Indian Patents. 240478:NOVEL SUBSTITUTED TRICYCLIC ORGANIC COMPOUND USEFUL FOR INHIBITING SPLA2 MEDIATED RELEASE OF FATTY ACIDS

Title of Invention	NOVEL SUBSTITUTED TRICYCLIC ORGANIC COMPOUND USEFUL FOR INHIBITING SPLA2 MEDIATED RELEASE OF FATTY ACIDS
Abstract	Novel tricyclics are disclosed together with the use of such compounds for inhibiting Spla2 mediated releases of fatty acids for treatment of conditions such as septic shock.

Full Text	This application claims the benefit of U.S. Serial No. 09/062,328 Tiled April 17, 1998 FIELD OF THE INVENTION: This invention relates to novel substituted tricyclic organic compounds useful for inhibiting sPL? 2 mediated release of fatty acids for conditions such as septic shock. BACKGROUND AND PRIOR ART The structure and physical properties of himan non-pancreatic secretory phospholipase A2 (hereinafter called, '"PLA2") has been thoroughly described in two articles, namely, "Cloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluid" by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 533 5- 5338, 1989; and "Structure and Properties of a Human Non- pancreatic Phospholipase A2" by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference. It is believed that SPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids. Thus, it is important to develop compounds which inhibit SPLA2 mediated release of fatty acids (e.g., arachidonic acid). Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of SPLA2 such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc. It is desirable to develop new compounds and trealment for sPLA2 induced diseases. DETAILED DESCRPTION Tricyclic compounds effective in inhibiting human SPLA2 mediated release of fatty acids are depicted in the general formula I below: wherein; Z is cyclohexenyl, or phenyl, R° is selected from groups (a), (b) and (c) where; (a) is - C Jalkynyl, carbocyclic radicals, or heterocyclic radicals, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(L)-R80; where, (L)-is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in -(L)- are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen only, (v) carbon, hydrogen, and one sulfur only, and (vi) an carbon, hydrogen, and oxygen only; and where R80 is a group selected from (a) or (b); R21 is a non-interfering substituent where f is 1-3; R1 is -NHNH2,-NH2/ or -CONH2; R2' is selected from the group consisting of -OH, and -0(CH2)tR5' where R5' is H, -CN, -NH2, -CONH2/ -CONR9R10 -NHS02R15; - CONHS02R15, where R15 is - (Ci-C6) alkyl or -CF3; phenyl or phenyl substituted with -C02H or -C02 (C1-C4) alkyl; and - (La) - (acidic group), wherein -(La)- is an acid linker having an acid linker length of 1 to 7 and t is 1-5; R3' is selected from non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt, thereof. The compounds of Formula I contemplated by this invention are selected from the group consisting of [9- benzyl-5-carbamoyl-l-fluorocarbazol-4-yl]oxyacetic acid, {9- [(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, {9-[(3-chlorophenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3- trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid, sodium salt, {9-[(2-methylphenyl)methyl]- 5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9- [(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(3-trifluoromethoxyphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, [9- benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid, [9- [(cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid, [9-[(cyclopentyl)methyl]-5-carbamoylcarbazol-4- yl]oxyacetic acid or a pharmaceutical]^ acceptable racemite, solvate, tautomer, optical isomer, prodrug derivative or salt thereof. This invention is also a pharmaceutical formulation comprising a compound selected from the group consisting of [9-benzyl-5-carbamoyl-l-fluorocarbazol-4- yl]oxyacetic acid, {9-[(phenyl)methyl]-5-carbamoyl-carba:ol- 4-yl}oxyacetic acid, {9-[(3-fluorophenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3- chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3-trifluoromethylphenyl)methyl]-5- carbamoylcarbazol-4-yl }oxyacetic acid, sodium salt, {9-[',2- methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(3-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9—[;3- trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, sodium salt, [9-benzyl-5-carbaraoyl-l- chlorocarbazol-4-yl]oxyacetic acid, [9-[(cyclohexyl)methyl]- 5-carbamoylcarbazol-4-yl]oxyacetic acid, and [9- [(cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid in association with one or more pharmaceutically acceptable diluents, carriers and excipients. This invention is also a method of inhibiting SPLA2 comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound selected from the group consisting of [9-benzyl-5-carbamoyl- l-fluorocarbazol-4-yl]oxyacetic acid, {9-[(phenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3- fluorophenyl)methyl]-5-carbamoylcarbazol-4-ylJoxyacetic acid, {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid, {9-[(3-trifluoromethylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(2- methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(3-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[ 3- trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4- yl)oxyacetic acid, sodium salt, [9-benzyl-5-carbamoyl-l- chlorocarbazol-4-yl]oxyacetic acid, [9-[(cyclohexyl)methyl]- 5-carbamoylcarbazol-4-yl]oxyacetic acid, and [9- [(cyclopentyl)methyl ]-5-carbamoylcarbazol-4-yl]oxyacetic acid. According to a further aspect of the present invention, there is provided a method of selectively inhibiting SPLA2 in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound selected from the group consisting of [9-benzyl-5-carbamoyl-l-fluorocarbazol-4- yl ] oxyacetic acid, {9- [ (phenyl) methyl ] -5-carbamoylcarbazol- 4-yl}oxyacetic acid, {9-[(3-fluorophenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, {9-{ chlorophenyl) methyl)-5-carbamoylcarbazol-4-yl)oxyacet i c acid, {9- [(3-tri fluoromethylphenyl J methyl]-5- carbamoylcarbazol-4-yl]oxyacetic acid, sodium salt, (9-[(2- methylphenyl)methyl ]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, (9-[(3-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(3- trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4- yDoxyacetic acid, sodium salt, [9-benzyl-5-carbamoyl-l- chlorocarbazol-4-yl)oxyacetic acid, [9-[(cyclohexyl)methyl]- 5-carbamoylcarbazol-4-yl]oxyacetic acid, and [9- [{cyclopentyl) methyl ]-5-carbamoylcarbazol-4-yl]oxyacetic acid. This invention, further provides a compound selected from the group consisting of [9-benzyl-5-carbamoyl-l- fluorocarbazol-4-yl]oxyacetic acid, {9-[(phenyl)-methyl]- 5-carbamoylcarbazol-4-yl}oxyacetic acid I, {9-[(3- fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, {9-[(3-trifluoromethylphenyl)methyl]- 5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9- [(2-methylphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, sodium salt, {9-[(3- methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(3-trifluoromethoxyphenyl)methyl] - 5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, [9- benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid, [9-[(eyelohexyl)methyl]-5-carbamoylcarbazol-4- yl]oxyacetic acid, and [9-[(cyclopentyl)methyl]-5- carbamoylcarbazol-4-yl]oxyacetic acid for use as a medicament in the treatment of inflammatory diseases such as, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathies, ankylosing spondylitis, Reiter's syndrome, psoriatic arthropathy, enteropathic spondylitis, juvenile arthropathy or juvenile ankylosing spondylitis, reactive arthropathy, infectious or post- infectious arthritis, gonococcal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with "vasculitic syndromes", polyarteritis nodosa, hypersensitivity vasculitis, Luegenec's granulomatosis, polymyalgia rheumatica, giant cell arteritis, calcium crystal deposition arthropathies pseudo gout, non- articular rheumatism, bursitis, tenosynovitis epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury, miscellaneous forms of arthritis, "Charcot joint" neuropathic joint disease, hemarthrosis, Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, sarcoidosis, hemochromatosis, sickle cell disease and other hemoglobinopathies, hyperlipoproteinemia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behcet's Disease, systemic lupus erythrematosus, or relapsing polychondritis; and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit SPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products. Other objects, features and advantages of the present invention will become apparent from the subsequent description and the appended claims. Definitions: As used herein, the term, "alkyl by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like. The term "alkyl" includes -(Ci-C2)alkyl, - (C1-C4)alkyl, -(C1-C6)alkyl, -(C5- C14)alkyl, and -(C1-C10)alkyl. The term "alkenyl" as used herein represents an olefinically unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl as well as dienes and trienes of straight and branched chains. The term "alkynyl" denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as well as di- and tri-ynes. The term "halo" means chloro, fluoro, bromo or iodo. The term "-(C1-C4)alkoxy", as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups, attached to the remainder of the molecule by the oxygen atom. The term "phenyl(C1-C4)alkyl" refers to a straight or branched chain alkyl group having from one to four carbon atoms attached to a phenyl ring which chain :s attached to the remainder of the molecule. Typical phenylalkyl groups include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, and phenylbutyl. The term "-(C1-C4)alkylthio" defines a straight or branched alkyl chain having one to four carbon atoms attached to the remainder of the molecule by a sulfur atom. Typical -(C1-C4)alkylthio groups include methylthio, ethylthio, propylthio, butylthio and the like. The term "-(C3-C14)cycloalkyl" includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl and the like. The term "-(C3-C14)cycloalkyl" includes and - (C3-C7)cycloalkyl. The term, "heterocyclic radical", refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyridyl, thienyl, fluorenyl, pyrrolyl, furanyl, thiophen/i, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl^ phthalazinyl, quinazolinyl, and quinoxalinyl. The term "carbocyclic radical" refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexeyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), where n is an integer from 1 to 8. The term, "non-interfering substituent", refers to radicals suitable for substitution at positions 1, 2, 3, 7 and/or 8 on the tricyclic nucleus (as depicted in Formula III) and radical(s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are hydrogen, -(C1-C14)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C7-C12)aralkyl, -(C7-C12)alkaryl, -(C3-C8)cycloalkyl, -(C3-C8)cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, - (C1-C6)alkoxy, -(C2-C6)alkenyloxy, -(C2-C6)alkynyloxy, - (C1-C12)alkoxyalkyl, -(C1-C12)alkoxyalkyloxy, -(C1-C12)alkylcarbonyl, -(C^-C^)alkylcarbonylamino, -(C1-C12)alkoxyamino, -(C1-C12)alkoxyaminocarbonyl, -(C1-C12)alkylamino, -(C1-C6)alkylthio, -(C1-C12)alkylthiocarbonyl, - (C1-C6)alkylsulfinyl, - (C1-C6)alkylsulfonyl, -(C1-C6)haloalkoxy, -(C1-C6)haloalkylsulfonyl, -(C1-C6)haloalkyl, -(C1-C6)hydroxyalkyl,-(CH2)nCN' -(CH2)nNR9R10, -C(0)0(C1-C6alkyl), -(CH2)n0(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio; - (C0NHS02) R15, where R15 is - (C1- C6) alkyl; -CF3 , naphthyl or - (CH2)^phenyl where s is 0-5; -CHO, -CF3, -OCF3, pyridyl, amino, amidino, halo, carbamyl, carboxyl, carbalkoxy, -(CH2)nC02H, cyano, cyanoguanidinyl, guanidino, hydrazide, hydrazine hydrazido, hydroxy/ hydroxyamino, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, furyl, thiophenyl -COR9, -CONR9R10, -NR9R10, - NCHCOR9, -S02R9, -OR9, -SR9, CH2S02R9, tetrazolyl or tetrazolyl substituted with - (C1-Ce) alkyl, phenyl or -(C1- C4)alkylphenyl, - (CH2) nOSi (Cj-Ce) alkyl and (Ci~ Ce)alkylcarbonyl; where n is from 1 to 8 and R9 and R10 are independently hydrogen, -CF3/ phenyl, - (C]-C4) alkyl, - (C1- C4) alkylphenyl or -phenyl (Cj-C^) alkyl The term, "acidic group" means an organic group which when attached to a tricyclic nucleus, through suitable linking atoms (hereinafter defined as the "acid linker"), acts as a proton donor capable of hydrogen bonding. Illustrative of an acidic group are the following: where n is 1 to 8, R89 is a metal or -(C1-C10)alkyl, and R99 is hydrogen or -(C1-C10)alkyl. The words, "acid linker" refer to a divalent linking group symbolized as, -(La)-, which has the function of joining the 5 or 6 position of the tricyclic nucleus to an acidic group in the general relationship: (tricyclic nucleus) ~(La)- Acidic Group The words, "acid linker length", refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group -(La)- that connects the 5 or 6 position of the tricyclic nucleus with the acidic group. The presence of a carbocyclic ring in -(La)- counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of -(La)-. Illustrative acid linker groups are; where t is 1 to 5, Q is selected from the group -(CH2)-, -O-, -NH-, and -S-, and R84 and R85 are each independently selected from hydrogen, -(C1-C10)alkyl, aryl, -(C1- C10)alkaryl, -(C1-C10)aralkyl, carboxy, carbalkoxy, and halo, when t is one (1), groups (a), (b), (c) and (d) have acid linker lengths of 3, 3, 2, and 2, respectively. The skilled artisan will appreciate that the position of the double bond in the center 5-membered ring depends on the position of the nitrogen atom as depicted below. The salts of the above tricyclics are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. Included within the definition of pharmaceutically acceptable salts are the relatively non- toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Phar. Sci., 66: 1-19 (1977)). Compounds of the invention may have chiral centers and exist in optically active forms. R- and S- isomers and racemic mixtures are contemplated by this invention. A particular stereoisomer may be prepared by known methods using stereospecific reactions with starting materials containing asymmetric centers already resolved or, alternatively, by subsequent resolution of mixtures off stereoisomers using known methods. Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic esters (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. Other preferred esters include morpholinoethyloxy, diethylglycolamide and diethylaminocarbonylmethoxy. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. The term "acid protecting group" is used herein as it is frequently used in synthetic organic chemistry, to refer to a group which will prevent an acid group from participating in a reaction carried out on some other functional group in the molecule, but which can be removed when it is desired to do so. Such groups are discussed by T. W. Greene in chapter 5 of Protective Groups in Organic Synthesis, John Wiley and Sons, New York, 1981, incorporated herein by reference in its entirety. Examples of acid protecting groups include ester or amide derivatives of the acid group, such as, methyl, methoxymethyl, methyl-thiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenyl, aryl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, t-butyl, cyclopentyl, triphenylmethyl, diphenylmethyl, benzyl, trimethylsilyl, N,N-dimethyl, pyrrolidinyl, piperidinyl, or o-nitroanilide. A preferred acid-protecting group is methyl. The compounds of formula I where Z is cyclohexene are prepared according to the following reaction Schemes I (a)-(b) and II. Wherein; R1 is -NH2, R3(a) is H, -O (C1-C4) alkyl, halo, - (C1-C6) alkyl, phenyl, - (C-i-C4) alkylphenyl; phenyl substituted with - (d-Ce) alkyl, halo, or -CF3; -CH2OSi (C1-C6) alkyl, furyl, thiophenyl, - (C1-C6) hydroxyalkyl, - (C1-C6) alkoxy (d- C6) alkyl, - (C1-C6) alkoxy (d-C6) alkenyl; or -(CH2)nR8 where R8 is H, -C0NH2, -NR9R10, -CN or phenyl where R9 and R10 are independently hydrogen, -CF3, phenyl, - (C1-C4) alkyl, - (C1-C4) alkylphenyl or -phenyl (d-C4) alkyl and n is 1 to 8; when R1 is -NHNH2, R3(a) is H, -O(d-C4) alkyl, halo, - (d- C6) alkyl, phenyl, - (d-C4) alkylphenyl; phenyl substituted with - (d-C6) alkyl, halo or -CF3; -CH2OSi(d- C6) alkyl, furyl, thiophenyl, - (d~C6) hydroxyalkyl, - (d - C6) alkoxy(d-C6) alkyl, - (d-C6) alkoxy (d-C6) alkenyl; or - (CH2)nR8 where R8 is H, -NR9R10, -CN or phenyl where R5 and R10 are independently hydrogen, -CF3, phenyl, -(d- C4) alkyl, - (C1-C4) alkylphenyl or -phenyl (C1-C4) alkyl and n is 1 to 8; R2la\| is -OCH3 or -OH. An appropriately substituted nitrobenzene (1) can be reduced to the aniline (2) by treatment with a reducing agent, such as hydrogen in the presence of Pd/C, preferably at room temperature. Compound (2) is N-alkylated at temperatures of from about 0 to 20°C using an alkylating agent such as an appropriately substituted aldehyde and sodium cyanoborohydride to form (3). Alternately, an appropriately substituted benzyl halide may be used for the first alkylation step. The resulting intermediate is further N-alkylated by treatment with 2-carbethoxy-6- bromocyclohexanone, preferably at temperatures of about 80°C to yield (4) or by treatment with potassium hexamethyldisilazide and the bromoketoester. The product (4) is cyclized to the tetrahydrocarbazole (5) by refluxing with ZnCl2 in benzene for from about 1 to 2 days, preferably at 80°C. (Ref 1). Compound (5) is converted to the hydrazide (6) by treatment with hydrazine at temperatures of about 100°C, or to the amide (7) by reacting with methylchloroaluminum amide in benzene. (Ref 2) Alternatively, (7) may be produced by treatment of (6) with Raney nickel active catalyst conversion to the amide will also be achieved in this procedure. Compounds (6) and (7) may be dealkylated, preferably at 0°C to room temperature, with a dealkylating agent, such as boron tribromide or sodium thioethoxide, to give compound (7) where R2 (a) is -OH, which may then be further converted to compound (9), by realkylating with a base, such as sodium hydride, and an alkylating agent, such as Br(CH2)mR^, where R^ is the carboxylate or phosphonic diester or nitrile as defined above. Conversion of R2 to the carboxylic acid may be accomplished by treatment with an aqueous base. When R2 is nitrile, conversion to the tetrazole may be achieved by reacting with tri-butyl tin azide or conversion to the carboxamide may be achieved by reacting with basic hydrogen peroxide. When R2 is the phosphonic diester, conversion to the acid may be achieved by reacting with a dealkylating agent such as trimethylsilyl bromide. The monoester may be accomplished by reacting the diester with an aqueous base. When R2 and R3 are both methoxy, selective demethylation can be achieved by treating with sodium ethanethiolate in dimethylformamide at 100°C. Ref 1 Julia, M.; Lenzi, J. Preparation d'acides tetrahydro-1, 2, 3,4-carbazole-l ou -4. Bull.Soc.Chim. France, 1962, 2262-2263. Ref 2 Levin, J.I.; Turos, E.; Weinreb, S.M. An alternative procedure for the aluminum-mediated conversion of esters to amides. Syn.Comm., 1982, 12, 989-993. An alternative synthesis of intermediate (5) is shown in Scheme 1(b), as follows. where PG is a protecting group; 3a R is as defined in Scheme 1, above. The aniline (2) is N-alkylated with 2-carbethoxy- 6-bromocyclohexanone in dimethyl formamide in the presence of sodium bicarbonate for 8-24 hours at 50°C. Preferred protecting groups include methyl, carbonate, and silyl groups, such as t-butyldimethylsilyl. The reaction product (4') is cyclized to (5') using the ZnCl2 in benzene conditions described in Scheme 1(a), above. N-alkylation of (5') to yield (5) is accomplished by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours. R.3(a) is as defined in Scheme I. As discussed in Scheme I above, carbazole (5) is hydrolyzed to the carboxylic acid (10) by treatment with an aqueous base, preferably at room temperature to about 100°c. The intermediate is then converted to an acid chloride utilizing, for example, oxalyl chloride and dimethylformamide, and then further reacted with a lithium salt of (S) or (R)-4-alkyl-2-oxazolidine at a temperature of about -75°C, to give (11a) and (lib), which are separable by chromatography. The diastereomers are converted to the corresponding enantiomeric benzyl esters (12) by brief treatment at temperatures of about 0°C to room temperature with lithium benzyl oxide. (Ref 3) The esters (12) are then converted to (7) preferably by treatment with methylchloroaluminum amide (Ref 2, above) or, alternately, by hydrogenation using, for example, hydrogen and palladium on carbon, as described above, to make the acid and then reacting with an acyl azide, such as diphenylphosphoryl azide followed by treatment with ammonia. Using the procedure described above in Scheme I, compound (9a) or (9b) may be accomplished. Ref 3 Evans, D.A.; Ennis, M.D.; Mathre, D.J. Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of alpha- substituted carboxylic acid derivatives. J.Am.Chem.Soc., 1982, 104, 1737-1738. Compounds of formula I where Z is phenyl can be prepared as follows in Schemes III (a) - (g), below. A 1,2, 3, 4-tetrahydrocarbazole-4-carboxamide or 4-carboxhydrazide (13) is dehydrogenated by refluxing in a solvent such as carbitol in the presence of Pd/C to produce the carbazole-4-carboxamide. Alternately, treatment of (13) with DDQ in an appropriate solvent such as dioxane yields carbozole (14). Depending on the substituent pattern oxidation as described above may result in de-alkylation of the nitrogen. For example when R3 is substituted at the 8- position with methyl, oxidation results in dealkylation of the nitrogen which may be realkylated by treatment with sodium hydride and the appropriate alkyl halide as described in Scheme I(a) above to prepare the deired product (14). The intermediates and final products may be isolated and purified by conventional techniques, for example by concentration of the solvents, followed by washing of the residue with water, then purification by conventional techniques, such as chromatography or recrystallization. It will be readily appreciated by the skilled artisan that the starting materials are either commercially available or can be readily prepared by known techniques from commercially available starting materials. All other reactants used to prepare the compounds in the instant invention are commercially available. Benzoic acid derivative(16) where X is preferably chlorine, bromine or iodine and the protecting group is preferably -CH3, are reduced to the corresponding aniline (25) with a reducing agent, such as stannous chloride in the presence of acid under the general conditions of Sakamoto et al, Chem Pharm. Bull. 35 (5), 1823-1828 (1987). Alternatively, reduction with sodium dithionite in the presence of a base, such as sodium carbonate in a noninterferring solvent, such as water, ethanol, and/or tetrahydrofuran affords starting material (16). Alternatively, reduction by hydrogenation over a sulfided platinum catalyst supported on carbon with hydrogen at 1 to 60 atmospheres in a noninterfering solvent, preferably ethyl acetate, to form a starting material (16). The reactions are conducted at temperatures from about 0 to 100°C. preferably at ambient temperature, and are substantially complete in about 1 to 48 hours depending on conditions. The aniline (25) and dione (15) are condensed under dehydrating conditions, for example, using the general procedure of Iida, et al., (Ref 5), with or without a noninterfering solvent, such as toluene, benzene, or methylene chloride, under dehydrating conditions at a temperature about 10 to 150°C. The water formed in the process can be removed by distillation, azetropic removal via a Dean-Stark apparatus, or the addition of a drying agent, such as molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate, and the like. The process can be performed with or without a catalytic amount of an acid, such a p-toluenesulfonic acid or methanesulfonic acid. Other examples of suitable catalysts include hydrochloric acid, phenylsulfonic acid, calcium chloride, and acetic acid. Examples of other suitable solvents include tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,1,2, 2- tetrachloroethane, chlorobenzene, bromobenzene, xylenes, and carbotetrachloride. The condensation of the instant process is preferably carried out neat, at a temperature about 100 to 150°C with the resultant water removed by distillation via a stream of inert gas, such as, nitrogen or argon. The reaction is substantially complete in about 30 minutes to 24 hours. Intermediate (26) may then be readily cyclized in the presence of a palladium catalyst, such as Pd(OAc)2 or Pd(PPh3)4 and the like, a phosphine, preferably a trialkyl- or triarylphosphine, such as triphenylphosphine, tri-o- tolylphosphine , or tricyclohexylphosphine, and the like, a base, such as, sodium bicarbonate, triethylamine, or diisopropylethylamine, in a noninterfering solvent, such as, acetonitrile, triethylamine, or toluene at a temperature about 25 to 200°C to form (19). Examples of other suitable solvents include tetrahydrofuran, benzene, dimethylsulfoxide, or dimethylformamide. Examples of other suitable palladium catalysts include Pd(PPh3)Cl2, Pd(OCOCF3)2, [ (CH3C6H4) 3P] 2PdCl2, [ (CH3CH2)3P]2PdCl2, [ (C6H„)3P]2PdCl2, and [ (C6Hb) 3P] 2PdBr2. Examples of other suitable phosphines include triisopropylphosphine, triethylphosphine, tricyclopentylphosphine, 1,2-bis(diphenylphosphino)ethane, 1, 3-bis(diphenylphosphino)propane, and 1,4- bis(diphenylphosphino)butane. Examples of other suitable bases include tripropyl amine, 2,2,6,6-tetramethylpiperidine, 1,5- diazabicyclo[2.2.2]octane (DABCO), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene, (DBN) sodium carbonate, potassium carbonate, and potassium bicarbonate. The cyclization of the instant process is preferably carried out with palladium(II)acetate as catalyst in the presence of either triphenylphosphine, tri-o- tolylphosphine, 1,3-bis(diphenylphosphino)propane, or tricyclohexylphosphine in acetonitrile as solvent and triethylamine as base at a temperature about 50 to 150°C. The reaction is substantially complete in about 1 hour to 14 days. Alternatively, a preferred process for cyclizat ion consists of the reaction of intermediate (26) with a palladacycle catalyst such as trans-di(u-acetato)-bis[o-( di- o-tolylphosphino)benzyl]dipalladium (II) in a solvent such as dimethylacetamide (DMAC) at 120-140°C in the presence of a base such as sodium acetate. Intermediate (19) may be alkylated with an alkylating agent XCH2R«, where X is halo in the presence of a base to form (20). Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride, and Triton B (N- benzyltrimethylammonium hydroxide). The reaction may or may not be carried out in the presence of a crown ether. Potassium carbonate and Triton B are preferred. The amount of alkylating agent is not critical, however, the reaction is best accomplished using an excess of alkyl halide relative to the starting material. A catalytic amount of an iodide, such as sodium iodide or lithium iodide may or may not be added to the reaction mixture. The reaction is preferably carried out in an organic solvent, such as, acetone, dimethylformamide, dimethylsulfoxide, or acetonitrile. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl ether. The reaction is conducted at temperatures from about -10 to 100°C. preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions. Optionally, a phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride may be employed. Intermediate (20) may by dehydrogenated by oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in a noninterfering solvent to form (21). Suitable solvents include methylene chloride, chloroform, carbon tetrachloride, diethyl ether, methyl ethyl ketone, and t-butyl methyl ether. Toluene, benzene, dioxane, and tetrahydrofuran are preferred solvents. The reaction is carried out at a temperature about 0 to 120 °c. Temperatures from 50 to 120°C are preferred. The reaction is substantially complete in about 1 to 48 hours depending on conditions. Intermediate (21) may be aminated with ammonia in the presence of a noninterfering solvent to form a (22). Ammonia may be in the form of ammonia gas or an ammonium salt, such as ammonium hydroxide, ammonium acetate, ammonium trifluoroacetate, ammonium chloride, and the like. Suitable solvents include ethanol, methanol, propanol, butanol, tetrahydrofuran, dioxane, and water. A mixture of concentrated aqueous ammonium hydroxide and tetrahydrofuran or methanol is preferred for the instant process. The reaction is carried out at a temperature about 20 to 100°C. Temperatures from 50 to 60°C are preferred. The reaction is substantially complete in about 1 to 4 8 hours depending on conditions. Alkylation of (22) is achieved by treatment with an alkylating agent of the formula XCH2R9 where X is halo and R70 is -C02R71, -S03R71,-P (0) (OR71) 2, or -P (O) (OR71) H, where R71 is an acid protecting group or a prodrug function, in the presence of a base in a noninterfering solvent to form (23). Methyl bromoacetate and t-butyl bromoacetate are the preferred alkylating agents. Suitable bases include potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium hydride, lithium hydride, and Triton B (N-benzyltrimethylammonium hydroxide) . The reaction may or may not be carried out in the presence of a crown ether. Cesium carbonate and Triton B are preferred. The amount of alkylating agent is not critical, however, the reaction is best accomplished using an excess of alkyl halide relative to the starting material. The reaction is preferably carried out in an organic solvent, such as, acetone, dimethylformamide, dimethylsulfoxide, or acetonitrile. Other suitable solvents include tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl ether. The reaction is conducted at temperatures from about -10 to 100°C. preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions. Optionally, a phase transfer reagent such as tetrabutylammonium bromide or tetrabutylammonium chloride may be employed. Intermediate (23) may be optionally hydrolyzed with a base or acid to form desired product (24) and optionally salified. Hydrolysis of (23) is achieved using a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, aqueous potassium carbonate, aqueous sodium carbonate, aqueous lithium carbonate, aqueous potassium bicarbonate, aqueous sodium bicarbonate, aqueous lithium bicarbonate, preferably sodium hydroxide and a lower alcohol solvent, such as, methanol, ethanol, isopropanol, and the like. Other suitable solvents include acetone, tetrahydrofuran, and dioxane. Alternatively, the acid protecting group may be removed by organic and inorganic acids, such as trifluoroacetic acid and hydrochloric acid with or withoat a noninterferring solvent. Suitable solvents include methylene chloride, tetrahydrofuran, dioxane, and acetone. The t-batyl esters are preferably removed by neat trifluoroacetic acid. The reaction is conducted at temperatures from about -10 to 100°C. preferably at ambient temperature, and is substantially complete in about 1 to 48 hours depending on conditions. The starting material (16) is prepared by esterifying compound (15) with a alkyl halide = XPG; where X is halo and PG is an acid protecting group, in the presence of a base, preferably potassium carbonate or sodium cabonate, in a noninterferring solvent, preferably dimethylformamide or dimethylsulfoxide. The preferred alicyl halide is methyl iodide. The reaction is conducted at temperatures from about 0 to 100°C. preferably at ambient temperature, and is substantially complete in about 1 to 4 8 hours depending on conditions. Alternatively the starting material (16) may be prepared by condensation with an alcohol HOPG, where PG is an acid protecting group, in the presence of a dehydrating catalyst such as, dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole. In addition, U.S. Patent No. 4,885,338 and Jpn. Kokai Tokkyo Koho 05286912, Nov 1993 Hesei teach a method for preparing 2-fluoro-5-methoxyaniline derivatives. Benzoic acid derivatives (16) (X= CI, Br, or I) and boronic acid derivative (27) (either commercially available or readily prepared by known techniques from commercially available starting materials) are condensed under the general procedure of Miyaura, et al., (Ref 8a) or Trecourt, et al., (Ref 8b) in the presence of a palladium catalyst, such as Pd(Ph3P)/j, a base, such as sodium bicarbonate, in an inert solvent, such as THF, toluene or ethanol, to afford compound (28). Compound (28) is converted to the carbazole product (29) by treatment with a trialkyl or triaryl phosphite or phosphine, such as, triethylphosphite or triphenyl phosphine, according to the general procedure of Cadogan, et al. (Ref 6). Compound (29) is N-alkylated with an appropriately substituted alkyl or aryl halide XCH2R4 in the presence of a base, such as sodium hydride or potassium carbonate, in a noninterfering solvent, such as toluene, dimethylformamide, or dimethylsulfoxide to afford carbazole (30). Compound (30) is converted to the corresponding amide (22) by treatment with boron tribromide or sodium thioethoxide, followed by ammonia or an ammonium salt, such as ammonium acetate, in an inert solvent, such as water or alcohol, or with methylchloroaluminum amide in an inert solvent, such as toluene, at a temperature between O to 110°C. When R3(al is substituted at the 8-position with chloro, de-alkylation of (30) with boron tribromide results in de-benzylation of the nitrogen as described above. Alkylation may be readily accomplished in a two step process. First, an O-alkylation by treatment with a haloalkyl acetate such as methyl bromo acetate using sodium hydride in tetrahydrofuran, followed by N- alkylation using for example a base such as sodium hydride and an appropriately substituted alkyl or aryl halide in dimethoxy formamide. Compound (22) can be converted to product carbazole product (24) as described previously in Scheme 111(b) above. Conversion to the desired prodrug may be accomplished by techniques known to the skilled artisan, such as for example, by treatment with a primary or secondary halide to make an ester prodrug. Alternatively, reduction of the nitro group of compound (28} with a reducing agent, such as hydrogen in the presence of palladium on carbon, in a noninterfering solvent, such as ethanol, at 1 to 60 atmospheres, at a temperature of 0 to 60°C affords the corresponding aniline (32). Compound (32) is converted to the carbazole (29) according to the general procedure described by Trecourt, et al. (Ref 8b). The aniline is treated with sulfuric acid and sodium nitrite, followed by sodium azide to form an intermediate azide which is cyclized to carbazole (29) by heating in an inert sovent, such as toluene. Compound (29) is converted to carbazole product (24) as described previously in Schemes III(b) and III (c). References: 8) a. N. Miyaura, et al., Synth. Commun. 11, 513 (1981) b. F. Trecourt, et al., Tetrahedron, 51, 11743 6) 6) J. Cadogan et al., J. Chem. Soc, 4831 (1965) In an aprotic solvent, preferably tetrahydrofuran, reduction of (40) is achieved using a reducing agent such as aluminum trihydride. Preferably, the reaction is conducted under inert atmosphere such as nitrogen, at room temperature. Sulfonylation may be achieved with an appropriate acylating agent in the presence of an acid scavenger such as triethyl amine. In a two-step, one-pot process, intermediate (50), prepared as described in Scheme 1(a) above, is first activated with an activating agent such as carbonyl diimidazole. The reaction is preferably run in an aprotic polar or non-polar solvent such as tetrahydrofuran. Acylation with the activated intermediate is accomplished by reacting with H2NSOR15 in the presence of a base, preferably diazabicycloundecene. Starting material (20) is O-alkylated with an alkyl halide or alkenyl halide, using a base such as NaH, in an aprotic polar solvent preferably anhydrous DMF, at ambient temperature under a nitrogen atmosphere. The process of aromatization from a cyclohexenone functionality to a phenol functionality can be performed by treating the tetrahydrocabazole intermediate (60) with a base such as NaH in the presence of methyl benzenesulfinate in an anhydrous solvent, such as 1,4- dioxane or DMF, to form the ketosulfoxide derivative. Upon heating at about 100°C for 1-2 hours, the ketosulfoxide derivative (60) is converted to the phenol derivative (61). Conversion of the ester (61) to the amide (62) can be achieved by treating a solution of (61) in an aprotic polar solvent such as tetrahydrofuran with ammonia gas. Phenolic O-alkylation of (62) with, for example, methyl bromoacetate can be carried out in anhydrous DMF at ambient temperature using Cs2C03 or K2C03 as a base to form (63). Desired product (64) can be derived from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H2O/CH3OH/THF solution at 50°C for 1-2 hours. When R22 is - (C1-C6) alkoxy (C1-C6) alkenyl, hydrogenation of the double bond can be performed by treating (63) in THF using Pt02 as a catalysis under a hydrogen atmosphere. Desired product can then be derived as described above in Scheme III(g) from the basic hydrolysis of ester (63) using LiOH or NaOH as a base in an H2O/CH3OH/THF solution at 50°C for 1-2 hours. The following list of abreviations are used in the Examples and Preparations. HC1 = hydrochloric acid EtOAc = ethyl acetate DMF = dimethyl formamide THF = tetrahydrofuran Et20 = diethyl ether H2O = water NaOH = sodium hydroxide EtOH = ethanol Na2SO« = sodium sulfate NaHC03 = sodium bicarbonate celite = diatomaceous earth CH2C12 = methylene chloride H2SO4 = sulfuric acid MeoH = methanol Rh/Al203 = rhodium on alumina DDQ = 2,3-dichloro-5,6-dicyano-l, 4-benzo- quinone TLC = thin layer chromotography NaH" = sodium hydride NH4OH = ammonium hydroxide LiOH = lithium hydroxide NH3 = ammonia Cs2C03 = cesium carbonate NH4oAc = ammonium acetate The following preparations of intermediates and examples of final products futher illustrate the preparation of the compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way. Preparation 1 Preparation of 5-Carbomethoxy-l,2-dihydro-9H-carbazol-4 (3H) - one from 2-bromo-3-nitrobenzoic acid a) Methyl 2-bromo-3-nitrobenzoate A solution of 2-bromo-3-nitrobenzoic acid (28.4 g, 115.0 mM), iodomethane (18.0 g, 127 mM), and potassium carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at room temperature for 72 hours. The mixture was poured into 1.5 liters of H2O. The resultant precipitate was collected by filtration and dried in vacuo to afford 28.79 g (96%) of methyl 2-bromo-3-nitrobenzoate as a white solid. XH NMR (DMS0-d6) 8 8.3 (dd, 1H, J=l and 8 Hz), 7.9 (dd, 1H, J=l a.nd 8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm"1) 2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e 259, 261. Elemental Analyses for CaH6N04Br: Calculated: C, 36.95; H, 2.33; N, 5.39. Found: C, 37.14; H, 2.37; N, 5.45. b) Methyl 2-bromo-3-aminobenzoate Hydrogen gas was passed through a solution of methyl 2- bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3% sulfided platinum on carbon in 25 mL ethyl acetate for 24 hours at room temperature. The catalyst was removed by filtration through celite. Concentration of the filtrate afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil. *H NMR (CDC13) 8 7.15 (t, 1H, J=8 Hz), 7.1 (dd, 1H, J=l and 8 Hz), 6.8 (dd, 1H, J=l and 8 Hz), and 3.95 (s, 3H) . IR (CHC13, cm"1) 3550, 3380, 2980, 2900, 1729, 1613, 1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230, 232. Elemental Analyses for CsHeNC^Br: Calculated: C, 41.77; H, 3.51; N, 6.09. Found: C, 42.01; H, 3.29; N, 6.00. b)' In an alternate procedure, Methyl 2-bromo-3- aminobenzoate may be prepared as follows: A solution of stannous chloride (15.0 g, 76.1 mM) in 30 mL of concentrated hydrochloric acid was slowly added to a solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM) in 90 mL ethanol at 15-30 °C over 1 hour. The mixture was then heated at 50-60 °C for 15 minutes. The mixture was cooled to room temperature and made alkaline by slow addition of solid sodium hydroxide maintaining a temperature of 30-35 °C. The resultant mixture was extracted three times with chloroform. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford 3.51 g (99%) of methyl 2-bromo-3-aminobenzoate as a yellow oil, identical in all respects to the material derived via catalytic hydrogenation described above. c) 3-(3-Carbomethoxy-2-bromoanilino)cyclohex-2-en-l-one A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g, 60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated at 125 °C under a stream of nitrogen for 4 h. The resultant solid was purified by HPLC on silica gel (elution with methylene chloride/ethyl acetate) to afford 17.2 g (88%) of 3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-l-one as a tan foam. 1H NMR (DMSO-d6) ? 8.75 (s, 1H), 7.6-7.4 (m, 3H) , 4.65 (s# 1H), 3.85 (s, 3H) , 2.6 (t, 2H, J=6 Hz), 2.15 (t, 2H, J=6 Hz), and 1.9 (m, 2H) . IR (CHC13, cm"1) 3400, 3004, 2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308, 1249, 1177, and 1144. MS (ES) m/e 322, 324, 326. Elemental Analyses for C14H14NO3Br: Calculated: C, 51.85; H, 4.32; N, 4.32. Found: C, 53.60; H, 4.73; N, 4.09. d) 5-Carbomethoxy-l,2-dihydro-9H-carbazol-4(3H)-one A suspension of 3-(3-carbomethoxy-2- bromoanilino)cyclohex-2-en-l-one (15.8 g, 48.8 mM), palladium acetate (1.12 g, 5.0 mM), tri-o-tolylphosphine (3.1 g, 10.0 mM), and triethylamine (6.3 g, 62.0 mM) in 120 mL acetonitrile was heated at reflux for 8 hours. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed twice with 1 N HC1, twice with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford '.1 g of a light brown foam. Purification by HPLC on silica gel (elution with gradient methylene chloride/ethyl acetate) afforded 9.2 g (78%) of the 5-carbomethoxy-l,2-dihydro-9H- carbazol-4(3H)-one as a yellow solid, identical with the material derived from 3-(3-carbomethoxy-2- chloroanilino)cyclohex-2-en-l-one, described above. 1H NKR (DMS0-d6) ? 7.5 (d, 1H, J=8 Hz), 7.25-7.1 (m, 2H), 5.7 ( = , 1H) , 3.8 (s, 3H), 2.95 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m , 2H). MS (ES) m/e 242, 244. A. 9-[(Phenyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol- 4(3H)-one A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol- 4(3H)-one (300 mg, 1.23 mM), benzyl bromide (210 mg, 1.23 mM), and potassium carbonate (170 mg, 1.23 mM) in 15 mL DMF was stirred at room temperature for 6 hours. The mixture was diluted with 80 mL H2O and chilled in the refrigerator. The resultant white precipitate was collected by filtration, washed with H2O, and dried in vacuo to afford 325 mg (79%) of the 9-[(phenyl)methyl]-5-carbomethoxy-l, 2- dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSC- d6) ? 7.7 (dd, 1H, J=l and 8 Hz), 7.45-7.0 (m, 7H) , 5.6 is,. 2H), 3.8 (s, 3H), 3.05 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 H2), and 2.2 (m , 2H). IR (KBr, cm"1) 3421, 1726, 1676, 1636, 1473, 1450, 1435, 1288, 1122, 764, 745, and 706. MS (ES) m/e 334. Elemental Analyses for C2iHi9N03: Calculated: C, 75.68; H, 5.71; N, 4.20. Found: C, 70.85; H, 5.53; N, 4.49. B. 9-[(Phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (a) A solution of the 9-[(phenyl)methyl]-5-carbomethoxy- l,2-dihydrocarbazol-4(3H)-one (1.5 g, 4.5 mM) and 2,3- dichloro-5,6-dicyano-l,4-benzoquinone (1.12 g, 5.0 mM) in 25 mL of toluene was stirred between 80-90 °C for 6 h. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride/ethyl acetate) to afford 420 tag (28%) of the 9-[ (phenyl) methyl]-4-hydroxy- 5-carbomethoxy carbazole as a yellow solid. 1H NMR (DMSO- d6) 6 10.25 (s, 1H), 7.7 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and 3.8 (s, 3H) . IR (CHC13, cm"1) 1723, 1685, 1621, 1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156, and 1138. MS (ES) m/e 330, 332. Elemental Analyses for C21H17NO3: Calculated: C, 76.13; H, 5.14; N, 4.23. Found: C, 75.90; H, 5.20; N, 4.46. (b) To a solution of the 9-[(phenyl)methyl]-5-carbomethoxy- l,2-dihydrocarbazol-4 (3H)-one (2.87 g, 8.61 mM) in 29 ml dioxane was added 60% sodium hydride in mineral oil (0.79 g, 19.8 mM) . The reaction was stirred 8 minutes, then methyl benzenesulfinate (1.80 ml, 13.8 mM) was added. The reaction was stirred an additional 1.5 h, then diluted with 43 ml dioxane and 1.13 ml acetic acid. The mixture was refluxed 1 h, diluted with ethyl acetate, and extracted with sat'd NaHC03 two times, then with brine. After drying (NaSCU) , evaporation in vacuo afforded 4.90 g. The mixture was purified by column chromatography on silica gel (elution with toluene/methylene chloride) to afford 2.31 g (81%) cf the 9-[(phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole_ lE NMR (DMSO-d6) 5 10.25 (s, 1H), 7.7 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H) , and 3.8 (s, 3H) . IR (CHC13, cm"1) 1723, 1685, 1621, 1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156, and 1138. MS (ES) m/e 330, 332. Elemental Analyses for C21H17NO3: Calculated: C, 76.13; H, 5.14; N, 4.23. Found: C, 75.90; H, 5.20; N, 4.46. C. 9-[(Phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole A solution of the 9-[(phenyl)methyl]-4-hydroxy-5- carbomethoxy carbazole (200 mg, 0.6 mM) in 4 mL MeOH and 4 0 mL concentrated aqueous ammonium hydroxide was sonicated for 30 h at 40-50 °C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HC1. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 50 mg (26%) of the 9-[(phenyl)methyl]-4-hydroxy-5- carbamoyl carbazole as a white solid. :H NMR (DMS0-d6) ? 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 J=l and 8 Hz), 7.5-7.1 (m, 9H), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H) . IR (KBr, cm"1) 3428, 3198, 3063, 1631, 1599, 1579, 1562, 1496, 1442, 1330, 1261, 1215, 775, and 697. MS (ES) m/e 315, 317. Elemental Analyses for C20Hi6N202: Calculated: C, 75.95; H, 5.06; N, 8.86. Found: C, 74.88; H, 5.40; N, 7.78. D. {9-[(Phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacet:Lc acid, methyl ester 40% Methanolic Triton B (0.11 ml, 0.24 iriM) was added to a solution of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (70 mg, 0.22 mM) in 20 mL DMF at 0 °C. After 15 minutes, methyl bromoacetate (70 mg, 0.44 mM) was added and the resultant mixture stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate, washed with 1 N HC1, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was combined with the crude material derived from a similar run utilizing 4 5 mg (0.14 mM [0.36 mM total]) of 9-[(phenyl)methyl]-4- hydroxy-5-carbamoyl carbazole. The combined residues were purified by column chromatography on silica gel (elution with ethyl acetate) to afford 76 mg (54%) of the {9- [(phenyl)methyl]-5-carbamoylcarbazol-4-yl)oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) ? 7.65 (d, 1H, J=8 Hz), 7.5 (br s, 1H), 7.4-7.15 (m, 9H), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H) , and 3.75 (S, 3H) . IR (KBr, cm"') 3367, 3200, 1760, 1643, 1579, 1496, 1452, 1427, 1216, 1157, 772, and 716. MS (FD) m/e 388. Elemental Analyses for C23H2ON2O4: Calculated: C, 71.13; H, 5.15; N, 7.22. Found: C, 70.77; H, 5.49; N, 6.79. E. {9-[(Phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt. A solution of the {9-[(phenyl(methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (10.1 mg, 0.025 mM) and 0.025 mL (0.025 mM) of 1 N NaOH in 3 mL of ethanol was stirred for 16 h at 25 °C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 7.1 mg (70%> of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, sodium salt as a white powder. 'H NMR (DMS0-d6) 5 7.6 (d, 1H, J=8 Hz), 7.5-7.05 (m, 11H), 6.55 1H, J=8 Hz), 5.75 (s, 2H) , and 4.3 (s, 2H) . IF. (KBr, cm"1) 3471, 1657, 1615, 1591, 1496, 1453, 1412, 1330, 1272, and 1151. MS (ES) m/e 373, 375, 397. Elemental Analyses for C22H;7N204Na: C, 66.67; H, 4.29; N, 7.07. Found C, 66.75; H, 4.55; N, 6.83. Example 2 Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1, 2, 3, 4- tetrahydrocarbazol-5-yl]oxyacetic acid A. Preparation of (2-chloro-4-fluorophenyl)- ethyl carbonate A solution of 19.16 g of 2-chloro-4-fluorophenol in 65.4 ml of 2 N aqueous sodium hydroxide solution was cooled in an ice bath and treated dropwise with 16.3 ml of ethyl chloroformate. After stirring at room temperature overnight, the two-phase reaction mixture was diluted with 100 ml of water and extracted with 300 ml of a 1:1 pentane/ether mixture. The extract was washed three times with 0.02 N sodium hydroxide solution, water and then brine. After drying and evaporation, 27.63 g (97%) of the subtitle compound were obtained. NMR (300 MHz, CDCI3): 5 7.23-7.18 (m, 2H); 7.00 (dt, J=8.4, 2.7, 1H); 4.35 (q, J=7.1, 2H) ; 1.40 (t, J=7.1, 3H). B. Preparation of (2-chloro-4-fluoro-5-nitrophenyl)- ethyl carbonate A solution of 27.63 g of (2-chloro-4-fluorophenyl)- ethyl carbonate in 60 ml of dichloromethane was cooled in an ice bath and treated dropwise with 31.86 g of a 1:2 mixture of fuming nitric acid (90%) and concentrated sulfuric acid. The reaction was stirred for 2 hours at room temperature a.nd then cooled with ice and treated with another 4.5 g of the same nitrating mixture. The reaction was stirred overnight at room temperature, poured into 200 ml of ice and water, and extracted twice with dichloromethane. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated to afford 33.01 g (99%) of the subtitle compound, mp. 50-51 C Elemental Analyses Calculated: C 41.01; H 2.68; N 5.31; Cl 13.45 Found: C 41.03; H 2.59; N 5.38; Cl 13.71 C. Preparation of 2-chloro-4-fluoro-5-nitroanisole A solution of 15.0 g of (2-chloro-4-fluoro-5- nitrophenyl)- ethyl carbonate in 100 ml of dimethyl formamide was treated with 18.6 g of cesium carbonate, 7.1 ml of iodomethane and 7 ml of methanol and stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with ether. The extracts were washed twice with water and then with brine, dried over magnesium sulfate and concentrated to afford 11.4g of the subtitle compound, mp. 69-70°C Ex. 57, C. Elemental Analyses Calculated: C 40.90; H 2.45; N 6.81; Cl 17.25 Found: C 41.20; H 2.48; N 6.70; Cl 17.44 D. Preparation of 2-fluoro-5-methoxyaniline A solution of 5.63 g of 2-chloro-4-fluoro-5- nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated. This residue was chromatographed on silica gel using hexane/ chloroform mixtures to afford 2.77 g (72%) of the subtitle compound. mp. 253-254°C. NMR (300 MHz, CDCI3): 6 6.88 (dd, J=10.6, 8.9, 1H); 6.32 (dd, J=7.4, 3.0, 1H); 6.20 (dt, J=8.9, 3.2,1H); 3.73 (s, 3H); 3.72 (br, 2H). E. Preparation of N-benzyl-2-fluoro-5-methoxyaniline This procedure was patterned after that of Tietze and Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath. Sodium cyanoborohydride (1.58 g) was added in small poroom temperature ions over 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was slurried in 40 ml of 1 N sodium hydroxide solution and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from hexane to afford 2.61 g and the mother liquors were chromatographed on silica gel using 20:1 hexane/ether to afford another 1.4 g of the subtitle compound (90%). mp. 56-58°C Elemental Analyses Calculated: C 72.71; H 6.10; N 6.06 Found: C 72.51; H 6.06; N 5.99 F. Preparation of ethyl 9-benzyl-5-methoxy-8-fluoro- 1,2, 3,4-tetrahydrocarbazole-4-carboxylate A solution of 0.62 g of N-benzyl-2-fluoro-5- methoxyaniline in 20 ml of dry tetrahydrofuran was cooled in an ice bath and treated with 11.3 ml of 0.5 M potassium bis(trimethylsilyl)amide in toluene. After stirring for 30 minutes, 0.74 g of 2-carboethoxy-6-bromocyclohexanone (Sheehan and Mumaw, JACS, 72, 2127 (1950)) in 4 ml of tetrahydrofuran was added and the reaction was allowed tc warm slowly to room temperature over two hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. This residue was chromatographed on silica gel using hexane/ ether mixtures to afford 0.796 g (74%) of N-alkylated intermediate diastereomers. This mixture was refluxed in 20 ml of benzene with 0.99 g of zinc chloride overnight. The solvent was evaporated and the residue was partitioned between 25 ml of 1 N HC1 and 25 ml of ethyl acetate and then extracted once more with ethyl acetate. The organic layers were washed with water and then brine, dried over magnesium sulfate and concentrated to afford 0.734 g (96%) of the subtitled compound. ESIMS m/e 382 (M++1) Elemental Analyses Calculated: C 72.42; H 6.34; N 3.67 Found: C 72.20; H 6.26; N 3.70 G. Preparation of 9-benzyl-5-methoxy-8-fluoro-1,2,3,4- tetrahydrocarbazole-4-carboxamide Ethyl 9-benzyl-5-methoxy-8-fluoro-1, 2, 3, 4- tetrahydrocarbazole-4-carboxylate (0.722 g) was treated similarly as described in Example 49, Part C and chromatographed on silica gel using 1% methanol in dichloromethane to afford 0.482 g (72%) of the subtitle compound. ESIMS m/e 353 (M++1) Elemental Analyses Calculated: C 71.57; H 6.01; N 7.95 Found: C 71.42; H 5.83; N 7.75 H. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4 - tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester 9-Benzyl-5-methoxy-8-fluoro-1, 2, 3, 4- tetrahydrocarbazole-4-carboxamide (0.170 g) was converted similarly as described in Example 49, Part D and chromatographed on silica gel using methanol/ 0-1% in dichloromethane to afford 85 mg. (50%) of the subtitle compound. mp. 183-185°C Elemental Analyses Calculated: C 67.31; H 5.65; N 6.82 Found: C 67.58; H 5.48; N 6.95 I. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4- tetrahydrocarbazol-5-yl]oxyacetic acid [9-Benzyl-4-carbamoyl-8-fluoro-1, 2, 3,4- tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester (71 mg) was hydrolyzed similarly as described in Example 50, Part D to afford 65 mg of the title compound. ESIMS m/e 397 (M++l), 395 (M+-1) NMR (300 MHz, d6-DMS0): ? 13.03 (br, 1H); 7.31-7.19 (m, 3H); 6.97 (d, J=7.4, 2H); 6.95 (br, 1H); 6.70 (d, J=3.8, 1H); 6.67 (dd, J=12.4, 3.9, 1H); 6.28 (dd„ J=8.5, 2.6, 1H); 5.39 (ABq, 2H); 4.64 (s, 2H); 3.92 (br, 1H); 2.71 (m, 1H); 2.44 (m, 1H); 2.02 (m, 2H); 1.76 (m, 2H) . Example 3 Preparation of [9-benzyl-5-carbamoyl-l-fluorocarbazol-4— yl]oxyacetic acid A. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-l- fluorocarbazole A solution of 0.458 g of 9-benzyl-5-methoxy-8-fluoro— 1,2, 3, 4-tetrahydrocarbazole-4-carboxamide in 13 ml of dry dioxane under nitrogen was treated with 0.59 g of 2,3- dichloro-5,6-dicyano-l,4-benzoquinone and refluxed for one hour. The reaction mixture was cooled and filtered and trie precipitate was washed with 15 ml of dioxane. The filtrate and washing were poured into saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts were washed with saturated sodium bicarbonate, with water and then with brine; dried over magnesium sulfate and concentrated. This residue was chromatographed on silica gel using dichloromethane/ 0-2% methanol to afford 0.45 g of subtitle compound. ESIMS m/e 34 9 (M++l) Elemental Analyses Calculated: C 72.42; H 4.92; N 8.04 Found: C 72.35; H 4.81; N 7.88 B. Preparation of [9-benzyl-5-carbamoyl-l-fluorocarbazol- 4-yl]oxyacetic acid methyl ester A solution of 0.45 g of 9-benzyl-5-carbamoyl-4-methoxy- 1-fluorocarbazole in 25 ml of dichloromethane was cooled in an ice bath treated dropwise with 12 ml of 1.0 M boron tribromide solution in dichloromethane. The reaction was allowed to warm to room temperature slowly over 2 hours and then quenched by pouring into ice and then adding 50 ml of 1 N HC1. The mixture was extracted with dichloromethane (3x200 ml) and the extracts were dried over magnesium sulfate and concentrated to afford 0.35 g (78%) of the demethylated intermediate. This intermediate (0.215 g) was alkylated and purified similarly to Example GH1, Part D to afford 0.166 g (64%) of the subtitle compound, mp. 190- 191°C Elemental Analyses Calculated: C 67.97; H 4.71; N 6.89 Found: C 67.81; H 4.94; N 6.96 C. Preparation of [9-benzyl-5-carbamoyl-l-fluorocarbazol- 4-yl]oxyacetic acid [9-Benzyl-5-carbamoyl-l-fluorocarbazol-4-yl]oxyacetic acid methyl ester (56 mg) was hydrolyzed and isolated similarly as described in Example 50, Part D to afford 54 mg of the title compound. FDMS m/e 392 (M+); ESIMS m/e 393 (M++1), 391 (M+-l) NMR (300 MHz, d6-DMSO): 6 12.92 (br, 1H); 7.70 (m, 2H); 7.45 (t, J=7.5, 1H); 7.39 (br, 1H); 7.28- 7.17 (m, 4H); 7.12 (d, J=7.2, 1H); 7.07 (d, J=7.0, 2H); 6.51 (dd, J=8.8, 2.7, 1H); 5.77 (s, 2H); 4.80 (s, 2H). Elemental Analyses Calculated: C 67.34; H 4.37; N 7.14 Found: C 66.92; H 4.49; N 6.77 A. 9-[(3-Fluorophenyl)methyl]-5-carbomethoxy-l,2- dihydrocarbazol-4(3H)-one 40% Methanolic Triton B (2.06 mL, 4.53 mM) was slowly- added dropwise to a solution of 5-carbomethoxy-l,2-dihydro- 9H-carbazol-4(3H)-one (930.0 mg, 3.82 mM) in 5 mL of DMF at 0 °C. After 5 minutes, 3-fluorobenzyl chloride (664.0 mg, 4.59 mM) was added and the resultant mixture stirred at 0 °C for 3 h, then at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed three times with 1 N HC1, three times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 502.3 mg (371) of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-l, 2- dihydrocarbazol-4(3H)-one as a yellow foam. 'H NMR (CDCI3) 8 7.4-7.2 (m, 4H) , 6.9 (m, 1H) , 6.7 (m, 2H) , 5.35 (s, 2H) , 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and 2.3 (m , 2H) . IR (CHC13, cm"1) 3050, 2950, 1725, 1654, 1464, 1451, 1440, 1288 and 1119. MS (ES) m/e 350, 352. Elemental Analyses for C2iHieN03F: Calculated: C, 71.78; H, 5.16; N, 3.99. Found: C, 72.00; H, 4.95; N, 4.11. B. 9-[(3-Fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole A solution of the 9-[(3-fluorophenyl)methyl]-5- carbomethoxy-l,2-dihydrocarbazol-4(3H)-one (434.0 mg, 1.23 mM) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (324.0 iug, 1.42 mM) in 20 mL of toluene was stirred between 70-80 °C for 5 h. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 137.0 mg (32%) of the 9-[(3- fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow foam. XH NMR (DMSO-d6) 5 10.2 (s, 1H) , 7.7 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.3 (m, 2H), 7.2 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 7.05-6.85 (m, 3H) , 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), and 3.85 (s, 3H) . IR (CHC13, cm"1) 3200 (br), 1687, 1597, 1452, 1442, 1285, and 1267. MS (ES) m/e 348, 350. Elemental Analyses for C2iH16N03F: Calculated: C, 72.20; H, 4.62; N, 4.01. Found: C, 72.30; H, 4.66; N, 4.04. C. 9-[(3-Fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole A solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy- 5-carbomethoxy carbazole (130.8 mg, 0.37 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 h at 4 0-50 °C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 57.4 mg (45%) of the 9-[(3-fluorophenyl)methyl]-4- hydroxy-5-carbamoyl carbazole as a white solid. JH NMR (DMS0-d6) 5 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=l and 8 Hz), 7.5 (m, 2H), 7.3 (m, 2H), 7.15- 7.0 (m, 2H), 6.95 (d, 1H, J=8 Hz), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H) . IR (CHC13, cm"1) 3431, 2200 (br), 1628, 1614, 1600, 1580, 1546, 1488, 1448, 1329, 1261, and 776. MS (ES) m/e 333, 335. Elemental Analyses for C20H15N2O2F: Calculated: C, 71.85; H, 4.52; N, 8.38. Found: C, 74.45; H, 6.01; N, 8.48. D. {9-[(3-Fluorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, tert-butyl ester 40% Methanolic Triton B (0.086 mL, 0.19 raM) was added to a solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5- carbamoyl carbazole (51.9 mg, 0.155 MM) in 3 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (87.8 mg, 0.44 mM) was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 44.0 mg (63%) of the {9-[ (3-fluorophenyl)methyl]- 5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. lE NMR (DMSO-d6) 6 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H) , and 1.45 (s, 9H) . IR (CHCl3, cm"1) 3450, 3400, 1746, 1674, 1592, 1457, 1369, and 1151. MS (FD) m/e 448. Elemental Analyses for C26H25N2O4F: Calculated: C, 69.63; H, 5.62; N, 6.25. Found: C, 69.35; H, 5.44; N, 6.23. E. {9-[(3-Fluorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid A solution of the {9-[(3-fluorophenyl)methyl]-5- carbamoylcarbazol-4-ylJoxyacetic acid, tert-butyl ester (40.0 mg, 0.089 mM) in 2 mL of trifluoroacetic acid was stirred at room temperature for 5 hours. The solvent was removed in vacuo. The residue was triturated with ethyl ether, then dried in vacuo to afford 35.0 mg (100%) of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4- ylloxyacetic acid as a white powder. lE NMR (DMSO-d6) 5 13.0 (br s, 1H), 7.75 (s, 1H) , 7.6 (d, 1H, J=8 Hz), 7.5-7.25 (m, 5H), 7.2-6.8 (m, 4H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H) , and 4.8 (s, 2H) . IR (KBr, cm"1) 3423, 3400, 1736, 1637, 1615, 1589, 1499, 1487, 1450, 1436, 1331, 1250, and 1156. MS (ES) m/e 391, 393. Elemental Analyses for C22HnN204F: Calculated: C, 67.34; H, 4.37; N, 7.14. Found: C, 67.63; H, 4.22; N, 7.35. A. 9-[(3-Chlorophenyl)methyl]-5-carbomethoxy-l, 2- dihydrocarbazol-4(3H)-one A suspension of 5-carbomethoxy~l,2-dihydro-9H-carbazol- 4(3H)-one (527.0 nag, 2.17 mM), 3-chlorobenzyl bromide (802.2 mg, 3.90 mM), a catalytic amount of sodium iodide (ca. 1 mg), and potassium carbonate (500.0 mg, 3.62 mM) was stirred at room temperature for 150 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 537.1 mg (67%) of the 9-[(3-chlorophenyl)methyl]-5-carbomethoxy-l,2- dihydrocarbazol-4(3H)-one as a yellow foam. 5H NMR (CDC13) 5 7.5-7.2 (m, 5H), 7.1 (s, 1H), 6.85 (m, 1H), 5.35 (s, 2H), 4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and 2.3 (m , 2H) . IR (CHC13, cm"1) 3050, 2950, 1725, 1654, 1464, 1444, 1432, 1288 and 1120. MS (ES) m/e 366, 368, 370. Elemental Analyses for C2iHieN03Cl: Calculated: C, 68.57; H, 4.93; N, 3.81. Found: C, 68.61; H, 4.92; N, 3.70. B. 9-[(3-Chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole A solution of the 9-[(3-chlorophenyl)methyl]-5- carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (480.5 mg, 1.31 mM) and 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (325.7 rag, 1.43 mM) in 50 mL of toluene was stirred between 70-80 °C for 3 hours. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 172.6 mg (36%) of the 9-[(3- chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a yellow foam. :K NMR (CDC13) 8 10.4 (s, 1H) , 8.05 (d, 1H, J=8 Hz), 7.6 (d, 1H, J=8 Hz), 7.4 (m, 2H), 7.3-7.1 (m, 3H) , 6.9-6.7 (m, 3H), 5.55 (s, 2H) , and 4.15 (s, 3H). IR (CHC13, cm"1) 3200 (br), 1684, 1598, 1442, 1428, 1331, 1285, and 1267. MS (ES) m/e 364, 366, 368. Elemental Analyses for C21H16N03C1: Calculated: C, 68.95; H, 4.41; N, 3.83. Found: C, 69.23; H, 4.52; N, 3.88. C. 9-[(3-Chlorophenyl) methyl]-4-hydroxy-5-carbamoyl carbazole A solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy- 5-carbomethoxy carbazole (156.2 mg, 0.43 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50 °C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HC1. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 69.7 mg (47%) of the 9-[(3-chlorophenyl)methyl]-4- hydroxy-5-carbamoyl carbazole as a white solid. JH NMR (DMS0-d6) 6 10.5 (s, 1H), 8.8 (br s, 1H) , 8.4 (br s, 1H) , 7.8 (dd, 1H, J=l and 8 Hz), 7.45 (m, 2H) , 7.3 (m, 3H), 7.2 (s, 1H), 7.1 (d, 1H, J=8 Hz), 6.95 (s, 1H) , 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H) . IR (CHC13, cm"1) 3433, 3202 (br) , 163 0, 1600, 1580, 1564, 1433, 1330, 1261, and 776. MS (ES) m/e 349, 351, 353. Elemental Analyses for C20H15N2O2CI: Calculated: C, 68.48; H, 4.31; N, 7.99. Found: C, 68.64; H, 4.55; N, 7.93. D. {9-[(3-Chlorophenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid, tert-butyl ester 40% Methanolic Triton B (0.053 mL, 0.12 mM) was added to a solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy- 5- carbamoyl carbazole (33.2 mg, 0.12 mM) in 2 mL IMF at room temperature. After 3 minutes, t-butyl bromoacetate (53.8 mg, 0.27 mM) was added and the resultant mixture stirred at room temperature for 20 h. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 42.1 mg (95%) of the (9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, tert-butyl ester as a white solid. lK NMR (DMS0-d6) 5 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CHC13, cm"1) 3450, 3400, 1744, 1676, 1591, 1457, 1369, and 1150. MS (FD) m/e 464, 466. Elemental Analyses for C26H25N204C1: Calculated: C, 67.17; H, 5.42; N, 6.03. Found: C, 67.17; H, 5.65; N, 5.97. E. {9-[(3-Chlorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid A solution of the {9-[(3-chlorophenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester (35.6 mg, 0.077 mM) in 2 inL of trifluoroacetic acid was stirred at room temperature for 6 hours. The solvent was removed in vacuo. The residue was triturated with ethyl acetate, then dried in vacuo to afford 31.4 mg (100%) of the {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid as a white powder. 1H NMR (DMSO-d6) 5 13.0 (br s, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.4- 7.25 (m, 7H), 7.2 (d, 1H, J=8 Hz), 7.0 (br t, 1H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H) , and 4.8 (s, 2H) . IR (KBr, cm"1) 3456, 3416, 3335, 1735, 1638, 1617, 1580, 1499, 1452, 143 1, 1431, 1329, 1255, 1157, 772, 764, and 717. MS (ES) m/e 407, 409, 411. Elemental Analyses for C22H17N204Cl: Calculated: C, 64.63; H, 4-19; N, 6.85. Found: C, 64.55; H, 4.12; N, 6.74. A. 9-[(3-Trifluoromethylphenyl)methyl]-5-carbomethoxy-l ,2- dihydrocarbazol-4(3H)-one 40% Methanolic Triton B (2.18 mL, 4.8 roM) was slowly added dropwise to a solution of 5-carbomethoxy-l, 2-dihydro- 9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at - 10 °C. After 30 minutes, 3- (trifluoromethyl)benzyl chloride (1.53 g, 6.0 mM) and sodium iodide (900 mg, 6.0 mM) were added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HC1, H2O, sat NaHC03/ and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.02 g (63%) of the 9-[(3-trifluoromethylphenyl)methyl]-5 - carbomethoxy -1,2-dihydrocarbazol-4(3H)-one as a tan solidL :H NMR (CDC13) 6 7.6 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 7.0 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H) . IR (KBr, cm"1) 1727 and 1652. MS (ES) m/e 400,- 402. Elemental Analyses for C22H18N03F3: Calculated: C, 65.83; H, 4.52; N, 3.49; F, 14.20. Found: C, 65.63; H, 4.58; N, 3.39; F, 14.14. B. 9-[(3-Trifluoromethylphenyl)methyl]-4-hydroxy-5- carbomethoxy carbazole A solution of the 9-[ (3-trifluoromethylphenyl)methyl]- 5-carbomethoxy-l,2-dihydrocarbazol-4(3H)-one (1.21 g, 3.00 mM) and 2, 3-dichloro-5,6-dicyano-l,4-benzoquinone (764 mg, 3.3 mM) in 25 mL of toluene was stirred between 80-90 °C for 7 hours. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 340.0 mg (28%) of the 9-[(3- trifluoromethylphenyl)methyl]-4-hydroxy-5-carbomethyoxy carbazole as a yellow solid. XH NMR (CDC13) 8 10.35 (s, 1H); 8.0 (d, 1H, J=8 Hz), 7.6-7.3 (m, 6H) , 7.05 (d, 1H, J=8 Hz) , 6.85 [VOL, 2H), 5.6 (s, 2H) , and 4.1 (s, 3H) . IR (CHC13, cm"1) 3378 and 1712. MS (ES) m/e 398, 400. Elemental Analyses for C22H]6N03F3: Calculated: C, 66.17; H, 4.04; N, 3.51. Found: C, 66.99; H, 4.12; N, 3.53; F. C. 9-[(3-Trifluoromethylphenyl)methyl]-4-hydroxy-5- carbamoyl carbazole A solution of the 9-[(3-trifluoromethylphenyl)methyl] - 4-hydroxy-5-carbomethoxy carbazole (250 mg, 0.625 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 30 h at 40-50 °C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HC1. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 120 mg (50%) of the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5- carbamoyl carbazole as a white solid. ^H NMR (DMSO-d6) 5 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.6-7.5 (m, 5H), 7.3 (t, 1H, J=8 Hz), 7.15 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H) . IR (KBr, cm"1) 3429, 3206, and 1630. MS (ES) m/e 383, 385. Elemental Analyses for C21H15N202F3: Calculated: C, 65.62; H, 3.93; N, 7.29. Found: C, 67.50; H, 4.00; N, 7.19. D. {9-[(3-Trifluoromethylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester 40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(3-trifluoromethylphenyl)methyl]-4- hydroxy-5-carbamoyl carbazole (115 mg, 0.3 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (95 mg, 0.6 mM) was added and the resultant mixture stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HC1, H2O, sat. NaHC03, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 120 mg (88%) of the {9-[(3- trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDC13) 8 7.5-7.2 {m, IE), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (br s, 1H) , 6.0 (br s, 1H), 5.55 (s, 2H), 4.9 {s, 2H), and 3.9 (s, 3H). IR (KBr, cm"1) 1763 and 1673. MS (ES) m/e 457. Elemental Analyses for C24H19N204F3: Calculated: C, 63.16; H, 4.20; N, 6.14. Found: C, 61.37; H, 4.19; N, 5.77. E. (9-[(3-Trifluoromethylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt. A solution of the {9-[(3-trifluoromethylphenyl)methyl]- 5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (91 mg, 0.153 mM) and 0.22 mL (0.22 mM) of 1 N NaOH in 8 mL of ethanol was stirred for 17 h at 25 °C. The ethanol was removed in vacuo. The resultant white precipitate was collected by filtration, washed with small amounts of EtOH and diethyl ether, then dried in vacuo to afford 75 mg (81%) of the {9-[(3-trifluoromethylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 'H NMR (DMS0-d6) ? 7.65 (s, 1H), 7.6 (m, 4H), 7.45 (t, 1H, J=8 Hz), 7.35 (t, 1H, J=8 Hz), 7.3 (t, LH, J=8 Hz), 7.2 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 7.05 id, 1H, J=8 Hz), 6.5 (d, 1H, J=8 Hz), 5.75 (s, 2H), and 4.3 (s, 2H) . IR (KBr, cm-1) 1665 and 1618. MS (ES) m/e 441, 443. Elemental Analyses for C23Hi6N204F3Na: Calculated: C, 59.49; H, 3.47; N, 6.03. Found: C, 60.69; H, 3.78; N, 5.75. A. 9-[(2-Methylphenyl)methyl]-5-carbomethoxy-l, 2- dihydrocarbazol-4(3H)-one A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol- 4(3H)-one (870 mg, 3.58 mM), a-bromo-o-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.21 g (98%) of the 9-[(2- methylphenyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol- 4(3H)-one as a dark oil. :H NMR (DMS0-d6) ? 7.5-7.2 (m, 4H), 7.15 (t, 1H, J=8 Hz), 7.0 (t, 1H, J=8 Hz), 6.15 (d, 3_H, J=8 Hz), 5.55 (s, 2H), 3.85 (s, 3H), 2.6 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H) , and 2.1 (m, 2H) . IR (CHC13, cm"1) 3010, 2952, 1724, 1671, 1653, 1604, 1460, 1444, 1290, 1174, and 1122. MS (ES) m/e 348.5. Elemental Analyses for C22H21NO3: Calculated: C, 76.08; H, 6.05; N, 4.03. Found C, 73.33; H, 6.36; N, 4.30. B. 9-[(2-Methylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole A solution of the 9-[(2-methylphenyl)methyl]-5- carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (1.2 g, 3.5 mM) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (800 rag, 3.6 mM) in 70 mL of toluene was stirred at 80-90 °C for 5 hours. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 260 mg (22%) of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5- carbomethyoxy carbazole as a yellow solid. ]H NMR (DMSO- d6) 6 10.25 (s, 1H), 7.5 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.3-7.1 (m, 4H), 6.9 (m, 2H), 6.6 (d, 1H, J=8 Hz), 6.1 (d, 1H, J=8 Hz), 5.65 (s, 2H), 3.8 (s, 3H), and 2.5 (s, 3H) . IR (KBr, cm"1) 3200, 1672, 1440, 1426, 1332, 1302, 1265, 1216, 1141, 761, 749, and 718. MS (ES) m/e 344, 346. Elemental Analyses for C22H19NO3: Calculated: C, 76.52; H, 5.51; N, 4.06. Found: C, 76.44; H, 5.66; N, 3.94. C. 9-[(2-Methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole A solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy- 5-carbomethoxy carbazole (260 mg, 0.75 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50 °C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturat ed brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 90 mg (36%) of the 9-[(2— methylphenyl)methyl]-A-hydroxy-5-carbamoyl carbazole as a tan solid. 1H NMR (DMSO-d6) ? 10.5 (s, 1H) , 8.8 (br s, 1H), 8.4 (br s, 1H) , 7.7 (m, 1H), 7.5 (m, 2H) , 7.3 (m, 2H) , 7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.7 (s, 2H) , and 2.5 (s, 3H) . IR (KBr, cm"1) 3451, 3191, 1627, 1600, 1584, 1562, 1435, 1329, 1322, 1263, and 774. MS (ES) m/e 329, 331. Elemental Analyses for C2iHi8N20;>: Calculated: C, 76.36; H, 5.45; N, 8.48. Found: C, 7 5.66; H, 5.79; N, 8.07. D. {9-[(2-Methylphenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid, methyl ester 40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5- carbamoyl carbazole (80 mg, 0.24 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 48 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (82%) of the {9-[(2-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. lH NMR (DMSO-d6) ? 7.56 (br s, 1H), 7.5-7.1 (m, 9H),~6.9 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H), 4.9 (s, 2H), 3.8 (s, 3H), and 2.5 (s, 3H). IR (KBr, cm" ') 3367, 3153, 1760, 1740, 1672, 1644, 1619, 1591, 1578, 1498, 1456, 1425, 1327, 1200, 1153, 1109, 1100, and 777. MS Elemental Analyses for C24H22N2O4: Calculated: C, 71.64; H, 5.47; N, 6.96. Found: C, 71.51; H, 5.56; N, 6.67. E. {9-[(2-Methylphenyl)dmethyl]-5-carbamoylcarbazol-4- yl]oxyacetic acid, sodium salt A suspension of the (9-[(2-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15.5 mg, 0.039 mM) and 0.04 mL (0.04 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 24 hours at 25 °C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 10 mg (63%) of the {9-[(2-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) 6 7.55 (br s, 1H) , 7.5-7.0 (m, 7H), 6.9 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.2 (d, 1H, J=8 Hz), 5.6 (s, 2H), 4.35 (s, 2H), and 2.5 (s, 3H) . IR (KBr, cm-1) 3390, 1656, 1613, 1595, 1573, 1498, 1455, 1408, 1325, 1332, and 719. MS (ES) m/e 387, 389. Elemental Analyses for C23Hi9N204: Calculated: C, 67.32; H, 4.63; N, 6.83. Found: C, 64.72; H, 4.44; N, 6.40. A. 9-[(3-Methylphenyl) methyl]-5-carbomethoxy-l,2- dihydrocarbazol-4(3H)-one A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol- 4(3H)-one (870 mg, 3.58 mM), a-bromo-m-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.18 g (95%) of the 9-[(3- methylphenyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol- 4(3H)-one as a dark oil. 1H NMR (DMSO-d6) ? 7.65 (dd, 1H, J=l and 8 Hz), 7.3-7.1 (m, 3H), 7.05 (d, 1H, J=8 Hz), 7.0 (s, 1H) , 6.85 (d, 1H, J=8 Hz), 5.5 (s, 2H) , 3.8 (s, 3H) , 3.0 (m, 2H) , 2.45 (m, 2H), 2.3 (s, 3H), and 2.1 (m, 2H) . IR {CHClj, cm-1) 3010, 2953, 1724, 1652, 1605, 1465, 1442, 1288, 1174, and 1119. MS (ES) m/e 348.5. Elemental Analyses for C22H2jN03: Calculated: C, 76.08; H, 6.05; N, 4.03. Found: C, 74.53; H, 6.03; N, 3.68. B. 9-[(3-Methylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole A solution of the 9-[(3-methylphenyl)methyl]-5- carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (1.18 g, 3.4 mM) and 2, 3-dichloro-5,6-dicyano-l,4-benzoquinone (800 mg, 3.6 mM) in 70 mL of toluene was stirred at 80-90 °C for 6 hoiir-s. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 300 mg (26%) of the 9-[(3-methylphenyl}methyl]-4-hydroxy-5- carbomethyoxy carbazole as a yellow solid. UH NMR (DMSO- d6) 8 10.2 (s, 1H), 7.65 (d, IE, J=8 Hz), 7.35 (t, 1H, J=8 Hz), 7.25 (t, 1H, J=8 Hz), 7.2-7.0 (m, 4H) , 6.9 (m, 2H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.85 (s, 3H) , and 2.2 (s, 3H) . IR (KBr, cm"1) 3200, 1673, 1596, 1440, 1426, 1394, 1265, 1216, 1152, 750, 711, and 694. MS (ES) m/e 344, 346. Elemental Analyses for C22H19N03: Calculated: C, 76.52; H, 5.51; N, 4.06. Found: C, 76.22; H, 5.55; N, 3.97. C. 9-[(3-Methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole A solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy- 5-carbomethoxy carbazole (300 mg, 0.87 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50 °C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HC1. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturat ed brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 114 mg (40%) of the 9-[(3- methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. :H NMR (DMSO-d6) 6 10.5 (s, 1H) , 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=l and 8 Hz), 7.4 (m, 2H) , 7.3 (t, 1H, J=8 Hz), 7.15-7.0 (m, 3H), 6.85 (d, 1H, a=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.65 (s, 2H) , and 2.25 (s, 3H) . IR (KBr, cm"1) 3434, 3203, 1629, 1599, 1579, 1552, 1443, 1330, 1262, 1214, and 776. MS (ES) m/e 329, 331. Elemental Analyses for C2iH18N202: Calculated: C, 76.36; H, 5.45; N, 8.48. Found: C, 77.56; H, 5.67; N, 8.26. D. {9-[(3-Methylphenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid, methyl ester 40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to a solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5- carbamoyl carbazole (100 mg, 0.30 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (115 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 80 mg (66%) of the {9-[(3- methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. lE NMR (DMSO-d6) ? 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.0 (m, 8H), 6.9 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H) , 4.9 (s, 2H), 3.75 (s, 3H) , and 2.2 (s, 3H) . IR (KBr, cm"1) 3367, 3157, 1760, 1642, 1589, 1499, 1455, 1424, 1328, 1216, 115^, 1102, 772, and 714. MS (FD) m/e 402. Elemental Analyses for C24H22N2O4: Calculated: C, 71.64; H, 5.47; N, 6.96. Found: C, 71.01; H, 5.60; N, 6.66. E. {9-[(3-Methylphenyl)methyl]-5-carbamoylcarbazol-4- yUoxyacetic acid, sodium salt A suspension of the {9-[(3-methylphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15.8 mg, 0.039 mM) and 0.04 mL (0.04 mM) of 1 N NaOH in 5 mL off ethanol was stirred for 24 h at 25 °C. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH, then dried in vacuo to afford 10 mg (62%) of the (9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (CMSO-d6) 5 7.55 (d, 1H, J=8 Hz), 7.5-7.0 (m, 9H), 6.85 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.6 (s, 2H) , 4.35 (s, 2H) , and 2.2 (s, 3H) . IR (KBr, cm"1) 3390, 1656, 1613, 1595, 1573, 1498, 1455, 1408, 1325, 1332, and 719. MS (ES) m/e 387, 389. Elemental Analyses for C23H19N204Na: Calculated: C, 67.32; H, 4.63; N, 6.83. Found: C, 61.20; H, 4.64; N, 6.06. EXAMPLE 9 Preparation of {9-[(3-trifluoromethoxypheny1)methyl]-5- carbamoylcarbazol-4-yl)oxyacetic acid, sodium salt A. 9-[(3-Trifluoromethoxyphenyl)methyl]-5-carbomethoxy- 1,2-dihydrocarbazol-4(3H)-one A suspension of 5-carbomethoxy-l, 2-dihydro-9H-carbazol- 4{3H)-one (935 mg, 3.85 mM), 3-trifluoromethoxybenzyl bromide (1.0 g, 3.93 mM), and potassium carbonate (531 mg, 3.85 mM) in 20 mL DMF was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.6 g (100%) of the 9-[(3-trifluoromethoxyphenyl)methyl]-5-carbomethoxy-l,2- dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMS0-d6) ? 7.7 (dd, 1H, J=l and 8 Hz), 7.45 (t, 1H, J=8 Hz), 7.3-7.1 (m, 4H), 7.05 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H) , 2.45 (m, 2H) , and 2.1 (m, 2H) . IR (CHC13, cm"1) 1729, 1647, 1439, 1259, 1176, and 1116. MS (ES) m/e 418. Elemental Analyses for C22Hl8N04F3: Calculated: C, 63.31; H, 4.32; N, 3.36. Found: C, 63.12; H, 4.35; N, 3.31. B. 9-[(3-Trifluoromethoxyphenyl)methyl]-4-hydroxy-5- carboiaethoxy carbazole A solution of the 9-[(3-trifluoromethoxyphenyl)methyl ] - 5-carbomethoxy-l,2-dihydrocarbazol-4(3H)-one (0.75 g, 1.8 mM) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (490 mg, 2.16 mM) in 70 mL of toluene was stirred at reflux for 6 hours. The mixture was purified directly by column chromatography on silica gel (elution with methylene chloride) to afford 300 mg (40%) of the 9-[(3- trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbomethyoxy carbazole as a yellow solid. :H NMR (DMSO-d6) ? 10.25 ( s, 1H), 7.7 (d, 1H, J=8 Hz), 7.5-7.0 {m, 8H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 3.85 (s, 3H). IR (KBr, cm"') 3200, 1673, 1441, 1268, 1217, 1173, and 753. MS (ES) m/e 414, 416. Elemental Analyses for C22H16NO3F3 Calculated: C. 63.61; H, 3.86; N, 3.37. Found: C, 63.40; H, 3.99; N, 3.43. C. 9-[(3-Trifluoromethoxyphenyl)methyl]-4-hydroxy-5- carbamoyl carbazole A solution of the 9-[(3-trifluoromethoxyphenyl)methyl]- 4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.62 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was stirred vigorously for 132 hours. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HC1. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 150 mg (60%) of the 9-[(3- trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6; 6 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=l and 8 Hz), 7.5-7.15 (m, 5H), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), an_d 5.65 (s, 2H) . IR (KBr, cm"1) 3431, 3203, 1629, 1601, 1580, 1548, 1446, 1330, 1261, 1215, and 777. MS (ES) m/e 399, 401. Elemental Analyses for C21HUN2O2F3: Calculated: C, 63.00; H, 3.75; N, 7.0. Found: C, 63.15; H, 4.07; N, 6.84. D. {9-[(3-Trifluoromethoxyphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester 40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4- hydroxy-5-carbamoyl carbazole (115 mg, 0.28 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (65 mg, 0.41 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 112 mg (83%) of the {9-[(3-trifluoromethoxyphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 2H NMR (DMSO-d6) ? 7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.5-7.0 (m, 9H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H) , 4.9 (s, 2H) , and 3.75 (s, 3H) . IR (KBr, cm"1) 3488, 3141, 1763, 1674, 1501, 1444, 1269, 1215, 1178, 1102, 772, and 714. MS (FD) m/e 472. Elemental Analyses for C24H]9N205F3: Calculated: C, 61.02; H, 4.03; N, 5.93. Found: C, 61.05; H, 4.17; N, 5.81. E. {9-[(3-Trifluoromethoxyphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt A suspension of the {9-[(3- trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid, methyl ester (22.4 mg, 0.047 mM) and 0.065 mL (0.065 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 24 hours at 25 °C. The solvent was removed in vacuo and the residue suspended in EtOH. The resultant whxte precipitate was collected by filtration, washed with a snail amount of EtOH, then dried in vacuo to afford 9 mg (41%) of the {9-[(3-trifluoromethoxyphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. MS (ES) m/e 457, 459. Example 10 Preparation of [9-benzyl-5-carbamoyl-l-methylcarbazol~ 4-yl]oxyacetic acid A. Preparation of 5-carbamoyl-4-methoxy-l-methylcarbazole A solution of 0.805 g of 9-benzyl-5-methoxy-8-methyl- 1,2,3,4-tetrahydrocarbazole-4-carboxamide in 24 ml of carbitol was treated with 1.1 g of 5% palladium on carbon and was refluxed for 6 hours open to the air. After cooling, the solution was filtered thourough a pad of celite and the pad was washed with ethyl acetate. The filtrates were diluted with ether and washed four times with water and dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using methanol/0-4% in dichloromethane to afford 0.166 g (28%) of debenzylated carbazole. ESIMS m/e 255 (M++1) , 253 (M+-l) NMR (300 MHz, CDCI3): 6 8.13 (br, 1H); 7.51 (d, J=8.1, 1H); 7.40 (t, J=7.6, 1H); 7.32 (d, J=7.2, 1H); 7.18 (d, J=7.8, 1H); 6.60 (d, J=8.0, 1H); 5.68 (br, 2H); 3.99 (s, 3H); 2.50 (s 3H). B. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-l- methylcarbazole A solution of 0.148 g of 5-carbamoyl-4-methoxy-l- methylcarbazole in 1.1 ml of dimethylformamide was added to 0.026 g of sodium hydride (60% in mineral oil) in 0.4 ml of dimethylformamide and stirred for 60 minutes at room temperature. Benzyl bromide (0.076 ml) was then added anci the reaction was stirred overnight. The reaction mixture was poured into 20 ml of saturated ammonium chloride solution and then extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was rinsed with hexane and dissolved in dichloromethane, filtered and concentrated to afford 0.21 g of the subtitle compound. FDMS m/e 344 (M+) Elemental Analyses Calculated: C 76.72; H 5.85; N 8.13 Found: C 75.20; H 6.19; N 7.54 C. Preparation of [9-benzyl-5-carbamoyl-l-methylcarbazol- 4-yl]oxyacetic acid methyl ester ] A solution of 0.23 g of 9-benzyl-5-carbamoyl-4-methoxy- 1-methylcarbazole in 4 ml of dimethylformamide was added to a 1 ml solution of sodium ethane thiolate (prepared from 0.116 g of sodium hydride 60% dispersion and 0.22 ml of ethanethiol under nitrogen) and heated at 110°C for 15 hours. The reaction mixture was cooled, poured into 20 ml of 1 N HC1 and extracted twice with ethyl acetate. The extracts were washed twice with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using methanol/0-1% in dichloromethane to afford 0.146 g (66%) of the demethylated intermediate. A solution of 0.146 g of this intermediate in 1.5 ml of dimethylformamide was added to 0.021 g of sodium, hydride (60% in mineral oil) in 0.5 ml of dimethylformamide. After stirring for 10 minutes at room temperature, 0.054 ml of methyl bromoacetate was added. After stirring for 5 hours at room temperature, the reaction mixture was poured into water and extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel using methanol/ 0-2% in dichloromethane to afford 0.10 g (56%) of the subtitle compound. mp. 228-230°C ESIMS m/e 403 (M++l) Elemental Analyses Calculated: C 71.63; H 5.51; N 6.96 Found: C 71.34; H 5.60; N 6.70 D. Preparation of l9-benzyl-5-carbamoyl-l-methylcarbazol- 4-yl]oxyacetic acid A slurry of 32 mg (0.0795 mmol) of I9-benzyl-5- carbamoyl-l-methylcarbazol-4-yl]oxyacetic acid methyl ester in 1 ml of tetrahydrofuran and 3.5 ml of methanol was treated with 0.3 ml of an aqueous 2 N sodium hydroxide solution and stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1:1 ethyl acetate/tetrahydrofuran and 0.2 N HC1 solution. After another extraction with 1:1 ethyl acetate/tetrahydrofuran, the extracts were washed with brine, dried over magnesium sulfate and concentrated to afford (27 mg) of the title compound, mp. 253-254°C. ESIMS m/e 389 (M++1), 387 (M+-1) NMR (300 MHz, d6-DMSO): 8 12.83 (br, 1H); 7.75 (br, 1H); 7.53 (d, J=8.2, 1H); 7.41- 7.34 (m, 2H); 7.28-7.17 (m, 3H); 7.07 (m, 2H); 6.90 (d, J=7.2, 2H) ; 6.49 (d, J=8.1, 1H); 5.89 (s, 2H); 4.79 (s, 2H) ; 2.52 (s, 3H). Example 11 Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3, tetrahydrocarbazol-5-yl]oxyacetic acid A. Preparation of (2-chloro-4-fluorophenyl)- ethyl carbonate A solution of 19.16 g of 2-chloro-4-fluorophenol in 65.4 ml of 2 N aqueous sodium hydroxide solution was cooled in an ice bath and treated dropwise with 16.3 ml of ethyl chloroformate. After stirring at room temperature overnight, the two-phase reaction mixture was diluted with. 100 ml of water and extracted with 300 ml of a 1:1 pentane/ether mixture. The extract was washed three times with 0.02 N sodium hydroxide solution, water and then brine. After drying and evaporation, 27.63 g (97%) of the subtitle compound were obtained. NMR (300 MHz, CDCI3): 6 7.23-7.18 (m, 2H) ; 7.00 (dt, J=8.4, 2.7, 1H); 4.35 (q, J=7.1, 2H) ; 1.40 (t, J=7.1, 3H). B. Preparation of (2-chloro-4-fluoro-5-nitrophenyl)- ethyl carbonate A solution of 27.63 g of (2-chloro-4-fluorophenyl)- ethyl carbonate in 60 ml of dichloromethane was cooled in an ice bath and treated dropwise with 31.8 6 g of a 1:2 mixture of fuming nitric acid (90%) and concentrated sulfuric acid. The reaction was stirred for 2 hours at room temperature and then cooled with ice and treated with another 4.5 g of the same nitrating mixture. The reaction was stirred overnight at room temperature, poured into 200 ml of ice and water, and extracted twice with dichloromethane. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated to afford 33.01 g (99%) of the subtitle compound, mp. 50-51 C Elemental Analyses Calculated: C 41.01; H 2.68; N 5.31; CI 13.45 Found: C 41.03; H 2.59; N 5.38; Cl 13.71 C. Preparation of 2-chloro-4-fluoro-5-nitroanisole A solution of 15.0 g of (2-chloro-4-fluoro-5- nitrophenyl)- ethyl carbonate in 100 ml of dimethyl formamide was treated with 18.6 g of cesium carbonate, 7.1 ml of iodomethane and 7 ml of methanol and stirred overnight at room temperature. The reaction mixture was poured into water and extracted twice with ether. The extracts were washed twice with water and then with brine, dried over magnesium sulfate and concentrated to afford 11.4g of the subtitle compound, mp. 69-70°C Ex. 57, C. Elemental Analyses Calculated: C 40.90; H 2.45; N 6.81; Cl 17.25 Found: C 41.20; H 2.48; N 6.70; Cl 17.44 D. Preparation of 2-fluoro-5-methoxyaniline A solution of 5.63 g of 2-chloro-4-fluoro-5- nitroanisole in 90 ml of ethanol and 5 ml of triethylamine was hydrogenated at room temperature under 60 pounds per square inch with 1.0 g of 5% palladium on carbon for four hours. The catalyst was filtered off and the solvent was evaporated. The residue was slurried in chloroform and filtered thourough a plug of silica gel and then evaporated. This residue was chromatographed on silica gel using hexane/ chloroform mixtures to afford 2.77 g (72%) of the subtitle compound, mp. 253-254°C. NMR (300 MHz, CDCI3) : 6 6.88 (dd, J=10.6, 8.9, 1H); 6.32 (dd, J=7.4, 3.0, 1H) ; 6.20 (dt, J=8.9, 3.2,1H); 3.73 (s, 3H); 3.72 (br, 2H). E. Preparation of N-benzyl-2-fluoro-5-methoxyaniline This procedure was patterned after that of Tietze ancd Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath. Sodium cyanoborohydride (1.58 g) was added in small poroom temperature ions over 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was slurried in 40 ml of 1 N sodium hydroxide solution and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from hexane to afford 2.61 g and the mother liquors were chromatographed on silica gel using 20:1 hexane/ether to afford another 1.4 g of the subtitle compound (90%). mp. 56-58°C Elemental Analyses Calculated: C 72.71; H 6.10; N 6.06 Found: C 72.51; H 6.06; N 5.99 F. Preparation of ethyl 9-benzyl-5-methoxy-8-fluoro- 1,2,3, 4-tetrahydrocarbazole-4-carboxylate A solution of 0.62 g of N-benzyl-2-fluoro-5- methoxyaniline in 20 ml of dry tetrahydrofuran was cooled in an ice bath and treated with 11.3 ml of 0.5 M potassium bis(trimethylsilyl)amide in toluene. After stirring for 30 minutes, 0.74 g of 2-carboethoxy-6-bromocyclohexanone (Sheehan and Mumaw, JACS, 72, 2127 (1950)) in 4 ml of tetrahydrofuran was added and the reaction was allowed to warm slowly to room temperature over two hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with ether. The extracts we:re washed with water and then with brine, dried over magnesium sulfate and concentrated. This residue was chromatograph on silica gel using hexane/ ether mixtures to afford 0.79 6 g (74%) of N-alkylated intermediate diastereomers. This mixture was refluxed in 20 ml of benzene with 0.99 g of zinc chloride overnight. The solvent was evaporated and the residue was partitioned between 25 ml of 1 N HCl and 25 mi of ethyl acetate and then extracted once more with ethyl acetate. The organic layers were washed with water and then brine, dried over magnesium sulfate and concentrated to afford 0.734 g (96%) of the subtitled compound. ESIMS m/e 382 (M++1) Elemental Analyses Calculated: C 72.42; H 6.34; N 3.67 Found: C 72.20; H 6-26; N 3.70 G. Preparation of 9-benzyl-5-methoxy-8-fluoro-l,2,3,4- tetrahydrocarbazole-4-carboxamide Ethyl 9-benzyl-5-methoxy-8-fluoro-l, 2,3,4- tetrahydrocarbazole-4-carboxylate (0.722 g) was treated similarly as described in Example 49, Part C and chromatographed on silica gel using 1% methanol in dichloromethane to afford 0.482 g (72%) of the subtitle compound. ESIMS m/e 353 (M++l) Elemental Analyses Calculated: C 71.57; H 6.01; N 7 . 95 Found: C 71.42; H 5.83; N 7.75 H. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3, 4- tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester 9-Benzyl-5-methoxy-8-fluoro-1, 2, 3, 4- tetrahydrocarbazole-4-carboxamide (0.170 g) was converted similarly as described in Example 49, Part D and chromatographed on silica gel using methanol/ 0-1% in dichlo route thane to afford 85 mg (50%) of the subtitle compound. mp. 183-185°C Elemental Analyses Calculated: C 67.31; H 5.65; N 6.82 Found: C 67.58; H 5.48; N 6.95 I. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1, 2, 3, 4- tetrahydrocarbazol-5-yl]oxyacetic acid [9-Benzyl-4-carbamoyl-8-fluoro-1,2,3,4- tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester (71 mcj) was hydrolyzed similarly as described in Example 50, Part D to afford 65 mg of the title compound. ESIMS m/e 397 (M++1), 395 (M+-1) NMR (300 MHz, d6-DMSO): 8 13.03 (br, 1H); 7.31-7.19 (m, 3H); 6.97 (d, J=7.4, 2H); 6.95 (br, 1H); 6.70 (d, J=3.8, 1H); 6.67 (dd, J=12.4, 3.9, 1H); 6.28 (dd, J=8.5, 2.6, 1H); 5.39 (ABq, 2H); 4.64 (s, 2H); 3.92 (br, 1H); 2.71 (m, 1H); 2.44 (m, 1H); 2.02 (m, 2H); 1.76 (m, 2H). Example 12 Preparation of [9-benzyl-5-carbamoyl-l-chlorocarbazol-4- yl]oxyacetic acid A. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-l- chlorocarbazole A solution of 1.0 g of 9-benzyl-5-methoxy-8-methyl- 1,2, 3, 4-tetrahydrocarbazole-4-carboxamide was oxidized similarly to Example 51, Part A and chromatographed on silica gel using dichloromethane/ 0-1% methanol to afford 0.66 g (67%) of the subtitle compound. FDMS m/e 364 (M+ ) Elemental Analyses Calculated: C 69.14; H 4.70; N 7.68; Cl 9.72 Found: C 69.40; H 4.64; N 7.49; Cl 9.98 B. Preparation of 5-carbamoyl-4-hydroxy-l-chlorocarbazo le A solution of 0.66 g of 9-benzyl-5-carbamoyl-4-methoxy- 1-chlorocarbazole in 40 ml of dichloromethane was cooled dn an ice bath treated dropwise with 14 ml of 1.0 M boron tribromide solution in dichloromethane. The reaction was allowed to warm to room temperature slowly over 2 hours and then quenched by pouring into ice and then adding 50 ml of 1 N HCl. The mixture was extracted with dichloromethane (3x200 ml) and the extracts were washed with brine, dried with magnesium sulfate and concentrated. The aqueous layers exhibited a precipitate and was then extracted twice with ethyl acetate, washed with brine, dried with magnesium sulfate and concentrated to afford 0.287 g of the subtitle compound. The first residue was chromatographed on silica gel using 0.5% methanol in dichloromethane to afford another 93 mg of the subtitle compound, (total yield 80%) ESIMS m/e 259 (M+-l) NMR (300 MHz, d6-DMS0): 6 11.79 (s, 1H); 10.76 (s, 1H); 8.87 (br s, 1H); 8.41 (br s, 1H); 7.77 (t, J=4.6, 1H); 7.48 (d, J=4.2, 2H); 7.34 (d, J=8.5, 1H); 6.54 (d, J=8.5, 1H). C. Preparation of [5-carbamoyl-l-chlorocarbazol-4- yl]oxyacetic acid methyl ester A solution of 0.28 g of 5-carbamoyl-4-hydroxy-l- chlorocarbazole in 6 ml of tetrahydrofuran was added to 0.043 g of sodium hydride (60% in mineral oil) in 1 ml of tetrahydrofuran and stirred for 60 minutes at room temperature. Methyl bromoacetate (0.11 ml) was then added and the reaction was stirred overnight. The reaction mixture was poured into 20 ml of saturated ammonium chlor ide solution and then extracted twice with ethyl acetate. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with chloroform and then 2:1 chloroform/ethyl acetate to afford 0.16 g (45%) of the subtitle compound. ESIMS m/e 333 (M++l), 335 (M++3) , 331 (M+-1) NMR (300 MHz, d6-DMS0) : 8 11.73 (s, 1H) ; 7.56 (d, J=8.1, 1H); 7.50 (br s, 1H); 7.43-7.35 (m, 2H); 7.18 (br s, 1H); 7.06 (d, J=7.8, 1H); 6.56 (d, J=8.6, 1H) ; 4.90 (s, 2H); 3.70 (s, 3H). D. Preparation of [9-benzyl-5-carbamoyl-l-chlorocarbazol~ 4-yl]oxyacetic acid methyl ester A solution of 78 mg of [5-carbamoyl-l-chlorocarbazol- 4-yl]oxyacetic acid methyl ester in 0.8 ml of dry dimethylformamide was added to 10 mg sodium hydride (60% in mineral oil) in 0.2 ml of dimethylformamide and stirred for 15 minutes. Benzyl bromide (0.031 ml) was then added and the reaction was stirred overnight. The reaction mixture was poured into water and acidified with 1 ml of 1 N HC1 solution and extracted twice with ethyl acetate. The extracts were washed with water (3x) and then with brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with methanol/0-2% in dichloromethane to afford 4 0 mg of the subtitle compound. ESIMS m/e 423 (M++l) 425 (M++3) NMR (300 MHz, CDCI3): 8 7.43-7.22 (m, 7H); 7.06 (d, J=7.3, 2H); 6.51 (d, J=8.6, 1H); 6.05 (s, 2H); 5.80 (br, 2H); 4.88 (s, 2H); 3.83 E. Preparation of [9-benzyl-5-carbamoyl-l-chlorocarbazo 1- 4-yl]oxyacetic acid [9-Benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyaceti acid methyl ester (15 mg) was hydrolyzed similarly as described in Example 50, Part D to afford 14 mg of the ti tie compound. mp. 240-2°C ESIMS m/e 409 (M++l), 411 (M++3), 407 (M+-l) NMR (300 MHz, d6-DMSO) : 8 12.94 (br, 1H) ; 7.-70 (br, 1H); 7.61 (d, J=8.3, 1H); 7.43 (t, 3=1.8, 1H) ; 7.36 (m, 2H); 7.28-7.19 (m, 3H); 7.13 (d, J=7.2, 1H); 6.99 (d, J=7.4, 2H); 6.63 (d, J=8.6, 1H); 6.08 (s, 2H); 4.83 (s, 2H). A. 9-[(Cyclohexyl)methyl]-5-carbomethoxy-l,2- dihydrocarbazol-4(3H)-one A 0 °C suspension of 5-carbomethoxy-l, 2-dihydro-9H- carbazol-4(3H)-one (1.0 g, 4.11 mmol), a catalytic amount of Nal (ca. 10 mg) and K2C03 (1.1 g, 8.22 mmol) in 10 mL of DMF was treated with cyclohexylmethyl bromide (0.631 mL, 4.52 mmol). After stirring overnight at ambient temperature, an additional 0.63 mL cyclohexylmethylbromide was added, and the resulting mixture was heated at 60 °C for 3 hours. Th.e mixture was poured into H2O (30 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed wit hi H2O (4 x 50 mL) , dried over anhydrous Na2S0,i, filtered and concentrated in vacuo. The residue was purified by radiai chromatography on silica gel (elution with a gradient of 20% to 40% EtOAc/hexanes) to afford 1.36 g (4.01 mmol; 97%) of 9-[(cyclohexyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazoi - 4(3H)-one as a white foam. IR (CHC13, cm"1) 3011, 2932, 2857, 1725, 1649, 1469, 1446, 1288 and 1120. MS (ES) m/e 340 (M+l), 453 (M+AcO") . FAB HRMS m/e, Calcd for C21H26N03: 340.1913. Found: 340.1916 (M+l). Elemental Analyses for C2iH25N03: Calculated: C, 74.31; H, 7.42; N, 4.13. Found: C, 72.65; H, 7.39; N, 4.70. B. 9-[(Cyclohexyl)methyl]-4-hydroxy-5-carbomethoxy carbazole A solution of 9-[(cyclohexyl)methyl]-5-carbomethoxy- 1,2-dihydrocarbazol-4(3H)-one (1.16 g, 3.42 mmol) and 2,3- dichloro-5,6-dicyano-l,4-benzoquinone (853 mg, 3.76 mmol) in 20 mL of toluene was heated at 80 CC for 3 hours. The mixture was purified directly by column chromatography on silica gel (elution with CH2C12) to afford 259 mg (0.768 mmol; 22%) of 9-[(cyclohexyl)methyl]-4-hydroxy-5- carbomethoxy carbazole as a yellow oil which slowly solidified. MS (ES) m/e 338 (M+l), 336 (M-l). Elemental Analyses for C2]H23N03: Calculated: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.95; H, 6.99; N, 4.42. C. 9-[(Cyclohexyl)methyl]-4-hydroxy-5-carbamoyl carbazoILe A solution of 9-[(cyclohexyl)methyl]-4-hydroxy-5- carbomethoxy carbazole (205 mg, 0.608 mmol) in 5 mL of THF and 20 mL of concentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped, and the mixture was heated at 35 °C with stirring until tic indicated complete consumption of starting material (20 hrs). The THF was evaporated, and the aqueous layer was filtered. The green solid precipitate was dissolved in THF and purified by radial chromatography on silica gel (elution with CH2C12). The resultant foam was triturated with ether to afford 138 mg (70%) of the title compound as an off-white solid. IR (KBr, cm"1) 3418, 3200, 3131, 1629, 1600, 1443, 1261, 778. 'FAB HRMS m/e, Calcd for C20H23N2°2: 323.1760. Found: 323.1760 (M+l). D. [9-[(Cyclohexyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid, methyl ester A mixture of 9-[(cyclohexyl) methyl]-4-hydroxy-5- carbamoyl carbazole (60 mg, 0.186 mmol) and Cs2C03 (150 mg; 0.460 mmol) in 2 mL of DMF was treated with methyl bromoacetate (0.023 mL; 0.242 mmol). The reaction was stirred for 2 hours at ambient temperature, then it was diluted with EtOAc and H2O (10 mL each). The aqueous layer was saturated with solid NaCl and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with H2O (2 x 25 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (elution with a gradient of 0% to 90% EtOAc/hexanes) followed by trituration with Et20/EtOAc afforded 45 mg (0.114 mmol; 61%) of title compound as an off-white solid. MS (ES) m/e 395 (M+l), 378 (M+H-NH3), 453 (M+AcCT) . Elemental Analyses for C23H26N20,i 0.3H2O: Calculated: C, 69.08; H, 6.71; N, 7.01. Found: C, 69.13; H, 6.71; N, 7.09. E. [9-[(Cyclohexyl)methyl]-5-carbamoylcarbazol-4- yl]oxyacetic acid A slurry of [9-[(cyclohexyl)methyl]-5- carbamoylcarbazol-4-yl]oxyacetic acid, methyl ester (20 mg, 0.051 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture stirred at room temperature for 2 h. The reaction was acidified with 0.2 N HC1, and the organics were removed in vacuo. The white precipitate was filtered away from the aqueous layer and rinsed with Et20 to afford 16 mg (0.042 mmol; 83%) the title acid as a white powder. MS (ES) m/e 381 (M+l), 364 (M+H-NH3) , 379 (M-l). Elemental Analyses for C22H^N204: Calculated: C, 69.46; H, 6.36; N, 7.36. Found: C, 69-34; H, 6.35; N, 7.29. A. 9-[(Cyclopentyl)methyl]-5-carbomethoxy-l,2- dihydrocarbazol-4(3H)-one A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol- 4(3H)-one (820 g, 3.37 mmol), a catalytic amount of Nal (ca. 10 mg) and KZC03 (930 mg, 6.74 mmol} in 6 mL of DMF was treated with cyclopentylmethyl chloride (JOC, 1964, 29, 421- 423; 400 mg, 3.37 mmol). After stirring overnight at ambient temperature, an additional 800 mg of cyclopentylmethyl chloride and 1 g of Nal were added, and the resulting mixture was heated at 80 °C overnight. An additional 800 mg of cyclopentylmethyl chloride and 2.2 g of Cs2C03 were added, and the reaction mixture was heated at 80 °C for 24 h. An additional 1.6 g of cyclopentylmethyl chloride was added, and the reaction mixture was heated at 80 CC for 3 d The mixture was poured into H2O (30 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SOt, filtered, and concentrated in vacuo. The residue was purified by radial chromatography on silica gel (elution with gradient of 10% to 40% EtOAc/hexanes) to afford" 775 mg (2.38 mmol; 71%) of 9-[(cyclopentyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol- 4(3H)-one as a brown foam. MS (ES) m/e 326 (M+l), 384 (M+AcCf) . Elemental Analyses for C20H23NO3: Calculated: C, 73.82; H, 7.12; N, 4.30. Found: C, 74.12; H, 7.21; N, 4.45. B. 9-[(Cyclopentyl)methyl]-4-hydroxy-5-carbomethoxy carbazole A solution of 9-[(cyclopentyl)methyl]-5-carbomethoxy- l,2-dihydrocarbazol-4(3H)-one (730 mg, 2.24 mmol) and 2,3- dichloro-5,6-dicyano-l,4-benzoquinone (560 mg, 2.47 mmol) in 20 mL of toluene was heated at 80 °C for 3 hours. The mixture was purified directly by column chromatography on silica gel (elution with CH2C12) to afford 140 mg (0.433 mmol; 19%) of 9-[(cyclopentyl)methyl]-4-hydroxy-5- carbomethoxy carbazole as a yellow oil which slowly solidified. MS (ES) m/e 324 (M+l), 322 (M-l). Elemental Analyses for C2oH2iN03'0.3H2O: Calculated: C, 73.06; H, 6.62; N, 4.26. Found: C, 73.19; H, 6.44; N, 4.40. C. 9-[(Cyclopentyl)methyl]-4-hydroxy-5-carbamoyl carbazole A solution of 9-[(cyclopentyl)methyl]-4-hydroxy-5- carbomethoxy carbazole (110 mg, 0.34 mmol) in 3 mL of THF and 20 mL ofconcentrated aqueous ammonium hydroxide was treated with a stream of NH3 gas to ensure saturation. The reaction vessel was capped, and the mixture heated to 35 °C with stirring until tic indicated complete consumption of starting material (20 h). The THF was evaporated, and the aqueous layer was filtered. The resultant solid was triturated with ether to afford 50 mg (0.162; 48%) of the title compound as a greenish-white solid. IR (KBr, cm""1) 3416, 3199, 3126, 1630, 1599. 1442, 1262, 778. 'FAB HRMS m/e, Calcd for C20H21N2O2: 309.1603. Found: 309.1607 (M+l).' D. [9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol-4- yl]oxyacetic acid, methyl ester A mixture of 9-[(cyclopentyl)methyl]-4-hydroxy-5- carbamoyl carbazole (45 mg, 0.146 mmol) and Cs2C03 (120 mg; 0.365 mmol) in 2 mL of DMF was treated with methyl bromoacetate (0.018 mL; 0.19 mmol). The reaction was stirred for 2 hours at ambient temperature, then it was diluted with EtOAc and H2O (10 mL each) . The aqueous layer was saturated with solid NaCl extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with H2O (2 x 25 mL) , dried over anhydrous Na2S04, filtered and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (elution with a gradient of 0% to 100% EtOAc/hexanes) followed by trituration with Et20/EtOAc afforded 26 mg (0.0683 mmol; 47%) of title compound as a tan solid. MS (ES) m/e 381 (M+l), 364 (M+H- NH3) , 439 (M+AcCf) . Elemental Analyses for C23H26N204- '0.1H2O: Calculated: C, 69.13; H, 6.38; N, 7.33. Found: C, 68.99; H, 6.39; N, 7.41. E. [9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol-4- yljoxyacetic acid A slurry of [9-I(cyclopentyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (20 mg, 0.065 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture stirred at room temperature for 2 hours. The reaction was acidified with 0.2 N HC1, and the organics were removed in vacuo. The white precipitate was filtered away from the aqueous layer and rinsed with Et20 to afford 15 mg (0.0409 mmol; 63%) the title acid as a white powder. MS (ES) m/e 367 (M+l), 350 (M+H-NH3) , 365 (M-l). Elemental Analyses for C2iH22N2(V 0.3H2O: Calculated: C, 67.84; H, 6.13; N, 7.53. Found: C, 67.73; H, 5.97; N, 7.70. The compounds described herein are believed to achieve their beneficial therapeutic action principally by direct inhibition of human SPLA2, and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, etc. The method of the invention for inhibiting SPLA2 mediated release of fatty acids comprises contacting SPLA2 with an therapeutically effective amount of a compound of Formula (I) selected from the group consisting [9-benzyl-5- carbamoyl-1-fluorocarbazol-4-yl]oxyacetic acid, {9- [(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, {9-[(3-chlorophenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, (9-[(3- trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetic acid, sodium salt, {9-[(2-methylphenyl)methyl]- 5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9- [(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacet ic acid, sodium salt, {9-[(3-trifluoromethoxyphenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, [9- benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid, [9- ((cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid, [9-[(cyclopentyl)methyl]-5-carbamoylcarbazol-4- yl]oxyacetic acid or its pharmaceutically acceptable salt. The compounds of the invention may be used in a method of treating a mammal (e.g., a human) to alleviate the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitus, trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis; wherein the method comprises administering to the mammal a compound of formula (I) in a therapeutically effective amount. A "therapeutically effective" amount is an amount sufficient to inhibit SPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products. The therapeutic amount of compound of the invention needed to inhibit SPLA2 may be readily determined by taking a sample of body fluid and assaying it for SPLA2 content b^' conventional methods. Throughout this document, the person or animal to be treated will be described as a "mammal", and it wiLl be understood that the most preferred subject is a human. However it must be noted that the study of adverse conditions of the central nervous system in non-human animals is only now beginning, an that some instances of such treatments are coming into use. Accordingly, use of: the present compounds in non-human animals is contemplated. It will be understood that the dosage ranges for other animals will necessarily be quite different from the doses administered to humans, and accordingly that the dosage ranges described be recalculated. For example, a small dog may be only l/10th of a typical human's size, and it will therefore be necessary for a much smaller dose to be used. The determination of an effective amount for a certain non- human animal is carried out in the same manner described below in the case of humans, and veterinarians are well accustomed to such determinations. As previously noted the compounds of this invention are useful for inhibiting SPLA2 mediated release of fatty acids such as arachidonic acid. By the term, "inhibiting" is meant the prevention or therapeutically significant reduction in release of SPLA2 initiated fatty acids by the compounds of the invention. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In general, the compounds of the invention are most desirably administered at a dose that will generally afford effective results without causing any serious side effects and can be administered either as a single unit dose, or if desired, the dosage may be divided into convenient subunits administered at suitable times throughout the day. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the route of administration, the age, weigh" and response of the individual patient, the condition being treated and the severity of the patient's symptoms. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention. Preferably the pharmaceutical formulation is in unit dosage form. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A "chronic" condition means a deteriorating condition of slow progress and long continuance. As such, it is treated when it is diagnosed and continued throughout the course of the disease. An "acute" condition is an exacerbation of short course followed by a period of remission. In an acute event, compound is administered at the onset of symptoms and discontinued when the symptoms disappear. Pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis and rheumatoid arthritis may occur as an acute event or a chronic event. Thus, the treatment of these conditions contemplates both acute and chronic forms. Septic shock and adult respiratory distress, on the other hand, are acute conditions treated when diagnosed. The compound can be administered by a variety o f routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the compounds of the invention together with a pharmaceutically acceptable carrier or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10S by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration. For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material. Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain fron about 1 to about 99 weight percent of the active ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter. Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil. The following pharmaceutical formulations 1 through 8 are illustrative only and are not intended to limit the scope of the invention in any way. "Active ingredient", refers to a compound according to Formula (I) or a pharmaceutical^ acceptable salt, solvate, or prodrug thereof. The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities. The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. The active ingredient is passed through a No. 4 5 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume. Formulation 8 An intravenous formulation may be prepared as follows: The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute. Assay Experiments Assay Example 1 The following chromogenic assay procedure was used to identify and evaluate inhibitors of recombinant human secreted phospholipase A2. The assay described herein has been adapted for high volume screening using 96 well microtiter plates. A general description of this assay method is found in the article, "Analysis of Human Synovial Fluid Phospholipase A2 on Short Chain Phosphatidylcholine-Mixed Micelles: Development of a Spectrophotometric Assay Suitable for a Microtiterplate Reader", by Laure J. Reynolds, Lori L. Hughes, and Edward A Dennis, Analytical Biochemistry, 204, pp. 190-197, 1992 (the disclosure of which is incorporated herein by reference): Reagents: (Sigma A-7030, product of Sigma Chemical Co. St. Louis MO, USA) TRIS HC1 (3.94 g/L) pH 7.5 (adjust with NaOH) ENZYME BUFFER - 0.05 NaOAc.3H2O, pH 4.5 0.2 NaCl Adjust pH to 4.5 with acetic acid DTNB - 5,5'-dithiobis-2-nitrobenzoic acid RACEMIC DIHEPTANOYL THIO - PC racemic 1,2-bis(heptanoylthio)-1, 2-dideoxy-sn- glycero-3-phosphorylcholine TRITON X-100™ prepare at 6.249 mg/ml in reaction buffer to equal lOuM TRITON X-100™ is a polyoxy ethylene non-ionic detergent supplied by Pierce Chemical Company, 3747 N. Meridian Road, Rockford, Illinois 61101. REACTION MIXTURE - A measured volume of racemic dipheptanoyl thio PC supplied in chloroform at a concentration of 100 mg/ml is taken to dryness and redissolved in 10 millimolar TRITON X-100™ nonionic detergent aqueous solution. Reaction Buffer is added to the solution, then DTNB to give the Reaction Mixture. The reaction mixture thus obtained contains ImM diheptanoly thio-PC substrate, 0.29 mm Triton X-100™ detergent, and 0.12 mm DTMB in a buffered aqueous solution at pH 7.5. Assay Procedure: 1. Add 0.2 ml reaction mixture to all wells; 2. Add 10 ul test compound (or solvent blank) to appropriate wells, mix 20 seconds; 3. Add 50 nanograms of SPLA2 (10 microliters) to appropriate wells; 4. Incubate plate at 40°C for 30 minutes; 5. Read absorbance of wells at 405 nanometers with an automatic plate reader. All compounds were tested in triplicate. Typically, compounds were tested at a final concentration of 5 ug/ml. Compounds were considered active when they exhibited 40% inhibition or greater compared to uninhibited control reactions when measured at 405 nanometers. Lack of color development at 4 05 nanometers evidenced inhibition- Compounds initially found to be active were reassayed to confirm their activity and, if sufficiently active, IC50 values were determined. Typically, the IC50 values (see, Table I, below) were determined by diluting test compound serially two-fold such that the final concentration in the reaction ranged from 45 ug/mL to 0.35 ug/ml. More potent inhibitors required significantly greater dilution. In all cases, % inhibition measured at 405 nanometers generated by enzyme reactions containing inhibitors relative to the uninhibited control reactions was determined. Each sample was titrated in triplicate and result values were averaged for plotting and calculation of IC50 values. IC50 were determined by plotting log concentration versus inhibition values in the range from 10-90% inhibition. Compounds of the instant invention were tested in Assay Example 1 and were found to be effective at concentrations of less than lOOuM. Assay Example 2 Method: Male Hartley strain guinea pigs (500-700g) were killed by cervical dislocation and their heart and lungs removed intact and placed in aerated (95% 02:5% C02) Krebs buffer. Dorsal pleural strips (4xlx25mm) were dissected from intact parenchymal segments (8x4x25mm) cut parallel to the outer edge of the lower lung lobes. Two adjacent pleural strips, obtained from a single lobe and representing a single tissue sample, were tied at either end and independently attached to a metal support rod. One rod was attached to a Grass force-displacement transducer Model FT03C, product of Grass Medical Instruments Co., Quincy, MA, USA). Changes in isometric tension were displayed on a monitor and thermal recorder (product of Modular Instruments, Malvern, PA). All tissues were placed in 10 ml jacketed tissue baths maintained at 37°C. The tissue baths were continuously aerated and contained a modified Krebs solution of the following composition (millimolar) NaCl, 118.2; KC1, 4.6; CaCl2-2H2O, 2.5; MgSO/j • 7H2O, 1.2; NaHC03, 24.8; KH2PO4, 1.0; and dextrose, 10.0. Pleural strips from the opposite lobes of the lung were used for paired experiments. Preliminary data generated from tension/response curves demonstrated that resting tension of 800mg was optimal. The tissues were allowed to equilibrate for 45 min. as the bath fluid was changed periodically. Cumulative concentration-response curves: Initially tissues were challenged 3 times with KCl (40 mM) to test tissue viability and to obtain a consistent response. After recording the maximal response to KCl, the tissues were washed and allowed to return to baseline before the next challenge. Cumulative concentration-response curves were obtained from pleural strips by increasing the agonist concentration (SPLA2) in the tissue bath by half-logio increments while the previous concentration remained in contact with the tissues (Ref.l, supra.). Agonist concentration was increased after reaching the plateau of the contraction elicited by the preceding concentration. One concentration-response curve was obtained from each tissue. To minimize variability between tissues obtained from different animals, contractile responses were expressed as a percentage of the maximal response obtained with the final KCl challenge. When studying the effects of various drugs on the contractile effects of SPLA2, the compounds and their respective vehicles were added to the tissues 30 minutes prior to starting the SPLA2 concentration-response curves. Statistical analysis: Data from different experiments were pooled and presented as a percentage of the maximal KCl responses (mean ± S.E.). To estimate the drug induced rightward shifts in the concentration response curves, the curves were analyzed simultaneously using statistical nonlinear modeling methods similar to those described by Waud (1976), Equation 26, p. 163, (Ref.2). The model includes four parameters: the maximum tissue response which was assumed the same for each curve, the ED50 for the control curve, the steepness of the curves, and the pA2, the concentration of antagonist that requires a two-fold increase in agonist to achieve an equivalent response. The Schild slope was determined to be 1, using statistical nonlinear modeling methods similar to those described by Waud (1976), Equation 27, p. 164 (Ref. 2). The Schild slope equal to 1 indicates the model is consistent with the assumptions of a competitive antagonist; therefore, the pA2 may be interpreted as the apparent KB, the dissociation constant of the inhibitor. To estimate the drug-induced suppression of the maximal responses, SPLA2 responses (10 ug/ml) were determined in the absence and presence of drug, and percent suppression was calculated for each pair of tissues. Representative examples of inhibitory activities are presented in Table 2, below. Ref. 1 - Van, J.M.: Cumulative dose-response curves. II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch. Int. Pharmacodyn. Ther., 143: 299-330, 1963. Ref. 2 - Waud, D.: Analysis of dose-response relationships, in Advances in General and Cellular Pharmacology eds Narahashi, Bianchi 1:145-178, 1976. Compounds of the instant invention were tested in Assay Example 2 and were found to be effective at concentrations below 20uM. Assay Example 3 SPLA2 Transgenic Mice Assay Materials & Methods The mice utilized in these studies were mature, 6-8 month old, ZnS04-stimulated, hemizygous line 2608a transgenic mice (Fox et. al. 1996). Transgenic mice from this line express human SPLA2 in the liver and other tissues and typically achieve levels of human SPLA2 in their circulation of approximately 173 +_ 10 ng/ml when maximally stimulated with ZnS04 (Fox, et al. 1996). The mice were housed under constant humidity and temperature and received food and water ad libitum. Animal room lighting was maintained on a 12-hour light/dark cycle and all experiments were performed at the same time of the day during the early morning light period. For intravenous testing, compounds or vehicle were administered as an IV bolus via the tail vein in a volume of 0.15 ml. Vehicle consisted of 1-5% dimethylsulfoxide, 1-51 ethanol and 10-30% polyethylene glycol 300 in H2O; the concentrations of these ingredients were adjusted according to the solubility of the compound. Mice were bled retro-orbitally prior to drug or vehicle administration and 30 minutes, 2 and 4 hours thereafter. Three to six mice were used for each dose. PLA2 catalytic activity in the serum was assayed with a modified phosphatidylcholine/deoxycholine mixed micelle assay (Fox, et al. 1996, Schadlich, et al., 1987) utilizing 3 mM sodium deoxycholate and 1 mM l-palmitoyl-2-oleoyl-sn- glycero-3-phosphocholine. For oral testing, compounds were dissolved in 1-5% ethanol/10-30% polyethylene glycol 300 in H2O or were suspended in 5% dextrose in H2O and administered by oral gavage. Serum was prepared from retro-orbital blood and assayed for PLA2 catalytic activity as above. References Fox, N., M. Song, J. Schrementi, J. D. Sharp, D. L. White, D. W. Snyder, L. W. Hartley, D. G. Carlson, N. J. Bach, R. D. Dillard, S. E. Draheim, J. L. Bobbitt, L. Fisher and E. D. Mihelich. 1996. Eur. J. Pharmacol. 308: 195. Schadlich, H.R., M. Buchler, and H. G. Beger, 1987, J. Clin. Chem. Clin. Biochem. 25, 505. Compounds of the instant invention were tested in Assay Example 3 and were found to be effective. While the present invention has been illustrated above by certain specific embodiments, it is not intended that these specific examples should limit the scope of the invention as described in the appended claims. We Claim: 1. A compound selected from the group consisting of (9-bcnzyl-5-carbamoyl-l- fluorocarbazol-4-yl]oxyacetic acid, {9-[(phenyl)mcthyI\|-5-carbamoylcarba/.ol-4- yl} oxyacctic acid, {9-\|(3-fluorophenyl)methyl\|-5-carbamoylcarbazol-4- yl} oxyacctic acid, {9-\|(3-chlorophcnyl)melhyl]-5-carbamoylcarbazol-4- yl} oxyacctic acid, {9-\|(3-trinuoromcthylphenyl)methyl\|-5-carbamoylcarba/.ol-4- yl}oxyacctic acid sodium salt. {9-\|(2-mcthylphenyl)mcthyl\|-5- carbamoylcarbazol-4-yl) oxyacctic acid sodium salt. }9-\|(3- mcthylphcnyl)mcthyl]-5-carbamoylcarbazol-4-yl}oxyacctic acid sodium salt. \|9- \| (3-trinuorornethoxyphcnyl)methyl ]-5-carbamoylcarbazol-4-yl }oxy acetic acid sodium salt. \|9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid, \|9- \|(cyclohcxyI)mclhyl \|-5-carbamoyIcarbazol-4-yl \|oxyacetic acid, \|9- \|(cyclopcntyl)methyl\|-5-carbamoylcarbazol-4-yI\|oxyacetic acid or a pharmaccutically acceptable racemate, solvate, tautomer. optical isomer, or salt thereof as herein described. 2. A compound as claimed in claim 1 which is (9-\|(phcnyl)mclhyl\|-5- carbamoylcarbazol-4-yl}oxyacetic acid, or a pharmaccutically acceptable racemate. solvate, tautomer, optical isomer, or salt, thereof. 3. A compound as claimed in Claim 1 which is \|9-benzyl-5-carbamoyl-l- fIuorocarbazol-4-yl\|oxyacetic acid or a pharmaccutically acceptable racemate. solvate, tautomer, optical isomer, or salt, thereof. 4. A compound as claimed in Claim 1 which is {9-\|(3-lluorophenyl)melhyl\|-5- carbamoylcarbazol-4-yl} oxyacctic acid or a pharmaccutically acceptable racemate, solvate, tautomer, optical isomer, or salt, thereof. 5. A compound as claimed in Claim 1 which is {9-\|(3-chlorophcnvl)incthyl\|o- carbamoylcarbazol-4-yl)oxyacetic acid or a pharmaceutical ly acceptable racemate. solvate, taulomer, optical isomer, or salt, thereof. 6. A compound as claimed in Claim 1 which is (9-( (3- trinuoromethylphenyl)methyl\|-5-carbamoylcarbazol-4-yl Joxyacetic acid sodium salt or a pharmaceutical ly acceptable racemate, solvate, tautomcr, optical isomer, or salt, thereof. 7. A compound as claimed in Claim 1 which is {9-f(2-methylphenyl)methyl\|-5- carbamoylcarbazol-4-yl}oxyacetic acid sodium salt or a pharmaceuticallv acceptable racemate, solvate, tautomer. optical isomer, or salt, thereof. 8. A compound as claimed in Claim 1 which is {9-((3-methylphenyl)methyi\|-5- carbamoylcarbazol-4-yl}oxyacetic acid sodium salt or a pharmaceutically acceptable racemate, solvate, tautomer. optical isomer, or salt, thereof. 9. A compound as claimed in Claim 1 which is !9-\|(3- trinuoromethoxyphenyl)methyl\|-5-carbamoylcarbazol-4-yi}oxyacetic acid sodium salt or a pharmaceutically acceptable racemate, solvate, tautomer. optical isomer, or salt, thereof. 10. A compound as claimed in claim 1 which is [9-benzyl-5-carbamoyl-l- chlorocarbazol-4-yl]oxyacetic acid or a pharmaceutically acceptable racemate. solvate, tautomcr, optical isomer, or salt thereof. 11. A compound as claimed in claim 1 which is \|9-\|(cyclohexyl)mclhyl\|-5- carbamoylcarba/ol-4-yl\|oxyacetic acid or a pharmaceutical^' acceptable raccmatc, solvate, tautomer, optical isomer, or salt thereof. 12. A compound as claimed in claim 1 which is \|9-\|(cyclopcniyl)mcthyl\|-5- carbamoylcarbazol-4-yl\|oxyacetic acid or a pharmaccutically acceptable racemate, solvate, tautomer. optical isomer, or salt thereof. 13. The compound as claimed in claim I. which is [9-\|(cyclohexyl)methyI\|-5- carbamoylcarbazol-4-yl\|oxyacetic acid sodium salt, represented by the formula 14. The compound as claimed in I. which is (9-f(cyclohexyI)mcthyl\|-5- carbamoylcarbazol-4-yl\|oxyacctic acid, represented by the formula 15. A compound as claimed in anyone of claims 1 to 14 wherein the salt is sodium. 16. A pharmaceutical formulation comprising a compound as claimed in anyone of claims 1 to 14 together with a pharmaceutical!}' acceptable carrier or diluent therefor. 17. A pharmaceutical formulation adapted for the treatment of a condition associated with inhibiting sPI,A2, containing a compound as claimed in anyone of Claims I to 14 together with a pharmaceutical!}' acceptable carrier or diluent thereof. Novel tricyclics are disclosed together with the use of such compounds for inhibiting Spla2 mediated releases of fatty acids for treatment of conditions such as septic shock.

Full Text

This application claims the benefit of U.S. Serial No. 09/062,328 Tiled
April 17, 1998
FIELD OF THE INVENTION:
This invention relates to novel substituted tricyclic organic compounds
useful for inhibiting sPL? 2 mediated release of fatty acids for conditions such as septic
shock.
BACKGROUND AND PRIOR ART
The structure and physical properties of himan
non-pancreatic secretory phospholipase A2 (hereinafter
called, '"PLA2") has been thoroughly described in two
articles, namely, "Cloning and Recombinant Expression of
Phospholipase A2 Present in Rheumatoid Arthritic Synovial
Fluid" by Seilhamer, Jeffrey J.; Pruzanski, Waldemar;
Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean;
and Johnson, Lorin K.; The Journal of Biological
Chemistry, Vol. 264, No. 10, Issue of April 5, pp. 533 5-
5338, 1989; and "Structure and Properties of a Human Non-
pancreatic Phospholipase A2" by Kramer, Ruth M.; Hession,
Catherine; Johansen, Berit; Hayes, Gretchen; McGray,
Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky,
R. Blake; The Journal of Biological Chemistry, Vol. 264,
No. 10, Issue of April 5, pp. 5768-5775, 1989; the
disclosures of which are incorporated herein by reference.
It is believed that SPLA2 is a rate limiting
enzyme in the arachidonic acid cascade which hydrolyzes
membrane phospholipids. Thus, it is important to develop
compounds which inhibit SPLA2 mediated release of fatty
acids (e.g., arachidonic acid). Such compounds would be
of value in general treatment of conditions induced and/or
maintained by overproduction of SPLA2 such as septic
shock, adult respiratory distress syndrome, pancreatitis,
trauma-induced shock, bronchial asthma, allergic rhinitis,
rheumatoid arthritis, etc.

It is desirable to develop new compounds and trealment for sPLA2
induced diseases.
DETAILED DESCRPTION
Tricyclic compounds effective in inhibiting
human SPLA2 mediated release of fatty acids are depicted
in the general formula I below:

wherein;
Z is cyclohexenyl, or phenyl,
R*° is selected from groups (a), (b) and (c) where;
(a) is - C Jalkynyl, carbocyclic radicals, or heterocyclic
radicals, or
(b) is a member of (a) substituted with one or more
independently selected non-interfering substituents;
or
(c) is the group -(L)-R80; where, (L)-is a divalent
linking group of 1 to 12 atoms selected from carbon,
hydrogen, oxygen, nitrogen, and sulfur; wherein the
combination of atoms in -(L)- are selected from the
group consisting of (i) carbon and hydrogen only,
(ii) one sulfur only, (iii) one oxygen only, (iv) one
or two nitrogen and hydrogen only, (v) carbon,
hydrogen, and one sulfur only, and (vi) an carbon,

hydrogen, and oxygen only; and where R80 is a group
selected from (a) or (b);
R21 is a non-interfering substituent where f is 1-3;
R1 is -NHNH2,-NH2/ or -CONH2;
R2' is selected from the group consisting of -OH, and
-0(CH2)tR5' where
R5' is H, -CN, -NH2, -CONH2/ -CONR9R10 -NHS02R15; -
CONHS02R15, where R15 is - (Ci-C6) alkyl or -CF3; phenyl
or phenyl substituted with -C02H or -C02 (C1-C4) alkyl;
and - (La) - (acidic group), wherein -(La)- is an acid
linker having an acid linker length of 1 to 7 and t
is 1-5;
R3' is selected from non-interfering substituent,
carbocyclic radicals, carbocyclic radicals
substituted with non-interfering substituents,
heterocyclic radicals, and heterocyclic radicals
substituted with non-interfering substituents;
or a pharmaceutically acceptable racemate, solvate,
tautomer, optical isomer, prodrug derivative or salt,
thereof.
The compounds of Formula I contemplated by this
invention are selected from the group consisting of [9-
benzyl-5-carbamoyl-l-fluorocarbazol-4-yl]oxyacetic acid, {9-
[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid,
{9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, {9-[(3-chlorophenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3-
trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid, sodium salt, {9-[(2-methylphenyl)methyl]-
5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-
[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, sodium salt, {9-[(3-trifluoromethoxyphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, [9-
benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid, [9-

[(cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic
acid, [9-[(cyclopentyl)methyl]-5-carbamoylcarbazol-4-
yl]oxyacetic acid or a pharmaceutical]^ acceptable racemite,
solvate, tautomer, optical isomer, prodrug derivative or
salt thereof.
This invention is also a pharmaceutical
formulation comprising a compound selected from the group
consisting of [9-benzyl-5-carbamoyl-l-fluorocarbazol-4-
yl]oxyacetic acid, {9-[(phenyl)methyl]-5-carbamoyl-carba:ol-
4-yl}oxyacetic acid, {9-[(3-fluorophenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3-
chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, {9-[(3-trifluoromethylphenyl)methyl]-5-
carbamoylcarbazol-4-yl }oxyacetic acid, sodium salt, {9-[',2-
methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, sodium salt, {9-[(3-methylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9—[;3-
trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, sodium salt, [9-benzyl-5-carbaraoyl-l-
chlorocarbazol-4-yl]oxyacetic acid, [9-[(cyclohexyl)methyl]-
5-carbamoylcarbazol-4-yl]oxyacetic acid, and [9-
[(cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic
acid in association with one or more pharmaceutically
acceptable diluents, carriers and excipients.
This invention is also a method of inhibiting
SPLA2 comprising administering to a mammal in need of such
treatment a therapeutically effective amount of a compound
selected from the group consisting of [9-benzyl-5-carbamoyl-
l-fluorocarbazol-4-yl]oxyacetic acid, {9-[(phenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(3-
fluorophenyl)methyl]-5-carbamoylcarbazol-4-ylJoxyacetic
acid, {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid, {9-[(3-trifluoromethylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(2-

methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, sodium salt, {9-[(3-methylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[ 3-
trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-
yl)oxyacetic acid, sodium salt, [9-benzyl-5-carbamoyl-l-
chlorocarbazol-4-yl]oxyacetic acid, [9-[(cyclohexyl)methyl]-
5-carbamoylcarbazol-4-yl]oxyacetic acid, and [9-
[(cyclopentyl)methyl ]-5-carbamoylcarbazol-4-yl]oxyacetic
acid.
According to a further aspect of the present
invention, there is provided a method of selectively
inhibiting SPLA2 in a mammal in need of such treatment
comprising administering to said mammal a therapeutically
effective amount of a compound selected from the group
consisting of [9-benzyl-5-carbamoyl-l-fluorocarbazol-4-
yl ] oxyacetic acid, {9- [ (phenyl) methyl ] -5-carbamoylcarbazol-
4-yl}oxyacetic acid, {9-[(3-fluorophenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, {9-{ chlorophenyl) methyl)-5-carbamoylcarbazol-4-yl)oxyacet i c
acid, {9- [(3-tri fluoromethylphenyl J methyl]-5-
carbamoylcarbazol-4-yl]oxyacetic acid, sodium salt, (9-[(2-
methylphenyl)methyl ]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, sodium salt, (9-[(3-methylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-[(3-
trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-
yDoxyacetic acid, sodium salt, [9-benzyl-5-carbamoyl-l-
chlorocarbazol-4-yl)oxyacetic acid, [9-[(cyclohexyl)methyl]-
5-carbamoylcarbazol-4-yl]oxyacetic acid, and [9-
[{cyclopentyl) methyl ]-5-carbamoylcarbazol-4-yl]oxyacetic
acid.
This invention, further provides a compound selected from
the group consisting of [9-benzyl-5-carbamoyl-l-
fluorocarbazol-4-yl]oxyacetic acid, {9-[(phenyl)-methyl]-
5-carbamoylcarbazol-4-yl}oxyacetic acid I, {9-[(3-

fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, {9-[(3-trifluoromethylphenyl)methyl]-
5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-
[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, sodium salt, {9-[(3-
methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, sodium salt, {9-[(3-trifluoromethoxyphenyl)methyl] -
5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, [9-
benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid,
[9-[(eyelohexyl)methyl]-5-carbamoylcarbazol-4-
yl]oxyacetic acid, and [9-[(cyclopentyl)methyl]-5-
carbamoylcarbazol-4-yl]oxyacetic acid for use as a
medicament in the treatment of inflammatory diseases such
as, septic shock, adult respiratory distress syndrome,
pancreatitis, trauma-induced shock, bronchial asthma,
allergic rhinitis, rheumatoid arthritis, cystic fibrosis,
stroke, acute bronchitis, chronic bronchitis, acute
bronchiolitis, chronic bronchiolitis, osteoarthritis,
gout, spondylarthropathies, ankylosing spondylitis,
Reiter's syndrome, psoriatic arthropathy, enteropathic
spondylitis, juvenile arthropathy or juvenile ankylosing
spondylitis, reactive arthropathy, infectious or post-
infectious arthritis, gonococcal arthritis, tuberculous
arthritis, viral arthritis, fungal arthritis, syphilitic
arthritis, Lyme disease, arthritis associated with
"vasculitic syndromes", polyarteritis nodosa,
hypersensitivity vasculitis, Luegenec's granulomatosis,
polymyalgia rheumatica, giant cell arteritis, calcium
crystal deposition arthropathies pseudo gout, non-
articular rheumatism, bursitis, tenosynovitis
epicondylitis (tennis elbow), carpal tunnel syndrome,
repetitive use injury, miscellaneous forms of arthritis,
"Charcot joint" neuropathic joint disease, hemarthrosis,
Henoch-Schonlein Purpura,

hypertrophic osteoarthropathy, multicentric
reticulohistiocytosis, arthritis associated with certain
diseases, sarcoidosis, hemochromatosis, sickle cell
disease and other hemoglobinopathies,
hyperlipoproteinemia, hypogammaglobulinemia,
hyperparathyroidism, acromegaly, familial Mediterranean
fever, Behcet's Disease, systemic lupus erythrematosus,
or relapsing polychondritis; and related diseases which
comprises administering to a mammal in need of such
treatment a therapeutically effective amount of the
compound of formula I in an amount sufficient to inhibit
SPLA2 mediated release of fatty acid and to thereby
inhibit or prevent the arachidonic acid cascade and its
deleterious products.
Other objects, features and advantages of the
present invention will become apparent from the subsequent
description and the appended claims.
Definitions:
As used herein, the term, "alkyl* by itself or
as part of another substituent means, unless otherwise
defined, a straight or branched chain monovalent
hydrocarbon radical such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl
tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl,
octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,
tetradecyl and the like. The term "alkyl" includes
-(Ci-C2)alkyl, - (C1-C4)alkyl, -(C1-C6)alkyl, -(C5-
C14)alkyl, and -(C1-C10)alkyl.
The term "alkenyl" as used herein represents an
olefinically unsaturated branched or linear group having
at least one double bond. Examples of such groups include
radicals such as vinyl, allyl, 2-butenyl, 3-butenyl,
2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl,
4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,

5-heptenyl, 6-heptenyl as well as dienes and trienes of
straight and branched chains.
The term "alkynyl" denotes such radicals as
ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as
well as di- and tri-ynes.
The term "halo" means chloro, fluoro, bromo or
iodo.
The term "-(C1-C4)alkoxy", as used herein,
denotes a group such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, t-butoxy and like groups, attached
to the remainder of the molecule by the oxygen atom.
The term "phenyl(C1-C4)alkyl" refers to a
straight or branched chain alkyl group having from one to
four carbon atoms attached to a phenyl ring which chain :s
attached to the remainder of the molecule. Typical
phenylalkyl groups include benzyl, phenylethyl,
phenylpropyl, phenylisopropyl, and phenylbutyl.
The term "-(C1-C4)alkylthio" defines a straight
or branched alkyl chain having one to four carbon atoms
attached to the remainder of the molecule by a sulfur
atom. Typical -(C1-C4)alkylthio groups include
methylthio, ethylthio, propylthio, butylthio and the like.
The term "-(C3-C14)cycloalkyl" includes groups
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,
cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl
and the like. The term "-(C3-C14)cycloalkyl" includes and
- (C3-C7)cycloalkyl.
The term, "heterocyclic radical", refers to
radicals derived from monocyclic or polycyclic, saturated or
unsaturated, substituted or unsubstituted heterocyclic
nuclei having 5 to 14 ring atoms and containing from 1 to 3
hetero atoms selected from the group consisting of nitrogen,
oxygen or sulfur. Typical heterocyclic radicals are

pyridyl, thienyl, fluorenyl, pyrrolyl, furanyl, thiophen/i,
pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl,
isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl,
carbazolyl, norharmanyl, azaindolyl, benzofuranyl,
dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl,
indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl,
anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl,
benzothiazolyl, purinyl, pryidinyl, dipyridylyl,
phenylpyridinyl, benzylpyridinyl, pyrimidinyl,
phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl^
phthalazinyl, quinazolinyl, and quinoxalinyl.
The term "carbocyclic radical" refers to radicals
derived from a saturated or unsaturated, substituted or
unsubstituted 5 to 14 membered organic nucleus whose ring
forming atoms (other than hydrogen) are solely carbon atoms.
Typical carbocyclic radicals are cycloalkyl, cycloalkenyl,
phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl,
xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl,
phenylcyclohexeyl, acenaphthylenyl, and anthracenyl,
biphenyl, bibenzylyl and related bibenzylyl homologues
represented by the formula (bb),

where n is an integer from 1 to 8.
The term, "non-interfering substituent", refers to
radicals suitable for substitution at positions 1, 2, 3, 7
and/or 8 on the tricyclic nucleus (as depicted in Formula
III) and radical(s) suitable for substitution on the
heterocyclic radical and carbocyclic radical as defined
above. Illustrative non-interfering radicals are hydrogen,
-(C1-C14)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl,

-(C7-C12)aralkyl, -(C7-C12)alkaryl, -(C3-C8)cycloalkyl,
-(C3-C8)cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl,
- (C1-C6)alkoxy, -(C2-C6)alkenyloxy, -(C2-C6)alkynyloxy,
- (C1-C12)alkoxyalkyl, -(C1-C12)alkoxyalkyloxy,
-(C1-C12)alkylcarbonyl, -(C^-C^)alkylcarbonylamino,
-(C1-C12)alkoxyamino, -(C1-C12)alkoxyaminocarbonyl,
-(C1-C12)alkylamino, -(C1-C6)alkylthio,
-(C1-C12)alkylthiocarbonyl, - (C1-C6)alkylsulfinyl,
- (C1-C6)alkylsulfonyl, -(C1-C6)haloalkoxy,
-(C1-C6)haloalkylsulfonyl, -(C1-C6)haloalkyl,
-(C1-C6)hydroxyalkyl,-(CH2)nCN' -(CH2)nNR9R10,
-C(0)0(C1-C6alkyl), -(CH2)n0(C1-C6 alkyl), benzyloxy,
phenoxy, phenylthio; - (C0NHS02) R15, where R15 is - (C1-
C6) alkyl; -CF3 , naphthyl or - (CH2)^phenyl where s is 0-5;
-CHO, -CF3, -OCF3, pyridyl, amino, amidino, halo, carbamyl,
carboxyl, carbalkoxy, -(CH2)nC02H, cyano, cyanoguanidinyl,
guanidino, hydrazide, hydrazine hydrazido, hydroxy/
hydroxyamino, nitro, phosphono, -SO3H, thioacetal,
thiocarbonyl, furyl, thiophenyl -COR9, -CONR9R10, -NR9R10, -
NCHCOR9, -S02R9, -OR9, -SR9, CH2S02R9, tetrazolyl or tetrazolyl
substituted with - (C1-Ce) alkyl, phenyl or -(C1-
C4)alkylphenyl, - (CH2) nOSi (Cj-Ce) alkyl and (Ci~
Ce)alkylcarbonyl; where n is from 1 to 8 and R9 and R10 are
independently hydrogen, -CF3/ phenyl, - (C]-C4) alkyl, - (C1-
C4) alkylphenyl or -phenyl (Cj-C^) alkyl
The term, "acidic group" means an organic group
which when attached to a tricyclic nucleus, through
suitable linking atoms (hereinafter defined as the "acid
linker"), acts as a proton donor capable of hydrogen
bonding. Illustrative of an acidic group are the
following:

where n is 1 to 8, R89 is a metal or -(C1-C10)alkyl, and
R99 is hydrogen or -(C1-C10)alkyl.
The words, "acid linker" refer to a divalent linking
group symbolized as, -(La)-, which has the function of
joining the 5 or 6 position of the tricyclic nucleus to an
acidic group in the general relationship:
(tricyclic nucleus) ~(La)- Acidic Group
The words, "acid linker length", refer to the
number of atoms (excluding hydrogen) in the shortest chain
of the linking group -(La)- that connects the 5 or 6
position of the tricyclic nucleus with the acidic group.
The presence of a carbocyclic ring in -(La)- counts as the
number of atoms approximately equivalent to the calculated
diameter of the carbocyclic ring. Thus, a benzene or
cyclohexane ring in the acid linker counts as 2 atoms in
calculating the length of -(La)-. Illustrative acid linker
groups are;

where t is 1 to 5, Q is selected from the group -(CH2)-,
-O-, -NH-, and -S-, and R84 and R85 are each independently
selected from hydrogen, -(C1-C10)alkyl, aryl, -(C1-
C10)alkaryl, -(C1-C10)aralkyl, carboxy, carbalkoxy, and
halo, when t is one (1), groups (a), (b), (c) and (d) have
acid linker lengths of 3, 3, 2, and 2, respectively.
The skilled artisan will appreciate that the
position of the double bond in the center 5-membered ring
depends on the position of the nitrogen atom as depicted
below.

The salts of the above tricyclics are an
additional aspect of the invention. In those instances
where the compounds of the invention possess acidic
functional groups various salts may be formed which are
more water soluble and physiologically suitable than the
parent compound. Representative pharmaceutically
acceptable salts include but are not limited to the alkali
and alkaline earth salts such as lithium, sodium,
potassium, calcium, magnesium, aluminum and the like.
Salts are conveniently prepared from the free acid by
treating the acid in solution with a base or by exposing
the acid to an ion exchange resin.
Included within the definition of
pharmaceutically acceptable salts are the relatively non-
toxic, inorganic and organic base addition salts of
compounds of the present invention, for example, ammonium,
quaternary ammonium, and amine cations, derived from
nitrogenous bases of sufficient basicity to form salts
with the compounds of this invention (see, for example, S.
M. Berge, et al., "Pharmaceutical Salts," J. Phar. Sci.,
66: 1-19 (1977)).
Compounds of the invention may have chiral
centers and exist in optically active forms. R- and S-
isomers and racemic mixtures are contemplated by this
invention. A particular stereoisomer may be prepared by
known methods using stereospecific reactions with starting
materials containing asymmetric centers already resolved

or, alternatively, by subsequent resolution of mixtures off
stereoisomers using known methods.
Prodrugs are derivatives of the compounds of the
invention which have chemically or metabolically cleavable
groups and become by solvolysis or under physiological
conditions the compounds of the invention which are
pharmaceutically active in vivo. Derivatives of the
compounds of this invention have activity in both their acid
and base derivative forms, but the acid derivative form
often offers advantages of solubility, tissue compatibility,
or delayed release in a mammalian organism (see, Bundgard,
H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam
1985). Prodrugs include acid derivatives, such as, esters
prepared by reaction of the parent acidic compound with a
suitable alcohol, or amides prepared by reaction of the
parent acid compound with a suitable amine. Simple
aliphatic esters (e.g., methyl, ethyl, propyl, isopropyl,
butyl, sec-butyl, tert-butyl) or aromatic esters derived
from acidic groups pendent on the compounds of this
invention are preferred prodrugs. Other preferred esters
include morpholinoethyloxy, diethylglycolamide and
diethylaminocarbonylmethoxy. In some cases it is desirable
to prepare double ester type prodrugs such as (acyloxy)
alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
The term "acid protecting group" is used herein as
it is frequently used in synthetic organic chemistry, to
refer to a group which will prevent an acid group from
participating in a reaction carried out on some other
functional group in the molecule, but which can be removed
when it is desired to do so. Such groups are discussed by T.
W. Greene in chapter 5 of Protective Groups in Organic
Synthesis, John Wiley and Sons, New York, 1981, incorporated
herein by reference in its entirety.

Examples of acid protecting groups include ester or amide
derivatives of the acid group, such as, methyl,
methoxymethyl, methyl-thiomethyl, tetrahydropyranyl,
methoxyethoxymethyl, benzyloxymethyl, phenyl, aryl, ethyl,
2,2,2-trichloroethyl, 2-methylthioethyl, t-butyl,
cyclopentyl, triphenylmethyl, diphenylmethyl, benzyl,
trimethylsilyl, N,N-dimethyl, pyrrolidinyl, piperidinyl,
or o-nitroanilide. A preferred acid-protecting group is
methyl.
The compounds of formula I where Z is
cyclohexene are prepared according to the following
reaction Schemes I (a)-(b) and II.

Wherein;
R1 is -NH2, R3(a) is H, -O (C1-C4) alkyl, halo, - (C1-C6) alkyl,
phenyl, - (C-i-C4) alkylphenyl; phenyl substituted with -
(d-Ce) alkyl, halo, or -CF3; -CH2OSi (C1-C6) alkyl, furyl,
thiophenyl, - (C1-C6) hydroxyalkyl, - (C1-C6) alkoxy (d-
C6) alkyl, - (C1-C6) alkoxy (d-C6) alkenyl; or -(CH2)nR8 where
R8 is H, -C0NH2, -NR9R10, -CN or phenyl where R9 and R10

are independently hydrogen, -CF3, phenyl, - (C1-C4) alkyl,
- (C1-C4) alkylphenyl or -phenyl (d-C4) alkyl and n is 1 to
8;
when R1 is -NHNH2, R3(a) is H, -O(d-C4) alkyl, halo, - (d-
C6) alkyl, phenyl, - (d-C4) alkylphenyl; phenyl
substituted with - (d-C6) alkyl, halo or -CF3; -CH2OSi(d-
C6) alkyl, furyl, thiophenyl, - (d~C6) hydroxyalkyl, - (d -
C6) alkoxy(d-C6) alkyl, - (d-C6) alkoxy (d-C6) alkenyl; or -
(CH2)nR8 where R8 is H, -NR9R10, -CN or phenyl where R5
and R10 are independently hydrogen, -CF3, phenyl, -(d-
C4) alkyl, - (C1-C4) alkylphenyl or -phenyl (C1-C4) alkyl and
n is 1 to 8;
R2la| is -OCH3 or -OH.
An appropriately substituted nitrobenzene (1)
can be reduced to the aniline (2) by treatment with a
reducing agent, such as hydrogen in the presence of Pd/C,
preferably at room temperature.
Compound (2) is N-alkylated at temperatures of
from about 0 to 20°C using an alkylating agent such as an
appropriately substituted aldehyde and sodium
cyanoborohydride to form (3). Alternately, an
appropriately substituted benzyl halide may be used for
the first alkylation step. The resulting intermediate is
further N-alkylated by treatment with 2-carbethoxy-6-
bromocyclohexanone, preferably at temperatures of about
80°C to yield (4) or by treatment with potassium
hexamethyldisilazide and the bromoketoester.
The product (4) is cyclized to the
tetrahydrocarbazole (5) by refluxing with ZnCl2 in benzene
for from about 1 to 2 days, preferably at 80°C. (Ref 1).
Compound (5) is converted to the hydrazide (6) by
treatment with hydrazine at temperatures of about 100°C,
or to the amide (7) by reacting with methylchloroaluminum

amide in benzene. (Ref 2) Alternatively, (7) may be
produced by treatment of (6) with Raney nickel active
catalyst

conversion to the amide will also be achieved in this
procedure.
Compounds (6) and (7) may be dealkylated,
preferably at 0°C to room temperature, with a dealkylating
agent, such as boron tribromide or sodium thioethoxide, to
give compound (7) where R2 (a) is -OH, which may then be
further converted to compound (9), by realkylating with a
base, such as sodium hydride, and an alkylating agent,
such as Br(CH2)mR^, where R^ is the carboxylate or
phosphonic diester or nitrile as defined above.
Conversion of R2 to the carboxylic acid may be
accomplished by treatment with an aqueous base. When R2 is nitrile,
conversion to the tetrazole may be achieved by
reacting with tri-butyl tin azide or conversion to the
carboxamide may be achieved by reacting with basic
hydrogen peroxide. When R2 is the phosphonic diester,
conversion to the acid may be achieved by reacting with a
dealkylating agent such as trimethylsilyl bromide. The
monoester may be accomplished by reacting the diester with
an aqueous base.
When R2 and R3 are both methoxy, selective
demethylation can be achieved by treating with sodium
ethanethiolate in dimethylformamide at 100°C.
Ref 1 Julia, M.; Lenzi, J. Preparation d'acides
tetrahydro-1, 2, 3,4-carbazole-l ou -4.
Bull.Soc.Chim. France, 1962, 2262-2263.

Ref 2 Levin, J.I.; Turos, E.; Weinreb, S.M. An
alternative procedure for the aluminum-mediated conversion
of esters to amides. Syn.Comm., 1982, 12, 989-993.
An alternative synthesis of intermediate (5) is
shown in Scheme 1(b), as follows.

where PG is a protecting group;
3a
R is as defined in Scheme 1, above.
The aniline (2) is N-alkylated with 2-carbethoxy-
6-bromocyclohexanone in dimethyl formamide in the presence
of sodium bicarbonate for 8-24 hours at 50°C. Preferred
protecting groups include methyl, carbonate, and silyl
groups, such as t-butyldimethylsilyl. The reaction product
(4') is cyclized to (5') using the ZnCl2 in benzene
conditions described in Scheme 1(a), above. N-alkylation of
(5') to yield (5) is accomplished by treatment with sodium

hydride and the appropriate alkyl halide in
dimethylformamide at room temperature for 4-8 hours.

R.3(a) is as defined in Scheme I.
As discussed in Scheme I above, carbazole (5) is
hydrolyzed to the carboxylic acid (10) by treatment with
an aqueous base, preferably at room temperature to about
100°c. The intermediate is then converted to an acid
chloride utilizing, for example, oxalyl chloride and
dimethylformamide, and then further reacted with a lithium

salt of (S) or (R)-4-alkyl-2-oxazolidine at a temperature
of about -75°C, to give (11a) and (lib), which are
separable by chromatography.
The diastereomers are converted to the
corresponding enantiomeric benzyl esters (12) by brief
treatment at temperatures of about 0°C to room temperature
with lithium benzyl oxide. (Ref 3) The esters (12) are
then converted to (7) preferably by treatment with
methylchloroaluminum amide (Ref 2, above) or, alternately,
by hydrogenation using, for example, hydrogen and
palladium on carbon, as described above, to make the acid
and then reacting with an acyl azide, such as
diphenylphosphoryl azide followed by treatment with
ammonia. Using the procedure described above in Scheme I,
compound (9a) or (9b) may be accomplished.
Ref 3 Evans, D.A.; Ennis, M.D.; Mathre, D.J. Asymmetric
alkylation reactions of chiral imide enolates. A practical
approach to the enantioselective synthesis of alpha-
substituted carboxylic acid derivatives. J.Am.Chem.Soc.,
1982, 104, 1737-1738.
Compounds of formula I where Z is phenyl can be
prepared as follows in Schemes III (a) - (g), below.

A 1,2, 3, 4-tetrahydrocarbazole-4-carboxamide or
4-carboxhydrazide (13) is dehydrogenated by refluxing in a
solvent such as carbitol in the presence of Pd/C to
produce the carbazole-4-carboxamide. Alternately,
treatment of (13) with DDQ in an appropriate solvent such
as dioxane yields carbozole (14).
Depending on the substituent pattern oxidation
as described above may result in de-alkylation of the
nitrogen. For example when R3 is substituted at the 8-
position with methyl, oxidation results in dealkylation of
the nitrogen which may be realkylated by treatment with
sodium hydride and the appropriate alkyl halide as
described in Scheme I(a) above to prepare the deired
product (14).
The intermediates and final products may be
isolated and purified by conventional techniques, for
example by concentration of the solvents, followed by
washing of the residue with water, then purification by
conventional techniques, such as chromatography or
recrystallization.
It will be readily appreciated by the skilled
artisan that the starting materials are either
commercially available or can be readily prepared by known
techniques from commercially available starting materials.
All other reactants used to prepare the compounds in the
instant invention are commercially available.

Benzoic acid derivative(16) where X is preferably
chlorine, bromine or iodine and the protecting group is
preferably -CH3, are reduced to the corresponding aniline
(25) with a reducing agent, such as stannous chloride in the
presence of acid under the general conditions of Sakamoto et
al, Chem Pharm. Bull. 35 (5), 1823-1828 (1987).
Alternatively, reduction with sodium dithionite in
the presence of a base, such as sodium carbonate in a
noninterferring solvent, such as water, ethanol, and/or
tetrahydrofuran affords starting material (16).
Alternatively, reduction by hydrogenation over a
sulfided platinum catalyst supported on carbon with hydrogen
at 1 to 60 atmospheres in a noninterfering solvent,
preferably ethyl acetate, to form a starting material (16).
The reactions are conducted at temperatures from
about 0 to 100°C. preferably at ambient temperature, and are
substantially complete in about 1 to 48 hours depending on
conditions.
The aniline (25) and dione (15) are condensed
under dehydrating conditions, for example, using the general
procedure of Iida, et al., (Ref 5), with or without a
noninterfering solvent, such as toluene, benzene, or
methylene chloride, under dehydrating conditions at a
temperature about 10 to 150°C. The water formed in the
process can be removed by distillation, azetropic removal
via a Dean-Stark apparatus, or the addition of a drying
agent, such as molecular sieves, magnesium sulfate, calcium
carbonate, sodium sulfate, and the like.
The process can be performed with or without a
catalytic amount of an acid, such a p-toluenesulfonic acid
or methanesulfonic acid. Other examples of suitable
catalysts include hydrochloric acid, phenylsulfonic acid,
calcium chloride, and acetic acid.

Examples of other suitable solvents include
tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,1,2, 2-
tetrachloroethane, chlorobenzene, bromobenzene, xylenes, and
carbotetrachloride.
The condensation of the instant process is
preferably carried out neat, at a temperature about 100 to
150°C with the resultant water removed by distillation via a
stream of inert gas, such as, nitrogen or argon.
The reaction is substantially complete in about 30
minutes to 24 hours.
Intermediate (26) may then be readily cyclized in
the presence of a palladium catalyst, such as Pd(OAc)2 or
Pd(PPh3)4 and the like, a phosphine, preferably a trialkyl-
or triarylphosphine, such as triphenylphosphine, tri-o-
tolylphosphine , or tricyclohexylphosphine, and the like, a
base, such as, sodium bicarbonate, triethylamine, or
diisopropylethylamine, in a noninterfering solvent, such as,
acetonitrile, triethylamine, or toluene at a temperature
about 25 to 200°C to form (19).
Examples of other suitable solvents include
tetrahydrofuran, benzene, dimethylsulfoxide, or
dimethylformamide.
Examples of other suitable palladium catalysts
include Pd(PPh3)Cl2, Pd(OCOCF3)2, [ (CH3C6H4) 3P] 2PdCl2,
[ (CH3CH2)3P]2PdCl2, [ (C6H„)3P]2PdCl2, and [ (C6Hb) 3P] 2PdBr2.
Examples of other suitable phosphines include
triisopropylphosphine, triethylphosphine,
tricyclopentylphosphine, 1,2-bis(diphenylphosphino)ethane,
1, 3-bis(diphenylphosphino)propane, and 1,4-
bis(diphenylphosphino)butane.
Examples of other suitable bases include tripropyl
amine, 2,2,6,6-tetramethylpiperidine, 1,5-
diazabicyclo[2.2.2]octane (DABCO), 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-

diazabicyclo[4.3.0]non-5-ene, (DBN) sodium carbonate,
potassium carbonate, and potassium bicarbonate.
The cyclization of the instant process is
preferably carried out with palladium(II)acetate as catalyst
in the presence of either triphenylphosphine, tri-o-
tolylphosphine, 1,3-bis(diphenylphosphino)propane, or
tricyclohexylphosphine in acetonitrile as solvent and
triethylamine as base at a temperature about 50 to 150°C.
The reaction is substantially complete in about 1 hour to 14
days.
Alternatively, a preferred process for cyclizat ion
consists of the reaction of intermediate (26) with a
palladacycle catalyst such as trans-di(u-acetato)-bis[o-( di-
o-tolylphosphino)benzyl]dipalladium (II) in a solvent such
as dimethylacetamide (DMAC) at 120-140°C in the presence of
a base such as sodium acetate.
Intermediate (19) may be alkylated with an
alkylating agent XCH2R«, where X is halo in the presence of
a base to form (20). Suitable bases include potassium
carbonate, sodium carbonate, lithium carbonate, cesium
carbonate, sodium bicarbonate, potassium bicarbonate,
potassium hydroxide, sodium hydroxide, sodium hydride,
potassium hydride, lithium hydride, and Triton B (N-
benzyltrimethylammonium hydroxide).
The reaction may or may not be carried out in the
presence of a crown ether. Potassium carbonate and Triton B
are preferred. The amount of alkylating agent is not
critical, however, the reaction is best accomplished using
an excess of alkyl halide relative to the starting material.
A catalytic amount of an iodide, such as sodium
iodide or lithium iodide may or may not be added to the
reaction mixture. The reaction is preferably carried out in
an organic solvent, such as, acetone, dimethylformamide,
dimethylsulfoxide, or acetonitrile. Other suitable solvents

include tetrahydrofuran, methyl ethyl ketone, and t-butyl
methyl ether.
The reaction is conducted at temperatures from
about -10 to 100°C. preferably at ambient temperature, and
is substantially complete in about 1 to 48 hours depending
on conditions. Optionally, a phase transfer reagent such as
tetrabutylammonium bromide or tetrabutylammonium chloride
may be employed.
Intermediate (20) may by dehydrogenated by
oxidation with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in
a noninterfering solvent to form (21).
Suitable solvents include methylene chloride,
chloroform, carbon tetrachloride, diethyl ether, methyl
ethyl ketone, and t-butyl methyl ether. Toluene, benzene,
dioxane, and tetrahydrofuran are preferred solvents. The
reaction is carried out at a temperature about 0 to 120 °c.
Temperatures from 50 to 120°C are preferred. The reaction is
substantially complete in about 1 to 48 hours depending on
conditions.
Intermediate (21) may be aminated with ammonia in
the presence of a noninterfering solvent to form a (22).
Ammonia may be in the form of ammonia gas or an ammonium
salt, such as ammonium hydroxide, ammonium acetate, ammonium
trifluoroacetate, ammonium chloride, and the like. Suitable
solvents include ethanol, methanol, propanol, butanol,
tetrahydrofuran, dioxane, and water. A mixture of
concentrated aqueous ammonium hydroxide and tetrahydrofuran
or methanol is preferred for the instant process. The
reaction is carried out at a temperature about 20 to 100°C.
Temperatures from 50 to 60°C are preferred. The reaction is
substantially complete in about 1 to 4 8 hours depending on
conditions.
Alkylation of (22) is achieved by treatment with
an alkylating agent of the formula XCH2R9 where X is halo

and R70 is -C02R71, -S03R71,-P (0) (OR71) 2, or -P (O) (OR71) H, where
R71 is an acid protecting group or a prodrug function, in
the presence of a base in a noninterfering solvent to form
(23). Methyl bromoacetate and t-butyl bromoacetate are the
preferred alkylating agents.
Suitable bases include potassium carbonate, sodium
carbonate, lithium carbonate, cesium carbonate, sodium
bicarbonate, potassium bicarbonate, potassium hydroxide,
sodium hydroxide, sodium hydride, potassium hydride, lithium
hydride, and Triton B (N-benzyltrimethylammonium hydroxide) .
The reaction may or may not be carried out in the presence
of a crown ether. Cesium carbonate and Triton B are
preferred.
The amount of alkylating agent is not critical,
however, the reaction is best accomplished using an excess
of alkyl halide relative to the starting material. The
reaction is preferably carried out in an organic solvent,
such as, acetone, dimethylformamide, dimethylsulfoxide, or
acetonitrile. Other suitable solvents include
tetrahydrofuran, methyl ethyl ketone, and t-butyl methyl
ether.
The reaction is conducted at temperatures from
about -10 to 100°C. preferably at ambient temperature, and
is substantially complete in about 1 to 48 hours depending
on conditions. Optionally, a phase transfer reagent such as
tetrabutylammonium bromide or tetrabutylammonium chloride
may be employed.
Intermediate (23) may be optionally hydrolyzed
with a base or acid to form desired product (24) and
optionally salified.
Hydrolysis of (23) is achieved using a base such
as sodium hydroxide, potassium hydroxide, lithium hydroxide,
aqueous potassium carbonate, aqueous sodium carbonate,
aqueous lithium carbonate, aqueous potassium bicarbonate,

aqueous sodium bicarbonate, aqueous lithium bicarbonate,
preferably sodium hydroxide and a lower alcohol solvent,
such as, methanol, ethanol, isopropanol, and the like. Other
suitable solvents include acetone, tetrahydrofuran, and
dioxane.
Alternatively, the acid protecting group may be
removed by organic and inorganic acids, such as
trifluoroacetic acid and hydrochloric acid with or withoat a
noninterferring solvent. Suitable solvents include methylene
chloride, tetrahydrofuran, dioxane, and acetone. The t-batyl
esters are preferably removed by neat trifluoroacetic acid.
The reaction is conducted at temperatures from
about -10 to 100°C. preferably at ambient temperature, and
is substantially complete in about 1 to 48 hours depending
on conditions.
The starting material (16) is prepared by
esterifying compound (15) with a alkyl halide = XPG; where X
is halo and PG is an acid protecting group, in the presence
of a base, preferably potassium carbonate or sodium
cabonate, in a noninterferring solvent, preferably
dimethylformamide or dimethylsulfoxide. The preferred alicyl
halide is methyl iodide. The reaction is conducted at
temperatures from about 0 to 100°C. preferably at ambient
temperature, and is substantially complete in about 1 to 4 8
hours depending on conditions.
Alternatively the starting material (16) may be
prepared by condensation with an alcohol HOPG, where PG is
an acid protecting group, in the presence of a dehydrating
catalyst such as, dicyclohexylcarbodiimide (DCC) or carbonyl
diimidazole.
In addition, U.S. Patent No. 4,885,338 and Jpn.
Kokai Tokkyo Koho 05286912, Nov 1993 Hesei teach a method
for preparing 2-fluoro-5-methoxyaniline derivatives.

Benzoic acid derivatives (16) (X= CI, Br, or I)
and boronic acid derivative (27) (either commercially
available or readily prepared by known techniques from
commercially available starting materials) are condensed
under the general procedure of Miyaura, et al., (Ref 8a)
or Trecourt, et al., (Ref 8b) in the presence of a
palladium catalyst, such as Pd(Ph3P)/j, a base, such as

sodium bicarbonate, in an inert solvent, such as THF,
toluene or ethanol, to afford compound (28).
Compound (28) is converted to the carbazole
product (29) by treatment with a trialkyl or triaryl
phosphite or phosphine, such as, triethylphosphite or
triphenyl phosphine, according to the general procedure of
Cadogan, et al. (Ref 6).
Compound (29) is N-alkylated with an
appropriately substituted alkyl or aryl halide XCH2R4 in
the presence of a base, such as sodium hydride or
potassium carbonate, in a noninterfering solvent, such as
toluene, dimethylformamide, or dimethylsulfoxide to afford
carbazole (30).
Compound (30) is converted to the corresponding
amide (22) by treatment with boron tribromide or sodium
thioethoxide, followed by ammonia or an ammonium salt,
such as ammonium acetate, in an inert solvent, such as
water or alcohol, or with methylchloroaluminum amide in an
inert solvent, such as toluene, at a temperature between O
to 110°C.
When R3(al is substituted at the 8-position with
chloro, de-alkylation of (30) with boron tribromide
results in de-benzylation of the nitrogen as described
above. Alkylation may be readily accomplished in a two
step process. First, an O-alkylation by treatment with a
haloalkyl acetate such as methyl bromo acetate using
sodium hydride in tetrahydrofuran, followed by N-
alkylation using for example a base such as sodium hydride
and an appropriately substituted alkyl or aryl halide in
dimethoxy formamide. Compound (22) can be converted to
product carbazole product (24) as described previously in
Scheme 111(b) above.
Conversion to the desired prodrug may be
accomplished by techniques known to the skilled artisan,

such as for example, by treatment with a primary or
secondary halide to make an ester prodrug.

Alternatively, reduction of the nitro group of
compound (28} with a reducing agent, such as hydrogen in
the presence of palladium on carbon, in a noninterfering
solvent, such as ethanol, at 1 to 60 atmospheres, at a
temperature of 0 to 60°C affords the corresponding aniline
(32). Compound (32) is converted to the carbazole (29)
according to the general procedure described by Trecourt,
et al. (Ref 8b). The aniline is treated with sulfuric
acid and sodium nitrite, followed by sodium azide to form
an intermediate azide which is cyclized to carbazole (29)
by heating in an inert sovent, such as toluene. Compound
(29) is converted to carbazole product (24) as described
previously in Schemes III(b) and III (c).
References:
8) a. N. Miyaura, et al., Synth. Commun. 11, 513 (1981)
b. F. Trecourt, et al., Tetrahedron, 51, 11743 6)
6) J. Cadogan et al., J. Chem. Soc, 4831 (1965)

In an aprotic solvent, preferably
tetrahydrofuran, reduction of (40) is achieved using a
reducing agent such as aluminum trihydride. Preferably,
the reaction is conducted under inert atmosphere such as
nitrogen, at room temperature.
Sulfonylation may be achieved with an
appropriate acylating agent in the presence of an acid
scavenger such as triethyl amine.

In a two-step, one-pot process, intermediate
(50), prepared as described in Scheme 1(a) above, is first
activated with an activating agent such as carbonyl
diimidazole. The reaction is preferably run in an aprotic
polar or non-polar solvent such as tetrahydrofuran.
Acylation with the activated intermediate is accomplished
by reacting with H2NSOR15 in the presence of a base,
preferably diazabicycloundecene.

Starting material (20) is O-alkylated with an
alkyl halide or alkenyl halide, using a base such as NaH,
in an aprotic polar solvent preferably anhydrous DMF, at
ambient temperature under a nitrogen atmosphere. The
process of aromatization from a cyclohexenone
functionality to a phenol functionality can be performed
by treating the tetrahydrocabazole intermediate (60) with
a base such as NaH in the presence of methyl
benzenesulfinate in an anhydrous solvent, such as 1,4-

dioxane or DMF, to form the ketosulfoxide derivative.
Upon heating at about 100°C for 1-2 hours, the
ketosulfoxide derivative (60) is converted to the phenol
derivative (61). Conversion of the ester (61) to the
amide (62) can be achieved by treating a solution of (61)
in an aprotic polar solvent such as tetrahydrofuran with
ammonia gas. Phenolic O-alkylation of (62) with, for
example, methyl bromoacetate can be carried out in
anhydrous DMF at ambient temperature using Cs2C03 or K2C03
as a base to form (63). Desired product (64) can be
derived from the basic hydrolysis of ester (63) using LiOH
or NaOH as a base in an H2O/CH3OH/THF solution at 50°C for
1-2 hours.
When R22 is - (C1-C6) alkoxy (C1-C6) alkenyl,
hydrogenation of the double bond can be performed by
treating (63) in THF using Pt02 as a catalysis under a
hydrogen atmosphere. Desired product can then be derived as
described above in Scheme III(g) from the basic hydrolysis
of ester (63) using LiOH or NaOH as a base in an
H2O/CH3OH/THF solution at 50°C for 1-2 hours.
The following list of abreviations are used in the
Examples and Preparations.
HC1 = hydrochloric acid
EtOAc = ethyl acetate
DMF = dimethyl formamide
THF = tetrahydrofuran
Et20 = diethyl ether
H2O = water
NaOH = sodium hydroxide
EtOH = ethanol
Na2SO« = sodium sulfate
NaHC03 = sodium bicarbonate
celite = diatomaceous earth

CH2C12 = methylene chloride
H2SO4 = sulfuric acid
MeoH = methanol
Rh/Al203 = rhodium on alumina
DDQ = 2,3-dichloro-5,6-dicyano-l, 4-benzo-
quinone
TLC = thin layer chromotography
NaH" = sodium hydride
NH4OH = ammonium hydroxide
LiOH = lithium hydroxide
NH3 = ammonia
Cs2C03 = cesium carbonate
NH4oAc = ammonium acetate
The following preparations of intermediates and
examples of final products futher illustrate the preparation
of the compounds of this invention. The examples are
illustrative only and are not intended to limit the scope of
the invention in any way.
Preparation 1
Preparation of 5-Carbomethoxy-l,2-dihydro-9H-carbazol-4 (3H) -
one from 2-bromo-3-nitrobenzoic acid

a) Methyl 2-bromo-3-nitrobenzoate
A solution of 2-bromo-3-nitrobenzoic acid (28.4 g,
115.0 mM), iodomethane (18.0 g, 127 mM), and potassium
carbonate (19.0 g, 137.4 mM) in 100 mL DMF was stirred at

room temperature for 72 hours. The mixture was poured into
1.5 liters of H2O. The resultant precipitate was collected
by filtration and dried in vacuo to afford 28.79 g (96%) of
methyl 2-bromo-3-nitrobenzoate as a white solid. XH NMR
(DMS0-d6) 8 8.3 (dd, 1H, J=l and 8 Hz), 7.9 (dd, 1H, J=l a.nd
8 Hz), 7.7 (t, 1H, J=8 Hz), and 3.9 (s, 3H). IR (KBr, cm"1)
2950, 1738, 1541, 1435, 1364, 1298, and 1142. MS (FD) m/e
259, 261.
Elemental Analyses for CaH6N04Br:
Calculated: C, 36.95; H, 2.33; N, 5.39.
Found: C, 37.14; H, 2.37; N, 5.45.
b) Methyl 2-bromo-3-aminobenzoate
Hydrogen gas was passed through a solution of methyl 2-
bromo-3-nitrobenzoate (0.20 g, 0.77 mM) and 0.1 g of 3%
sulfided platinum on carbon in 25 mL ethyl acetate for 24
hours at room temperature. The catalyst was removed by
filtration through celite. Concentration of the filtrate
afforded 0.175 g (99%) of methyl 2-bromo-3-aminobenzoate as
a yellow oil. *H NMR (CDC13) 8 7.15 (t, 1H, J=8 Hz), 7.1
(dd, 1H, J=l and 8 Hz), 6.8 (dd, 1H, J=l and 8 Hz), and 3.95
(s, 3H) . IR (CHC13, cm"1) 3550, 3380, 2980, 2900, 1729, 1613,
1465, 1451, 1434, 1324, 1266, and 1025. MS (FD) m/e 230,
232.
Elemental Analyses for CsHeNC^Br:
Calculated: C, 41.77; H, 3.51; N, 6.09.
Found: C, 42.01; H, 3.29; N, 6.00.
b)' In an alternate procedure, Methyl 2-bromo-3-
aminobenzoate may be prepared as follows:
A solution of stannous chloride (15.0 g, 76.1 mM) in 30
mL of concentrated hydrochloric acid was slowly added to a
solution of methyl 2-bromo-3-nitrobenzoate (4.0 g, 15.4 mM)
in 90 mL ethanol at 15-30 °C over 1 hour. The mixture was

then heated at 50-60 °C for 15 minutes. The mixture was
cooled to room temperature and made alkaline by slow
addition of solid sodium hydroxide maintaining a temperature
of 30-35 °C. The resultant mixture was extracted three
times with chloroform. The extracts were washed with brine,
dried over sodium sulfate, filtered and concentrated to
afford 3.51 g (99%) of methyl 2-bromo-3-aminobenzoate as a
yellow oil, identical in all respects to the material
derived via catalytic hydrogenation described above.
c) 3-(3-Carbomethoxy-2-bromoanilino)cyclohex-2-en-l-one
A mixture of methyl 2-bromo-3-aminobenzoate (13.2 g,
60.0 mM) and 1,3-cyclohexanedione (8.4 g, 75 mM) was heated
at 125 °C under a stream of nitrogen for 4 h. The resultant
solid was purified by HPLC on silica gel (elution with
methylene chloride/ethyl acetate) to afford 17.2 g (88%) of
3-(3-carbomethoxy-2-bromoanilino)cyclohex-2-en-l-one as a
tan foam. 1H NMR (DMSO-d6) ? 8.75 (s, 1H), 7.6-7.4 (m, 3H) ,
4.65 (s# 1H), 3.85 (s, 3H) , 2.6 (t, 2H, J=6 Hz), 2.15 (t,
2H, J=6 Hz), and 1.9 (m, 2H) . IR (CHC13, cm"1) 3400, 3004,
2954, 1732, 1607, 1588, 1573, 1513, 1464, 1436, 1412, 1308,
1249, 1177, and 1144. MS (ES) m/e 322, 324, 326.
Elemental Analyses for C14H14NO3Br:
Calculated: C, 51.85; H, 4.32; N, 4.32.
Found: C, 53.60; H, 4.73; N, 4.09.
d) 5-Carbomethoxy-l,2-dihydro-9H-carbazol-4(3H)-one
A suspension of 3-(3-carbomethoxy-2-
bromoanilino)cyclohex-2-en-l-one (15.8 g, 48.8 mM),
palladium acetate (1.12 g, 5.0 mM), tri-o-tolylphosphine
(3.1 g, 10.0 mM), and triethylamine (6.3 g, 62.0 mM) in 120
mL acetonitrile was heated at reflux for 8 hours. The
solvent was removed in vacuo. The residue was dissolved in
methylene chloride, washed twice with 1 N HC1, twice with

H2O, once with saturated brine, dried over anhydrous
magnesium sulfate, filtered, and concentrated to afford '.1 g
of a light brown foam. Purification by HPLC on silica gel
(elution with gradient methylene chloride/ethyl acetate)
afforded 9.2 g (78%) of the 5-carbomethoxy-l,2-dihydro-9H-
carbazol-4(3H)-one as a yellow solid, identical with the
material derived from 3-(3-carbomethoxy-2-
chloroanilino)cyclohex-2-en-l-one, described above. 1H NKR
(DMS0-d6) ? 7.5 (d, 1H, J=8 Hz), 7.25-7.1 (m, 2H), 5.7 ( = ,
1H) , 3.8 (s, 3H), 2.95 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz),
and 2.1 (m , 2H). MS (ES) m/e 242, 244.

A. 9-[(Phenyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol-
4(3H)-one
A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol-
4(3H)-one (300 mg, 1.23 mM), benzyl bromide (210 mg, 1.23
mM), and potassium carbonate (170 mg, 1.23 mM) in 15 mL DMF
was stirred at room temperature for 6 hours. The mixture was
diluted with 80 mL H2O and chilled in the refrigerator. The
resultant white precipitate was collected by filtration,
washed with H2O, and dried in vacuo to afford 325 mg (79%)
of the 9-[(phenyl)methyl]-5-carbomethoxy-l, 2-

dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSC-
d6) ? 7.7 (dd, 1H, J=l and 8 Hz), 7.45-7.0 (m, 7H) , 5.6 is,.
2H), 3.8 (s, 3H), 3.05 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 H2),
and 2.2 (m , 2H). IR (KBr, cm"1) 3421, 1726, 1676, 1636,
1473, 1450, 1435, 1288, 1122, 764, 745, and 706. MS (ES) m/e
334.
Elemental Analyses for C2iHi9N03:
Calculated: C, 75.68; H, 5.71; N, 4.20.
Found: C, 70.85; H, 5.53; N, 4.49.
B. 9-[(Phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole
(a) A solution of the 9-[(phenyl)methyl]-5-carbomethoxy-
l,2-dihydrocarbazol-4(3H)-one (1.5 g, 4.5 mM) and 2,3-
dichloro-5,6-dicyano-l,4-benzoquinone (1.12 g, 5.0 mM) in 25
mL of toluene was stirred between 80-90 °C for 6 h. The
mixture was purified directly by column chromatography on
silica gel (elution with methylene chloride/ethyl acetate)
to afford 420 tag (28%) of the 9-[ (phenyl) methyl]-4-hydroxy-
5-carbomethoxy carbazole as a yellow solid. 1H NMR (DMSO-
d6) 6 10.25 (s, 1H), 7.7 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6 (s, 2H), and
3.8 (s, 3H) . IR (CHC13, cm"1) 1723, 1685, 1621, 1597, 1568,
1496, 1453, 1442, 1392, 1286, 1267, 1156, and 1138. MS (ES)
m/e 330, 332.
Elemental Analyses for C21H17NO3:
Calculated: C, 76.13; H, 5.14; N, 4.23.
Found: C, 75.90; H, 5.20; N, 4.46.
(b) To a solution of the 9-[(phenyl)methyl]-5-carbomethoxy-
l,2-dihydrocarbazol-4 (3H)-one (2.87 g, 8.61 mM) in 29 ml
dioxane was added 60% sodium hydride in mineral oil (0.79 g,
19.8 mM) . The reaction was stirred 8 minutes, then methyl
benzenesulfinate (1.80 ml, 13.8 mM) was added. The reaction
was stirred an additional 1.5 h, then diluted with 43 ml

dioxane and 1.13 ml acetic acid. The mixture was refluxed 1
h, diluted with ethyl acetate, and extracted with sat'd
NaHC03 two times, then with brine. After drying (NaSCU) ,
evaporation in vacuo afforded 4.90 g. The mixture was
purified by column chromatography on silica gel (elution
with toluene/methylene chloride) to afford 2.31 g (81%) cf
the 9-[(phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole_
lE NMR (DMSO-d6) 5 10.25 (s, 1H), 7.7 (d, 1H, J=8 Hz), 7.4
(t, 1H, J=8 Hz), 7.4-7.0 (m, 8H), 6.6 (d, 1H, J=8 Hz), 5.6
(s, 2H) , and 3.8 (s, 3H) . IR (CHC13, cm"1) 1723, 1685, 1621,
1597, 1568, 1496, 1453, 1442, 1392, 1286, 1267, 1156, and
1138. MS (ES) m/e 330, 332.
Elemental Analyses for C21H17NO3:
Calculated: C, 76.13; H, 5.14; N, 4.23.
Found: C, 75.90; H, 5.20; N, 4.46.
C. 9-[(Phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole
A solution of the 9-[(phenyl)methyl]-4-hydroxy-5-
carbomethoxy carbazole (200 mg, 0.6 mM) in 4 mL MeOH and 4 0
mL concentrated aqueous ammonium hydroxide was sonicated for
30 h at 40-50 °C. The mixture was diluted with ethyl acetate
and acidified to pH 1 with 5 N HC1. The aqueous layer was
extracted three times with ethyl acetate. The combined
organic extracts were washed with saturated brine, dried
over magnesium sulfate, filtered, and concentrated. The
residue was purified by column chromatography on silica gel
(elution with gradient methylene chloride/ethyl acetate) to
afford 50 mg (26%) of the 9-[(phenyl)methyl]-4-hydroxy-5-
carbamoyl carbazole as a white solid. :H NMR (DMS0-d6) ?
10.5 (s, 1H), 8.8 (br s, 1H), 8.4
J=l and 8 Hz), 7.5-7.1 (m, 9H), 6.6 (d, 1H, J=8 Hz), and 5.8
(s, 2H) . IR (KBr, cm"1) 3428, 3198, 3063, 1631, 1599, 1579,
1562, 1496, 1442, 1330, 1261, 1215, 775, and 697. MS (ES)
m/e 315, 317.

Elemental Analyses for C20Hi6N202:
Calculated: C, 75.95; H, 5.06; N, 8.86.
Found: C, 74.88; H, 5.40; N, 7.78.
D. {9-[(Phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacet:Lc
acid, methyl ester
40% Methanolic Triton B (0.11 ml, 0.24 iriM) was added to
a solution of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl
carbazole (70 mg, 0.22 mM) in 20 mL DMF at 0 °C. After 15
minutes, methyl bromoacetate (70 mg, 0.44 mM) was added and
the resultant mixture stirred at room temperature for 5 h.
The mixture was diluted with ethyl acetate, washed with 1 N
HC1, H2O, and saturated brine, dried over magnesium sulfate,
filtered, and concentrated. The residue was combined with
the crude material derived from a similar run utilizing 4 5
mg (0.14 mM [0.36 mM total]) of 9-[(phenyl)methyl]-4-
hydroxy-5-carbamoyl carbazole. The combined residues were
purified by column chromatography on silica gel (elution
with ethyl acetate) to afford 76 mg (54%) of the {9-
[(phenyl)methyl]-5-carbamoylcarbazol-4-yl)oxyacetic acid,
methyl ester as a white solid. 1H NMR (DMSO-d6) ? 7.65 (d,
1H, J=8 Hz), 7.5 (br s, 1H), 7.4-7.15 (m, 9H), 7.1 (d, 1H,
J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H) , and
3.75 (S, 3H) . IR (KBr, cm"') 3367, 3200, 1760, 1643, 1579,
1496, 1452, 1427, 1216, 1157, 772, and 716. MS (FD) m/e 388.
Elemental Analyses for C23H2ON2O4:
Calculated: C, 71.13; H, 5.15; N, 7.22.
Found: C, 70.77; H, 5.49; N, 6.79.
E. {9-[(Phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, sodium salt.
A solution of the {9-[(phenyl(methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (10.1
mg, 0.025 mM) and 0.025 mL (0.025 mM) of 1 N NaOH in 3 mL of

ethanol was stirred for 16 h at 25 °C. The resultant white
precipitate was collected by filtration, washed with a small
amount of EtOH, then dried in vacuo to afford 7.1 mg (70%>
of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, sodium salt as a white powder. 'H NMR
(DMS0-d6) 5 7.6 (d, 1H, J=8 Hz), 7.5-7.05 (m, 11H), 6.55 1H, J=8 Hz), 5.75 (s, 2H) , and 4.3 (s, 2H) . IF. (KBr, cm"1)
3471, 1657, 1615, 1591, 1496, 1453, 1412, 1330, 1272, and
1151. MS (ES) m/e 373, 375, 397. Elemental Analyses for
C22H;7N204Na: C, 66.67; H, 4.29; N, 7.07. Found C, 66.75; H,
4.55; N, 6.83.
Example 2
Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1, 2, 3, 4-
tetrahydrocarbazol-5-yl]oxyacetic acid
A. Preparation of (2-chloro-4-fluorophenyl)- ethyl
carbonate
A solution of 19.16 g of 2-chloro-4-fluorophenol in
65.4 ml of 2 N aqueous sodium hydroxide solution was cooled
in an ice bath and treated dropwise with 16.3 ml of ethyl
chloroformate. After stirring at room temperature
overnight, the two-phase reaction mixture was diluted with
100 ml of water and extracted with 300 ml of a 1:1
pentane/ether mixture. The extract was washed three times
with 0.02 N sodium hydroxide solution, water and then brine.
After drying and evaporation, 27.63 g (97%) of the subtitle
compound were obtained. NMR (300 MHz, CDCI3): 5 7.23-7.18
(m, 2H); 7.00 (dt, J=8.4, 2.7, 1H); 4.35 (q, J=7.1, 2H) ;
1.40 (t, J=7.1, 3H).

B. Preparation of (2-chloro-4-fluoro-5-nitrophenyl)- ethyl
carbonate
A solution of 27.63 g of (2-chloro-4-fluorophenyl)-
ethyl carbonate in 60 ml of dichloromethane was cooled in an
ice bath and treated dropwise with 31.86 g of a 1:2 mixture
of fuming nitric acid (90%) and concentrated sulfuric acid.
The reaction was stirred for 2 hours at room temperature a.nd
then cooled with ice and treated with another 4.5 g of the
same nitrating mixture. The reaction was stirred overnight
at room temperature, poured into 200 ml of ice and water, and
extracted twice with dichloromethane. The extracts were
washed with water and then with brine, dried over magnesium
sulfate and concentrated to afford 33.01 g (99%) of the
subtitle compound, mp. 50-51 C
Elemental Analyses
Calculated: C 41.01; H 2.68; N 5.31; Cl 13.45
Found: C 41.03; H 2.59; N 5.38; Cl 13.71
C. Preparation of 2-chloro-4-fluoro-5-nitroanisole
A solution of 15.0 g of (2-chloro-4-fluoro-5-
nitrophenyl)- ethyl carbonate in 100 ml of dimethyl
formamide was treated with 18.6 g of cesium carbonate, 7.1
ml of iodomethane and 7 ml of methanol and stirred overnight
at room temperature. The reaction mixture was poured into
water and extracted twice with ether. The extracts were
washed twice with water and then with brine, dried over
magnesium sulfate and concentrated to afford 11.4g of the
subtitle compound, mp. 69-70°C Ex. 57, C.
Elemental Analyses
Calculated: C 40.90; H 2.45; N 6.81; Cl 17.25
Found: C 41.20; H 2.48; N 6.70; Cl 17.44

D. Preparation of 2-fluoro-5-methoxyaniline
A solution of 5.63 g of 2-chloro-4-fluoro-5-
nitroanisole in 90 ml of ethanol and 5 ml of triethylamine
was hydrogenated at room temperature under 60 pounds per
square inch with 1.0 g of 5% palladium on carbon for four
hours. The catalyst was filtered off and the solvent was
evaporated. The residue was slurried in chloroform and
filtered thourough a plug of silica gel and then evaporated.
This residue was chromatographed on silica gel using hexane/
chloroform mixtures to afford 2.77 g (72%) of the subtitle
compound. mp. 253-254°C. NMR (300 MHz, CDCI3): 6 6.88 (dd,
J=10.6, 8.9, 1H); 6.32 (dd, J=7.4, 3.0, 1H); 6.20 (dt,
J=8.9, 3.2,1H); 3.73 (s, 3H); 3.72 (br, 2H).
E. Preparation of N-benzyl-2-fluoro-5-methoxyaniline
This procedure was patterned after that of Tietze and
Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g
of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in
48 ml of methanol was treated with 3.43 g of zinc chloride
and then cooled in an ice bath. Sodium cyanoborohydride
(1.58 g) was added in small poroom temperature ions over 30
minutes and the reaction was stirred for five hours at room
temperature. After evaporation of the solvent, the residue
was slurried in 40 ml of 1 N sodium hydroxide solution and
then extracted twice with ether. The extracts were washed
with water and then with brine, dried over magnesium sulfate
and concentrated. The residue was recrystallized from
hexane to afford 2.61 g and the mother liquors were
chromatographed on silica gel using 20:1 hexane/ether to
afford another 1.4 g of the subtitle compound (90%). mp.
56-58°C

Elemental Analyses
Calculated: C 72.71; H 6.10; N 6.06
Found: C 72.51; H 6.06; N 5.99
F. Preparation of ethyl 9-benzyl-5-methoxy-8-fluoro-
1,2, 3,4-tetrahydrocarbazole-4-carboxylate
A solution of 0.62 g of N-benzyl-2-fluoro-5-
methoxyaniline in 20 ml of dry tetrahydrofuran was cooled in
an ice bath and treated with 11.3 ml of 0.5 M potassium
bis(trimethylsilyl)amide in toluene. After stirring for 30
minutes, 0.74 g of 2-carboethoxy-6-bromocyclohexanone
(Sheehan and Mumaw, JACS, 72, 2127 (1950)) in 4 ml of
tetrahydrofuran was added and the reaction was allowed tc
warm slowly to room temperature over two hours. The
reaction was quenched with saturated ammonium chloride
solution and extracted twice with ether. The extracts were
washed with water and then with brine, dried over magnesium
sulfate and concentrated. This residue was chromatographed
on silica gel using hexane/ ether mixtures to afford 0.796 g
(74%) of N-alkylated intermediate diastereomers. This
mixture was refluxed in 20 ml of benzene with 0.99 g of zinc
chloride overnight. The solvent was evaporated and the
residue was partitioned between 25 ml of 1 N HC1 and 25 ml
of ethyl acetate and then extracted once more with ethyl
acetate. The organic layers were washed with water and then
brine, dried over magnesium sulfate and concentrated to
afford 0.734 g (96%) of the subtitled compound. ESIMS m/e
382 (M++1)
Elemental Analyses
Calculated: C 72.42; H 6.34; N 3.67
Found: C 72.20; H 6.26; N 3.70

G. Preparation of 9-benzyl-5-methoxy-8-fluoro-1,2,3,4-
tetrahydrocarbazole-4-carboxamide
Ethyl 9-benzyl-5-methoxy-8-fluoro-1, 2, 3, 4-
tetrahydrocarbazole-4-carboxylate (0.722 g) was treated
similarly as described in Example 49, Part C and
chromatographed on silica gel using 1% methanol in
dichloromethane to afford 0.482 g (72%) of the subtitle
compound. ESIMS m/e 353 (M++1)
Elemental Analyses
Calculated: C 71.57; H 6.01; N 7.95
Found: C 71.42; H 5.83; N 7.75
H. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4 -
tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester
9-Benzyl-5-methoxy-8-fluoro-1, 2, 3, 4-
tetrahydrocarbazole-4-carboxamide (0.170 g) was converted
similarly as described in Example 49, Part D and
chromatographed on silica gel using methanol/ 0-1% in
dichloromethane to afford 85 mg. (50%) of the subtitle
compound. mp. 183-185°C
Elemental Analyses
Calculated: C 67.31; H 5.65; N 6.82
Found: C 67.58; H 5.48; N 6.95
I. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-
tetrahydrocarbazol-5-yl]oxyacetic acid
[9-Benzyl-4-carbamoyl-8-fluoro-1, 2, 3,4-
tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester (71 mg)
was hydrolyzed similarly as described in Example 50, Part D
to afford 65 mg of the title compound. ESIMS m/e 397
(M++l), 395 (M+-1) NMR (300 MHz, d6-DMS0): ? 13.03 (br,
1H); 7.31-7.19 (m, 3H); 6.97 (d, J=7.4, 2H); 6.95 (br, 1H);

6.70 (d, J=3.8, 1H); 6.67 (dd, J=12.4, 3.9, 1H); 6.28 (dd„
J=8.5, 2.6, 1H); 5.39 (ABq, 2H); 4.64 (s, 2H); 3.92 (br,
1H); 2.71 (m, 1H); 2.44 (m, 1H); 2.02 (m, 2H); 1.76 (m, 2H) .
Example 3
Preparation of [9-benzyl-5-carbamoyl-l-fluorocarbazol-4—
yl]oxyacetic acid
A. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-l-
fluorocarbazole
A solution of 0.458 g of 9-benzyl-5-methoxy-8-fluoro—
1,2, 3, 4-tetrahydrocarbazole-4-carboxamide in 13 ml of dry
dioxane under nitrogen was treated with 0.59 g of 2,3-
dichloro-5,6-dicyano-l,4-benzoquinone and refluxed for one
hour. The reaction mixture was cooled and filtered and trie
precipitate was washed with 15 ml of dioxane. The filtrate
and washing were poured into saturated sodium bicarbonate
solution and extracted three times with ethyl acetate. The
extracts were washed with saturated sodium bicarbonate, with
water and then with brine; dried over magnesium sulfate and
concentrated. This residue was chromatographed on silica
gel using dichloromethane/ 0-2% methanol to afford 0.45 g of
subtitle compound. ESIMS m/e 34 9 (M++l)
Elemental Analyses
Calculated: C 72.42; H 4.92; N 8.04
Found: C 72.35; H 4.81; N 7.88
B. Preparation of [9-benzyl-5-carbamoyl-l-fluorocarbazol-
4-yl]oxyacetic acid methyl ester
A solution of 0.45 g of 9-benzyl-5-carbamoyl-4-methoxy-
1-fluorocarbazole in 25 ml of dichloromethane was cooled in
an ice bath treated dropwise with 12 ml of 1.0 M boron

tribromide solution in dichloromethane. The reaction was
allowed to warm to room temperature slowly over 2 hours and
then quenched by pouring into ice and then adding 50 ml of 1
N HC1. The mixture was extracted with dichloromethane
(3x200 ml) and the extracts were dried over magnesium
sulfate and concentrated to afford 0.35 g (78%) of the
demethylated intermediate. This intermediate (0.215 g) was
alkylated and purified similarly to Example GH1, Part D to
afford 0.166 g (64%) of the subtitle compound, mp. 190-
191°C
Elemental Analyses
Calculated: C 67.97; H 4.71; N 6.89
Found: C 67.81; H 4.94; N 6.96
C. Preparation of [9-benzyl-5-carbamoyl-l-fluorocarbazol-
4-yl]oxyacetic acid
[9-Benzyl-5-carbamoyl-l-fluorocarbazol-4-yl]oxyacetic
acid methyl ester (56 mg) was hydrolyzed and isolated
similarly as described in Example 50, Part D to afford 54 mg
of the title compound. FDMS m/e 392 (M+); ESIMS m/e 393
(M++1), 391 (M+-l) NMR (300 MHz, d6-DMSO): 6 12.92 (br,
1H); 7.70 (m, 2H); 7.45 (t, J=7.5, 1H); 7.39 (br, 1H); 7.28-
7.17 (m, 4H); 7.12 (d, J=7.2, 1H); 7.07 (d, J=7.0, 2H); 6.51
(dd, J=8.8, 2.7, 1H); 5.77 (s, 2H); 4.80 (s, 2H).
Elemental Analyses
Calculated: C 67.34; H 4.37; N 7.14
Found: C 66.92; H 4.49; N 6.77

A. 9-[(3-Fluorophenyl)methyl]-5-carbomethoxy-l,2-
dihydrocarbazol-4(3H)-one
40% Methanolic Triton B (2.06 mL, 4.53 mM) was slowly-
added dropwise to a solution of 5-carbomethoxy-l,2-dihydro-
9H-carbazol-4(3H)-one (930.0 mg, 3.82 mM) in 5 mL of DMF at
0 °C. After 5 minutes, 3-fluorobenzyl chloride (664.0 mg,
4.59 mM) was added and the resultant mixture stirred at 0 °C
for 3 h, then at room temperature for 20 hours. The mixture
was diluted with ethyl acetate, washed three times with 1 N
HC1, three times with H2O, once with saturated brine, dried
over anhydrous magnesium sulfate, filtered, and
concentrated. The residue was purified by column
chromatography on silica gel (elution with gradient
methylene chloride/ethyl acetate) to afford 502.3 mg (371)
of the 9-[(3-fluorophenyl)methyl]-5-carbomethoxy-l, 2-
dihydrocarbazol-4(3H)-one as a yellow foam. 'H NMR (CDCI3)
8 7.4-7.2 (m, 4H) , 6.9 (m, 1H) , 6.7 (m, 2H) , 5.35 (s, 2H) ,
4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and
2.3 (m , 2H) . IR (CHC13, cm"1) 3050, 2950, 1725, 1654, 1464,
1451, 1440, 1288 and 1119. MS (ES) m/e 350, 352.

Elemental Analyses for C2iHieN03F:
Calculated: C, 71.78; H, 5.16; N, 3.99.
Found: C, 72.00; H, 4.95; N, 4.11.
B. 9-[(3-Fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy
carbazole
A solution of the 9-[(3-fluorophenyl)methyl]-5-
carbomethoxy-l,2-dihydrocarbazol-4(3H)-one (434.0 mg, 1.23
mM) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (324.0 iug,
1.42 mM) in 20 mL of toluene was stirred between 70-80 °C
for 5 h. The mixture was purified directly by column
chromatography on silica gel (elution with methylene
chloride) to afford 137.0 mg (32%) of the 9-[(3-
fluorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a
yellow foam. XH NMR (DMSO-d6) 5 10.2 (s, 1H) , 7.7 (d, 1H,
J=8 Hz), 7.4 (t, 1H, J=8 Hz), 7.3 (m, 2H), 7.2 (d, 1H, J=8
Hz), 7.1 (d, 1H, J=8 Hz), 7.05-6.85 (m, 3H) , 6.6 (d, 1H, J=8
Hz), 5.65 (s, 2H), and 3.85 (s, 3H) . IR (CHC13, cm"1) 3200
(br), 1687, 1597, 1452, 1442, 1285, and 1267. MS (ES) m/e
348, 350.
Elemental Analyses for C2iH16N03F:
Calculated: C, 72.20; H, 4.62; N, 4.01.
Found: C, 72.30; H, 4.66; N, 4.04.
C. 9-[(3-Fluorophenyl)methyl]-4-hydroxy-5-carbamoyl
carbazole
A solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-
5-carbomethoxy carbazole (130.8 mg, 0.37 mM) in 5 mL THF and
20 mL concentrated aqueous ammonium hydroxide was sonicated
for 5 h at 4 0-50 °C. The mixture was diluted with ethyl
acetate and acidified to pH 1 with 5 N HCl. The aqueous
layer was extracted twice with ethyl acetate. The combined
organic extracts were washed with saturated brine, dried
over magnesium sulfate, filtered, and concentrated. The

residue was purified by column chromatography on silica gel
(elution with gradient methylene chloride/ethyl acetate) to
afford 57.4 mg (45%) of the 9-[(3-fluorophenyl)methyl]-4-
hydroxy-5-carbamoyl carbazole as a white solid. JH NMR
(DMS0-d6) 5 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H),
7.8 (dd, 1H, J=l and 8 Hz), 7.5 (m, 2H), 7.3 (m, 2H), 7.15-
7.0 (m, 2H), 6.95 (d, 1H, J=8 Hz), 6.85 (d, 1H, J=8 Hz), 6.6
(d, 1H, J=8 Hz), and 5.7 (s, 2H) . IR (CHC13, cm"1) 3431, 2200
(br), 1628, 1614, 1600, 1580, 1546, 1488, 1448, 1329, 1261,
and 776. MS (ES) m/e 333, 335.
Elemental Analyses for C20H15N2O2F:
Calculated: C, 71.85; H, 4.52; N, 8.38.
Found: C, 74.45; H, 6.01; N, 8.48.
D. {9-[(3-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, tert-butyl ester
40% Methanolic Triton B (0.086 mL, 0.19 raM) was added
to a solution of the 9-[(3-fluorophenyl)methyl]-4-hydroxy-5-
carbamoyl carbazole (51.9 mg, 0.155 MM) in 3 mL DMF at room
temperature. After 3 minutes, t-butyl bromoacetate (87.8 mg,
0.44 mM) was added and the resultant mixture stirred at room
temperature for 5 hours. The mixture was diluted with ethyl
acetate, washed four times with H2O, and saturated brine,
dried over magnesium sulfate, filtered, and concentrated.
The residue was purified by column chromatography on silica
gel (elution with gradient methylene chloride/ethyl acetate)
to afford 44.0 mg (63%) of the {9-[ (3-fluorophenyl)methyl]-
5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as
a white solid. lE NMR (DMSO-d6) 6 7.6 (d, 1H, J=8 Hz),
7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s,
2H) , and 1.45 (s, 9H) . IR (CHCl3, cm"1) 3450, 3400, 1746,
1674, 1592, 1457, 1369, and 1151. MS (FD) m/e 448.

Elemental Analyses for C26H25N2O4F:
Calculated: C, 69.63; H, 5.62; N, 6.25.
Found: C, 69.35; H, 5.44; N, 6.23.
E. {9-[(3-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid
A solution of the {9-[(3-fluorophenyl)methyl]-5-
carbamoylcarbazol-4-ylJoxyacetic acid, tert-butyl ester
(40.0 mg, 0.089 mM) in 2 mL of trifluoroacetic acid was
stirred at room temperature for 5 hours. The solvent was
removed in vacuo. The residue was triturated with ethyl
ether, then dried in vacuo to afford 35.0 mg (100%) of the
{9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-
ylloxyacetic acid as a white powder. lE NMR (DMSO-d6) 5
13.0 (br s, 1H), 7.75 (s, 1H) , 7.6 (d, 1H, J=8 Hz), 7.5-7.25
(m, 5H), 7.2-6.8 (m, 4H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H) ,
and 4.8 (s, 2H) . IR (KBr, cm"1) 3423, 3400, 1736, 1637,
1615, 1589, 1499, 1487, 1450, 1436, 1331, 1250, and 1156. MS
(ES) m/e 391, 393.
Elemental Analyses for C22HnN204F:
Calculated: C, 67.34; H, 4.37; N, 7.14.
Found: C, 67.63; H, 4.22; N, 7.35.

A. 9-[(3-Chlorophenyl)methyl]-5-carbomethoxy-l, 2-
dihydrocarbazol-4(3H)-one
A suspension of 5-carbomethoxy~l,2-dihydro-9H-carbazol-
4(3H)-one (527.0 nag, 2.17 mM), 3-chlorobenzyl bromide (802.2
mg, 3.90 mM), a catalytic amount of sodium iodide (ca. 1
mg), and potassium carbonate (500.0 mg, 3.62 mM) was stirred
at room temperature for 150 hours. The mixture was diluted
with ethyl acetate, washed five times with H2O, once with
saturated brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated. The residue was purified by
column chromatography on silica gel (elution with gradient
methylene chloride/ethyl acetate) to afford 537.1 mg (67%)
of the 9-[(3-chlorophenyl)methyl]-5-carbomethoxy-l,2-
dihydrocarbazol-4(3H)-one as a yellow foam. 5H NMR (CDC13)
5 7.5-7.2 (m, 5H), 7.1 (s, 1H), 6.85 (m, 1H), 5.35 (s, 2H),
4.05 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.65 (t, 2H, J=6 Hz), and
2.3 (m , 2H) . IR (CHC13, cm"1) 3050, 2950, 1725, 1654, 1464,
1444, 1432, 1288 and 1120. MS (ES) m/e 366, 368, 370.
Elemental Analyses for C2iHieN03Cl:
Calculated: C, 68.57; H, 4.93; N, 3.81.
Found: C, 68.61; H, 4.92; N, 3.70.

B. 9-[(3-Chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy
carbazole
A solution of the 9-[(3-chlorophenyl)methyl]-5-
carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (480.5 mg, 1.31
mM) and 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone (325.7 rag,
1.43 mM) in 50 mL of toluene was stirred between 70-80 °C
for 3 hours. The mixture was purified directly by column
chromatography on silica gel (elution with methylene
chloride) to afford 172.6 mg (36%) of the 9-[(3-
chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole as a
yellow foam. :K NMR (CDC13) 8 10.4 (s, 1H) , 8.05 (d, 1H,
J=8 Hz), 7.6 (d, 1H, J=8 Hz), 7.4 (m, 2H), 7.3-7.1 (m, 3H) ,
6.9-6.7 (m, 3H), 5.55 (s, 2H) , and 4.15 (s, 3H). IR (CHC13,
cm"1) 3200 (br), 1684, 1598, 1442, 1428, 1331, 1285, and
1267. MS (ES) m/e 364, 366, 368.
Elemental Analyses for C21H16N03C1:
Calculated: C, 68.95; H, 4.41; N, 3.83.
Found: C, 69.23; H, 4.52; N, 3.88.
C. 9-[(3-Chlorophenyl) methyl]-4-hydroxy-5-carbamoyl
carbazole
A solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-
5-carbomethoxy carbazole (156.2 mg, 0.43 mM) in 5 mL THF and
20 mL concentrated aqueous ammonium hydroxide was sonicated
for 5 hours at 40-50 °C. The mixture was diluted with ethyl
acetate and acidified to pH 1 with 5 N HC1. The aqueous
layer was extracted twice with ethyl acetate. The combined
organic extracts were washed with saturated brine, dried
over magnesium sulfate, filtered, and concentrated. The
residue was purified by column chromatography on silica gel
(elution with gradient methylene chloride/ethyl acetate) to
afford 69.7 mg (47%) of the 9-[(3-chlorophenyl)methyl]-4-
hydroxy-5-carbamoyl carbazole as a white solid. JH NMR

(DMS0-d6) 6 10.5 (s, 1H), 8.8 (br s, 1H) , 8.4 (br s, 1H) ,
7.8 (dd, 1H, J=l and 8 Hz), 7.45 (m, 2H) , 7.3 (m, 3H), 7.2
(s, 1H), 7.1 (d, 1H, J=8 Hz), 6.95 (s, 1H) , 6.6 (d, 1H, J=8
Hz), and 5.7 (s, 2H) . IR (CHC13, cm"1) 3433, 3202 (br) , 163 0,
1600, 1580, 1564, 1433, 1330, 1261, and 776. MS (ES) m/e
349, 351, 353.
Elemental Analyses for C20H15N2O2CI:
Calculated: C, 68.48; H, 4.31; N, 7.99.
Found: C, 68.64; H, 4.55; N, 7.93.
D. {9-[(3-Chlorophenyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid, tert-butyl ester
40% Methanolic Triton B (0.053 mL, 0.12 mM) was added
to a solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy- 5-
carbamoyl carbazole (33.2 mg, 0.12 mM) in 2 mL IMF at room
temperature. After 3 minutes, t-butyl bromoacetate (53.8 mg,
0.27 mM) was added and the resultant mixture stirred at room
temperature for 20 h. The mixture was diluted with ethyl
acetate, washed four times with H2O, once with saturated
brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by column
chromatography on silica gel (elution with gradient
methylene chloride/ethyl acetate) to afford 42.1 mg (95%) of
the (9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, tert-butyl ester as a white solid. lK
NMR (DMS0-d6) 5 7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55
(d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H).
IR (CHC13, cm"1) 3450, 3400, 1744, 1676, 1591, 1457, 1369,
and 1150. MS (FD) m/e 464, 466.
Elemental Analyses for C26H25N204C1:
Calculated: C, 67.17; H, 5.42; N, 6.03.
Found: C, 67.17; H, 5.65; N, 5.97.

E. {9-[(3-Chlorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid
A solution of the {9-[(3-chlorophenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester
(35.6 mg, 0.077 mM) in 2 inL of trifluoroacetic acid was
stirred at room temperature for 6 hours. The solvent was
removed in vacuo. The residue was triturated with ethyl
acetate, then dried in vacuo to afford 31.4 mg (100%) of the
{9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid as a white powder. 1H NMR (DMSO-d6)
5 13.0 (br s, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.4-
7.25 (m, 7H), 7.2 (d, 1H, J=8 Hz), 7.0 (br t, 1H), 6.6 (d,
1H, J=8 Hz), 5.7 (s, 2H) , and 4.8 (s, 2H) . IR (KBr, cm"1)
3456, 3416, 3335, 1735, 1638, 1617, 1580, 1499, 1452, 143 1,
1431, 1329, 1255, 1157, 772, 764, and 717. MS (ES) m/e 407,
409, 411.
Elemental Analyses for C22H17N204Cl:
Calculated: C, 64.63; H, 4-19; N, 6.85.
Found: C, 64.55; H, 4.12; N, 6.74.

A. 9-[(3-Trifluoromethylphenyl)methyl]-5-carbomethoxy-l ,2-
dihydrocarbazol-4(3H)-one
40% Methanolic Triton B (2.18 mL, 4.8 roM) was slowly
added dropwise to a solution of 5-carbomethoxy-l, 2-dihydro-
9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at -
10 °C. After 30 minutes, 3- (trifluoromethyl)benzyl chloride
(1.53 g, 6.0 mM) and sodium iodide (900 mg, 6.0 mM) were
added and the resultant mixture stirred at room temperature
for 25 hours. The mixture was diluted with ethyl acetate,
washed five times with H2O, 1 N HC1, H2O, sat NaHC03/ and
saturated brine, dried over anhydrous magnesium sulfate,
filtered, concentrated, and dried in vacuo. The residue was
purified by column chromatography on silica gel (elution
with gradient methylene chloride/ethyl acetate) to afford
1.02 g (63%) of the 9-[(3-trifluoromethylphenyl)methyl]-5 -
carbomethoxy -1,2-dihydrocarbazol-4(3H)-one as a tan solidL
:H NMR (CDC13) 6 7.6 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 7.0
(d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6
Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H) . IR (KBr, cm"1)
1727 and 1652. MS (ES) m/e 400,- 402.
Elemental Analyses for C22H18N03F3:
Calculated: C, 65.83; H, 4.52; N, 3.49; F, 14.20.
Found: C, 65.63; H, 4.58; N, 3.39; F, 14.14.
B. 9-[(3-Trifluoromethylphenyl)methyl]-4-hydroxy-5-
carbomethoxy carbazole
A solution of the 9-[ (3-trifluoromethylphenyl)methyl]-
5-carbomethoxy-l,2-dihydrocarbazol-4(3H)-one (1.21 g, 3.00
mM) and 2, 3-dichloro-5,6-dicyano-l,4-benzoquinone (764 mg,
3.3 mM) in 25 mL of toluene was stirred between 80-90 °C for
7 hours. The mixture was purified directly by column
chromatography on silica gel (elution with methylene
chloride) to afford 340.0 mg (28%) of the 9-[(3-

trifluoromethylphenyl)methyl]-4-hydroxy-5-carbomethyoxy
carbazole as a yellow solid. XH NMR (CDC13) 8 10.35 (s, 1H);
8.0 (d, 1H, J=8 Hz), 7.6-7.3 (m, 6H) , 7.05 (d, 1H, J=8 Hz) ,
6.85 [VOL, 2H), 5.6 (s, 2H) , and 4.1 (s, 3H) . IR (CHC13, cm"1)
3378 and 1712. MS (ES) m/e 398, 400.
Elemental Analyses for C22H]6N03F3:
Calculated: C, 66.17; H, 4.04; N, 3.51.
Found: C, 66.99; H, 4.12; N, 3.53; F.
C. 9-[(3-Trifluoromethylphenyl)methyl]-4-hydroxy-5-
carbamoyl carbazole
A solution of the 9-[(3-trifluoromethylphenyl)methyl] -
4-hydroxy-5-carbomethoxy carbazole (250 mg, 0.625 mM) in 5
mL THF and 20 mL concentrated aqueous ammonium hydroxide was
sonicated for 30 h at 40-50 °C. The mixture was diluted with
ethyl acetate and acidified to pH 1 with 5 N HC1. The
aqueous layer was extracted three times with ethyl acetate.
The combined organic extracts were washed with saturated
brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by column
chromatography on silica gel (elution with gradient
methylene chloride/ethyl acetate) to afford 120 mg (50%) of
the 9-[(3-trifluoromethylphenyl)methyl]-4-hydroxy-5-
carbamoyl carbazole as a white solid. ^H NMR (DMSO-d6) 5
10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H,
J=8 Hz), 7.6-7.5 (m, 5H), 7.3 (t, 1H, J=8 Hz), 7.15 (d, 1H,
J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.8
(s, 2H) . IR (KBr, cm"1) 3429, 3206, and 1630. MS (ES) m/e
383, 385.
Elemental Analyses for C21H15N202F3:
Calculated: C, 65.62; H, 3.93; N, 7.29.
Found: C, 67.50; H, 4.00; N, 7.19.

D. {9-[(3-Trifluoromethylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to
a solution of the 9-[(3-trifluoromethylphenyl)methyl]-4-
hydroxy-5-carbamoyl carbazole (115 mg, 0.3 mM) in 5 mL DMF
at room temperature. After 15 minutes, methyl bromoacetate
(95 mg, 0.6 mM) was added and the resultant mixture stirred
at room temperature for 22 hours. The mixture was diluted
with ethyl acetate, washed four times with H2O, 1 N HC1,
H2O, sat. NaHC03, and saturated brine, dried over magnesium
sulfate, filtered, and concentrated. The residue was
purified by column chromatography on silica gel (elution
with ethyl acetate) to afford 120 mg (88%) of the {9-[(3-
trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, methyl ester as a white solid. 1H NMR
(CDC13) 8 7.5-7.2 {m, IE), 7.1 (d, 1H, J=8 Hz), 7.0 (d, 1H,
J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (br s, 1H) , 6.0 (br s,
1H), 5.55 (s, 2H), 4.9 {s, 2H), and 3.9 (s, 3H). IR (KBr,
cm"1) 1763 and 1673. MS (ES) m/e 457.
Elemental Analyses for C24H19N204F3:
Calculated: C, 63.16; H, 4.20; N, 6.14.
Found: C, 61.37; H, 4.19; N, 5.77.
E. (9-[(3-Trifluoromethylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt.
A solution of the {9-[(3-trifluoromethylphenyl)methyl]-
5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (91
mg, 0.153 mM) and 0.22 mL (0.22 mM) of 1 N NaOH in 8 mL of
ethanol was stirred for 17 h at 25 °C. The ethanol was
removed in vacuo. The resultant white precipitate was
collected by filtration, washed with small amounts of EtOH
and diethyl ether, then dried in vacuo to afford 75 mg (81%)

of the {9-[(3-trifluoromethylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a
white powder. 'H NMR (DMS0-d6) ? 7.65 (s, 1H), 7.6 (m,
4H), 7.45 (t, 1H, J=8 Hz), 7.35 (t, 1H, J=8 Hz), 7.3 (t, LH,
J=8 Hz), 7.2 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 7.05 id,
1H, J=8 Hz), 6.5 (d, 1H, J=8 Hz), 5.75 (s, 2H), and 4.3 (s,
2H) . IR (KBr, cm-1) 1665 and 1618. MS (ES) m/e 441, 443.
Elemental Analyses for C23Hi6N204F3Na:
Calculated: C, 59.49; H, 3.47; N, 6.03.
Found: C, 60.69; H, 3.78; N, 5.75.

A. 9-[(2-Methylphenyl)methyl]-5-carbomethoxy-l, 2-
dihydrocarbazol-4(3H)-one
A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol-
4(3H)-one (870 mg, 3.58 mM), a-bromo-o-xylene (662 mg, 3.58
mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF
was stirred at room temperature for 20 hours. The mixture
was diluted with ethyl acetate, washed with H2O and
saturated brine, dried over anhydrous magnesium sulfate,
filtered, concentrated to afford 1.21 g (98%) of the 9-[(2-
methylphenyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol-

4(3H)-one as a dark oil. :H NMR (DMS0-d6) ? 7.5-7.2 (m,
4H), 7.15 (t, 1H, J=8 Hz), 7.0 (t, 1H, J=8 Hz), 6.15 (d, 3_H,
J=8 Hz), 5.55 (s, 2H), 3.85 (s, 3H), 2.6 (m, 2H), 2.4 (m,
2H), 2.4 (s, 3H) , and 2.1 (m, 2H) . IR (CHC13, cm"1) 3010,
2952, 1724, 1671, 1653, 1604, 1460, 1444, 1290, 1174, and
1122. MS (ES) m/e 348.5.
Elemental Analyses for C22H21NO3:
Calculated: C, 76.08; H, 6.05; N, 4.03.
Found C, 73.33; H, 6.36; N, 4.30.
B. 9-[(2-Methylphenyl)methyl]-4-hydroxy-5-carbomethoxy
carbazole
A solution of the 9-[(2-methylphenyl)methyl]-5-
carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (1.2 g, 3.5 mM)
and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (800 rag, 3.6
mM) in 70 mL of toluene was stirred at 80-90 °C for 5 hours.
The mixture was purified directly by column chromatography
on silica gel (elution with methylene chloride) to afford
260 mg (22%) of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-
carbomethyoxy carbazole as a yellow solid. ]H NMR (DMSO-
d6) 6 10.25 (s, 1H), 7.5 (d, 1H, J=8 Hz), 7.4 (t, 1H, J=8
Hz), 7.3-7.1 (m, 4H), 6.9 (m, 2H), 6.6 (d, 1H, J=8 Hz), 6.1
(d, 1H, J=8 Hz), 5.65 (s, 2H), 3.8 (s, 3H), and 2.5 (s, 3H) .
IR (KBr, cm"1) 3200, 1672, 1440, 1426, 1332, 1302, 1265,
1216, 1141, 761, 749, and 718. MS (ES) m/e 344, 346.
Elemental Analyses for C22H19NO3:
Calculated: C, 76.52; H, 5.51; N, 4.06.
Found: C, 76.44; H, 5.66; N, 3.94.

C. 9-[(2-Methylphenyl)methyl]-4-hydroxy-5-carbamoyl
carbazole
A solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-
5-carbomethoxy carbazole (260 mg, 0.75 mM) in 10 mL THF and
30 mL concentrated aqueous ammonium hydroxide was sonicated
for 5 hours at 40-50 °C. The mixture was diluted with ethyl
acetate and acidified to pH 1 with 5 N HCl. The aqueous
layer was extracted three times with ethyl acetate. The
combined organic extracts were washed with H2O and saturat ed
brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by column
chromatography on silica gel (elution with gradient
hexanes/ethyl acetate) to afford 90 mg (36%) of the 9-[(2—
methylphenyl)methyl]-A-hydroxy-5-carbamoyl carbazole as a
tan solid. 1H NMR (DMSO-d6) ? 10.5 (s, 1H) , 8.8 (br s,
1H), 8.4 (br s, 1H) , 7.7 (m, 1H), 7.5 (m, 2H) , 7.3 (m, 2H) ,
7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8
Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.7 (s, 2H) ,
and 2.5 (s, 3H) . IR (KBr, cm"1) 3451, 3191, 1627, 1600,
1584, 1562, 1435, 1329, 1322, 1263, and 774. MS (ES) m/e
329, 331.
Elemental Analyses for C2iHi8N20;>:
Calculated: C, 76.36; H, 5.45; N, 8.48.
Found: C, 7 5.66; H, 5.79; N, 8.07.
D. {9-[(2-Methylphenyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid, methyl ester
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to
a solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-
carbamoyl carbazole (80 mg, 0.24 mM) in 8 mL DMF at room
temperature. After 3 minutes, methyl bromoacetate (115 mg,
0.72 mM) was added and the resultant mixture stirred at room
temperature for 48 hours. The mixture was diluted with

ethyl acetate, washed with H2O, 1 N HCl, H2O, and saturated
brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by column
chromatography on silica gel (elution with ethyl acetate) to
afford 80 mg (82%) of the {9-[(2-methylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a
white solid. lH NMR (DMSO-d6) ? 7.56 (br s, 1H), 7.5-7.1
(m, 9H),~6.9 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s,
2H), 4.9 (s, 2H), 3.8 (s, 3H), and 2.5 (s, 3H). IR (KBr, cm"
') 3367, 3153, 1760, 1740, 1672, 1644, 1619, 1591, 1578,
1498, 1456, 1425, 1327, 1200, 1153, 1109, 1100, and 777. MS
Elemental Analyses for C24H22N2O4:
Calculated: C, 71.64; H, 5.47; N, 6.96.
Found: C, 71.51; H, 5.56; N, 6.67.
E. {9-[(2-Methylphenyl)dmethyl]-5-carbamoylcarbazol-4-
yl]oxyacetic acid, sodium salt
A suspension of the (9-[(2-methylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15.5
mg, 0.039 mM) and 0.04 mL (0.04 mM) of 1 N NaOH in 5 mL of
ethanol was stirred for 24 hours at 25 °C. The resultant
white precipitate was collected by filtration, washed with a
small amount of EtOH, then dried in vacuo to afford 10 mg
(63%) of the {9-[(2-methylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a
white powder. 1H NMR (DMSO-d6) 6 7.55 (br s, 1H) , 7.5-7.0
(m, 7H), 6.9 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8 Hz), 6.6 (d,
1H, J=8 Hz), 6.2 (d, 1H, J=8 Hz), 5.6 (s, 2H), 4.35 (s, 2H),
and 2.5 (s, 3H) . IR (KBr, cm-1) 3390, 1656, 1613, 1595,
1573, 1498, 1455, 1408, 1325, 1332, and 719. MS (ES) m/e
387, 389.

Elemental Analyses for C23Hi9N204:
Calculated: C, 67.32; H, 4.63; N, 6.83.
Found: C, 64.72; H, 4.44; N, 6.40.

A. 9-[(3-Methylphenyl) methyl]-5-carbomethoxy-l,2-
dihydrocarbazol-4(3H)-one
A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol-
4(3H)-one (870 mg, 3.58 mM), a-bromo-m-xylene (662 mg, 3.58
mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF
was stirred at room temperature for 16 hours. The mixture
was diluted with ethyl acetate, washed with H2O and
saturated brine, dried over anhydrous magnesium sulfate,
filtered, concentrated to afford 1.18 g (95%) of the 9-[(3-
methylphenyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol-
4(3H)-one as a dark oil. 1H NMR (DMSO-d6) ? 7.65 (dd, 1H,
J=l and 8 Hz), 7.3-7.1 (m, 3H), 7.05 (d, 1H, J=8 Hz), 7.0
(s, 1H) , 6.85 (d, 1H, J=8 Hz), 5.5 (s, 2H) , 3.8 (s, 3H) , 3.0
(m, 2H) , 2.45 (m, 2H), 2.3 (s, 3H), and 2.1 (m, 2H) . IR

{CHClj, cm-1) 3010, 2953, 1724, 1652, 1605, 1465, 1442, 1288,
1174, and 1119. MS (ES) m/e 348.5.
Elemental Analyses for C22H2jN03:
Calculated: C, 76.08; H, 6.05; N, 4.03.
Found: C, 74.53; H, 6.03; N, 3.68.
B. 9-[(3-Methylphenyl)methyl]-4-hydroxy-5-carbomethoxy
carbazole
A solution of the 9-[(3-methylphenyl)methyl]-5-
carbomethoxy-1,2-dihydrocarbazol-4(3H)-one (1.18 g, 3.4 mM)
and 2, 3-dichloro-5,6-dicyano-l,4-benzoquinone (800 mg, 3.6
mM) in 70 mL of toluene was stirred at 80-90 °C for 6 hoiir-s.
The mixture was purified directly by column chromatography
on silica gel (elution with methylene chloride) to afford
300 mg (26%) of the 9-[(3-methylphenyl}methyl]-4-hydroxy-5-
carbomethyoxy carbazole as a yellow solid. UH NMR (DMSO-
d6) 8 10.2 (s, 1H), 7.65 (d, IE, J=8 Hz), 7.35 (t, 1H, J=8
Hz), 7.25 (t, 1H, J=8 Hz), 7.2-7.0 (m, 4H) , 6.9 (m, 2H), 6.6
(d, 1H, J=8 Hz), 5.6 (s, 2H), 3.85 (s, 3H) , and 2.2 (s, 3H) .
IR (KBr, cm"1) 3200, 1673, 1596, 1440, 1426, 1394, 1265,
1216, 1152, 750, 711, and 694. MS (ES) m/e 344, 346.
Elemental Analyses for C22H19N03:
Calculated: C, 76.52; H, 5.51; N, 4.06.
Found: C, 76.22; H, 5.55; N, 3.97.
C. 9-[(3-Methylphenyl)methyl]-4-hydroxy-5-carbamoyl
carbazole
A solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-
5-carbomethoxy carbazole (300 mg, 0.87 mM) in 10 mL THF and
30 mL concentrated aqueous ammonium hydroxide was sonicated
for 5 hours at 40-50 °C. The mixture was diluted with ethyl
acetate and acidified to pH 1 with 5 N HC1. The aqueous

layer was extracted three times with ethyl acetate. The
combined organic extracts were washed with H2O and saturat ed
brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by column
chromatography on silica gel (elution with gradient
hexanes/ethyl acetate) to afford 114 mg (40%) of the 9-[(3-
methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an
off-white solid. :H NMR (DMSO-d6) 6 10.5 (s, 1H) , 8.8 (br
s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=l and 8 Hz), 7.4 (m,
2H) , 7.3 (t, 1H, J=8 Hz), 7.15-7.0 (m, 3H), 6.85 (d, 1H, a=8
Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.65 (s,
2H) , and 2.25 (s, 3H) . IR (KBr, cm"1) 3434, 3203, 1629,
1599, 1579, 1552, 1443, 1330, 1262, 1214, and 776. MS (ES)
m/e 329, 331.
Elemental Analyses for C2iH18N202:
Calculated: C, 76.36; H, 5.45; N, 8.48.
Found: C, 77.56; H, 5.67; N, 8.26.
D. {9-[(3-Methylphenyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid, methyl ester
40% Methanolic Triton B (0.45 mL, 0.99 mM) was added to
a solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-
carbamoyl carbazole (100 mg, 0.30 mM) in 8 mL DMF at room
temperature. After 3 minutes, methyl bromoacetate (115 mg,
0.72 mM) was added and the resultant mixture stirred at room
temperature for 24 hours. The mixture was diluted with ethyl
acetate, washed with H2O, and saturated brine, dried over
magnesium sulfate, filtered, and concentrated. The residue
was purified by column chromatography on silica gel (elution
with ethyl acetate) to afford 80 mg (66%) of the {9-[(3-
methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic
acid, methyl ester as a white solid. lE NMR (DMSO-d6) ?
7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.45-7.0 (m, 8H), 6.9

(d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.65 (s, 2H) , 4.9 (s,
2H), 3.75 (s, 3H) , and 2.2 (s, 3H) . IR (KBr, cm"1) 3367,
3157, 1760, 1642, 1589, 1499, 1455, 1424, 1328, 1216, 115^,
1102, 772, and 714. MS (FD) m/e 402.
Elemental Analyses for C24H22N2O4:
Calculated: C, 71.64; H, 5.47; N, 6.96.
Found: C, 71.01; H, 5.60; N, 6.66.
E. {9-[(3-Methylphenyl)methyl]-5-carbamoylcarbazol-4-
yUoxyacetic acid, sodium salt
A suspension of the {9-[(3-methylphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (15.8
mg, 0.039 mM) and 0.04 mL (0.04 mM) of 1 N NaOH in 5 mL off
ethanol was stirred for 24 h at 25 °C. The resultant white
precipitate was collected by filtration, washed with a small
amount of EtOH, then dried in vacuo to afford 10 mg (62%) of
the (9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, sodium salt as a white powder. 1H NMR
(CMSO-d6) 5 7.55 (d, 1H, J=8 Hz), 7.5-7.0 (m, 9H), 6.85 (d,
1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.6 (s, 2H) , 4.35 (s,
2H) , and 2.2 (s, 3H) . IR (KBr, cm"1) 3390, 1656, 1613, 1595,
1573, 1498, 1455, 1408, 1325, 1332, and 719. MS (ES) m/e
387, 389.
Elemental Analyses for C23H19N204Na:
Calculated: C, 67.32; H, 4.63; N, 6.83.
Found: C, 61.20; H, 4.64; N, 6.06.

EXAMPLE 9
Preparation of {9-[(3-trifluoromethoxypheny1)methyl]-5-
carbamoylcarbazol-4-yl)oxyacetic acid, sodium salt

A. 9-[(3-Trifluoromethoxyphenyl)methyl]-5-carbomethoxy-
1,2-dihydrocarbazol-4(3H)-one
A suspension of 5-carbomethoxy-l, 2-dihydro-9H-carbazol-
4{3H)-one (935 mg, 3.85 mM), 3-trifluoromethoxybenzyl
bromide (1.0 g, 3.93 mM), and potassium carbonate (531 mg,
3.85 mM) in 20 mL DMF was stirred at room temperature for 17
hours. The mixture was diluted with ethyl acetate, washed
with H2O and saturated brine, dried over anhydrous magnesium
sulfate, filtered, concentrated to afford 1.6 g (100%) of
the 9-[(3-trifluoromethoxyphenyl)methyl]-5-carbomethoxy-l,2-
dihydrocarbazol-4(3H)-one as a foam. 1H NMR (DMS0-d6) ?
7.7 (dd, 1H, J=l and 8 Hz), 7.45 (t, 1H, J=8 Hz), 7.3-7.1
(m, 4H), 7.05 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0
(m, 2H) , 2.45 (m, 2H) , and 2.1 (m, 2H) . IR (CHC13, cm"1)
1729, 1647, 1439, 1259, 1176, and 1116. MS (ES) m/e 418.
Elemental Analyses for C22Hl8N04F3:
Calculated: C, 63.31; H, 4.32; N, 3.36.
Found: C, 63.12; H, 4.35; N, 3.31.

B. 9-[(3-Trifluoromethoxyphenyl)methyl]-4-hydroxy-5-
carboiaethoxy carbazole
A solution of the 9-[(3-trifluoromethoxyphenyl)methyl ] -
5-carbomethoxy-l,2-dihydrocarbazol-4(3H)-one (0.75 g, 1.8
mM) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (490 mg,
2.16 mM) in 70 mL of toluene was stirred at reflux for 6
hours. The mixture was purified directly by column
chromatography on silica gel (elution with methylene
chloride) to afford 300 mg (40%) of the 9-[(3-
trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbomethyoxy
carbazole as a yellow solid. :H NMR (DMSO-d6) ? 10.25 ( s,
1H), 7.7 (d, 1H, J=8 Hz), 7.5-7.0 {m, 8H), 6.6 (d, 1H, J=8
Hz), 5.7 (s, 2H), and 3.85 (s, 3H). IR (KBr, cm"') 3200,
1673, 1441, 1268, 1217, 1173, and 753. MS (ES) m/e 414, 416.
Elemental Analyses for C22H16NO3F3
Calculated: C. 63.61; H, 3.86; N, 3.37.
Found: C, 63.40; H, 3.99; N, 3.43.
C. 9-[(3-Trifluoromethoxyphenyl)methyl]-4-hydroxy-5-
carbamoyl carbazole
A solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-
4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.62 mM) in 10
mL THF and 30 mL concentrated aqueous ammonium hydroxide was
stirred vigorously for 132 hours. The mixture was diluted
with ethyl acetate and acidified to pH 1 with 5 N HC1. The
aqueous layer was extracted three times with ethyl acetate.
The combined organic extracts were washed with H2O and
saturated brine, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified by column
chromatography on silica gel (elution with gradient
hexanes/ethyl acetate) to afford 150 mg (60%) of the 9-[(3-
trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl
carbazole as an off-white solid. 1H NMR (DMSO-d6; 6 10.5

(s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=l
and 8 Hz), 7.5-7.15 (m, 5H), 7.1 (d, 1H, J=8 Hz), 7.0 (d,
1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), an_d
5.65 (s, 2H) . IR (KBr, cm"1) 3431, 3203, 1629, 1601, 1580,
1548, 1446, 1330, 1261, 1215, and 777. MS (ES) m/e 399, 401.
Elemental Analyses for C21HUN2O2F3:
Calculated: C, 63.00; H, 3.75; N, 7.0.
Found: C, 63.15; H, 4.07; N, 6.84.
D. {9-[(3-Trifluoromethoxyphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to
a solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-
hydroxy-5-carbamoyl carbazole (115 mg, 0.28 mM) in 8 mL DMF
at room temperature. After 3 minutes, methyl bromoacetate
(65 mg, 0.41 mM) was added and the resultant mixture stirred
at room temperature for 23 hours. The mixture was diluted
with ethyl acetate, washed with H2O, and saturated brine,
dried over magnesium sulfate, filtered, and concentrated.
The residue was purified by column chromatography on silica
gel (elution with ethyl acetate) to afford 112 mg (83%) of
the {9-[(3-trifluoromethoxyphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a
white solid. 2H NMR (DMSO-d6) ? 7.6 (d, 1H, J=8 Hz), 7.55
(br s, 1H), 7.5-7.0 (m, 9H), 6.6 (d, 1H, J=8 Hz), 5.7 (s,
2H) , 4.9 (s, 2H) , and 3.75 (s, 3H) . IR (KBr, cm"1) 3488,
3141, 1763, 1674, 1501, 1444, 1269, 1215, 1178, 1102, 772,
and 714. MS (FD) m/e 472.
Elemental Analyses for C24H]9N205F3:
Calculated: C, 61.02; H, 4.03; N, 5.93.
Found: C, 61.05; H, 4.17; N, 5.81.

E. {9-[(3-Trifluoromethoxyphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt
A suspension of the {9-[(3-
trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid, methyl ester (22.4 mg, 0.047 mM) and
0.065 mL (0.065 mM) of 1 N NaOH in 5 mL of ethanol was
stirred for 24 hours at 25 °C. The solvent was removed in
vacuo and the residue suspended in EtOH. The resultant whxte
precipitate was collected by filtration, washed with a snail
amount of EtOH, then dried in vacuo to afford 9 mg (41%) of
the {9-[(3-trifluoromethoxyphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a
white powder. MS (ES) m/e 457, 459.
Example 10
Preparation of [9-benzyl-5-carbamoyl-l-methylcarbazol~
4-yl]oxyacetic acid
A. Preparation of 5-carbamoyl-4-methoxy-l-methylcarbazole
A solution of 0.805 g of 9-benzyl-5-methoxy-8-methyl-
1,2,3,4-tetrahydrocarbazole-4-carboxamide in 24 ml of
carbitol was treated with 1.1 g of 5% palladium on carbon
and was refluxed for 6 hours open to the air. After
cooling, the solution was filtered thourough a pad of celite
and the pad was washed with ethyl acetate. The filtrates
were diluted with ether and washed four times with water and
dried over magnesium sulfate and concentrated. The residue
was chromatographed on silica gel using methanol/0-4% in
dichloromethane to afford 0.166 g (28%) of debenzylated
carbazole. ESIMS m/e 255 (M++1) , 253 (M+-l) NMR (300 MHz,
CDCI3): 6 8.13 (br, 1H); 7.51 (d, J=8.1, 1H); 7.40 (t,
J=7.6, 1H); 7.32 (d, J=7.2, 1H); 7.18 (d, J=7.8, 1H); 6.60
(d, J=8.0, 1H); 5.68 (br, 2H); 3.99 (s, 3H); 2.50 (s 3H).

B. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-l-
methylcarbazole
A solution of 0.148 g of 5-carbamoyl-4-methoxy-l-
methylcarbazole in 1.1 ml of dimethylformamide was added to
0.026 g of sodium hydride (60% in mineral oil) in 0.4 ml of
dimethylformamide and stirred for 60 minutes at room
temperature. Benzyl bromide (0.076 ml) was then added anci
the reaction was stirred overnight. The reaction mixture
was poured into 20 ml of saturated ammonium chloride
solution and then extracted twice with ethyl acetate. The
extracts were washed with water and then with brine, dried
over magnesium sulfate and concentrated. The residue was
rinsed with hexane and dissolved in dichloromethane,
filtered and concentrated to afford 0.21 g of the subtitle
compound. FDMS m/e 344 (M+)
Elemental Analyses
Calculated: C 76.72; H 5.85; N 8.13
Found: C 75.20; H 6.19; N 7.54
C. Preparation of [9-benzyl-5-carbamoyl-l-methylcarbazol-
4-yl]oxyacetic acid methyl ester ]
A solution of 0.23 g of 9-benzyl-5-carbamoyl-4-methoxy-
1-methylcarbazole in 4 ml of dimethylformamide was added to
a 1 ml solution of sodium ethane thiolate (prepared from
0.116 g of sodium hydride 60% dispersion and 0.22 ml of
ethanethiol under nitrogen) and heated at 110°C for 15
hours. The reaction mixture was cooled, poured into 20 ml
of 1 N HC1 and extracted twice with ethyl acetate. The
extracts were washed twice with water and then with brine,
dried over magnesium sulfate and concentrated. The residue
was chromatographed on silica gel using methanol/0-1% in
dichloromethane to afford 0.146 g (66%) of the demethylated

intermediate. A solution of 0.146 g of this intermediate in
1.5 ml of dimethylformamide was added to 0.021 g of sodium,
hydride (60% in mineral oil) in 0.5 ml of dimethylformamide.
After stirring for 10 minutes at room temperature, 0.054 ml
of methyl bromoacetate was added. After stirring for 5
hours at room temperature, the reaction mixture was poured
into water and extracted twice with ethyl acetate. The
extracts were washed with water and then with brine, dried
over magnesium sulfate and concentrated. The residue was
chromatographed on silica gel using methanol/ 0-2% in
dichloromethane to afford 0.10 g (56%) of the subtitle
compound. mp. 228-230°C ESIMS m/e 403 (M++l)
Elemental Analyses
Calculated: C 71.63; H 5.51; N 6.96
Found: C 71.34; H 5.60; N 6.70
D. Preparation of l9-benzyl-5-carbamoyl-l-methylcarbazol-
4-yl]oxyacetic acid
A slurry of 32 mg (0.0795 mmol) of I9-benzyl-5-
carbamoyl-l-methylcarbazol-4-yl]oxyacetic acid methyl ester
in 1 ml of tetrahydrofuran and 3.5 ml of methanol was
treated with 0.3 ml of an aqueous 2 N sodium hydroxide
solution and stirred overnight at room temperature. The
solvent was evaporated and the residue was partitioned
between 1:1 ethyl acetate/tetrahydrofuran and 0.2 N HC1
solution. After another extraction with 1:1 ethyl
acetate/tetrahydrofuran, the extracts were washed with
brine, dried over magnesium sulfate and concentrated to
afford (27 mg) of the title compound, mp. 253-254°C. ESIMS
m/e 389 (M++1), 387 (M+-1) NMR (300 MHz, d6-DMSO): 8
12.83 (br, 1H); 7.75 (br, 1H); 7.53 (d, J=8.2, 1H); 7.41-
7.34 (m, 2H); 7.28-7.17 (m, 3H); 7.07 (m, 2H); 6.90 (d,

J=7.2, 2H) ; 6.49 (d, J=8.1, 1H); 5.89 (s, 2H); 4.79 (s, 2H) ;
2.52 (s, 3H).
Example 11
Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3, tetrahydrocarbazol-5-yl]oxyacetic acid
A. Preparation of (2-chloro-4-fluorophenyl)- ethyl
carbonate
A solution of 19.16 g of 2-chloro-4-fluorophenol in
65.4 ml of 2 N aqueous sodium hydroxide solution was cooled
in an ice bath and treated dropwise with 16.3 ml of ethyl
chloroformate. After stirring at room temperature
overnight, the two-phase reaction mixture was diluted with.
100 ml of water and extracted with 300 ml of a 1:1
pentane/ether mixture. The extract was washed three times
with 0.02 N sodium hydroxide solution, water and then brine.
After drying and evaporation, 27.63 g (97%) of the subtitle
compound were obtained. NMR (300 MHz, CDCI3): 6 7.23-7.18
(m, 2H) ; 7.00 (dt, J=8.4, 2.7, 1H); 4.35 (q, J=7.1, 2H) ;
1.40 (t, J=7.1, 3H).
B. Preparation of (2-chloro-4-fluoro-5-nitrophenyl)- ethyl
carbonate
A solution of 27.63 g of (2-chloro-4-fluorophenyl)-
ethyl carbonate in 60 ml of dichloromethane was cooled in an
ice bath and treated dropwise with 31.8 6 g of a 1:2 mixture
of fuming nitric acid (90%) and concentrated sulfuric acid.
The reaction was stirred for 2 hours at room temperature and
then cooled with ice and treated with another 4.5 g of the
same nitrating mixture. The reaction was stirred overnight
at room temperature, poured into 200 ml of ice and water, and
extracted twice with dichloromethane. The extracts were

washed with water and then with brine, dried over magnesium
sulfate and concentrated to afford 33.01 g (99%) of the
subtitle compound, mp. 50-51 C
Elemental Analyses
Calculated: C 41.01; H 2.68; N 5.31; CI 13.45
Found: C 41.03; H 2.59; N 5.38; Cl 13.71
C. Preparation of 2-chloro-4-fluoro-5-nitroanisole
A solution of 15.0 g of (2-chloro-4-fluoro-5-
nitrophenyl)- ethyl carbonate in 100 ml of dimethyl
formamide was treated with 18.6 g of cesium carbonate, 7.1
ml of iodomethane and 7 ml of methanol and stirred overnight
at room temperature. The reaction mixture was poured into
water and extracted twice with ether. The extracts were
washed twice with water and then with brine, dried over
magnesium sulfate and concentrated to afford 11.4g of the
subtitle compound, mp. 69-70°C Ex. 57, C.
Elemental Analyses
Calculated: C 40.90; H 2.45; N 6.81; Cl 17.25
Found: C 41.20; H 2.48; N 6.70; Cl 17.44
D. Preparation of 2-fluoro-5-methoxyaniline
A solution of 5.63 g of 2-chloro-4-fluoro-5-
nitroanisole in 90 ml of ethanol and 5 ml of triethylamine
was hydrogenated at room temperature under 60 pounds per
square inch with 1.0 g of 5% palladium on carbon for four
hours. The catalyst was filtered off and the solvent was
evaporated. The residue was slurried in chloroform and
filtered thourough a plug of silica gel and then evaporated.
This residue was chromatographed on silica gel using hexane/
chloroform mixtures to afford 2.77 g (72%) of the subtitle
compound, mp. 253-254°C. NMR (300 MHz, CDCI3) : 6 6.88 (dd,

J=10.6, 8.9, 1H); 6.32 (dd, J=7.4, 3.0, 1H) ; 6.20 (dt,
J=8.9, 3.2,1H); 3.73 (s, 3H); 3.72 (br, 2H).
E. Preparation of N-benzyl-2-fluoro-5-methoxyaniline
This procedure was patterned after that of Tietze ancd
Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g
of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in
48 ml of methanol was treated with 3.43 g of zinc chloride
and then cooled in an ice bath. Sodium cyanoborohydride
(1.58 g) was added in small poroom temperature ions over 30
minutes and the reaction was stirred for five hours at room
temperature. After evaporation of the solvent, the residue
was slurried in 40 ml of 1 N sodium hydroxide solution and
then extracted twice with ether. The extracts were washed
with water and then with brine, dried over magnesium sulfate
and concentrated. The residue was recrystallized from
hexane to afford 2.61 g and the mother liquors were
chromatographed on silica gel using 20:1 hexane/ether to
afford another 1.4 g of the subtitle compound (90%). mp.
56-58°C
Elemental Analyses
Calculated: C 72.71; H 6.10; N 6.06
Found: C 72.51; H 6.06; N 5.99
F. Preparation of ethyl 9-benzyl-5-methoxy-8-fluoro-
1,2,3, 4-tetrahydrocarbazole-4-carboxylate
A solution of 0.62 g of N-benzyl-2-fluoro-5-
methoxyaniline in 20 ml of dry tetrahydrofuran was cooled in
an ice bath and treated with 11.3 ml of 0.5 M potassium
bis(trimethylsilyl)amide in toluene. After stirring for 30
minutes, 0.74 g of 2-carboethoxy-6-bromocyclohexanone
(Sheehan and Mumaw, JACS, 72, 2127 (1950)) in 4 ml of
tetrahydrofuran was added and the reaction was allowed to

warm slowly to room temperature over two hours. The
reaction was quenched with saturated ammonium chloride
solution and extracted twice with ether. The extracts we:re
washed with water and then with brine, dried over magnesium
sulfate and concentrated. This residue was chromatograph on silica gel using hexane/ ether mixtures to afford 0.79 6 g
(74%) of N-alkylated intermediate diastereomers. This
mixture was refluxed in 20 ml of benzene with 0.99 g of zinc
chloride overnight. The solvent was evaporated and the
residue was partitioned between 25 ml of 1 N HCl and 25 mi
of ethyl acetate and then extracted once more with ethyl
acetate. The organic layers were washed with water and then
brine, dried over magnesium sulfate and concentrated to
afford 0.734 g (96%) of the subtitled compound. ESIMS m/e
382 (M++1)
Elemental Analyses
Calculated: C 72.42; H 6.34; N 3.67
Found: C 72.20; H 6-26; N 3.70
G. Preparation of 9-benzyl-5-methoxy-8-fluoro-l,2,3,4-
tetrahydrocarbazole-4-carboxamide
Ethyl 9-benzyl-5-methoxy-8-fluoro-l, 2,3,4-
tetrahydrocarbazole-4-carboxylate (0.722 g) was treated
similarly as described in Example 49, Part C and
chromatographed on silica gel using 1% methanol in
dichloromethane to afford 0.482 g (72%) of the subtitle
compound. ESIMS m/e 353 (M++l)
Elemental Analyses
Calculated: C 71.57; H 6.01; N 7 . 95
Found: C 71.42; H 5.83; N 7.75

H. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1,2,3, 4-
tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester
9-Benzyl-5-methoxy-8-fluoro-1, 2, 3, 4-
tetrahydrocarbazole-4-carboxamide (0.170 g) was converted
similarly as described in Example 49, Part D and
chromatographed on silica gel using methanol/ 0-1% in
dichlo route thane to afford 85 mg (50%) of the subtitle
compound. mp. 183-185°C
Elemental Analyses
Calculated: C 67.31; H 5.65; N 6.82
Found: C 67.58; H 5.48; N 6.95
I. Preparation of [9-benzyl-4-carbamoyl-8-fluoro-1, 2, 3, 4-
tetrahydrocarbazol-5-yl]oxyacetic acid
[9-Benzyl-4-carbamoyl-8-fluoro-1,2,3,4-
tetrahydrocarbazol-5-yl]oxyacetic acid methyl ester (71 mcj)
was hydrolyzed similarly as described in Example 50, Part D
to afford 65 mg of the title compound. ESIMS m/e 397
(M++1), 395 (M+-1) NMR (300 MHz, d6-DMSO): 8 13.03 (br,
1H); 7.31-7.19 (m, 3H); 6.97 (d, J=7.4, 2H); 6.95 (br, 1H);
6.70 (d, J=3.8, 1H); 6.67 (dd, J=12.4, 3.9, 1H); 6.28 (dd,
J=8.5, 2.6, 1H); 5.39 (ABq, 2H); 4.64 (s, 2H); 3.92 (br,
1H); 2.71 (m, 1H); 2.44 (m, 1H); 2.02 (m, 2H); 1.76 (m, 2H).
Example 12
Preparation of [9-benzyl-5-carbamoyl-l-chlorocarbazol-4-
yl]oxyacetic acid
A. Preparation of 9-benzyl-5-carbamoyl-4-methoxy-l-
chlorocarbazole
A solution of 1.0 g of 9-benzyl-5-methoxy-8-methyl-
1,2, 3, 4-tetrahydrocarbazole-4-carboxamide was oxidized

similarly to Example 51, Part A and chromatographed on
silica gel using dichloromethane/ 0-1% methanol to afford
0.66 g (67%) of the subtitle compound. FDMS m/e 364 (M+ )
Elemental Analyses
Calculated: C 69.14; H 4.70; N 7.68; Cl 9.72
Found: C 69.40; H 4.64; N 7.49; Cl 9.98
B. Preparation of 5-carbamoyl-4-hydroxy-l-chlorocarbazo le
A solution of 0.66 g of 9-benzyl-5-carbamoyl-4-methoxy-
1-chlorocarbazole in 40 ml of dichloromethane was cooled dn
an ice bath treated dropwise with 14 ml of 1.0 M boron
tribromide solution in dichloromethane. The reaction was
allowed to warm to room temperature slowly over 2 hours and
then quenched by pouring into ice and then adding 50 ml of 1
N HCl. The mixture was extracted with dichloromethane
(3x200 ml) and the extracts were washed with brine, dried
with magnesium sulfate and concentrated. The aqueous layers
exhibited a precipitate and was then extracted twice with
ethyl acetate, washed with brine, dried with magnesium
sulfate and concentrated to afford 0.287 g of the subtitle
compound. The first residue was chromatographed on silica
gel using 0.5% methanol in dichloromethane to afford another
93 mg of the subtitle compound, (total yield 80%) ESIMS m/e
259 (M+-l) NMR (300 MHz, d6-DMS0): 6 11.79 (s, 1H); 10.76
(s, 1H); 8.87 (br s, 1H); 8.41 (br s, 1H); 7.77 (t, J=4.6,
1H); 7.48 (d, J=4.2, 2H); 7.34 (d, J=8.5, 1H); 6.54 (d,
J=8.5, 1H).
C. Preparation of [5-carbamoyl-l-chlorocarbazol-4-
yl]oxyacetic acid methyl ester
A solution of 0.28 g of 5-carbamoyl-4-hydroxy-l-
chlorocarbazole in 6 ml of tetrahydrofuran was added to

0.043 g of sodium hydride (60% in mineral oil) in 1 ml of
tetrahydrofuran and stirred for 60 minutes at room
temperature. Methyl bromoacetate (0.11 ml) was then added
and the reaction was stirred overnight. The reaction
mixture was poured into 20 ml of saturated ammonium chlor ide
solution and then extracted twice with ethyl acetate. The
extracts were washed with water and then with brine, dried
over magnesium sulfate and concentrated. The residue was
chromatographed on silica gel eluting with chloroform and
then 2:1 chloroform/ethyl acetate to afford 0.16 g (45%) of
the subtitle compound. ESIMS m/e 333 (M++l), 335 (M++3) ,
331 (M+-1) NMR (300 MHz, d6-DMS0) : 8 11.73 (s, 1H) ; 7.56 (d,
J=8.1, 1H); 7.50 (br s, 1H); 7.43-7.35 (m, 2H); 7.18 (br s,
1H); 7.06 (d, J=7.8, 1H); 6.56 (d, J=8.6, 1H) ; 4.90 (s, 2H);
3.70 (s, 3H).
D. Preparation of [9-benzyl-5-carbamoyl-l-chlorocarbazol~
4-yl]oxyacetic acid methyl ester
A solution of 78 mg of [5-carbamoyl-l-chlorocarbazol-
4-yl]oxyacetic acid methyl ester in 0.8 ml of dry
dimethylformamide was added to 10 mg sodium hydride (60% in
mineral oil) in 0.2 ml of dimethylformamide and stirred for
15 minutes. Benzyl bromide (0.031 ml) was then added and
the reaction was stirred overnight. The reaction mixture
was poured into water and acidified with 1 ml of 1 N HC1
solution and extracted twice with ethyl acetate. The
extracts were washed with water (3x) and then with brine,
dried over magnesium sulfate and concentrated. The residue
was chromatographed on silica gel eluting with methanol/0-2%
in dichloromethane to afford 4 0 mg of the subtitle compound.
ESIMS m/e 423 (M++l) 425 (M++3) NMR (300 MHz, CDCI3): 8
7.43-7.22 (m, 7H); 7.06 (d, J=7.3, 2H); 6.51 (d, J=8.6, 1H);
6.05 (s, 2H); 5.80 (br, 2H); 4.88 (s, 2H); 3.83

E. Preparation of [9-benzyl-5-carbamoyl-l-chlorocarbazo 1-
4-yl]oxyacetic acid
[9-Benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyaceti acid methyl ester (15 mg) was hydrolyzed similarly as
described in Example 50, Part D to afford 14 mg of the ti tie
compound. mp. 240-2°C ESIMS m/e 409 (M++l), 411 (M++3),
407 (M+-l) NMR (300 MHz, d6-DMSO) : 8 12.94 (br, 1H) ; 7.-70
(br, 1H); 7.61 (d, J=8.3, 1H); 7.43 (t, 3=1.8, 1H) ; 7.36 (m,
2H); 7.28-7.19 (m, 3H); 7.13 (d, J=7.2, 1H); 6.99 (d, J=7.4,
2H); 6.63 (d, J=8.6, 1H); 6.08 (s, 2H); 4.83 (s, 2H).

A. 9-[(Cyclohexyl)methyl]-5-carbomethoxy-l,2-
dihydrocarbazol-4(3H)-one
A 0 °C suspension of 5-carbomethoxy-l, 2-dihydro-9H-
carbazol-4(3H)-one (1.0 g, 4.11 mmol), a catalytic amount of
Nal (ca. 10 mg) and K2C03 (1.1 g, 8.22 mmol) in 10 mL of DMF
was treated with cyclohexylmethyl bromide (0.631 mL, 4.52
mmol). After stirring overnight at ambient temperature, an

additional 0.63 mL cyclohexylmethylbromide was added, and
the resulting mixture was heated at 60 °C for 3 hours. Th.e
mixture was poured into H2O (30 mL) and extracted with EtOAc
(2 x 25 mL). The combined organic layers were washed wit hi
H2O (4 x 50 mL) , dried over anhydrous Na2S0,i, filtered and
concentrated in vacuo. The residue was purified by radiai
chromatography on silica gel (elution with a gradient of 20%
to 40% EtOAc/hexanes) to afford 1.36 g (4.01 mmol; 97%) of
9-[(cyclohexyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazoi -
4(3H)-one as a white foam. IR (CHC13, cm"1) 3011, 2932,
2857, 1725, 1649, 1469, 1446, 1288 and 1120. MS (ES) m/e 340
(M+l), 453 (M+AcO") . FAB HRMS m/e, Calcd for C21H26N03:
340.1913. Found: 340.1916 (M+l).
Elemental Analyses for C2iH25N03:
Calculated: C, 74.31; H, 7.42; N, 4.13.
Found: C, 72.65; H, 7.39; N, 4.70.
B. 9-[(Cyclohexyl)methyl]-4-hydroxy-5-carbomethoxy
carbazole
A solution of 9-[(cyclohexyl)methyl]-5-carbomethoxy-
1,2-dihydrocarbazol-4(3H)-one (1.16 g, 3.42 mmol) and 2,3-
dichloro-5,6-dicyano-l,4-benzoquinone (853 mg, 3.76 mmol) in
20 mL of toluene was heated at 80 CC for 3 hours. The
mixture was purified directly by column chromatography on
silica gel (elution with CH2C12) to afford 259 mg (0.768
mmol; 22%) of 9-[(cyclohexyl)methyl]-4-hydroxy-5-
carbomethoxy carbazole as a yellow oil which slowly
solidified. MS (ES) m/e 338 (M+l), 336 (M-l).
Elemental Analyses for C2]H23N03:
Calculated: C, 74.75; H, 6.87; N, 4.15.
Found: C, 74.95; H, 6.99; N, 4.42.

C. 9-[(Cyclohexyl)methyl]-4-hydroxy-5-carbamoyl carbazoILe
A solution of 9-[(cyclohexyl)methyl]-4-hydroxy-5-
carbomethoxy carbazole (205 mg, 0.608 mmol) in 5 mL of THF
and 20 mL of concentrated aqueous ammonium hydroxide was
treated with a stream of NH3 gas to ensure saturation. The
reaction vessel was capped, and the mixture was heated at 35
°C with stirring until tic indicated complete consumption of
starting material (20 hrs). The THF was evaporated, and the
aqueous layer was filtered. The green solid precipitate was
dissolved in THF and purified by radial chromatography on
silica gel (elution with CH2C12). The resultant foam was
triturated with ether to afford 138 mg (70%) of the title
compound as an off-white solid. IR (KBr, cm"1) 3418, 3200,
3131, 1629, 1600, 1443, 1261, 778. 'FAB HRMS m/e, Calcd for
C20H23N2°2: 323.1760. Found: 323.1760 (M+l).
D. [9-[(Cyclohexyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid, methyl ester
A mixture of 9-[(cyclohexyl) methyl]-4-hydroxy-5-
carbamoyl carbazole (60 mg, 0.186 mmol) and Cs2C03 (150 mg;
0.460 mmol) in 2 mL of DMF was treated with methyl
bromoacetate (0.023 mL; 0.242 mmol). The reaction was
stirred for 2 hours at ambient temperature, then it was
diluted with EtOAc and H2O (10 mL each). The aqueous layer
was saturated with solid NaCl and extracted with EtOAc (2 x
10 mL). The combined organic layers were washed with H2O (2
x 25 mL), dried over anhydrous Na2S04, filtered and
concentrated in vacuo. Purification of the crude residue by
flash chromatography on silica gel (elution with a gradient
of 0% to 90% EtOAc/hexanes) followed by trituration with
Et20/EtOAc afforded 45 mg (0.114 mmol; 61%) of title
compound as an off-white solid. MS (ES) m/e 395 (M+l), 378
(M+H-NH3), 453 (M+AcCT) .

Elemental Analyses for C23H26N20,i 0.3H2O:
Calculated: C, 69.08; H, 6.71; N, 7.01.
Found: C, 69.13; H, 6.71; N, 7.09.
E. [9-[(Cyclohexyl)methyl]-5-carbamoylcarbazol-4-
yl]oxyacetic acid
A slurry of [9-[(cyclohexyl)methyl]-5-
carbamoylcarbazol-4-yl]oxyacetic acid, methyl ester (20 mg,
0.051 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated
with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture
stirred at room temperature for 2 h. The reaction was
acidified with 0.2 N HC1, and the organics were removed in
vacuo. The white precipitate was filtered away from the
aqueous layer and rinsed with Et20 to afford 16 mg (0.042
mmol; 83%) the title acid as a white powder. MS (ES) m/e
381 (M+l), 364 (M+H-NH3) , 379 (M-l).
Elemental Analyses for C22H^N204:
Calculated: C, 69.46; H, 6.36; N, 7.36.
Found: C, 69-34; H, 6.35; N, 7.29.

A. 9-[(Cyclopentyl)methyl]-5-carbomethoxy-l,2-
dihydrocarbazol-4(3H)-one
A suspension of 5-carbomethoxy-l,2-dihydro-9H-carbazol-
4(3H)-one (820 g, 3.37 mmol), a catalytic amount of Nal (ca.
10 mg) and KZC03 (930 mg, 6.74 mmol} in 6 mL of DMF was
treated with cyclopentylmethyl chloride (JOC, 1964, 29, 421-
423; 400 mg, 3.37 mmol). After stirring overnight at
ambient temperature, an additional 800 mg of
cyclopentylmethyl chloride and 1 g of Nal were added, and
the resulting mixture was heated at 80 °C overnight. An
additional 800 mg of cyclopentylmethyl chloride and 2.2 g of
Cs2C03 were added, and the reaction mixture was heated at 80
°C for 24 h. An additional 1.6 g of cyclopentylmethyl
chloride was added, and the reaction mixture was heated at
80 CC for 3 d The mixture was poured into H2O (30 mL) and
extracted with EtOAc (3 x 10 mL). The combined organic
layers were dried over anhydrous Na2SOt, filtered, and
concentrated in vacuo. The residue was purified by radial
chromatography on silica gel (elution with gradient of 10%
to 40% EtOAc/hexanes) to afford" 775 mg (2.38 mmol; 71%) of
9-[(cyclopentyl)methyl]-5-carbomethoxy-l,2-dihydrocarbazol-
4(3H)-one as a brown foam. MS (ES) m/e 326 (M+l), 384
(M+AcCf) .
Elemental Analyses for C20H23NO3:
Calculated: C, 73.82; H, 7.12; N, 4.30.
Found: C, 74.12; H, 7.21; N, 4.45.
B. 9-[(Cyclopentyl)methyl]-4-hydroxy-5-carbomethoxy
carbazole
A solution of 9-[(cyclopentyl)methyl]-5-carbomethoxy-
l,2-dihydrocarbazol-4(3H)-one (730 mg, 2.24 mmol) and 2,3-
dichloro-5,6-dicyano-l,4-benzoquinone (560 mg, 2.47 mmol) in
20 mL of toluene was heated at 80 °C for 3 hours. The

mixture was purified directly by column chromatography on
silica gel (elution with CH2C12) to afford 140 mg (0.433
mmol; 19%) of 9-[(cyclopentyl)methyl]-4-hydroxy-5-
carbomethoxy carbazole as a yellow oil which slowly
solidified. MS (ES) m/e 324 (M+l), 322 (M-l).
Elemental Analyses for C2oH2iN03'0.3H2O:
Calculated: C, 73.06; H, 6.62; N, 4.26.
Found: C, 73.19; H, 6.44; N, 4.40.
C. 9-[(Cyclopentyl)methyl]-4-hydroxy-5-carbamoyl carbazole
A solution of 9-[(cyclopentyl)methyl]-4-hydroxy-5-
carbomethoxy carbazole (110 mg, 0.34 mmol) in 3 mL of THF
and 20 mL ofconcentrated aqueous ammonium hydroxide was
treated with a stream of NH3 gas to ensure saturation. The
reaction vessel was capped, and the mixture heated to 35 °C
with stirring until tic indicated complete consumption of
starting material (20 h). The THF was evaporated, and the
aqueous layer was filtered. The resultant solid was
triturated with ether to afford 50 mg (0.162; 48%) of the
title compound as a greenish-white solid. IR (KBr, cm""1)
3416, 3199, 3126, 1630, 1599. 1442, 1262, 778. 'FAB HRMS
m/e, Calcd for C20H21N2O2: 309.1603. Found: 309.1607
(M+l).'
D. [9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol-4-
yl]oxyacetic acid, methyl ester
A mixture of 9-[(cyclopentyl)methyl]-4-hydroxy-5-
carbamoyl carbazole (45 mg, 0.146 mmol) and Cs2C03 (120 mg;
0.365 mmol) in 2 mL of DMF was treated with methyl
bromoacetate (0.018 mL; 0.19 mmol). The reaction was stirred
for 2 hours at ambient temperature, then it was diluted with
EtOAc and H2O (10 mL each) . The aqueous layer was saturated
with solid NaCl extracted with EtOAc (2 x 10 mL). The

combined organic layers were washed with H2O (2 x 25 mL) ,
dried over anhydrous Na2S04, filtered and concentrated in
vacuo. Purification of the crude residue by flash
chromatography on silica gel (elution with a gradient of 0%
to 100% EtOAc/hexanes) followed by trituration with
Et20/EtOAc afforded 26 mg (0.0683 mmol; 47%) of title
compound as a tan solid. MS (ES) m/e 381 (M+l), 364 (M+H-
NH3) , 439 (M+AcCf) .
Elemental Analyses for C23H26N204- '0.1H2O:
Calculated: C, 69.13; H, 6.38; N, 7.33.
Found: C, 68.99; H, 6.39; N, 7.41.
E. [9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol-4-
yljoxyacetic acid
A slurry of [9-I(cyclopentyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (20 mg,
0.065 mmol) in 0.3 mL of THF and 0.1 mL of MeOH was treated
with 0.1 mL of 1 N aq LiOH (0.1 mmol), and the mixture
stirred at room temperature for 2 hours. The reaction was
acidified with 0.2 N HC1, and the organics were removed in
vacuo. The white precipitate was filtered away from the
aqueous layer and rinsed with Et20 to afford 15 mg (0.0409
mmol; 63%) the title acid as a white powder. MS (ES) m/e
367 (M+l), 350 (M+H-NH3) , 365 (M-l).
Elemental Analyses for C2iH22N2(V 0.3H2O:
Calculated: C, 67.84; H, 6.13; N, 7.53.
Found: C, 67.73; H, 5.97; N, 7.70.
The compounds described herein are believed to
achieve their beneficial therapeutic action principally by
direct inhibition of human SPLA2, and not by acting as
antagonists for arachidonic acid, nor other active agents

below arachidonic acid in the arachidonic acid cascade,
such as 5-lipoxygenases, cyclooxygenases, etc.
The method of the invention for inhibiting SPLA2 mediated
release of fatty acids comprises contacting SPLA2 with an
therapeutically effective amount of a compound of Formula
(I) selected from the group consisting [9-benzyl-5-
carbamoyl-1-fluorocarbazol-4-yl]oxyacetic acid, {9-
[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid,
{9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, {9-[(3-chlorophenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, (9-[(3-
trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-
yl}oxyacetic acid, sodium salt, {9-[(2-methylphenyl)methyl]-
5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, {9-
[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacet ic
acid, sodium salt, {9-[(3-trifluoromethoxyphenyl)methyl]-5-
carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt, [9-
benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid, [9-
((cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic
acid, [9-[(cyclopentyl)methyl]-5-carbamoylcarbazol-4-
yl]oxyacetic acid or its pharmaceutically acceptable salt.
The compounds of the invention may be used in a
method of treating a mammal (e.g., a human) to alleviate
the pathological effects of septic shock, adult
respiratory distress syndrome, pancreatitus, trauma,
bronchial asthma, allergic rhinitis, and rheumatoid
arthritis; wherein the method comprises administering to
the mammal a compound of formula (I) in a therapeutically
effective amount. A "therapeutically effective" amount is
an amount sufficient to inhibit SPLA2 mediated release of
fatty acid and to thereby inhibit or prevent the
arachidonic acid cascade and its deleterious products.
The therapeutic amount of compound of the invention needed
to inhibit SPLA2 may be readily determined by taking a

sample of body fluid and assaying it for SPLA2 content b^'
conventional methods.
Throughout this document, the person or animal
to be treated will be described as a "mammal", and it wiLl
be understood that the most preferred subject is a human.
However it must be noted that the study of adverse
conditions of the central nervous system in non-human
animals is only now beginning, an that some instances of
such treatments are coming into use. Accordingly, use of:
the present compounds in non-human animals is
contemplated. It will be understood that the dosage
ranges for other animals will necessarily be quite
different from the doses administered to humans, and
accordingly that the dosage ranges described be
recalculated. For example, a small dog may be only l/10th
of a typical human's size, and it will therefore be
necessary for a much smaller dose to be used. The
determination of an effective amount for a certain non-
human animal is carried out in the same manner described
below in the case of humans, and veterinarians are well
accustomed to such determinations.
As previously noted the compounds of this
invention are useful for inhibiting SPLA2 mediated release
of fatty acids such as arachidonic acid. By the term,
"inhibiting" is meant the prevention or therapeutically
significant reduction in release of SPLA2 initiated fatty
acids by the compounds of the invention. By
"pharmaceutically acceptable" it is meant the carrier,
diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the
recipient thereof.
In general, the compounds of the invention are
most desirably administered at a dose that will generally

afford effective results without causing any serious side
effects and can be administered either as a single unit
dose, or if desired, the dosage may be divided into
convenient subunits administered at suitable times
throughout the day.
The specific dose of a compound administered
according to this invention to obtain therapeutic or
prophylactic effects will, of course, be determined by the
particular circumstances surrounding the case, including,
for example, the route of administration, the age, weigh"
and response of the individual patient, the condition
being treated and the severity of the patient's symptoms.
Typical daily doses will contain a non-toxic dosage level
of from about 0.01 mg/kg to about 50 mg/kg of body weight
of an active compound of this invention.
Preferably the pharmaceutical formulation is in
unit dosage form. The unit dosage form can be a capsule
or tablet itself, or the appropriate number of any of
these. The quantity of active ingredient in a unit dose of
composition may be varied or adjusted from about 0.1 to
about 1000 milligrams or more according to the particular
treatment involved. It may be appreciated that it may be
necessary to make routine variations to the dosage
depending on the age and condition of the patient. The
dosage will also depend on the route of administration.
A "chronic" condition means a deteriorating
condition of slow progress and long continuance. As such,
it is treated when it is diagnosed and continued
throughout the course of the disease. An "acute"
condition is an exacerbation of short course followed by a
period of remission. In an acute event, compound is
administered at the onset of symptoms and discontinued
when the symptoms disappear.

Pancreatitis, trauma-induced shock, bronchial
asthma, allergic rhinitis and rheumatoid arthritis may
occur as an acute event or a chronic event. Thus, the
treatment of these conditions contemplates both acute and
chronic forms. Septic shock and adult respiratory
distress, on the other hand, are acute conditions treated
when diagnosed.
The compound can be administered by a variety o f
routes including oral, aerosol, rectal, transdermal,
subcutaneous, intravenous, intramuscular, and intranasal.
Pharmaceutical formulations of the invention are
prepared by combining (e.g., mixing) a therapeutically
effective amount of the compounds of the invention
together with a pharmaceutically acceptable carrier or
diluent therefor. The present pharmaceutical formulations
are prepared by known procedures using well known and
readily available ingredients.
In making the compositions of the present
invention, the active ingredient will usually be admixed
with a carrier, or diluted by a carrier, or enclosed
within a carrier which may be in the form of a capsule,
sachet, paper or other container. When the carrier serves
as a diluent, it may be a solid, semi-solid or liquid
material which acts as a vehicle, or can be in the form of
tablets, pills, powders, lozenges, elixirs, suspensions,
emulsions, solutions, syrups, aerosols (as a solid or in a
liquid medium), or ointment, containing, for example, up
to 10S by weight of the active compound. The compounds of
the present invention are preferably formulated prior to
administration.
For the pharmaceutical formulations any suitable
carrier known in the art can be used. In such a
formulation, the carrier may be a solid, liquid, or
mixture of a solid and a liquid. Solid form formulations

include powders, tablets and capsules. A solid carrier
can be one or more substances which may also act as
flavoring agents, lubricants, solubilisers, suspending
agents, binders, tablet disintegrating agents and
encapsulating material.
Tablets for oral administration may contain
suitable excipients such as calcium carbonate, sodium
carbonate, lactose, calcium phosphate, together with
disintegrating agents, such as maize, starch, or alginic
acid, and/or binding agents, for example, gelatin or
acacia, and lubricating agents such as magnesium stearate,
stearic acid, or talc.
In powders the carrier is a finely divided solid
which is in admixture with the finely divided active
ingredient. In tablets the active ingredient is mixed
with a carrier having the necessary binding properties in
suitable proportions and compacted in the shape and size
desired. The powders and tablets preferably contain fron
about 1 to about 99 weight percent of the active
ingredient which is the novel compound of this invention.
Suitable solid carriers are magnesium carbonate, magnesium
stearate, talc, sugar lactose, pectin, dextrin, starch,
gelatin, tragacanth, methyl cellulose, sodium
carboxymethyl cellulose, low melting waxes, and cocoa
butter.
Sterile liquid form formulations include
suspensions, emulsions, syrups and elixirs.
The active ingredient can be dissolved or
suspended in a pharmaceutically acceptable carrier, such
as sterile water, sterile organic solvent or a mixture of
both. The active ingredient can often be dissolved in a
suitable organic solvent, for instance aqueous propylene
glycol. Other compositions can be made by dispersing the
finely divided active ingredient in aqueous starch or

sodium carboxymethyl cellulose solution or in a suitable
oil.
The following pharmaceutical formulations 1
through 8 are illustrative only and are not intended to
limit the scope of the invention in any way. "Active
ingredient", refers to a compound according to Formula (I)
or a pharmaceutical^ acceptable salt, solvate, or prodrug
thereof.

The active ingredient, starch and cellulose are
passed through a No. 45 mesh U.S. sieve and mixed
thoroughly. The aqueous solution containing
polyvinylpyrrolidone is mixed with the resultant powder,
and the mixture then is passed through a No. 14 mesh U.S.
sieve. The granules so produced are dried at 50°C and
passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate and talc,
previously passed through a No. 60 mesh U.S. sieve, are
then added to the granules which, after mixing, are
compressed on a tablet machine to yield tablets each
weighing 150 mg.

The active ingredient, cellulose, starch, and
magnesium stearate are blended, passed through a No. 45
mesh U.S. sieve, and filled into hard gelatin capsules in
200 mg quantities.

The active ingredient is passed through a No. 60
mesh U.S. sieve and suspended in the saturated fatty acid
glycerides previously melted using the minimum heat
necessary. The mixture is then poured into a suppository
mold of nominal 2 g capacity and allowed to cool.

The active ingredient is passed through a No. 4 5
mesh U.S. sieve and mixed with the sodium carboxymethyl
cellulose and syrup to form a smooth paste. The benzoic
acid solution, flavor and color are diluted with a portion
of the water and added, with stirring. Sufficient water is
then added to produce the required volume.

Formulation 8
An intravenous formulation may be prepared as
follows:

The solution of the above ingredients generally is
administered intravenously to a subject at a rate of 1 ml
per minute.
Assay Experiments
Assay Example 1
The following chromogenic assay procedure was
used to identify and evaluate inhibitors of recombinant
human secreted phospholipase A2. The assay described
herein has been adapted for high volume screening using 96
well microtiter plates. A general description of this
assay method is found in the article, "Analysis of Human
Synovial Fluid Phospholipase A2 on Short Chain
Phosphatidylcholine-Mixed Micelles: Development of a
Spectrophotometric Assay Suitable for a Microtiterplate
Reader", by Laure J. Reynolds, Lori L. Hughes, and Edward
A Dennis, Analytical Biochemistry, 204, pp. 190-197, 1992
(the disclosure of which is incorporated herein by
reference):
Reagents:

(Sigma A-7030, product of Sigma Chemical Co.
St. Louis MO, USA)
TRIS HC1 (3.94 g/L)
pH 7.5 (adjust with NaOH)
ENZYME BUFFER -
0.05 NaOAc.3H2O, pH 4.5
0.2 NaCl
Adjust pH to 4.5 with acetic acid
DTNB -
5,5'-dithiobis-2-nitrobenzoic acid
RACEMIC DIHEPTANOYL THIO - PC
racemic 1,2-bis(heptanoylthio)-1, 2-dideoxy-sn-
glycero-3-phosphorylcholine
TRITON X-100™ prepare at 6.249 mg/ml in
reaction buffer to equal lOuM
TRITON X-100™ is a polyoxy ethylene non-ionic
detergent supplied by
Pierce Chemical Company,
3747 N. Meridian Road, Rockford, Illinois
61101.
REACTION MIXTURE -
A measured volume of racemic dipheptanoyl thio
PC supplied in chloroform at a concentration of 100 mg/ml
is taken to dryness and redissolved in 10 millimolar
TRITON X-100™ nonionic detergent aqueous solution.
Reaction Buffer is added to the solution, then DTNB to
give the Reaction Mixture.
The reaction mixture thus obtained contains ImM
diheptanoly thio-PC substrate, 0.29 mm Triton X-100™

detergent, and 0.12 mm DTMB in a buffered aqueous solution
at pH 7.5.
Assay Procedure:
1. Add 0.2 ml reaction mixture to all wells;
2. Add 10 ul test compound (or solvent blank) to
appropriate wells, mix 20 seconds;
3. Add 50 nanograms of SPLA2 (10 microliters) to
appropriate wells;
4. Incubate plate at 40°C for 30 minutes;
5. Read absorbance of wells at 405 nanometers with an
automatic plate reader.
All compounds were tested in triplicate.
Typically, compounds were tested at a final concentration
of 5 ug/ml. Compounds were considered active when they
exhibited 40% inhibition or greater compared to
uninhibited control reactions when measured at 405
nanometers. Lack of color development at 4 05 nanometers
evidenced inhibition- Compounds initially found to be
active were reassayed to confirm their activity and, if
sufficiently active, IC50 values were determined.
Typically, the IC50 values (see, Table I, below) were
determined by diluting test compound serially two-fold
such that the final concentration in the reaction ranged
from 45 ug/mL to 0.35 ug/ml. More potent inhibitors
required significantly greater dilution. In all cases, %
inhibition measured at 405 nanometers generated by enzyme
reactions containing inhibitors relative to the
uninhibited control reactions was determined. Each sample
was titrated in triplicate and result values were averaged
for plotting and calculation of IC50 values. IC50 were
determined by plotting log concentration versus inhibition
values in the range from 10-90% inhibition.

Compounds of the instant invention were tested
in Assay Example 1 and were found to be effective at
concentrations of less than lOOuM.
Assay Example 2
Method:
Male Hartley strain guinea pigs (500-700g) were
killed by cervical dislocation and their heart and lungs
removed intact and placed in aerated (95% 02:5% C02) Krebs
buffer. Dorsal pleural strips (4xlx25mm) were dissected
from intact parenchymal segments (8x4x25mm) cut parallel
to the outer edge of the lower lung lobes. Two adjacent
pleural strips, obtained from a single lobe and
representing a single tissue sample, were tied at either
end and independently attached to a metal support rod.
One rod was attached to a Grass force-displacement
transducer Model FT03C, product of Grass Medical
Instruments Co., Quincy, MA, USA). Changes in isometric
tension were displayed on a monitor and thermal recorder
(product of Modular Instruments, Malvern, PA). All
tissues were placed in 10 ml jacketed tissue baths
maintained at 37°C. The tissue baths were continuously
aerated and contained a modified Krebs solution of the
following composition (millimolar) NaCl, 118.2; KC1, 4.6;
CaCl2-2H2O, 2.5; MgSO/j • 7H2O, 1.2; NaHC03, 24.8; KH2PO4,
1.0; and dextrose, 10.0. Pleural strips from the opposite
lobes of the lung were used for paired experiments.
Preliminary data generated from tension/response curves
demonstrated that resting tension of 800mg was optimal.
The tissues were allowed to equilibrate for 45 min. as the
bath fluid was changed periodically.

Cumulative concentration-response curves:
Initially tissues were challenged 3 times with
KCl (40 mM) to test tissue viability and to obtain a
consistent response. After recording the maximal response
to KCl, the tissues were washed and allowed to return to
baseline before the next challenge. Cumulative
concentration-response curves were obtained from pleural
strips by increasing the agonist concentration (SPLA2) in
the tissue bath by half-logio increments while the
previous concentration remained in contact with the
tissues (Ref.l, supra.). Agonist concentration was
increased after reaching the plateau of the contraction
elicited by the preceding concentration. One
concentration-response curve was obtained from each
tissue. To minimize variability between tissues obtained
from different animals, contractile responses were
expressed as a percentage of the maximal response obtained
with the final KCl challenge. When studying the effects
of various drugs on the contractile effects of SPLA2, the
compounds and their respective vehicles were added to the
tissues 30 minutes prior to starting the SPLA2
concentration-response curves.
Statistical analysis:
Data from different experiments were pooled and
presented as a percentage of the maximal KCl responses
(mean ± S.E.). To estimate the drug induced rightward
shifts in the concentration response curves, the curves
were analyzed simultaneously using statistical nonlinear
modeling methods similar to those described by Waud
(1976), Equation 26, p. 163, (Ref.2). The model includes
four parameters: the maximum tissue response which was
assumed the same for each curve, the ED50 for the control
curve, the steepness of the curves, and the pA2, the

concentration of antagonist that requires a two-fold
increase in agonist to achieve an equivalent response.
The Schild slope was determined to be 1, using statistical
nonlinear modeling methods similar to those described by
Waud (1976), Equation 27, p. 164 (Ref. 2). The Schild
slope equal to 1 indicates the model is consistent with
the assumptions of a competitive antagonist; therefore,
the pA2 may be interpreted as the apparent KB, the
dissociation constant of the inhibitor.
To estimate the drug-induced suppression of the
maximal responses, SPLA2 responses (10 ug/ml) were
determined in the absence and presence of drug, and
percent suppression was calculated for each pair of
tissues. Representative examples of inhibitory activities
are presented in Table 2, below.
Ref. 1 - Van, J.M.: Cumulative dose-response
curves. II. Technique for the making of dose-response
curves in isolated organs and the evaluation of drug
parameters. Arch. Int. Pharmacodyn. Ther., 143: 299-330,
1963.
Ref. 2 - Waud, D.: Analysis of dose-response
relationships, in Advances in General and Cellular
Pharmacology eds Narahashi, Bianchi 1:145-178, 1976.
Compounds of the instant invention were tested in
Assay Example 2 and were found to be effective at
concentrations below 20uM.

Assay Example 3
SPLA2 Transgenic Mice Assay
Materials & Methods
The mice utilized in these studies were mature, 6-8
month old, ZnS04-stimulated, hemizygous line 2608a
transgenic mice (Fox et. al. 1996). Transgenic mice from
this line express human SPLA2 in the liver and other
tissues and typically achieve levels of human SPLA2 in
their circulation of approximately 173 +_ 10 ng/ml when
maximally stimulated with ZnS04 (Fox, et al. 1996). The
mice were housed under constant humidity and temperature
and received food and water ad libitum. Animal room
lighting was maintained on a 12-hour light/dark cycle and
all experiments were performed at the same time of the day
during the early morning light period.
For intravenous testing, compounds or vehicle were
administered as an IV bolus via the tail vein in a volume
of 0.15 ml. Vehicle consisted of 1-5% dimethylsulfoxide,
1-51 ethanol and 10-30% polyethylene glycol 300 in H2O;
the concentrations of these ingredients were adjusted
according to the solubility of the compound. Mice were
bled retro-orbitally prior to drug or vehicle
administration and 30 minutes, 2 and 4 hours thereafter.
Three to six mice were used for each dose. PLA2 catalytic
activity in the serum was assayed with a modified
phosphatidylcholine/deoxycholine mixed micelle assay (Fox,
et al. 1996, Schadlich, et al., 1987) utilizing 3 mM
sodium deoxycholate and 1 mM l-palmitoyl-2-oleoyl-sn-
glycero-3-phosphocholine.
For oral testing, compounds were dissolved in 1-5%
ethanol/10-30% polyethylene glycol 300 in H2O or were
suspended in 5% dextrose in H2O and administered by oral

gavage. Serum was prepared from retro-orbital blood and
assayed for PLA2 catalytic activity as above.
References
Fox, N., M. Song, J. Schrementi, J. D. Sharp, D. L.
White, D. W. Snyder, L. W. Hartley, D. G. Carlson, N. J.
Bach, R. D. Dillard, S. E. Draheim, J. L. Bobbitt, L.
Fisher and E. D. Mihelich. 1996.
Eur. J. Pharmacol. 308: 195.
Schadlich, H.R., M. Buchler, and H. G. Beger, 1987, J.
Clin. Chem. Clin.
Biochem. 25, 505.
Compounds of the instant invention were tested
in Assay Example 3 and were found to be effective.
While the present invention has been illustrated
above by certain specific embodiments, it is not intended
that these specific examples should limit the scope of the
invention as described in the appended claims.

We Claim:
1. A compound selected from the group consisting of (9-bcnzyl-5-carbamoyl-l-
fluorocarbazol-4-yl]oxyacetic acid, {9-[(phenyl)mcthyI|-5-carbamoylcarba/.ol-4-
yl} oxyacctic acid, {9-|(3-fluorophenyl)methyl|-5-carbamoylcarbazol-4-
yl} oxyacctic acid, {9-|(3-chlorophcnyl)melhyl]-5-carbamoylcarbazol-4-
yl} oxyacctic acid, {9-|(3-trinuoromcthylphenyl)methyl|-5-carbamoylcarba/.ol-4-
yl}oxyacctic acid sodium salt. {9-|(2-mcthylphenyl)mcthyl|-5-
carbamoylcarbazol-4-yl) oxyacctic acid sodium salt. }9-|(3-
mcthylphcnyl)mcthyl]-5-carbamoylcarbazol-4-yl}oxyacctic acid sodium salt. |9-
| (3-trinuorornethoxyphcnyl)methyl ]-5-carbamoylcarbazol-4-yl }oxy acetic acid
sodium salt. |9-benzyl-5-carbamoyl-l-chlorocarbazol-4-yl]oxyacetic acid, |9-
|(cyclohcxyI)mclhyl |-5-carbamoyIcarbazol-4-yl |oxyacetic acid, |9-
|(cyclopcntyl)methyl|-5-carbamoylcarbazol-4-yI|oxyacetic acid or a
pharmaccutically acceptable racemate, solvate, tautomer. optical isomer, or salt
thereof as herein described.
2. A compound as claimed in claim 1 which is (9-|(phcnyl)mclhyl|-5-
carbamoylcarbazol-4-yl}oxyacetic acid, or a pharmaccutically acceptable
racemate. solvate, tautomer, optical isomer, or salt, thereof.
3. A compound as claimed in Claim 1 which is |9-benzyl-5-carbamoyl-l-
fIuorocarbazol-4-yl|oxyacetic acid or a pharmaccutically acceptable racemate.
solvate, tautomer, optical isomer, or salt, thereof.
4. A compound as claimed in Claim 1 which is {9-|(3-lluorophenyl)melhyl|-5-
carbamoylcarbazol-4-yl} oxyacctic acid or a pharmaccutically acceptable
racemate, solvate, tautomer, optical isomer, or salt, thereof.

5. A compound as claimed in Claim 1 which is {9-|(3-chlorophcnvl)incthyl|o-
carbamoylcarbazol-4-yl)oxyacetic acid or a pharmaceutical ly acceptable
racemate. solvate, taulomer, optical isomer, or salt, thereof.
6. A compound as claimed in Claim 1 which is (9-( (3-
trinuoromethylphenyl)methyl|-5-carbamoylcarbazol-4-yl Joxyacetic acid sodium
salt or a pharmaceutical ly acceptable racemate, solvate, tautomcr, optical isomer,
or salt, thereof.
7. A compound as claimed in Claim 1 which is {9-f(2-methylphenyl)methyl|-5-
carbamoylcarbazol-4-yl}oxyacetic acid sodium salt or a pharmaceuticallv
acceptable racemate, solvate, tautomer. optical isomer, or salt, thereof.
8. A compound as claimed in Claim 1 which is {9-((3-methylphenyl)methyi|-5-
carbamoylcarbazol-4-yl}oxyacetic acid sodium salt or a pharmaceutically
acceptable racemate, solvate, tautomer. optical isomer, or salt, thereof.
9. A compound as claimed in Claim 1 which is !9-|(3-
trinuoromethoxyphenyl)methyl|-5-carbamoylcarbazol-4-yi}oxyacetic acid
sodium salt or a pharmaceutically acceptable racemate, solvate, tautomer. optical
isomer, or salt, thereof.
10. A compound as claimed in claim 1 which is [9-benzyl-5-carbamoyl-l-
chlorocarbazol-4-yl]oxyacetic acid or a pharmaceutically acceptable racemate.
solvate, tautomcr, optical isomer, or salt thereof.

11. A compound as claimed in claim 1 which is |9-|(cyclohexyl)mclhyl|-5-
carbamoylcarba/ol-4-yl|oxyacetic acid or a pharmaceutical^' acceptable
raccmatc, solvate, tautomer, optical isomer, or salt thereof.
12. A compound as claimed in claim 1 which is |9-|(cyclopcniyl)mcthyl|-5-
carbamoylcarbazol-4-yl|oxyacetic acid or a pharmaccutically acceptable
racemate, solvate, tautomer. optical isomer, or salt thereof.
13. The compound as claimed in claim I. which is [9-|(cyclohexyl)methyI|-5-
carbamoylcarbazol-4-yl|oxyacetic acid sodium salt, represented by the formula

14. The compound as claimed in I. which is (9-f(cyclohexyI)mcthyl|-5-
carbamoylcarbazol-4-yl|oxyacctic acid, represented by the formula

15. A compound as claimed in anyone of claims 1 to 14 wherein the salt is sodium.
16. A pharmaceutical formulation comprising a compound as claimed in anyone of
claims 1 to 14 together with a pharmaceutical!}' acceptable carrier or diluent
therefor.
17. A pharmaceutical formulation adapted for the treatment of a condition associated
with inhibiting sPI,A2, containing a compound as claimed in anyone of Claims I
to 14 together with a pharmaceutical!}' acceptable carrier or diluent thereof.

Novel tricyclics are disclosed together with the use of such compounds for inhibiting
Spla2 mediated releases of fatty acids for treatment of conditions such as septic shock.

Documents:

347-CAL-1999-(05-01-2012)-FORM-27.pdf

347-cal-1999-abstract.pdf

347-cal-1999-claims.pdf

347-CAL-1999-CORRECTED LETTER PATENT.pdf

347-CAL-1999-CORRESPONDENCE 1.1.pdf

347-CAL-1999-CORRESPONDENCE 1.3.pdf

347-CAL-1999-CORRESPONDENCE-1.4.pdf

347-cal-1999-correspondence.pdf

347-CAL-1999-CORRESPONDENCE1.2.pdf

347-CAL-1999-CORRESPONDENCE1.5.pdf

347-cal-1999-description (complete).pdf

347-cal-1999-examination report.pdf

347-cal-1999-form 1.pdf

347-cal-1999-form 13.pdf

347-cal-1999-form 18.pdf

347-cal-1999-form 2.pdf

347-cal-1999-form 26.pdf

347-CAL-1999-FORM 27.pdf

347-cal-1999-form 3.pdf

347-cal-1999-form 5.pdf

347-cal-1999-granted-abstract.pdf

347-cal-1999-granted-claims.pdf

347-cal-1999-granted-correspondence.pdf

347-cal-1999-granted-description (complete).pdf

347-cal-1999-granted-examination report.pdf

347-cal-1999-granted-form 1.pdf

347-cal-1999-granted-form 13.pdf

347-cal-1999-granted-form 18.pdf

347-cal-1999-granted-form 2.pdf

347-cal-1999-granted-form 26.pdf

347-cal-1999-granted-form 3.pdf

347-cal-1999-granted-form 5.pdf

347-cal-1999-granted-reply to examination report.pdf

347-cal-1999-granted-specification.pdf

347-CAL-1999-OFFICIAL LETTER.pdf

347-CAL-1999-OTHERS 1.1.pdf

347-CAL-1999-OTHERS 1.3.pdf

347-cal-1999-others.pdf

347-CAL-1999-OTHERS1.2.pdf

347-cal-1999-reply to examination report.pdf

347-cal-1999-specification.pdf

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Patent Number

240478

Indian Patent Application Number

347/CAL/1999

PG Journal Number

20/2010

Publication Date

14-May-2010

Grant Date

12-May-2010

Date of Filing

16-Apr-1999

Name of Patentee

ELI LILLY ADN COMPANY

Applicant Address

LILLY CORPORATE CENTER, CITY OF INDIANAPOLIS, STATE OF INDIANA

Inventors:

#	Inventor's Name	Inventor's Address
1	JOLIE ANNNE BASTIAN	1028 MORNING SUN LANE BEECH GROVE, INDIANA 46107
2	NICHOLAS JAMES BACH	7215 SOUTH MERIDIAN STREET INDIANAPOLIS, INDIANA 46217
3	GARY ALAN HITE	4305 SOUTH ASBURY STREET INDIANAPOLIS, INDIANA 46227
4	MICHAEL DEAN KINNICK	343 SOUTHCREEK DRIVE, SOUTH INDIANAPOLIS, INDIANA 46217
5	EDWARD DAVID MIHELICH	10998 SPRING MILL LANE, CARMEL, INDIANA 46032
6	JOHN MICHAEL MORIN, JUNIOR	9 ROSELAWN AVENUE, BROWNSBURG, INDIANA 46112
7	DANIEL JON SALL	376 LEISURE LANE, GREENWOOD, INDIANA 46142
8	ROBERT THEODORE VASILEFF	4651 CHERRY LANE, INDIANAPOLIS, INDIANA 46228

PCT International Classification Number

A61P 29/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	09/062,328	1998-04-17	U.S.A.