6.1, 3.1Hz), 5.72 (q, 1H, J =6.7 Hz). Anal. Calc'd for C₁₁H₅O₃F₄Br: C, 38.74; H, 1.48.

Found: C, 38.82; H, 1.56.

EXAMPLE 44

ΑΡ/Γ,' 9 9/01677

<img file="AP1149A_D0068.tif" />

COOH

Ό 'CF₃

-Bromo- 6 -methyl-2 -1 rif luoromethy1-2H-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: mp 237-238 °C. ¹H NMR (CDC1₃) 7.59 (s, 1H), 7.27 (m,

1H) , 6.91 (d, 1H, J =1.4 Hz), 5.69 (q, 1H, J =6.9 Hz), 2.20 (s, 3H). Anal. Calc'd for C₁₂H₈O₃F₃Br: C, 42.76; H, 2.39.

Found: C, 43.34; H, 2.56.

112

EXAMPLE 45

<img file="AP1149A_D0069.tif" />

Er

-Bromo- 5 - f luoro -2 -trif luoromethyl -2H-1-benzopyran- 3 carboxylic acid

2-Bromo-5-fluorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 221.7-223.3 °C. ¹H NMR (CDCI3) 7.81 (s, 1H) , 7.38 (dd, 1H, u’=7.3, 5.8 Hz), 6.58 (t, 1H, J =8.9 Hz), 5.71 (q, 1H, J =6.7 Hz). Anal. Calc'd for C₁₁H₅O₃F₄Br: C, 38.74; H, 1.48. Found: C, 38.70; H, 1.54.

EXAMPLE 46

<img file="AP1149A_D0070.tif" />

6-Chloro-8-f luoro-2-trif luoromethyl“2H-l-benzopyran-3cariooxylic acid

4-Chloro-2-fluorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 190.8-193.0 °C. ^ΧΗ NMR (CDCl₃/300 MHz) 7.77 (s, 1H) ,

7.19 (d of d, 1H, J = 2.2 and 9.7 Hz), 7.07 (t, 1H, J = 1.8 Hz), 5.76 (q, 1H, J = 6.7 Hz). FABLRMS m/z 295 (M-H).

APO 0 114 9

113

EIHRMS m/z 295.9876 (M+ Calc'd 295.9863). Anal. Calc'd for ^C11^H5C1F₄°3^: C, 44.54; H, 1.70. Found: C, 44.36; H, 1.85.

EXAMPLE 47

<img file="AP1149A_D0071.tif" />

-Bromo- 8 -methoxy- 2 - trif luoromethyl -2H- 1-benzopyr an- 3 carboxylic acid

4-Bromo-2-methoxysalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp dec. at 244 °C. NMR (CD₃OD/300 MHz) 7.71 (s, IH), 7.18 (d, IH, J = 2.2 Hz), 7.11 (d, IH, J = 2.2 Hz), 5.77 (q _H__F/ IH, J=7.2 Hz), 3.84 (s, 3H). FABLRMS m/z 351 (m-H). Anal. Calc'd for C₁₂^H8^BrF3°5^{: C}' 40.82; H, 2.28. Found: C, 40.83; H, 2.30.

EXAMPLE 48

<img file="AP1149A_D0072.tif" />

APT/ 99/01677

7-(Ν,Ν-Diethylamino)-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid

4-(Ν,Ν-Diethylamino)salicylaldehyde was converted to the title compound by a procedure similar to that described

114 in Example 1: mp 214.4-215.4 °

<td> (S,</td><td> 1H) ,</td><td> 7.06</td><td> (d,</td><td> 1H, J</td>

<td> 2.3</td><td> Hz) ,</td><td> 5.60</td><td> (q</td><td> H-F,</td>

<td> Hz) ,</td><td> 1.16</td><td> (t,</td><td> 6H,</td><td> J = 7.1</td>

FA3HRKS m/z 316.1145 (M + H ⁺ , Calc'd for C-j_5H-_LgF₃NO₃ : C, 57. C, 57.14; H, 5.08; N, 4.44.

C. ¹H NMR (CD₃OD/3 00 MHz)

8.6 Hz) , 6.34 (dd, 1H, J = J=1.2 Hz), 3.38 (q, 4H, J =

Hz) . ESLRMS m/z 316 (M + H) .

Calc'd 316.1161). Anal.

14; H, 5.11; N, 4.44. Found:

EXAMPLE 49

<img file="AP1149A_D0073.tif" />

- [ [ (Phenylmethyl) amino] sulfonyl] -2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid

Step 1. Preparation of ethyl 6-chlorosulfonvl-2trifluoromethvl-2H-l-benzopyran-3-carboxylate.

Chlorosulfonic acid (50.0 mL) was cooled to 15 °C and ethyl 2 -trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 10, Step 2) (6.21 g, 22.83 mmol) was added. 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 onto ice (500 mL) with vigorous stirring 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 brine (2 x 250 mL). Hexanes (50 mL) were added and the solution was dried over sodium sulfate. The solvent was removed in vacuo to afford the ester as a yellow solid (7.41 g, 87%): mp 97.2-98.4 °C. ^ΧΗ NMR (CDCl₃, 300 MHz) 7.97 (dd, 1H, J = 8.6,2.2. Hz), 7.92 (d, 1H, J = 2.2 Hz), 7.73 (s, 1H), 7.17

AP Ο Ο 1 149

115 (d, ΙΗ, J = 2.2 Hz), 5.82 (q _H__F, 1H, J=7.2 Hz), 4.28-4.39 (m, 2H) , 1.35 (t, 3H, J = 7.0 Hz). FABLRMS m/z 376 (M+Li⁺).

Step 2. Preparation of ethyl 65 f Γ (phenvlmethvl)amino1sulfonvn-2-trifluoromethvl-2K-lbenzopyran-3-carboxylate.

The sulfonyl chloride from Step 1 (451.0 mg,

1.22 mmol) and benzylamine (600 mg, 5.62 mmol) were mixed in diethyl ether (25 mL) for 1 hour at room temperature. The solution was washed with IN HCI (2 x 25 mL), saturated sodium bicarbonate (2 x 25 mL) , and brine (2 x 25 mL) . The solution was dried over sodium sulfate and dried in vacuo. The aminosulfonyl was obtained by crystallization from hexanes (431 mg, 84%): mp 128.2-131.9 °C. ¹H NMR (CDC1₃, 300 MHz) 7.76 (dd, 1H, J = 8.4, 2.2. Hz),

7.70 (d, 1H, J =2.2 Hz), 7.67 (s, 1H), 7.12-7.30 (m, 5H), 7.05 (d, 1H, J = 8.4 Hz), 5.78 (q _H__F, 1H,

J=7.2 Hz), 4.68 (m, 2H), 4.19-4.32 (m, 2H), 1.37 (t, 3H, J = 7.0 Hz), FABLRMS m/z 442 (M + H⁺) .

» FABHRMS m/z 442.0936 (M + H⁺, C₂oH₁9F₃N0₅S Calc'd

442.0916).

Step 3. Preparation of 6-ίί(phenvlmethvl)aminolsulfonvll-225 trifluoromethvl-2H-l-benzopyran-3-carboxylic acid.

The acid was converted from the ester (step 2) via the method similar to that described in Example 1, step 2: mp 223.3-224.4 °C ^ΣΗ NMR (CD₃OD/300 MHz)

7.31-7.80 (m, 3H), 7.15-7.25 (m, 5H), 7.06 (d, 1H, J 30 = 8.3 Hz), 5.87 (q _H__Fj 1H, J=7.2 Hz), 4.11 (s, 2H).

FABLRMS m/z 420 (M + Li⁺). FABHRMS m/z 414.0589 (M + H⁺ Calc'd 414.0623). Anal. Calc'd for ^C18^H14^F3^NO5^{S: C}' ⁵²·³⁰'· ^H' 3.41; N, 3.39. Found: C,

5,16; H, 3.44; N, 3.32.

AP/?’ 9 9/01677

116

EXAMPLE 50

<img file="AP1149A_D0074.tif" />

OH

6-[(Dimethylamino)sulfonyl]-2-trifluoromethyl-2H-lbenzopyraa-3-carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 49: mp 201.2202.5 °C. ¹H NMR (CD₃OD/300 MHz) 7.90 (s, 1H), 7.82 (d, 1H, J = 2.2 Hz), 7.76 (dd, 1H, J = 8.6, 2.2 Hz),

7.19 (d, 1H, J = 8.6 Hz), 5.91 (q _H__F, 1H, J=7.2

Hz), 2.70 (s, 6H). FABLRMS m/z 352 (M + H⁺).

FABHRMS m/z 352.0466 (M + H⁺ Calc'd 352.0467).

Anal. Calc'd for C-j_₃H₁2^F3^I'fO5S: C, 44.45; H, 3.44; N, 3.99. Found: C, 4.42; H, 3.45; N, 3.96.

EXAMPLE 51

H&lt;

OH

6-Aminosulfonyl-2-trii luoromethyl-2H- 1-benzopyran-3carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 49: mp 187.9-189.8 °C. NMR (CD₃OD/300 MHz) 7.58-7.88 (m, 3H), 7.12 (d, J = 8.3 Hz), 5.87 (q _H__Fi 1H, J=7.2 Hz). FABLRMS m/z 324 (M + H⁺).

ΑΡ ο ο 1 1 4 9

117

FABHRMS m/z 324.0156 (Μ + H⁺ Calc'd 324.0154). Anal. Calc'd for C₁₁H₈F₃NO_sS * 0.74 H₂0: C, 39.26; H, 2.84; N, 4.16. Found: C, 39.33; H, 2.82; N, 4.11.

EXAMPLE 52

<img file="AP1149A_D0075.tif" />

6- (Methylamino) sulfonyl-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 49: mp 207-.6-208.6 °C. NMR (CD₃OD/300 MHz) 7.83-7.97 (m, 3H), 7.19 (d, IH, J = 8.5 Hz), 5.91 (q _K__F/ IH, J=1.2 Hz), 3.11 (s, 3H). FABLRMS m/z 338 (M + H⁺). FABHRMS m/z 338.0331 (M + H⁺ Calc'd 338.0310). Anal. Calc'd for C₁₂H₁₁F₃NO₅S: C, 42.73; H, 2.99; N, 4.15. Found: C, 42.91; H, 3.06; N, 4.04.

EXAMPLE 53

<img file="AP1149A_D0076.tif" />

tZ 9 I 0 / 6 6 Zj/dV

6-[(4-Morpholino)sulfonyl]-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 49: mp 215.2-219.3 °C · NMR (CD₃OD/300 MHz) 7.88 (S, IK), 7.81 (d, IH, J = 2.2 Hz), 7.74

118 (dd, IH, J = 8.6, 2.2 Hz) 5.90 (q _H__F, IH, J=7.2

3.70 (m, 4H) , 2.94-2.97 (n, 4H) . FABLRMS m/z 394

FABHRMS 394.0567 (M + H^4-, C₁₅H₁₅F₃NOgS Calc'd 394

Hz), 3.54(M + H⁺). 0572).

EXAMPLE 54

<img file="AP1149A_D0077.tif" />

6- [ (1,1-Dimethylethyl) amin.osulf onyl] -2-trifluoromethyl-2H-lbenzopyrai'„-3-carboxylic acid

The title compound Wes prepared by a similar procedure to that described in Example 49: mp 229.3-233.5 °C NMR (CD₃OD/300 MHz) 7.82-7,87 (m, 3H), 7.12 (d, IH, J = 8.6 Hz), 5.87 (q _H__F/ IH, J=7.2 Hz), 1.18 (s, 9H) . FABLRMS m/z 380 (M + H⁺). Anal. Calc'd for C₁₅H₁₆F₃NO₅S: C, 47.49; H, 4.25; N, 3.69. Found: C, 47.95; H, 4.48; N, 3.55.

EXAMPLE 55

<img file="AP1149A_D0078.tif" />

6- [ (2-Me thy lpropyl) amino:,ulf onyl] -2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 49: mp 190.6-192.4 °C.· ¹H NMR (CD3OD/3OO MHz) 7.77-7.84 [m, 3H), 7.13 (d, IH, J = 8.4 Hz),

AP Ο Ο 1 Η 9

119

5.86 (q _H__F/ IH, ϋ=Ί.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. Calc'd for C₁₅H_l6F₃NO₅S: C, 47.49; H, 4.25; N, 3.69. Found: C, 47.61; H, 3.34; N, 3.55.

EXAMPLE 56

<img file="AP1149A_D0079.tif" />

6-Methylsulf onyl-2-trif luoromethyl-2H-l-benzopyran-3carboxylie acid

Step 1. Preparation of 6-chlorosulfonvl-2(trifluoromethvl)-2H-l-benzopyran-3-carboxylic acid.

To chlorosulfonic acid (50.0 mL) chilled to -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 over ice (100 mL) with two diethyl ether(2 x 75 mL) extractions. The diethyl ether layers were combined, washed with water (2 x 75 mL), and brine (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-lbenzopyran-3-carboxylic acid was isolated as a white solid: mp 169-174. ^XH NMR (CD₃OD/300 MHz) 8.18 (d, IH, J = 2.7 Hz), 8.06 (dd, IK, J =8.7, 2.7 Hz), 7.93 (s, IH), 7.28 (d, IH, J = 8.7 Hz), 6.00 (q, IH, J = 6.6 Hz). EIHRMS m/z

324.9977 (M+, Calcd 324.9994) .

Step 2. Preparation of 6-methvlsulfonvl-2(trifluoromentvl)-2H-l-benzopvran-3-carboxylic acid

AP/TZ 99/01677

120

A slurry of the chlorosulfonyl intermediate (Example

49, Step 1) (493 mg, 1.44 mmol), sodium bicarbonate (362 mg, 4.32 mmol), and sodium bisulfite (181 mg, 1.44 mmol) in water (1.5 mL)was heated to 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, followed by the addition of sodium hydroxide solution (50% NaOH soln., 0.10 mL) and water (3.0 mL) . Ihe solution was reluxed 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 :xiL) , water (2 x 25 mL) , and brine (2 x 25 mL) , dried over sodium sulfate, filtered and concentrated in vacuo yielding the title compound as an off white solid. (231 mg , 50 % yield): mp 208.3-212.4°C. ^FH NMR (CD₃OD, 300 MHz) 7.97 (d, 1H, 2.2 Hz), 7.91 (1H, dd, J = 8.7, 2.2 Hz), 7.19 (d, 1H, J = 8.7 Hz), 5.91 (q _H__F/ IK,

J=7.2 Hz), 3.11 (s, IK) HRLRMS m/z 321 (M - H)FABLRMS m/z 321 (M - K). Anal. Calc'd Eor C₁₂H₉F₃O₅S*0.61 H₂O: C, 43.26; H, 3.09. Found: C, 43.24; H, 3.09.

EXAMPLE 57

<img file="AP1149A_D0080.tif" />

8-Chloro-6- [ [ (phenylmethyl) amino] sulfonyl] -2trif luoromethyl-2H-l benzopyran-3-carboxylic acid

The title compound was prepared by a similar procedure to .that described in Example 49: mp 167.0-173.8 °C ^FH NMR

ΑΡ ύ 0 1 1 4 9

121 (CD₃OD/300 MHz) 7.78 (s, 1H) , 7.72 (d, 1H, J = 2.0 Hz), 7.64 (d, 1H, J = 2.0 Hz). 7.44 (s, 1H) , 7.15-7.23 (m, 5H) , 6.01 (q _H__F/ 1H, J=7.2 Hz) , 4.08-4.15 (m, 2H) . FABLRMS m/z 454 (M + Li⁺)- Anal. Calc'd for C₁₆H₁₃C1F₃NO₅S: C, 48.28; H, 2.93; 5 N, 3.13. Found: C, xx; Η, xx; N, xx .

EXAMPLE 58

<img file="AP1149A_D0081.tif" />

6-N/N-Diethyla2ninosulfoiiyl-2-trif luoromethyl-2H-lbenzopyran-3-carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 49: mp 23 8-240 °C. NMR (CD₃OD/300 MHz) 7.88 (s, 1H) , 7.85 (d, 1H, J = 2.2 Hz), 7.79 (dd, 1H, J = 8.5, 2.2 Hz), 7.14 (d, 1H, J = 8.5 Hz), 5.88 (q _H__F; 1H, J = 7.2 Hz), 3.24 (q, 2H, J = 7.3 Hz), 1.11 (t, 3H,

J = 7.3 Hz). FABHRMS m/z 380.0763 (M+H⁺, Calc'd 380.0780). Anal. Calc'd for C_F5Hi5F₃NO4S: C, 47.49; H, 4.25; H, 3.69.

ΑΡ/Γ/ΐ 9 / 0 1 6 77

Found: C, 47.62; H, 4.30; N, 3.72

EXAMPLE 59

<img file="AP1149A_D0082.tif" />

O

OH

CF₃

O

122

6-Phenylacetyl-2-trif '.i.uorometbyl-2H-l-beiizopyran-3carboxylic acid

Step 1. Preparation of ethyl 6-phenvlacetvl-2trifIuoromethvl-2H-l-benzoPvran-3 -carboxylate .

2-Trifluoromethyl~2H-I-benzopyran-3carboxylic acid (Example 1))) (1.32 g, 4.85 mmol) was cooled to 0 °C in dichloromethane (50 mL) .

Aluminum chloride (2.58 g, 19.5 mmol) was added and a dark red solution resulted. A solution of phenylacetyl chloride (1.8 g, 12.1 mmol) in di chloromethane (10.0 mL) was added dropwise over 40 minutes. The solution was warmed to room temperature and stirred fo:;· 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 HCI (2 x 10 0 mL) , and saturated sodium bicarbonate (3 x 100 mL) .

Hexanes (20 mL) were added and the solution was extracted with brine (1 x 100 mL) . The solution was dried over sodium sulfci.te and solvent was removed in vacuo. The crude ester was purified by flash chromatography over silica gel (with ethyl acetate as eluant) to afford the ester that was crystllized from diethyl ether/hexanes (830 mg,

44%) : mp 136.2-138.0 °C. ³H NMR (CDCl₃/300 MHz)

7.98 (dd, 2H, J = 8.4, 2.0 Hz), 7.90 (d, IH, J =

2.0 Hz), 7.29 (s, IH) , 7.22 - 7.38 (m, 5H) , 7.02 (d, IH, J — 8.4 Hz) , 5.75 (g H—F TH, J⁼1.2 Hz) ,

4.25 - 4.40 (m, 2H), 4.21 (s, 2H), 1.34 (t, 3H, J = 7.0 Hz). FABLRMS m/z 393(M + H⁺).

Step 2. Preparation of 6-phenvlacetvl-2-trifluoromethyl-2H1-benzopyran-3-carboxvlic ecid.

AP 0 0 114 9

123

The acid was converted from the ester (Step 1) via a method similar to that described in Example 1, step 2: mp 159.0-164.0 °C ¹H NMR (CD₃OD/300 MHz) 8.04-8.16 (m, 3H), 7.87 (s, IH) , 7.05-7.30 (m, 5H) , 5.86 (q h-F, ^1H' ^=7.2 Hz),

4.31 (s, 2H) . FABLRMS m/z 3 63 (M + H⁺) . Anal. Calc'd for ^c19^H13^F3°4*° ’^{29 h}2^{0: C}' ⁶²·θ⁸'' ^H, 3.73. Found: C, 62.04; H, 4.03 .

EXAMPLE 60

<img file="AP1149A_D0083.tif" />

6- (2,2-Dimethylpropylcarbonyl) -2-tri£luoromethyl-2H-lbenzopyran-3-carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 59: mp 198-200 °C. ^-H NMR (CD3OD/3OO MHz) 7.98-8.06 (m, 2H) , 7.88 (s, IH), 7.07 (d,

IH, J = 8.9 Hz), 5.86 (q _H-F, ^1H, ^J = ⁷·² Hz), 2.88 (s, 2H),

1.05 (s, 9H). FABHRMS m/z 343.1175 (M+H⁺, C17H18F3O4 requires 343.1157). Anal. Calc'd for C17H17F3O4: C, 59.65;

H, 5.01. Found: C, 59.70; H, 4.97.

EXAMPLE 61

<img file="AP1149A_D0084.tif" />

124

6,8-Dicbloro-7-methoxy-2-trif luoromethyl-2H-l-benzopyran-3carboxylic acid

Step 1: Preparation of ethyl 7-methoxv-2-trifluoromethvlbenzopvran-2H-3-carboxvlcite.

4-Methoxysalicylalde;hyde (2.38 g, 15.64 mmol),

K2^CO3 (2.16 g, 15.64 mmol.) and ethyl 4,4,4trifluorocrotonate (2.8 mL, 3.16 g, 18.77 mmol) were dissolved in DMF (1C mL) . The reaction was stirred at room temperature for 24 hours, diluted with water and extracted with Et2O. The combined

Et₂O phases were washed with water, dried over

MgSO^, filtered and concentrated in vacuo yielding an oil. Trituration with, hexanes induced crystallization. Collection of the solid by vacuum filtration yielded the ester as a light brown crystalline solid (1.80 a, 38%): mp 78-80 °C.

NMR (CDCl₃/300 MHz) δ 7.61) (s. 1H) , 7.14 (d, 1H, J = 8.1 Hz), 6.59-6.50 (m, 2H), 5.68 (q, 1H, 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) . FA3HRMS m/z

303.0849 (M+H Calc'd 303.3844). Anal. Calc'd for ^C14^H13^F3°4^{: C}' ⁵⁵·⁶³'· H, 4.34. Found: C, 55.47; H,

4.31.

Step 2. Preparation of ethyl 6,-8-dichloro-7-methoxv-2trifluoromethvl-benzopvran-2H-3-carboxvlate .

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 was sparged with nitrogen causing the reaction to become straw colored. Zinc (0.86 g, 13.40 mmol) was added to this solution with vigorous stirring. After 45 minutes, additional zinc [0.86 g, 13.40 mmol) was added and the reaction was stirred overnight. The

WO 98/47890

PCT/US98/07677

APO 0 1149

127 = 7.2 Hz). FABHRMS m/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd for C₁₅H₉O3F3 + 3.31 % H₂O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.

EXAMPLE 63

<img file="AP1149A_D0085.tif" />

2-Trif luoromefchyl-3H-naph.tho [2,1-b]pyran-3-carboxylic acid

2-Hydroxy-napth-1 -aldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 244.7-249.8 °C. ^ΧΗ NMR (CDCl₃/300 MHz) 8.61 (s, 1H),

8.09 (d, 1H, J = 8.3 Hz), 7.90 (d, 1H, J = 8.9 Hz), 7.82 (d, 15 1H, J = 8.3 Hz), 7.63 (t, 1H, J = 8.1 Hz), 7.47 (t, 1H, J =

8.1 Hz), 7.23 (d, 1H, J = 9.1 Hz), 5.84 (q, 1H, J = 6.8 Hz). ¹⁹F NMR (CDCl₃/282 MHz) -79.56 (d, J = 7.3 Hz). FABLRMS m/z

295 (M+H). FABHRMS m/z 295.0560 (M+H, Calc'd 295.0582) . Anal. Calc'd for Cx5H₉F₃O₃: C, 61.23; H, 3.08. Found: C,

60.85; H, 3.12.

EXAMPLE 64

<img file="AP1149A_D0086.tif" />

ΑΡ/Γ,' 99/01677

128

2-Trif luoromethyl-2H-nap]itho [2,3-b]pyran-3-carboxylic acid

3-Kydroxynapthalene-2-carboxylic

3-hydroxynapthalene-2-carboxaldehyde to that described in Example 24, hydroxynap thal ene - 2 - c arbox aldehyde title compound by a procedure Example 1: mp decompose &gt;300 °C.

<td> (s,</td><td> IH) ,</td><td> 7.90</td><td> (s,</td><td> IH) ,</td><td> 7.84 (d,</td>

<td> IH,</td><td> J =</td><td colspan="2"> 8.2 Hz ) ,</td><td> 7.50</td><td> (t, IH,</td>

<td> 8.2</td><td> Hz) ,</td><td> 7.34</td><td> (s,</td><td> IH) ,</td><td> 5.77 (q,</td>

<td> 294</td><td> .0474</td><td> (M+,</td><td colspan="3"> Calc'd 294.C504) .</td>

acid was converted to by a similar procedure Steps 1 &amp; 2. The 3was converted to the similar to that described in iH NMR (CD3OD/3OO MHz) 7.99 IH, J = 8.2 Hz), 7.74 (d, = 8.2 Hz), 7.39 (t, IH, J = IH, J= 6.6 Hz). EIHRMS m/z

EXAMPLE

<img file="AP1149A_D0087.tif" />

6-Chloro-2-trifluoromethyl-2H-l-benzothiopyran-3-carboxylic acid

Step 1: Synthesis of 5-chloro-thiosalicvlaldehvde,

Tetramethylethylenedi amine (TMEDA)(10.44 mL, 8.035 g,

69.15 mmol) was added via syringe to n-BuLi (43.22 mL of 1.6 M in hexanes, 69.15 mmol) and the solution was chilled to 0 °C. A solution of 4-chlorothiophenol (5.00 g, 34.57 mmol)· in cyclohexane (25 mL) was added with stirring over 1 hour. The resulting tan slurry was stirred overnight at room temperature, chilled to 0 °C, and DMF (2.94 mL, 2.78 g,

38.03 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 30 hours and became a powcsry suspension. A mixture of 2 N HCl and ice was added to the reaction mixture until the pH

APO 0 114 9

125 crude mixture was diluted with. EtOH and filtered through diatomaceous earth. The filtrate was concentrated in vacuo yielding a crystalline mass.

This solid was dissolved in EtOAc, washed with 2N

HCI, brine, dried over MgSO₄, filtered and concentrated in vacuo yielding an oil. The oil was dissolved in a minimum of isooctane, inducing crystallization. Vacuum filtration of the suspension yielded tan needles (1.078 g) which were recrystallized from isooctane yielding the dichloro ester as tan crystals (0.71 g, 43%) of suitable purity to use in the next step: mp 113.3-115.1 °C.

3-H NMR (acetone-dg/300 MHz) 7.88 (s, IH) , 7.63 (s,

IH), 6.02 (q, IH, J = 6.8 Hz), 4.38-4.22 (m, 2H),

3.93 (s, 3H) , 1.31 (t, 3H, J =7.1 Hz). ¹⁹F NMR (acetone-dg/282 MHz) -80.00 (d, J = 7.2 Hz).

Step 3: Preparation of 6,8-dichloro-7-methoxv-2trifluoromethyl-benzopyran-2H-3-carboxylic acid.

To a stirred solution of the dichloro ester from Step 2 (0.686 g, 1.848 mmol) in THF (10 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 H2O and washed with diethyl ether. The resulting aqueous phase was sparged with nitrogen and acidified with 2N HCI solution causing the solution to become turbid. Filtration of this suspension yielded the title compound as a white powder (0.559 g, 88 %) : mp 195.6-199.1 °C. ^XH NMR (CDCl₃/3 00 MHz) 7.90 (s, IH) ,

7.64 (s, IH), 6.01 (q, IH, J = 6.8 Hz), 3,94 (s, 3H). ¹⁹F

NMR (CDCl₃/282 MHz) -79.63 (d, J = 7.1 Hz). FABLRMS m/z 349 (M+Li) . EIHRMS m/z 341.9681 (M+, Calc' d 341.9673) .

Anal. Calc'd for C]_2^H7^cl2^F3°4 ^{: C}' 42.01; H, 2.06. Found: C, 41.76; H, 2.14.

AP/T 9 9 / 0 1 6 77

6

EXAMPL3 62

<img file="AP1149A_D0088.tif" />

2-Trifluoromethyl-2H-napht:bo [1,2-bjpyran-3-carboxylic acid

Step 1. Preparation of ethvi 2-trifluoromethvl-3Knaphthopvran-carboxvlate.

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) dissolved in anhydrous dimethylformamide (DM?) and treated with anhydrous K2CO3 (13.8 g, 0.100 mol) . The solution was maintained at room temperature for 50 hours and diluted with water. The solution was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over anhydrous M0SO4_r filtered and concentrated in vacuo to afford 4.8 g of an oil. The oil was purified by HPLC, eluting with hexanes: ethyl acetate (30:1). The appropriate fractions were concentrated to afford 1.6 g (10%) of the napthopyran ester as a yellow solid.

Step 2. Preparation of 2-trifluoromethvl-3H-naphthopvrancarboxvlic 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 HCI, whereupon a solid formed that was isolated by filtration. The solid was washed with 20 mL of water to afford 0.7 g (95%) of the title compound as a yellow -solid: mp 245.9-248.6 °C. NMR. (acetone-d£/3 00 MHz) 8.57 (;, IH) , 8.28 (d, IH, J = 8.7 Hz), 8.03 , (d, IH, J = 9.0 Hz) , 7.,93 (d, IH, J = 8.7) , 7.67 (m,

IH) , 7.50 (m, IH), 7.28 (d, IH, J =9.0), 5.96 (q _H-F' IH, ^J

APO 0 114 9

129 became acidic (pH = 1). During this addition, the mixture warmed and became first red and then pale yellow. This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO₄, filtered ana. concentrated in vacuo yielding a clear redbrown oil. This oil was triturated with hexanes yielding a red-brown semisolid. This semisolid was purified by plug flash chromatography over silica gel, eluting with 1:1, hexanes:dichloromethane to afford 5-chlorothiosalicylaldehyde (0.858 g, 14%) as an intensely yellow solid suitable for use without further purification.

Step 2: Preparation of ethvl 6-chloro-2-trifluoromethvlbenzo-l-thiopyran-2-H-3-carboxvlate.

5-Chloro-thiosalicylaldehyde (Step 1) (0.84 g, 4.86 mmol) was added to DMF (3 mL) and ethyl 4,4,4trifluorocrotonate (1.10 mL, 1.22 g). With stirring, K2CO3 (0.67 g, 4.86 mmol) was added causing the reaction to become a deep red. After stirring overnight at room temperature, the reaction was diluted with diethyl ether and washed with water, saturated NaHCO3 solution, aqueous KKSO4 solution (0.25 M), brine, dried over MgSO₄, filtered and concentrated in vacuo yielding an oil. The oil was purified by flash chromatography (5:1; hexanes: ethyl acetate) yielding upon concentration ethyl 6-chloro-2-trifluoromethyl-benzo-1thiopyran-2-H-3-carboxylate as a bright orange solid (0.492 g, 31%); mp 94.6-97.4 °C NMR (acetone dg/300 MHz) δ

8.01 (s, 1H), 7.71 (d, 1H, J = 2.2 Hz), 7.50 (d, 1H, J = 8.5 Hz}, Ί.44 (d of d, 1H, J = 2.3, 8.3 Hz}, 5.07 (q, 1H, J =

8.5 Hz), 4.42-4.23 (m, 2H), 1.35 ( t, 3H, J = 7.1 Hz) .

FABLRMS m/z 329 (M+Li) .

Step 3: Preparation of 6-chloro-2-trifluoromethvl-benzo-1thiopvran-2-H-3-carboxylic acid.

To a stirred solution of the ester from Step 2 (0.413 g, 1.280 mmol) in THF: EtOH : H₂O (7 : 2 : 1, 10 mL) was

LL 9 I 0 i 6 6

130 added NaOH solution (0.56 mL of 2.5 N solution, 1.408 mmol} with stirring. 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 HC'.. caused precipitation of a flocculent yellow precipitate. Vacuum filtration of the suspension yielded 6-chlor:&gt;-2-trif luoromethyl-benzo-1thiopyran-2H-3-carboxylic acid as a yellow powder (0.25 g,

%) : mp 188.8-198.7 °C i-H NMR (acetone dg/300 MHz) δ 8.02 (s, 1H) , 7.71 (d, 1H, J = 2.22 Hz), 7.50 (d, l.H, J = 8.5 Hz), 7.44 (d of d, 1 H, J 2.2, 8.5 Hz), 5.05 (q, 1H, J =

8.6 Hz). ¹⁹F NMR (Acetone dg/282 MHz) d -75.22 (d, J =

8.7 Hz). FABLRMS m/z 301 (M+Li); ESLRMS (neg. ion) m/z 293 (M-H).

EXAMPLE 66

<img file="AP1149A_D0089.tif" />

(S) -6-Chloro-2-trif luorome thyl-2H-l-benzopyran-3-carboxylic acid

To a solution of 6-chloro-2-trifluoromethyl-2H-lbenzopyran-3-carboxylic acid (Example 1, Step 2)(12.00 g, 43.07 mmol) and (S) (-)-a-methylbenzylamine (2.61 g, 21.54 mmol) in methyl-tert-butyl ether (30 mL) was slowly added nheptane (200 mL) until the mixture became cloudy. The mixture was heated (steam lath) to boiling and set aside for 24 h during which time crystals formed. Filtration of the suspension yielded a crystalline product (5.5 g) which was recrystallized from methyl-tert-butyl ether (30 mL) and nheptane (200 mL) yielding upon filtration a white solid (3.1

APO 0 1149

131

g) . This solid was dissolved in EtOAc (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2 x 50 mL) , dried over MgSO₄ and concentrated in vacuo yielding a white solid. Recrystallization of this solid from methyl-t-butyl ether/n-heptane yielded the title compound as the highly enriched isomer, a white solid (2.7 g, 45%): mp 126.7-128.9 °C. Ή NMR (CDCl₃/300 MHz) 7.78 (s, IH) , 7.3-7.1 (m, 3H) ,

6.94 (d, IH, J = 8. 7 Hz) , 5.66 (q, IH, J = 6.9 Hz) . Anal. Calc'd for C_1;H₆O₃F₃C1: C, 47.42; H, 2.17; N, 0.0. Found: C, 47.53; H, 2.14; N, 0.0. This compound was determined to have an optical purity of greater than 90% ee.

Procedure for determining optical purity.

To a solution of the free acid (title compound) (0.005 g, 0.017 mmol) in ethyl acetate (1.5 mL) in a test tube was added (trimethylsilyl) diazomethane (3 0 pL of 2.0 N solution in hexanes, 60 mmol) . The resulting yellow solution was warmed until the solution began to gently boil and then was allowed to cool to room temperature and stand for 0.08 hours. With vigorous mixing, the solution was quenched with aqueous 1 N HCI (1.5 mL) . The layers were separated and a sample of the ethyl acetate fraction (0.3 mL) was transferred to a vial, concentrated under a stream of nitrogen, was diluted with hexane (total of 1 mL) and a sample (10 pL) analyzed by chiral chromatography. The HPLC utilized a Daicel ChiralPak AD column eluting with 10% isopropanol-hexane at 0.5 mL/min using a UV detector set at 254 nM.

LL 9 J. 0 / 6 6 ,'_7dV

EXAMPLE 67

<img file="AP1149A_D0090.tif" />

132 (S) -6-trif luorometh.oxy-2-trifluorometh.yl-2H-l-ben.zopyran-3carboxylic acid

To a solution of 6-trifluoromethoxy-2(trifluoromethyi) -2H-l-ber.zopyran-3-carboxylic acid (Example 16)(17.72 g, 54.00 mmol) and (-)-cinchonidine (7.95 g, 27.04 mmol) in methyl-tert-butyl ether (100 mL) heated on a steambath was added n-heptane (2 00 mL) . The mixture was heated on the steam bath to boiling and allowed to cool for 4 h during which time crystals formed. Filtration of the suspension yielded a crystalline solid (18.7 g) . This solid was dissolved in 2-butanone (3 0 mL) followed by the addition of n-heptane (500 mL) . After standing for 16 hours, the resulting suspension was filtered yielded a white solid (10.3 g) . This solid was dissolved in ethyl acetate (150 mL) , washed with 1 N hydrcchloric acid (100 mL) and brine (2 x 50 mL) , dried over MgSO₄. filtered, and concentrated in vacuo yielding a viscous yellow oil (5.2 g, 59%) : ^XH NMR (acetone-dg-/300 MHz) 7.16 (s, IH) , 6.77 (d, IH, J = 2.7 Hz),

6.94 (d, IH, J = 8.7 Hz), 5.64 (m, IH) , 6.39 (d, IH, J = 8.7 Hz) 5.13 (σ, IH, J = 7.2 Hz). Anal. Calc'd for C_i2H₆O₄F₆: C, 43.92; H, 1.84; N, 0.0. Found: C, 43.79; H, 1.83; N, 0.0. This compound was determined to have an optical purity of greater than 90% ee. Chiral purity was determined as describe in Example 66.

<img file="AP1149A_D0091.tif" />

(S)-6-Chloro-7-(1,1-dimettylethyl)-2-(trifluoromethyl)-2H-1benzopyrar-3-carboxylic acid

AP Ο Ο 1 14 9

133

To a solution of 6-chloro-7-(1,1-dimethylethyl)-2trifluoromethyl-2H-l-benzopyran-3-carboxylic acid (Example 8)(11.4 g, 34.1 mmol) and (S)-(-)-2-amino-3-phenyl-1propanol (2.57 g, 17.00 mmol) was added η-heptane (200 mL) and. the mixture set aside for 16 h. The resulting suspension was filtered yielding a solid (3.8 g) . This solid was recrystallized from 2-butanone (20 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.0 g) .

This solid was dissolved in ethyl acetate (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2 x 50 mL), dried over MgSO₄ and concentrated in vacuo yielding a white solid. This solid was recrystallized from n-heptane yielding the title compound of high optical purity as a crystalline solid(1.7 g, 30%) : mp 175.4-176.9 °C. ^XH NMR (acetone-d^/300 MHz) 7.86 (s, 1H) , 7.52 (s, 1H), 7.12 (s,

1H), 5.83 (q, 1H, J =7.1 Hz), 1.48 (s, 9H). Anal. Calc'd for C₁₅H₁₄O₃F₃C1: 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. This compound was determined to have an optical purity of greater than 90% ee. Chiral purity was determined as describe in Example 66.

EXAMPLE 69

<img file="AP1149A_D0092.tif" />

APT/ 9 9 / 0 1 6 77

6- [ [ (2-Furanylmethyl)amino3 sulfonyl] -2- (trifluoromethyl) -2H l-benzopyran-3-carboxylic acid

The title compound was prepared by a similar procedure to that described in Example 49: mp 170-173 °C. ^H NMR (CD3OD/3OO MHz) 7.78 (s, 1H), 7.66-7.76 (m, 2H), 7.18-7.22 (m, 1H), 7.00-7.08 (m, 1H), 6.12-6.18 (m, 1H), 6.02-6.06

134 (m, 1H) , 5.25 (q, 1H, J -- 7.0 Hz), 4.13 (s, 2H) . EIHRMS m/z 403.0332 (M+, Calc'd &lt;03.0337).

EXAMPLE 7 0

<img file="AP1149A_D0093.tif" />

6- [ (Phenylmethyl) sulfonyl] -2- (trifluoromethyl) -2H-1benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared analogous to the procedure described in Example 56·. mp 172176 °C. NMR (CD₃OD/300 MHz)7.73 (s, 1H) , 7.43-7.56 (m,

2E) , 7.21-7.33 (m, 3H) , 7.20-7.21 (m, 3H), 5.88 (q, 1H, J =

7.0Hz), 4.83 (s, 2H). EIHRMS m/z 398.0399 (M+, Calc'd

398.0436).

EXAMPLE 71

<img file="AP1149A_D0094.tif" />

6-[[(Phenylethyl)amino]sulfonyl]-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared analogous to the procedure described in Example 49: mp 187190 °C. ^ΧΗ NMR (CD3OD/3OO MHz) 7.82 (s, 1H), 7.74-7.90 (m,

ΑΡ υ Ο 114 9

135

2Η) , 7.08-7.29 (m, 6Η) , 5.89 (q, 1Η_Ζ J =6.8), 3.12 (t, 2H,

J = 7.3 Hz), 2.72 (t, J = 7.3 Hz). EIHRMS m/z 427.0675 (M+, Calc'd 427.0701)

EXAMPLE 72

<img file="AP1149A_D0095.tif" />

7-Chloro-2-trifluoromethyl-2H-l-benzopyran-3carboxylic acid

4-Chlorosalicylic acid was converted to 3chlorosalicylaldehyde by a procedure similar to that described in Example 24, Steps 1 &amp; 2. The 3chlorosalicylaldehyde was converted to the title compound by a procedure similar to Example 1: mp 175.2-177.6 °C. -^H NMR (acetone-d^/300 MHz) 7.90 (ε, 1H), 7.51 (d, 1H, J =7.8 Hz), 7.12 (m, 2H), 5.86 (q _H__F, 1H, J = 7.2 Hz). FABHRMS m/z

285.0114 (M+Li, Calc'd 285.0118). Anal. Calc'd for C₁₁H₆C1F₃O₃: C, 47.42; H, 2.17; Cl, 12.72. Found: C, 47.54; H, 2.37; Cl, 12.85.

EXAMPLE 73

<img file="AP1149A_D0096.tif" />

AP!?! 9 9 / 0 1 6 77

6-Chloro-8-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid .4 ·'

136

Step 1. Preparation of 3-iodo-5-chlorosalicvlaldehyde

N-lodosuccinimide (144.0 g, 0.641 mole) was added to a solution of 5-chlorosalicyaldehyde (100 g, 0.638 mole) in dimethylformamide (400 mL) . The reaction mixture was stirred for two days at ro:?m temperature. Additional Niodosuccinimide (20 g, 0.039 mole) was added and the stirring was continued for an additional 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 (3CO mb, 5%), and brine (300 mL) .

It was dried over MgSO₄, and was concentrated to dryness to afford the desired aldehyde as a pale yellow solid (162 g, 90%) : mp 84.8-86.7 °C. H NMR (CDCl/300 MHz) 11.67 (s,

1H), 9.71 (s, 1H), 7.92 (d, 1H, J =2.5 Hz), 7.54 (d, 1H, J = 2.6 Hz). FABLRMS m/z 281.0 (M-H). ESHRMS m/z 280.8851 (M-H, Calc'd. 280.88630).

Step 2. Preparation of ethyl 6-chloro-8-iodo-2(trifluoromethvl)-2H-l-benzspvran-3-carboxvlate

5-Chloro-3-iodosalicylaldehyde (20 g, 70.8 mmol), ethyl 4,4,4-trifluorocrotonate (17.85 g, 106 mmol), and triethylamine (14.33 g, 142 mmol) were dissolved 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). It was extracted with 10% HCI (2 x 200 mL) , saturated aqueous NaHCO₃ (2 x 200 mL) , and water (2 x 200 mL). The ethyl acetate phase was dried over MgSO₄, filtered and evaporated to yield a brown solid. It was then run through a plug of silica with ethyl acetate-hexane (1:20) . The solvent was evaporated to give a yellow solid, that was recrystallized in hexane to afford the ester as a white solid (19.61 g, 64%) : mp 92.1-93.9 °C. ^XK NMR (CDC1/300 MHz) 7.71 (d, 1H, J = 2.2 Hz), 7.56 (s, 1H) , 7.20 (d, 1H, J = 2.2 Hz) , 5.81 (q, 1H, 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, Calc'd. 431.9237).

AP 0 01 14 9

137

Step 3. Preparation of 6-chloro-8-iodo-2-(trifluoromethyl)2H-l-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. 2.2 Hz), 7.71 (s, IH, J = 7.0 Hz). 403.8924) . Anal. Found: C, 33.13;

H NMR (CD₃OD/300 MHz) 7.77 (d, IH, J = IH) , 7.41 (d, IH, (7=2.2 Hz), 5.87 (q, EIHRMS m/z 403.8893 (M-H, Calc'd.

Calc'd for C^CIF-JO.,: C, 32.66; H, 1.25 H, 1.29.

<img file="AP1149A_D0097.tif" />

8-Bromo-6 - chloro - 2-trif luoromethyl - 2H-1-benzopyran-3carboxylic acid

Step 1. Preparation of ethyl 8-bromo-6-chloro-2trifluoromethyl-2H-1-benzopyran-3-carboxylate

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) was stirred in Ν,Ν-dimethylformamide (5 mL) at 95° C for 18 h. Water (100 mL) was added and the mixture was extracted with ether (3 x 50 xnL). The combined organic extracts were washed with sodium hydroxide (10 mL) and water (2 x 50 mL). After drying over MgSO₄ and concentrating, the mixture filtered through of a pad of silica eluting with ethyl acetatehexanes (1:4) . The eluant 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-dg/300 MHz) 7.90 (s, IH), 7.65 (d, H, J = 2.4 Hz), 7.61 (d, H, J = 2.4 Hz),

138

6.03 (q _H__F, IK, J = 6.9 Hz), 4.34 (m, 2H) , 1.33 (t, 3H, J = 7.5 Hz). ESHRMS m/z 384.9435 (M-H, Calc'd 384.9454). Anal. Calc'd for C-^H^BrClF-^C^ : C, 40.50; H, 2.35. Found: C, 40.61; H, 2.40.

Step 2. Preparation of 8-bromo-6-chloro-2-trifluoromethyl2H-l-benzopvran-3-carboxvl1c acid

Ethyl 8-bromo-6-chlor :&gt;-2 -trifluoromethyl-2H-1benzopyran-3-caboxylate {0.3 g) , ethanol (15 mL) , tetrahydrofuran (10 mL) , and sodium hydroxide solution (10 mL, 2.5 N) were stirred at room temperature for 16 h. Hydrochloric acid (1 N) was added until the mixture was acidic to pH paper. The addition of water (50 mL) caused the formation of a precipitate which was collected by filtration yielding the title compound as a white solid (0.2 g, 72%) : mp 227.8-228.9 °C. -H NMR (acetone-dg/300 MHz)

7.90 (s, 1H) , 7.65 (dd, 2H, J = 2.4 and J = 28.8 Hz), 6.00 (q _H__F, 1H, J = 7.2 Hz). FABHRMS m/z 356.9134 (M+H, Calc'd 356.9141). Anal. Calc'd for C₁₁H₅BrClF₃O₃: C, 36.96; H, 1.41. Found: C, 37.05; H, 1.33.

EXAMPLE 75

<img file="AP1149A_D0098.tif" />

6-Formyl-2- (trif luoromethyl) -2H-l-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl 6-formvl-2-(trifluoromethyl)2H-l-benzopvran-3-carboxvlate.

A 50 mL round bottom f'.Lask was charged with 5formylsalicylaldehyde (3.21 g, 21.39 mmol), ethyl 4,4,4trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol),

APO 0 114 9

139 dimethylformamide (15 mL) and potassium carbonate (2.95 g, 21.39 mmol) and heated to 60 °C for 12 hours. Additional ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol) was added and the reaction heated for 16 hours at 75 °C. After cooling to room temperature, the reaction was partitioned between H₂O and diethyl ether. The organic phase was washed with saturated NaHCO₃ solution, KHSO₄solution (0.25 M) , brine, treated with decolorizing carbon (warmed gently) . The resulting black suspension was dried over MgSO₄, vacuum filtered through diatomaceous earth, and concentrated in vacuo yielding an orange crystalline mass. This material was recrystallized from hot hexanes yielding the ester (1.51 g, 24 %) as orange crystals: mp 84.3-86.2 °C. NMR (acetone-dg/300 MHz) 9.96 (s, 1H) , 8.06 (d, 1H,

J = 2Hz), 8.02 (s, 1H) , 7.99 (dd, 1H, J = 8.5, 2.0Hz), 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 (M+H). EIHRMS m/z 300.0605 (M+, Calc'd 300.0609). Anal. Calc'd for C₁₄H₁₁F₃O₄: C, 56.01; H, 3.69. Found: C, 56.11; H,

3.73.

Step 2. Preparation of 6-formvl-2-(trifluoromethyl)-2H-1benzopvran-3-carboxvlic acid.

The ester (Step 1) was converted to the acid via a method similar to that described in Example 1, Step 2: mp 211.3-215.7 °C. ¹H NMR (acetone-d^/300 MHz) 9.97 (s, 1H) ,

8.07 (d, 1H, J = 2.0Hz), 8.03 (s, 1H) , 8.00 (dd, 1H, J =

8.3, 2.0 Hz), 7.25 (d, 1H, J= 8.5 Hz), 5.98 (q, 1H, J = 6.9 Hz). FABLRMS m/z 273 (M+H). EIHRMS m/z 272.0266 (M+, Calc'd 272.0296). Anal. Calc'd for C₁₂H₇F₃O₄: C, 52.95; H, 2.59. Found: C, 52.62; H, 2.58.

APT/ 9 9 / 0 1 6 77

EXAMPLE 76

140

<img file="AP1149A_D0099.tif" />

6-Chloro-8-Fomyl-2- (trifluoromethyl) -2H-1-benzopyran-3carboxylic acid

Step 1. Preparation of 4-chloro-2,6bis(hydroxymethyl)phenol.

Potassium hydroxide ( 84.82 g, 1.30 mole) was dissolved in HjO (200 mL) in a two 1:.ter 3-neck round bottom flask fitted with thermocouple, mechanical stirrer, and stopper. With stirring, 4-chlorophenol (12 8.56 g, 1.0 mole) was added with cooling (ice bath) resulting in the temperature rising to 26 °C. Formalin (230 mL of 37% aqueous solution, 2.83 mole) was added portion-wi.;;e maintaining the temperature below 25 °C. The reaction was warmed to 35 °C for 48 hours. To this solution was added aqueous acetic acid (80.0 mL,

84.1 g, 1.40 mole in 800 mL H₂0) causing the solution to become turbid. Vacuum filtration of the suspension yielded a tan solid. The solid was stirred with acetone (100 mL) and the insoluble product collected by vacuum filtration.

The solution was diluted with hexanes yielding several crops of the diol as fine tan needles (35.0 g, 19%). mp 160.6163.3 °C. ¹H NMR (acetone-d^ NaOD, D₂0/300 MHz) 6.69 (s,

2H) , 4.48 (s, 4H), 7.88 (d, IH, J = 2.6 Hz), 7.75 (d, IH, J =2.6 Hz), 6.08 (q, IH, J= 6.9 Hz). ESLRMS m/z 206 (M+NH/). ESHRMS m/z 187.C131 (M-H, Calc'd 187.0162).

Step 2. Preparation of 5-chloro-3-formvl-salicvlaldehvde.

To a stirred suspension of diol (Step 1) (33.0 g, 0.18 mole) in chloroform (1.5 L) in a 2 L round bottom flask was added manganese dioxide (133 g, 1.60 mole) and the resulting suspension heated to a gentle reflux for 10 hours. The reaction was allowed to cool to room temperature, was filtered through diatomaceous earth, concentrated in vacuo, presorbed on silica gel and purified by flash chromatography

ΑΡΰ 0 114 9

141 (hexane/ethyl acetate) yielding the as a mustard colored powder dialdehyde (22.42 g, 67 %): mp 120.7-122.8 °C. This solid was of suitable purity to use in the next step without further purification.

Step 3. Preparation of ethvl 6-chloro-8-formvl-2(trifluoromethvl)-2H-l-benzoovran-3-carboxvlate .

A stirred solution of the dialdehyde (Step 2)(1.13 g, 6.14 mmol), dimethyl sulfoxide (6 mL) , ethyl 4,4,4trifluorocrotonate (1.37 mL, 1.55g, 9.21 mmoL) and triethylamine (1.71 mL, 1.24g, 12.28 mmol) in a round bottom flask fitted with condenser was heated to 80 °C for 8 h.

Upon cooling to room temperature the reaction was diluted with diethyl ether (100 mL) and the resulting mixture washed with aqueous sodium bicarbonate solution (3 X 75 mL) , IN HCI solution (3 X 70 mL) , and brine (1 X 75 mL) , dried over MgSO₄, filtered and concentrated in vacuo yielding a tan powder. This powder was taken up in hot hexane-ethyl acetate and filtered to remove insoluble matter. Upon cooling of the filtrate, crystallization followed by vacuum filtration yielded the desired ester as tan crystals (0.726 g, 35%): mp 118.1-119.7 °C. This material was of suitable purity to use without further purification.

Step 4. Preparation of 6-chloro-8-formvl-2(trifluoromethvl)-2H-l-benzopyran-3-carboxylic acid.

To a stirred solution of the ester (Step 3)(0.284 g, 0.849 mmol) in THF:EtOH:H₂O (7:2:1, 5 mL) was added aqueous NaOH solution (0.41 mL of 2.5 M, 1.02 mmol). After stirring 40 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H₂O, washed •with diethyl ether, sparged with nitrogen to remove trace diethyl ether, and acidified with concentrated HCI yielding a suspension. Vacuum filtration of the suspension yielded the title compound as a pale yellow powder (0.160 g, 23 %) . mp· 243.3-252.4 °C. ¹H NMR (acetone-dg/300 MHz) 10.39 (s,

APT/ 99/01677

142

1H), 7.98 (s, IH), 7.88 (c, 1H, J= 2.6 Hz), 7.75 (d, IH, J =2.6 Hz), 6.08 (q, IH, J = 6.9 Hz). FABLRMS m/z 307 (M+H). ESHRMS m/z 304.9839 (M-H, Calc'd 304.9828). Anal. Calc'd for C₁₂K6^C11^F3°4^{: 47}-⁰¹; H, 1.97. Found: C,

46.64; H,1.86.

EXAMPLE 77

<img file="AP1149A_D0100.tif" />

6-Bromo-7-(1,1-dime thy 1 echyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid

7-(1,l-Dimethylethyl-2-(trifiuoromethyl)-2H-1benzopyran-3-carboxylic acid (Example 12)(0.6 g, 2 mmol), chloroform (50 mL), iron filings (0.01 g, 0.2 mmol) , and bromine (0.48 g, 3.00 mmol) were stirred at reflux for 16 h. The mixture was allowed to cool and was washed with brine (2 x 50 mL) . After drying over MgSO₄, the mixture was filtered, concentrated in vacuo, and the residue crystallized from ether-hexanes yielding the title compound as a white solid (0.5 g, 66%): mp 198.6-199.9 °C. ³H NMR (acetone-d^/3 00 MHz) 7.85 (s, IH) , 7.72 (s, III) , 7.13 (s,

IH), 5.83 (q, IH, J = 7.2 Hz), 1.5 (ε, 9H). Anal. Calc'd for C_lsH₁₄O₃F₃Br: C, 47.52; H, 3.72; N, 21.07. Found: C,

47.42; H, 3.68; N, 21.15.

EXAMPLE 78

ΑΡ ϋ 0114 9

143

<img file="AP1149A_D0101.tif" />

5/ 6-Dichloro-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid

5,6-Dichlorosalicylaldehyde was prepared by the procedure described in Cragoe, E.J.; Schultz, E.M., U.S. Patent 3 794 734, 1974. This salicylaldehyde was converted to the title compound by a similar procedure to that described in Example 1: mp 211.5-213.5 °C. ¹H NMR (acetoned₆/300 MHz) 8.09 (s, IH), 7.63 (d, IH, J = 8.9 Hz), 7.12 (d,

IH, J = 8.9 Hz), 5.94 (q, IH, J = 7.0 Hz). ESLRMS m/z 311 (M-H) . EIHRMS m/z 311.9583 (M+, Calc'd 311.9568). Anal. Calc'd for C₁₁H₅Cl₂F₃O₃: C, 42.20; H, 1.61. Found: C,

42.33; H, 1.67.

EXAMPLE 79

<img file="AP1149A_D0102.tif" />

LL 9 I 0 / 6 6 /L'dV

6-Cyano-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl 6-Γ(hvdroxvimino)methvll-2(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.

A 50 mL round bottom flask was charged with hydroxylamine HCI (0.255 g, 3.67 mmol), ethyl 6-formyl-2(trifluoromethyl)-2H-l-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 H₂O (2 mL) . The reaction was stirred at room temperature for 18 hours, then diluted with

144

H₂0 and diethyl ether. The; layers were separated and the organic phase washed with H₂O, brine, dried over MgSO₄, filtered, and concentrated in vacuo yielding an orange semicrystalline mass. Recrystallization of this solid from hot ethyl acetate and isooctane yielded the oxime (0.578 g,

55%): mp 113.0-116.2 °C. ¹H NMR (acetone-d^/300 MHz) 10.46 (s, ca.l exch.), 8.11 (s, 2H) , 7.92 (s, 1H), 7.72 (d, 1H, J = 2Hz)), 7.68 (dd, 1H, J = 8.5, 2.0Hz), 7.07 (d, 1H, J = 8.5 Hz), 5.89 (q, 1H, J = 7.1 Hz), 4.43-4.22 (m, 2H), 1.34 9t,

3H, J - 7.3 Hz). FABLRMS m/z 316 (M+H). EIHRMS m/z 315.0719 (M+, Calc'd 315.C733). Anal. Calc'd for ^c14^h12^f3^N1°4^{: C}' ⁵³·³⁴'· ^H' ³·84; N 4.44. Found: C, 53.85;

H, 3.90; N, 4.19.

Step 2. Preparation of ethvl 6-cyano-2-(trifluoromethvl)2H-l-benzopyran-3-carboxylase.

To a stirred solution of oxime (Step 1)(0,264 g, 0.840 mmol) in dioxane (4.5 mL) in a 25 mL pear-shaped flask was added trifluoroacetic anhydride (0.130 mL, 0.194 g, 0.924 mmol) and triethylamine (0.1.40 mL, 0.102 g, 1.008 mmol).

The reaction was stirred at room temperature for 12 hours, then heated to 85 °C for 4 hours. After cooling to room temperature, aqueous HCI (50 ml, IN HCL) was added, and the resulting mixture extracted with ethyl acetate . The ethyl acetate phase was washed with chilled aqueous HCI (IN), brine, dried over Na₂SO₄, fiZ.tered, concentrated in vacuo yielding a pale yellow oil. This oil was resubmitted to similar reaction conditions. After dissolution of the pale yellow oil in dioxane (4.5 mL), trifluoroacetic anhydride (0.130 mL, 0.194 g, 0.924 mmol) and triethylamine (0.140 mL, 0.102 g, 1.008 mmol) were then added. After stirring 3 hours at room temperature, more triethylamine 0.50 mL, 0.3 6 g, 3.6 mmol) was added and then heated to 85 °C for 3 hours. After cooling to room temperature, aqueous HCI (50 ml, IN HCL) was added, and the resulting mixture extracted with ethyl acetate . The ethyl acetate phase was washed with

AP O 0 114 9

145 chilled aqueous HCl (IN), brine, dried over Na₂SO₄, filtered, concentrated in vacuo yielding a pale yellow oil. Addition of hexanes induced crystallization followed by vacuum filtration yielded the title compound (O.lOlg, 40 %) as a yellow powder: mp 101.6-106.1 °C. ^FH NMR (acetoned^/300 MHz) 7.97 (d, IH, J = 2.2 Hz), 7.95 (s, IH), 7.82 (dd, IH, J = 8.5, 2.0Hz), 7.24 (d, IH, J = 8.5 Hz), 6.01 (q, IH, J = 7.1 Hz), 4.38-4.24 (m, 2H), 1.34 (t, 3H, 7.3

Hz). FABLRMS m/z 298 (M+H). EIHRMS m/z 297.0575 (M+, Calc'd 297.0613).

Step 3. Preparation of 6-cvano-2-(trifluoromethyl)-2H-1benzopvran-3-carboxvlic acid.

To a stirred solution of the ester (Step 2)(0.077 g,

0.259 mmol) in THF-EtOH-H₂O (7:2:1, 2 mL) in a 5 mL pearshaped flask was added aqueous NaOH (0.13 mL, 2.5 N solution) in one portion. After stirring for 6 hours at room temperature the solution was partially concentrated in vacuo to remove most of the THF and EtOH. The resulting solution was diluted with H₂O and washed with diethyl ether. The resulting aqueous phase was sparged with nitrogen to remove trace diethyl ether and was acidified with concentrated HCl yielding a sticky suspension. The suspension was extracted with diethyl ether and the ether was dried over MgSO₄, filtered and concentrated in vacuo yielding a pale yellow oil. This oil was crystallized from methylene chloride-hexanes yielding the title compound (0.041 g, 59 %) as a tan powder: mp 185.1-186.1 °C. ^FH NMR (acetone-d^/300 MHz) 7.99-7.94 (m, 2H), 7.83 (dd, IH, J =

8.5, 2.0 Hz), 7.25 (d, IH, J = 8.5 Hz), 5.99 (q, IH, J= 7.0 Hz). FABLRMS m/z 270 (M+H). EIHRMS m/z 269.0316 (M+, Calc'd 269.0300).

LL 9 t. 0 / 6 6 zJ/dV

EXAMPLE 80

146

<img file="AP1149A_D0103.tif" />

6-Hydroxymethyl-2- (trif luorome thyl) -2H-l-ben.zopyran.-3carbo;«ylic acid

To a chilled (ice bath), stirred solution of 6-formyl2- (trifluoromethyl) -2H-l-ben zopyran-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 Na3H„ (0.020 g, 0.528 mmol) in two portions. The reaction was allowed to warm to room temperature and more NaBH₄ (0.050 g, 1.322 mmol) was added. The total reaction time was 3 hours. The reaction was quenched wdth aqueous HCI (1 N solution) and was extracted with chloroform. The organic phase was dried over MgSO₄, filtered ar. d concentrated in vacuo yielding a foam. This crude product was purified by flash chromatography (silica gel 60, eluant 1:1, hexane-ethyl Acetate with 2 % acetic acid). The product collected from the chromatography was recrystallized from hexanes and ethyl acetate, and collected by vacuum filtration yielding the title compound (0.042 g, 31 %) as a very pale yellow powder: mp 177.5-180.8 °C. ¹H NMR (c.cetone-d^/3 00 MHz) 7.89 (s,

1H) , 7.44 (s, 1H) , 7.41 (d, 2H, J = 8.3 Hz), 6.99 (d, 1H, J = 8.3Hz), 5.80 (q, 1H, J= 7.3 Hz), 4.59 (s, 2H). FABLRMS m/z 275 (M+H). EIHRMS m/z 274.0417 (M+, Calc'd 274.0453). Anal. Calc'd for 2₁₂^H9^F3°4^{: C}' 52.57; H, 3.31. Found: C, 52.43; H, 3.34.

EXAMPLE 81 hf₂c.

<img file="AP1149A_D0104.tif" />

ΑΡυ ϋ 1 ns

147

6- (Difluoromethyl) -2- (trif luorome thyl) -2H-l-benzopyran-3carboxylic acid

Step 1. Preparation of ethvi 6-(alfluoromethvl)-2(trifluorornethyl)-2H-l-benzopyran-3-carboxylate .

Ethyl 6-formyl-2-trifluoromethyl-2H-l-benzopyran-3carboxylate (Example 75, Step 1)(1.672 g, 5.569 mmol) in methylene chloride (1.5 mL) was added to methylene chloride (1.5 mL) and diethylaminosulfur trifluoride (DAST) (0.74 mL, 0.898 g, 5.569 mmol) over 0.07 hours via syringe. After stirring for 20 hours the reaction was poured into aqueous HCI (2.0 N) and the mixture was extracted with diethyl ether. The ethereal phase was washed with dilute aqueous HCI (2.0 N), saturated NaHCO₃ solution, brine, dried over MgSO₄, filtered and concentrated in vacuo yielding a clear colorless oil. This oil was purified by flash chromatography (Silica gel 60, Eluant (5:1; Hexanes : Ethyl Acetate) yielding ethyl 6-dif luoromethyl-2-trif luoromethyl2H-l-benzopyran-3-carboxylate (0.96 g, 54 %) as an oil which solidified upon standing. This product was of sufficient purity to be used in the next step without further purification:

7.74 (s, IH), Hz), 6.90 (t, 4.40-4.25 (m, ¹H NMR (acetone-d^/300 MHz) 7.97 (s, IH) ,

7.65 (d, IH, J = 8.5 Hz), 7.18 (d, IH, J = 8.5 IH, J = 56.0 Hz), 5.94 (q, IH, J = 7.0 Hz) ,

2H), 1.34 (t, 3H, J = 7.0 Hz).

AP/?,’ 99*01677

Step 2. Preparation of 6-(difluoromethvl)-2(trifluoromethvl)-2H-l-benzopyran-3-carboxylic acid.

Aqueous NaOH (1.31 mL, 3.277 mmol, 2.5 M solution) was added in one portion to the ester (Step 1)(0.880 g, 2.731 mmol) in THF:EtOH:H₂O (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 was diluted with H₂O. The resulting aqueous solution was washed with diethyl ether, sparged with nitrogen to remove trace ether, and acidified with concentrated HCI. The resulting oily suspension was

148 extracted with diethyl ether. The combined organic phases were dried over MgSO₄, filtered and concentrated in vacuo yielding the title compound (0.483 c, 60%) as an oil which solidified as a white crystalline mass: mp 134.7-136.2 °C.. !h NMR (acetone-dg-/3 00 MHz! 7.97 (s, IH) , 7.73 (s, IH) , 7.67 (dd, IH, J = 8.5, 1.0 Hz), 7.17 (d, IH, J= 8.,5 Hz), 6.89( t, IK, J = 56.2 Hz), 5.90 iq, IH, J = 7.1 Hz). FAB-ESLRMS m/z 293 (M-H). EIHRMS m/z 293.0235 (M-H, Calc'd 293.0237). Anal. Calc'd for C^^FgC^: C, 49.00; H, 2.40. Found: C, 48.78; H,2.21.

EXJ’lMPLE 82

<img file="AP1149A_D0105.tif" />

2,6-Bis (trifluoromethyl) -2 H-l-benzopyran-3-carboxylic acid

Step 1. Preparation of Ethyl 2,6-bis(trifluoromethyl)-4oxo-4H-l-benzopvran-3-carboxylate.

To a stirred solution of ethyl 4,4,4trifluoroacetoacetate (3.22 mL, 4.06 g, 22.07 mmol) in toluene (100 mL) was added portion-wise sodium hydride (0.971 g, of 60 % oil dispersion reagent, 22.07 mmol) causing gas evolution. After gas evolution has subsided, 2fluoro-5-(trifluoromethyl)benzoyl chloride (5.00 g, 22.07 mmol) was added. The reaction was stirred at room temperature for 24 hours, then heated to 105 °C for 24 hours. After cooling to room temperature, the reaction was diluted with diethyl ether and the resulting solution was washed with H_;O and brine, dried over MgS0₄, filtered and concentrated in vacuo yielding a slightly sticky white solid. This solid was triturated with hexanes yielding the desired ester(3.05 g, 39 %) as a white powder: mp 116-120.1 °C. NMR (CDCl₃/300 MHz) 8.52 (d, 2H, J =1.6 Hz), 8.03

APO 0 114 8

149 (dd, 1H, J = 8.9, 2.2Hz), 7.71 (d, IK, 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. Calc'd for C₁₄HgFgO₄: C, 47.45; H, 2.28.

Found: C, 47.59; H, 2.43.

Step 2. Preparation of ethvl 2,6-bis(trifluoromethyl)-4oxo-dihydrobenzopyran-3-carboxvlate.

A 250 mL round bottom flask was charged with ethyl 2,6bis (trifluoromethyl) -benzopyran-4-one-3-carboxylate (Step 1) (2.307 g, 6.513 mmol) and THF (20 mL) yielding a pale yellow solution. Ethanol (20 mL) was added and the reaction chilled in an ice-salt bath. While maintaining the reaction temperature at below 9 °C, NaBH, (0.246 g, 6.513 mmol) was added in two portions and the mixture stirred 1 h. The crude reaction mixture was poured into a vigorously stirred mixture of ice (200 mL) and concentrated HCI (12 N, 5 mL) yielding a precipitate. Vacuum filtration of the resulting suspension yielded the desired keto ester (2.204 g, 87%) as faint pink powder of suitable purity to use in the next step without further purification: mp 71.8-76.9 °C. ^H NMR (acetone-dg/300 MHz) 12,71 (br s, 1H exch), 8.01 (d, 1H, J =

<td> 2.0 Hz), 8.01</td><td> (d,</td><td> 1H,</td><td> J = 2.0 Hz), 7.88</td><td> (dd, 1H, J = 8.7,</td>

<td> 1.8 Hz), 7.31</td><td> (d,</td><td> 1H,</td><td> J = 8.7Hz), 5.98</td><td> (q, 1H, J = 6.6 Hz),</td>

<td> 4.51-4.28 (m,</td><td> 2H)</td><td> , 1.</td><td> 35 (t, 3H, J = 7.0</td><td> Hz). FABLRMS m/z</td>

AP,?,' 9 9'0 1 6 77

355 (M-H). ESHRMS m/z 355.0394 (M-H, Calc'd 355.0405). Anal. Calc'd for C₁₄H₁QFgO₄: C, 47.21; H, 2.83. Found: C, 47.31; H.2.97.

Step 3. Preparation of ethvl 2,6-bis(trifluoromethvl)-4trifluoromethanesulfonato-2H-l-benzopyran-3-carboxvlate.

A 50 mL 3-neck Morton flask fitted with addition funnel, 2 stoppers was charged with 2.6-di-tertbutylpyridine (1.576 g, 1.50 mmol), methylene chloride (12 mL) , and then via syringe was added trifluoromethanesulfonic anhydride (1.08 mL, 1.80 g, 1.25 mmol). To this solution was added dropwise a solution the keto ester (Step 2) (1.822

150 g, 5.115 mmol) in methylene chloride (10 mL) over 0.33 h and the reaction stirred for 48 h. The resulting off-white suspension was transferred to a 100 mL round bottom flask and was concentrated in vacuo. The residue was suspended in diethyl ether (50 mL) and vacuum filtered to remove salts. The filtrate was further di'Luted with diethyl ether (50 mL) and was washed with ice cold HCI solution (2 N), brine, and dried over Na₂CO₃, filtered cind concentrated in vacuo yielding the desired triflate (1.64 g, 66%) as a tan clumpy powder of suitable purity tc use in the next step without further purification.

Step 4. Preparation of ethvl 2,6-bis(trifluoromethvl)-2H-1benzopvran-3-carboxylate.

A 25 mL pear flask was charged with LiCl (0.136 g,

3.219 mmol), affixed to a high vacuum line and heated with a heat gun removing superficial, water. The flask was allowed to cool to room temperature, and tetrakis(triphenylphosphine)palladium(0)(0.124 g, 0.107 mmol) and THF (2 mL) were added. A reflux condenser was affixed to the flask and the apparatus was purged with nitrogen. A solution of the triflate(Step 3)(0.524 g, 1.073 mmol)in THF (2 mL) and tri-n-butyltin hydride (0.32 mL, 0.34 g, 1.18 mmol) were added sequentially via syringe. The resulting light orange solution was heated to 50 °C with stirring for 1 h, 60 °C for one hour, and 65 °C for one hour. The reaction was allowed to cool to room temperature and was poured into 2 N HCI, stirred, and extracted with hexanes.

The hexane phase was dried over MgSO₄, filtered and concentrated yielding a light brown oil. The oil was dissolved in hexane and was washed with aqueous ammonium fluoride solution. The resulting hexane phase was dried over MgSO₄, filtered and concentrated in vacuo yielding a dull yellow oily solid which solidified as a flaky powder (0.443 g). This solid was purified by flash silica chromatography (eluant: hexanes-methylene chloride, 4:1) yielding ethyl 2,6-di-trifluoromethyl-2H-l-benzopyran-3APO 0 114 9

151 carboxylate(Ο .069 g, 19 %) as a white crystalline solid of suitable purity to proceed with the next step.

Steo 5. Preparation of-2,6-bis(trifluoromethvl)-2H-lfaenzopvran-3-carboxylic acid.

To a stirred solution of the ester (Step 4) (0.065 g,

0.191 mmol) in THF-EtOH-HjO (7:2:1, 1 mL) was added NaOH solution (0.084 mL, 0.210 mmol)in one portion at room temperature and allowed to' stir overnight. The reaction was partially concentrated in vacuo yielding a pale yellow clear syrup. The syrup was diluted with water (5 mL) and brine (ImL) and was washed with diethyl ether (3X5 mL) . The resulting aqueous phase was sparged with nitrogen to remove trace ether. With stirring, concentrated HCI was added to the aqueous phase causing the formation of a very fine white precipitate. This suspension was extracted with diethyl ether and the ether dried over Na₅SO₄, filtered, and concentrated by slow evaporation at atmospheric pressure.

The resulting product was recrystallized from hexanes and ethyl acetate yielding the title compound (0.038 g, 64 %) as a fine tan powder: mp 143.5-145.2 °C. NMR (acetoned₆/300 MHz) 11.97-11.67 (br s, 1H), 8.03 (s, 1H), 7.92 (s,

1H) , 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, Calc'd 311.0143).

EXAMPLE 83

<img file="AP1149A_D0106.tif" />

APT,' 9 9 / 0 1 6 77 , 6,7-Trichloro-2- (trif luor ome thyl) -2H-l-ben.zopyran.-3carboxylic acid.

152

3, 4, 5-Trichlorophenol was conve rted to 4, 5, 6-trichlorosalicylaldehyde via a procedure similar to that described in example 11, Step 1.

The 4, 5. 6-trichlrosalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp

236.2-239.3 °C. ¹HNMR (ei,cetone-dg-/3 0 0 MHz) 8.05 (s, 1H) ,

7.40 (s, 1H), 5.99 (q, 1H, J - 7.0 Hz). ESLRMS m/z 345 (ΜΗ). ESHRMS m/z 344.9113 (M-H, Calc'd 344.9100). Anal. Calc'd for CiiH₄Cl₃F₃O₃ + 0.89 wt % HjO: C, 37.68; H, 1.25; Cl, 30.33. Found: C, 37.48; H,1.25; Cl, 30.33.

EXAMPLE 84

<img file="AP1149A_D0107.tif" />

5,7, S-Trichloro-2- (trii luoromethyl) -2H-l-benzopyran-3carboxylic acid

2, 3, 4-Trichlorophenol was converted to 3, 4, 5-trichlorosalicylaldehyde via a procedure similar to that described : n Example 11, Step 1.

The 3, 4, 5-trichlrosalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp

222.0-225.3 °C. NMR (a::etone-d£/300 MHz) 7.94 (s, 1H) ,

7.78 (s, 1H), 6.07 (q, 1H, J = 7.0 Hz). ESLRMS m/z 345 (ΜΗ). EIHRMS m/z 344.9117 (M-H, Calc'd 344.9100). Anal. Calc'd for C₁₁H₄C1₃F₃O₃ +- :..56 wt % Κ,Ο: C, 37.43; H, 1.32; Cl, 30.13. Found: C, 37.79; H,0.93; Cl, 29.55.

EXAMPLE 85

AP Ο Ο 1 14 9

<img file="AP1149A_D0108.tif" />

7-Ethyl-2-trif luoromethyl-2H-l-benzopyran-3carboxylic 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. NMR (CDC1₃/300 MHz) 7.84 (s, 1H), 7.15 (d, 1H, J= 7.5

Hz), 6.84 (m, 2H), 5.66 (q, 1H, 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. Calc'd for C₁₃H₁₁F₃O₃: C, 57.36; H, 4.07. Found: C, 57.25; H, 4.10.

EXAMPLE 86

<img file="AP1149A_D0109.tif" />

APT/ 99/01677

6-(Methylsulfinyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid

Step 1. Preparation of ethyl 6-(methvlsulfinvl)-2(trifluoromethyl)-2H-l-benzopyran-3-carboxylate.

Ethyl 6-(methylthio)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylate (Example 2, Step 2) (1.014 g, 3.18 mmol) in methylene chloride was chilled to -50 °C (dry ice acetone). With stirring, meta-chloroperbenzoic acid (0.91 g of 60 % reagent, 3.18 mmol) was added and reaction allowed to proceed for 3 hours. Aqueous NaHSO₃ solution (40 mL 0.25 M) was poured into the reaction. More methylene chloride was added and the layers mixed, then separated. The organic

154 phase was washed with aqueous NaHSO₃ solution, aqueous saturated NaHCO₃ solution, brine, dried over MgSO₄, filtered and concentrated yielding an oil. The oil was diluted with isooctane (2 mL) and concentrated yielding an oil which upon standing crystallized. Hexanes was added, the solution was heated, and methylene ch..oride added until partial dissolution occurred. After cooling and standing overnight the suspension was vacuum filtered yielding the sulfoxide substituted ethyl ester 10.753 g, 71%) as white needles: mp 92.2-98.4 °C. This ester was of sufficient purity to be used without further purification.

Step 2. Preparation of 6-(methylsulfinvl)-2 (trifluoromethyl)-2H-l-benzopyran-3-carboxvlic acid.

To a stirred solution of the ester (Step 1)(0.683 g, 2.043 mmol) in THF:EtOH:F₂O (7:2:1, 4 mL) was added aqueous NaOH solution (0.98 mL of 2.5 M, 2.45 mmol). After stirring 12 hours, the reaction was partially concentrated in vacuo to remove the organic solvents. The residue was diluted with H₂O, washed with diechyl ether, sparged with nitrogen to remove trace diethyl ether, and acidified with concentrated HCI yielding a oily suspension. The suspension was extracted with diethyl ether, and the resulting organic phase dried over MgSO4, filtered, and diluted with hexanes. Upon concentration in vacuo the title acid was obtained as a sticky white powder(0.425 g, 68 %): mp 148.3-151.0 °C.

NMR (acetone-d^/300 MHz) 7.99 (s, 1H), 7.82 (s, 1H), 7.787.68 (m, 1H) , 7.24 (d, 1H.. J = 8.3 Hz), 5.92 (q, 1H, J = 7.1 Hz), 2.73 (s, 3H) . FABLRMS m/z 307 (M+H). ESHRMS m/z 305.0098 (M-H, Calc'd 305.0095). Anal. Calc'd for ^C12^H9^F3°4^S1^{: C}' 47.06; H, 2.96; S, 10.47. Found: C, 46.69; H,2.86; S, 10.45.

EXAMPLE 87

ΑΡΟΟΙ149

155

<img file="AP1149A_D0110.tif" />

5,8-Dichloro-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid

2,5-Dichlorophenol was converted to 3,6dichlorosalicylaldehyde via a procedure similar to that described in Example 2, Step 1. The 3,6dichlorosalicylaldehyde was converted to the title compound by a similar procedure to that described in Example 11,

Steps 2 &amp; 3 : mp 205.7-207.1 °C. ¹H NMR (acetone-d^/300 MHz)

8.02 (s, 1H), 7.53 (d, 1H, J = 8.7 Hz), 7.22 (d, 1H, J= 8.7 Hz), 6.04 (q, 1H, J= 7.1 Hz). FABLRMS m/z 311 (M-H). ESHRMS m/z 310.9506 (M-H, Calc'd 310.9490). Anal. Calc'd for C₁₁H₅Cl₂F3O3 + 0.63 wt % H₂O; C, 41.94; H, 1.67. Found: C, 41.54; H,1.27.

EXAMPLE 88

<img file="AP1149A_D0111.tif" />

AP/77-9 9 / 0 1 6 77

6-(Pentafluoroethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3carboxylic acid

Step 1. Preparation of ethyl 6-(pentafluoroethvl)-2(trifluoromethvl)-2H-l-benzopyran-3-carboxvlate.

Potassium pentafluoropropionate (0.476 g, 2.35 mmol) was dissolved in toluene (6 mL) and DMF (6 mL). The vessel was fitted with a distilling head, and Cul (0.471 g, 2.474 ^smmol) was added with stirring. The reaction was heated to

156

120 °C, removing the toluene by distillation. Ethyl 6-iodo2- (trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 72, Step 3)(0.469 g, 1.108 mmol) was added and the reaction was heated to 150 °C for 2 hours. The reaction was allowed to cool to room temperature and was partitioned between diethyl ether and H₂O. The organic phase was dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel 60, eluant: hexanes- ethyl acetate, 8:1) yielding, upon concentration of the solution, the desired ester (0.096 g, 21%) as a tan solid mass of suitable purity to use without further purification: NMR. (acetone-dg/300 MHz) 8.04 (s,

IH) , 7.91 (d, IH, J = 2.2 Hz) , 7.74 (dd, IH, J = 8.7, 2.2 Hz), 6.00 (q, IH, J =7.1 Hz), 4.42-4.24 (m, 2H), 1.34 (t,

3H, J = 7.3 Hz).

Steo 2. Preparation of 6-(pentaflu.oroethvl)-2(trifluoromethyl) -2H-l-benzopvran-3-carboxylic acid.

To a stirred solution of the ethyl ester (Step 1)(0.090 g, 0.231 mmol) in THF :EtOH:H₂O (7 :2 :1) (4 mL) was added aqueous NaOH solution (0.11 mL, 2.5 M) . After stirring 16 hours, the reaction was partially concentrated in vacuo to remove the organic solvents, diluted with H₂O, and washed with diethyl ether. The resulting aqueous phase was acidified with concentrated HCI, extracted with diethyl ether, dried over MgS0₄, filtered and concentrated in vacuo yielding an oil. The oil was purified by flash chromatography (silica, hexanes-ethyl acetate, 3:1 with 5 % acetic acid). This procedure yielded the title acid (0.020 g, 24 %) as a white powder: mp 162.3-164.7 °C. ^-H NMR (acetone-dg/300 MHz) 8.05 (s, IH) , 7.90 (s, IH) , 7.74 (d,

IH, J = 8.7 Hz), 7.29 (d, IH, J = 8.7 Hz), 5.97 (q, IH, J =

6.8 Hz). FABLRMS m/z 361 (M-H) . ESHRMS m/z 361.0111 (M-H, Calc'd 361.0094).

Apo 0 114 9

157

EXAMPLE 89

<img file="AP1149A_D0112.tif" />

6-(1, 1-Dimethylethyl) -2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic 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. NMR (acetone-d₆/300 MHz) 7.89 (s, IH) ,

7.5-7.4 (m, 2H) , 6.93 (d, IH, J = 8.4 Hz), 5.76 (q, IH, J = 7.2 Hz), 1-3 (s, 9H) . Anal. Calc'd for C₁₅H₁₅O₃F₃: C, 60.00;

H, 5.04. Found: C, 59.93; H, 5.12.

EXAMPLE 90

<img file="AP1149A_D0113.tif" />

ΑΡ/Γ7 99/01677

5- (Hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H20 pyrano[2,3-c]pyridine-3-carboxylic acid

3-Hydroxylmethyl-5-methyl-4-formylpyridine was converted to the title compound by a procedure similar to that described in Example 1: mp 76.1-80.1 °C. ^XH NMR (acetone-d^/300 MHz) 8.15 (s, 2H), 5.93 (q, IH, J = 7.2

Hz), 1.3 (s, 9H) 5.30 (br s, IH), 4.79 (br s, IH), 2.41 (s, 3H). ESHRMS m/z 288.0485 (M+H, Calc'd 288.0483).

158

EXAMPLE 91

Ο

<img file="AP1149A_D0114.tif" />

‘0 cf₃

ΌΗ

2- (Trifluoromethyl) -6- [ (trif luoromethyl) thio] -2H-1benzopyran-3-carboxylic acid

4-(Trifluoromethoxy)phenol was converted to 5(trifluoromethoxy)salicylaldehyde via a procedure similar to that described in Example 2, Step 1. The 5(trifluoromethoxy)salicylaldehyde was converted to the title compound by a similar procedure to that described in Example 11, Steps 2 5:3: mp 139.1-143.2 °C. ³H NMR (acetone-d^/300

MHz) 7.95 (s, IH), 7.88 id, 2H, J =2.4 Hz), 7.71-7.75 (m, IH) , 6.93 (d, IH, J = 8.7 Hz) , 5.91 (q, IH, J = 6.9 Hz) . Anal. Calc'd for C₁₂H₆O₃F₃S: C, 41.87; H, 1.76. Found: C, 41.94; H, 1.84.

E&gt;,SAMPLE 92 ‘OH

6- (Trifluoromethyl) 3-dioxolo [4,5-g] [1]benzopyran-7carboxylic 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 H NMR (ace1:.one-d^/300 MHz) 7.77 (s, IH) , 6.95 (s, IH) , 6.12 (s, IH) , 6.05 (d, 2H, J= 0.90 Hz), 5.91

APO01149

159 (q, 1H, J = 7.2 Hz). Anal. Calc'd for C₁₂H₇O₅F₃: C, 50.01; H, 2.45. Found: C, 50.02; H, 2.50.

EXAMPLE 93

<img file="AP1149A_D0115.tif" />

8-Ethoxy-2-trif luoromethyl-2H-1-benz opyr an-3 carboxylic acid

2-Ethoxyphenol was converted to 3-ethoxysalicylaldehyde via a procedure similar to that described in Example 11,

Step 1. The 3-ethoxysalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 159.4-160.9 °C. NMR (acetone-d₅/300 MHz)

7.86 (s, IH), 6.97-7.14 (m, 3H) , 5.83 (q _H__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, Calc'd 289.0686). Anal. Calc'd for C₁₃H_l:LF3O4: C, 54.17; H, 3.85. Found: C, 54.06; H,

3.83.

L L 9 I 0 / 6 6 . J/d V

EXAMPLE 94 o

OH cr cf₃ xoi

6-Chloro-2,7-bis (trif luoromethyl) -2H-l-benzopyran-3carboxylic acid

160

4-Chloro-3- (trifluoromethyl)phenol was converted to the title compound by a procedure similar to that described in Example 11: mp 180.9-182.4 °C. ^XH NMR (acetone-dg-/300 MHz)

7.96 (s, 1H) , 7.84 (s, lli), 7.47 (s, 1H) , 5.96 (q, 1H, J’ =

6.8 Hz), 2.50 (s, 3H) . FABLRMS m/z 345 (M-H). FABHRMS m/z 344.9767 (M-H, Calc'd 344.9753). Anal. Calc'd for

C₁₂H₅ClF_sO₃: C, 41.58; H, 3..45,- Cl, 10.23. Found: C, 41.57;

H, 1.50; Cl, 10.33.

EXAMPLE 95

<img file="AP1149A_D0116.tif" />

5-Methoxy-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid

6-Methoxysalicylalde.hyde was converted to the title compound by a similar procedure to that described in Example 11, Steps 2 &amp; 3: mp 204.5^:.-206.7 °C. ^XH NMR (acetone-d^/300

MHz) 8.08 (s, 1H), 7.38 (dd, 1H, J = 8.5 Hz 8.3 Hz), 6.74 (d, 1H, J= 8.5 Hz), 6.65 (d, 1H, J= 8.3 Hz), 5.80 (q, 1H,

J = 7.2 Hz), 3.94 (s, 3H). FABLRMS m/z 273 (M-H). EIHRMS m/z 274.0444 (M+, Calc'd 274.0453). Anal. Calc'd for C₁₂H₉F₃O₄: C, 52.57; H, 3.31. Found: C, 52.47; H, 3.34.

EXAMPLE 96

<img file="AP1149A_D0117.tif" />

AP0 Ο 1 14 9

161

6-Benzoyl-2- (trif luoromethyl) -2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of ethvl 6-benzovl-2- (trifluoromethvl) 5 2H-l-benzopyran-3-carboxvlate.

Ethyl 2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylate (Example 10, Step 1)(1.59 g, 5.8 mmol) was dissolved in 1,2dichloroethane (3 mL) and added to a 0 °C suspension of aluminum chloride (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 HCI and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCI, saturated sodium bicarbonate, brine, dried over MgSO₄ and concentrated in vacuo. The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to afford the ester as a white crystalline solid (0.26 g, 12%): mp 114.7-116.1 °C. ^XH

NMR (CDC1₃/300MHz) 7.82 (dd, 1H, 8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J= 8.7 Hz), 5.79 (q, 1H, J = 6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J = 7.2 Hz) .

Step 2. Preparation of 6-benzovl-2-trifluoromethvl-2H-lbenzopvran-3-carboxvlic acid.

The ester from Step 1 (0.24 g, 0.64 mmol) was dissolved in THF (2 mL) and ethanol (2 mL), treated with 2.5 N sodium , hydroxide (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 HCI yielding a solid. The solid was collected by filtration and was recrystallized from ethanol-water to yield a white solid (0.14 g, 64%): mp 269.8-270.8 °C. ^XH NMR (acetone-d£/300

MHz) 8.04 (s, 1H), 7.99 (d, 1H, J = 2.0 Hz), 7.88 (dd, 1H, J = 8.5 Hz 2.0 Hz), 7.79 (m, 2H), 7.68 (m, 1H), 7.57 (m, 1H),

ΑΡ/Γ7 9 9 A0 1 6 77

162

7.23 (d, 1H, J=8.6Hz), 5.98 (q, IH, J=7.0Hz). FABLRMS m/z 347 (M-H). ESHRMS m/z 347.0560 (M-H, Calc'd 347.0531). Anal. Calc'd for C₁₈H_UF₃O₄: C, 62.08; H, 3.18. Found: C, 61.48; H, 3.22.

EXAMPLE 97

<img file="AP1149A_D0118.tif" />

6- (4-Chlorobenzoyl) -2- (trifluoromethyi) -2H-1-benzopyran-3carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared analogous to the procedure described in Example 96: mp 268.3-269.4 °C. ^lH NMR (acetone-d^/300 MHz) 8.03 (s, IH),

7.99 (d, IH, J = 2.0 Hz), 7.89 (dd, 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, IH, J = 8.5 Hz), 5.98 (q, IH, J = 7.1 Hz) . FABLRMS m/z 381 (M-H). ESHRMS m/z 381.0135 (M-H, Calc'd 381.0141). Anal. Calc'd for C₁₈H₁₀ClF₃O₄: C, 55.49; H, 2.63; Cl, 9.26. Found:

C, 56.35; H, 2.66; Cl, 9.34.

EXAMPLE 98

<img file="AP1149A_D0119.tif" />

6- (4-Hydroxybenzoyl) -2- (tr if luoromethyl) - 2 H-l-benzopyran- 3carboxylic acid

APU 0 114 9

163

The 2H-l-benzopyran-3-carboxylic acid was prepared analogous to the procedure described in Example 96: mp 234.0-239.5 °C. NMR (acetone-d£/300 MHz) 8.03 (s, IH) ,

7.92 (d, 1H, J = 2.0 Hz), 7.83 (dd, IH, J = 8.5 Hz 2.0 Hz),

7.74 (d, 2H, J = 8.7 Hz), 7.20 (d, IH, J = 8.5 Hz), 7.00 (d, IH, J = 8.7 Hz) , 5.94 (q, IH, J = 7.1 Hz) . ESHRMS m/z 363.0471 (M-H, Calc'd 363.0480).

EXAMPLE 99

<img file="AP1149A_D0120.tif" />

£19 10/66

6-Phenoxy-2- (trifiuoromethyl) -2H-1-benzopyran-3-carboxylic acid

4-Phenoxyphenol was converted to 5phenoxysalicylaldehyde by a similar procedure to that described in Example 2, Step 1. 5-Phenoxysalicylaldehyde was converted into the title compound by a similar procedure t * «· to that described in Example 11, Steps 2 &amp; 3: mp 184.9-186.4 ςΤ °C. Ή NMR (acetone-d^/300 MHz) 7.90 (s, IH) , 7.39 (m, 2H) ,

7.20 (d, IH, J =2.0 Hz), 7.08 (m, 3H) , 7.02 (m, 2H), 5.98 (q, IH, J = 7.2 Hz). FABLRMS m/z 335 (M-H). FABHRMS m/z 337.0663 (M+H, Calc'd 337.0687). Anal. Calc'd for C₁₇H_UF₃O₄:

C, 60.72; H, 3.30. Found: C, 60.62; H, 3.29.

EXAMPLE 100

<img file="AP1149A_D0121.tif" />

164

8-Ch.loro-6- (4-ch.loropbanoxy) -2-trifluoromethyl) -2H-1benzopyraj:t-3-carboxylic acid

Step 1. Preparation of 5-phenoxvsalicvlaldehvde.

Ethyl magnesium bromide (67.5 mL of an approximately

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 diethyl ether (35 mL) was added resulting in the evolution of gas. The reaction was heated to 80 °C causing distillation of the diethyl ether. Toluene (300 mL) , HMPA (23.4 mL, 24.059 g, 134.26 mmol), and paraformaldehyde (10.07 g, 335.65 mmol) were added and the reaction was heated to 85 °C for 4 hours. The reaction was cooled to room temperature and was acidified with 2N HCI.

The resulting layers were separated and the organic phase 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 yielding a yellow oil. The oil was purified by silica flash chromatography (hexanes-ethyl acetate, 95:5). Concentration in vacuo of the desired fractions provided the salicylaldehyde as a pale yellow powder (12.0 g, 42%', of suitable purity to use in subsequent steps .

Step 2. Preparation of 3-chloro-5-(4chlorophenoxv)salicylaldehyde.

To a stirred solution of the salicylaldehyde (Step 1)(

0.981 g, 4.58 mmol) in aceiic acid (20 mL) was added chlorine gas via a tube un7.il the yellow color of chlorine persisted. After stirring for four hours at room temperature the reaction was sparged with nitrogen and diluted with water (50 mL) . The resulting oily suspension was extracted with methylene chloride. The methylene chloride phase was washed with sodium bisulfite solution, dried over MgSO₄, filtered and concentrated in vacuo

APU 0 114 9

165 providing the dichlorinated salicylaldehyde as a yellow oil (0.66 g, 51%) of suitable purity for use in subsequent steps without further purification.

5, Step 3. Preparation of ethyl 8-chloro-6-(4-chlorophenoxv)2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylate.

A mixture of the dichlorinated salicylaldehyde (Step 2) (0.66 g, 2.3 mmol), triethylamine (0.49 g, 4.8 mmol), ethyl 4,4,4-trifluorocrotonate (0.59 g, 3.5 mmol) in dimethyl 10 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 3 N HCI (50 mL) , aqueous potassium carbonate solution (10 weight %, 2 X 30 mL), and brine. The organic 15 phase was dried over MgSO₄, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash silica chromatography (hexanes-ethyl acetate, 9:1) providing the substituted 2H-l-benzopyran (0.39 g, 39%) of suitable purity to use in subsequent steps without further 20 purification.

Step 4. Preparation of 8-chloro-6-(4-chlorophenoxv)-2(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid.

To a solution of the substituted 2H-l-benzopyran ethyl 25 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 HCI yielded a solid which was collected by vacuum filtration. This solid · 30 was recrystallized from ethanol-water yielding the title compound as yellow crystals (0.134 g, 38%): mp 227.8-228.9 °C. Έ NMR (acetone-d^/300 MHz) 7.93 (s, IH) , 7.42 (d, 2H, J = 8.9 Hz), 7.24 (s, 2H), 7.12 (d, 2H, J = 8.9 Hz), 5.97 (q,

IH, J = 7.1 Hz) . FABLRMS m/z 403 (M-H) . FABHRMS m/z

405,9790 (M+H, Calc' d 405.9801) . Anal. Calc'd for C₁₇H₉C1₂F₃O₄ ' + -2.33% H,O: C, 49.22; H, 2.45. Found: C, 49.19; H, 2.27.

LL 9 I 0 i6 6 , J/dy

166

EXAMPLE 101

<img file="AP1149A_D0122.tif" />

2- (Trifluoromethyl) -6- [4- (trifluoromethyl)phenoxy) -2H-1benzopyran-3-carboxylic acid

4- (4-Trif luoromethy lphenyl) phenol was converted to 5(4-trif luoromethylphenyl) salicylaldehyde via a procedure similar to that described i:i Example 2, Step 1. The 5-(4trifluoromethylphenyl)salicylaldehyde was converted to the title compound by a similar procedure to that described in Example 11, Steps 2 &amp; 3: mp 153.5-154.4 °C. ^lH NMR (acetoned^/300 MHz) 7.91 (s, 1H), 7.71 (d, 2H, J = 8.9 Hz), 7.33 (s, 1H, J = 2.8 Hz), 7.15 (m, 4E) , 5.86 (q, 1H, J = 7.1 Hz). FABLRMS m/z 403 (M-H) . ESHIiMS m/z 403.0399 (M-H, Calc'd 403.0405). Anal. Calc'd for C_lsH₁₀F₆O₄: C, 53.48; H, 2.49. Found: C, 53.52; H, 2.55.

EXAMPLE 102

<img file="AP1149A_D0123.tif" />

8- (l-Methylethyl) -2-tri:: luoromethyl-2H-lbenzopyran-3-carboxylic acid

4-(4-Methoxyphenyl)phenol was converted to the title compound by a procedure similar to that described in Example 2: mp 210.5-211.5 °C. NMR

ΑΡϋ 0 114 9

167

<td> (acetone-cJ^/300 MHz) 7</td><td> .86</td><td> (s,</td><td> IH), 7.35 (d, IH, J</td>

<td> = 7.7 Hz), 7.28 (s, IH</td><td> , J</td><td> = 7</td><td> .5 Hz), 7.04 (t, IH,</td>

<td> J = 7.7 Hz), 5.85 (q,</td><td> IH,</td><td> J =</td><td> 7.2 Hz), 3.33 (sept</td>

<td> IH, J = 7.1 Hz), 1.25</td><td> (d,</td><td> 6H,</td><td> J - 7.1 Hz) . Anal.</td>

<td> Calc'd for Ci4^Hi3^F3°3 :</td><td> c,</td><td> 58.</td><td> 74; H, 4.58. Found:</td>

C, 58.65; Η, 4.60.

EXAMPLE 103

<img file="AP1149A_D0124.tif" />

6-Chloro-8-(1-methylethyl) -2-trifluorometbyl-2H-lbenzopyran-3-carboxylic acid

8- (1-Methylethyl) -2- (trifluorornethyl) -2H-1benzopyran-3-carboxylic acid (Example 6) was converted to the title compound by a procedure similar to that described in Example 9. mp 185.4-

<td> 189.2 °C. ^-H</td><td> NMR</td><td> (acetone-d^/300</td><td> MHz) 7.87</td><td> (s,</td>

<td> IH), 7.38 (d,</td><td> IH,</td><td> J = 2.4 Hz), 7.</td><td> 34 (d, IH,</td><td> J =</td>

<td> 2.4 Hz), 5.90</td><td> (q,</td><td> IH, J = 7.3 Hz)</td><td> , 3.31 (m,</td><td> IH) ,</td>

<td> 1.24 (d, 6H,</td><td> j =</td><td> 6.8 Hz). Anal.</td><td> Calc'd for</td><td></td>

<td> C15H14CIF3O3:</td><td> c,</td><td> 52.43; H, 3.77;</td><td> Cl, 11.05.</td><td></td>

Found: C, 52.58; H, 3.79; Cl, 10.96.

£4910/66 , J/dV

EXAMPLE 104

<img file="AP1149A_D0125.tif" />

168

6- (4-Chlorophenoxy) -2- (trifluoromethyl)-2H-l-benzopyran-3carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared from 6-phenoxy-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid (Example 99) as the starting material by a procedure similar to that described in Example 9: mp 140.5-142.5 °C.

Ή NMR (acetone-dg-/3 00 MHz) 7.90 (s, 1H) , 7.39 (d, 2H, J = 9.1Hz), 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, Calc'd 369.0141). Anal. Calc'd for C₁₇H₁₀ClF₃O₄+ 0.96% H₂O: C, 54.55; H, 2.80. Found: C, 54.38; H, 2.90.

EXAMPLE 105

<img file="AP1149A_D0126.tif" />

8-Chloro-2- (trifluoromethyl) -6- [4- (trifluoromethyl)phenoxy] 2H-l-benzopyr.;m-3-carboxylic acid

The benzopyran-3-carboxylic acid was prepared using 2(tri fluoromethyl) - 6- [4 - (tri fluoromethyl) phenoxy) -2H-1benzopyran-3-carboxylic acid (Example 101) as the starting material by a similar procedure to that described in Example 100: mp 223.7-226.0 °C. ^XH NMR (acetone-d₆/300 MHz) 7.94 (s,

1H), 7.74 (d, 2H, J = 8.5 Hz), 7.35 (m, 2H) 7.25 (d, 2H, J *

8.5 Hz), 6.00 (q, 1H, J =7.0 Hz). FABLRMS m/z 437 (M-H). ESHRMS m/z 437.0000 (M-H, Calc'd 437.0015). Anal. Calc'd for C₁₈H₉ClF_eO₄: C, 49.28; H, 2.07; Cl, 8.08. Found: C,

49.42; H, 2.12; Cl, 8.17.

APO 0 114 9

169

EXAMPLE 106

<img file="AP1149A_D0127.tif" />

3- (Trif luoromethyl) -3H-benzofuro[3,2-f ] [l]benzopyran-2carboxylic acid

2-Hydroxydibenzofuran was converted to the title compound by a procedure similar to that described in Example 2: mp 253.5-254.6 °C. ^XH NMR (acetone-d£/300 MHz) 8.54 (s,

1H) , 8.23 (d, 1H, J = 7.5 Hz), 7.71 (s, 1H) , 7.62 (m, 1H) , 7.50 (m, 1H) , 7.23 (d, 1H, 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, Calc'd 333.0375). Anal. Calc'd for C₁₇H₉F₃O₄: C, 61.09; H, 2.71. Found: C, 60.95; H, 2.80.

EXAMPLE 107

<img file="AP1149A_D0128.tif" />

ΑΡ/Γ' 9 9 ! 0 1 6 77

6-Chloro-8-cyano-2- (trifluoromethyl) -2H-1-benzopyran-3carboxylic acid

Step 1. Preparation of ethyl 6-chloro-8(hvdroxviminomethvl) -2- (trifluoromethvl) -2H-l-benzopvran-3carboxvlate.

Hydroxylamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate (1.50 g, 19.4 mmol), and a mixture of ethanol-water

170 (80:20, 15 mL) were stirred at room temperature for 0.4 hours. The aldehyde (Example 76, Step 3) (3.07 g, 9.0 mmol) was dissolved in a solution of ethanol-water (4:1, 25 mL) and added to this mixture and stirred at 100 °C for 1 hour. The reaction was filtered hot and the filtrate allowed to cool to room temperature. An orange solid crystallized in the filtrate which was collected by vacuum filtration. The solid was dissolved in ethyl acetate and the solution washed with water, brine, dried over MgSC\, concentrated in vacuo. The resulting solid was recrystallized from ethyl acetatehexane yielding the oxime as a tan powder (1.50 g, 47%) : mp

186.6-187.6 °C. ^XK NMR (e.cetone-d^/300 MHz) 10.87 (s, IH) ,

8.34 (s, IH), 7.90 (s, IH), 7.77 (d, IH, J = 2.6 Hz), 7.60 (d, IH, J = 2.6 Hz) , 6.02 (q, IH, J = 7.1 Hz) , 4.35 (m, 2H),

1.34 (t, 3H, J = 7.0 Hz).

Step 2. Preparation of ethyl 6-chloro-8-cvano-2trif luoromethyl-2H-1-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 ethyl acetate, washed with saturated NaHCO₃, brine, dried over MgSO₄, and concentrated ii: vacuo to give a brown oil (1.09 g) . The oil was purified by flash chromatography (10:1; hexanes: ethyl acetate) yielding upon concentration the title compound as a white solid (0.51 g, 88%): mp 114.6115.6 °C. H NMR (CDC1₃/3(SO MHz) 7.65 (s, IH) , 7.53 (d, IH,

J = 2.4 Hz), 7.44 (d, IH, J = 2.4 Hz), 5.87 (q, IH, J = 6.4 Hz), 4.36 (m, 2H) , 1.37 (::, 3H, J = 6.5 Hz).

Step 3. Preparation of 6-chloro-8-cvano-2(trifluoromethyl)-2H-l-be]tzopyran-3-carboxvlic acid.

The ester from Step 2 (0.51 g 1.5 mmol) was dissolved in THF (5 mL) and ethanol (5 mL) , treated with 2.5N sodium hydroxide (1.2 mL, 3.0 mmcl), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCI, extracted with

APOO1149

171 ethyl acetate, washed with water, brine, dried over MgSO₄, concentrated in vacuo, and recrystallized from diethyl ether /hexane to give a white powder (0.10 g, 21%): mp 238.1-239.7 °C. 'HNMR (acetone-d^/300 MHz) 7.97 (s, 1H) , 7.92 (d, 1H, J = 2.4 Hz), 7.89 (d, 1H, J = 2.4 Hz), 6.14 (q, 1H, J = 6.6 Hz). FABLRMS m/z 302 (M-H). ESHRMS m/z 301.9819 (M-H, Calc'd 301.9832). Anal. Calc'd for C₁₂H₅C1F₃NO₃: C, 47.47; H, 1.66; N, 4.61. Found: C, 47.41; H, 1.70; N, 4.55.

EXAMPLE 108

<img file="AP1149A_D0129.tif" />

6-Chloro-8- [ (hydr oxy imino) methyl] -2- (trifluoromethyl) -2H-1benzopyran-3-carboxylic acid

The 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: mp 246.9-247.9

AR'?,’ 9 9 / 0 1 6 77

<td> °C . H NMR</td><td> (acetone-d^/3 00</td><td> MHz)</td><td> 10.90 (brs, 1H), 8.35</td><td> (s, «ί</td>

<td> 1H), 7.92</td><td> (s, 1H), 7.78 (d,</td><td> 1H,</td><td> J = 2.6 Hz), 7.61 (d,</td><td> 1H, J</td>

<td> = 2.6 Hz),</td><td> 5.98 (q, 1H, J =</td><td> 7.0</td><td> Hz). FABLRMS m/z 320</td><td> (M-H) .</td>

ESHRMS m/z 319.9959 (M-H, Calc'd 319.9937). Anal. Calc'd for C₁₂H₇C1F₃NO₄: C, 44.81; H, 2.19; N, 4.35. Found: C, 44.92; H, 2.25; N, 4.26.

EXAMPLE 109

172

<img file="AP1149A_D0130.tif" />

6-Chloro-8- (hydroxymethyl) -2- (trifluoromethyl) -2H-1benzopyrar-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 80 using the carboxylic acid (Example 76, step 4) as the starting material: mp 174.6-178.9 °C. ^XH NMR (acetone10 d^/300 MHz) 7.90 (s, IH), 7.57 (d, IH, J = 2.6 Hz), 7.47 (d,

IH, J=2.6Hz), 5.87 (q, IH, J =7.0 Hz), 4.70 (s, 2H). FABLRMS m/z 309 (M+H). ESHRMS m/z 306.9981 (M-H, Calc'd 306.9985). Anal. Calc'd for C₁₂H_eClF₃O₃ (3.81 wt.% H₂O) : C, 47.37; H, 3.08. Found: C, 47.33; H, 2.82.

EXAMPLE 110

<img file="AP1149A_D0131.tif" />

8- (lH-Beazimidazol-2-yl) -6 -chloro-2- (trif luoromethyl) -2H-1benzopyran-3-carboxylic acid

Step 1. Preparation of ethyl 8-(lH-Benzimidazol-2-vl)-6chloro-2- (trif luoromethyl) -2H-l-benzopvran-3-carboxylate.

AP O 0 114 9

173

A solution of the aldehyde (Example 76, Step 3) (0.33 g, 0.99 mmol) and 1,2-phenylenediamine (0.11 g, 1.02 mmol) in nitrobenzene (20 mL) was heated to 150 °C for 1.8 hours. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgSO₄, and concentrated in vacuo and purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to give the ester as a brown solid (0.18 g, 43%) which was used in the next step without further purification.

Step 2. Preparation of 8-(lH-enzimidazol-2-vl)-6-chloro-2trifluoromethvl-2H-l-benzopvran-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 15 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 HCI, filtered and recrystallized from ethanol-water to give a tan solid (0.09 g, 52%) : mp &gt;300 °C. ^XH NMR (acetone-d^/300MHz) 8.59 (d, IH,

J = 2.6 Hz), 8.03 (s, IH), 7.73 (d, IH, J = 2.6 Hz), 7.67 (brs, 2H) , 7.28 (m, 2H) , 6.13 (q, IH, J= 6.8 Hz). FABLRMS m/z 395 (M-H{³⁷C1}). ESHRMS m/z 393.0262 (M-H, Calc'd 393.0254). Anal. Calc'd for C₁₈H₁₀ClF₃N₂O₃ (2.88 wt % H₂O) : C, 53.19; H, 2.80; N, 6.89. Found: C, 53.22; H, 2.90; N, 6.80.

EXAMPLE 111

<img file="AP1149A_D0132.tif" />

ΑΡ,'ΓΎ 9 9 Ό 1 6 77

7-(1, l-Dimethylethyl) -2- (pentafluoroethyl) -2H-l-benzopyran3-carboxylic acid

174

Step 1. Preparation of et.hvl 3-hvdroxv-4,4,5,5,5pentafluoropentanoate.

A solution of ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (41.32 g, 0.18 mole) in diethyl ether (70 mL) was cooled to 0 °C and treated with NaBH₄ (7.09 g, 0.19 mole).

The reaction was allowed to warm to room temperature and stirred for 2 hours before quenching with 1 N HCI (200 mL) . The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1 N HCI, urine, dried over MgSO₄, and concentrated in vacuo to g:.ve the hydroxy ester as a clear oil (46.40 g) which was used in the next step without further purification.

Step 2. Preparation of ethvl 4,4.5,5,5-pentafluoro-2pentenoate.

The hydroxy ester from Step 1 (46.40 g, 0.18 mole) was stirred at 120 °C with P₂O₅ (25.59 g, 0.09 mole) for 2.6 hours then vacuum distilled (95 torr, 45-64 °C) to give the ester as a clear oil (13,70 g, 35%) : ^XH NMR (CDCl₃/300 MHz) 6.78 (m, 1H) , 6.57 (dt, 1H, J = 15.9 Hz 2.0 Hz), 4.30 (q,

2H, J = 7.3 Hz), 1.34 (t, ΞΗ, J = 7.1 Hz).

Step 3. Preparation of ethyl 7-(1,1-Dimethvlethvl)-2(pentafluoroethvl) -2H-l-ber.zopyran-3-carboxylate.

A mixture of 4-fcerfc-bu tylsalicylaldehyde 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) . With stirring, K₂CO₃ (1.10 g, 9.0 mmol) was added causing the reaction to become deep red. The reaction was stirred at room temperature for 100 hours, acidified with 3 N HCI, diluted with ethyl acetate and washed with saturated NaHCO₃solution, brine, dried over MgSO , filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with. 10% ethyl acetate/hexanes to afford a yellow oil (1.72 g, 70%) : ^XH NMR (CDC1₃/300 MHz) 7.76 (s, 1H) , 7.14 (d, 1H, J= 8.1 Hz), 7.04

175 (dd, 1H, J = 8.1 Hz 1.8 Hz), 6.94 (s, 1H), 5.92 (dd, 1H, ΰ = 22.4 Hz 3.0 Hz) , 4.3 2 (m, 2H) , 1.3 5 (t, 3H, J = 7.2 Hz) ,

1.30 (s, 9H).

5teo 4. Preparation of 7-(1.1-Dimethvlethvl)-2(pentafluoroethvl) -2H-l-benzopyran-3-carboxvlic acid.

The ester from Step 3 (1.58 g 4.2 0 mmol) was dissolved 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 HCI yielding a suspension. The solid was collected by filtration and was recrystallized from ethanol-water to yield a yellow solid (0.76 g, 52%); mp 171.0-173.5 °C. H NMR (acetone-d_s/300 MHz) 7.93 (s, 1H) ,

7.39 (d, 1H, J = 8.1 Hz) , 7.18 (dd, IK, J = 8.1 Hz 1.8 Hz) , 7.02 (s, 1H) , 6.01 (dd, 1H, J= 23.1 Hz 3.2 Hz), 1.32 (s, 9 H) . FABLRMS m/z 351 (M+H) . STHRMS m/z 350.0945 (M+, Calc'd 350.0941). Anal. Calc'd for C₁₆H_X5F₅O₃: C, 54.86; H, 4.32. Found: C, 54.88; H, 4.32.

EXAMPLE 112

<img file="AP1149A_D0133.tif" />

6-Chloro-8- (methoxymethyl) -2- (trif luoromethyl) -2H-1benzopyran-3-carboxylic acid

Step 1. Preparation of ethvl 6-chloro-8-(hvdroxvmethvl)-2(trif luoromethyl) -2H-l-benzopvran-3-carboxvlate.

A suspension of the aldehyde (Example 76, Step 3) (4.78 g, 14.3 mmol) was cooled to 0 °C and treated with Na3H₄ (0.33 g, 4.8 mmol) . The solution was stirred for 10 minutes then

Δ 0 114 9

176

WO 98/473SC

PCT/US98/07677 quenched with 3N HCI, extracted with ethyl acetate, washed with saturated NaHCO₃, brine, dried over MgSO₄, and concentraced 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 c, 75^s:;) . '14 NM?. (CDC1₃/300 MHz) 7.66 (s, IK) , 7.41 (d, 1H, J = 2.4 Hz), 7.17 (d, 1H, J = 2.4 Hz),

5.75 (q, IK, u = 6.8 Hz), 4.71 (s, 2H) , 4.33 (m, 2H) , 1.85 (brs, IK), 1.36 (t, 3H, J - 7.1). This solid was used in the next step without further purification.

Steo 2. Preparation of el (tri f luorornethvl) -2H-l-bei

:.hyl 6-chloro-8- (methoxvmethvl) -2:.zoovran-3-carboxvlate .

:&gt; 1 (0.44 g, 1.3 mmol), silver ) and 2,6-di-tert-butylpyridine .ssolved in methylene chloride (3 ated with methyl iodide (0.40 g, :S allowed to warm and stirred at iours. The reaction was filtered λ and the filtrate was washed with brine, dried over MgSO„, and Iding a brown oil. This oil was

The alcohol from Ste triflate (0.36 g, 1.4 mmol (0.37 g, 1.9 mmol) were d: mL·) cooled to 0 °C and tre 2.8 mmol). The reaction w: room temperature for 4.6 1 through diatomaceous eartl 3N HCI, saturated NaKCO₃, concentrated in vacuo yie purified by flash chromatography ove: with 10% ethyl acetate-hexanes to af: 1-benzopyran (0.19 g, 41%: as a whit; for use without further purification 7.63 (s, 1H), 7.39 (d, 1H. J = 2.6 H: Hz), 5.72 (q, 1H, J = 6.8 Hz), 4.44 3.41 (s, 3H) , 1.85 (brs, IK) , 1.33

<td> lica</td><td> gel, eluting</td>

<td> . the</td><td> substituted 2H</td>

<td colspan="2"> ly solid suitable</td>

<td> NMR</td><td> (CDCl₃/30 0 MHz)</td>

<td> 7.13</td><td> (d, 1H, «7=2.</td>

<td> 2H) ,</td><td> 4.30 (m, 2H),</td>

<td> H, J</td><td> = 7.1).</td>

9 /0 1 6 77 i .

Cu &lt;

Step 3, Preparation o~ 6-Chioro-8-(methoxymethyl)—2 — tn~luorornethvl — 2H—1 -benzoovran-3 —carbcxvlic acid.

The ester from Step 2 was hydrolyzed via a procedure similar to that described in Example 1, Step 2. mp 166.7168.0 °C. ^:H NMR (acetone-c^/300 MHz) 7.90 (s, 1H), 7.50 (d,

1H, J = 2.6), 7.46 (d, 1H, J = 2.4 Hz), 5.92 (q, 1H, J =

Hz), 4.49 (s, 2H) , 3.42 (;·;, 3H) . FABLRMS m/z 321 (M-H).

7.1

ΑΡ ο ο 1 1 4 8

177

ESHRMS m/z 321.0141 (M-H, Calc'd 321.0141). Anal. Calc'd for C₁₃H₁₀ClF₃O₄: C, 48.39; H, 3.12. Found: C, 48.45; H, 3.11.

EXAMPLE 113

<img file="AP1149A_D0134.tif" />

6-Chloro-8- (benzyloxymethyl) -2- (trif luoromethyl) -2H-1benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 112: mp

133.8-135.4 °C. ^XH NMR (acetone-d^/300 MHz) 7.90 (s, IH) ,

7.54 (d, IH, J = 2.6), 7.51 (d, IH, J = 2.4 Hz), 7.42 (m,

5H) , 5.91 (q, IH, J =7.1 Hz), 4.68 (s, 2H), 4.63 (s, 2H) . FABLRMS m/z 399 (M+H). ESHRMS m/z 397.0454 (M-H, Calc'd 397.0461). Anal. Calc'd for C₁₉H₁₃ClF₃O₄: C, 57.23; H, 3.54; Cl, 8.89. Found: C, 57.34; H, 3.63; Cl, 8.77.

EXAMPLE 114

<img file="AP1149A_D0135.tif" />

ΑΡ/Γ7 9 9 / 0 1 6 77

6-Chloro-8-ethenyl-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid

Step-1. Preparation of ethenvl-6-chloro-8-ethenvl-2(trifluoromethvl)-2H-l-benzopvran-3-carboxylate.

178

In a 100 mL round bottomed flask under N₂, ethyl 8bromo-6-chloro-2-trifluoromethyl-2H-benzopyran-3-carboxylate (Example 74, Step 1)(2.21 g, 5.73 mmol) was dissolved in toluene (30 mL of anhydrous reagent).

Tetrakis (triphenylphosphir.e)palladium(0) (0.132 g, 0.115 mmol) was added, followed by tributylethyenylstannane (2.0 g, 6.31 mmol). The resulting solution was heated to reflux for 5 hours. The reaction mixture was allowed to cool to room temperature, was poured into 50 mL of 20% ammonium fluoride solution and stirred 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 yield a yellow oil. The crude material was purified by flash chromatography(0.5% ethyl acetate in hexanes) to afford the ester as a yellow solid (0.86 g,

45%) : mp 75.9-77.2 °C. *H NMR (CDCl₃/300 MHz) 7.64 (s, IH) , 7.45 (d, IH, J = 2.5 Hz) , 'M2 (d, IH, J = 2.6 Hz) , 6.92 (dd, IH, J = 17.7 Hz, 11.3 Hz), 5.81 (d, IH, J = 17.7 Hz),

5.76 (q, IH, J = 6.8 Hz), '5.41 (d, 2H, J = 11.1 Hz), 4.3620 4.29 (m, 2H), 1.36 (t, 3H, J=1.3 Hz). FABLRMS m/z 350.1 (M+NHf). ESHRMS m/z 350.0796 (M+NH/, Calc'd. 350.0771).

Anal. Calc'd. for C₁₅H₁₂C1F₃C, + 4.07% H₂O: C, 51.95; H, 3.94.

Found:

C, 51.67; H, 3.69

Step 2 . Preparation of 6-t::hloro-8-ethenvl-2(trif luoromethyl) -2H-l~ben::;opyran-3-carboxylic acid.

The ester (Step 1) (0.350 g, 1.05 mmol) was dissolved in a solution of THF: ethane: 1:water (7 :2 :1; 10 mL) , was treated with sodium hydroxr.de (0.46 mL, 1.05 mmol of a 2.5 N solution), and stirred at room temperature for 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 acidified viith 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 MgSO&lt;, filtered, and evaporated to yield a yellow solid, which, was recrystallized in diethyl ether-hexane to afford the title compound as a yellow solid

APO Ο 1 14 9

179 (0.288 g, 90%); mp 183.2-185.8 °C. NMR (CDC1/300 MHz)

7.77 (s, IH), 7.49 (d, IH, J - 2.2 Hz), 7.16 (d, IH, J = 2.4 Hz), 6.93 (dd, IH, J = 11.3, 17.7 Hz), 5.82 (d, IH, J = 17.7 Hz), 5.74 (q, IH, J = 6.9 Hz), 5.43 (d, IH, J = 11.1 Hz). FABLRMS m/z 303 (M-H).. ESHRMS m/z 303.0014 (M-H, Calc'd. 303.003582). Anal. Calc'd. for C₁₃H_eClF₃O₃ + 1.58 % H₂O: C, 50.44; H, 2.78. Found: C, 50.42; H, 2.65.

EXAMPLE 115

<img file="AP1149A_D0136.tif" />

6-Chloro-8-ethynyl-2- (trifiuoromethyl) -2H-l-benzopyran-3carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 114: mp 186.2-189.0 °C. H NMR (acetone-d^/300 MHz) 7.87 (s, IH),

7.60 (d, IH, J = 2.4 Hz), 7.51 (d, IH, J = 2.4 Hz), 5.95 (q, IH, J= 7.0 Hz), 4.02 (s, IH). FABLRMS m/z 301 (M-H).

ESHRMS m/z 300.9875 (M-H, Calc'd 300.9879). Anal. Calc'd. for C₁₃H₆C1F₃O₃: C, 51.59; H, 2.00; Cl, 11.71. Found: C, 51.26; H, 2.06; Cl, 11.40.

AP/?/ 9 9 / 0 1 6 77

EXAMPLE 116

<img file="AP1149A_D0137.tif" />

s

180

6-Chloro-8- (2-thienyl) -2 - (trifluoromethyi) -2H-l-benzopyrsm3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 114: mp 257.5-258.8 °C. ^XH NMR (c.cetone-d^/300 MHz) 7.91 (s, IH) ,

7.79 (d, IH, J = 2.4 Hz), 7.74-7.72 (m, IH) , 7.62-7.61 (m,

IH) , 7.51 (d, IH, J = 2.4 Hz), 7.19-7.16 (m, IH) , 6.04 (q, IH, J = 7.1 Hz) . FABLRMS m/z 359 (M-H) . ESHRMS m/z 358.9747 (M-H, Calc'd. 358.9756). Anal. Calc'd. for C₁₅H₈C1F₃O₃S: C, 49.94; H, 2.24; Cl, 9.83; S, 8.89. Found:

C, 50.26; H, 2.45; Cl, 9.(2; S, 9.00.

EXAMPLE 117 ci

6-Chloro-8- (2-furanyl) -2- (trifluoromethyi) -2H-l-benzopyran3-carboxylic acid

The 2K-l-benzopyran-3-cart oxylic acid was prepared by a procedure similar to the method described in Example 114: mp

171.5-173.3 °C. ^XH NMR (acetone-d^/300 MHz) 7.93 (s, IH) ,

7.82 (d, IH, J= 2.6 Hz), 7.72-7.71 (m, IH) , 7.50 (d, IH, J = 2.6 Hz), 7.16 (d, IH, J = 2.4 Hz), 6.65-6.63 (m, IH) , 6.11 (q, IH, J = 7.1 Hz) . FABLRMS m/z 343 (M-H) . ESHRMS m/z 342.9995 (M-H, Calc'd. 342.9985). Anal. Calc'd. for C₁₅H₈C1F₃O₄+ 1.31 % HjO: C, 51.59; H, 2.46; Cl, 10.15. Found: C, 51.57; H, 2.33; Cl, 10.14.

EXAMPLE 118

AP C ΰ 1 14 9

<img file="AP1149A_D0138.tif" />

6-Chloro-8-(5-chloro-l-pentynyl)-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid

Step 1. Preparation of ethvl 6-chloro-8-(5-chloro-loentvnvl)-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxvlate.

Ethyl 6-chloro-8-iodo-2-trifluoromethyl-2H-1benzopyran-3-carboxylate (Example 73, Step 2) (1.50 g, 3.47 mmol), tetrakis-(triphenylphosphine)palladium(0) (0.2 g,

0.174 mmol), copper(I)iodide (0.066 g, 0.347 mmol), and triethylamine (1.05 g, 10.4 mmol) were dissolved, in toluene (50 mL). 5-Chloro-l-pentyne (0.53 g, 5.20 mmol) was added via syringe and the mixture stirred for 18 hours at room temperature. The reaction was diluted with diethyl ether (50 mL), extracted with 0.5 N HCI (2 x 25 mL), and water (2 x 25 mL). The organic phase was dried over MgSO₄, filtered, and evaporated to yield an orange oil. The crude material was purified by flash chromatography in 2% ethyl acetate in hexane. Recrystallization from hexane afforded the ester as a white solid (0.96 g, 68%): mp 84.8-85.9 °C. ^XH NMR (CDC1,/3OO MHz) 7.61 (s, 1H) , 7.33 (d, 1H, J = 2.6 Hz), 7.14 (d, 1H, J = 2.6 Hz), 5.79 (q, 1H, J = 6.7 Hz), 4.37-4.29 (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/). ESHRMS m/z 424.0694 (M+NH/, Calc'd.

424.0694). Anal. Calc'd. for C_ltH,₅Cl₂F₃O₃: C, 53.09; H,3.71;, Cl,17.41. Found: C, 53.02; H, 3.90; Cl, 17.63.

Step 2. Preparation of 6-chloro-8-(5-chloro-l-pentvnvl)-2(trifluoromethvl)-2H-l-benzopyran-3-carboxylic acid.

&gt; &gt; a

182

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 (0.45' mL, 1.23 mmol of a 2.5 N so-lution) , 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 acidified with concent.rated HCI. The organic layer was separated, and the aqt.eous phase was extracted with diethyl ether (2 x 10 mL) . The combined extracts were dried over MgSO₄, filtered, and evaporated to yield a yellow solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a yellow solid (0.371 g, 80%): mp 154.4-156.4 °C. ^XH NMR (acetone-dg/300 MHz) 7.88 (s, 1H) ,

7.53 (d, 1H, J= 2.4 Hz), 7.44 (d, 1H, 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, Calc'd. 376.9959). Anal. Calc'd. for C₁₆H₁₁C1.F₃O₃+ 1.18 % H₂O: C, 50.08; H, 3.02; Cl, 18.48.

Found: C, 50.11; H, 2.73; Cl, 18.28.

EXAMPLE 119

<img file="AP1149A_D0139.tif" />

6-Chloro-8- (1-pentynyl,) -2-(trif luoromethyl) -2H-l-benzopyran3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118: mp 168.1-171.2 °C. *H NMR (CDCl₃/300 MHz) 7.75 (s, 1H), 7.37 (d, 1H, J=2.6Hz), 7.15 (d, 1H, J= 2.4 Hz), 5.77 (1, 1H,

APO 0 1148

183

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. FA3LRMS m/z 345 (M+H). ESHRMS m/z 343.0373 (M-H, Calc'd. 343.0349). Anal. Calc'd.. for C₁₆H₁₂C1F₃O₃ + 0.69 % HjO: C, 55.36; H, 3.56. Found: C,

55.21; H, 3.62.

EXAMPLE 120

<img file="AP1149A_D0140.tif" />

6-Chloro-8- (phenylethynyl) -2- (trifluoromethyl) -2H-1benzopyran-3-carboxylic acid

The 2H-1-benzopyran-3-carboxylic acid was prepared by a 15 procedure similar to the method described in Example 118: mp

190.1-192.1 °C. NMR (CDCl₃/300 MHz) 7.92 (s, 1H) , 7.617.57 (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, Calc'd. 377.0192). Anal. Calc'd. for C₁₉H₁₀ClF₃O₃: C, 60.26; H, 2.66;

Cl, 9.36. Found: C, 60.09; H, 2.73; Cl, 9.09.

EXAMPLE 121

<img file="AP1149A_D0141.tif" />

APT/ 9 9 / 0 1 6 77

184

6-Chloro-8- (3,3-dimethyl-1-butynyl) -2- (trifluoromethyl)-2Hl-benzopyran-3-carboxylic acid £02

The 2H-l-benzopyrci.n-3-carboxylic acid was prepared by a procedure similar to the method described in Example 113: mp 218.3-222.4 °C. ³H NMR (acetone-dg/300 MHz) 7.87 (s, IH) ,

7.51 (d, IH, J = 2.4 Hz), 7.38 (d, IH, J = 2.6 Hz), 5.92 (q, IH, J = 6.9 Hz), 1.32 · s, 9H) . FABLRMS m/z 359 (M+H).

ESHRMS m/z 357.0490 (M-H, Calc'd. 357.0505). Anal. Calc'd.

C, 56.92; H, 3.93; Cl, 9.88. Found: C,

C₁₇H_UC1F₃O₃:

56.63; H, 3.94; Cl, 10.03

EXAMPLE 122

<img file="AP1149A_D0142.tif" />

6-Chloro-8- [ (4-chlorophenyl) ethynyl] -2- (trifluoromethyl) -2H1-benzopyran-3-carboxylic acid

The 2H-l-benzopyrc.n-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118: mp 210.4-211.4 °C. Ή NKR (CDC1₃/3 00 MHz) 7.75 (s, IH) , 7.487.43 (m, 3H) , 7.36 (s, IH) , 7.33 (s, IH) , 7.22 (d, IH, ,T = ' 2.6 Hz), 5.82 (q, IH, 0' = 6.6 Hz). FABLRMS m/z 411 (M-H). ESHRMS m/z 410.9802 (M-H, Calc'd. 410.980259). Anal.

Calc'd. for C₂₀H₁₂C₁₂F₃O₃: C, 55.23; H, 2.20; Cl, 17.16.

Found: C, 55.22; H, 2.07; Cl, 17.39.

EXAMPLE 123

ΑΡν 0 114 9

185

<img file="AP1149A_D0143.tif" />

6-Chloro-8- [ (4-methoxyphenyl) ethynyl] -2- (trifluoromethyl) 5 2 H-l-benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118: mp 217.7-218.7 °C. Ή NMR (CDCl₃/300 MHz) 7.75 (s, IH) , 7.5110 7.47 (m, 3H) , 7.18 (d, 1H, J= 2.4 Hz), 6.91-6.88 (m, 2H) ,

5.82 (1, IH, J = 6.7 Hz). ESLRMS m/z 407 (M-H). ESHRMS m/z 407.0293 (M-H, Calc'd 407.0298). Anal. Calc'd for

C_2CH,_sC1F₃O₄: C, 58.77; H, 2.96; Cl, 8.67. Found: C, 58.68;

H, 2.85; Cl, 9.15.

EXAMPLE 124

<img file="AP1149A_D0144.tif" />

ART/ 9 9 / 0 1 6 77

6- (Phenylethynyl) -2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118 using ethyl 6-iodo-2-(trif luoromethyl) -2H-l-benzopyran-3carboxylate (Example 24, Step 3) as the starting material:

186

<td colspan="2"> mp 240.1-241.3 °C.</td>

<td> IK) ,</td><td> 7.70-7.69 (m,</td>

<td> 3H) ,</td><td> 7.10 (d, IH,</td>

<td> Calc'</td><td> 'd. 343.0582).</td>

<td> 3.22</td><td> Found: C,</td>

’Ή NMR (acetone-d^/300 MHz) 7.94 (s,

IH) , '/.61-7.53 (m, 3H) , 7.44-7.41 (m,

J = 7 .:.. Hz). ESHRMS m/z 343.0550 (M-H,

Anal. Calc'd. for C.gH^FjO/. C, 66.29; 66.26; H, 3.29.

H,

Ei (CAMPLE 125

<img file="AP1149A_D0145.tif" />

S-Ch.loro-8- (4-chlorophenyl) -2- (trif luoromethyl) -2H-1benzopyrii.n-3-carboxylic acid

Step 1. Preparation of ebhvl 6-chloro-8-(4-chlorophenvl)-2(trif luor omethyl) -2H-l-bg:nzopyran-3-carboxvlate.

Ethyl 6-chloro-8-ioc.o-2- (trifluoromethyl) -2H-1benzopyran-3-carboxylate (Example 73, Step 2)(1.3 g, 3.02 mmol), potassium carbonate (1.25 g, 9.06 mmol), 4chorophenylboronic acid (0.52 g, 3.33 mmol), and tetrakis (triphenylphosphine)palladium(0) (0.174 g, 0,151 mmol) were added 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 washed with 1 N HCl (2 x 25 mL), saturated aqueous scdium bicarbonate (2 x 25 mL), and water (2 x 25 mL) . The organic phase was dried over MgSO.,, filtered, and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography using 1% ethyl acetate ir. hexane yielding a white solid. Recrystallization from hexane afforded the ester as a white solid (0.79 g, 64%) : mp 114.2-115.9 °C. *H NMR (CDCl_s/300

AP b υ 1 14 9

187

<td> MHz)</td><td> 7.69</td><td> (s, 1H),</td><td> 7.41 (s, 4H)</td><td> , 7.30 (d, 1H, J = 2</td><td> .4 Hz),</td>

<td> 7.22</td><td> (d,</td><td> 1H, J = 2</td><td> . 6 Hz), 5.70</td><td> (q, 1H, J = 6.9 Hz),</td><td> 4.37-</td>

<td> 4.29</td><td> (m,</td><td> 2H), 1.35</td><td> (t, 3H, J =</td><td> 7.1 Hz). ESLRMS m/z</td><td> 434</td>

<td> (M+NH</td><td> /&gt;·</td><td> FABHRMS</td><td> m/z 434.0574</td><td> (M+NH/, Calc'd. 434.</td><td> 0538).</td>

Anal. Calc'd. for C₁₉H₁₃C1₂F₃O₃: C, 54.70; H, 3.14; Cl, 17.00. Found: C, 54.79; H, 3.18; Cl, 16.65.

Step 2. Preparation of 6-chloro-8-(4-chlorophenvl)-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 was removed in vacuo and the residue was dissolved in water (10 mL) . Diethyl ether (10 mL) was added and the mixture acidified with concentrated HCI. 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 yield a white solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.40 g, 86%) : mp 205.5-207.3 °C. Ή NMR (CDCl₃/300 MHz)

7.81 (s, 1H), 7.42(s, 4H), 7.34 (d, 1H, J =2.4 Hz), 7.25 (s, 1H), 5.69 (q, 1H, J = 6.8 Hz). FABLRMS m/z 387 (M-H).

ESHRMS m/z 386.9788 (M-H, Calc'd. 386.980259). Anal.

Calc'd. for C₁₇H₉C1₂F₃O₃: C, 52.47; H, 2.33; Cl, 18.22.

Found: C, 52.38; H, 2.47; Cl, 18.20.

EXAMPLE 126

LL 9 10 I 6 6 /J.'dV

<img file="AP1149A_D0146.tif" />

188 •10

6-Chloro-8- ( 3 -me t honypheny 1) -2- (trifluoromethyl) -2H-Xbenzopyran-3-carboxylic acid

Step 1. Preparation of ethvl 6-chloro-8-(3-methoxvphenvl) 2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylate.

In a 100 mL round bottomed flask under nitrogen, ethyl

6-chloro-8-iodo-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylate (Example 73, Step 2) (1.00 g, 2.31 mmol) and 3methoxyphenylboronic acid (0.3 69 g, 2.43 mmol) were dissolved in 1-propanol (50 mL) . The mixture was stirred at room temperature for 0.5 hours, allowing for 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 mL) . The reaction mixture was heated to reflux for 3 hours. After cooling to room temperature the mixture was extracted with ethyl acetate (1 X 150 mL, 2 x 25 mL) . The combined organic phases were washed with saturated aqueous NaHCO₃ (50 mL) and brine (2 x 50 mL) , dried over MgSC,, filtered, and concentrated in vacuo to yield a yellow oil. The crude material was purified by flash chromatography in 0.5% ethyl acetate in hexane yielding a white solid. The solid was recrystallized from hexane yielding the desired ester as a white solid

<td> (0.60 g,</td><td> 63%)</td><td> : mp</td><td> 93.7-95.1 °C.</td>

<td> (s, 1H),</td><td> 7.35-</td><td> -7.32</td><td> (m, 2H), 7.22</td>

<td> 7.03 (m,</td><td> 2H) ,</td><td> 6.96-</td><td> -6.93 (m, 1H),</td>

<td> 4.34-4.31</td><td> . (m,</td><td> 2H) ,</td><td> 1.3Ξ (t, 3H,</td>

413 (M+H). ESHRMS m/z 413.0765 Anal. Calc'd. for C₂₀H₁₆ClF₃O₄: C, ^lH NMR (CDCl₃/300 MHz) 7.69 1H, J = 2.6 Hz) , 7..05J = 6.7 HZ) , FABLRMS m/z 413.076747) . 91; Cl, 8.59.

(d,

5.72 (q, 1H, J = 7.1 Hz) . (M+H, Calc'd.

58.19; H, 3.

Found: C, 58.33; H, 4.10; Cl, 8.61.

Step 2. Preparation of 6-chloro-8-(3-methoxyphenyl)-2(trif luoromethyl) -2H-l-benzopyran-3-carboxvlic acid.

The ester from 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 solution, 0.727 mmol), and stirre,d at room temperature for 18 hours.

APO 0 1149

189

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 HCI. The ether layer was separated, and the aqueous phase was extracted with ether (2 x 10 mL).

The ether extracts were combined, dried over MgSO₄, filtered, and concentrated in vacuo to yield a white solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.23 g, 81%): mp 173.1-177.4 °C. Έ NMR (CDCl₃/300 MHz) 7.81 (s, IH) , 7.391Ό 7.37 (m, 2H), 7.05-7.04 (m, 2H) , 6.97-6.94 (m, IH), 5.71 (q, IH, J = 6.7 Hz), 3.85 (s, 3H). ESHRMS m/z 383.0278 (M-H, Calc'd. 383.029796). Anal. Calc'd. for C_1SH₁₂C1F₃O₄: C,

56.20; H, 3.14; Cl, 9.21. Found: C, 55.90; H, 3.11; Cl, 9.48.

EXAMPLE 127

<img file="AP1149A_D0147.tif" />

AP/?/ 9 9 / 0 1 6 77

6-Chloro-8- [ (4-methylthio)phenyl] -2- (trifluorornethyl) -2H-1benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 126: mp 211.4-212.5 °C ^XH NMR (acetone-d^/300 MHz) 7.94 (s, IH),

7.57 (d, IK, J = 2.6 Hz), 7.53-7.50 (m, 2H), 7.45 (d, IH, J = 2.6 Hz), 7.39-7.36 (m, 2H), 5.87 (q, IH, J = 7.1 Hz), 2.55 (s, 3H) . ESHRMS m/z 399.0051 (M-H, Calc'd. 399.0069).

Anal. Calc'd. for C₁₈H₁₂ClF₃O₃S: C, 53.94; H, 3.02; Cl, 8.84; S, 8.00. Found: C, 53.86; H, 2.82; Cl, 8.91; S, 8.21.

EXAMPLE 128

190

<img file="AP1149A_D0148.tif" />

6-Chloro-8- [ (4-methylsul I: onyl) phenyl 3 -2- (trifluoromethyl) 2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of e'::hvl-6-chloro-8-i(4-methvlsulfonvl)phenyl] -2- (trif luoromethyl) -2H-l-benzopyrari-3carboxvlate.

Oxone™ (1.44 g, 2.34 mmol) was dissolved in H₂0 (10 mL) and then chilled to 5 °C. A solution of ethyl 6-chloro-8I (4-methyl thio) phenyl] -2- (trifluorometnyl) -2H-l-benzopyran3-carboxylate (Example 127, ethyl ester)(0.5 g, 1.17 mmollin methanol (20 mL) was slowly added to the reaction mixture and the solution was stirred at room temperature for 5 hours. The methanol was chen 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 yield a yellow solid.

This solid was recrystallized in ether-hexane to afford the sulfone as a white solid (0.46 g, 84%): mp 139.2-146.2 °C. *H NMR (CDC1₃/300 MHz) 8.C3(s, 1H) , 8.00 (s, 1H) , 7.70 (d,

2H, J = 2.4 Hz), 7.28 (d, 1H, J = 2.6 Hz), 5.71 (q, 1H, J = 6.9 Hz), 4.35-4.32 (m, 2H) , 3.11(s, 3H) , 1.35 (t, 3H, J = 7.2 Hz). FA3LRMS m/z 467 (M+Li). ESHRMS m/z 478.0707 (M+NH/, Calc'd. 478.070281) . Anal. Calc'd. for C₂₀H₁₆ClF₃O₅S: C, 52.12; H, 3.50; Cl, 7.69. Found: C, 52.17; H, 3.36; Cl, 7.77.

Step 2. Preparation of &lt;·-chloro-8-Γ (4methvlsulf onvl) phenyl] -2- (trif luoromethvl) -2H-l-benzopvra.n3-carboxylic acid.

APC 01149

191

The sulfone from Step 1 (0.300 g, 0.651 mmol) was dissolved in a solution of TKF: ethanol: water (7:2:1; 10 mL) . It was treated with sodium hydroxide (0.26 mL, 0.651 mmol of &lt;» a 2.5 N solution), and stirred at room temperature for 18 5 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 mL) . Diethyl ether (10 mL) was and the mixture acidified with concentrated HCI. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2 x 10 mL) . The combined organic extracts were dried over MgSO₄, filtered, and evaporated to yield a white solid. Recrystallization of this solid in ether-hexane afforded the title compound as a white solid (0.20 g, 73%) : mp 286.5-287.8 °C. Ή NMR (acetone-d^/300

MHz) 8.07 (d, 2H, J= 6.7 Hz), 7.97 (s, IH) , 7.84 (d, 2H, J = 6.7 Hz) , 7.67 (d, IH, J = 2.6 Hz) , 7.55 (d, IH, J = 2.6

Hz), 5.92 (q, IH, J =7.1 Hz), 3.20 (s, IH) . ESHRMS m/z 430.9947 (M-H, Calc'd. 430.996782). Anal. Calc'd. for C₁₈H₁₂C1F₃O₅S: C, 49.95; H, 2.80; Cl, 8.19. Found: C, 50.04;

H, 2.80; Cl, 8.25.

EXAMPLE 129

<img file="AP1149A_D0149.tif" />

LL 9 1 0 i 6 6 /J/dV

6-Chloro-8-phenyl-2- (trifluoromethyl) -2H-l-benzopyran-3carboxylic acid

Step 1, Preparation of ethyl 6-chloro-8-phenyl-2(trifluoromethyl) -2H-l-benzoovran-3-carboxylate.

A mixture of ethyl 6-chloro-8-hromo-2(trif luoromethyl) -2H-l-benzopyran-3-carboxylate (Example 74, Step 1)(2.0 g, 5.2 mmol), tetrakis(triphenylphosphine)

192 palladium(O) (2.15 g, 1.7 mmol), triphenylphosphine (0.013 g, 0.05 mmol), and tributylphenyltin (1.9 mL, 5.7 mmol) in toluene (60 mL) was heated to 110 °C for 3 days. The reaction mixture was allowed to cool to room temperature and filtered through a plug of silica gel eluting 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 desired product were combined and concentrated in vacuo. To remove the remaining tin impurities the mixture was taken up in THF (10 mL) and aqueous ammonium fluoride solution (10 wt %, 20 mL) and stirred at room temperature for 2 hours. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSC,, filtered, and concentrated in vacuo to afford the ester as an oil (1.30 g, 65%). ^XH

NMR (CDClj/3 00 MHz) 7.67 (.=,, 1H) , 7.47-7.3 6 (m, 5H) , 7.31 (d, 1H, J = 2.6 Hz) , 7.18 (d, 1H, J = 2.4 Hz), 5.69 (q, 1H, J = 6.8 Hz), 4.30 (m, 2H), 1.33 (t, 3H, J = 7.1 Hz) . ¹⁵FNMR (CDCl₃/282 MHz) d -78.27 (d, J = 7.2 Hz). FABLRMS m/z 383 (M+H) . ESHRMS m/z 400.0937 (M+NH₄, Calc'd 400.0927)

Steo 2. Preparation of 6-chloro-8-phenvl-2-trifluoromethvl2H-l-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) was 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 taken up in ethyl acetate and acidified with 3 N HCI. The solution was extracted with ethyl acetate. The extracts were combined, dried over MgSC₄, filtered, and concentrated in vacuo yielding a yellow solid. Recrystallization from ethyl acetate-hexanes afforded the title compound as a pale yellow solid (0.42 g, 46%) : mp :.96.3-197.7 °C. ^XH NMR (CDCl₃/300

MHz) d 7.65 (s, 1H) , 7.4C-7.23 (m, 6H) , 7.15 (s, 1H), 5.63 (q, 1H, J = 6.5 Hz), 3.3 i: (broad s, 1H) . ^1SF NMR (CDCl₃/282 MHz)d -78.71 (d, J = 5.8 Hz). FABLRMS m/z 355 (M+H). ESHRMS m/z 353.0198 (M-H, Calc'd 353.0192) .

APC 0 1149

193

EXAMPLE 130

<img file="AP1149A_D0150.tif" />

6-Bromo-8-f luoro-2- (trifiuoromethyl) -2H-1-benzopyran-3carboxylic acid

4-Bromo-2-fluorophenol was converted to the title 10 compound by a procedure similar to that described in Example

2: mp 206-208 °C. ^-H NMR (CD₃OD/300 MHz) 7.78 (s, IH) , 7.367.48 (m, 2H) , 5.87 (q, IH, J = 6.8 Hz). EIHRMS m/z 339.9349 (Calc'd 339.9358). Anal. Calc'd for C₁₁H₅BrF₄O₃ : C 38.74, H 1.48; Found C 38.97, H, 1.60.

EXAMPLE 131

<img file="AP1149A_D0151.tif" />

6- (4-Fluorophenyl) -2- (trifiuoromethyl) -2H-l-benzopyran-3carboxylic acid

The 2H-1-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-3carboxylate (Example 24, Step 3) as the starting material: mp 207-210 °C. ^-H NMR (CD₃OD/300 MHz) 7.87 (s, IH) , 7.547.64 (m, 4H), 7.10-7.20 (m, 2H), 7.03 (d, IH, J =9.4 Hz), 5.77 (q, IH, J = 7.0 Hz). EIHRMS m/z 338.0573 (Calc'd

194

338.0566) Anal. Calc'd for C_X1H₆F₃IO₃ + 1.25% K₂0: C, 59.62; H,

3.08. Found C, 59.61; H, 3.09 .

EXAMPLE 132

<img file="AP1149A_D0152.tif" />

ΌΗ

6-Pheny 1-2- (trif luoromethyl) -2H-l-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 ethyl 6-iodo-2-(trifluoromethyl) -2H-1-benzopyran-3carboxylate (Example 24, Step 3) as the starting material: mp 197-198 °C. NMR (CD₃OD/300 MHz) 7.87 (s, 1H) , 7.287.64 (m, 7H) , 7.03 (d, 1H, J = 6.8 Hz), 5.76 (q, 1H, J = 7.0 Hz). EIHRMS m/z 320.0604 (M+, Calc'd 320.0660). Anal.

Calc'd for C₁₇H_UF₃O₃; C, 63.75; H 3.46. Found C, 63.56; H,

3.46.

EXAMPLE 133

ΌΗ

Cl

8-Chloro-6-fluoro-2- (trifluoromethyl) -2H-1 -benzopyran-3carboxylic acid

2-Chloro-4-fluorophenol was converted to the title compound by a procedure similar to that described in Example

2: mp 240-241 °C. ^H NMR ICD₃OD/300 MHz) 7.77 (s, 1H) , 7.26

ΑΡΰ 0 1149

195 (dd, 1Η, J = 8.3, 2.9), 7.14 (dd, 1H, J =8.1, 2.9), 5.87 (q, 1H, J = 6.8 Hz). EIHRMS m/z 295.9836 (Calc'd 295.9863). Anal. Calc'd for C^HjClF.O, : C, 44.54; H, 1.70. Found C, 44.70; H, 1.73.

EXMAPLE 134

<img file="AP1149A_D0153.tif" />

6,8-Diiodo-2-(trifluoromethyl)-2H-l-benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 1: mp

243-244 °C. !h NMR (CD₃OD/300 MHz) 8.07 (d, 1H, J = 2.0 Hz),

7.71 (s, 1H) , 7.70 (d, 1H, J = 2.0 Hz), 5.89 (q, 1H, J = 6.8 Hz). ESHRMS m/z 494.8174 (Calc'd for M-H 494.8202) Anal. Calc'd for C^F^O,: C, 26.64; H, 1.02. Found C, 26.75; H, 1.06.

EXAMPLE 135

<img file="AP1149A_D0154.tif" />

APT/ 9 9 / 0 1 6 77

6- (5-Chloro-2-thienyl)-2-(trifluoromethyl)-2H-l-benzopyran3-carboxylic acid

The 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-3carboxylate (Example 72, Step 3) as the starting material: mp 205-206 °C. ^-H NMR (CP3OD/3OO MHz) 7.83 (s, IH) , 7,507.58 (m, 2H), 7.14 (d, IM, J = 4.0 Hz), 7.00 (d, IH, J = 8.86 Hz), 6.93 (d, IH, J = 4.0 Hz), 5.77 (q, IH, J = 7.0 Hz). EIHRMS m/z 359.981'.) (M+, Calc'd 359.9835). Anal. Calc'd for C₁₅H_BC1F₃O₃S: C, 49.94; H 2.24. Found C, 50.14; H, 2.29 .

EXAMPLE 136

<img file="AP1149A_D0155.tif" />

6- (2-thienyl) -2-(trililuoromethyl) -2H-1-benzopyran-3carboxylic acid

The 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-3carboxylate (Example 24, Step 3) as the starting material: mp 209-212 °C. NMR |CD₃OD/300 MHz) 7.83 (s, IH) , 7.587.62 (m, 2H) , 7.30-7.38 (m, 2H) , 6.80-7.09 (m, 2H), 5,76 (q, IH, J = 7.0 Hz) FABHRMS m/z 325.0153 (Calc'd for M-H 325.0146)

EXAMPLE 137

<img file="AP1149A_D0156.tif" />

6- (4-Chlorophenyl)-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylic acid

ΑΡΰ Ο 1 14 9

197

The 2Η-1-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-35 carboxylate (Example 24, Step 3) as the starting material: mp 212-213 °C. ¹H NMR (CD₃OD/300 MHz) 7.89 (s, 1H), 7.567.66 (m, 4H), 7.40-7.48 (m, 2H), 7.04-7.10 (m, 1H), 5.77 (q, 1H, J = 7.0 Hz). ESHRMS m/z 353.0190 (Calc'd for M-H 353.0192). Anal. Calc'd for C₁₇H₁₀ClF₃O₃: C, 57.56; H, 2.84.

Found C, 57.41; H, 2.82.

EXAMPLE 138

<img file="AP1149A_D0157.tif" />

6- (4-Bromophenyl) -2- (trif luoromethyl) -2H-l-benzopyran-3carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a 20 procedure similar to the method described in Example 126:

using ethyl 6-iodo-2-(trifluoromethyl)-2H-l-benzopyran-3carboxylate (Example 24, Step 3) as the starting material: mp 215-216 °C. NMR (CD₃OD/300 MHz)7.89 (s, 1H), 7.06-7.71 (m, 6H) , 7.04-7.06 (m, 1H), 5.78 (q, 1H, J = 6.8 Hz). ESHRMS m/z 396.9681 (Calc'd for M-H 396.9687).

EXAMPLE 139

O'

<img file="AP1149A_D0158.tif" />

ΑΡ/Γ/ 9 9 /0 1 6 77

198

6- (Ethynyl) -2-(trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 118 using ethyl 6-iodo-2-(trifluoromethyl) -2H-l-benzopyran-3carboxylate (Example 24, Step 3) as the starting material: mp 198-200 °C. NMR (CD3OD/3OO MHz) 7.80 (s, 1H), 7.47 (dd, 1H, J = 8.5, 2.0 Hz), 7.41 (d, 1H, J = 2.0 Hz), 6.97 (d, 1H, J = 8.5 Hz) , 5.71 (q, 1H, J = 6.8 Hz), 3.06 (s, 1H) . ESHRMS m/z 267.0271 (Calc'd for M-H 267.0269) Anal. Calc'd for C₁₃H₇F₃O₃ + 1.06% HjO: C, 57.60; H, 2.72. Found C, 57.59;

H, 2.62.

EXAMPLE 140

<img file="AP1149A_D0159.tif" />

6-Methyl-2- (trifluoromethyl) -2H-l-benzopyran-3-carboxylic acid

4-Methylsalicylaldehyde was converted to the title compound by a procedure similar to that described in Example 1: mp 191.8-193.0 °C. fri NMR (acetone-dg/300 MHz) 7.80 (s,

1H), 7.72-7.73 (m, 2H), 6.90 (d, 1H, J = 8.4 Hz), 5.91 (q, 1H, J = 7.2 Hz). Anal. Calc'd for C₁₂H₉O₃F₃: C, 55.82; H,

3.51. Found: C, 55.89; H, 3.49.

EXAMPLE 141

APO 0 1149

<img file="AP1149A_D0160.tif" />

6-Chloro-8-(4-methoxyphenyl)-2-trifluoromethyl-2H-l benzopyran-3-carboxylic acid

The 2H-l-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 126: mp 194.0-196.0 °C. 'HNMR (CDCl₃/300 MHz) 7.81 (s, IH) , 7.44

<td> (Ξ,</td><td> IH), 7.41 (s,</td><td> IH), 7.34 (d,</td><td> IH,</td><td> J = 2.4 Hz),7.</td><td> 21 (d, IH,</td>

<td> J =</td><td> 2.4 Hz), 6.99</td><td> (s, IH), 6.96</td><td> (s,</td><td> IH), 5.69 (q,</td><td> IH, J =</td>

<td> 6.7</td><td> Hz), 3.86 (s,</td><td> 3H) . FABLRMS</td><td> m/z</td><td> 402.2 (M+NH₄) .</td><td> ESHRMS</td>

m/z 383.0267 (M-H, Calc'd. 383.029796). Anal. Calc'd. for C_1BH₁₂C1F₃O₄: C, 56.20; H, 3.14; Cl, 9.21. Found: ' C, 56.08 ,Η, 3.11; Cl, 9.13.

EXAMPLE 142

<img file="AP1149A_D0161.tif" />

AP, ~ 9 9 / 0 1 6 77

6-Chloro-2-(trifluoromethyl)-4-ethenyl-2H-l-benzopyran-3carboxylic acid

Step 1: Preparation of ethyl 3-(5-chloro-2-hvdroxvt&gt;henvl)3-oxo-propionate

A solution of lithium hexamethyldisilazide (800 mL of 1.0 M solution in THF, 800.0 mmol) was chilled to -78 °C under a nitrogen atmosphere. A solution of 5-chloro-2hydroxyacetophenone (45.493 g, 266.67 mmol) in THF (130 mL)

200 was added dropwise tc the stirred solution over 0.5 hour.

The reaction was helc. at -78 °C for 1 hour, warmed to -10 °C for 2 hours, warmed to 0 °C for 1 hour, then cooled to -78 °C. Diethyl carbonate (35.54 mL, 34.65 g, 29.34 mmol) was added via syringe in one portion. The temperature was maintained at -78 °C for 0.5 hour, warmed to room temperature over 0.5 hour, and stirred for 3 hours. The crude reaction mixture was carefully poured over a mixture of rapidly stirred ice (1200 mL)/cone HCI (222 mL) . The layers were separatee, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SC&gt;4, filtered and concentrated in vacuo yielding an oil that began to crystallize. Hexanes (150 mL) was added ar.d crystallization proceeded. The crystalline product was collected by vacuum filtration to afford the title compound (29.04 g, 45%) as tan crystalline needles: mp 71.8-73.1 °C. ^H NMR (CDCI3/3OO MHz) 7.63 (d,

IH, J=2.4Hz), 7.45 (dd, IH, J =8.9, 2.6), 6.98 (d, IH, J = 8.9 Hz), 4.25 (q, 2 H, J = 7.3 Hz), 3.98 (s, 2H) , 1.29 (t, 3H, 7.3 Hz). FABLRMS! m/z 249 (M+Li) . EIHRMS m/z 242.0346 (M+, Calc'd 242.0346). Anal. Calc'd for C11H11CIO4: C, 54.45; H, 4.57. Found: C, 54.48; H, 4.62.

Step 2. Preparation of ethvl 2-(trifluoromethyl)-6-chloro4-ΟΧΟ-4Η-1-benzopvrari-3-carboxylate.

The keto-ester (Step 1) (19.2 g, 79.1 mmol), was added to 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 3 6 hours, then heated tc: reflux for 4 hours. After cooling to room temperature, the suspension was poured over rapidly stirred (mechanical stirrer) ice (300 mL) and aqueous HCI (12 N, 50 mL) . The resulting organic phase was separated from the clear mixture, was washed with water ( 5 X 500 mL) , brine (1 X 500 mL) , dried over MgSO₄, filtered and concentrated in vacuo yielding tan solid which was dried under high vacuum. This sample was partially dissolved in

APC 01 14 9

201 heptane (100 mL) and ethyl acetate (12 mL) with heating on a steam bath, was filtered to remove insoluble material. The filtrate was allowed to cool to room temperature yielding the desired 4-oxo-4H-l-benzopyran as a fluffy tan solid .(14.17 g, 56%) : mp 106.7-108.6 °C. This material was of suitable purity to use in the next step without further purification.

Step 3. Preparation of ethyl 2- (trifluoromethvl)-4-oxodihvdro-l-benzopyran-3-carboxylate.

A stirred, chilled (0 °C) solution of the ketone (Step 2) (6.92 g, 21.58 mmol) in tetrahydrofuran (40 mL) and ethanol (50 mL) was treated portion-wise with sodium borohydride (NaBH₄, 0.41 g, 10.79 mmol). After 3 h additional sodium borohydride (0.30 g, 7.93 mmol) was added portion-wise over 1 hour. The reaction was poured into rapidly stirred cold aqueous HCI (15 mL of 12 N HCI diluted to 300 mL). During the addition a precipitate formed, that was collected by vacuum filtration and dried under high vacuum yielding the desired substituted 4-oxo-dihydro-1benzopyran as a white powder (6.92 g, 99%): mp 80.2-84.9 °C. ^XH NMR (CDCl₃/300 MHz) 12.60 (br s, IH) , 7.69 (d, IH, J =

2.6 Hz) , 7.34 (dd, IH, &lt;7=2,6, 8.7 Hz) , 6.93 (d, IH, J =

8.7 Hz), 5.59 (q, IH, 6.6 Hz), 4.46-4.23 (m, 2H), 1.35 (t, 3H, J = 7.0 Hz) . FABLRMS m/z 329 (M+Li) . EIHRMS m/z 322.0213 (M+, Calc'd 322.0220). Anal. Calc'd for Cl^Cl^O, with 3.57% water: C, 46.67; H, 3.41. Found: C, 46.62; H, 3.14.

Step 4. Preparation of ethyl 6-chloro-4(trifluoromethanesulfonoxy)-2-(trifluorornethyl)-2H-1benzopyran-3-carboxylate.

A 50 mL Morton flask fitted with septa and addition funnel was charged with 2,6-di-tert-butylpyridine (1.782 g, 8.679 mmol), methylene chloride (15 mL), and trifluoromethanesulfonic anhydride (1.22 mL, 2.04 g, 7.23 mmol) followed by the dropwise addition of the chroman-4-one

AP/?/ 9 9 / 0 1 6 77

202 (Step 3) (2.145 g, 5.786 mmol) in methylene chloride (12 mL) over 0.3 3 hour. After £;tirring for 16 h at room temperature, the reactien was concentrated in vacuo and diluted with diethyl ether (50 mL) yielding a suspension.

The suspension was vacuum filtered and the filtrate washed with cold 2 N HCI and brine, dried over MgSO4, filtered and concentrated in vacuo yielding the desired triflate as a light yellow powder (1.45 g, 55%) of suitable purity to use without further purificei.tion: mp 79.2-80.4 °C. ³H NMR (CDCl₃/300 MHz) 7.40 9s, IH) , 7.37 (d, IH, J= 2.4 Hz), 7.02-6.99 (m, IH), 5.92 (q, IH, J= 6.6 Hz), 4.47-4.32 (m, 2H), 1.39 (t, 3H, J = 7 2 Hz).

Step 5. Preparation of ethyl 6-chloro-4-ethenvl-2(trifluoromethyl)-2H-l-benzopvran-3-carboxvlate.

Ethyl 6-chloro-4-trifluoromethanesulfoxy-2(trifluoromethyl)-2H-l~benzopyran-3-carboxylate (Step 4) (1.50 g, 3.30 mmol) was dissolved in anhydrous THF (40 mL) in a 100 mL round bottomed flask under nitrogen.

Tetrakis(triphenylphosphine)palladium(0) (0.267 g, 0.231 mmol) and lithium chloride (0.140 g, 3.3 mmol) were added, followed by tributylethenylstannane (1.15 g, 3.6 mmol). The resulting solution was heated to reflux for 18 hours. GCMS analysis indicated the starting material had been consumed. The reaction mixture wa:·: allowed to cool to room temperature and was poured into 20% ammonium fluoride solution (50 mL). After stirring 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 MgS0₄, filtered, and concentrated in vacuo yielding a brown oil. The crude material was purified by flash column chromatography (hexane) to afford the ester as a yellow oil, which crystallized upon standing (0.760 g, 69%) : mp 51.9-53.2 °C. H NMR (CDCl₃/300 MHz) 7.46 (d, IH, J= 2.4 Hz), 7.28-7.14 (m, 2H), 6.96 (d, IH, J = 8.7 Hz), 5.77-5.71 (m, 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 303.2 (M+H). ESHRMS m/z 333.0510 (M+H, Calc'd.333.050532 . Anal. Calc'd for C₁₅H₁₃C1F₃O₃ (1.14

C, 53.46;

APV 0 114 9

203 wt % H₂O) : C, 53.53; H, 3.72; Cl, 10.53. Found:

H, 3.42; Cl, 10.70.

Step 6. Preparation of 6-chloro-4-ethenvl-25 trifluoromethvl-2H-l-benzopvran-3-carboxylic acid.

The ester from Step 5 (0.300 g, 0.902 mmol) was dissolved in a THF-EtOH-H₂0 mixture (10 mL, 7:2:1) and treated with sodium hydroxide (0.360 mL, 0.902 mmol of a 2.5 N solution) . This solution was 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 acidified by the addition of concentrated HCI. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2 x 10 mL) .

The ether extracts were combined, dried over MgSO₄, filtered, and concentrated in vacuo yielding a yellow solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.163 g, 59%): mp 143.0-145.0 °C. 1H NMR (CDCl₂/300 MHz 7.49 (d, 1H, J = 2.6

Hz), 7.33-7.17 (m, 2H), 6.99 (d, 1H, J= 8.5 Hz), 5.82-5.72 (m, 2H) , 5.42 (d, 1H, J = 17.9 Hz). ESHRMS m/z 303.00207 (M-H, Calc'd. 303.003582). Anal. Calc'd for C₁₃H₈C1F₃O₃ (1.10 wt % H₂O): C, 50.69; H, 2.74; Cl, 11.51. Found: C, 50.57; H, 2.37; Cl, 11.75.

EXAMPLE 143

<img file="AP1149A_D0162.tif" />

AP/?' 9 9 ,'O 1 6 77

6-Chloro-2- (trifluoromethyl) -4-phenyl-2H-l-benzopyran-3carboxylic acid

204

The 2H-l-benzopyr.:m-3-carboxylic acid was prepared from ethyl 6-chloro-4-(trif i.uoromethanesulf onoxy) -2{trifluoromethyl)-2H-1-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 1H NMR (DMSO-_di/300 MHz). 7.46-7.39 (m, 4H) , 7.20-7.13 (m, 3H) , 6.52 (d, 1H, 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, Calc'd. 353.019232).

Anal. Calc'd. for C_l7H₁₀ClF₃O₃: C. 57.56; H, 2.84; Cl, 10.17.

•10 Found: C, 57.18; H, 2.66; Cl, 10.17.

EXAMPLE 144

<img file="AP1149A_D0163.tif" />

6-Chloro-4- (2-thienyl) -2- (trif luoromethyl) -2H-l-benzopyran3-carboxylic acid

The 2H-l-benzopyrcin-3-carboxylic acid was prepared from ethyl 6~chloro-4-(trifluoromethanesulfonoxy)-Σι trif luoromethyl) -2H-l~benzopyran-3-carboxylate (Example 142, Step 4) using a procedure similar to that described in Example 142, Steps 5-6: mp 200.8-206.7 °C. Ή NMR (CDCl₃/300 MHz) 7.52(dd, 1H, J= 1.21, 5.04 Hz), 7.28 (dd, 1H, J =

2.42, 8.67 Hz), 7.15 (cld, 1H, J = 1.21, 3.42 Hz), 6.98-6.93 (m, 2H) , 5.83 (q, 1H, t^r = 6.9 Hz). FABLRMS m/z 378 (M+NH₄) . Anal. Calc’d. for C₁₅H₈C ).F₃O₃S: 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.

*ne η 1 1 A 9

205

EXAMPLE 145

<img file="AP1149A_D0164.tif" />

6-Methyl-2- (trifluoromethyl) -2H-l-benzothiopyran-3carboxylie acid

Step 1. Preparation of 5-methyl-2-mercaptobenzaldehyde.

Tetramethylethylenediamine (TMEDA)(12.6 mL, 83.5 mmol) was added via syringe to n-BuLi (33 mL of 1.6 M in hexanes,

82.5 mmol) and the solution was chilled to 0 °C. A solution of p-thiocresol (4.53 g, 36.5 mmol) in cyclohexane (40 mL) was added with stirring over 5 minutes. The resulting tan slurry was stirred overnight at room temperature, chilled to

0 °C, and DMF (4.0 mL, 3.77 g, 51.6 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 1.3 hours. The reaction mixture was added to 3 N HCI (150 mL). This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo yielding a brown oil. This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate-hexanes to afford 5-methyl-2mercaptobenzaldehyde (4.47 g, 69%) as an intensely yellow solid suitable for use without further purification.

Step 2. Preparation of ethyl 6-methvl-2-(trifluoromethvl)2H-l-benzothioovran-3-carboxylate.

The 5-methyl-2-mercaptobenzaldehyde (Step 1) (3.25 g,

21.3 mmol) was added to DMF (5 mL) and ethyl 4,4,4trifluorocrotonate (4.32 g, 25.7 mmol). With stirring, KjCO₃

APT; 9 9/01677

206 (3.78 g, 27.3 mmol) was added causing the reaction to become a deep red. The reaction was stirred at room temperature for 20 hours, acidified witli 3N HCI, diluted with ethyl acetate and washed with water, saturated NaHCO₃ solution, brine, dried over MgSO₄, filtered and concentrated in vacuo yielding an oil. The oil was crystallized from diethyl ether-petroleum ether to give ethyl 6-methyl-2(trif luoromethyl)-2H-l-benzothiopyran-3-carboxylate as a light yellow solid (4.47 g, 69%): mp 93.1-94.7 °C. ^XH NMR (acetone-d6/300 MHz) 7.94 (s, IH), 7.41 (s, IH), 7.31 (d,

IH, J = 7.9 Hz), 7.25 (d, IH, J = 7.9 Hz), 4.96 (q, IH, J =

8.5 Hz), 4.33 (m, 2H), 2.34 (s, 3H), 1.35 (t, 3H, J= 7.0 Hz). FABLRMS m/z 3 09 (l-i+Li).

Step 3. Preparation of 6-methvl-2-(trifluoromethyl)-2H-1benzothiopyran-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 HCI, filtered, and recrystallized from diechyl 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-d£/300 MHz) 7.95 (s, IH), 7.42 (s, IH), 7.31 (d, IH, J =8.1 Hz), 7.25 (d, IH, J =8.1 Hz), 4.94 (q, IH, J= 8.7 Hz), 2.34 (s, 3H). FABLRMS m/z 281 (M+Li). EIHRMS m/z 274.0250 (M+, Calc'd 274.0275).

Anal. Calc'd for C_l2H_sF₃O.,S : C, 52.55; H, 3.31. Found: C, 52.54; H, 3.35.

EXAMPLE 146

AP Ο Ο 114 9

207

<img file="AP1149A_D0165.tif" />

6_Ζ 8-Dimethyl-2-(trifluoromethyl)-2H-l-benzothiopyran-3carboxylic acid

The 2H-l-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: mp 220-225 °C (dec). ^XH NMR (acetone-d£/300 MHz) 11.5 (brs, 1H), 7.94 (s, 1H), 7.26 (s, 1H) 7.14 (s, 1H), 4.98 (q,

1H, J= 8.7 Hz), 2.34 (s, 3H) , 2.31 (s, 3H) . FABLRMS m/z

295 (M+Li). EIHRMS m/z 288.0431 (M+, Calc'd 288.0432).

Anal. Calc'd for C^F.O.S: C, 54.16; H, 3.85. Found: C, 54.10; H, 3.91.

EXAMPLE 147

<img file="AP1149A_D0166.tif" />

AP/?/ 9 9 / 0 1 6 77

6-(1,1-Dimethylethyl)-2-(trifluoromethyl)-2H-120 benzothiopyran-3-carboxylic acid

The 2H-l-benzothiopyran-3-carboxylic acid was prepared, by a procedure similar to the method described in Example 145: mp 183.8-184.6 °C. ³H NMR (acetone-c?6/300 MHz) 8.04 (s,

1H) , 7.68 (d, 1H, J = 2.2 Hz), 7.46 (dd, 1H, J = 8.3 Hz 2.2

Hz), 7.37 (d, 1H, J = 8.3 Hz), 4.94 (q, 1H, J = 8.7 Hz),

1.34 (s, 9H) . FABLRMS m/z 334 (M+NHJ . ESHRMS m/z 334.1087 300 MHz) 7.52(dd, 1H, J = 1.21, 5.04 Hz), 7.28 (dd, 1H, J =

208

2.42, 8.67 Hz), 7.15 (dd, 1H, (m, 2H), 5.83 (q, 1H, J = 6.9 Anal. Calc'd. for C₁₅H₈C1F₃O₃S : S, 8.89. Found: C, 50.02; H, 8.89.(M+NH₄, Calc'd 334.1089) , C, 56.95; H, 4.78. Found: C,

J= 1.21, 3.42 Hz), 6.98-6.93 Hz) . FABLRMS m/z 37 8 (M+NHJ , C, 49.94; H, 2.24; Cl, 9.83; 1.98; Cl, 9.34; S,

Anal. Calc'd for C,₅H₁₅F₃O₂S: 57.03; H, 4.83.

EXAMPLE 148

<img file="AP1149A_D0167.tif" />

7-Methyl-2 - (trif lucromethyl) -2H-l-benzothiopyran-3carboxylic acid

The 2H-l-benzothioi?yran-3-carboxylic acid was prepared by a procedure similar t:o the method described in Example 145: mp 186.6-191.9 °C. Ή NMR (acetone-dd/300 MHz) 7.96 (s, 1H), 7.49 (dd, 1H, G= 7.6 Hz 2.82 Hz), 7.27 (s, 1H), 7.14 (d, 1H, J = 7.6 Hz), 4.96 (q, 1H, J = 5.3 Hz), 2.36 (s, 3H) . ESHRMS m/z 273.02(14 (M-H, Calc ' d 273.0197) . Anal. Calc'd for C₁₂H₉F₃O₂S (3.32 wt % H₂O) : C, 50.81; H, 3.57.

Fcund: C, 50.79; H, 3.44.

EXAMPLE 149

<img file="AP1149A_D0168.tif" />

6,7-Dimethyl-2- (trif luoromethyl) -2H-l-henzothiopyran-3carboxylic acid

APO 0 114 9

209

The 2H-l-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: mp 235-237 °C. ³H NMR (acetone-&lt;36/300 MHz) 7.90 (s,

1H) , 7.33 (s, 1H) , 7.19 (ε, 1H) , 4.91 (q, 1H, J= 8.7 Hz),

2.28 (s, 3H) , 2.26 (s, 3H) . FABLRMS m/z 295 (M+Li). EIHRMS m/z 288.0439 (M+, Calc'd 288.0432). Anal. Calc'd for C₁₃H_1XF₃O₂S: C, 54.16; H, 3.85. Found: C, 54.13; H, 3.85.

EXAMPLE 150

<img file="AP1149A_D0169.tif" />

; 99/01677

8-Methyl-2-(trifluoromethyl)-2H-l-benzothiopyran-315 carboxylic acid ί ·

The 2H-l-benzothiopyran-3-carboxylic acid was prepared Ch by a procedure similar to the method described in Example 145: mp 224-225 °C. ^XH NMR (acetone-d6/300 MHz) 11.60 (br s,

1H) , 8.00 (s, 1H), 7.44 (d, 1H, J = 6.7 Hz), 7.31 (d, 1H, J = 6.8 Hz), 7.21 (m, 1H), 5.05 (q, 1H, J= 8.5 Hz), 2.38 (s,

3H) . FABLRMS m/z 292 (M+NH₄) . ESHRMS m/z 292.0591 (M+NH₄,

Calc'd 292.0619). Anal. Calc'd for C₁₂H₉F₃O₂S: C, 52.55; H,

3.31. Found: C, 52.63; H, 3.38.

EXAMPLE 151

<img file="AP1149A_D0170.tif" />

210

2- (Trifluoromethyl) -211-l-benzothiopyran-3-carboxylic acid

The 2H-l-benzothio;:&gt;yran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 145: mp 187-190 °C. ^XH NMR (acetone-d6/300 MHz) 8.01 (s,

1H), 7.60 (d, 1H, J=7.5Hz), 7.45 (m, 2H), 7.31 (m, 1H), 4.98 (q, 1H, J = 8.7 Hz). ESHRMS m/z 259.0070 (M-H, Calc'd 259.0041). Anal. Calc'd for C_irH₇F₃O₂S: C, 50.77; H, 2.71. Found: C, 50.75; H, 2.7 ii.

EXAMPLE 152

<img file="AP1149A_D0171.tif" />

6-Chloro-7-methyl-2-(trifluoromethyl)-2H-l-benzothiopyran-3 carboxylic acid

Step 1. Preparation of N,N-dimethvl-Q-(4-chloro2-formvl-5-methvlphenvl) thiocarbamate.

A mixture of 5-chloro-4-methylsalicylaldehyde (12.96 g

76.0 mmol) and triethyl.-unine (11.58 g, 114.4 mmol) was dissolved in anhydrous DMF (15 mL) treated with N,Ndimethylthiocarbamoyl chloride (11.25 g, 91.0 mmol) and stirred at room temperature for 16 hours. The reaction was treated with 3 N HCI (51 mL) and filtered to give an orange solid. The solid was dissolved in ethyl acetate washed with 3 N HCI, water, brine, dried over anhydrous MgSO4, filtered and concentrated in vac.io to afford a brown solid (16.79 g) which was recrystallized from diethyl ether/hexane to give the O-aryl chiocarbamate as a tan solid (4.92 g, 25%): ^XH

APO Ο 1 1 4 9

211 ·, NMR (acetone-d£/300 MHz) 9.96 (s, 1H), 7.80 (s, 1H), 7.19 (s, 1H), 3.46 (s, 3H), 3.42 (s, 3H) , 2.43 (s, 3H) .

Step 2. Preparation of N,N-dimethvl-S-(4-chloro-2-formvl-55 methvlphenvl) thiocarbamate ,

The O-aryl thiocarbamate (Step 1) (4.92 g, 19.1 mmol) was dissolved in N, 27-dimethylaniline (25 mL) and immersed in and stirred at 200 °C for 1.5 hours. The reaction mixture was cooled to room temperature and poured into a mixture of

3 N HCl (200 mL) and ice. Filtration gave a brown semisolid which was dissolved in ethyl acetate, washed with 3 N HCI, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the S-arylthiocarbamate 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(trifluorornethvl)-2H-l-benzothiopyran-3-carboxvlate.

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 HCI, brine, dried over MgSO₄, 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, K^COj (3.23 g, 23.4 mmol) was added causing the reaction to become a 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 MgSO₄, filtered and concentrated in vacuo to give a yellow solid (6.36 g) which was used in the next step without further purification.

ΑΡ/Γ,' 9 9 ' 0 1 6 77

212

Step 4. Preparation of 6-chloro-7-methvl-2(trifluoromethvl) -2H-l-l:&gt;enzothiopyran-3 -carboxvlic acid

The ester from Step 3 (2.02 g, 6.0 mmol) was dissolved in THF (10 mL) and ethanol (10 mL) , treated with 2.5· N sodium hydroxide (5.5 ml.,, 13.8 mmol), and stirred at room temperature for 4.8 hour. s . The reaction mixture was concentrated in vacuo, acidified with 3 N HCI yielding a suspension. The solid was collected by filtration and was recrystallized from ethanol-water to yield the title compound as a yellow soZ.id (0.20 g, 11%) : mp 240.5-241.7 °C. Ή NMR (acetone-d£/3Q0MH:s) 7.99 (s, 1H) , 7.67 (s, 1H), 7.43 (s, 1H), 4.99 (q, 1H, J= 8.5 Hz), 2.39 (s, 3H). FABLRMS m/z 307 (M-H). FABHRMS m/z 306.9831 (M-H, Calc'd 306.9807) Anal. Calc'd for C_J2H_BC1F,O₂S: C, 46.69; H, 2.61; Cl, 11.48.

Found: C, 46.78; H, 2.61; Cl, 11.41.

EXAMPLE 153

<img file="AP1149A_D0172.tif" />

7-Chloro-2- (trifluoromethyl) -2H-l-benzothiopyran-3carboxylic acid

The 2H-l-benzothioryran-3-carboxylic acid was prepared 25 by a procedure similar to the method described in Example

152: mp 225.7-227.3 °C. Ή NMR (acetone-d£/300 MHz) 8.02 (s 1H), 7.63 (d, 1H, J = 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 m/z 292.9646 (M-H, Calc'd 292.9651).

EXAMPLE 154

APO01149

213

Ο

Cl

Cl

<img file="AP1149A_D0173.tif" />

ΌΗ

6,7-Dichloro-2- (trifluoromethyl) -2H-l-benzothiopyran-3carboxylic acid

The 2H-l-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 152: mp 262.5-263.5 °C. ^XH NMR (acetone-d6/300 MHz) 8.04 (s, IH), 7.90 (s, IH), 7.74 (s, IH), 5.09 (q, IH, J =8.5 Hz). ESHRMS m/z 326.9242 (M-H, Calc'd 326.9261).

EXAMPLE 155

O

ΌΗ

ΑΡ/Γ, 9 9 / 0 1 6 77

2-(Trifluoromethyl)-6-[(trifluoromethyl)thio]-2H-1benzothiopyran-3-carboxylic acid

The 2H-l-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 152: mp 129.3-132.4 °C. ^XH NMR (acetone-d6/300 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, IH, J = 8.5 Hz). ESHRMS m/z 358.9630 (M-H, Calc'd 358.9635).

214

EXAMPLE 156

CK ^.co₂h

<img file="AP1149A_D0174.tif" />

6,8-Dichloro-2-trifluoromethyl-2H-lbenzothiopyran-3-carboxylic acid

The 2H-l-benzothiopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 152: mp 217.9-220.3 °C.

NMR (acetone-d^/300 MHz) 12.50-11.20 (br s, IH exch.), 8.06 (s, IH), 7.75 (d, IH, J =2.0 Hz), 7.64 (d, IH,. J = 2.2 Hz), 5.23 (q, IH, J = 8.5 Hz). ESLRMS m/z 327 (M-H). ESHRMS m/z 326.9272 (M-H, Calc'd 326.9261).

EXAMPLE 157

Cl

<img file="AP1149A_D0175.tif" />

co₂h fi ^0F’

6-Chloro-l,2-dihydro-2- (trifluoromethyl)-3quinolinecarboxylic acid

Step 1. Preparation of 2-amino-5chlorobenzaldehvde.

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 dieitomaceous earth and concentrated in vaci/o to afford the 2-amino-5chlorobenzaldehyde as a dark solid (4.14 g, 81%): mp 74-76 °C. ^XH NMR :CDC1₃, 300 MHz) 9.80 (s, IH) ,

AP t0 1 149

215

7.42 (s, IH), 7.23 (d, IH, J=7.0Hz), 6.60 (d,

IK, J = 7.0 Hz) .

Step 2. Preparation of ethvl 6-chloro-l,25 dihvdro-2-(trifluoromethyl)-3quinolinecarboxvlate.

The 2-amino-5-chlorobenzaldehyde from Step 1 (15.0 g, 96 mmol), anhydrous potassium carbonate (27.6 g, 200 mmol), and ethyl 4,4,410 trifluorocrotonate (34 mL, 200 mmol) were mixed in anhydrous dime thy formamide (60 mL) and heated at ©

100 C for 7 hours. The contents were allowed to cool and 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 MgSO₄, 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). Fractions containing the desired product were combined, concentrated in vacuo and the residue recrystallized from ethyl acetate-hexanes to afford the ethyl 6-chloro-l,225 dihydro-2-(trifluoromethyl)-3-quinolinecarboxylate as a yellow solid (16.36 g, 56%): mp 132.6-134.2 °C. 'H NMR (CDC1₃, 300 MHz) 7.61 (s, IH) , 7.10 (m, 2H) , 6.55 (d, IH, J = 8.0 Hz), 5.10 (q, IH, J =

6.0 Hz), 4.55 (brs, IH), 4.23 (m, 2H), 1.32 (t,

3H, J = 7.0 Hz). FABHRMS m/z 306.0468 (M+H*,

Calc'd 306.0509). Anal. Calc'd for C^NO^Cl:

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-dihvdro-2(trif luoro-methvl) -3 -cruinolinecarboxvlic acid.

The ester from Step 2 (1.7 g, 5.6 mmol) and //9(0/66 /J,'dV

216

2.5 N sodium hydroxide (4.4 mL, 11 mmol) were mixed in tetrahydrofuran (25 mL), methanol (10 mL), and water (25 mL) . After stirring overnight, contents were concentrated in vacuo to remove the THF and methanol. The aqueous solution remaining was extracted with diethyl ether (2 x 100 mL) .

The resulting aqueous layer was acidified with 2 N HCI causing the precipitation of an oil. The oil was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1). Fractions containing the desired product were combined, and concentrated in vacuo. The residue was triturated with dichloromethane, and filtered to afford the 6-chlcro-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-d , 300 MHz) 7.69 (s, 1H), 7.36 (s,

1H), 7.15 (d, IK, J = 8.0 Hz), 6.83 (d, 1H, J =

8.0 Hz), 6.60 (brs, 1H) , 5.20 (m, 1H) . ESHRMS m/z

276.0040 (M-K,Calc'd 276.0039). Anal. Calc'd for

C₂₁H,NO₂F₃C1 + 2.6% HO: C, 46.39; H, 2.98; N, 4.92. 2

Found: C, 45.99; H, 2.54; N, 4.85.

EXAMPLE 158

<img file="AP1149A_D0176.tif" />

6,8-Dichloro-l,2-dihydro-2-(trifluoromethyl)-3quinolinecarboxylic acid

The 1,2-dihydrc.-3-quinolinecarboxylic acid was prepared by a procedure similar to that

A?V 0 114 9

217 described in Example 157: mp 223.4-225.7 C. ^lH NMR (acetone-d₆, 300 MHz) 7.82 (s, 1H) , 7.40 (m, 2H), 6.53 (brs, 1H), 5.40 (m, 1H). ESHRMS m/z 309.9657 (M-H, Calc'd 309.9649). Anal. Calc'd for

C^HJiOjFjClj: C, 42.34; H, 1.94; N, 4.49. Found: C, 42.20; H, 1.74; N, 4.52.

EXAMPLE 159

F· •CO₂H

H 'CF₃

6,7-Difluoro-1,2-dihydro-2-(trifluoromethy1)-3quinolinecarboxylic 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. ^XH * NMR (acetone-d_{, 300 MHz) 7.79 (s, 1H) , 7.32 (m,

1H), 6.71 (m, 1H), 6.64 (brs, 1H), 5.21 (m, 1H). 20 ESHRMS m/z 278.0262 (M-H, Calc'd 278.0240). Anal

Calc'd for C^jNOjF, + 1.58% H₂O: C, 46.58; H, 2.31; N, 4.94. Found: C, 46.20; H, 2.07; N, 4.54.

ro »*.

cn co

I J CL

EXAMPLE 160

<img file="AP1149A_D0177.tif" />

6-Iodo-l,2-dihydro-2-(trifluoromethyl)-3quinolinecarboxylic acid

218

Steo 1. Preparation of ethyl 6-iodo-l.2-dihvdro2- (trif luoromethyl) - 3-cruinolinecarboxylate .

A mixture of 5-:Lodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol), diazbicyclo[2.2.2]-undec-7-ene (32.2 g, 212.0 mmol)., and ethyl 4,4,4trifluorocrotonate (35.7 g, 212.0 mmol) in 1,3dimethyl-3,4,5,6-tetrahydro-2 (IH) -pyrimidinone (48 mL) was heated at 60 °C for 8 hours. The solution was cooled to room temperature and the solution poured into ethyl acetate-hexanes (1:1, 500 mL) . The solution was extracted with 2.5 N aqueous hydrochloric acid (2 x 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 upon standing. Vacuum filtration of this suspension yielded ethyl 6-iodo-l,2-dihydro-2(trifluoromethyl)-3-quinolinecarboxylate as fine yellow crystals (19.3 g, 50 % yield): mp 137-138 °C. ^XH NMR (CDC1₃, 300 MHz) 7.62 (s, IH) , 7.367.48 (m, 2H), 6.43 (d, J = 8.2 Hz), 5.36 (brs,

IH) , 5.11 (q, IH, J := 7.1 Hz), 4.25 -4.35 (m, 2H) , 1.34 (t, 3H, J = 7.0 Hz). ESHRMS m/z 395.9716 (ΜΗ, Calc'd 395.9708).

Step 2. Preparation of 6-iodo-l,2-dihvdro-2(trifluoromethyl)-3-guinolinecarboxylic acid

Hydrolysis of t:ie ester (Step 1) was performed by a procedure similar to that described in Example 157, Step 3, yielding the carboxylic acid.

.mp 188-192 °C. *H NMR (CD₃OD/300 MHz) 7.668 (s,

IH) , 7.46 (d, IH, J = 2.2 Hz), 7.39 (dd, IH, J = 8.4, 2.2 Hz), 6.52 (d, IH, J = 8.4 Hz), 5.01 (q, IH, J = 7.5 Hz). ESilRMS m/z 367.9401 (M, Calc'd 367.9395).

APO 0 114 9

219

EXAMPLE 161

<img file="AP1149A_D0178.tif" />

6-Bromo-l,2-dihydro-2-(trifluorornethyl)-3quinolinecarboxylic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 160: mp 185-186 °C. “H NMR (CD₃OD/300 MHz) 7.68 (s, IH) , 7.31 (d, IH, J = 2.2 Hz), 7.23 (dd, IH, J = 8.7, 2.2 Hz), 6.64 (d, IH,

J = 8.7 Hz) , 5.01 (q, IH, &lt;7 = 7.5 Hz) . EIHRMS m/z

319.9519 (M, Calc'd 319.9534). Anal. Calc'd for

C_xlH₇BrF₃NO₂: C, 41.02; H, 2.19; N, 4.35; Found: C, 41.27, H, 2.23, N, 4.26.

EXAMPLE 162

<img file="AP1149A_D0179.tif" />

1,2-Dihydro-6-(trifluoromethoxy)-2(trifluorornethyl)-3-quinolinecarboxylic acid

Step 1. Preparation of 2-amino-5(trifluoromethoxy)benzoic acid.

5-(Trifluoromethoxy)isatin (15.0 g, 65 mmol) and potassium hydroxide pellets (4 g) were mixed o

in water (35 mL) and cooled to 0 C. With vigorous stirring, a solution of 30% aqueous

220 hydrogen peroxide (11.7 g), potassium hydroxide pellets (5.8 g), and water (80 mL) was added dropo wise keeping the temperature below 10 C. After o

stirring 1 hour at 0 C, glacial acetic acid (22 mL) was added drop-wise, causing foaming and formation of a precipitate. The contents were stirred overnight and filtered to afford the 2amino-5-trifluorometnoxybenzoic acid as an amber solid (12.5 g, 87 %), A small amount was recrystallized from ;=thyl acetate-hexanes to afford amber needles for an analytical sample and the remaining compouid was used without further purification: mp 142.5-144.2 C. ^XH NMR (CDC1₃, 300 MHz) 7.98 (s, IH), 7.18 (d, IH, J = 8.0 Hz) 6.62 (d, IH, J = 8.0 Hz), 6.40 (brs, 2H). Anal. Calc'd for C_sH₆NO₃F₃: C, 43.45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35.

Steo 2. Preparation of 2-amino-5(trifluoromethoxy)benzyl alcohol.

The 2-amino-5-t::*ifluoromethoxybenzoic acid (2.0 g, 9.0 mmol) in tetrahydrofuran (20 mL) was added dropwise to 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) wa:;; added drop-wise and the reaction stirred 0.5 hours. After diluting with diethyl ether (50 mL'· , the organic layer was washed with 0.1 M aqueous sodium meta-bisulfite (2 x 10 mL) and 2.5 N aeneous sodium hydroxide (2 x 10 mL). The organic layer was diluted further with hexanes (50 mL) and washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄, and concentrated in vacuo leaving an timber oil (1.9 g) which solidified. The solz.d was recrystallised from

ΑΡν ϋ114 9

221 ethyl acetate-hexanes to afford the 2-amino-5trifluoromethoxybenzyl alcohol as a light amber solid (1.44 g, 77%) : mp 75.9-77.6 °C . ²H NMR (CDC1,, 300 MHz) 7.00 (m, 2H) , 6.65 (d, 1H, J = .8.0 Hz), 4.05 (s, 2H) , 3.25 (brs, 3H)'. ESHRMS m/z 208.0592 (M+H*, Calc' d 208.0585) . Anal. Calc'd for C₈H₈NO₂F₃: 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) were refluxed in chloroform (200 mL) 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 apparatus) at 50 C (0.1 mm) to afford a yellow solid (7.2 g). The solid was recrystallized from hexanes to afford the desired 2-amino-5(trifluoromethoxy)-benzaldehyde as yellow crystals (4.4 g, 46%); mp. 42-44 °C. Ή NMR (CDC1₃, 300 MHz) 9.81 (s, 1H), 7.36 (s, 1H), 7.20 (d, 1H, J = 9.0 Hz), 6.64 (d, 1H, J = 9.0 Hz). EIHRMS m/z 205.0328 (M*, Calc' d 205.0350) .

ΑΡ/Γ/ 9 9 0 1 6 7 7

Step 4. Preparation of ethyl 1,2-dihvdro-6(trifluoro-methoxy)-2(trifluoromethvl)-330 cminolinecarboxvlate.

The 2-amino-5- (trifluoromethoxy)benzaldehyde from Step 3 (5.3 g, 26 mmol), anhydrous potassium carbonate (6.9 g, 50 mmol), and ethyl 4,4,4trifluorocrotonate (7.7 mL, 50 mmol) were mixed in anhydrous dimethylformamide (50 mL) and heated at o

C for 6 hours. The reaction was allowed to

222 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 ethyl acetate extracts were combined and washed with brine (200 mL), dried over MgSO₄, and concentrated in vacuo yielding an oil (9.6 g) . The oil was purified by flash chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1( . Fractions containing the desired product were combined, concentrated in vacuo, and the residue recrystallized from ethyl acetate-hexanes to afford the ethyl 1,2-dihydro-6(trifluoromethoxy)-2-(trifluoromethyl)-3quinolinecarboxylate as a yellow solid (4.05 g,

32%) : mp. 123-125 °C. ^XH NMR (CDCl,, 300 MHz) 7.65 (s, 1H), 7.02 (m, 2H(, 6.60 (m, 1H), 5.10 (m, 1H), 4.60 (brs, 1H), 4.28 (m, 2H), 1.32 (t, 3H, J = 7.0 Hz). ESHRMS m/z 356.0698 (M-H, Calc'd 356.0721). Anal. Calc'd for C^H^NO.F,: C, 47.34; H, 3.12; N, 3.94. Found: C, 47.37; H, 3.04; N, 3.93.

Step 5. Preparation cf 1,2-dihydro-6(trifluoromethoxy)-2-(trifluoromethyl)-3cruinolinecarboxvlic cicid.

The ethyl 1,2-dihydro-6-(trifluoromethoxy)2(trifluoromethyl)-3-quinolinecarboxylate from Step 4 (880 mg, 2.5 mmol) and 2.5 N aqueous sodium hydroxide (2 mL) were mixed in methanol (15 mL) and water (15 mL). Che solution was heated on a steam bath for 2 hours. The reaction was allowed to cool to room temperature and was extracted with diethyl ether (50 mL). The aqueous layer was acidified (pH = 1) with 3 N HCI and 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 was · crystallized from cold dichloromethane-hexanes to

AP I Ο 1 14 9

223 afford the 1,2-dihydro-6-(trifluoromethoxy)2 (trifluoromethyl) -3-quinolinecarboxylic acid as yellow needles (0.727 g, 89%): mp 127.7-128.9 C. &gt;H NMR (CDC1₃, 3 00 MHz) 7.80 (s, 1H) , 7.05 (m, 2H) ,

6.62 (d, 1H, J =8.0 Hz), 5.13 (m, 1H), 4.62 (brs,

1H). ESHRMS m/z 326.0252 (M-H, Calc'd 326.0252). Anal. Calc'd for C₁₂H_NO₃F₆: C, 44.05; H, 2.16; N, 4.28. Found: C, 43.89; H, 2.04; N, 4.24.

EXAMPLE 163

<img file="AP1149A_D0180.tif" />

6-(Trifluoromethyl)-1,2-dihydro-215 (trifluoromethyl)-3-quinolinecarboxylic acid

Step 1. Preparation of N-(4trifluoromethvlohenvl)-2,2-dimethvlorooanamide.

A solution of dichloromethane (200 mL), 420 aminobenzotrifluoride (32.0 g, 199 mmol) and triethylamine (40 g, 396 mmol) was cooled to 0 °C under a dry nitrogen atmosphere. Trimethylacetyl chloride (32.9 g, 273 mmol) was added drop-wise over 2 hours, maintaining the temperature below 10 °C. After the 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 afford a white solid, N-(4-trifluoromethylphenyl)-2,2dimethylpropanamide (48.0 g, 98%): mp 157-159 °C.

^XH NMR (CDCl₃/300 MHz) 7.61 (ab, 4H, J = 8.7, Δν =

ΑΡ/Γ/ 9 9/0167’

224

28.6 Hz), 7.47 (br ε, 1H), 1.33 (s, 9H) . ESHRMS m/z 246.1123 (M+H’, Calc'd 246.1106). Anal.

Calc'd for C₁₂H₁₄F₃NO: C, 58.77; H, 5.75; N, 5.71. Found: C, 58.28; H, 5.79; N, 5.65.

Step 2. Preparation of N-Γ2-formvl-4(trifluoromethyl) ofenvl1-2.2-dimethyl propanamide .

A 1 liter three neck round bottom flask equipped with equalizing addition funnel, magnetic stirer and temperature monitoring device was charged with N-(4-t rifluromethylphenyl)-2,2dimethyl propanamide (10.13 g, 41.4 mmol) and anhydrous tetrahydrafuran (150 mL). The reaction was chilled to -78 °C under nitrogen followed by slow addition of n-butyllithium (50 ml, 2.5 M in hexanes, 124 mmol) ever 0.5 hours, such that the temperature of the reaction did not rise above 65°C. The contents were held at -78 °C for one hour, O °C for two hours, then chilled back to -78 °C. Excess Ν,Ν-dimethylformamide (100 mL, 1.37 mol) was added. The: contents were warmed to room temperature and stii'red for two hours. Aqueous 1 N HCI 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 afford 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-4trifluoromethylphenyl)-2,2-dimethylpropanamide as a solid (7.36 g, 65%): mp 69-73 °C. ^XH NMR (CDCl₃/300 MHz) 11.5 (br s, 1H), 9.99 (s, 1H),

8.67 (d, 1H, J = 8.8 Hz), 7.94 (d, 1H, J = 1.6

APC 0 114 9

225

Hz), 7.83 (m, IH, ) , 1.37 (s, 9H) . ESHRMS m/z

274.1060 (M + H\ Calc'd 274.1055). Anal. Calc'd for C₁₃H,₄F₃NO₂: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.15; H, 5.43; N, 5.01.

Step 3. Preparation of ethyl 6-(trifluoromethvl) 1.2- dihvdro-2- (trifluoromethyl )-3cruinolinecarboxvlate .

To a suspension of N-(2-formyl-4-(trifluoromethylphenyl) -2,2-dimethyl propanamide (Step 2) (921 mg, 3.7 mol) and lithium hydride (115 mg,

14.5 mmol) in dimethyl sulfoxide (10 mL) was added ethyl 4,4,4-trifluorocrotonate (2.83 g, 16.8 mmol) and the contents warmed to 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 afford a yellow solid. The product was purified by flash chromatography (silica gel, eluant: ethyl acetatehexanes, 1:9) to yield, upon concentration of the appropriate fractions, ethyl 6-trifluoromethyl1.2- dihydro-2-(trifluoromethyl)-3quinolinecarboxylate as a yellow solid (65 mg, ££910/66 .'2,'dV

5%) : mp 138-139 °C. ^XH NMR (CDCl₃/300 MHz) 7.67 (s, IH), 7.26 (s, IH), 7.04 (d, IH, J =6.6 Hz), 6.62 (m, IH, ) , 5.14 (in, IH) , 4.60 (brs, IH) , 4.32 (m, 2H) , 1.35 (t, 3H, J = Ί.Ό Hz). ESHRMS m/z 338.0592 (M-H Calc'd 338.0616). Anal. Calc'd for ^Ci3^Hh^F3^NO2^{: 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-trif luoromethyl ³⁵ 1&gt; 2-dihvdro-2-(trifluoromethyl)-3cruinolinecarboxvlic acid.

226

Ethyl 6-trifluoromethyl-l, 2-dihydro-2 (trif luoromethyl) -3 -ciuinolinecarboxylate from Step 3 (45 mg, 0.13 mmol) was suspended in methanoltetrahydrofuran- water (10 mL, 7:2:1). Lithium hydroxide (24 mg, 0.52 mmol) was added, and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1 N HCl added until pH = 1. The organic solvent was removed in vauco to afford 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 ammonaum sulfate (2 X 20 mL) , dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 6-trifluoromethyl1,2-dihydro-2 - (trifluoromethyl) -3quinolinecarboxylic acid as a yellow solid, (0.041 g, 0.132 mmol, 99%) : mp 150-156 °C. *H NMR (CD₃OD/3 00 MHz) 7.78 (s, 1H) , 7.48 (s, 1H) , 7.40 (m, 1H) , 6.81 (m, 1HI , 5.17 (m, 1H) . ESHRMS m/z 310.0307 (M-H, Calc'd 310.0303).

EX,AMPLE 164

ΌΗ

6-Cyano-1, 2-dihy:lro-2 - (trif luoromethyl) -3quinolinecarboxylic acid

Step 1. Preparation of ethyl 6-cvano-l,2-dihvdro2- (trif luorornethvl) -3-cruinolinecarboxvlate.

Ν, N-Dimethyl for inamide (5 mL) was degassed with nitrogen for thirty minutes in a three neck round bottom flask equipped with a condenser,

ΑΡι01149

227 temperature monitoring, nitrogen purge and heating mantle. Ethyl 6-iodo-1,2-dihydro-2(trifluoromethyl)-3-quinolinecarboxylate (Example 158) (0.522 g, 1.32 mmol) and zinc cyanide (0.102 g, 0.792 mmol) were added to the N,Ndimethylf ormamide and stirred vigorously for ten minutes. Tetrakis(triphenylphosphine) pa 11 adium(0) (0.068 g, 0.53 mmol) was added and the contents gently warmed to 80 °C for

2 hours under a nitrogen atmosphere. Ethyl acetate (20 mL) was added, followed by extraction with aqueous 2 N ammonium hydroxide (2 X 10 mL), water (2 X 10 mL), saturated ammonium chloride (2 X 10 mL), dried over sodium sulfate and solvent 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, ethyl 6-cyano-l,2-dihydro-2-(trifluoromethyl)-320 quinolinecarboxylate as a yellow solid (188 mg,

48%) : mp 211-212 °C. ^XH NMR (CDCl₃/300 MHz) 7.68 (s, IH) , 7.43 (m, 2H) , 6.69 (d, IH, J = 8.3 Hz), 5.22 (m, IH), 4.98 (br s, IH), 1.30 (m, 2H), 1.36 (t, 3H, J = 7.1 Hz). EIHRMS m/z 314.1147 (M+NH/,

Calc'd 314.1116). Anal. Calc'd for C^H^FjNjO,: C, 56.76; H, 3.74; N, 9.46. Found: C, 56.44; H, 4.03; N, 9.29.

Step 2. Preparation of 6-cvano-l,2-dihvdro-23 0 (trifluoromethyl) -3-cruinolinecarboxvlic acid.

To a suspension of ethyl 6-cyano-l,2-dihydro2-(trifluoromethyl)-3-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 gently heated to reflux· for two hours. The contents were cooled to room

AP/?/ 9 9/01677

228 temperature and 1 N aqueous hydrochloric acid added until pH = 1. The organic solvent was removed in vacuo to afford a suspension of crude yellow solid. Diethyl ether (20 mL) was added, and the solution was washed with water (2 X 20 mL) , saturated ammonr.um sulfate (2 X 20 mL) , dried over sodium sulfate imd filtered. The filtrate was concentrated in vacuo to yield 6-cyano-l,2dihydro-2- (trif luoromethyl) -3-quinolinecarboxylic acid as a yellow sol:.d, (116 mg, 95%) : mp 238-240 °C. ^XH NKR (CD₃OD/300 MHz) 7.75 (s, IH) , 7.56 (m,

IH) , 7.43 (m, IH) , 6.79 (d, IH, J = 8.5 Hz) 5.19 (q, IH, J = 7.1 Hz). EIHRMS m/z 267.0405 (M-H,

Calc'd 267.0381). Anal. Calc'd for Ο_ΚΗ₃₁Ε₃Ν₂Ο,: C, 53.74; H, 2.63; N, 10.45. Found: C, 53.99; H,

2.89; N, 10.19.

EXAMPLE 165

<img file="AP1149A_D0181.tif" />

6-Ch.loro-l, 2-dihydro- l-methyl-2- (trifiuoromethyl)3-quinolinecarboxylic acid

Step 1. Preparation cf ethyl 6-chloro-l, 2dihvdro-l-methvl-2- (trifiuoromethyl)-3cruinolinecarboxvlate .

Ethyl 6-chloro-l,2-dihydro-2(trifiuoromethyl) -3-quinolinecarboxylate (Example 157, Step 2)(1.28 g, 4.21 mmol), tetrabutylammonium iodide (0.36 g, 0.92 mmol) and aqueous NaOH(50%, 2 mL) were stirred vigorously in methylene chloride (40 mL). Dimethyl sulfate

ΑΡϋ Ο 1 Η 9

229 (2.12 g, 16.84 mmol) was added to the dark orange mixture via syringe over 2 hours. Hexane (5 mL) was added, and the solution was washed with water (2 X 20 mL), saturated ammonium chloride solution (2X20 mL) , dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the crude ester as a yellow solid. The solid was purified by flash chromatography (silica gel,50 g; ethyl acetate-hexanes, 1:19) to yield, upon concentration of the appropriate fractions, ethyl 6-chloro-l, 2-dihyaro-l-methyl-2(trif luoromethyl)-3-quinoline- carboxylate (1.2 g, 90% yield) : mp 118-120 °C. ^XH NMR (CD₃OD/300 MHz) 7.71 (s, 1H), 7.30-7.26 (m, 2H), 6.77-6.74 (m,

1H) , 5.12 (q, 1H, 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, Calc'd 320.0665) Anal. Calc'd for C₁₄H₁₃F₃NO₂C1: C, 52.60; H, 4.10; N, 4.38. Found: C, 52.57; H, 4.14; N, 4.32.

Step 2. Preparation of 6-chloro-l,2-dihvdro-lmethvl-2- (trifluoromethyl) -3-quinolinecarboxvlic acid

Ethyl 6-chloro-l,2-dihydro-l-methyl-2(trif luoro-methyl) -3-quinolinecarboxylate (1.21 g,

3.78 mmol) was suspended in methanoltetrahyrofuran-water (20 mL, 7:2:1). Lithium hydroxide (0.262 g, 6.24 mmol) was added, and the mixture was gently heated to reflux for two hours. The reaction was cooled to room temperature and 1

0 N HCI added until pH = 1. The organic solvent was removed in vauco to afford a suspension of crude yellow solid. Diethyl ether (20 mL) was added, and the resulting solution was washed with water (2 X 20 mL) , saturated ammonium chloride (2 X 20 mL) , dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the

ART/ 9 9 / 0 1 6 77

230 product as a yellow solid, 6-chloro-l,2-dihydro-lmethyl-2- (trif luoromethyl) -3-quinoline-carboxylic acid. (1.08 g, 98% yield): mp 208-209 °C. ^ΧΗ NMR (CD3OD/3OO MHz) 7.69 (d, 1H, J = 2.5 Hz), 7.28-

<td> 7.24 (m, 2H),</td><td> 6.</td><td> 73 (dd,</td><td> 1H,</td><td> J = 9.5, 2.5 Hz), 5.13</td>

<td> (q, 1H, J = 7</td><td> .0)</td><td> , 3.16</td><td> (s,</td><td> 3H). Anal. Calc'd for</td>

<td> C₁₂H₉F₃NO₂C1:</td><td> C,</td><td> 49.42;</td><td> H,</td><td> 3.11; N, 4.80; Cl,</td>

<td> 12.16. Found:</td><td> c,</td><td> 49.88;</td><td> H,</td><td> 3.29; N, 4.59; Cl,</td>

12.42

EXAMPLE 166

<img file="AP1149A_D0182.tif" />

6-Chloro-l,2-dihydro-2- (trifluoromethyl)-1- [ [4(trif luoromethyl) phenyl] methyl ] -3 cjuinolinecarboxylic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 165: mp 229-231 °C. ^XH NMR (CD₃OD/300 MHz) 7.77 (s, 1H), 7.58 (d, 2H, J = 8.0 Hz), 7.39 (d, 2H, J 8.0 Hz), 7.30 (d, 1H, J = 2.4), 7.13 (dd, 1H, J =8.9, 2.4 Hz), 6.75 (d, 1H, J = 8.9 Hz), 5.27 (q, 1H, J = 7.0 Hz), 4.90 (ab, 2H, J = 16.7 Hz, Δν = 95.2 Hz). EIHRMS m/z 434.0401 (Calc'd for M-H 434.0383) Anal. Calc'd for C„H,₄F_SNO₂C1: C, 52.13; H, 3.22; N, 3.22; Found; C, 52.36; H, 2.91; N, 3.21.

ΑΡ ο ο 1 14 9

231

EXAMPLE 167 ο

Cl

<img file="AP1149A_D0183.tif" />

ci

ΌΗ

6-Chloro-l- [ (4-chlorophenyl)methyl] -1,2-dihydro-2(trifluoromethyl) -3-quinolinecarboxylic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 165: mp 250-253 °C. ^rH NMR (CD₃OD/3 00 MHz) 7.74 (s, 1H) , 7.32-7.13 (m, 6H) , 6.76 (d, 1H, J = 8.7 Hz), 5.22 (q, 1H, J = 7.0 Hz), 4.81 (ab, 2H, J = 16.3 Hz, Δν = 54.7 Hz). ESHRMS m/z 400.0105 (M-H, Calc'd 400.0119).

L L 9 I· 0 1 6 6 ZJ/dV

EXAMPLE 168 o

Cl

ΌΗ

O \

6-Chloro-l, 2-dihydro-2- (trif luoromethyl) -1- [ [4(methoxy)phenyl]methyl] -3-quinolinecarboxylic acid

232

The 1,2-dihyd.ro -3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 165: mp 196-197 °C. Ή NMR (CD₃OD/300 MHz) 7.71 (s, IH) , 7.27-7.26 (m, IH) , 7.18-7.12 (m, 3H) , 6.85-6.81 (m, 3H), 5.16 (q, IH, J = 7.1 Hz), 4.69 (a):», 2H, J = 15.3 Hz, Δν = 111.8 ESHRMS m/z 396.0625 (M-H,

Hz), 3.73 (s, 3H)

Calc'd 396.0614).

52.13; H, 3.22; N, 3 22. 2.91; N, 3.21.

Aral. Calc'd for C_xsH₁₄F_sNO₂Cl: C, Found: C, 52.36; H,

EXAMPLE 169

<img file="AP1149A_D0184.tif" />

6-Chloro-l-[(4-cyanophenyl)methyl]-1,2dihydro-1!- (trifluoromethyl) -3quino!. inecarboxyl ic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 165: mp 258-260 °C. ^XH NMR (CD₃OD/300 MHz) 7.78 is, IH) , 7.66 (d, 2H, &lt;7 = 8.2 Hz), 7.41 (d, 2H, J =· 8.2 Hz), 7.33 &lt;d, IH, &lt;7 = 2.7 Hz), 7.15 (dd, IE, J = 8.7, 2.7 Hz), 6.71 (d, IH, 7 = 8.7 Hz), 5.31 (q, IH, J = 7.0 Hz), 4.94 (ab, 2H, J = 17.1, Δν = 91.8 Hz). ESHRMS m/z

APO01149

233

391.0443 (M-H, Calc'd 391.0461). Anal. Calc'd for C_1SH₁₂F₃N₂O₂C1 + 0.53 % H₂O: C, 57.79; H, 3.55; N, 7.09; Found: C, 57.26; H, 3.17; N, 6.78.

EXAMPLE 170

<img file="AP1149A_D0185.tif" />

6-Chloro-l, 2-dihydro-l- [ (4-nitrophenyl)methyl] -210 (trif luoromethyl)-3-cpiiiiolinecarbo3cylic acid

The 1,2-dihydro-3-quinolinecarboxylic acid was prepared by a procedure similar to that described in Example 165: mp 225-228 °C. ^XH NMR (CD₃OD-3% TFA/300 MHz) 8.14 (d, 2H, J = 8.8 Hz),

7.77 (s, IH) , 7.42 (d, 2H, J = 8.8 Hz), 7.29 (d, IH, J = 2.4 Hz) , 7.11 (dd, IH, J = 8.9, 2.4 Hz) , 6.67 (d, IH, J = 8.9 Hz), 5.27 (q, IK, J = 6.8 Hz), 4.93 (ab, 2H, J= 17.2 Hz, Δν = 95.0 Hz).

ESHRMS m/z 411.0327 (M-H, Calc'd 411.0359).

EXAMPLE 171

<img file="AP1149A_D0186.tif" />

AP/?/ 9 9 / 0 1 6 77

AP ο Ο 1 1 4 9

23^ acceotao_e sc.; -.is carboxyl; wrererr 2' is seiecced from.

fiuoronec nyl. c.ilcrenec.iy i , crc.ilcrcr.sc.iy 1, c ri ch ic rone c cy1, csica f luoroschy 1, hepcafiecrcprcoyi, erflucrcechyi, erfiucrcpropy1, drchiereechyi , erchiorcprocyi, cifiucromechyi, and errf iucrcr.echyl; aic wherein R· is one or -era radreais ssiecced fren hydride, chloro, fiuoro, drone, redo, mechyi, echyi, rsopropyi, cerc-bucyi, eucyr, isebueyi, oencyi, hexyl, nechoxy, schoxy, isoprepyiexy, csrcbucyioxy, errfiucrenechvl, erfiucromechyi , diechyisnr.io, X-phenyinechyiaminosclfcnvi, Nohsnvischν1anrnosu1cοnv1, N-(2furyimechyi)anrresuifenyi, nrcro, N,Ndimethyiamincsulfonyl, arninosulfonyi, Nmechyiamrrcsulf e.iyi , N-echyisuifonyl, 2,2d ins c h vise h y i anr no s u 1 f ο n y i,

N- (2£2910/66 ,'i/dV ropy!', amrresuifenyi, M-morphclincsulfcnyi, ulfonyl. cencyicarbonvi, 2,2icrepvlcarbciyi, pheiyiacscyi aid phenyl; '.· cececher wren ring A ferns a ica_; cr an isomer or nec.iy mechyisul: drmechylc: or whersr; laphchyl :

C Γιο ΓΠλοC2 — •crca.s ss_s_ ;cno, rccc, n are wnerern η rs ere or nor;

•yr, echyi, isopropyl, esre

ΑΡ ϋ u ι ι x

235 butyl, «lechozy · trio luorc.methyi, trif luoromethcxy, X'-phenyimethyiamrncsuifcnyl, Xphenylethylaminosuifonyi, &gt;1— &lt;2 — furylmethyl) amrnosulf or.yl, X, Xdixmethyiaminosu1for.yl. X-methyiamincsulfonyi, N;2, 2-dtmetnyieiny1;amincsuifonyi, me thylcropy iammcsul f onyi, N-morphoiinosui fonyi, methylsulfonyl, cenoyicarbonyl, and phenyl; or wherein R² together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceotabie salt thereof.

·*&gt;

25. A compound of Claim 24 selected from compounds, and oneir isomers and pharmaceutically-acceptable salts, cf the group consisting of

6- chicro-2-trifluorcmethyl-2H-l-bencopyran-2carbcxvlic .acid;

c-ch1c ro-7-metry1-2-1 r i f1uo rome thyi-2H-ibenzoovran-2 - carboxylic acid;

S- (1-methvieth vl -2-trif iucromethy1-2Η-1-. bencopyran-2 - carboxylic acid;

S-chioro-7-(1,1-cimetnyiethyi)-2-trifiuorcmethyl2ri-1 - benz co yr an - 2 - carboxylic acid_;

S-chioro-3- (1--.5 thy ie thyl) - 2-trif luoromethy1-2Ri-benoopyran-j-carboxylic acid;

-1 r i f iuo rome t hy1-2 R-nap n thopyran-3-carbo xyi1b Ξ c i C f

7- (1, 1-dimethylethyl, -2-trifiuorcmetnyi-2R-lbenoopyran-2-carboxylib acid;

o-bromc-2-trifl.oromethyi-2R-l-benocpyran-2API?: 9 9 / 0 1 6 77 ;arboxvi.

<img file="AP1149A_D0187.tif" />

ΑΠΟ 0 114 9

236

MgSO₄, and concentrated in vacuo to give a brown oil (1.02 g) . This oil was purified by flash chromatography over silica gel, eluting with 10% ethyl acetate/hexanes to afford a brown oil (0.77 g, 58%) : H NMR (CDC1/300 MHz) 7.72 (d, IH, J =

3.4 Hz), 7.34 (m, 2H) , 6.99 (d, IH, J = 8.5 Hz), 5.71 (q, IH, J= 6.8 Hz), 4.83 (q, IH, J = 6.4 Hz), 4.33 (m, 2H), 1.35 (t, 3H, J =7.1 Hz), 0.11 (s, 9H) . FABLRMS m/z 443 (M+H).

Step 2. Preparation of 6-(l-hvdroxv-2,2,2trifluoroethvl) -2-trif luoromethvl-2H-l-benzopvran3-carboxylic acid.

The ester from Step 1 (0.15g 0.34 mmol) was 15 dissolved in THF (2 mL) and ethanol (2 mL) , treated with 2.5 N NaOH(l mL, 2.5 mmol), and stirred at room temperature for 18.6 hours. The reaction mixture was concentrated in vacuo, acidified with 3 N HCI, extracted with ethyl acetate, washed with 3 N HCI, brine, dried over MgSO₄, and concentrated in vacuo to give a yellow oil which was recrystallized from ethyl acetate/hexane to yield a white solid (0.03 g,

25%) : mp 114-120 °C. ^XH NMR (acetone-d^/300 MHz)

7.94 (s, IH), 7.65 (s, IH) , 7.60 (dd, IH, J = 8.2

Hz 2.0 Hz) , 7.11 (d, IH, J = 8.3 Hz) , 5.87 (q, IH, J = 7.0 Hz) , 5.24 (q, IH, J = 7.0 Hz) . FABLRMS m/z 341 (M-H) . ESHRMS m/z 341.0241 (M-H, Calc'd 341.0249) .

EXAMPLE 174

<img file="AP1149A_D0188.tif" />

ART,' 9 9 / 0 1 6 77

6-Chloro-2- (triflouromethyl) -1, 2APu01149

237 dibydro[1,8]napthyridine-3-carboxylic acid

Step 1. Preparation of N-r5-chloropyridin-2-vl1 2,2-dimethylpropanamide.

To 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, was added dropwise to trimethylacetyl chloride (10.60 ml, 0.09 mmol) in methylene chloride (15 mL). The reaction was allowed to warm to room temperature while stirring overnight. The resulting mixture was washed with water, brine, and was dried over MgSO₄ and filtered. Concentration of the filtrate in vacuo provided 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 affording the amide as a white solid (14.96 g,

90%); mp 51.4 - 53.4 °C. 'h NMR (CDCl₃/300 MHz)

8.25-8.15 (m, 2H), 8.00 (br s, 1H), 7.68-7.60 (m,

1H), 1.28 (s, 9H). Anal. Calc'd for C H NOCl:

13 3

C, 56.47; H, 6.16; N, 13.17 Found: C, 56.72; H, 6.34; N, 12.88.

Step 2. Preparation of N-ί5-chloro-325 formvlpvridin-2-vl]-2,2-dimethvlpropanamide.

To a chilled (-78 °C) , stirred solution of the amide (Step 1)(5.0 g, 0.024 mole) in tetrahydrofuran (100 mL) was added t-butyl lithium (1.7M in pentane, 32.4 mL, 0.055 mole) dropwise.

Dimethylformamide (2.3 mL, 0.03 mole) was added dropwise at -78 °C over 3 hours and the mixture allowed to warm room temperature. The reaction was quenched with ice water (200 mL) and extracted with ethyl acetate. The resulting organic phase was dried over MgSO₄ and was concentrated in vacuo to a volume of 20 mL. A white solid precipitated

238 which was collected by filtration yielding the formylated product (Ξ .24 g, 56%) : mp 168.7-170.8 °C. h NMR (CDClj/300 MHz) 10.60 (br s, IH) , 9.88 (s, IK), 8.57 (s, IH) , 8.00 (s, IH) , 1.28 (s, 9H) . 5 Anal. Calc'd for C H NOCl: C, ,54.89; H, 5.44; N,

II 2 2

11.64 Found: C, 54.87; H, 5.42; N, 11.40.

Step 3. Preparation 2-amino-5-chloro-3formvlpyridine.

The produce of Step 2 (2.7 g, 11 mmol) and 3

N HCI (50 mL) were heated at reflux for 2 hours. The reaction was allowed to cool to room temperature and was concentrated in vacuo yielding a light yellow solid (2.1 g) . The solid was partitioned between esthyl acetate and 2.5 N NaOH solution. The ethyl acetate layer was dried over MgSO₄ and concentrate:! in vacuo providing a solid (1.7'g). The solid was recrystallized from ethyl acetate to give the desired substituted pyridine as yellow needles (1.2 g, 68%) : mp 176.1-177.3 C.

HNMR (CDCl₃/300 MHz) 9.80 (s, IH) , 8.21 (s, IH) , 7.75 (s, IK), 6.75 (br s, 2H). Anal. Calc'd for CHNOCI: C, 46.03; 1, 3.22; N, 17.89 Found: C, €52 —

45.90; H, 3.24; N, 17.80.

Step 4. Preparation of ethyl 6-chloro-2(triflouromethyl) -1,1 -dihvdro Γ1,81 napthvridine-3carboxvlate.

The substituted pyridine from Step 3 (1.7 g, 30 11 mmol), anhydrous potassium carbonate (3.0 g, 22 mmol), and ethyl 4,4,4-trifluorocrotonate (3.3 mL, 22 mmol) were mixed in anhydrous dimethylformamide (20 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

AP G Ο 1 1 4 9

239 extracted with more ethyl acetate (100 mL) . The combined organic extracts were washed with brine (100 mL) , dried over MgSO₄, and concentrated in vacuo yielding a waxy amber solid The solid was triturated with diethyl ether providing the ester as a yellow solid (613 mg, 18%). A small amount was recrystallized from ethyl acetate for analytical data: mp 180.1-181.9 C. H NMR (CDCl/300 MHz) 7.99 (s, 1H), 7.61 (s, 1H), 7.39 (s, 1H) , 6.00 (br s, 1H), 5.33-5.20 (m, 1H) , 4.404.23 (m, 2H), 1.40-1.30 (m, 3H). Anal. Calc'd for C H NOFCl: C, 47.00; H, 3.29; N, 9.13 Found:

10 2 2 3

C, 46.83; H, 3.03; N, 9.18.

Step 5. Preparation of 6-chloro-2(trifluoromethyl)-1,2-dihvdro Γ1,81napthvridine-3carboxvlic acid.

The ester from Step 4 (1.3 g, 4.4 mmol) and

2.5 N sodium hydroxide solution (3.5 mL, 9 mmol) were 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 was 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 HCI causing the precipitation of a yellow solid (1.1 g). The solid was triturated with ethanol-acetone and collected by vacuum filtration providing the title compound as a yellow solid (276 mg, 23%) : mp 287.4-288.4 °C.

H NMR (acetone-d£/300 MHz) 11.50 (br s, 1H) ,

8.03 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.28 (br s, 1H), 5.42-5.30 (m, 1H). Anal. Calc'd for

C HNOFC1: C, 43.11; H, 2.17; N, 10.05 Found:

6 2 2 3 .

C, 42.88; H, 2.03; N, 10.06.

LL 9 t 0 / 6 6 /i,

240

EXAMPLE 175

<img file="AP1149A_D0189.tif" />

(S)-6,8-Dichloro-2-(trifluoromethyl)-2H-1benzopyran-3-carboxylic acid

6,8-Dichloro-2-'trifluoromethyl)-2H-110 benzopyran-3-carboxy],ic acid (Example 32) (3 00 g, 1.04 mol) was added to ethyl acetate (750 mL).

The mixture was stirred for 5 minutes, warmed to 70 °C and held at this temperature for 5 minutes. The resulting solution was cooled to 50 °C and (r) - (-)-α-methylbenzylamine (58 g, 0.48 mol)was added. Heptane (1880 mL) was added and the mixture stirred for 0.5 hour, then stirring was discontinued. The reaction was allowed to cool to 22 °C and stand for 8 hours. The salt crystallized during this 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 mm) for 24 hours to give the salt(35 g, 16 %).

A three-neck 2 I, round bottom flask was purged with nitrogen and was charged with deionized water (750 mL) and the salt (103 g, 0.24 mole; This material v;as obtained using a similar procedure to that described above). To the resulting stirred suspension was added concentrated HCI (37 mL) drop-wise over 0.5 hours with good stirring below 20 °C causing the free carboxylic acid to precipitate. After stirring

ΑΡυ 0 114 9

241 for 2 hours, the suspension was vacuum filtered and the solid 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. 1H NMR (acetonedg/300 MHz) 7.94 (s, 1H), 7.60 (s, 2H), 6.04 (q,

1H, J = 6.8 Hz). ESHRMS m/z 310.9489 (M-H, Calc'd

310.9450) . This compound was determined to have an optical purity of greater than 90% ee. The optical purity was determined by the method described in Example 66.

BIOLOGICAL EVALUATION

Rat Carrageenan Foot Pad Edema Test

The carrageenan foot edema test was performed with materials, reagents and procedures essentially as described by Winter, et al. , (Proc. Soc. Exp. Biol. Med&gt; , 111, 544 (1962)). Male Sprague-Dawley rats were selected in each group so that the average body weight was as close as possible. Rats were fasted with free access to water for over sixteen hours prior to the test. The rats were dosed

LT orally (1 mL) with compounds suspended in vehicle containing 0.5% methylcellulose and 0.025% surfactant, or with vehicle alone. One hour later a subplantar injection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% saline was administered and the volume of the injected foot was measured with a displacement plethysmometer connected to a pressure transducer with a digital indicator. Three hours after the injection of the carrageenan, the volume of the foot was again measured. The average foot swelling in a group of drug-treated animals was compared with that of a group of placebo-treated animals and the percentage inhibition of edema was determined (Otterness and Bliven, Laboratory Models for Testing NSAIDs, in Non-steroidal AntiInflammatory Drugs, (J. Lombardino, ed. 1985)). The %

99/01677

242 inhibition shows t.he % decrease from control paw volume determined in this procedure and the data for selected compounds in this invention are summarized in Table I.

TABLE I.

RAT PAW EDEMA ANALGESIA % Inhibition % Inhibition

Example @ 30mq/kg bcdv weight @ 30mq/kq body weight 1 57 58

Evaluation of COX-1 and COX-2 activity in vitro

The compounds of this invention exhibited inhibition in vitro of COX-2. The CDX-2 inhibition activity of the compounds of this invention illustrated in the Examples was determined by the following methods.

a. Preparation of recombinant COX baculoviruses Recombinant COX-1 and COX-2 were prepared as described by Gierse et al, [U. Eiochem., 305, 479-84 (1995)]. A 2.0 kb fragment containing the coding region of either human or murine COX-1 or human or murine COX-2 was cloned into a BamHl site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-1 and COX-2 in a manner similar to the method of D.R. O'Reilly et al (laculovirus Expression Vectors: A Laboratory Manual (1992)). Recombinant baculoviruses were isolated by transfecting 4 pg of baculovirus transfer vector DNA into SF9 insect cells (2χ10θ) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate· method. See M.D. Summers and G.E. Smith, A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses were purified by three rounds of plague purification and high titer (10^-10^ pfu/mL) stocks of virus were prepared. For large scale production, SF9 insect cells were

AP 0 0 1 14 9 infected in 10 liter fermentors (0.5 x 10⁵/mL) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1. After 72 hours the cells were centrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% 3—[(3— cholamidopropyl) dimethylammonio]-1-propanesulf onate (CHAPS) . The homogenate was centrifuged at 10,000xG for 30 minutes, and the resultant supernatant was stored at -80°C before being assayed for COX activity.

b. Assay for COX-1 and COX-2 activity

COX activity was assayed as PGE2 formed/pg protein/time using an ELISA to detect the prostaglandin released. CHAPSsolubilized insect cell membranes containing the appropriate COX enzyme were incubated in a potassium phosphate buffer (50 mM, pH 8.0) containing epinephrine, phenol, and heme with the addition of arachidonic acid (10 μΜ) . Compounds were pre-incubated with the enzyme for 10-20 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was stopped after ten minutes at 37 °C/room temperature by transferring 40 μΐ of reaction mix into 160 μΐ ELISA buffer and 25 μΜ indomethacin. The PGE2 formed was measured by standard ELISA technology (Cayman Chemical) . Results are shown in Table II.

c. Fast assay for COX-1 and COX-2 activity

COX activity was assayed as PGE2 formed/pg protein/time using an ELISA to detect the prostaglandin released. CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme were incubated in a potassium phosphate buffer (0.05 M Potassium phosphate, pH 7.5, 2 μΜ phenol, 1 μΜ heme, 300 μΜ epinephrine) with the addition of 20 μΐ of 100 μΜ arachidonic acid (10 μΜ) . Compounds were pre-incubated with the enzyme for 10 minutes at 25 °C prior to the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was

AP?,' 9 9 / 0 1 6 77

244 stopped after two minutes at 3 7 °C/room temperature bytransferring 40 μΐ of reaction mix into 160 μΐ ELISA buffer

<td colspan="2"> and 25 μΜ indomethacin.</td><td colspan="3"> The PGE2 formed was measured</td>

<td> standard</td><td colspan="2"> ELISA technology (Cayman</td><td> Chemical) .</td><td> Results</td>

<td> shown in</td><td> Table II.</td><td></td><td></td><td></td>

<td></td><td></td><td> TABLE II</td><td> •</td><td></td>

<td> Example</td><td> COX-2*</td><td> COX-1*</td><td> COX-2</td><td> COX-1</td>

<td></td><td> IC^pM .</td><td></td><td></td><td></td>

<td> 1</td><td> 0.3</td><td> 45</td><td></td><td></td>

<td> 2</td><td> &lt;0.1</td><td> 78</td><td> &lt;0.1</td><td> 5.0</td>

<td> 6</td><td> &lt;0.1</td><td> &gt;100</td><td></td><td></td>

<td> 7</td><td> 0.1</td><td> 16</td><td> &lt;0.1</td><td> 1.0</td>

<td> 8</td><td> &lt;0.1</td><td> 61</td><td> &lt;0.1</td><td> 21</td>

<td> 9</td><td> &lt;0.1</td><td> 1.4</td><td> &lt;0.1</td><td> &lt;0.1</td>

<td> 12</td><td> 7</td><td> 55</td><td></td><td></td>

<td> 13</td><td> .3</td><td> &gt;100</td><td></td><td></td>

<td> 14</td><td> &gt;100</td><td> &gt;100</td><td></td><td></td>

<td> 15</td><td> &gt;0.1</td><td> 11</td><td> 133.6</td><td> 44</td>

<td> 16</td><td> &lt;0.1</td><td> 24</td><td> 1.4</td><td> 51</td>

<td> 18</td><td> 12</td><td> &gt;100</td><td></td><td></td>

<td> 21</td><td> 11</td><td> 3.5</td><td></td><td></td>

<td> 22</td><td> &gt;100</td><td> &gt;100</td><td></td><td></td>

<td> 23</td><td> 7</td><td> &gt;100</td><td> 24</td><td> &gt;100</td>

<td> 25</td><td> &gt;100</td><td> 78</td><td></td><td></td>

<td> 26</td><td> &gt;100</td><td> 20</td><td></td><td></td>

<td> 27</td><td> 67</td><td> &gt;100</td><td></td><td></td>

<td> 29</td><td> &lt;0.1</td><td> &gt;100</td><td></td><td></td>

<td> 30</td><td> &lt;0.1</td><td> 1.2</td><td> 16</td><td> 3.8</td>

<td> 31</td><td> &lt;0.1</td><td> 94</td><td></td><td></td>

<td> 32</td><td> 0.3</td><td> 31</td><td> 0.3</td><td> 0.7</td>

<td> 33</td><td> &lt;0.1</td><td> 5.7</td><td> 8.2</td><td> 28</td>

<td> 35</td><td> 2.2</td><td> 8.9</td><td> 1.7</td><td> 11</td>

<td> 38</td><td> 0.2</td><td> 6.2</td><td> 25.7</td><td> 57</td>

<td> 39</td><td> 0.2</td><td> 45</td><td> 1.3</td><td> &gt;100</td>

<td> 40</td><td> &lt;0.1</td><td> 24</td><td> 74</td><td> 43 .</td>

ΔΡ ϋ Ο 1 14 9 ^ΜΓ 245

TABLE II. Cont.

<td></td><td> Example</td><td> COX-2’</td><td> cox-Γ</td><td> COX-2</td><td colspan="2"> COX-1</td>

<td></td><td></td><td> IC„ UM</td><td> IC^UM</td><td rowspan="2"> ΙΟ^μΜ &lt;0.1</td><td rowspan="2"> 11</td><td></td>

<td> 5</td><td> 42</td><td> &lt;0.1</td><td> 2.3</td><td></td>

<td></td><td> 43</td><td> 99</td><td> 85</td><td></td><td></td><td></td>

<td></td><td> 44</td><td> 0.3</td><td> 72</td><td> 21</td><td> &gt;100</td><td></td>

<td></td><td> 45</td><td> 0.2</td><td> 47</td><td> 46</td><td> &gt;100</td><td></td>

<td></td><td> 46</td><td> 0.2</td><td> 24</td><td> 74</td><td> 43</td><td></td>

<td> 10</td><td> 47</td><td> 1.9</td><td> 31</td><td> 1.7</td><td> &gt;100</td><td></td>

<td></td><td> 49</td><td> 24</td><td> &gt;100</td><td> 31</td><td> &gt;100</td><td></td>

<td></td><td> 50</td><td> 79</td><td> &gt;100</td><td></td><td></td><td></td>

<td></td><td> 52</td><td> 20</td><td> &gt;100</td><td></td><td></td><td></td>

<td></td><td> 53</td><td> 8</td><td> 13</td><td> 6</td><td> &gt;100</td><td></td>

<td> 15</td><td> 54</td><td> 19</td><td> &gt;100</td><td></td><td></td><td></td>

<td></td><td> 55</td><td> 46</td><td> &gt;100</td><td> 53</td><td> &gt;100</td><td></td>

<td></td><td> 56</td><td> 12</td><td> &gt;100</td><td> 29</td><td> &gt;100</td><td></td>

<td></td><td> 57</td><td> 21</td><td> 10</td><td> 21</td><td> &gt;100</td><td></td>

<td></td><td> 59</td><td> 43</td><td> &gt;100</td><td></td><td></td><td></td>

<td> 20</td><td> 63 65</td><td> 1.4 &lt;0.1</td><td> &gt;100 1.0</td><td></td><td></td><td> O «k</td>

<td></td><td> 66</td><td> 82</td><td> 38</td><td> &lt;0.1</td><td> 16.9</td><td> cn</td>

<td></td><td> 67</td><td> &lt;0.1</td><td> 30</td><td> &lt;0.1</td><td> 6.7</td><td> cn</td>

<td></td><td> 81</td><td> &lt;0.1</td><td> 10.5</td><td> &lt;0.1</td><td> 1.6</td><td> i:</td>

<td> 25</td><td> 82</td><td> &lt;0.1</td><td> 16</td><td> &lt;0.1</td><td> 5.6</td><td> U</td>

<td></td><td> 83</td><td> &lt;0.1</td><td> 9.6</td><td> &lt;0.1</td><td> 1.4</td><td> &lt;</td>

<td></td><td> 84</td><td> 0.1</td><td> 25</td><td> &lt;0.1</td><td> 2.8</td><td></td>

<td></td><td> 88</td><td> &lt;0.1</td><td> 12.4</td><td> &lt;0.1</td><td> 6.4</td><td></td>

<td></td><td> 91</td><td> &lt;0.1</td><td> 23</td><td> 0.2</td><td> 36</td><td></td>

<td> 30</td><td> 96</td><td> 0.2</td><td> &gt;100</td><td> 0.3</td><td> 100</td><td></td>

<td></td><td> 97</td><td> 0.2</td><td> 78</td><td> 0.1</td><td> 25</td><td></td>

<td></td><td> 98</td><td> 2.0</td><td> &gt;100</td><td> 1.5</td><td> 19</td><td></td>

<td></td><td> 99</td><td> 0.2</td><td> 36</td><td> &lt;0.1</td><td> 23</td><td></td>

<td></td><td> 101</td><td> &lt;0.1</td><td> 18</td><td> &lt;0.1</td><td> 16</td><td></td>

<td> 35</td><td> 103</td><td> 36</td><td> 61</td><td></td><td></td><td></td>

<td></td><td> 104</td><td> &lt;0.1</td><td> 24</td><td> &lt;0.1</td><td> 8.2</td><td></td>

<td></td><td> 105</td><td> 0.3</td><td> 4.5</td><td> 0.2</td><td> 0.1</td><td></td>

TABLE II. Cont.

246

<td> Example</td><td> COX-2’</td><td> COX-1* IC_UM</td><td rowspan="2"> COX-2 &lt;0.1</td><td> COX-1</td>

<td> 106</td><td> 0.2</td><td> 21</td><td> 5.7</td>

<td> 114</td><td> &lt;0.1</td><td> &lt;0.1</td><td> &lt;0.1</td><td> &lt;0.1</td>

<td> 115</td><td> &lt;0.1</td><td> &lt;0.1</td><td> &lt;0.1</td><td> &lt;0.1</td>

<td> 116</td><td> &lt;0.1</td><td> &lt;0.1</td><td> &lt;0.1</td><td> &lt;0.1</td>

<td> 120</td><td> &lt;0.1</td><td> 98</td><td> &lt;0.1</td><td> 33</td>

<td> 125</td><td> &lt;0.1</td><td> 0.2</td><td> &lt;0.1</td><td> &lt;0.1</td>

<td> 129</td><td> 0.2</td><td> 2.6</td><td> &lt;0.1</td><td> 0.3</td>

<td> 138</td><td> 0.3</td><td> 42.5</td><td> &lt;0.1</td><td> 11.1</td>

<td> 152</td><td> &lt;0.1</td><td> 74</td><td> &lt;0.1</td><td> 10</td>

<td> 154</td><td> 0.5</td><td> 68.5</td><td> &lt;0.1</td><td> 37</td>

<td> 155</td><td> &lt;0.1</td><td> 1.6</td><td> &lt;0.1</td><td> &lt;0.1</td>

<td> 156</td><td> &lt;0.1</td><td> 0.8</td><td> &lt;0.1</td><td> 0.1</td>

<td colspan="2"> * fast assay Also embraced</td><td> within this</td><td> invention is</td><td> a class</td>

pharmaceutical compc.sitions comprising the active compounds of Formula I in association with one or more non-toxic, pharmacex:.tically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as carrier materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

The phrase co •therapy (or combination-therapy) , in defining use of a cyclooxygenase-2 inhibitor agent and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of t?iese agents in a substantially

AP c· ο 1 14 9

247 simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.

The phrase ”therapeutically-effective” is intended 5 to qualify the amount of each agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or 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 route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, preferably in the range of about

0.5 to 500 mg and most preferably between about 1 and 100 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.5 and about 20 mg/kg body weight and most preferably between about 0.1 to 10 mg/kg body weight, may be 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

APT,9 9 / 0 1 6 77

248 compounds of this invention to the affected area two to four times a day.

For inflammations of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical 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 most preferably 0.4 to 15% w/w. When formulated, in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-inwater cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The-topical formulation may desirably include a compound which enhar ces absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers: include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the p/iase may comprise merely an emulsifier, it may comprise a mixture of at least one

AP0₂J)₉1 1 4 9 emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil 5 and a fat. Together, the emulsifier (s) with or without .stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the socalled emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers 10 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 suitable oils or fats for the 15 formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable 20 product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl 25 palmitate, butyl stearate, 2-ethylhexyl palmitate or a f

blend of branched chain esters may be used. These may be &lt;

used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to. 10% and particularly about 1.5% w/w.

ZZ9I.0/6⁶'

250

For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants; appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, celatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulc.ted for convenient administration.

Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylme thyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one cr more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may 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 pharmaceutical art.

All mentioned references are incorporated by reference as if here written. The priority document, USSN 60/044,485 is also incorporated by reference.

Although this invention has been described with respect to specific embodimencs, the details of these embodiments are not to be construed as limitations.