AU2708699A - Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment - Google Patents

Carboxylic acids and acylsulfonamides, compositions containing such compounds and methods of treatment Download PDF

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AU2708699A
AU2708699A AU27086/99A AU2708699A AU2708699A AU 2708699 A AU2708699 A AU 2708699A AU 27086/99 A AU27086/99 A AU 27086/99A AU 2708699 A AU2708699 A AU 2708699A AU 2708699 A AU2708699 A AU 2708699A
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Prior art keywords
naphthyl
phenyl
propyl
methoxy
thienyl
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AU27086/99A
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AU756333B2 (en
Inventor
Michel Belley
Michel Gallant
Yves Gareau
Helene Juteau
Marc Labelle
Nicolas Lachance
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Merck Frosst Canada and Co
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Merck Frosst Canada and Co
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Priority claimed from PCT/CA1999/000212 external-priority patent/WO1999047497A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/64—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Quinoline Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Indole Compounds (AREA)

Description

WO 99/47497 PCT/CA99/00212 5 CARBOXYLIC ACIDS AND ACYLSULFONAMIDES, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT BACKGROUND OF THE INVENTION 10 The present invention relates to compounds which are useful for treating or preventing prostaglandin mediated diseases, methods of treatment and pharmaceutical compositions containing such compounds. The compounds are structurally different from conventional NSAIDs and opiates, and are antagonists of the pain and 15 inflammatory effects of E-type prostaglandins. Two review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists: Eicosanoids: From Biotechnology to Therapeutic Applications, Folco, Samuelsson, Maclouf, 20 and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154 and Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87. An article from The British Journal of Pharmacology (1994, 112, 735-740) suggests that Prostaglandin E 2
(PGE
2 ) exerts allodynia through the EPi receptor subtype and hyperalgesia through EP 2 and EP 3 receptors in the 25 mouse spinal cord. Thus, selective prostaglandin ligands, agonists or antagonists, depending on which prostaglandin E receptor subtype is being considered, have anti-inflammatory, antipyretic and analgesic properties, and in addition inhibit hormone-induced uterine 30 contractions. Moreover, the compounds have anti-cancer effects. The compounds have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects. 35 - 1- WO 99/47497 PCT/CA99/00212 5 SUMMARY OF THE INVENTION The present invention relates to compounds represented by formula I:
R
1
R
2
R
3 -HET 0 A X-B Z 10 as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein: HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from 0, S(O)n and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; 15 A is a one or two atom moiety and is selected from the group consisting of: -W-, -C(O)- , -C(R 7
)
2 -W- , -W-C(R 7
)
2 - , -CR7(OR20)_ -C(R7)2 - , -C(R 7
)
2
-C(OR
20
)R
7 - , -C(R) 2 - C(R 7
)
2 - or -CR 7
=CR
7 - , wherein W represents 0, S(O)n or NR17, with n as previously defined and R1 7 as defined below; 20 X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from 0, S(O)n and N(O)m , and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents 0, S(O)n , NR17, a bond or -CR18 = CR18-; 25 B represents - (C(R18)2)p-Y- (C(R 1 8 )2)q wherein p and q are independently 0-3, such that when Y represents 0, S(O)n , NR17 or -CR1 8 = CR18- , p + q = 0-6, and when Y represents a bond, p + q is 1-6; Z is OH or NHSO 2 R19 30 R' R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4
_
9 , (C(R 4 )2)pSR 5 , -(C(R 4
)
2
)OR
8 , -(C(R 4
)
2 )pN(R 6
)
2 , CN, NO2, -(C(R 4
)
2 )pC(R 7
)
3 , C0 2 R', -CON(R) 2 or -(C(R 4
)
2 )pS(O),,R', wherein n and p are as previously defined; 35 each R 4 is independently H, F, CF 3 or lower alkyl, -2- WO 99/47497 PCT/CA99/00212 5 or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from 0, S(O)n or N(O)m; each R' is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , lower alkyl-HET, lower alkenyl-HET or -(C(R") 2 )pPh(R")o 10 2; each R' is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph, Bn and when two R' groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from 0, S(O)n or 15 N(O)m; each R' is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from 0, S(O)n and N(O)m; 20 each R 8 represents H or R5; each R' is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R1 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , Ph(R")0-3, CH 2 Ph(R")0-3 or N(RI)2 ; 25 each R" is independently lower alkyl, SR 2 0 , OR 2 0 , N(R) 2 ,
-CO
2 R", -CON(R) 2 , -C(O)R", CN, CF3, NO 2 or halogen; each R 2 is independently H, lower alkyl or benzyl; each R 3 is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R) 2 , C0 2 R , CN, CF3 or NO 2 ; 30 R" and R1 5 are independently lower alkyl, halogen, CF3, OR1 6 , S(O)R' or C(R16) 2 0R 7 ; each R1 6 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 ; each R" is independently H, lower alkyl or Bn; 35 each R' 8 is independently H, F or lower alkyl, and when two R18 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from 0, S(O)n or N; -3- WO 99/47497 PCT/CA99/00212 5 each R 9 is lower alkyl, lower alkenyl, lower alkynyl, CF3, HET(Ra)4_9, lower alkyl-HET(Ra)4-9 or lower alkenyl-HET(Ra)4_9; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl,
CF
3 or Ph(R") 2 and 10 each Ra is independently selected from the group consisting of: H, OH, halo, CN, NO2, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1-6alkylamino, di-C1-6alkylamino, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O) C2 15 6alkynyl, CO2H, CO2C1-6alkyl, C02C2-6alkenyl, and C02C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C1.6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, CO2H, CO2C1-6alkyl, 20 CO2C2-6alkenyl, CO2C2-6alkynyl, NH2, NHC1-6alkyl and N(C1-6alkyl)2. Pharmaceutical compositions are also included which are comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier. A method of treating or preventing a prostaglandin 25 mediated disease is also included which is comprised of administering to a mammalian patient in need thereof, a compound of formula I in an amount which is effective for treating or preventing a prostaglandin mediated disease. 30 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to carboxylic acids and acylsulfonamides, which are ligands at prostaglandin receptors, as well as a method for treating or preventing a prostaglandin mediated disease comprising administering to a patient in need of such a treatment of an 35 amount of compound of Formula I which is effective for treating or preventing a prostaglandin mediated disease. The invention described in this patent application is described using the following definitions unless otherwise indicated. -4- WO 99/47497 PCT/CA99/00212 5 HET represents a 5-12 membered aromatic ring system containing 0-3 heteroatoms selected from 0, S(O)n and N wherein n is 0, 1 or 2. HET may be substituted with up to three substituents on the aromatic ring system, R1, R 2 and R 3 . "Aromatic ring systems" as used herein includes aryl and heteroaryl groups such as benzene, 10 naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,2-methylenedioxybenzene and pyrrole. 15 HET 2 is a subset of HET and represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl. Aryl refers to aromatic 6-10 membered groups having 1-2 rings and alternating (resonating) double bonds. Examples include 20 phenyl, biphenyl and naphthyl. Heteroaryl refers to aromatic 5-12 membered groups having alternating (resonating) double bonds and containing from 1-4 heteroatoms selected from 0, S(O)n and N. Examples include the following: : quinoline, furan, benzofuran, thiophene, benzothiophene, 25 thiazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, oxazole, indole, isoindole, pyridine, isoquinoline, imidazole, thiazole, triazole, 1,3 methylene dioxobenzene, pyrrole and naphthyridine, Heterocyclyl refers to non-aromatic 5-12 membered cyclic groups having 1-4 heteroatoms selected from 0, S(O)n and N. Examples 30 of heterocyclic groups are piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran and morpholine. X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from 0, S(O)n and N(O)m, and optionally substituted with R14 and R15, and A and B are 35 attached to the aryl or heteroaryl group X in positions which are ortho relative to each other. Examples are selected from the group consisting of: phenyl, naphthyl, biphenyl, quinoline, furan, benzofuran, pyridyl, pyrrole, thiophene, benzothiophene, thiazole, benzothiazole, 1,2,5 -5- WO 99/47497 PCT/CA99/00212 5 thiadiazole, triazole, 1,2-methylenedioxybenzene, thienopyridine, oxazole and indole. The terms alkyl, alkenyl, and alkynyl mean linear, branched, and cyclic structures and combinations thereof. "Lower alkyl" means alkyl groups of from 1 to 7 carbon 10 atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, s- and t-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, and the like. When propyl and butyl are recited without the isomeric form being specified, these include all isomers thereof. 15 "Lower alkenyl" means alkenyl groups of 2 to 7 carbon atoms. Examples of lower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2 methyl-2-butenyl, cyclopropen-1-yl, cyclohexen-3-yl and the like. When cis or trans is not specified, both are intended in pure form as well as in 20 the form of a mixture of isomers. "Lower alkynyl" means alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 3 methyl-1-pentynyl, 2-heptynyl, 2-(cyclopropyl)ethenyl, 3-(cyclobutyl)-1 propynyl and the like. 25 Halogen (halo) includes F, Cl, Br and I. The following abbreviations have the indicated meanings: AIBN = 2.2'-azobisisobutyronitrile B.P. = benzoyl peroxide Bn = benzyl 30 CC1 4 = carbon tetrachloride D = -O(CH2)30 DAST diethylamine sulfur trifluoride DCC dicyclohexyl carbodiimide DCI l-(3-dimethylaminopropyl)-3-ethyI 35 carbodiimide DEAD diethyl azodicarboxylate DIBAL diisobutyl aluminum hydride DME ethylene glycol dimethylether DMAP 4-(dimethylamino)pyridine 40 DMF NN-dimethylformamide DMSO dimethyl sulfoxide Et3N 3triethylamine LDA = lithium diisopropylamide -6- WO 99/47497 PCT/CA99/00212 5 m-CPBA = metachloroperbenzoic acid NBS = N-bromosuccinimide NSAID = non-steroidal anti-inflammatory drug PCC = pyridinium chlorochromate PDC = pyridinium dichromate 10 Ph = phenyl 1,2-Ph = 1,2-benzenediyl Pyr = pyridinediyl Qn = 7-chloroquinolin-2-yl Rs = -CH2SCH2CH2Ph 15 r.t. = room temperature rac. = racemic THF = tetrahydrofuran THP = tetrahydropyran-2-yl 20 Alkyl group abbreviations Me = methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl 25 n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl c-Pr = cyclopropyl 30 c-Bu = cyclobutyl c-Pen = cyclopentyl c-Hex = cyclohexyl It is intended that the definition of any substituent (e.g., R , 66 35 R , etc.) in a particular molecule be independent of its definition elsewhere in the molecule. Thus, -N(R )2 represents -NHH, -NHCH3' NHC H,, and the like. In one aspect of the invention, the invention relates to a compound represented by formula I: 40
R
1
R
2
R
3 - HET 0 A X-B Z as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein: -7- WO 99/47497 PCT/CA99/00212 5 HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from 0, S(O)n and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; A is a one or two atom moiety and is selected from the group consisting of: -W-, -C(O)- , -C(R 7
)
2 -W- , -W-C(R 7
)
2 - , 7(OR20) 10 -C(R) 2 - , -C(R 7
)
2
-C(OR
2 0
)R
7 - , -C(R 7
)
2 - C(R) 2 or CR =CR , wherein W represents 0, S(O)n or NR1 7 , with n as previously defined and R1 7 as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from 0, S(O)n and 15 N(O)m , and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents 0, S(O)n , NR17, a bond or -CR18 = CR1 8 -; B represents - (C(Rl8)2)p-Y- (C(R18)2)q wherein p and q are independently 0-3, such that when Y represents 0, 20 S(O)n , NR17 or -CR18 = CR18- , p + q = 0-6, and when Y represents a bond, p + q is 1-6; Z is OH or NHSO 2
R'
9 R1 R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra)4_ 9 , 25 (C(R 4 )2)pSR 5 , -(C(R 4
)
2
)OR
8 , -(C(R 4
)
2 )pN(R 6
)
2 , CN, NO2, -(C(R 4
)
2 )pC(R 7
)
3 , C0 2
R
9 , -CON(R) 2 or
-(C(R
4
)
2 )pS(O)nR' 0 , wherein n and p are as previously defined; each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to 30 six atoms, optionally containing one heteroatom selected from 0, S(O)n or N(O)m; each R 5 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , lower alkyl-HET, lower alkenyl-HET or -(C(R 8
)
2 )pPh(R")o 2. 35 each R' is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph, Bn and when two R' groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, -8- WO 99/47497 PCT/CA99/00212 5 optionally containing an additional heteroatom selected from 0, S(O)n or N(O)m; each R' is independently H, F, CF 3 or lower alkyl, and when two R' groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing 10 from 0-2 heteroatoms selected from O, S(O)n and N(O)m; each R 8 represents H or R5; each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R' 0 is independently lower alkyl, lower alkenyl, lower 15 alkynyl, CF 3 , Ph(R")0-3, CH 2 Ph(R")0-3 or N(R 6
)
2 ; each R" is independently lower alkyl, SR 20 , OR 20 , N(R 6
)
2 -C0 2 R", -CON(R) 2 , -C(O)R", CN, CF3, NO 2 or halogen; each R 12 is independently H, lower alkyl or benzyl; each R1 3 is independently H, halo, lower alkyl, O-lower 20 alkenyl, S-lower alkyl, N(R) 2 , CO 2 R", CN, CF 3 or NO 2 ; R" and R1 5 are independently lower alkyl, halogen, CF3, OR1 6 , S(O).R1 6 or C(R16) 2 0R 7 ; each R" is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 ; 25 each R 7 is independently H, lower alkyl or Bn; each R' 8 is independently H, F or lower alkyl, and when two R1 8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from 0, S(O)n or N; 30 each R' 9 is lower alkyl, lower alkenyl, lower alkynyl, CF3 HET(Ra)4_9, lower alkyl-HET(Ra)4-9 or lower alkenyl-HET(Ra)4_9; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R 3
)
2 and 35 each Ra is independently selected from the group consisting of: H, OH, halo, CN, N02, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -9- WO 99/47497 PCT/CA99/00212 5 C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1-6alkylamino, di-C1 6alkylamino, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O) C2-6alkynyl, CO2H, CO2C1-6alkyl, C02C2-6alkenyl, and C02C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: 10 hydroxy, halo, aryl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, CO2H, CO2C1-6alkyl, CO2C2-6alkenyl, CO2C2-6alkynyl, NH2, NHC1-6alkyl and N(C1-6alkyl)2. In another embodiment of the invention, the invention 15 relates to compounds represented by formula I:
R
1
R
2
R
3 -HET 0 A X-B Z as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein: 20 HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from 0, S(O)n and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; A is a one or two atom moiety and is selected from the group consisting of: -W-, -C(O)- , -C(R 7
)
2 -W- , -W-C(R 7
)
2 - , -CR7(OR20)_ 25 C(R) 2 - , -C(R 7
)
2
-C(OR
20
)R
7 - , -C(R) 2 - C(R) 2 or CR =CR , wherein W represents 0, S(O)n or NR17, with n as previously defined and R 1 7 as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from 0, S(O)n and 30 N(O)m , and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents 0, S(O)n , NR17, a bond or -CR18 = CR18-; B represents - (C(R18)2)p-Y- (C(Rl 8 )2)q - 10 - WO 99/47497 PCT/CA99/00212 V 5 wherein p and q are independently 0-3, such that when Y represents 0, S(O)n , NR17 or -CR1 8 = CR18- , p + q = 0-6, and when Y represents a bond, p + q is 1-6; Z is OH or NHSO 2 R19
R
1
R
2 and R 3 independently represent H, halogen, lower 10 alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4
_
9 ,
-(C(R
4 )2)pSR 5 , -(C(R 4
)
2
),OR
8 , -(C(R 4
)
2 )pN(R 6
)
2 , CN, NO2, -(C(R4)2)pC(R7)3, -C0 2
R
9 , -CON(R) 2 or -(C(R 4
)
2 )pS(O)nR' 0 , wherein n and p are as previously defined; each R 4 is independently H, F, CF3 or lower alkyl, 15 or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from 0, S(O)n or N(O)m; each R' is independently lower alkyl, lower alkenyl, lower alkynyl, CF, lower alkyl-HET, lower alkenyl-HET or -(C(R) 2 )pPh(R")0 20 2. each R' is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from 0, S(O)n or 25 N(O)m; each R 7 is independently H, F, CF 3 or lower alkyl, and when two R' groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from 0, S(O)n and N(O)m; 30 each R8 represents H or R5; each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R 1 is independently lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph(R")0-3, CH 2 Ph(R")o-3 or N(R6)2 ; 35 each R" is independently lower alkyl, SR 2 0 , OR 2 0 , N(R) 2 ,
-CO
2 R", -CON(R) 2 , -C(O)R, CN, CF3, NO 2 or halogen; each R 12 is independently H, lower alkyl or benzyl; -11- WO 99/47497 PCT/CA99/00212 5 each R" is independently H, halo, lower alkyl, O-lower alkenyl, S-lower alkyl, N(R) 2 , CO 2 R", CN, CF3 or NO 2 ; R" and R15 are independently lower alkyl, halogen, CF3,
OR
16 , S(O).R 6 or C(R16) 2 0R 7 ; each R' is independently H, lower alkyl, lower alkenyl, Ph, 10 Bn, CHF2 or CF 3 . each R' is independently H, lower alkyl or Bn; each R' 8 is independently H, F or lower alkyl, and when two R1 8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one 15 heteroatom chosen from O, S(O)n or N; each R" is lower alkyl, lower alkenyl, lower alkynyl, CF, HET2(Ra)4.
9 , lower alkyl-HET 2 (Ra)4_9 or lower alkenyl-HET 2 (Ra)4.
9 , wherein HET 2 represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl; 20 each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CHF 2 , CF 3 or Ph(R 3
)
2 and each Ra is independently selected from the group consisting of: 25 H, OH, halo, CN, N02, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1-6alkylamino, di-C1 6alkylamino, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O) C2-6alkynyl, CO2H, CO2C1-6alkyl, CO2C2-6alkenyl, and C02C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of 30 alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, CO2H, CO2C1-6alkyl, C02C2-6alkenyl, CO2C2-6alkynyl, NH2, NHC1-6alkyl and N(C1-6alkyl)2. 35 An embodiment of the present invention which is of particular interest is represented by formula I wherein HET represents a member selected from the group consisting of: benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, -12 - WO 99/47497 PCT/CA99/00212 5 thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,2-methylenedioxybenzene and pyrrole. More particularly, an embodiment of the present invention is represented by formula I wherein HET is selected from the group 10 consisting of: benzene, biphenyl, naphthylene, indole, thiophene, benzofuran and quinoline. Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I. Another embodiment of the present invention that is of 15 particular interest is represented by formula I wherein A represents a one or two atom moiety and is selected from the group consisting of: S, S(O), S02, CH2, -C(O)- , -OCH2-, -CHOH- , -C(OH)(CH3)- and -CH2-0-. More particularly, A is selected from the group consisting of: : S, S(O), S02, CH2, -C(O)-. Within this subset of compounds of the invention, all 20 other variables are as originally described with respect to formula I. Another embodiment of the present invention that is of particular interest is represented by formula I wherein X represents phenyl optionally substituted with R' and R . Within this subset of compounds of the invention, all other variables are as originally 25 described with respect to formula I. More particularly, X represents phenyl and R" and R" are absent or represent halo. Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I. Another embodiment of the present invention that is of 30 particular interest is represented by formula I wherein B is CH=CH or 1,2-cyclopropyl, and in particular, where B is CH=CH in the E-isomeric form. Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I. Another embodiment of the present invention that is of 35 particular interest is represented by formula I wherein Z is NHSO 2
R
19 . Within this subset of compounds of the invention, all other variables are as originally described with respect to formula I. -13 - WO 99/47497 PCT/CA99/00212 5 Another embodiment of the present invention that is of particular interest is represented by formula I wherein Z is NHSO 2
R'
9 and R" represents a member selected from the group consisting of: lower alkyl and HET(Ra)3. Within this aspect of the invention, HET is selected from the group consisting of: phenyl, thienyl, naphthyl, 10 furanyl, thiazolyl, imidazolyl and indolyl. Another embodiment of the present invention that is of particular interest is represented by formula I wherein Z is NHSO 2 R19 and R' represents benzene or thiophene, substituted with R'R 2
R
3 . Another embodiment of the present invention that is of 15 particular interest is represented by formula I wherein Z represents OH. Within this subset, all other variables are as originally defined. A subset of compounds that is of particular interest is defined with respect to formula I wherein: 20 HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; 25 A represents a one or two atom moiety and is selected from the group consisting of: S, S(O), S02, CH2, -C(O)- , -OCH2- , -CHOH- , C(OH)(CH3 )- and -CH2-0-; X represents phenyl optionally substituted with RM and R 1; B is CH=CH; 30 Z is NHSO 2 R1 9 and
R
19 represents a member selected from the group consisting of: lower alkyl and HET(Ra)3. Examples of compounds of the present invention are shown in Tables I and II below. 35 Table I - 14- WO 99/47497 PCT/CA99/00212
R
1
R
2
R
3 - HET 0 A X-B NHSO 2
R'
9 Ia (Compounds 1-323 and 347-454) 5 R1R2R3-Het A X B R 9 Cpd 1-naphthyl CH2 1,2-Ph CH=CH Ph(F), 1 2-naphthyl S(O)2 1,2-Ph CH=CH Ph(F), 2 3-methylindol CH2 1,2-Ph CH=CH 2-thienyl 3 -1-yl 2-naphthyl CH, 1,2-Ph CH=CH 2-thienyl 4 2-naphthyl S(O), 1,2-Ph CH=CH phenyl 5 3-methylindol S(0) 2 1,2-Ph CH=CH 2-thienyl 6
-
1 -yl 2-naphthyl S(0) 2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 7 phenyl 3,4-dichloro CH 2 1,2-Ph CH=CH 2-thienyl 8 phenyl 2-naphthyl S(O)2 1,2-Ph CH=CH 2-thienyl 9 2,4-dichloro CH 2 1,2-Ph CH=CH 2-thienyl 10 phenyl 1-naphthyl S(O)2 1,2-Ph CH=CH Ph(F), 11 1-naphthyl S(0) 2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 12 phenyl 2-naphthyl S(O)2 1,2-Ph 1,2-c-propyl 2-thienyl 13 3,4-chloro CH 2 1,2-Ph CH=CH 2-thienyl 14 fluoro phenyl 1-naphthyl CH2 1,2-Ph CH=CH 2-thienyl 15 3,4-dichloro S(0) 2 1,2-Ph CH=CH 2-thienyl 16 phenyl 4-methylthio CH2 1,2-Ph CH=CH 2-thienyl 17 phenyl 4-chlorophenyl CH2 1,2-Ph CH=CH 2-thienyl 18 2-naphthyl S 1,2-Ph CH=CH 2-thienyl 19 2-naphthyl O-CH, 1,2-Ph CH=CH 2-thienyl 20 2-naphthyl S(O) 1,2-Ph CH=CH 2-thienyl 21 1-naphthyl S(O)2 1,2-Ph CH=CH phenyl 22 2-benzofuranyl CH, 1,2-Ph CH=CH 2-thienyl 23 -15- WO 99/47497 PCT/CA99/00212 RlR 2
R
3 -Het A X B R 9 Cpd 3,5-dichloro CH2 1,2-Ph CH=CH 2-thienyl 24 phenyl 1-naphthyl S(0) 2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 25 phenyl 1-naphthyl S(O), 1,2-Ph CH=CH 2-thienyl 26 3-(1,2-(methylene CH2 1,2-Ph CH=CH 2-thienyl 27 dioxy)benzene) 2-naphthyl 0 1,2-Ph CH=CH 2-thienyl 28 RS-2-phenyl CH2 1,2-Ph CH 2 -0 2-thienyl 29 Rs-2-phenyl CH 2 1,2-Ph CH 2
-CH
2 2-thienyl 30 2-naphthyl S(O), 1,2-Ph CH,-0 2-thienyl 31 3-((2-(Qn)vinyl)) CH2 1,2-Ph CH 2 -0 2-thienyl 32 phenyl 2-(6-benzyloxy) CH2 1,2-Ph CH=CH 2-thienyl 33 naphthyl 3-((2-(Qn)vinyl)) SO 1,2-Ph CH 2 -0 2-thienyl 34 phenyl 3-((2-(Qn)vinyl)) -CHOH 1,2-Ph CH 2 -0 2-thienyl 35 phenyl 3-((2-(Qn)vinyl)) S(0)2 1,2-Ph CH 2 -0 phenyl 36 phenyl 3-((2-(Qn)vinyl)) O-CH2 1,2-Ph CH 2 -0 2-thienyl 37 phenyl 3-tolyl-D-3-phenyl O-CH 1,2-Ph CH 2 -0 2-thienyl 38 3-((2-(Qn)vinyl)) CH(OH -1,2-Ph CH 2 -0 phenyl 39 phenyl CH __ 3-((2-(Qn)vinyl)) S 1,2-Ph CH 2 -0 2-thienyl 40 phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph CHR 2 -0 phenyl 41 phenyl 3-((2-(Qn)vinyl)) C=O 1,2-Ph CH20 2-thienyl 42 phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph C(CH 3
)
2 -0 2-thienyl 43 phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph CHR 2 -0 2-thienyl 44 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-thienyl 45 2-(6-benzyloxy) CH2 1,2-Ph CH=CH 2-methoxy-5- 46 naphthyl _ bromophenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3,4-dichloro 47 I _phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-fluoro 48 phenyl -16- WO 99/47497 PCT/CA99/00212 R1R 2
R
3 -Het A X B R 9 Cpd 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-chloro 49 _phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-propyl 50 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2,5-dichloro 51 thienyl 2-naphthyl CH, 1,2-Ph 1,2-c-propyl styryl 52 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3-chloro-4- 53 fluorophenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-methoxy 54 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3-bromo 55 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 56 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 57 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 58 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2,4-difluoro 59 phenyl 2-naphthylCR 1,2-Ph 1,2-c-propyl 4-butyl-phenyl 60 2-naphthyl CH2 1,2-Ph 1,2-c-propyl butyl 61 2-naphthyl CH2 12-Ph 1,2-c-propyl 2,5-dimethoxy 62 phenyl 2-naphthyl CH2 12-Ph 1,2-c-propyl 3-trifluoro 63 methylphenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3,5-difluoro 64 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3,5-dichloro 65 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 66 methyl)ethyl) phenyl 2-naphthyl CH2 12-Ph 1,2-c-propyl 4-(hydroxy 67 methyl)phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3-(hydroxy 68 methyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(methyl 69 sulfonyl)phenyl 2-naphthyl CH2 12-Ph 1,2-c-propyl 3-(methyl 70 _ sulfonyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(propyl 71 1___ _ 1sulfonyl)phenyl 1 -17 - WO 99/47497 PCT/CA99/00212
R
1 R2R 3 -Het A X B R 9 Cpd 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro- 72 methyl)-hydroxy _methyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 73 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 74 methyl) ethyl)phenyl 2-naphthyl CH2 12-Ph 1,2-c-propyl 4-dimethyl 75 aminophenyl 2-naphthyl CH 1,2-Ph 1,2-c-propyl cyclohexyl 76 2-naphthyl CH 1,2-Ph 1,2-c-propyl cyclopentyl 77 2-naphthyl CR 1,2-Ph 1,2-c-prop _ 4-morpholinyl 78 2-naphthyl CR 1,2-Ph l,2-c-propyl 2-naphthyl 79 2-naphthyl CH 1,2-Ph 1,2-c-propyl 2-thiazolyl 80 2-naphthyl CR 1,2-Ph 1,2-c-propyl 1-imidazolyl 81 2-naphthyl CR 1,2-Ph 1,2-c-propyl 2-furanyl 82 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 83 furanyl 2-naphthyl CH 1,2-Ph 1,2-c-propyl 2-pyridinyl 84 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 85 pyridinyl 2-naphthyl CH, 1,2-Ph 1,2-c-propyl 3-indolyl 86 2-naphthyl CR 1,2-Ph 1,2-c-propyl 4-nitrophenyl 87 2-naphthyl CH 1,2-Ph 1,2-c-propyl 4-cyanophenyl 88 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 89 methyl)ethyl) phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(hydroxy 90 methyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(hydroxy 91 methyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 92 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 93 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,4-difluoro 94 phenyl 2-naphthyl S(0) 2 1,2-Ph 1,2-c-propyl 4-(methyl 95 sulfonyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(methyl 96 sulfonyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(propyl 97 sulfonyl)phenyl -18 - WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 9 Cpd 2-naphthy 102 1,2-Ph 1,2-c-propyl 4-butyl-phenyl 98 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 ) 99 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro 100 methyl)-hydroxy methyl)phenyl 2-naphthyl ) 1,2-Ph 1,2-c-propyl 3-bromophenyl 101 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 102 _ phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 103 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-isopropyl 104 _ phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 105 methyl) ethyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-methoxy 106 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-dimethyl 107 aminophenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,4-dichloro 108 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,4-difluoro 109 phenyl 2-naphthyl _j _ 1,2-Ph 1,2-c-propyl 4-fluorophenyl 110 2-naphthyl S 1,2-Ph 1,2-c-propyl cyclohexyl 111 2-naphthyl S(O)2 1,2-Ph 1,2-c-propyl cyclopentyl 112 2-naphthyl S 1,2-Ph 1,2-c-propyl 4-morpholinyl 113 2-naphthyl _ S(__ 1,2-Ph 1,2-c-propyl butyl 114 2-naphthyl S(O)2 1,2-Ph 1,2-c-propyl 4-chlorophenyl 115 2-naphthyl O 1,2-Ph 1,2-c-propy1 4-propylphenyl 116 2-naphthyl _S(L_ 1,2-Ph 1,2-c-propyl 2-naphthyl 117 2-naphthyl S(0)2 1,2-Ph 1,2-c-propyl 2-thiazolyl 118 2-naphthyl jO 1,2-Ph 1,2-c-propy1 1-imidazolyl 119 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 120 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-trifluoro 121 _methylphenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 122 thienyl 2-naphthyl S(O)2 1,2-Ph 1,2-c-propyl 2-furanyl 123 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 124 furanyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-pyridinyl 125 -19- WO 99/47497 PCT/CA99/00212 RlR 2
R
3 -Het A X B R 9 Cpd 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-styryl 126 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,5-difluoro- 127 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,5-dichloro- 128 Sphenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 129 pyridinyl 2-naphthyl S(O), 1,2-Ph 1,2-c-propyl 3-indolyl 130 2-naphthyl S(O), 1,2-Ph 1,2-c-propyl 4-nitrophenyl 131 2-naphthyl SK 1,2-Ph 1,2-c-propl 4-cyanophenyl 132 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-chloro-4- 133 fluorophenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 )- 134 -1-y1 phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-isopropyl 135 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,4-dichloro 136 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,4-difluoro 137 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-fluorophenyl 138 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-chlorophenyl 139 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-propylphenyl 140 -1-y2 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 141 -1-Y1 thienyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-styryl 142 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-chloro-4-fluorc 143 -1-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-methoxy 144 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-bromophenyl 145 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 146 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 147 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 148 -1-y1 phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,4-difluoro 149 -1-yl 1 1 phenyl -20- WO 99/47497 PCT/CA99/00212
R
1 R2R 3 -Het A X B R 9 Cpd 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-butylphenyl 150
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1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl n-butyl 151 -1-y1 3-methylindol CH2 12-Ph 1,2-c-propyl 2,5-dimethoxy 152 -1-yl phenyl 3-methylindol CH2 12-Ph 1,2-c-propyl 3-trifluoro 153 -1-yl methylphenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,5-difluoro 154 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,5-dichloro 155 -1-yl phenyl 3-methylindol CH2 12-Ph 1,2-c-propyl 4-((1-hydroxy-1- 156 -1-y1 methyl)ethyl) phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-(hydroxy 157 -1-y1 methyl)phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-(hydroxy 158 -1-yl methyl)phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-(methyl 159 -1-y1 sulfonyl)phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-(methyl 160 -1-y1 sulfonyl)phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-(propyl 161 -1-yl sulfonyl)phenyl 3-methylindol CH2 12-Ph 1,2-c-propyl 4-((bis-trifluoro 162 -1-y1 methyl)hydroxy methyl)phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 163 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 164 -1-y1 methyl) ethyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-dimethyl 165 -1-yl aminophenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl cyclohexyl 166
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1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl cyclopentyl 167
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1 -y1 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-morpholinyl 168
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1 -y1 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-naphthyl 169
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1 -yl I I I _ -21- WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B Cpd 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-thiazolyl 170 -1-y1 3-methylindol CH2 1,2-Ph 1,2-c-propyl 1-imidazolyl 171 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-furanyl 172 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 173 -1-yl furanyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-pyridinyl 174 -1-yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 175 -1-yl pyridinyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-indolyl 176 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-nitrophenyl 177 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-cyanophenyl 178 -1-y2 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 ) 179 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-isopropyl 180 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3,4-dichloro 181 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1, 2 -c-propyl 3,4-difluoro 182 -1-yl phenyl 3-methylindol SO2 12-Ph 1,2-c-propyl 4-fluorophenyl 183 -1-y2 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-chlorophenyl 184 -1-y2 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-propylphenyl 185
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1 -y 1 3-methylindol SO2 12-Ph 1,2-c-propyl 2,5-dichloro-3- 186 -1-y1 thienyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 2-styryl 187 -1-y2 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-chloro-4- 188 -1-yl fluorophenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-methoxy 189 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3-bromo 190 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 191 -1-y1 I I phenyl -22- WO 99/47497 PCT/CA99/00212 R1R2R 3 -Het A X B R1 9 Cpd 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 192 -1-yl phenyl 3-methylindol S02 1,2-Ph 1,2-c-propyl 2-carbomethoxy 193 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2,4-difluoro 194 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-butylphenyl 195 -1-yl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl n-butyl 196
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1 -yl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 197 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-trifluoromethy -198 -1-yIl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3,5-difluoro 199 -1-yl phenyl 1-(3-methyl) SO 2 1,2-Ph 1,2-c-propyl 3,5-dichloro 200 indolyl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 201 -1-y1 methyl)ethyl) phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(hydroxy 202 -1-y1 methyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-(hydroxy 203 -1-yl methyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(methyl 204 -1-yl sulfonyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-(methyl 205 -1-yl sulfonyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(propyl 206 -1-yl sulfonyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro 207 -1-yl methyl)hydroxy methyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 208 -1-y1 phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 209 -1-yl methyl)ethyl) phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-dimethyl 210 -1-yl aminophenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl cyclohexyl 211
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1 -yl I I I __ -23- WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B Cpd 3-methylindol SO 2 1,2-Ph 1,2-c-propyl cyclopentyl 212 -1-yi 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-morpholinyl 214 -1-ye 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-naphthyl 214 -1-y1 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-thiazolyl 215
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1 -y 1 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 1-imidazolyl 216 -1-ya 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-furanyl 217 -1-y1 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 218 -1-y1 furanyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-pyridinyl 219 -1-y1 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-4-chloro) 220 -1-yl pyridinyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3-indolyl 221 -1-y1 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-nitrophenyl 222 -1-y1 3-methylindol S 2 1,2-Ph 1,2-c-propyl 4-cyanophenyl 223 -1-yl 2-naphthyl CH2 1,2-Ph CH=CH 3,5-di-(CF3) 224 phenyl 2-naphthyl CH2 1,2-Ph CH=CH 4-isopropyl 225 phenyl 2-naphthyl CH 2 1,2-Ph CH=CH 2,3-dichloro 226 phenyl 2-naphthyl
CH
2 1,2-Ph CH=CH 3,4-difluoro 227 phenyl 2-naphthyl CH, 1,2-Ph CH=CH 4-chlorophenyl 228 2-naphthyl CH 1,2-Ph CH=CH 4-fluorophenyl 229 2-naphthyl CH 2 1,2-Ph CH=CH 2,5-dichloro-3- 230 thienyl 2-naphthyl
CH
2 1,2-Ph CH=CH 3-chloro-4-fluorc 231 phenyl 2-naphthyl CH 2 1,2-Ph CH=CH 4-methoxy 232 phenyl 2-naphthyl CH 1,2-Ph CH=CH butyl 233 2-naphthyl CH 2 1,2-Ph CH=CH 3-trifluoro 234 methylphenyl -24- WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 19 Cpd 2-naphthyl CH2 1,2-Ph CH=CH 4-((1-hydroxy-1- 235 methyl)ethyl) phenyl 2-naphthyl CH2 1,2-Ph CH=CH 4-(methyl 236 __________ CH____ _____ CH=sufonyl)phenyl 2-naphthyl CH2 12-Ph CH=CH 4-(benzyloxy) 237 phenyl 2-naphthyl CH, 1,2-Ph CH=CH cyclohexyl 238 2-naphthyl CH 1,2-Ph CH=CH 4-morpholinyl 239 2-naphthyl CH 1,2-Ph CH=CH 2-thiazolyl 240 2-naphthyl CH, 1,2-Ph CH=CH 2-furanyl 241 2-naphthyl CH 1,2-Ph CH=CH 2-pyridinyl 242 2-naphthyl CH 1,2-Ph CH=CH 4-cyanophenyl 243 2-naphthyl S02 1,2-Ph CH=CH 3,5-di-(CF 3 ) 244 phenyl 2-naphthyl S02 1,2-Ph CH=CH 4-isopropyl 245 phenyl 2-naphthyl SO 2 1,2-Ph CH=CH 2,3-dichloro 246 phenyl 2-naphthyl SO 2 1,2-Ph CH=CH 3,4-difluoro 247 ____________ so_ _ __ phenyl 2-naphthyl S 1,2-Ph CH=CH 4-chlorophenyl 248 2-naphthyl so, 1,2-Ph CH=CH 4-fluorophenyl 249 2-naphthyl SO2 1,2-Ph CH=CH 2,5-dichloro-3- 250 thienyl 2-naphthyl SO 2 1,2-Ph CH=CH 3-chloro-4- 251 fluorophenyl 2-naphthyl SO2 1,2-Ph CH=CH 4-methoxy 252 phenyl 2-naphthyl SO2 1,2-Ph CH=CH butyl 253 2-naphthyl SO 2 1,2-Ph CH=CH 3-trifluoro 254 methylphenyl 2-naphthyl SO 2 1,2-Ph CH=CH 4-((1-hydroxy-1- 255 methyl)ethyl) ____ ____ ____ _____ phenyl 2-naphthyl S2 1,2-Ph CH=CH 4-(methyl 256 __________ so L2-Psufonyl)phenyl 2-naphthyl SO2 1,2-Ph CR=C 4-(benzyloxy) 257 phenyl 2-naphthyl SO9 1,2-Ph CH=CH cyclohexyl 258 2-naphthyl so, 1,2-Ph CH=CH 4-morpholinyl 259 2-naphthyl SO, 1,2-Ph CH=CH 2-thiazolyl 260 2-naphthyl SO2 1,2-Ph CH=CH 2-furanyl 261 2-naphthyl SO, 1,2-Ph CH=CH 2-pyridinyl 262 - 25 - WO 99/47497 PCT/CA99/00212 R1R2R3-Het A X B R 9 Cpd 2-naphthyl SO 1,2-Ph CH=CH 4-cyanophenyl 263 2-naphthyl CH2-0 1,2-Ph CH=CH 3,5-di-(CF 3 ) 264 phenyl 2-naphthyl CH2-0 1,2-Ph CH=CH 4-isopropyl 265 phenyl 2-naphthyl CH 2 -0 1,2-Ph CH=CH 2,3-dichloro 266 phenyl 2-naphthyl CH 2 -0 1,2-Ph CH=CH 3,4-difluoro 267 phenyl 2-naphthyl O-CH2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 268 phenyl 2-naphthyl 0-CH2 1,2-Ph CH=CH 4-isopropyl 269 phenyl 2-naphthyl O-CH 2 1,2-Ph CH=CH 2,3-dichloro 270 phenyl 2-naphthyl O-CH 2 1,2-Ph CH=CH 3,4-difluoro 271 phenyl 2-naphthyl S 1,2-Ph CH=CH 3,5-di-(CF 3 ) 272 phenyl 2-naphthyl S 1,2-Ph CH=CH 4-isopropyl 273 phenyl 2-naphthyl S 1,2-Ph CH=CH 2,3-dichloro 274 phenyl 2-naphthyl S 1,2-Ph CH=CH 3,4-difluoro 275 phenyl 2-(6-benzyloxy) SO2 1,2-Ph CH=CH 2-thienyl 276 naphthyl 2-(6-benzyloxy) S 1,2-Ph CH=CH 2-thienyl 277 naphthyl 2-(6-benzyloxy) SO2 1,2-Ph 1,2-c-propyl 2-thienyl 278 naphthyl 2-(6-benzyloxy) S 1,2-Ph 1,2-c-propyl 2-thienyl 279 naphthyl 2-(5-benzyloxy) SO2 1,2-Ph CH=CH 2-thienyl 280 naphthyl 2-(5-benzyloxy) S 1,2-Ph CH=CH 2-thienyl 281 naphthyl 2-(5-benzyloxy) SO2 1,2-Ph 1,2-c-propyl 2-thienyl 282 naphthyl 2-(5-benzyloxy) S 1,2-Ph 1,2-c-propyl 2-thienyl 283 naphthyl 2-(6-(4-trifluoro SO2 1,2-Ph CH=CH 2-thienyl 284 methyl)benzyloxy) naphthyl I I I __ -26- WO 99/47497 PCT/CA99/00212 RlR 2
R
3 -Het A X B R 9 Cpd 2-(6-(4-trifluoro CH2 1,2-Ph CH=CH 2-thienyl 285 methyl)benzyloxy)) naphthyl 2-(6-(4-trifluoro CH2 12-Ph 1,2-c-propyl 2-thienyl 286 methyl)benzyl oxy))naphthyl 2-(6-(4-trifluoro CH2 1,2-Ph 1,2-c-propyl 2-thienyl 287 methyl)benzyl oxy))naphthyl __________ 1-(6-benzyloxy) SO 2 12-Ph CH=CH 2-thienyl 288 naphthyl 1-(6-benzyloxy) C2 1,2-Ph CH=CH 2-thienyl 289 naphthyl naphthyl 2-(6-(3,4-difluoro C2 1,2-Ph CH=CH 2-thienyl 291 benzyloxy)) naphthyl 2-(6-(4-fluoro CH2 1,2-Ph 1,2-c-propyl 2-thienyl 292 benzyloxy)) naphthyl 2-(7-benzyloxy) S2 1,2-Ph C=Cr 2-thienyl 293 naphthyl naphthyl 2-(6-(3,4-difluoro CR 2 1,2-Ph CH=CH 3,4-difluoro 295 benzyloxy)) phenyl naphthyl 2-(6-(4-fluoro CH2 1,2-Ph 1,2-c-propyl 3,4-difluoro 296 benzyloxy)) phenyl naphthyl 2-(7-benzyloxy) SO2 12-Ph CR=CR 3,5-di-(CF 3 ) 297 naphthyl _________phenyl __ 2-(6-(3,4-dfluoro SO2 1,2-Ph C=Cr 3,5-di-(CF 3 ) 298 benzyloxy)) phenyl naphthyl 2-(6-(3,4-difluoro C2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 299 benzyloxy)) phenyl naphthyl 2-(7-benzyloxy) SO2 1,2-Ph 1,2-c-propyl 3,4-difluoro 300 naphthyl phenyl 2-naphthyl CH2 1,2-Ph CH=CH 2-methoxy-5- 301 L_ I_ _bromophenyl -27- WO 99/47497 PCT/CA99/00212
R
1 R2R 3 -Het A X B R 9 Cpd 2-naphthyl CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 302 bromophenyl 2-naphthyl CH2 4-Cl-1,2-Ph CH=CH 2-thienyl 303 2-naphthyl SO 1,2-Ph CH=CH 2-methoxy-5- 304 bromophenyl 2-naphthyl SO2 1,2-Ph CH=CH 2-methoxy-5- 305 bromophenyl 2-naphthyl 0 1,2-Ph CH=CH 2-methoxy-5- 306 bromophenyl 2-(5-benzyloxy) CH2 1,2-Ph CH=CH 2-methoxy-5- 307 naphthyl bromophenyl 2-(5-benzyloxy) SO2 1,2-Ph CH=CH 2-methoxy-5- 308 naphthyl bromophenyl 2-(5-benzyloxy) S 1,2-Ph CH=CH 2-methoxy-5- 309 naphthyl bromophenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 310 bromophenyl 1,2-Ph SO 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 311 bromophenyl 2-naphthyl S 1,2-Ph 1,2-c-propyl 2-methoxy-5- 312 bromophenyl 2-naphthyl CH2-0 1,2-Ph CH=CH 2-methoxy-5- 313 bromophenyl 2-naphthyl S 1,2-Ph CH=CH 2-methoxy-5- 314 bromophenyl 3-methyl SO 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 315 indol-1-yl bromophenyl 3-methyl S 1,2-Ph 1,2-c-propyl 2-methoxy-5- 316 indol-1-yl bromophenyl 3-methyl CH2-0 1,2-Ph CH=CH 2-methoxy-5- 317 indol-1-yl bromophenyl 3-methyl S 1,2-Ph CH=CH 2-methoxy-5- 318 indol-1-yl bromophenyl 3-methyl O-CH 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 319 indol-1-yl bromophenyl 3-methyl SO 1,2-Ph 1,2-c-propyl 2-methoxy-5- 320 indol-1-yl bromophenyl 3-methyl CH 2 -0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 321 indol-1-yl bromophenyl 3-methyl S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 322 indol-1-yl bromophenyl 3-methyl SO 2 4-Cl-1,2-Ph 1,2-c-propyl 2-methoxy-5- 323 indol-1-yl I 1 1 bromophenyl -28- WO 99/47497 PCT/CA99/00212 RlRA 2
R
3 -Het A X B W' 9 Cp 2-(7-fluoro) 02 4- C1-1,2-Ph CH=CH 2-thienyl34 naphthyl ___________ 2-(7-fluoro) 0 4-C1-1,2-Ph CH=CR 2-thienyl 348 naphthyl ___________ 2-(7-fluoro) S 4-C1-1,2-Ph CH=CH 2-thienyl 349 naphthyl _____________ 2-(7-fluoro) CR 2 4-C1-1,2-Ph CR=CH 2-thienyl 350 naphthyl__ _ _ _ __ _ _ _ _ ____ ___ 2-(7-fluoro) CH 2 6-C1-1,2-Ph CH=CH 2-thienyl 351 naphthyl_____________ _ _ _ _ _ _ 2-(7-fluoro) CH 2 4-C1-1,2-Ph 1,2-c-Pr 2-thienyl 352 naphthyl__ _ _ _ __ _ _ _ _ ____ ___ 2-(7-fluoro) CH 2 3-1-1,2-Ph CH=CH 2-thienyl 353 naphthyl __________ 2-(7-fluoro) S0 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 354 naphthyl _____ _____bromophenyl __ 2-(7-fluoro) 0 4-C1-1,2-Ph CH=CH 2-methoxy-5- 355 naphthyl ______________bromophenyl 2-(7-fluoro) S 4-C1-1,2-Ph CH=CH 2-methoxy-5- 356 naphthyl ____ ____ _____bromophenyl 2-naphthyl CR 2 4 ,5-C12- CH=CH 2-methoxy-5- 357 _____1,2-Ph ______bromophenyl 2-(7-fluoro) CR 2 6-C1-1,2-Ph CH=CH 2-methoxy-5- 358 naphthyl ____ ____ _____bromophenyl __ 2-(7-fluoro) CR 2 4-C1-1,2-Ph 1,2-c-Pr 2-methoxy-5- 359 naphthyl ______________bromophenyl 2-(7-fluoro) CR 2 3-C1-1,2-Ph CH=CH 2-methoxy-5- 360 naphthyl ____ ____ _____bromophenyl 2-(7-fluoro) S0 2 4-C1-1,2-Ph CH=CH 2-trifluoro 361 naphthyl methoxy-5 ______________ ______ ________ _________ chiorophenyl _ _ 2-(7-fluoro) 0 4-C1-1,2-Ph CR=CR 2-trifluoro 362 naphthyl methoxy-5 _______________ _______chiorophenyl __ 2-(7-fluoro) S 4-C1-1,2-Ph CR=CR 2-trifluoro 363 naphthyl methoxy-5 _______________chlorophenyl 2-(7-fluoro) CR 2 4-C1-1,2-Ph CR=CR 2-trifluoro 364 naphthyl methoxy-5 ______________ _____ ________ _________ chiorophenyl _ _ 2-(7-fluoro) CR 2 6-C1-1,2-Ph CR=CR 2-trifluoro 365 naphthyl methoxy-5 ______________ _____ ________ _________ chiorophenyl -29- WO 9L9/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 1 9 2-(7-fluoro) CH 2 4-C1-1,2-Ph 1,2-c-Pr 2-trifluoro 366 naphthyl methoxy-5 ________ _________chlorophenyl 2-(7-fluoro) CH 2 3-C1-1,2-Ph CH=CH 2-trifluoro 367 naphthyl methoxy-5 __________chlorophenyl 2-(7-fluoro) S0 2 4-C1-1,2-Ph CH=CH 2-thienyl 368 naphthyl __________ 2-(7-fluoro) 0 4-C1-1,2-Ph CH=CH 2-thienyl 369 naphthyl____ __ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(7-fluoro) S 4-C1-1,2-Ph CH=CH 2-thienyl 370 naphthyl____ __ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(7-fluoro) CH 2 4-C1-1,2-Ph CH=CH 2-thienyl 371 ,naplithyl _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2-(7-fluoro) CH 2 6-CI-1,2-Ph CH=CH 2-thienyl 372 naphthyl____ __ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(7-fluoro) CH 2 4-C1-1,2-Ph 1,2-c-Pr 2-thienyl 373 naphthyl____ __ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(7-fluoro) CR 2 3-C1-1,2-Ph CH=CH 2-thienyl 374 naphthyl__ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ 2-(7-fluoro) 502 4-C1-1,2-Ph CH=CH 2-methoxy-5- 375 naphthyl ______________bromophenyl 2-(6-fluoro) 0 4-C1-1,2-Ph CH=CH 2-methoxy-5- 376 naphthyl ______________bromophenyl 2-(6-fluoro) S 4-CJ-1,2-Ph CH=CH 2-methoxy-5- 377 naphhyl ____ _______ ________bromophenyl 2-(6-fluoro) CR 2 4- C1-1,2-Ph CH=CH 2-methoxy-5- 378 naplithyl _________bromophenyl 2-(6-fluoro) CR 2 6-C1-1,2-Ph CH=CH 2-methoxy-5- 379 naphthyl ______________bromophenyl 2-(6-fluoro) CH 2 4-C1-1,2-Ph 1,2-c-Pr 2-methoxy-5- 380 naphthyl ____ ____ _____bromophenyl 2-(6-fluoro) CR 2 3- C1-1,2-Ph CH=CH 2-methoxy-5- 381 naphthyl ______________bromophenyl 2-(7-chloro) S0 2 4-C1-1,2-Ph CH=CH 2-thienyl38 naphthyl _________ 2-(7-chloro) 0 4-C1-1,2-Ph CH=CH 2-thienyl 383 naphthyl _____ 2-(7-chloro) S 4-C1-1,2-Ph CR=CR 2-thienyl 384 naphthyl__ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ 2-(7-chloro) CR 2 4-C1-1,2-Ph CR=CR 2-thienyl 385 naphthyl _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2-(7-chloro) CR 2 6-C1-1,2-Ph CH=CH 2-thienyl 386 naphthyl ___ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ -30- WO 99/47497 PCT/CA99/0021 2 Rlp,2R 3 -Het A X B W' 9 Cp 2-(7-chloro) CR 2 4-C 1-1,2-Ph 1,2-c-Pr 2-thienyl 387 naphthyl____ __ _ _ _ ________ 2-(7-chloro) CR 2 3-C 1-1,2-Ph CH=CH 2-thienyl 388 naphthyl____________ 2-(6,7-difluoro) SO 2 4-C1-1,2-Ph CR=CH 2-thienyl 389 naphthyl _________ 2-(6,7-difluoro) 0 4-C1-1,2-Ph CH=CH 2-thienyl 390 naphthyl ___________ 2-(6,7-difluoro) S 4-C1-1,2-Ph CH=CH 2-thienyl 391 naphthyl______________ 2-(6,7-difluoro) CR 2 4-C1-1,2-Ph CH=CH 2-thienyl 392 naphthyl _______ 2-(6,7-difluoro) CR 2 6-C1-1,2-Ph CR=CH 2-thienyl 393 naphthyl ____________ 2-(6,7-difluoro) CR 2 4-C1-1,2-Ph 1,2-c-Pr 2-thienyl 394 naphthyl_____________ 2-(6,7-difluoro) CR 2 3-C1-1,2-Ph CH=CH 2-thienyl 395 naphthyl__ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(6,7-difluoro) S0 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 396 naphthyl _____ _____bromophenyl 2-(6,7-difluoro) 0 4-C1-1,2-Ph CR=CR 2-methoxy-5- 397 naphthyl ______________bromophenyl __ 2-(6,7-difluoro) S 4-C1-1,2-Ph CR=CH 2-methoxy-5- 398 naphthyl ____ ____ _____bromophenyl __ 2-(6,7-difluoro) CR 2 4-C1-1,2-Ph CR=CR 2-methoxy-5- 399 naphthyl ____ ____ _____bromophenyl 2-(6,7-difluoro) CR 2 6-C1-1,2-Ph CR=CR 2-methoxy-5- 400J naphthyl ____ ____ _____bromophenyl __ 2-(6,7-difluoro) CR 2 4- Cl-1,2-Ph 1,2-c-Pr 2-methoxy-5- 401 naphthyl ____ ____ _____bromophenyl 2-(6,7-difluoro) CR 2 3-C1-1,2-Ph CR=CR 2-methoxy-5- 402 naphthyl ______________bromophenyl 2-(5,7-difluoro) CR 2 4-C1-1,2-Ph CR=CR 2-methoxy-5- 403 naphthyl ______________bromophenyl __ 2-(5,7-difluoro) S 4-C1-1,2-Ph CR=CR 2-methoxy-5- 404 naphthyl _________bromophenyl __ 2-(5,7-difluoro) 0 4-C1-1,2-Ph CR=CR 2-methoxy-5- 405 naphthyl ____ _____bromophenyl __ 2-(5,7-difluoro) S0 2 4-C1-1,2-Ph CR=CR 2-methoxy-5- 406 naphthyl ___ ___________bromophenyl 2-(6-fluoro) S0 2 4-C1-1,2-Ph CR=CR 2-methoxy-5- 407 quinolinyl ____ ____ _____bromophenyl 2-(6-fluoro) S 4-C1-1,2-Ph CR=CR 2-methoxy-5- 408 quinolinyl I___ I____ I_____ bromophenyl I_ -31- WO 99/47497 PCT/CA99/00212
R
1 R2R 3 -Het A X B R 9 pd 2-(6-fluoro) CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 409 quinolinyl bromophenyl 2-(6-fluoro) CH2 1,2-Ph CH=CH 2-methoxy-5- 410 quinolinyl bromophenyl 2-(6-fluoro) 0 4-C-1,2-Ph CH=CH 2-methoxy-5- 411 quinolinyl bromophenyl 2-(6-fluoro) CH 2 4-C-1,2-Ph 1,2-c-Pr 2-methoxy-5- 412 quinolinyl bromophenyl 2-(5,7-difluoro)- SO 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 413 quinolinyl bromophenyl 2-(5,7-difluoro)- S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 414 quinolinyl bromophenyl 2-(5,7-difluoro)- CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 415 quinolinyl bromophenyl 2-(5,7-difluoro)- CH2 1,2-Ph CH=CH 2-methoxy-5- 416 quinolinyl bromophenyl 2-(5,7-difluoro)- 0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 417 quinolinyl bromophenyl 2-(5,7-difluoro)- CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-methoxy-5- 418 quinolinyl bromophenyl 3,4-dichloro SO 2 4-C-1,2-Ph CH=CH 2-methoxy-5- 419 phenyl bromophenyl 3,4-dichloro S 4-C-1,2-Ph CH=CH 2-methoxy-5- 420 phenyl bromophenyl 3,4-dichloro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 421 phenyl bromophenyl 3,4-dichloro CH2 1,2-Ph CH=CH 2-methoxy-5- 422 phenyl bromophenyl 3,4-dichloro 0 4-C-1,2-Ph CH=CH 2-methoxy-5- 423 phenyl bromophenyl 3,4-dichloro CH 2 4-C-1,2-Ph 1,2-c-Pr 2-methoxy-5- 424 phenyl bromophenyl 3,4-dichloro CH 2 5-Cl-1,2-Ph CH=CH 2-methoxy-5- 425 phenyl bromophenyl 4-chloro S02 4-C-1,2-Ph CH=CH 2-methoxy-5- 426 phenyl bromophenyl 4-chloro S 4-C-1,2-Ph CH=CH 2-methoxy-5- 427 phenyl bromophenyl 4-chloro CH 2 4-C-1,2-Ph CH=CH 2-methoxy-5- 428 phenyl bromophenyl 4-chloro CH2 1,2-Ph CH=CH 2-methoxy-5- 429 phenyl bromophenyl 4-chloro 0 4-C-1,2-Ph CH=CH 2-methoxy-5- 430 phenyl I _bromophenyl -32- WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 9 Cpd 4-chloro CH 2 4-C-1,2-Ph 1,2-c-Pr 2-methoxy-5- 431 phenyl bromophenyl 4-chloro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 432 phenyl bromophenyl 3,4-dichloro SO 2 4-Cl-1,2-Ph CH=CH 2-thienyl 433 phenyl 3,4-dichloro S 4-Cl-1,2-Ph CH=CH 2-thienyl 434 phenyl 3,4-dichloro CH 2 4-Cl-1,2-Ph CH=CH 2-thienyl 435 phenyl 3,4-dichloro CH 2 1,2-Ph CH=CH 2-thienyl 436 phenyl 3,4-dichloro 0 4-Cl-1,2-Ph CH=CH 2-thienyl 437 phenyl 3,4-dichloro CH 2 4-C-1,2-Ph CH=CH 2-thienyl 438 phenyl 3,4-dichloro CH 2 5-Cl-1,2-Ph CH=CH 2-thienyl 439 phenyl 4-chloro S02 4-Cl-1,2-Ph CH=CH 2-thienyl 440 phenyl 4-chloro S 4-Cl-1,2-Ph CH=CH 2-thienyl 441 phenyl 4-chloro CH 2 4-Cl-1,2-Ph CH=CH 2-thienyl 442 phenyl 4-chloro CH 2 1,2-Ph CH=CH 2-thienyl 443 phenyl 1-(5-chloro) CH 2 3,2-Pyr CH=CH 2,4-(Me)2- 444 indolyl thiazol-5-yl 1-(5-chloro) CH 2 3,2-Pyr CH=CH 2-thienyl 445 indolyl 1-(6-(4-chloro) CH 2 4-F-1,2-Ph CH=CH 3-chloro-4- 446 phenyl)indolyl fluorophenyl 2-(6-difluoro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 447 methoxy) bromophenyl naphthyl 2-naphthyl CH 2 4-MeO- CH=CH 2-methoxy-5- 448 1,2-Ph bromophenyl 2-naphthyl CH 2 5-Cl-1,2-Ph CH=CH 2-methoxy-5- 449 bromophenyl 2-(6-chloro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 450 naphthyl) bromophenyl 1-(5-phenyl CH 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 451 methoxy) bromophenyl indolyl -33- WO 99/47497 PCT/CA99/00212
R
1 R2R 3 -Het A X B W' 9 Cp 2-(benzoib] CR 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 452 thiophenyl _____bromophenyl __ 5-(1-benzyl) CH2 4-F-1,2-Ph CH=CH 2-methoxy-5- 453 indoly _____romophenyl __ 1-(6-4-chloro) CR 2 4-F-1,2-Ph ICH=CH ,2-methoxy-5- 454 phenyl)indolyl I________ _____bromophenyl 5 Table II
R
1 R 2 R 3 -HET 0 A X-B OH 1-b (Compounds 324-346 and 455-542) RlR2R$-Het A X B Cpd 2-naphthyl S(O), 1,2-phenyl CH=CR 324 2-naphthyl S 1,2-phenyl CH=CH 325 4-methylthiophenyl CH, 1,2-phenyl CH=CH 326 3-methylindol-1-yl CR 2 -1,2-phenyl CH=CH 327 3-chloro-4-fliuorophenyl CR 9 1,2-phenyl CR=CH 328 4-chlorophenyl CR 9 1,2-phenyl CR=CH 329 2-naphthyl CH, 1,2-phenyl CH=CH 330 2-naphthyl S(0)2 1,2-phenyl 1,2-c-propyl 331 2-naphthyl S(0), 1,2-phenyl CH,-CH, 332 2-.naphthyl S 1,2-phenyl CH=CH 333 3,4-dichiorophenyl S(O), 1,2-phenyl CH2-CH, 334 3,4-dichlorophenyl CR, 1,2-phenyl CH=CR 335 2-(6-benzyloxy)naphthyl CR, 12pnyl CR=CR 336 2-(6-benzyloxy)naphthyl CR,. 1,2-phenyl 1,2-c-propyl 337 2-(6-benzyloxy)naphthyl SO2 1,2-phenyl 1,2-c-propyl 338 2-(6-benzyloxy)naphthyl CH9-O 1,2-phenyl 1,2-c-propyl 339 2-(6-benzyloxy)naphthyl 0-CR, 1,2-phenyl 1,2-c-propyl 340 2-(6-benzyloxy)naphthyl ISO, 1,2-phenyl ICR=CR 341 2-(6-benzyloxy)naphthyl ICR,-O 11,2-phenyl CR=CR 3421 -34- WO 99/47497 PCT/CA99/00212 RlR 2
R
3 -Het A X B Cpd 2-(6-benzyloxy)naphthyl 0-CH 1,2-phenyl CH=CH 343 2-(6-benzyloxy)naphthyl S 1,2-phenyl CH=CH 344 2-(7-benzyloxy)naphthyl SO, 1,2-phenyl CH=CH 345 2-(6-(4-trifluoromethyl) CH 2 1,2-phenyl CH=CH 346 benzyloxy))naphthyl 2-(6-fluoro)naphthyl SO 2 4-Cl-1,2-Ph CH=CH 455 2-(6-fluoro)naphthyl S 4-Cl-1,2-Ph CH=CH 456 2-(6-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 457 2-(6-fluoro)naphthyl CH, 1,2-Ph CH=CH 458 2-(6-fluoro)naphthyl 0 4-Cl-1,2-Ph CH=CH 459 2-(6-fluoro)naphthyl CH, 4-Cl-1,2-Ph 1,2-c-Pr 460 2-(7-fluoro)naphthyl SO2 4-Cl-1,2-Ph CH=CH 461 2-(7-fluoro)naphthyl S 4-Cl-1,2-Ph CH=CH 462 2-(7-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 463 2-(7-fluoro)naphthyl CH, 1,2--Ph CH=CH 464 2-(7-fluoro)naphthyl 0 4-Cl-1,2-Ph CH=CH 465 2-(7-fluoro)naphthyl CH, 4-Cl-1,2-Ph 1,2-c-Pr 466 2-(6-chloro)naphthyl SO, 4-Cl-1,2-Ph CH=CH 467 2-(6-chloro)naphthyl S 4-Cl-1,2-Ph CH=CH 468 2-(6-chloro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 469 2-(6-chloro)naphthyl CH, 1,2-Ph CH=CH 470 2-(6-chloro)naphthyl 0 4-Cl-1,2-Ph CH=CH 471 2-(6-chloro)naphthyl CH, 4-Cl-1,2-Ph 1,2-c-Pr 472 2-(7-chloro)naphthyl SO 2 4-Cl-1,2-Ph CH=CH 473 2-(7-chloro)naphthyl S 4-Cl-1,2-Ph CH=CH 474 2-(7-chloro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 475 2-(7-chloro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 476 2-(7-chloro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 477 2-(7-chloro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 478 2-(6,7-difluoro)naphthyl SO, 4-Cl-1,2-Ph CH=CH 479 2-(6,7-difluoro)naphthyl S 4-Cl-1,2-Ph CH=CH 480 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 481 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 482 2-(6,7-difluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 483 2-(6,7-difluoro)naphthyl CH, 4-Cl-1,2-Ph 1,2-c-Pr 484 2-(6,7-difluoro)naphthyl CH 9 4-Cl-1,2-Ph CH=CH 485 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 486 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 487 2-(6,7-difluoro)naphthyl CH, 1,2-Ph CH=CH 488 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 489 2-(6,7-difluoro)naphthyl CH, 4-Cl-1,2-Ph 1,2-c-Pr 490 3-methyl-5-fluoro SO2 4-Cl-1,2-Ph CH=CH 491 indol-1-yl I I 1 -35- WO 9-9/47497 PCT/CA99/00212 RlR 2
R
3 -Het A X B Cpd 3-methyl-5-fluoro S 4-Cl-1,2-Ph CH=CH 492 indol-1-yl 3-methyl-5-fluoro CH 2 4-Cl-1,2-Ph CH=CH 493 indol-1-yl 3-methyl-5-fluoro CH 2 1,2-Ph CH=CH 494 indol-1-yl 3-methyl-5-fluoro CH 2 4-Cl-1,2-Ph CH=CH 495 indol-1-yl 3-methyl-5-fluoro CH 2 4-Cl-1,2-Ph CH=CH 496 indol-1-yl 2-(6-fluoro)quinolinyl SO 2 4-Cl-1,2-Ph CH=CH 497 2-(6-fluoro)quinolinyl S 4-Cl-1,2-Ph CH=CH 498 2-(6-fluoro)quinolinyl CH, 4-Cl-1,2-Ph CH=CH 499 2-(6-fluoro)quinolinyl CH, 4-Cl-1,2-Ph CH=CH 500 2-(6-fluoro)quinolinyl 0 4-Cl-1,2-Ph CH=CH 501 2-(6-fluoro)quinolinyl CH2 4-Cl-1,2-Ph CH=CH 502 2-(6-difluoromethoxy)- S02 4-Cl-1,2-Ph CH=CH 503 naphthyl 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 504 naphthyl 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 505 naphthyl 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 506 naphthyl 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 507 naphthyl 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 508 naphthyl 2-(7-difluoromethoxy)- S02 4-Cl-1,2-Ph CH=CH 509 naphthyl 2-(7-difluoromethoxy)- S 4-Cl-1,2-Ph CH=CH 510 naphthyl 2-(7-difluoromethoxy)- CH 2 4-Cl-1,2-Ph CH=CH 511 naphthyl 2-(7-difluoromethoxy)- CH 2 4-Cl-1,2-Ph CH=CH 512 naphthyl 2-(7-difluoromethoxy)- 0 4-Cl-1,2-Ph CH=CH 513 aphthyl 2-(7-difluoromethoxy)- CH 2 4-Cl-1,2-Ph CH=CH 514 naphthyl 2-(6-methoxy)naphthyl SO, 4-Cl-1,2-Ph CH=CH 515 2-(6-methoxy)naphthyl S 4-Cl-1,2-Ph CH=CH 516 2-(6-methoxy)naphthyl CH2 4-Cl-1,2-Ph CH=CH 517 2-(6-methoxy)naphthyl CH, 4-Cl-1,2-Ph CH=CH 518 -36- WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B Cpd 2-(6-methoxy)naphthyl 0 4-Cl-1,2-Ph CH=CH 519 2-(6-methoxy)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 520 2-(6-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 521 2-(6-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 522 2-(6-fluoro)naphthyl CH 9 4-Cl-1,2-Ph CH=CH 523 2-(6-fluoro)naphthyl CH2 4-Cl-1,2-Ph CH=CH 524 2-(6-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 525 2-(6-fluoro)naphthyl CH 9 4-Cl-1,2-Ph CH=CH 526 2-(7-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 527 2-(7-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 528 2-(7-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 529 2-(7-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 530 2-(7-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 531 2-(7-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 532 2-naphthyl CH 2 4,5-Cl2-1,2-Ph CH=CH 533 2-naphthyl CH 4-Cl-1,2-Ph CH=CH 534 3,4-dichlorophenyl CH 2 4-Cl-1,2-Ph CH=CH 535 2-naphthyl CH, 4-Cl-1,2-Ph CH=CH 536 4-chlorophenyl CH, 4-Cl-1,2-Ph CH=CH 537 1-(5-phenylmethoxy) CH 2 4-F-1,2-Ph CH=CH 538 indolyl 2-(benzo [b] thiophenyl) CH, 4-F-1,2-Ph CH=CH 539 5-(1-benzyl)indolyl CH, 4-F-1,2-Ph CH=CH 540 1-(6-(4-chloro)phenyl) CH 2 4-F-1,2-Ph CH=CH 541 indolyl 1-(5-chloro)indolyl CH 2 3,2-Pyr CH=CH 542 5 Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, 10 enantiomerically pure forms and pharmaceutically acceptable salts thereof. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. 15 The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a -37 - WO 99/47497 PCT/CA99/00212 5 pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, 10 ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted 15 amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2 diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, 20 glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts 25 may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, 30 pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. It will be understood that in the discussion of methods of 35 treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts. The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature and the -38 - WO 99/47497 PCT/CA99/00212 5 severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 10 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary 15 depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the 20 total composition. Dosage unit forms will generally contain from about 1 mg to about 2 g of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg. For the treatment of any of the prostanoid mediated diseases compound I may be administered orally, topically, parenterally, by 25 inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded 30 animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, solutions, aqueous or oily suspensions, dispersible 35 powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents -39- WO 99/47497 PCT/CA99/00212 5 selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. 10 These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, 15 stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be 20 coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or 25 kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active material in 30 admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally 35 occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or -40- WO 99/47497 PCT/CA99/00212 5 condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more 10 preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, 15 sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an 20 anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting 25 agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oily phase may be a 30 vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation 35 products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents. -41- WO 99/47497 PCT/CA99/00212 5 Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous 10 suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a 15 solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this 20 purpose any bland fixed oil may be employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Compound I may also be administered in the form of suppositories for rectal administration of the drug. These compositions 25 can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, gels, solutions or 30 suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient. 35 The ability of the compounds of Formula I to interact with prostaglandin receptors makes them useful for treating, preventing or reversing undesirable symptoms caused by prostaglandins in a mammalian, especially human subject. This mimicking or antagonism -42- WO 99/47497 PCT/CA99/00212 5 of the actions of prostaglandins indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent or ameliorate prostaglandin mediated diseases and conditions in mammals and especially in humans: Pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated 10 with influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, 15 burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures as well as immune and autoimmune diseases. In addition, such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer. Compound I may also be 20 of use in the treatment and/or prevention prostaglandin-mediated proliferation disorders such as may occur in diabetic retinopathy and tumor angiogenesis. Compound I will also inhibit prostanoid-induced smooth muscle contraction by antagonizing contractile prostanoids or mimicking relaxing prostanoids and hence may be use in the treatment 25 of dysmenorrhea, premature labor, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, the treatment of glaucoma, for the prevention of bone loss (treatment of osteoporosis) and for the promotion of bone formation (treatment of fractures) and other bone diseases such as Paget's disease. 30 By virtue of its prostanoid or prostanoid antagonist activity, compound I will prove useful as an alternative to NSAID'S particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent 35 history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; thrombosis, occlusive vascular diseases; those prior to surgery or taking anti-coagulants. Compound I -43 - WO 99/47497 PCT/CA99/00212 5 will also be useful as a cytoprotective agent for patients under chemotherapy. Compound of Formula I, will be useful as a partial or complete substitute for conventional antiinflammatory or analgesic compounds in preparations wherein they are presently co-administered 10 with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating prostaglandin
E
2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of Formula I as defined above and one or more ingredients such as another pain reliever 15 including acetaminophen or phenacetin; a COX-2 selective NSAID; a conventional NSAID; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, 20 propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; another prostaglandin ligand including misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; a diuretic; a sedating or non-sedating antihistamine. In addition, the invention 25 encompasses a method of treating prostaglandin E 2 mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effective amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above. 30 Compounds of the present invention can be prepared according to the following methods. Temperatures are in degrees Celsius. Boronic acids and esters can be prepared from the corresponding halide according to literature procedure and reference 35 cited therein (Charette, A.B.; Giroux, A. J. Org. Chem. 1996, 61, 8718; Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508; Miyaura, N.; Suzuki, A. Chem. Rev, 1995, 95, 2457; Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62, 6458; Watanabe, T. -44- WO 99/47497 PCT/CA99/00212 5 Miyaura, N.; Suzuki, A. Synlett, 1992, 207; Maddaford, S.; Keay, B.A. J. Org. Chem. 1994, 59, 6501; Cristofoli, W.A.; Keay, B.A. Tetrahedron Lett. 1991, 32, 5881; Passafaro, M.S.; Keay, B.A. . Tetrahedron Lett. 1996, 37, 429; Serafin, B.; Makosza, M. Tetrahedron, 1963, 19, 821). In some cases, the triflate, the tin or the zinc derivatives may be used instead of the 10 boronic acid. Method A Cinnamic ester 1 is treated with a brominating agent such as NBS in a refluxing inert solvent such as CC1 4 , with the use of an 15 initiator like benzoyl peroxide or light. The resulting benzylic bromide is reacted in a Suzuki coupling reaction with the appropriate boronic acid or ester, a catalyst such as tetrakis(triphenylphosphine) palladium and cesium fluoride or Na2CO3 or a base in an inert refluxing solvent such as DME at 80-90' C. The new cinnamic ester 3 is hydrolyzed with aqueous 20 sodium hydroxide to afford the acid 4 that is converted to the cinnamic sulfonamide 5 with a coupling reagent such as DCC or DCI in CH 2 C1 2 at r.t. -45- WO 99/47497 PCT/CA99/00212 5 Method B Cinnamic ester 2 is treated with an aryl or heteroaryl mercaptan, alcohol or amine, and with a base such as a hydride or an amine in benzene or THF at 0-23" C. The resulting cinnamic ester 6 is converted to 7 according to Method A. 10 If W= sulfur, it is oxidized to the sulfoxide or sulfone 8 with hydrogen peroxide, m-CPBA or other peracetic acid. The cinnamic ester 8 is converted to 9 according to Method A. Method C 15 The aldehyde 11 is prepared by an addition-elimination of a mercapto, hydroxy or amino aryl or heteroaryl with a base such as
K
2
CO
3 in refluxing CHC1 3 . If needed a higher boiling point solvent can be used. This type of rection can also be performed with CuO in DMF. An Emmons-Horner type reaction (or Wittig) in toluene at r.t. followed 20 by Method A (or oxidation as described in Method B) results in the cinnamic sulfonamide 13. Method D Acetal 14 that came from an acetalization from a suitably 25 substituted bromo benzaldehyde is converted to the Grignard reagent with magnesium in an etheral solvent at reflux and quenched with an aryl or heteroaryl ketone. The alcohol 16 is reacted with an halide and a base (or protected as the o-nitrobenzyl, and removed at the end of the sequence) to furnish the compound 17. Deprotection of the acetal under 30 standard conditions followed by Method C gives 18. Method E Alcohol 16 is converted to an acetate with acetyl chloride (or acetic anhydride and an amine base) and coupled with a Grignard 35 reagent and a copper salt at low temperature. The alcohol 16 could also be converted to the bromide and treated in a similar way to yield 20. Alternatively the tetrametyl acetal (R= methyl) version of alcohol 16 can be treated with TiCl 4 /Me 2 Zn (or R 7 2 Zn) at -30 "C. Compound 20 is then -46- WO 99/47497 PCT/CA99/00212 5 converted to the cinnamic sulfonamide 21 according to Method D. Also, 22 can be treated with Al(R 7
)
3 in toluene at 80 "C for 24h and 23 converted to the aldehyde with n-BuLi/DMF followed by an Emmons-Horner reaction and Method A to yield compound 21. 10 Method F A suitably substituted bromo toluene 24 is treated with n Buli at low temperature and quenched with an aryl or heteroaryl aldehyde. The resulting alcohol is oxidized to the ketone with PDC, PCC, MnO 2 or other typical oxidizing agent. The carbonyl is treated with SF 4 , 15 MoF 6
-BF
3 (or converted to a thioacetal and treated with nitrosonium BF 4 pyridiniumeHF) to yield the difluoride. Benzylic bromination with NBS followed by oxidation with N-methylmorpholine N-oxide at 100 "C in dioxane for 4 h, yielded compound 25 that is converted to cinnamic sulfonamide 26 with Method C. 20 Method G The appropriately substituted methyl bromo(or triflate) benzoate 27 is converted to compound 28 by a Suzuki coupling reaction followed by hydrogenation. A Stille coupling reaction could also be used. 25 Benzylic bromination or benzylic oxidation followed by treatment with a brominating agent such as CBr/triphenylphosphine gives compound 29 which can be treated with a boronic acid, or a tin compound (Stille) to furnish compound 30. Reduction of the ester with DIBAL, oxidation with MnO 2 and Method C gives compound 31. 30 Method H Compound 29 (one R 7 = H) is treated with triphenyl phosphine to give the salt and, with a base such as LDA, is converted to compound 32 with the aryl or heteroaryl ketone. The halide 29 can also 35 be converted the Grignard reagent and added to the ketone. Dehydration under acidic conditions results in compound 32. Reduction of the double bond under standard conditions, followed by Methods G and C gives compound 33. From compound 32, cyclopropanation with -47 - WO 99/47497 PCT/CA99/00212 5 diazomethane and palladium (0) followed by Methods G, C and A gives compound 34. -48- WO 99/47497 PCT/CA99/00212 5 Method I The (heterocyclic) vinylic bromide 35 is reacted in a Suzuki coupling reaction with an aryl or hetero aryl boronic acid and converted to a new borane by 9-BBN addition followed by a second Suzuki reaction with compound 14. Compound 37 thus formed is reduced by 10 hydrogenolysis ( Hjmetal or diimide) and deprotection followed by Method C gives cinnamic sulfonamide 39. Method J Ketone 40 which comes from oxidation of the corresponding 15 alcohol is reacted with a phosphonium salt or phosphono ester with a base such as LDA to give the cinnamic ester 41. Method A yields 42 and reduction of the double bond by the previously mentioned method gives the acyl sulfonamide 43. 20 Method K Cinnamic ester 3 is reduced to 44 by the previously mentioned method. a Alkylation with a base such as LDA followed by an alkylating agent results in 45 after conversion to the acyl sulfonamide. 25 Method L Cinnamic ester 3 is reduced to 46 with DIBAL and the double bond converted to a cyclopropane by a Simmons-Smith reaction, or similar reactions recently described in the literature. Compound 47 is then oxidized and the cinnamic sulfonamide 48 is prepared according to 30 Method A. Method M Ester 49 which can come from the homologation of the appropriately substituted methyl ortho-toluate, is treated with a base and 35 with an alkylating agent to furnish compound 50. Benzylic bromination and Suzuki coupling gives an intermediate ester. Homologation according to J. Amer. Chem. Soc.; 1985, 1429; J. Org. Chem. 1992, 7194, -49 - WO 99/47497 PCT/CA99/00212 5 followed by alkylation with a base such as LDA and an alkylating agent furnishes acylsulfonamide 51 by Method A. Compound 50 can also be converted to the benzylic bromide and to compound 52 by Method A. 10 Method N Suitably substituted compound 53 is treated with a boronic acid to give compound 54 which is reduced with LDA to the alcohol 55. Treatment with phosgene followed with the appropriate sulfonamide gives compound 56. This can also be prepared by mixing phosgene and 15 the sulfonamide at 140 0 C to generate the isocyanate. Compound 54 is treated with a Grignard reagent to give the corresponding alcohol and as previously described, converted to compound 57. 20 Method 0 Ester 58 is treated with Lawesson's reagent, DAST and light to give the benzylic alcohol 59. The procedure according to Method N yields compound 60. 25 Method P Compound 59 is brominated as described earlier (or iodinated) and reacted in a SN 2 type reaction with an ester and a base such as LDA to furnish ester 61. Method A gives the acylsulfonamide 62. 30 Method Q Compound 55 is treated with NH 3 /Ph 3 P/DEAD (or treated with CBr 4 /Ph 3 P and the bromide converted to the amine 63 with ammonia). Treatment with phosgene followed by sulfonamide yields 64, 35 treatment of which with a base and an alkyl or benzylic halide gives compounds 65. Method R -50 - WO 99/47497 PCT/CA99/00212 5 Aldehyde 10 is treated with a silylated source of hydroxyl or thiol at 80-130 "C, and the silyl group removed by fluoride treatment. Compound 66 is then treated with an aryl or heteroaryl methylene bromide with a base such as a tertiary amine in CHC1 3 or benzene to yield aldehyde 67. Emmons-Horner (or Wittig reaction) with LDA 10 results in compound 68 via Method A. Method S In the case of an amine an alternative to method R can be used. A suitably substituted nitro aldehyde 69 is converted to compound 15 70 as described earlier and the nitro group reduced with standard methods. Mono-alkylation followed by displacement with an aryl or heteroaryl methylene bromide and processing by Method A yields cinnamic sulfonamide 71. 20 Method T A suitably substituted bromo toluene 24 is converted to the anion in an etheral solvent at low temperature and trapped with an aldehyde of an aryl or heteroaryl. The resulting alcohol is oxidized with MnO 2 , Jones' reagent, PDC, PCC or any other oxidant. Benzylic 25 bromination followed by oxidation with N-methyl morpholine N-oxide, yields a ketoaldehyde. Emmons-Horner and Method A gives the cinnamic sulfonamides 72. Generic structures 4, 5, 7, 9, 13, 18, 21, 26, 31, 33, 34, 39, 42, 30 43, 45, 48, 51, 52, 56, 57, 60, 62, 64, 65, 68, 71 and 72 are representative of the compounds of the present invention. It is also noted that where the chemistry allows in the generic schemes, alternate embodiments of -A-, such as heteroaryl groups, can be substituted for phenyl in the schemes. -51- WO 99/47497 PCT/CA99/00212 Method A 0 ~ Br0 14 OMe NBS OMe R R2 R15 R15 2 HET
HET-B(OH)
2 R14 OMe Hydrolysis Pd(O)IOe R15 3 HET O HET R14 OH H2NSO2R R4- NHSO 2
R
19 DCI R 5 R 4 R15 5 -52- WO 99/47497 PCT/CA99/00212 Method B W-HET Base Method A 2 +HW-HET ------ OMe R 15 6 [Ox] when W sulfur W-HET S(O)n-HE-T 0 R14- NHSO 2
R
1 9 OMe R15 7 R 15 (O)n-HET Method A 0 R1
NHSO
2
R
19 R n 9 5 Method C F W-HET CHO CHO RHW-HET R1 Emmons-Horner
R
15
K
2
CO
3
R
15 10 11 W-HET W-HET '1 R~ NHSO 2
R
19
R
1 5 Method B 12 R15 13 -53- WO 99/47497 PCT/CA99/00212 Method D Br 0 R HET R14-1 0 1-Mg 0 15 HO 0 2- H R R 20 -Br HET R 7
R
1 4- Base 14 R15 16 R= H, Methyl 7 HET R R 7 HET
R
20 o R R 20 0 0 14 0 R
R
14
-
NHSO
2
R
19 Deprotection 15 Method C, A R15 5 R18 -54 - WO 99/47497 PCT/CA99/00212 Method E
R
7 HET R c AcO O R Li 2 CuCl 4 16Protection 'O R 16 R14 R
R
7 -MgX R15 9 R R 7 HET
R
7 HET R O R O R R O R - R14- NHSO2RI9 R14- Method D NO
R
15 20 R15 21 Method A
R
7 HET R 7 HET 1- n-Buli HO R 2-DMF Br Br 3- Emmons-Horner R144 AI(R 7
)
3 R14 5 R15 22 tol/80 C/24h R15 23 -55 - WO 99/47497 PCT/CA99/00212 Method F Br 0 HET R14 1-Buli/-78 0 C '
SF
4 2-HET-CHO R 14 R15 3-[Ox] or DAST 24R1 F HET F F HET F R14- CHO / 1-NBSR R15 2- xN or DMSO
R
15 25 F HET F 0 Method C, A R1 NHS0 2 Rl 9 26 5 R15 -56 - WO 99/47497 PCT/CA99/00212 Method G Br 1
R
7
R
7
R
7
R
7 CO2Me CO2Me R14- B(OH) 2
R
14
-
2- Hydrogenation R15 2R15 28 27
R
7 BrR7 1- [Ox]
CO
2 Me HET-B(OH) 2 2- CBr 4 /Ph3P R14 Pd(0), R15 29 HET
R
7
R
7 H ET
CO
2 Me 1- Reduction
R
7
R
7 2-MnO 2 CHO R14~R 1 -~ R15 R,4 30
R
15 30a HET Method C, A R0 R 7 R14
NHSO
2
R'
9 5 R 15 31 -57- WO 99/47497 PCT/CA99/00212 Method H HET R 7 HET 1- Ph 3 P CO 2 Me Hydrogenation R 14
CO
2 Me 29 R1 2- Base O R15 7 32
R
7 Het Method G, C, A 1- CH 2
N
2 /Pd 2- Method G, C, A HET R7 HET R 0 R 14 NHSO2R19 14~
NHSO
2
R
19 Ri5 R1 33 5 R15 34 Method I R7 HET R7 B
R
7 HET 1- 9-BBN
R
7 r HET-B(OH) 2 2-14/ Pd(O) 0 RO R) R14- R36 L37 35 R 5 1- [Red] 2- Hydrolysis R7 R H E7 HET R7 HET R7 Method C,A CHO R14
NHSO
2
R
1 9 R1 39 R 15 38 - 58- WO 99/47497 PCT/CA99/00212 Method J R18 0 +R1 O R 1 8 Ph 3 P
CO
2 Me R or Base ' CO 2 Me R0 R 18 R1 40 R1 R15 (EtO) 2 P CO 2 Me 41 HE
R
18 o Method A R 1 4- 1 NHSO 2
R
1 9 [Red] qRi R15 42 HET
R
18 0
SNHSO
2
R
1 R15 5 43 Method K HET HET 0 0 OMe [Red] R14-- OMe
R
15 3 R15 44 H ETO 1-Base 0
R
18 -Br R 14
NHSO
2
R
9 2- Method A /, R 18
R
18 R15 45 -59- WO 99/47497 PCT/CA99/00212 Method L HET O HET R14 OMe Reduction
R
14 OH R15 3 R 15 46 HET
CH
2 1 2 /Zn, R14 OH 1 ethOX d Qt 2- Method A R15 47 HET O R14
NHSO
2
R
19 5
R
15 48 -60- WO 99/47497 PCT/CA99/00212 Method M
R
18
R
18 14 CO 2 Me Base 14 CO 2 Me 2-R 18 -R R15 R15 49 50 1- NBS 2- Het-B(OH) 2 1-NBS HET 2-Method A
R
18
R
18 NHSO 2
R
1 9 R14_1 HET 1 O
R
8
R
18 R15 52 R 14 - CO 2 Me R15 I Homologation HET
R
18
R
1 . CO 2 Me \9 :NR14-1 HET R R15
R
18
R
18
NHSO
2
R
1 9 R4 R18 R18 5R15 51 -61 - WO 99/47497 PCT/CA99/00212 Method N Br HET HET
CO
2 Me CO 2 Me I OH R
HET-B(OH)
2 R R R15 R15 R15 53 54 55 Rl BMg-X 1- Phosgene 2-NH 2
SO
2
R
1 9 HET or
R
18
R
18 O=C=NS0 2
R
1 9 OH R14---O HET R4 0 NHSO 2 L ~ R9 1- Phosgene R15 2-NH 2
SO
2
R
19 56 or
O=C=NSO
2
R'
9 HET
R
18
R
18 O 0 )"NHSO 2 R19 R14 R15 5 57 -62- WO 99/47497 PCT/CA99/00212 Method 0 HET HET 0
NO
2 F F R 0 1- ,4 OH Lawesson 2- DAST R15 3- Light R15 58 59 1-Phosgene HET O 2-NH 2
SO
2
R
19 F F or R 14 -- 0 NHS 2
R'
9 O=C=NS0 2
R
1 9 R15 5 60 -63- WO 99/47497 PCT/CA99/00212 Method P HET HET F F F F R OH Bromination R14- Br R15 R15 59 O HET F OR F 0 F R 14 - OR Method A R ~ F Base R15 61 H ET F F 0 4 F F NHSO 2
R
19 R15 5 62 -64- WO 99/47497 PCT/CA99/00212 Method Q HET HET 14OH H4H L NH 2 1-CBr 4 /Ph 3 P R / 2- NH 4 OH R15
R
15 55 63 1- Phosgene HET 2-NH 2
SO
2
R
19 or 14 N NHSO 2
R
19
O=C=NSO
2
R
19
R
15 64 HET 0 Base/ R1 7 -X NO '' N NHSO 2
R
19 R14-- R17 R15 5 65 -65- WO 99/47497 PCT/CA99/00212 Method R W-H 1-Ph 3 SiSH or $ 4 CHO HET Ph3SiOH R1 -- F1 -I 10 2- Deprotection
R
15 CHO 66 BaseR1
R
7
R
7 NBS R 7
R
7 67 Het H et BrW= Sulfur Emmons-Horner LIDA HET RHET w R N NHS0 2
R
19 Method A lL O
R
15 5 68 -66- WO 99/47497 PCT/CA99/00212 Method S
NO
2
NO
2 0 R1 CHO Emmons-Horner R14 OR R15 LDA R15 69 70
NH
2 0 R 7 _X NHR 7 0 R14- OR Base R14 OR [Red] Q-~ R15 R15 R7
R
7 Het
NR
7 0 R 7
R
7 NHS02Rl9Het xBr R14NHSO 2
R
19 Method A HtB 5
R
15 71 Base -67- WO 99/47497 PCT/CA99/00212 Method T 1- Mg or n-Buli 2- O HO HET Br H fHET BuIi/-78 0 C R1 R1 t DMSO 24 NaHCO 3 Br HET 0 HET 1- [Ox] CHO 2- NBS R 4 3- \+0-/ N R15 1- Emmons Horner 2- Method A 0 HET 0 R14 NHSO 2
R
19 5 R15 72 ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY Biological activity and thus utility for the compounds of formula I as modulators of prostaglandin mediated diseases can be 10 demonstrated in accordance with the following assayswhich demonstrate prostanoid antagonist or agonist activity in vitro and in vivo and their selectivity. The prostaglandin receptors investigated were DP, EPJ, EP 2 , EP 3 , EP 4 , FP, IP and TP. 15 Stable expression of prostanoid receptors in the human embryonic kidney (HEK) 293(ebna) cell line -68 - WO 99/47497 PCT/CA99/00212 5 Prostanoid receptor cDNAs corresponding to full length coding sequences were subcloned into the appropriate sites of mammalian expression vectors and transfected into HEK 293(ebna) cells. HEK 293(ebna) cells expressing the individual cDNAs were grown under selection and individual colonies were isolated after 2-3 weeks of 10 growth using the cloning ring method and subsequently expanded into clonal cell lines. Prostanoid receptor binding assays HEK 293(ebna) cells are maintained in culture, harvested 15 and membranes are prepared by differential centrifugation, following lysis of the cells in the presence of protease inhibitors, for use in receptor binding assays. Prostanoid receptor binding assays are performed in 10 mM MES/KOH (pH 6.0) (EPs, FP and TP) or 10 mM HEPES/KOH (pH 7.4) (DP and IP), containing 1 mM EDTA, 10 mM divalent cation and the 20 appropriate radioligand. The reaction is initiated by addition of membrane protein. Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations. Non-specific binding is determined in the presence of 1 gM of the corresponding non-radioactive prostanoid. Incubations are conducted for 60 min at room temperature 25 or 30 'C and terminated by rapid filtration. Specific binding is calculated by subtracting non specific binding from total binding. The residual specific binding at each ligand concentration is calculated and expressed as a function of ligand concentration in order to construct sigmoidal concentration-response curves for determination of ligand 30 affinity. Prostanoid receptor agonist and antagonist assays Whole cell second messenger assays measuring stimulation (EP 2 , EP 4 , DP and IP in HEK 293(ebna) cells) or inhibition 35 (EP 3 in human erythroleukemia (HEL) cells) of intracellular cAMP accumulation or mobilization of intracellular calcium (EP 1 , FP and TP in HEK 293(ebna) cells stably transfected with apo-aequorin) are performed to determine whether receptor ligands are agonists or -69- WO 9-9/47497 PCT/CA99/00212 5 antagonists. For cAMP assays, cells are harvested and resuspended in HBSS containing 25 mM HEPES, pH 7.4. Incubations contain 100 RM RO-20174 (phosphodiesterase type IV inhibitor, available from Biomol) and, in the case of the EP 3 inhibition assay only, 15 jiM forskolin to stimulate cAMP production. Samples are incubated at 37 0 C for 10 min, 10 the reaction is terminated and cAMP levels are then measured. For calcium mobilization assays, cells are charged with the co-factors reduced glutathione and coelenterazine, harvested and resuspended in Ham's F12 medium. Calcium mobilization is measured by monitoring luminescence provoked by calcium binding to the intracellular 15 photoprotein aequorin. Ligands are added in dimethylsulfoxide which is kept constant at 1 % (v/v) in all incubations. For agonists, second messenger responses are expressed as a function of ligand concentration and both EC 50 values and the maximum response as compared to a prostanoid standard are calculated. For antagonists, the 20 ability of a ligand to inhibit an agonist response is determined by Schild analysis and both KB and slope values are calculated. Rat Paw Edema Assay The method is the same as described in Chan et al (J. 25 Pharmacol. Exp. Ther. 274: 1531-1537, 1995). LPS-Induced Pyrexia in Conscious Rats The method is the same as described in Chan et al (J. Pharmacol. Exp. Ther. 274: 1531-1537, 1995). 30 LPS-Induced Pyrexia in Conscious Squirrel Monkeys The method is the same as described in Chan et al (Eur. J. Pharmacol. 327: 221- 225, 1997). 35 Acute Inflammatory Hyperalgesia Induced by Carrageenan in Rats The method is the same as described in Boyce et al (Neuropharmacology 33: 1609-1611, 1994). -70- WO 99/47497 PCT/CA99/00212 5 Adjuvant-Induced Arthritis in Rats Female Lewis rats (body weight -146-170 g) were weighed, ear marked, and assigned to groups (a negative control group in which arthritis was not induced, a vehicle control group, a positive control group administered indomethacin at a total daily dose of 1 mg/kg and 10 four groups administered with a test compound at total daily doses of 0.10-3.0 mg/kg) such that the body weights were equivalent within each group. Six groups of 10 rats each were injected into a hind paw with 0.5 mg of Mycobacterium butyricum in 0.1 mL of light mineral oil (adjuvant), and a negative control group of 10 rats was not injected with 15 adjuvant. Body weights, contralateral paw volumes (determined by mercury displacement plethysmography) and lateral radiographs (obtained under Ketamine and Xylazine anesthesia) were determined before (day -1) and 21 days following adjuvant injection, and primary paw volumes were determined before (day -1) and on days 4 and 21 20 following adjuvant injection. The rats were anesthetized with an intramuscular injection of 0.03 - 0.1 mL of a combination of Ketamine (87 mg/kg) and Xylazine (13 mg/kg) for radiographs and injection of adjuvant. The radiographs were made of both hind paws on day 0 and day 21 using the Faxitron (45 kVp, 30 seconds) and Kodak X-OMAT TL 25 film, and were developed in an automatic processor. Radiographs were evaluated for changes in the soft and hard tissues by an investigator who was blinded to experimental treatment. The following radiographic changes were graded numerically according to severity: increased soft issue volume (0-4), narrowing or widening of joint spaces (0-5) 30 subchondral erosion (0-3), periosteal reaction (0-4), osteolysis (0-4) subluxation (0-3), and degenerative joint changes (0-3). Specific criteria were used to establish the numerical grade of severity for each radiographic change. The maximum possible score per foot was 26. A test compound at total daily doses of 0.1, 0.3, 1, and 3 mg/kg/day, 35 indomethacin at a total daily dose of 1 mg/kg/day, or vehicle (0.5% methocel in sterile water) were administered per os b.i.d. beginning post injection of adjuvant and continuing for 21 days. The compounds were -71- WO 99/47497 PCT/CA99/00212 5 prepared weekly, refrigerated in the dark until used, and vortex mixed immediately prior to administration. The invention is illustrated in connection with the following non-limiting Examples. All the end products of the formula I were analyzed by NMR, TLC and mass spectrometry. 10 Intermediates were analyzed by NMR and TLC. Most compounds were purified by flash chromatography on silica gel. Recrystallization and/or swish (suspension in a solvent followed by filtration of the solid) with a solvent such as ether:hexane 1:1. The course of reactions was followed by thin layer 15 chromatography (TLC) and reaction times are given for illustration only. Temperatures are in degrees Celsius. The compounds of the examples are numbered in accordance with the compounds that appear in Tables I and II. 20 EXAMPLE 1 N-((E)-3-{2-[4-(METHYLTHIO)BENZYL]PHENYLI-2-PROPENOYL)-2 THIOPHENESULFONAMIDE (17) 25 Step 1: Methyl (E)-3-(2-methylphenyl)-2-propenoate To 2-methylcinnamic acid (100g; 617 mmol) in 1.2 L of DMF was added DBU (112.6 g; 740 mmol) and 15 min later methyl iodide (131.3 g; 925 mmol) and left overnight. The solution was diluted in ether and washed with HCl (10%), H 2 0 and brine. The solvent was removed to 30 give 106.8 g of the title compound. 1 H NMR (CDCl 3 ) 5 2.4 (3H, s), 3.8 (3H, s), 6.35 (1H, d), 7.15 (1H, t), 7.22 (1H, t), 7.5 (1H, d) and 7.95 (1H, d). The ethyl ester can be prepared as well in the same way or from the 2-methyl benzaldehyde ( 5.00 g; 41.6 mmol) and triethyl 35 phosphonoacetate (9.9 mL; 50.0 mmol) in 150 mL ot toluene at 0 CC, to which was added portionwise NaH (63.0 mmol). After 2 h of stirring the mixture was quenched with NH 4 0Ac (25%) and extracted with EtOAc. The solvent was removed to give 7.1 g of the ethyl cinnamate. -72- WO 99/47497 PCT/CA99/00212 5 Step 2: Ethyl (E)-3-[2-(bromomethyl)phenvll-2-propenoate To the previous ethyl cinnamate (20.0 g; 105 mmol) and NBS (19.64 g; 110.3 mmol) in refluxing CC1 4 was added benzoyl peroxide (1.27 g) and the mixture was stirred for 12 h. The solution was cooled to r.t. and filtered. The solvent was removed and the crude oil purified by 10 silica gel chromatography (5% EtOAc in hexane) to yield 14.18 g of the title compound. 1 H NMR (CDCl 3 ) 6 1.30 (3H, t), 4.25 (2H, q), 4.60 (2H, s), 6.45 (1H, d), 7.30 (3H, m), 7.57 (1H, m) and 8.05 (1H, d). - 73 - WO 99/47497 PCT/CA99/00212 5 Step 3: Ethyl (E)-3-{2-[4-(methvlthio)benzyllphenvll-2-propenoate A mixture of the previous benzyl bromide (0.50 g; 1.86 mmol), 4-(methylthio)benzeneboronic acid (0.63 g; 3.7 mmol) CsF (1.13 g) and ( Ph 3
P)
4 Pd (0.11 g) in 10 mL of DME was heated to reflux for 10 h. The mixture was cooled to r.t. and quenched with NH 4 0Ac (25%) and 10 extracted with EtOAc. The organic phases were combined, dried and the solvent removed. Purification by silica gel chromatography (10% EtOAc in hexane) yielded 0.35 g of the title compound. 'H NMR (CDCl 3 ) 8 1.27 (3H, t), 2.41 (3H, s), 4.08 (2H, s), 4.21 (2H, q), 6.30 (111, d), 7.00 (1H, d), 7.1-7.4 (6H, m), 7.55 (1H, d) and 7.97 (1H, 15 d). Step 4: (E)-3-{2-[4-Methylthio)benzyll phenvll-2-propenoic acid Hydrolysis of the previous ester (0.34 g; 1.1 mmol) was run in THF/MeOH (6 mL/3 mL) with 2 equivalent of a 2N NaOH solution for 4 20 h. The solution was diluted with EtOAc and quenched with HCl (10%). The organic phase was dried over Na 2
SO
4 and the solvent removed. Purification was done by a swish in hexane to yield 0.21 g of the title compound. 'H NMR (CDCl 3 ) 8 2.42 (3H, s), 4.09 (2H, s), 6.31 (1H, d), 7.00 25 7.35 (7H, m), 7.50 (1H, d) and 8.07 (1H, d). Step 5: N-((E)-3-{2--[4-(methylthio)benzyllphenyll-2-propenoyl)-2 thiophenesulfonamide (17) 2-Thiophenesulfonamide was prepared from the 30 corresponding sulfonyl chloride with 2.2 equivalent of NH 4 0H in THF at 0 "C. The solution was brought to r.t. and left 2 h. It was then quenched with NaHCO 3 and extracted with EtOAc. The organic phase was dried over Na 2
SO
4 and the solvent removed. The crude product was crystallized in toluene/EtOAc. 35 To the previous acid (100 mg; 0.35 mmol), 2 thiophenesulfonamide (60 mg; 0.37 mmol), DMAP (86 mg; 0.7 mmol) in 2 mL of CH2Cl was added DCI (134 mg; 0.7 mmol) and the mixture was stirred overnight. The solution was diluted with EtOAc and quenched -74- WO 99/47497 PCT/CA99/00212 5 with HCl (10%). The organic phase was dried over Na 2
SO
4 and the solvent removed. Purification by silica gel chromatography (5% MeOH in
CH
2 Cl 2 ) yielded 87 mg of the title compound. 1 H NMR (CDCl 3 ) S 2.40 (3H, s), 4.01 (2H, s), 6.33 (1H, d), 6.9 7.3 (8H, m), 7.49 (1H, d), 7.61 (1H, s), 7.89 (1H, s) and 8.03 (1H, d). The 10 product was converted to the sodium salt with 1 equivalent of NaOH and freeze dried. Elemental analysis calcd. for C21H 1 8 NNaO 3
S
3 .1/2H 2 0: C, 54.77; H, 4.13; N, 3.04; S, 20.88; Found: C, 54.55; H, 4.01; N, 3.06; S, 20.58. 15 EXAMPLE 2 N-((E)-3-{2-[(3-METHYL-1H-1-INDOLYL)METHYL]PHENYL}-2 PROPENOYL)-2-THIOPHENESULFONAMIDE (3) Step 1: Ethyl (E)-3-{2-[(3-methyl-1H-1-indolyl)methyllphenylL-2 20 propenoate To benzylic bromide (400 mg, 1.49 mmol) of step 2 in example 1 and skatole (200mg, 1.51 mmol) in 6 mL of DMF was added portionwise 1.6 equivalent of NaH. The reaction mixture was left for 6 h and quenched with NH 4 OAc (25%) and diluted with EtOAc. The organic 25 phase was dried over Na2SO4, filtered and the solvent removed. Purification by silica gel chromatography (10% EtOAc inhexane) yielded 260mg of the title compound. 'H NMR (CDCl 3 ) 8 1.2 (3H, t), 2.3 (3H, s), 4.25 (2H, q), 5.4 (2H, s), 6.35 (1H, d), 6.65 (1H, d), 6.8 (1H, s), 7.1-7.3 (5H, m), 7.56 (2H, d) and 30 7.97 (1H, d). Step 2: (E)-3-{2-[(3-methyl-1H-1-indolyl)methyll phenvl}-2-propenoic acid The hydrolysis of the previous ester (260 mg) was done according to Step 4 of example 1 to yield 212 mg of the title compound. 35 HRMS calcd. for C 19
H
7
NO
3 + H+= 292.1337; Found: 292.1337. Step 3: N2-((E)-3-{2-[(3-methyl-1H-1-indolvl)methyllphenyl}-2-propenoyl) 2-thiophenesulfonamide (3) - 75 - WO 99/47497 PCT/CA99/00212 5 The coupling reaction of the previous acid (196 mg; 0.67 mmol) was done according to step 5 of example 1 to yield 134 mg of the title compound. 'H NMR (acetone-d.) 8 2.39 (3H, s), 5.57 (2H, s), 6.65 (2H, m), 7.03 (3H, m), 7.27 (4H, m), 7.5 (1H, d), 7.63 (1H, d), 7.87 (1H, d), 7.95 (1H, 10 s) and 8.14 (1H, d). HRMS calcd. for C 2 3
H
2 0
N
2 0 3
S
2 + H*= 437.0994; Found: 437.0992. EXAMPLE 3 15 N-{(E)-3-[2-(2-NAPHTHYLMETHYL)PHENYL]-2-PROPENOYL}-2 THIOPHENESULFONAMIDE (4) Step 1: Ethyl (E)-3-[2-(2-naphthylmethyl)phenvll-2-propenoate The benzyl bromide (500 mg) of example 1, step 2 was 20 treated with 2-naphthylboronic acid according to the same procedure previously described to yield 360 mg of the title compound. 'H NMR (CDCl 3 ) 8 1.30 (3H, t), 4.27(2H, q), 4.33 (2H, s), 6.48 (1H, d), 7.2-7.4 (4H, m), 7.45 (2H, m), 7.55 (1H, s), 7.62 (1H, d), 7.8 (3H, m) and 8.15 (1H, d). 25 Step 2: (E)-3-[2-(2-naphthylmethyl)phenvll-2-propenoic acid The hydrolysis of the previous ester (300 mg) was done according to Step 4 of example 1 to yield 202 mg of the title compound. 1H NMR (CDCl 3 ) 8 4.29 (2H, s), 6.32 (1H, d), 7.2-7.4 (6H, m), 30 7.5 (1H, s), 7.62 (1H, d), 7.73 (3H, m) and 8.19 (1H, d). Step3: N-{(E)-3-[2-(2-naphthylmethyl)phenyll-2-propenovll-2 thiophenesulfonamide (4) The coupling reaction of the previous acid (100 mg; 0.35 35 mmol) was done according to step 5 of example 1 to yield 60 mg of the title compound. 'H NMR (CDC1 3 ) 8 4.24 (2H, s), 6.31 (1H, d), 7.02 (1H, m), 7.15-7.8 (12H, m), 7.84 (1H, m) and 8.08 (1H, d). -76- WO 99/47497 PCT/CA99/00212 5 The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 4
H
18 NNaO3S 2
.H
2 0: C, 60.87; H, 4.22; N, 2.96; S, 13.54; Found: C, 60.36; H, 4.25; N, 3.29; S, 12.53. - 77- WO 99/47497 PCT/CA99/00212 5 EXAMPLE 4 N-{(E)-3-[2-(3,4-DICHLOROBENZYL)PHENYL-2-PROPENOYL}-2 THIOPHENESULFONAMIDE (8) Step 1: Ethyl (E)-3-[2-(3,4-dichlorobenzvl)phenvll-2-propenoate 10 The benzyl bromide (500 mg) of example 1, step 2 was treated with 3,4-dichlorobenzeneboronic acid according to the same procedure described in step 3 of example 1 to yield 410 mg of the title compound. 'H NMR (CDCl,) 5 1.30 (3H, t), 4.03 (2H, s), 4.23 (2H, q), 6.28 15 (1H, d), 6.90 (1H, dd), 7.1-7.4 (5H, m), 7.57 (1H, d) and 7.89 (1H, d). Step 2: (E)-3-[2-(3,4-dichlorobenzyl)phenvll-2-propenoic acid The hydrolysis of the previous ester (400 mg) was done according to Step 4 of example 1 to yield 296 mg of the title compound. 20 'H NMR (CDCl 3 ) 4.07 (2H, s), 6.31 (1H, d), 6.93 (1H, dd), 7.1 7.4 (5H, m), 7.50 (1H, d) and 7.99 (1H, d). Step 3: N-{(E)-3-[2-(3,4-dichlorobenzyl)phenyll-2-propenoyll-2 thiophenesulfonamide (8) 25 The coupling reaction of the previous acid (170 mg; 0.55 mmol) was done according to step 5 of example 1 to yield 110 mg of the title compound. 'H NMR (CDCl 3 ) 6 4.07 (2H, s), 6.33 (1H, d), 6.85 (1H, d), 7.07 (3H, m), 7.24 (2H, m), 7.32 (1H, t), 7.53 (1H, d), 7.63 (1H, d), 7.88 (1H, d) 30 and 7.97 (1H, d). The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 20 H1 4 Cl 2 NNaO 3
S
2 .1/2H 2 0: C, 49.7; H, 3.1; N, 2.9; S, 13.27; Found: : C, 49.46; H, 2.9; N, 2.86; S, 13.73; 35 - 78- WO 99/47497 PCT/CA99/00212 5 EXAMPLE 5 N-((E)-3-{2-[(2-NAPHTHYLOXY)METHYL]PHENYL)-2-PROPENOYL)-2 THIOPHENESULFONAMIDE (20) Step 1: Ethyl (E)-3-{2-[naphthyloxy)methvllphenvl}-2-propenoate 10 The benzyl bromide (250 mg, 0.93 mmol) of step 2 in example 1 and 2-naphthol (147 mg) in 5 mL of DMF were treated with cesium carbonate (394 mg) at 40 "C for 12 h. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over Na 2
SO
4 , filtered and the solvent removed. Purification by silica gel 15 chromatography (10% EtOAc in hexane) yielded 245 mg of the title compound. 'H NMR (CDCl 3 ) 8 1.2 (3H, t), 4.22 (2H, q), 5.28 (2H, s), 6.41 (1H, d), 7.22 (2H, m), 7.3-7.5 (4H, m), 7.55 (1H, m), 7.64 (1H, m), 7.75 (3H, m) and 8.05 (1H, d). 20 Step 2: (E)-3-{2-[naphthyloxv)methyllphenvl}-2-propenoic acid Hydrolysis of the previous ester (245 mg, 0.74 mmol) was done according to step 4 of example 1 to yield 185 mg of the title compound. 25 'H NMR (CDCl 3 ) 6 5.27 (2H, s), 6.45 (1H, d), 7.15-7.25 (2H, m), 7.32 (1H, t), 7.42 (3H, m), 7.55 (1H, d), 7.67 (1H, d), 7.77 (3H, m) and 8.11 (1H, d). Step 3: N-((E)-3-{2-[(2-naphthyloxy)methyllphenyll-2-propenovl)-2 30 thiophenesulfonamide (20) The coupling reaction of the previous acid (150 mg; 0.49 mmol) was done according to step 5 of example 1 to yield 77 mg of the title compound. 'H NMR (CDCl 3 ) 6 5.2 (2H, s), 6.39 (1H, d), 7.02 (1H, s), 7.1 35 7.2 (2H, m), 7.3-7.4 (4H, m), 7.53 (3H, m), 7.71 (3H, m), 7.83 (1H, s) and 8.07 (1H, d). The product was converted to the sodium salt with 1 equivalent of NaOH. -79- WO 99/47497 PCT/CA99/00212 5 Elemental analysis calcd. for C2H2 8 NNaO 4
S
2 .3/2H 2 0: C, 57.82; H,4.21; N, 2.81; Found: : C, 58.31; H, 3.96; N, 2.91. EXAMPLE 6 N-{(E)-3-[2-(2-NAPHTHYLSULFINYL)PHENYL]-2-PROPENOYL}-2 10 THIOPHENESULFONAMIDE (21) Step 1: 2-(2-naphthylthio)benzaldehyde A mixture of 2-thionaphthol (5.29 g; 33 mmol), 2 fluorobenzaldehyde (3.73 g; 33 mmol) and potassium carbonate (4.57 g; 33 15 mmol) in 28 mL of iso-propanol was heated to reflux for 12 h. The mixture was cooled to r.t., diluted with water and filtered. The solution was diluted with EtOAc and washed with water, brine and dry over MgSO 4 . The crude product (7.9 g) was used as is for the next step. 1 H NMR (CDCl 3 ) 6 7.07 (1H, d), 7.32 (2H, m), 7.42 (1H, d), 7.51 20 (2H, m), 7.78 (1H, m), 7.83 (2H, d), 7.88 (1H, s), 7.95 (1H, s) and 10.39 (1H, s). Step 2: Ethyl (E)-3-[2-(2-naphthylthio)phenyll-2-propenoate The previous aldehyde (7.72 g; 29.2 mmol) was converted to 25 the ethyl ester according to step 1 of example 1 to furnish 6.36 g of the title compound. 1 H NMR (CDCl 3 ) 8 1.24 (3H, t), 4.21 (2H, q), 6.36 (1H, d), 7.28 (4H, in), 7.42 (2H, m), 7.61 (1H, d), 7.72 (4H, m) and 8.28 (1H, d). 30 Step 3: Ethyl (E)-3-[2-(2-naphthylsulfinvl)phenyll-2-propenoate The previous ester (3.00 g; 8.97 mmol) in 45 mL of dichloromethane was treated with 1.1 equivalent of mCPBA at 0 "C for 1 h. The mixture was quenched with sodium thiosulfite and extracted with EtOAc. The organic phase was dry over Na 2
SO
4 and the crude 35 purified by silica gel chromatography (30% EtOAc in hexane) to yield 2.35 g of the title compound. 'H NMR (CDCl 3 ) 6 1.34 (3H, t), 4.27 (2H, q), 6.26 (1H, d), 7.42 (2H, m), 7.53 (4H, in), 7.77 (2H, m), 7.88 (2H, m), 8.07 (2H, d), 8.22 (1H, s) and 8.28 (2H, m). -80 - WO 99/47497 PCT/CA99/00212 5 Step 4: Ethyl (E)-3-[2-(2-naphthylsulfinyl)phenyll-2-propenoic acid The previous ester (1.20 g; 3.43mmol) was hydrolyzed according to the procedure of step 4 of example 1 to yield 1.08 g of the title compound. 10 1H NMR (methanol-d 6 ) 6 6.23 (1H, d), 7.33 (1H, dd), 7.45 (3H, m), 7.53 (1H, t), 7.62 (1H, d), 7.8 (3H, m), 7.98 (1H, d), 8.05 (1H, d) and 8.27 (1H, s). Step 5: 2-{(E)-3-[2-(2-naphthylsulfinvl)phenvll-2-propenoyl}-2 15 thiophenesulfonamide (21) The coupling reaction of the previous acid (500 mg; 1.55 mmol) was done according to step 5 of example 1 to yield 416 mg of the title compound. 'H NMR (methanol-d 6 ) 8 6.19 (1H, d), 7.1 (1H, m), 7.22 (1H, 20 dd), 7.45 (3H, m), 7.55 (2H, m), 7.67 (1H, d), 7.72-7.85 (4H, m), 7.99 (1H, d), 8.1 (1H, d) and 8.17 (1HI, s). The sodium salt was prepared with 1N NaOH. Elemental analysis calcd. for C 23
H
16 NNaO 4
S
3 .1/2H 2 0: C, 55.36; H,3.40; N, 2.81; S, 19.27; Found: : C,55.00; H, 3.62; N, 2.81; S, 18.18. 25 EXAMPLE 7 N-{(E)-3-[2-(2-NAPHTHYLOXY)PHENYLI-2-PROPENOYL}-2 THIOPHENESULFONAMIDE (28) 30 Step 1: Ethyl (E)-3-[2-(2-naphthyloxv)phenyll-2-propenoate 2-fluoro benzaldehyde (3.0 g; 24.2 mmol), 2-naphthol (24.2 mmol) and potassium carbonate (26.6 mmol) were heated at reflux in dimethyl acetamide for 2 h. The mixture was cooled to r.t., diluted with EtOAc and washed with water and brine. The organic phase was dried 35 over Na 2
SO
4 , filtered and the solvent removed. Purification by silica gel chromatography (10% EtOAc in hexane) yielded 3.4 g of the title compound. -81- WO 99/47497 PCT/CA99/00212 5 'H NMR (CDCl 3 ) 8 6.93 (1H, d), 7.17-7.23 (1H, m), 7.28 (1H, dd), 7.37 (1H, s), 7.37 (3H, m), 7.7 (1H, d), 7.84 (2H, m), 7.94 (1H, d) and 10.53 (1H, s). Step 2: Ethyl (E)-3- [2-(2-naphthyloxy)phenvll -2-propenoate 10 The previous aldehyde (2.00 g; 8.0 mmol) was converted to the title compound according to step 1 of example 1 to yield 2.52 g. 1H NMR (CDCl 3 ) 6 1.25 (311, t), 4.21 (2H, q), 6.55 (1H, d), 6.9 (1H, d), 7.15 (1H, t), 7.25 (3H, m), 7.42 (2H, m), 7.65 (2H, m), 7.83 (2H, t) and 8.02 (1H, d). 15 Step 3: (E)-3- [2-(2-naphthyloxv)phenyll -2-propenoic acid The previous ester (2.52 g; 7.9 mmol) was hydrolyzed according to the procedure of step 4 of example 1 to yield 1.57 g of the title compound. 20 'H NMR (CDCl 3 ) 6 6.62 (1H, d), 7.03 (1H, d), 7.2-7.5 (6H, m), 7.78 (1H, d) and 7.88-8.03 (4H, m). HRMS calcd. for C19H1403 + H+= 291.1021; Found: 291.1022. Step 4: N-{(E)-3-[2-(2-naphthyloxv)phenvll-2-propenovl}-2 25 thiophenesulfonamide (28) The coupling reaction of the previous acid (1.00 g; 3.4 mmol) was done according to step 5 of example 1 to yield 790 mg of the title compound. 'H NMR (CDCl 3 ) 6 6.91 (1H, d), 6.97 (111, d), 7.15(1H, dd), 7.24 (1H, t), 7.29 30 1H, dd), 7.37 (1H, d), 7.40-7.55 (311, m), 7.74-7.83 (211, m), 7.92 (211, m) and 7.99 (211, M). The sodium salt was prepared with 1N NaOH. HRMS calcd. for C 23
H,
6 NNaO 4
S
2 + H+= 458.0497; Found:458.0497. 35 EXAMPLE 8 THIOPHENE-2-SULFONYL CARBAMIC ACID [2-(2 NAPHTHYLSULFONYL)PHENYLlMETHYL ESTER (31) Step 1: [2-(2-naphthylthio)phenvll methanol -82 - WO 99/47497 PCT/CA99/00212 5 To 2-(2-naphthylthio) benzaldehyde (7.24 g; 27.4 mmol from Example 6, step 1) in 70 mL of methanol and 30 mL of THF at 0 C was added NaBH 4 (54.8 mml) portionwise. After 1h at 0 "C, the solution was brought to r.t. and quenched with water. After dilution with EtOAc, the solution was washed with water and brine. The organic phase was dry 10 over Na2SO4, filtered and the crude purified by silica gel chromatography to yield 6.71 g of the title compound. 'H NMR (acetone-d) S 4.29 (1H, t), 4.7 (2H, d), 7.29 (2H, m), 7.35-7.52 (4H, m), 7.71 (2H, m), 7.77 (1H, m) and 7.83 (2H, M). 15 Step 2: [2-(2-Naphthylsulfonyl)phenyll methanol To the previous sulfide (500 mg; 1.88 mmol) in 8 mL of dichloromethane at 0 *C was added m-CPBA (5.64 mmol) and let stirred for 2 h. The mixture was diluted with EtOAc and washed with NaOH (1N) and brine. The organic phase was dry over Na2SO4, filtered and the 20 crude purified by silica gel chromatography (40% EtOAc in hexane) to yield 390 mg of the title compound. 'H NMR (acetone-d) 84.37 (1H, t), 4,9 (2H, d), 7.57 (1H, dt), 7.65-7.80 (4H, m), 7.82 (1H, d), 8.0-8.1 (2H, m), 8.2 (2H, m) and 8.63 (1H, s). 25 Step 3: 2-Thiophenesulfonvl isocyanate A mixture of 2-thiophenesulfonylamide (1.5 g) and oxalyl chloride (6 mL) in 10 mL of 1,2-dichloroethane was refluxed for 14h. The solvent was removed under vacuum and the crude used as is for the 30 next step. Step 4: To the alcohol of step 2 (250 mg; 0.84 mmol) in ether at 0 0 C was added the previous isocyanate (2 equivalent) and let stirred 1h at 0 35 "C. The solution was quenched with water and extracted with EtOAc. The organic phase dry over Na 2
SO
4 , filtered and the crude purified by silica gel chromatography (5% CH30H in CH 2 Cl 2 ) to yield 300 mg of the title compound. -83 - WO 99/47497 PCT/CA99/00212 5 1 H NMR (CDCl 3 ) 6 5.55 (2H, s), 7.08 (1H, m), 7.55-7.72 (6H, m), 7.82 (2H, m), 8.0 (1H, d), 8.07 (1H, d), 8.2 (2H, m) and 8.66 (1H, s). The sodium salt was prepared with 1N NaOH. Elemental analysis calcd. for C 2 2 H 16 NNaO 6 S3.2H 2 0: C, 48.44; H,3.67; N, 2.57; S, 17.63; 10 Found: : C,48.86; H, 3.13; N, 2.63; S, 16.46. -84- WO 99/47497 PCT/CA99/00212 5 EXAMPLE 9 N-({2-[2-(2-NAPHTHYLMETHYL)PHENYL]CYCLOPROPYLI CARBONYL-2-THIOPHENESULFONAMIDE (45) Step 1: Ethyl 2-[2-(2-naphthylmethyl)phenvll-1-cyclopropanecarboxylate 10 The ethyl ester (300 mg; 0.95 mmol) of step 1 in example 3 and Pd(OAc) 2 (10 mg) were treated with diazomethane at 00 C for 1h. The solvent was removed and the crude oil purified by silica gel chromatography (5% EtOAc in hexane) to yield 300 mg of the title compound. 15 'H NMR (CDCl3) 8 1.1 (3H, t), 1.27 (1H, m), 1.45 (1H, m), 1.7 (1H, m), 2.53 (1H, m), 3.98 (2H, m), 4.29 (2H, s), 7.0 (1H, m), 7.18 (3H, m), 7.27 (1H, m), 7.39 (2H, m), 7.48 (1H, s) and 7.75 (3H, m). Step 2: 2-[2-(2-naphthylmethyl)phenyll-l-cyclopropanecarboxylic acid 20 The previous ester (300 mg; 0.91 mmol) was hydrolyzed according to the procedure of step 4 of example 1 to yield 230 mg of the title compound. 'H NMR (CDCl 3 ) 8 1.45 (1H, m), 1.6 (1H, m), 1.8 (1H, m), 2.67 (1H, m), 4.33 (2H, s), 7.1 (1H, m), 7.24 (4H, m), 7.41 (2H, m), 7.58 (1H, s) 25 and 7.78 (3H, m). Step 3: N-({2-[2-(2-naphthylmethyl)phenvllcvclopropvl}carbonyl-2 thiophenesulfonamide (45) The coupling reaction of the previous acid (230 mg; 0.76 30 mmol) was done according to step 5 of example 1 to yield 100 mg of the title compound. 'H NMR (CDCl 3 ) 8 1.32 (1H, m), 1.48 (1H, m), 1.63 (1H, m), 2.6 (1H, m), 4.13 (2H, s), 6.97 (2H, m), 7.12 (4H, m), 7.38 (3H, m), 7.52 (1H, d), 7.65 (2H, m) and 7.79 (2H, m). The sodium salt was prepared with 1N 35 NaOH. Elemental analysis calcd. for C 25
H
20 NNaO3S 2 .1/2H 2 0: C, 62.75; H, 4.39; N, 2.93; S, 13.4; Found: : C,62.25; H, 4.24; N, 3.02; S, 12.15. -85 - WO 99/47497 PCT/CA99/00212 5 EXAMPLE 10 N-((E)-3-(2-(6-BENZYLOXY-2-NAPHTHYL)METHYL)PHENYL)-2 PROPENOYL)-5-BROMO-2-METHOXYBENZENESULFONAMIDE (46) (E)-3-(2-(6-benzylox-2-naphthyl)methyl)phenvl)-2-propenoic acid 10 Step 1: [(6-bromo-2-naphthyl)oxyl(phenvl)methane To a mixture of 6-bromo-2-naphthol (1.99 g, 8.9 mmol) and benzyl bromide (1.2 ml, 1.1 equiv.) in DMF (18 ml) at 0"C was added a suspension of NaH 80% in oil (324 mg, 1.2 equiv.) and the mixture was stirred at 0*C for an hour and at r.t. for another hour. After addition of 15 half saturated NH 4 Cl, the product was extracted in i-PrOAc, washed with 1 N HCl, dried over Na2SO4 and concentrated to yield 2.84 g of an oil. Step 2: 6-benzyloxv-2-naphthaleneboronic acid To a solution of the previous bromide (940 mg, 3.00 mmol) in 20 THF (15 ml) at -78"C was added n-BuLi 1.6 M in hexanes (2.2 ml, 1.2 equiv.) and the mixture was stirred at -78*C for 15 min. Tri-isopropyl borate (0.97 ml, 1.4 equiv.) was added and the reaction mixture was warmed to r.t. After addition of 2 N HC1, the product was extracted in EtOAc, dried over Na2SO4 and concentrated to yield a solid. This solid 25 was washed with ether:hexane 1:1 to yield 679 mg of pure material. 'H NMR (Acetone-d 6 :DMSO-d 6 ) 8 5.27 (2H, s), 7.22 (1H, dd), 7.33 (1H, dd), 7.40 (3H, m), 7.54 (2H, d), 7.63 (2H, s), 7.72 (1H, d), 7.83 (1H, d), 7.90 (1H, d), 8.36 (1H, s). 30 Step 3: Ethyl (E)-3-(2-{[6-benzvloxy)-2-naphthyllmethyllphenvl)-2 propenoate A mixture of the previous boronic acid (1.05 g, 3.8 mmol), Pd(Ph 3
P)
4 (185 mg), the benzylic bromide of step 2 in example 1 (1.07 g, 4.0 mmol), 2 M aq. Na 2 COs (4 ml) and toluene (8 ml) was degazed and 35 stirred at 100* C under nitrogen for 4 h. After addition of half saturated
NH
4 Cl, the product was extracted in EtOAc, dried over Na 2
SO
4 and concentrated. Purification by flash chromatography with EtOAc:toluene:hexane 2.5:75:25 yielded 1.17 g of the title compound as an oil. -86- WO 9-9/47497 PCT/CA99/00212 5 Step 4: (E)-3-(2-{[6-(benzyloxv)-2-naphthvllmethyllphenvl)-2-propenoic acid The previous ester was hydrolyzed according to the procedure of step 4 of example 1 to yield the title compound. 10 Step 5: 5-Bromo-2-methoxvbenzenesulfonamide To 5-bromo-2-methoxybenzenesulfonyl chloride (45g; 157.6 mmol, from Lancaster Chemical) at 0"C in THF , was added concentrated NH40H (42.5 mL) and the reaction mixture was brought to 15 r.t. for 2 h. The reaction mixture was diluted with EtOAc, extracted with NaHCO 3 (2X), brine, and the organic phase was dried over MgSO 4 . The solvent was removed to give the title compound. Step 6: N-((E)-3-(2-(6-benzyloxv-2-naphthyl)methyl)phenvl)-2-propenovl) 20 5-bromo-2-methoxvbenzenesulfonamide (46) To the acid from step 5 (190 mg, 0.482 mmol) in CH 2 Cl 2 was added DMF (10 gL) and oxalyl chloride (60 gL) at 0*C and the mixture was warmed to r.t. for an hour and concentrated to dryness. The resulting acid chloride was redissolved in CH2Cl 2 :THF 1:1 (10 mL) and 5 25 bromo-2-methoxybenzenesulfonamide (154 mg, 1.2 equiv., from step 6) and Et 3 N (135 gL, 2 equiv.) were added at 0*C. The mixture was then warmed to r.t. for an hour, 0.5 N HCl was added and the product was extracted in i-PrOAc, dried over Na 2 SO4 and purified by flash chromatography with EtOAc:toluene:acetic acid 20:80:1 to yield 93 mg of 30 a white solid. 'H NMR (CDCl 3 ) S MS (APCI, neg.) 643.3, 641.8, 640.0 (M-1), 393.2. EXAMPLE 11 35 N-{(E)-3-[2-NAPHTHYLMETHYL)PHENYL)]-2-PROPENOYL}-5 BROMO-2-METHOXY-1-BENZENESULFONAMIDE (301) Step 1: N-{(E)-3-[2-naphthylmethyl)phenyl)1-2-propenovll-5-bromo-2 methoxy-1-benzenesulfonamide (301) -87 - WO 99/47497 PCT/CA99/00212 5 The carboxylic acid (400 mg; 1.22 mmol) of example 3 step 2 was coupled with 5-bromo-2-methoxy-1-benzenesulfonyl chloride according to the procedure of step 5 in example 1 to yield 284 mg of the title compound. 'H NMR (acetone-d 6 -DMSO-d 6 ) 8 3.85 (3H, s), 4.31 (2H, s), 10 6.65 (1H, d), 7.15 (1H, d), 7.3 (1H, m), 7.35-7.50 (4H, m), 7.55-7.65 (2H, m), 7.7-7.9 (5H, m) and 8.01 (1H, d). The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 27
H
21 BrNNaO 4 S.1/2H 2 0: C, 57.15; H,3.88; N, 2.47; Found: : C, 56.88; H, 3.73; N, 2.52. 15 EXAMPLE 12 N-{(E)-3-[5-CHLORO-2-(2-NAPHTHYLMETHYL)PHENYL]-2 PROPENOYLI-2-THIOPHENESULFONAMIDE (303) 20 Step 1: 5-chloro-2-methylbenzaldehyde To a solution of 2-bromo-4-chlorotoluene ( 20.0 g; 97.3 mmol) in 300 mL of THF at -78 "C was added dropwise a 2.5 M solution of n-BuLi (102.2 mmol). After 30 min of stirring at that temperature, 1 formylpiperidine (11.4 mL) in 10 mL of THF was added and the solution 25 left for 1 h. It was brought to 0 "C , quenched with NH 4 0Ac (25%) and diluted with EtOAc. The organic phase was dried over Na2SO4, filtered and the solvent removed to yield 13.3 g of the title compound. 'H NMR (CDCla) S 2.6 (3H, s), 7.15 (1H, d), 7.4 (1H, d), 7.75 (1H, s) and 10.2 (1H, s). 30 Step 2: Ethyl (E)-3-(5-chloro-2-methylphenvl)-2-propenoate The previous aldehyde (13.3 g; 86.0 mmol) was converted to the ethyl cinnamate according to step 1 of example 1 to yield 16.67 g. 'H NMR (CDCl 3 ) 6 1.2 (3H, t), 2.26 (3H, s), 4.15 (2H, q), 6.21 35 (1H, d), 6.99 (1H, d), 7.13 (2H, m), 7.39 (1H, s) and 7.73 (1H, d). Step 3: Ethyl (E)-3-[2-(bromomethyl)-5-chlorophenvll-2-propenoate -88- WO 99/47497 PCT/CA99/00212 5 The previous ester (16.66 g; 74.1 mmol) was converted to the benzylic bromide according to step 2 of example 1 to yield 9.0 g of the title compound. 'H NMR (CDCl 3 ) S 1,2 (3H, t), 4.25 (2H, q), 4.5 (2H, s), 6.4 (1H, d), 7.28 (2H, s), 7.55 (1H, s) and 7.95 (1H, d). 10 Step 4: Ethyl (E)-3- [5-chloro-2-(2-naphthylmethyl)phenyll -2-propenoate The previous benzylic bromide was coupled in a Suzuki type reaction with 2-naphthylboronic acid according to step 3 of example 1 to yield 1.14 g of the title compound. 15 'H NMR (CDCl 3 ) 8 1.15 (3H, t), 4.09 (2H, q), 4.12 (2H, s), 6.2 (1H, d), 7.03 (1H, d), 7.15 (2H, m), 7.3 (2H, m), 7.37 (1H, s), 7.45 (1H, s), 7.65 (3H, m) and 7.87 (1H, d). Step 5: (E)-3-[5-chloro-2-(2-naphthylmethyl)phenyll-2-propenoic acid 20 The hydrolysis of the previous ester (1.14 g) was done according to Step 4 of example 1 to yield 0.99 g of the title compound. 'H NMR (CDC1 3 ) 54.23 (2H, s), 6.31 (1H, d), 7.12 (1H, d), 7.22 (1H, m), 7.3 (1H, m), 7.42 (2H, m), 7.48 (1H, s), 7.59 (1H, s), 7.75 (3H, m) and 8.05 (1H, d). 25 Step 6: N-I(E)-3-[5-chloro-2-(2-naphthylmethyl)phenvll -2-propenoyl}-2 thiophenesulfonamide (303) The coupling reaction of the previous acid (400 mg; 1.22 mmol) was done according to step 5 of example 1 to yield 272 mg of the 30 title compound. 'H NMR (acetone-d 6 ) S 4.25 (2H, s), 6.58 (1H, d), 7.0 (1H, t), 7.23 (2H, m), 7.33 (1H, m), 7.39 (2H, m), 7.5-7.6 (2H, m), 7.55 (5H, m) 7.86 (1H, m) and 8.04 (1H, d). The product was converted to the sodium salt with 1 35 equivalent of NaOH. Elemental analysis calcd. for
C
24 H1 7 ClNNaO 3
S
2 .1/2H 2 0: C, 57.76; H,3.64; N, 2.81; S, 12.84; Found: : C, 57.78; H, 3.62; N, 2.86; S, 12.85. -89- WO 99/47497 PCT/CA99/00212 5 EXAMPLE 13 (E)-3-{4-CHLORO-2-[6-FLUORO-2-NAPHTHYL)METHYL]PHENYL}-2 PROPENOIC ACID SODIUM SALT (457) Step 1: Ethyl (E)- 3 -(5-chloro-2-methylphenvl)-2-propenoate 10 To 2-bromo-4-chloro toluene (20.0g; 97.3 mmol) in 300 mL of THF at -78 oC was added n-BuLi 2.5 M (40.8 mL) dropwise. After 20 min. 1-formylpiperidine (11.4 mL; 103.0 mmol) in 10 mL of THF was added dropwise. After 30 min the reaction mixture was brought to 0 0 C and quenched with HCl (10%) and diluted with EtOAc. The organic 15 phase was collected, dry and the solvent evaporated to yield 13.3g (89%) of 5-chloro-2-methylbenzaldehyde. This crude aldehyde was mixed with 1.1 equivalent of triethyl phosphonoacetate in THF. Sodium hydride 80% (1.3 equivalent ) was added portionwise and 1 h later the reaction was quenched with 25% NH4CL. The reaction mixture was diluted with 20 EtOAc and the organic phase collected, dried and the solvent removed. The crude oil was purified on a short pad of silica gel using 5% EtOAc in hexane to afford 16.67 g of the title compound. Alternatively, this procedure can be done in one reaction vessel. At the end of the first step, the flask is brought to rt and 25 the phosphonoacetate in THF is added. 1H NMR (CDCl3) 8 1.21 (3H, t), 2.27 (3H, s), 4.15 (2H, q), 6.22 (1H, d), 6.95-7.15 (3H, in), 7.40 (1H, s) and 7.75 (1H, d). Step 2: Ethyl(E)-3-[2-(bromomethyl)-5-chlorophenvll-2-propenoate 30 The bromination was done according to step 2 of example 1 to provide the title compound in 45% yield. 'H NMR (CDCl 3 ) 6 1.32 (3H, t), 4.27 (2H, q), 4.52 (2H, s), 6.43 (1H, d), 7.30 (2H, s), 7.55 (1H, s) and 7.93 (2H, d). 35 Step 3: 6-Fluoro-2-naphthol A solution of 2 -(4-fluorophenyl)acetyl chloride (5.0g; 29 mmol) in CH 2 Cl 2 was added to AIC1 3 (7.73g;58 mmol) in CH 2 C1 2 at -20 0 C over 30 min. Trimethylsilyl acetylene (9.96g; 101.43 mmol) was added also over 30 min and stirred at -10 'C for 1h. The mixture was poured in -90- WO 99/47497 PCT/CA99/00212 5 ice and extracted with EtOAc. The organic phase was washed with water, NaHCO3 and brine. After purification by gel silica chromatography (10% EtOAc in hexane) 2.43 g (36%) of 3-(trimethylsilyl) 6-chloro-2-naphthol was collected. The desylilation was done with TFA in CH 2 Cl 2 at rt overnight. Purification by gel silica chromatography (10% 10 EtOAc in hexane) afforded the title compound in 69% yield. 'H NMR (CDCl 3 ) 6 7.10-7.20 (3H, m), 7.37 (1H, dd) and 7.65 (2H, m). Step 4: Ethyl (E)-3-14-chloro-2-[(6fluoro-2-naphthyl)methvllphenyll-2 15 propenoate The naphthol of Step 3 was converted to the triflate with triflic anhydride/pyridine in CH 2 C1 2 at 0 0 C. This was coupled with the organozinc of the benzyl bromide of step 2 in example 13, with dppf and Pd(dba) 2 . This yielded the title compound in 47% yield after purification 20 by silica gel chromatography (10% EtOAc in hexane). 'H NMR (CDCl 3 ) 8 1.25 (3H, t), 4.20 (2H, q), 6.30 (1H, d), 7.10 7.27 (4H, m), 7.38 (1H, dd), 7.48 (1H, s), 7.57 (1H, dd), 7.66 (2H, m) and 7.95 (1H, d). 25 Step 5: (E)-3-{4-Chloro-2-[(6-fluoro-2-naphthyl)methyll phenyll-2 propenoic acid, sodium salt The hydrolysis of the ester of Step 4 (1.03g; 2.7 mmol) was done according to step 4 of example 1 to yield 800mg (87%) of the title compound. The sodium salt was prepared with 1N NaOH. 30 1H NMR (CDCl3) 8 4.21 (2H, s), 6.30 (1H, d), 7.10-7.40 (4H, m), 7.38 (1H, dd), 7.45 (1H, s), 7.58 (1H, d), 7.68 (2H, m) and 8.05 (1H, d). LRMS for M-1= 339. EXAMPLE 14 35 5-BROMO-N((E)-3-{5-CHLORO-2-[(6-FLUORO-2-NAPHTHYL 2)METHYL]PHENYLI-2-PROPENOYL)-2 METHOXYBENZENESULFONAMIDE SODIUM SALT (378) -91- WO 99/47497 PCT/CA99/00212 5 Step 1: 5-Bromo -N-((E)-3-{5-chloro-2-[(6-fluoro-2 naphthyl)methyll phenyll-2-propenovl)-2-methoxybenzenesulfonamide The coupling reaction of the acid of Example 1 Step 5 with 5 bromo-2-methoxybenzesulfonamide (500 mg; 1.47 mmol) was done according to step 5 of example 1 to yield 662 mg (77%) of the title 10 compound. The sodium salt was prepared with 1N NaOH. 1H NMR (DMSO-d6) 8 3.78 (3H, s), 4.22 (2H, s), 6.53 (1H, d), 7.17 (1H, d), 7.27 (1H, d), 7.35 (2H, m), 7.47 (1H, dd), 7.51 (1H, s), 7.58 (1H, d), 7.64 (1H, dd) and 7.75-7.90 (5H, m). LRMS for M-1= 588. 15 EXAMPLE 15 (E)-3-{5-CHLORO-2-[(6-CHLORO-2-NAPHTHYL)METHYL]PHENYLI-2 PROPENOIC ACID SODIUM SALT (469) 20 Step 1: 6-Chloro-2-naphthol The title compound was prepared from 2-(4 fluorophenyl)acetyl chloride according to step 3 of example 13. 1H NMR (CDCl 3 ) 8 7.10 (2H, m), 7.34 (1H, dd), 7.55-7.67 (2H, m) and 7.72 (1H, s). 25 Step 2: Ethyl (E)-3-{5-chloro-2-[(6-chloro-2-naphthyl)methll phenyl}-2 propenoate The title compound was prepared according to step 4 of example 13 in 30% yield. 30 'H NMR (CDCl 3 ) 6 1.23 (3H, t), 4.20 (4H, m), 6.29 (1H, d), 7.10 (1H, d), 7.22 (2H, m), 7.33 (1H, dd), 7.42 (1H, s), 7.53 (1H, d), 7.61 (2H, d), 7.70 (1H, s) and 7.91 (1H, d). Step 3: (E)-3-{5-Chloro-2-[(6-chloro-2-naphthyl)methvllphenyll-2 35 propenoic acid, sodium salt The hydrolysis of the ester of Step 2 (620 mg; 1.6 mmol) was done according to step 4 of example 1 to yield 500mg (87%) of the title compound. -92- WO 99/47497 PCT/CA99/00212 5 'H NMR (CDCl 3 ) 6 4.22 (2H, s), 6.30 (1H, d), 7.15 (1H, d), 7.20-7.39 (3H, m), 7.43 (1H, s), 7.56 (1H, s), 7.62 (2H, t), 7.75 (1H, s) and 8.02 (1H, d). Elemental analysis calcd for C 2 0
H
1 3 Cl 2 NaO 2
-H
2 0 : C, 60.48; H, 3.78; Found C, 60.68, H, 3.63. 10 -93- WO 99/47497 PCT/CA99/00212 5 EXAMPLE 16 5-BROMO-N((E)-3-{5-CHLORO-2-[(6-CHLORO-2-NAPHTHYL 2)METHYL]PHENYL}-2-PROPENOYL)-2 METHOXYBENZENESULFONAMIDE, SODIUM SALT (450) 10 Step 1: 5-Bromo -N-((E)-3-{5-chloro-2-[(6-chloro-2 naphthyl)methyllphenyll-2-propenovl)-2-methoxybenzenesulfonamide The coupling reaction of the acid of Example 15 Step 3 (500 mg; 1.4 mmol) was done according to step 5 of example 1 with 5-bromo 2-methoxybenzesulfonamide to yield 662 mg (74%) of the title compound. 15 The sodium salt was prepared with 1N NaOH. 1H NMR (DMSO-d6) 8 3.78 (3H, s), 4.22 (2H, s), 6.53 (1H, d), 7.20 (1H, d), 7.30-7.40 (2H, m), 7.45 (2H, m), 7.55 (1H, s), 7.59 (1H, s), 7.79 (3H, m), 7.85-7.92 (2H, m) and 7.98 (1H, d). Elemental analysis calcd for C27H19BrCl2NNaO4S .2H20: 20 C, 49.01; H, 3.33; N, 2.14; Found C, 48.89, H, 3.47; N, 2.11. EXAMPLE 17 (E)-3-(5-CHLORO-2-{[6-DIFLUOROMETHOXY)-2 NAPHTHYLIMETHYLIPHENYL-2-PROPENOIC ACID, SODIUM SALT 25 (505) Step 1: 6-Bromo-2-difluoromethoxynaphthalene Methyl chlorodifluoroacetate (5.3 mL) was added dropwise to 6-bromonaphthol (10.25 g; 45.9 mmol) and potassium carbonate (7.61g; 30 55.1 mmol) at 90 OC in 160 mL of DMF for 6 h. Purification by gel silica chromatography (3% EtOAc in hexane) gave 4.80 g (38%) of the title compound. 1H NMR (CDCl3) 6 6.61 (1H, t), 7.31 (1H,dd), 7.48 (1H, d), 7.56 (1H, dd), 7.67 (1H, d), 7.72 (1H, d) and 8.01 (1H, d). 35 Step 2: Ethyl (E)-3-(5-chloro-2-{ [6-difluoromethoxy)-2 naphthyllmethyllphenvl)-2-propenoate -94 - WO 99/47497 PCT/CA99/00212 5 The corresponding boronic acid of the previous halide was coupled according to step 3 of example 1 of the title compound in 57% yield. 1H NMR (CDCl3) 8 1.25 (3H, t), 4.22 (4H, m), 6.28 (1H, d), 6.53 (1H, t), 7.11 (1H, d), 7.25 (2H, m), 7.45 (2H, d), 7.55 (1H, d), 7.72 (2H, t) 10 and 7.92 (1H, d). Step 3: (E)-3-(5-Chloro-2-1[6-difluoromethoxv)-2-naphthyllmethyllphenvl) 2-propenoic acid, sodium salt The hydrolysis of the ester of Step 2 (1.9 g; 4.7 mmol) was 15 done according to step 4 of example 1 to yield 600mg of the title compound. 1H NMR of sodium salt (DMSO-d6) 8 4.20 (2H, s), 6.29 (1H, d), 7.10-7.40 (6H, m), 7.58 (3H, m) and 8.84 (2H, t). HRMS calc'd for C21H14O3F2ClNa +H= 411.0575; Found: 20 411.0577. EXAMPLE 18 5-BROMO-N-[(E)-3-(5-CHLORO-2-{[6-DIFLUOROMETHOXY)-2 NAPHTHYLMETHYL)-2-PROPENOYL]-2 25 METHOXYBENZENESULFONAMIDE, SODIUM SALT (447) Step 1: 5-Bromo -N-[(E)-3-(5-chloro-2-{[6-difluoromethoxy)-2 naphthyllmethyllphenvl)-2-propenovll-2-methoxvbenzennesulfonamide The coupling reaction of the acid of Example 17 Step 3 30 (1.00g; 2.57 mmol) was done according to step 5 of example 1 with 5 bromo-2-methoxybenzesulfonamide to yield 915 mg (56%) of the title compound. The sodium salt was prepared with 1N NaOH. 1H NMR of sodium salt DMSO-d6) 8 3.66 (3H, s), 4.18 (2H, s), 6.36 (1H, d), 6.92 (1H, d), 7.20-7.35 (5H, m), 7.48 (2H, m), 7.55-7.65 (3H, 35 m) and 7.80 (3H, M). LRMS for M-1= 634. - 95- WO 99/47497 PCT/CA99/00212 5 EXAMPLE 19 (E)-3-[2-(3,4-DICHLOROBENZYL)-5-CHLOROPHENYL]-2-PROPENOIC ACID, SODIUM SALT (535) Step 1: Ethyl (E)-3-[2-(3,4-dichlorobenzyl)-5-chlorophenyl)-2-propenoate 10 The benzyl bromide of step 2 of example 13 was treated with 3,4-dichlorobenzeneboronic acid according to the procedure described in step 3 of example 1 to yield the title compound in 67% yield. 1H NMR (CDCl3) 8 1.30 (3H, t), 4.00 (2H, s), 4.23 (2H, q), 6.30 (1H, d), 6.90 (1H,dd), 7.09 (1H, d), 7.15 (1H, s), 7.28 (1H, m), 7.32 (1H, d), 15 7.55 (1H, d) and 7.79 (1H, d). Step 2: (E)-3-[2-(3.4-Dichlorobenzyl)-5-chlorophenvl)-2-propenoic acid, sodium salt The hydrolysis of the ester of Step 1 (1.00 g; 2.7 mmol) was 20 done according to step 4 of example 1 to yield 907 mg (98%) of the title compound. 1H NMR (CDCl3) 8 3.95 (2H, s), 6.30 (1H, d), 6.86 (1H, d), 7.08 (2H, m), 7.32 (2H, m), 7.55 (1H, s) and 7.90 (1H, d). LRMS for M-1= 339. 25 EXAMPLE 20 5-BROMO-N-{(E)-3-[5-CHLORO-2-(3,4-DICHLOROBENZYL)PHENYL]-2 PROPENOYL}-2-METHOXYBEZENESULFONAMIDE, SODIUM SALT 30 (421) Step 1: 5-Bromo-N-{(E)-3-[5-chloro-2-)3,4-dichlorobenzvl)phenyll-2 propenoyll-2-methoxvbenzenesulfonamide The coupling reaction of the acid of Example 19 Step 2 (0.600 35 g; 1.75 mmol) was done according to step 5 of example 1 with 5-bromo-2 methoxybenzesulfonamide to yield 548 mg (53%) of the title compound. The sodium salt was prepared with 1N NaOH. -96- WO 99/47497 PCT/CA99/00212 5 1H NMR (DMSO-d6) 6 3.85 (3H, s), 4.10 (2H, s), 6.54 (1H, s), 7.01 (1H, d), 7.22 (1H, d), 7.32 (2H, m), 7.40-7.50 (2H, m), 7.56 (1H, s), 7.67 (1H, d), 7.86 (1H, d), 7.91 (1H, s) and 12.37 (1J, s). LRMS for M-1= 586. 10 EXAMPLE 21 5-BROMO-N-{(E)-3-[4-CHLORO-2-(2-NAPHTHYLMETHYL)PHENYL]-2 PROPENOYLI-2-METHOXYBENZENESULFONAMIDE, SODIUM SALT (449) 15 Step 1: Ethyl (E)-3-{4-chloro-2-[(2-naphthylmethyl)phenyll-2-propenoate 2-Bromo-5-chloro toluene (20.0 g) was converted to the corresponding aldehyde and then to the cinnamate according to step 1 of example 13. This cinnamate was converted to the benzylic bromide according to step 2 of example 1 and coupled via a Suzuki coupling 20 reaction according to step 3 of example 1 with naphthalene boronic acid to yield the title compound. 'H NMR (CDCl 3 ) 8 1.30 (3H, t), 4.22 (4H, m), 6.29 (1H, d), 7.15-7.27 (3H, m), 7.42 (2H, m), 7.52 (2H, m), 7.75 (3H, m) and 7.99 (1H, d). 25 Step 2: (E)-3-{4-Chloro-2-[(2-naphthylmethyl)phenvl}-2-propenoic acid (530) The hydrolysis of the ester of Step 1 (0.56 g; 1.57 mmol) was done according to step 4 of example 1 to yield 450 mg (88%) of the title compound. 30 'H NMR (CDCl 3 ) 5 4.24 (2H, s), 6.30 (1H, d), 7.20-7.30 (3H, m), 7.42 (2H, m), 7.51 (2H, m), 7.75 (3H, m) and 8.09 (1H, d). LRMS for M-1= 321. Step 3: 5-Bromo-N-{ [(E)-3- [4-chloro-2-(2 35 naphthylmethyl)phenyllpropenovl}-2-methoxvbenzenesulfonamide The coupling reaction of the acid of Step 2 (0.296 g; 0.89 mmol) was done according to step 5 of example 1 with 5-bromo-2 methoxybenzesulfonamide to yield 213 mg (42%) of the title compound. The sodium salt was prepared with 1N NaOH. -97- WO 99/47497 PCT/CA99/00212 5 'H NMR (ACETONE-MEOH-d 6 ) 8 3.70 (3H, s), 4.20 (2H, s), 6.44 (1H, d), 6.95 (2H, m), 7.25 (3H, m), 7.40 (2H, m), 7.55 (3H, m), 7.75 (3H, m), 7.95 (1H, d) and 8.02 (1H, d). LRMS for M-1= 568. -98- WO 99/47497 PCT/CA99/00212 5 EXAMPLE 22 (E)-3-[5-METHOXY-2-(2-NAPHTHMETHYL)PHENYL-2-PROPENOIC ACID, SODIUM SALT (534) Step 1: (2-Bromo-4-methoxyphenyl)(2-naphthyl)methanone 10 AlCl3 (17.48 g; 131.1 mmol) was added portionwise to a mixture of 3-bromocresol (16.04 g; 87.4 mmol) and 2-naphthoyl chloride (25.00 g; 131.1 mmol) in 50 mL of CHCl3 gave 14.0 g (47%) of the title compound. 1H NMR (CDCl3) 8 3.78 (31, s), 6.92 (1H, dd), 7.19 (1H, d), 15 7.38 (iH, d), 7.50 (1H, t), 7.59 (1H, t), 7.89 (3H, m), 7.95 (1H, dd) and 8.18 (1H, s). Step 2: 2-(2-Bromo-4-methoxvbenzyl)naphtalene To the methanone of Step 1 (14.0 g) and triethylsilane (15 20 mL) in 15 mL of CHCl3 was added TFA and was heated to 50 0 C overnight. The solution was cooled and quenched with NaOH (2N) to provide the title compound in 82% yield. 1H NMR (CDCl3) 6 3.75 (3H, s), 4.20 (2H, s), 6.75 (1H, dd), 7.07 (1H, d), 7.12 (1H, s), 7.30 (1H, d), 7.42 (2H, m), 7.58 (1H, s) and 7.76 25 (3H, m). Step 3: Ethyl (E)-3-[5-methoxv-2-(2-naphthylmethyl)phenyll-2 propenoate The naphthalene of Step 2 was converted to the 30 corresponding aldehyde according to the step 1 of example 13 in 98% yield. This aldehyde was then converted to the cinnamate according to step 1 of example 13 in 90% yield. 1H NMR (CDCl3) 8 3.70 (3H, s), 4.11 (4H, m), 6.20 (1H, d), 6.77 (1H, dd), 6.99 (1H, d), 7.03 (1H, d), 7.15 (1H, d), 7.30 (2H, m), 7.39 (1H, 35 s), 7.60-7.70 (3H, m) and 7.90 (1H, s). Step 4: (E)-3-[5-Methoxy-2-(2-naphthmethyl)phenyll-2-propenoic acid -99- WO 99/47497 PCT/CA99/00212 5 The hydrolysis of the ester of Step 3 (2.83 g; 8.2 mmol) was done according to step 4 of example 1 to yield 2.16 g (83%) of the title compound. The sodium salt was prepared with 1N NaOH. 1H NMR (CDCl3) 8 3.70 (3H, s), 4.13 (2H, s), 6.20 (1H, d), 6.80 10 (1H, dd), 7.02 (2H, m), 7.15 (1H, d), 7.29 (2H, m), 7.39 (1H, s), 7.62 (3H, m) and 8.03 (1H, d). LRMS calcd for M-1= 317. 15 EXAMPLE 23 5-BROMO-2-METHOXY-N-{(E)-3-[5-METHOXY-2-(2 NAPHTHYLMETHYL)PHENYL]-2 PROPENOYL}BENZENESULFONAMIDE SODIUM SALT (448) 20 Step 1: 5-Bromo-2-methoxv-N-{(E)-3-[5-methoxy-2-(2 naphthylmethyl)phenyll-2-propenoyl}benzenesulfonamide The coupling reaction of the acid of Example 22 Step 4 (0.600 g; 1.88 mmol) was done according to step 5 of example 1 with 5-bromo-2 methoxybenzesulfonamide to yield 573 mg (57%) of the title compound. 25 The sodium salt was prepared with 1N NaOH. 1H NMR (CDCl3) 8 3.72 (3H, s), 3.77 (3H, s), 4.13 (2H, s), 6.40 (1H, d), 6.70 (1H, d), 6.85 (1H, dd), 7.02 (1H, d), 7.10-7.20 (2H, m), 7.37 (3H, m), 7.57 (1H, dd), 7.60-7.80 (3H, m),7.95 (1H, d), 8.15 (1H, d) and 9.12 (1H, broad s). 30 LRMS calcd for M-1= 564. EXAMPLE 24 (E)-3-[5-CHLORO-2-(4-CHLOROBENZYL)PHENYL]-2-PROPENOIC 35 ACID SODIUM SALT (537) Step 1: Ethyl(E)-3-[5-chloro-2-(4-chlorobenzyl)phenvll-2-propenoate - 100 - WO 99/47497 PCT/CA99/00212 5 The benzyl bromide of step 2 of example 13 was coupled in a Suzuki coupling reaction with 4-chlorobenzene boronic acid according to the procedure of step 2 example 1 to yield 69% of the title compound. 1H NMR (CDCl3) 8 1.30 (3H, t), 4.02 (2H, s), 4.22 (2H, q), 6.29 (1H, d), 6.99 (2H, d), 7.08 (1H, d), 7.20-7.30 (3H, m), 7.52 (1H, s) and 7.83 10 (1H, d). Step 2: (E)-3-[5-Chloro-2-(4-chlorobenzvl)phenvll-2-propenoic acid The hydrolysis of the ester of Step 1 (1.14 g; 3.4 mmol) was done according to step 4 of example 1 to yield 860 mg (83%) of the title 15 compound. The sodium salt was prepared with 1N NaOH. 1H NMR (CDCl3) 8 4.04 (2H, s), 6.30 (1H, d), 7.00 (2H, d), 7.10 (1H, d), 7.23 (2H, d), 7.29 (1H, d), 7.55 (1H, s) and 7.95 (1H, d). LRMS called for M-1= 305. 20 EXAMPLE 25 (E)-3-{2-[(5-(PHENYLMETHOXY)INDOLYL)METHYL]-5 FLUOROPHENYL}-N-[(5-BROMO-2-METHOXYPHENYL)SULFONYL] 2-PROPENAMIDE (451) 25 Step 1: Ethyl (E)-3-(5-fluoro-2-methylphenyl)-2-propenoate 5-Fluoro-2-methylbenzaldehyde (40.58 g; 294 mmol) was converted to the ethyl cinnamate according to step 1 of example 1 to yield 40.81 g. of the title compound. 30 1H NMR (acetone-d) 6 1.29 (3H, t), 2.40 (3H, s), 4.23 (2H, q), 6.49 (1H, d), 7.07 (1H, td), 7.29 (1H, dd), 7.46 (1H, dd) and 7.87 (1H, dd). Step 2: Ethyl (E)-3-[2-(bromomethyl)-5-fluorophenyll-2-propenoate The ester of Step 1(40.80 g; 196 mmol) was converted to the 35 benzylic bromide according to step 2 of example 1 to yield 24.17 g of the title compound. 'H NMR (acetone-d 6 ) 6 1.30 (3H, t), 4.24 (2H, q), 4.81 (2H, s), 6.62 (1H, d), 7.18 (1H, td), 7.58 (2H, m) and 8.02 (1H, dd). - 101 - WO 9.9/47497 PCT/CA99/00212 5 Step 3: Ethyl (E)-3-{2-[(5-(phenylmethoxy)indolyl)methyl]-5 fluorophenvl}-2-propenoate The benzylic bromide of Step 2 (3.16 g; 11.0 mmol) was coupled with 5-(phenylmethoxy)indole according to the same procedure described in step 1 of example 2 to yield 2.27 g of the title compound. 10 'H NMR (acetone-d 6 ) S 1.27 (3H, t), 4.20 (2H, q), 5.11 (2H, s), 5.59 (2H, s), 6.43 (1H, dd), 6.52 (1H, d), 6.80 (1H, dd), 6.86 (1H, dd), 7.08 (1H, td), 7.19 (1H, d), 7.22 (1H, d), 7.31 (2H, m), 7.38 (2H, m), 7.50 (2H, m), 7.55 (1H, dd) and 8.01 (1H, dd). 15 Step 4: (E)-3-{2-[(5-(Phenylmethoxy)indolyl)methyl]-5-fluorophenyll-2 propenoic acid (493) The hydrolysis of the ester of Step 3 (2.27 g) was done according to step 4 of example 1 to yield 2.07 g of the title compound. 'H NMR (acetone-d 6 ) 6 5.11 (2H, s), 5.62 (2H, s), 6.43 (1H, dd), 20 6.53 (1H, d), 6.75 (1H, dd), 6.86 (1H, dd), 7.08 (1H, td), ), 7.19 (1H, d), 7.25 (1H, d), 7.31 (2H, m), 7.38 (2H, m), 7.50 (2H, m), 7.56 (1H, dd) and 8.04 (1H, dd). Elemental analysis calcd. for C 25
H
2 0 FN03.2H 2 0: C, 68.64; H, 5.53; N, 3.20; Found: C, 68.16; H, 4.95; N, 3.06. 25 Step 5: (E)-3-{2-[(5-(Phenylmethoxy)indolyl)methyl-5-fluorophenyl}-N [(5-bromo-2-methoxyphenyl)sulfonyll-2-propenamide The acid of Step 5 (2.06; 5.13 mmol) was coupled with 5 bromo-2-methoxybenzenesulfonamide of example 10, step 5 according to step 5 of example 1 to yield 2.44 g of the title compound. 30 'H NMR (acetone-d 6 ) 6 3.93 (3H, s), 5.10 (2H, s), 5.59 (2H, s), 6.39 (1H, dd), 6.73 (1H, dd), 6.78 (1H, d), 6.81 (1H, dd), 7.09 (1H, td), ), 7.18 (1H, d), 7.24 (3H, m), 7.32 (1H, m), 7.39 (3H, m), 7.49 (2H, m), 7.82 (1H, dd), 8.01 (1H, dd) and 8.09 (1H, d). Elemental analysis calcd. for C32H2 6 BrFN 2 Os2: C, 59.17; H, 4.03; N, 4.31; S, 4.94; Found: C, 59.07; H, 35 4.01; N, 4.34; S, 5.16. EXAMPLE 26 - 102 - WO 99/47497 PCT/CA99/00212 5 (E)-3-[2-(BENZO[B]THIOPHEN-2-YLMETHYL)-5-FLUOROPHENYL]-N [(5-BROMO-2-METHOXYPHENYL)SULFONYL]-2-PROPENAMIDE SODIUM SALT (452) Step 1: Ethyl (E)-3-[2-(benzo[bithiophen-2-vlmethyl)-5-fluorophenyll-2 10 propenoate The ester (901 mg, 3.14 mmol) of example 13, step 2 was coupled with benzo[b]thiophene-2-boronic acid (from Lancaster Chemical) in DME according to the same procedure described in step 3 of example 10 to yield 657 mg of the title compound. 15 'H NMR (acetone-d) S 1.22 (3H, t), 4.16 (2H, q), 4.43 (2H, s), 6.50 (1H, d), 7.03 (1H, s), 7.15-7.35 (3H, m), 7.47 (1H, dd), 7.56 (1H, dd), 7.69 (1H, dd), 7.78 (1H, dd) and 8.00 (1H, dd). Step 2: (E)-3-[2-(benzo[bithiophen-2-vlmethyl)-5-fluorophenyll-2 20 propenoic acid (539) The hydrolysis of the ester of Step 1 (657 mg) was done according to step 4 of example 1 to yield 345 mg of the title compound. 'H NMR (acetone-d 6 ) S 4.45 (2H, s), 6.51 (1H, d), 7.04 (1H, d), 7.2-7.3 (3H, m), 7.49 (1H, dd), 7.57 (1H, dd), 7.70 (1H, d), 7.80 (1H, m) and 25 8.01 (1H, dd). Elemental analysis calcd. for C18HI 3 FO2S: C, 69.21; H, 4.19; Found: C, 68.96; H, 4.15. Step 3: (E)-3-[2-(Benzo[b]thiophen-2-ylmethyl)-5-fluorophenyl]-N-[(5 bromo-2-methoxyphenyl)sulfonyll-2-propenamide 30 The previous acid (264 mg; 0.85 mmol) was coupled with 5 bromo-2-methoxybenzenesulfonamide of example 10, step 5 according to step 5 of example 1 to yield 287 mg of the title compound. 1H NMR (acetone-d 6 ) S 3.83 (3H, s), 4.43 (2H, s), 6.77 (1H, d), 7.00 (1H, d), 7.13 (iH, d), 7.2-7.3 (3H, m), 7.41 (1H, dd), 7.49 (1H, dd), 7.65 35 (1H, dd), 7.78 (2H, m), 7.96 (1H, dd)HH and 8.05 (1H, d). The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 2 5 Hl 8 BrFNNaO 4
S
2
-H
2 0: C, 50.01; H, 3.36; N, 2.33; Found: C, 49.84; H, 3.22; N, 2.41. - 103 - WO 99/47497 PCT/CA99/00212 5 EXAMPLE 27 N-(E)-[(5-BROMO-2-METHOXYPHENYL)SULFONYL-3-(5-FLUORO-2 {[1-BENZYLINDOL-5-YL]METHYL}PHENYL)-2-PROPENAMIDE SODIUM SALT (453) 10 Step 1: Ethyl (E)-3-[5-fluoro-2-(indol-5-vlmethyl)phenvll-2-propenoate The ester (1.83 g, 6.37 mmol) of example 13, step 2 was coupled with 5-indolyl boronic acid and NaHCO 3 in DME according to the procedure described in step 3 of example 10 to yield 1.08 g of the title compound. 15 'H NMR (acetone-d 6 ) 8 1.26 (3H, t), 4.17 (2H, q), 4.21 (2H, s), 6.37 (1H, m), 6.44 (1H, d), 6.94 (1H, dd), 7.14 (1H, td), 7.27-7.37 (4H, m), 7.51 (1H, dd), 8.05 (1H, dd) and 10.13 (1H, s). Step 2: Ethyl (E)-3-(5-fluoro-2-{[1-benzvlindol-5-vllmethyllphenvl)-2 20 propenoate The indole of Step 1 (621 mg; 1.92 mmol) was coupled with benzyl bromide according to the procedure described in step 1 of example 2 to yield 678 mg of the title compound. 'H NMR (acetone-d) 8 1.26 (3H, t), 4.17 (4H, m), 5.32 (2H, s), 25 6.43 (2H, m), 6.95 (1H, dd), 7.1-7.4 (11H, m), 7.49 (1H, dd) and 8.08 (1H, dd). Step 3: (E)-3-(5-Fluoro-2-{[1-benzylindol-5-yllmethyl}phenyl)-2-propenoic acid) (540) 30 The hydrolysis of the ester of Step 2 (678 mg) was done according to step 4 of example 1 to yield 276 mg of the title compound. 'H NMR (acetone-d) 8 4.20 (2H, s), 5.38 (2H, s), 6.39 (1H, d), 6.45 (1H, d), 6.95 (1H, d), 7.1-7.3 (10H, m), 7.48 (1H, d) and 8.04 (1H, dd). Elemental analysis calcd. for C 25
H
20 FN0 2 : C, 77.91; H, 5.23; N, 3.63; 35 Found: C, 78.52; H, 5.46; N, 3.66. Step 4: N-(E)-[(5-Bromo-2-methoxyphenyl)sulfonyl]-3-(5-fluoro-2-{[1 benzylindol-5-vllmethyllphenvl)-2-propenamide - 104
-
WO 99/47497 PCT/CA99/00212 5 The acid of Step 3 (219 mg; 0.57 mmol) was coupled with 5 bromo-2-methoxybenzenesulfonamide of example 10, step 5 according to step 5 of example 1 to yield 149 mg of the title compound. 'H NMR (acetone-d) 8 3.82 (3H, s), 4.18 (2H, s), 5.38 (2H, s), 6.36 (1H, dd), 6.72 (1H, d), 6.90 (1H, dd), 7.1-7.4 (12H, m), 7.78 (1H, dd), 10 7.98 (1H, dd) and 8.05 (1H, d). The acid was converted to the sodium salt with 1 equivalent of NaOH. Elemental analysis calcd. for C 32
H
2 5 BrFN 2 NaO 4 S. 1/2H 2 0: C, 57.84; H, 3.94; N, 4.22; Found: C, 57.61; H, 3.86; N, 4.16. - 105 - WO 99/47497 PCT/CA99/00212 5 EXAMPLE 28 N-(E)-[(2,4-DIMETHYL(1,3-THIAZOL-5-YL))SULFONYL-3-{3-[(5 CHLOROINDOLYL)METHYL1(2-PYRIDYL)1-2-PROPENAMIDE (444) Step 1: Ethyl (E)-3-(3-methyl-2-pyridyl)-2-propenoate 10 To a solution of 2-bromo-3-methylpyridine (10.36 g; 60.2 mmol) in 120 mL of THF at -100 "C was added dropwise a 1.6 M solution of n-BuLi (65.6 mmol). After 20 min of stirring at that temperature, 1 formylpiperidine (7.65 g) in 10 mL of THF was added and the solution was warmed to r.t.. After 30 min of stirring at r.t., triethyl 15 phosphonoacetate (13.7 mL; 69.1 mmol) was added dropwise below 30 "C. After 1 h of stirring, the mixture was quenched with NH 4 0Ac (25%) and extracted with EtOAc. The solvent was removed and the crude oil was purified by silica gel chromatography (25% EtOAc in hexane) to yield 10.32 g of the title compound. 20 'H NMR (acetone-d 6 ) S 1.29 (3H, t), 2.46 (3H, s), 4.22 (2H, q), 6.99 (1H, d), 7.27 (1H, dd), 7.64 (1H, dt), 7.90 (1H, d) and 8.45 (1H, m). Step 2: Ethyl (E)-3-[3-(bromomethyl)-2-pvridvll-2-propenoate The ester of Step 1 (5.93 g; 31.0 mmol) was converted in 25 benzene to the benzylic bromide according to the procedure described in step 2 of example 1 to yield 1.83 g of the title compound. 1H NMR (acetone-d 6 ) S 1.30 (3H, t), 4.25 (2H, q), 4.88 (2H, s), 7.10 (1H, d), 7.41 (1H, dd), 7.91 (1H, dd), 8.03 (1H, d) and 8.60 (1H, dd). 30 Step 3: Ethyl (E)-3-{3-[(5-chloroindolyl)methyll-2-pyridvl}-2-propenoate The benzylic bromide of Step 2 (1.33 g; 4.91 mmol) was coupled with 5-chloroindole according to the procedure described in step 1 of example 2 to yield 1.22 g of the title compound. 'H NMR (acetone-d 6 ) 6 1.28 (3H, t), 4.22 (2H, q), 5.78 (2H, s), 35 6.57 (1H, d), 6.94 (1H, d), 7.04 (1H, d), 7.11 (1H, dd), 7.27 (1H, dd), 7.43 (2H, m), 7.63 (1H, d), 7.99 (1H, d) and 8.53 (1H, d). Step 4: (E)-3-{3-[(5-Chloroindolvl)methyll-2-pyridyll-2-propenoic acid (542) - 106 - WO 99/47497 PCT/CA99/00212 5 The hydrolysis of the ester of Step 3 (283 mg) was done according to step 4 of example 1 to yield 291 mg of the title compound. 'H NMR (acetone-d 6 ) 3 5.81 (2H, s), 6.57 (1H, d), 6.88 (1H, d), 7.05 (1H, d), 7.11 (1H, dd), 7.26 (1H, dd), 7.43 (2H, m), 7.63 (1H, d), 8.02 (1H, d) and 8.54 (1H, d). Elemental analysis calcd. for 10 C H ClN202.1/4H20: C, 64.36; H, 4.29; N, 8.83; Found: C, 64.63; H, 4.43; N, 8.65. Step 5: N-(E)-[(2.4-Dimethyl(1,3-thiazol-5-yl))sulfonyll-3-13-[(5 chloroindolvl)methyll (2-pyridvl)}-2-propenamide 15 The acid of Step 4 (283 mg; 0.90 mmol) was coupled with 2,4 dimethyl-1,3-thiazole-5-sulfonamide (from Maybridge Chemical) according to step 5 of example 1 to yield 315 mg of the title compound. 'H NMR (acetone-d) 8 2.64 (3H, s), 2.69 (3H, s), 5.81 (2H, s), 6.56 (1H, d), 6.84 (1H, d), 7.09 (1H, dd), 7.26 (1H, dd), 7.31 (1H, d), 7.41 (2H, 20 m), 7.62 (1H, d), 8.05 (1H, d) and 8.51 (1H, d). Elemental analysis calcd. for C 2 2
H
1 9
CN
4 0 3
S
2 : C, 54.26; H, 3.93; N, 11.50; S, 13.17; Found: C, 54.69; H, 4.03; N, 11.18; S, 12.89. EXAMPLE 29 25 N-{(E)-3-[5-CHLORO-2-(2-NAPHTHYLMETHYL)PHENYL]-2 PROPENOYL-2-METHOXYBENZENESULFONAMIDE (302) The coupling reaction of the acid (3.00 g; 9.1 mmol) of Step 5 in Example 12 was done with 5-bromo-2-methoxybenzesulfonamide (2.56g; 9.6 mmol) according to Step 5 of Example 1 to yield 4.13g (79 %) of 30 the title compound. The sodium salt was prepared with 1N NaOH. 'H NMR (DMSO-d) d 3.76 (3H, s), 4.25 (2H, s), 6.52 (1H, d), 7.15 (1H, d), 7.26 (1H, d), 7.36 (1H, d), 7.41-7.52 (4H, m), 7.58 (1H, s), 7.69 (1H, m), 7.78 (1H, d), 7.82 (3H, m), 7.89 (1H, d) and 12.38 (1H, br s). 35 Elemental analysis: Calcd. for C27H2OBrClNNaO4S.H20: C, 53.08; H, 3.64; N, 2.29; Found: C, 53.25; H, 3.89; N, 2.91. - 107 - WO 99/47497 PCT/CA99/00212 5 These intermediates were prepared according to the literature: 5-fluoro-2-methylbenzaldehyde: Servis, K. L.; Fang, K.-N. J. Am. Chem. Soc. 1968, 90, 6712 6717. 10 5-indolyl boronic acid: Yang, Y.; Martin, A. R. Heterocycles 1992, 34, 1395-1398. - 108 -

Claims (28)

1. A compound represented by formula I: R 1 R 2 R 3 -HET 0 A X-B Z 10 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from 0, S(O)n and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; A is a one or two atom moiety and is selected from the group 15 consisting of: -W-, -C(O)- , -C(R 7 ) 2 -W- , -W-C(R) 2 - , -CR7(OR20)_ -C(R) 2 - , -C(R 7 ) 2 -C(OR 2 0 )R 7 - , -C(R 7 ) 2 - C(R 7 ) 2 - or -CR 7 =CR 7 - , wherein W represents 0, S(O)n or NR17, with n as previously defined and R1 7 as defined below; X represents a 5-10 membered monocyclic or bicyclic aryl or 20 heteroaryl group having 1-3 heteroatoms selected from 0, S(O)n and N(O)m , and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents 0, S(O)n , NR17, a bond or -CR18 = CR18-; B represents - (C(R 1 8 )2)p-Y- (C(R 1 8 )2)q 25 wherein p and q are independently 0-3, such that when Y represents 0, S(O)n, NR17 or -CR18 = CR18- , p + q = 0-6, and when Y represents a bond, p + q is 1-6; Z is OH or NHSO 2 R 19 R' R 2 and R3 independently represent H, halogen, lower 30 alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra)4_ 9 , (C(R 4 )2)pSR 5 , -(C(R 4 ) 2 )OR 8 , -(C(R 4 ) 2 )pN(R 6 ) 2 , CN, NO2, -(C(R 4 ) 2 )pC(R) 3 , C0 2 R 9 , -CON(R) 2 or -(C(R 4 ) 2 )pS(O)nR 10 , wherein n and p are as previously defined; each R 4 is independently H, F, CF 3 or lower alkyl, - 109 - WO 9-9/47497 PCT/CA99/00212 5 or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from 0, S(O)n or N(O)m; each R' is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , lower alkyl-HET, lower alkenyl-HET or -(C(R 18 ) 2 )pPh(R")o 10 2; each R' is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF3, Ph, Bn and when two R' groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, optionally containing an additional heteroatom selected from 0, S(O)n or 15 N(O)m; each R' is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing from 0-2 heteroatoms selected from 0, S(O)n and N(O)m; 20 each R 8 represents H or R5; each R' is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; each R 0 is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , Ph(R")0-3, CH 2 Ph(R")0-3 or N(R6)2 ; 25 each R 11 is independently lower alkyl, SR 2 0 , OR 20 , N(R 6 ) 2 , -CO 2 R", -CON(R) 2 , -C(O)R", CN, CF3, NO 2 or halogen; each R 2 is independently H, lower alkyl or benzyl; each R1 3 is independently H, halo, lower alkyl, 0-lower alkenyl, S-lower alkyl, N(R 6 ) 2 , CO 2 R", CN, CF 3 or NO 2 ; 30 R" and R 1 5 are independently lower alkyl, halogen, CF3, OR 16 , S(O),R1 6 or C(R16) 2 0R1 7 ; each R1 6 is independently H, lower alkyl, lower alkenyl, Ph, Bn or CF 3 ; each R" is independently H, lower alkyl or Bn; 35 each R' 8 is independently H, F or lower alkyl, and when two Ri 8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one heteroatom chosen from 0, S(O)n or N; -110- WO 99/47497 PCT/CA99/00212 5 each R 19 is lower alkyl, lower alkenyl, lower alkynyl, CF 3 , HET(Ra)4_9, lower alkyl-HET(Ra)4_9 or lower alkenyl-HET(Ra)4_9; each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF 3 or Ph(R 3 ) 2 and 10 each Ra is independently selected from the group consisting of: H, OH, halo, CN, N02, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1-6alkylamino, di-C1 6alkylamino, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O) C2-6alkynyl, 15 CO2H, CO2C1-6alkyl, C02C2-6alkenyl, and CO2C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, 20 CO2H, CO2C1-6alkyl, C02C2-6alkenyl, C02C2-6alkynyl, NH2, NHCi 6alkyl and N(C1-6alkyl)2.
2. A compound represented by formula I: 25 R 1 R 2 R 3 - HET 0 A X-B Z or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein: HET represents a 5-12 membered monocyclic or bicyclic aromatic ring system containing 0-3 heteroatoms selected from 0, S(O)n 30 and N(O)m wherein m is 0 or 1 and n is 0, 1 or 2; A is a one or two atom moiety and is selected from the group consisting of: -W-, -C(O)- , -C(R 7 ) 2 -W- , -W-C(R 7 ) 2 - , -CR 7 (OR 2 0 )_ -C(R7 )2- , -C(R 7 ) 2 -C(OR 20 )R 7 - , -C(R 7 ) 2 - C(R) 2 - or -CR 7 =CR 7 - , wherein W represents 0, S(O)n or NR17, with n as previously defined and R1 7 as 35 defined below; -111- WO 99/47497 PCT/CA99/00212 5 X represents a 5-10 membered monocyclic or bicyclic aryl or heteroaryl group having 1-3 heteroatoms selected from 0, S(O)n and N(O)m , and optionally substituted with R14 and R15, and A and B are attached to the aryl or heteroaryl group ortho relative to each other; Y represents 0, S(O)n , NR17, a bond or -CR18 = CR1 8 -; 10 B represents - (C(Rl 8 )2)p-Y- (C(R 1 8 )2)q wherein p and q are independently 0-3, such that when Y represents 0, S(O)n , NR 1 7 or -CR1 8 = CR18- , p + q = 0-6, and when Y represents a bond, p + q is 1-6; Z is OH or NHSO 2 R' 9 ; 15 R1 R 2 and R 3 independently represent H, halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkenyl-HET(Ra) 4 _ 9 , -(C(R 4 )2)pSR 5 , -(C(R 4 ) 2 )OR 8 , -(C(R 4 ) 2 )pN(R 6 ) 2 , CN, NO 2 , -(C(R 4 ) 2 )pC(R)3, -C0 2 R 9 , -CON(R 6 ) 2 or -(C(R 4 ) 2 )pS(O)nR, wherein n and p are as previously defined; 20 each R 4 is independently H, F, CF 3 or lower alkyl, or two R 4 groups are taken in conjunction and represent a ring of up to six atoms, optionally containing one heteroatom selected from 0, S(O)n or N(O)m; each R' is independently lower alkyl, lower alkenyl, lower 25 alkynyl, CF 3 , lower alkyl-HET, lower alkenyl-HET or -(C(R) 2 )pPh(R")O 2; each R 6 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CF, Ph, Bn and when two R 6 groups are attached to N they may be taken in conjunction and represents a ring of up to 6 atoms, 30 optionally containing an additional heteroatom selected from 0, S(O)n or N(O)m; each R' is independently H, F, CF 3 or lower alkyl, and when two R 7 groups are presents, they may be taken in conjunction and represent an aromatic or aliphatic ring of 3 to 6 members containing 35 from 0-2 heteroatoms selected from 0, S(O)n and N(O)m; each R8 represents H or R5; each R 9 is independently H, lower alkyl, lower alkenyl, lower alkynyl, Ph or Bn; -112- WO 99/47497 PCT/CA99/00212 5 each R" is independently lower alkyl, lower alkenyl, lower alkynyl, CF 3 , Ph(R")0-3, CH 2 Ph(Ru)0-3 or N(R 6 ) 2 ; each R" is independently lower alkyl, SR 2 0 , OR 2 0 , N(R)2, -CO 2 R", -CON(R 6 ) 2 , -C(O)R", CN, CF3, NO 2 or halogen; each R 2 is independently H, lower alkyl or benzyl; 10 each R" is independently H, halo, lower alkyl, 0-lower alkenyl, S-lower alkyl, N(R) 2 , CO 2 R", CN, CF 3 or NO 2 ; R" and R1 5 are independently lower alkyl, halogen, CF3, OR1 6 , S(O)nR1 6 or C(R16) 2 0R 7 ; each R" is independently H, lower alkyl, lower alkenyl, Ph, 15 Bn, CHF2 or CF 3 . each R" is independently H, lower alkyl or Bn; each R" is independently H, F or lower alkyl, and when two R' 8 groups are present, they may be taken in conjunction and represent a ring of 3 to 6 members comprising carbon atoms and optionally one 20 heteroatom chosen from 0, S(O)n or N; each R" is lower alkyl, lower alkenyl, lower alkynyl, CF 3 , HET2(Ra)4_9, lower alkyl-HET 2 (Ra)49 or lower alkenyl-HET 2 (Ra)4_9, wherein HET 2 represents a member selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, imidazolyl and indolyl; 25 each R 20 is independently H, lower alkyl, lower alkenyl, lower alkynyl, CHF2 , CF 3 or Ph(R 3 ) 2 and each Ra is independently selected from the group consisting of: 30 H, OH, halo, CN, N02, amino, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, C1-6alkylamino, di-Ci 6alkylamino, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O) C2-6alkynyl, CO2H, CO2C1-6alkyl, C02C2-6alkenyl, and C02C2-6alkynyl, said alkyl, alkenyl, alkynyl and the alkyl portions of 35 alkylamino and dialkylamino being optionally substituted with 1-3 of: hydroxy, halo, aryl, C1-6 alkoxy, C2-6alkenyloxy, C2-6alkynyloxy, CF3, C(O)C1-6alkyl, C(O)C2-6alkenyl, C(O)C2-6alkynyl, CO2H, CO2C1-6alkyl, CO2C2-6alkenyl, CO2C2-6alkynyl, NH2, NHC1-6alkyl and N(C1-6alkyl)2. -113- WO 99/47497 PCT/CA99/00212 5
3. A compound in accordance with claim 1 wherein: HET represents a member selected from the group consisting of: benzene, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, 10 thiazole, imidazole, benzothiazole, triazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole, 1,3 methylenedioxobenzene and pyrrole.
4. A compound in accordance with claim 3 wherein: 15 HET is selected from the group consisting of: phenyl, biphenyl, naphthyl, indole, thiophene, benzofuran and quinoline.
5. A compound in accordance with claim 1 wherein: A represents a one or two atom moiety and is selected from 20 the group consisting of: S, S(O), SO2, CH2, -C(O)- , -OCH2-, -CHOH-, -C(OH)(CH3)- and -CH2-0-.
6. A compound in accordance with claim 5 wherein: A is selected from the group consisting of: : S, S(O), S02, 25 CH2 and -C(O)-.
7. A compound in accordance with claim 1 wherein: X represents phenyl optionally substituted with R" and R1 5 30
8. A compound in accordance with claim 7 wherein X represents phenyl and RM and R' are absent or represent halo.
9. A compound in accordance with claim 1 wherein: B represents CH=CH or 1,2-cyclopropyl. 35
10. A compound in accordance with claim 9 wherein: B represents CH=CH in the E-isomeric form. -114- WO 99/47497 PCT/CA99/00212 5
11. A compound in accordance with claim 9 wherein: Z is NHSO 2 R19.
12. A compound in accordance with claim 11 wherein: Z is NHSO 2 R 19 and R" 9 represents a member selected from 10 the group consisting of: lower alkyl and HET(Ra)3.
13. A compound in accordance with claim 12 wherein: R19 represents HET(Ra)3 and HET is selected from the group consisting of: phenyl, thienyl, naphthyl, furanyl, thiazolyl, 15 imidazolyl and indolyl.
14. A compound in accordance with claim 12 wherein: Z is NHSO 2 R1 9 and R1 9 represents benzene or thiophene, substituted with (Ra) 3 . 20
15. A compound in accordance with claim 1 wherein: Z represents OH.
16. A compound in accordance with claim 1 wherein: 25 HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, indole, tetrazole, imidazole, benzoxazole and pyrrole; 30 A represents a one or two atom moiety and is selected from the group consisting of: S, S(O), S02, CH2, -C(O)- , -OCH2- , -CHOH- , C(OH)(CH3 )- and -CH2-0-; X represents phenyl optionally substituted with R1 4 and R 1 5 ; B is CH=CH; 35 Z is NHSO 2 R 9 and R' 9 represents a member selected from the group consisting of: lower alkyl and HET(Ra) 3 . -115- WO 99/47497 PCT/CA99/00212 5
17. A compound in accordance with claim 1 wherein: HET represents a member selected from the group consisting of: phenyl, naphthalene, biphenyl, pyridine, quinoline, isoquinoline, furan, benzofuran, thiophene, benzothiophene, oxazole, thiazole, imidazole, benzothiazole, 1,2,5-thiadiazole, thienopyridine, 10 indole, tetrazole, imidazole, benzoxazole and pyrrole; A represents a one or two atom moiety and is selected from the group consisting of: S, S(O), S02, CH2, -C(O)- , -OCH2- , -CHOH-, -C(OH)(CH3 )- and -CH2-0-; X represents phenyl optionally substituted with R" and R 1 5 ; 15 B is CH=CH; Z is OH.
18. A compound represented in one of the following tables: 20 Table I R 1 R 2 R 3 - HET 0 A X-B NHSO 2 R 19 la (Compounds 1-323 and 347-454) R 1 R2R 3 -Het A X B RC 1-naphthyl CH 1,2-Ph CH=CH Ph(F), 2-naphthyl S(O)2 1,2-Ph CH=CH Ph(F), 2 3-methylindol CH2 12-Ph CH=CH 2-thienyl 3 -1-yl 2-naphthyl CR 1,2-Ph CH=CH 2-thienyl 4 2-naphthyl S(0), 1,2-Ph CH=CH phenyl 5 3-methylindol S(O) 2 1,2-Ph CH=CH 2-thienyl 6 -1-yl I -116- WO 99/47497 PCT/CA99/00212 R1R2R 3 -Het A X B R 9 Cpd 2-naphthyl S(0) 2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 7 phenyl 3,4-dichloro CH 2 1,2-Ph CH=CH 2-thienyl 8 phenyl 2-naphthyl S(O), 1,2-Ph CH=CH 2-thienyl 9 2,4-dichloro CH 2 1,2-Ph CH=CH 2-thienyl 10 phenyl 1-naphthyl S(O), 1,2-Ph CH=CH Ph(F), 11 1-naphthyl S(0) 2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 12 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-thienyl 13 3,4-chloro CH 2 1,2-Ph CH=CH 2-thienyl 14 fluoro phenyl 1-naphthyl CH, 1,2-Ph CH=CH 2-thienyl 15 3,4-dichloro S(0) 2 1,2-Ph CH=CH 2-thienyl 16 phenyl 4-methylthio CH 2 1,2-Ph CH=CH 2-thienyl 17 phenyl 4-chlorophenyl CH 1,2-Ph CH=CH 2-thienyl 18 2-naphthyl S 1,2-Ph CH=CH 2-thienyl 19 2-naphthyl O-CH2 1,2-Ph CH=CH 2-thienyl 20 2-naphthyl S(O) 1,2-Ph CH=CH 2-thienyl 21 1-naphthyl S(0)2 1,2-Ph CH=CH phenyl 22 2-benzofuranyl CH 1,2-Ph CH=CH 2-thienyl 23 3,5-dichloro CH 2 1,2-Ph CH=CH 2-thienyl 24 phenyl 1-naphthyl S(0)2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 25 phenyl 1-naphthyl S(0)2 1,2-Ph CH=CH 2-thienyl 26 3-(1,2-(methylene CH 2 1,2-Ph CH=CH 2-thienyl 27 dioxy)benzene) 2-naphthyl 0 1,2-Ph CH=CH 2-thienyl 28 RS-2-phenyl CH 2 1,2-Ph CH 2 -0 2-thienyl 29 RS-2-phenyl CH 2 1,2-Ph CH 2 -CH 2 2-thienyl 30 2-naphthyl S(O), 1,2-Ph CH 9 -0 2-thienyl 31 3-((2-(Qn)vinyl)) CH 2 1,2-Ph CH 2 -0 2-thienyl 32 phenyl 2-(6-benzyloxy) CH 2 1,2-Ph CH=CH 2-thienyl 33 naphthyl 3-((2-(Qn)vinyl)) SO 1,2-Ph CH 2 -0 2-thienyl 34 phenyl I I 3-((2-(Qn)vinyl)) -CHOH 1,2-Ph CH 2 -0 2-thienyl 35 phenyl - I -F I I -117- WO 99/47497 PCT/CA99/00212 RlR 2 R 3 -Het A X B R 9 Cpd 3-((2-(Qn)vinyl)) S(0) 2 1,2-Ph CH 2 -0 phenyl 36 phenyl 3-((2-(Qn)vinyl)) O-CH 2 1,2-Ph CH 2 -0 2-thienyl 37 phenyl 3-tolyl-D-3-phenyl 0-CH2 1,2-Ph CH 2 -0 2-thienyl 38 3-((2-(Qn)vinyl)) CH(OH -1,2-Ph CH 2 O phenyl 39 phenyl CHi 3-((2-(Qn)vinyl)) S 1,2-Ph CH 2 -0 2-thienyl 40 phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph CH 2 -0 phenyl 41 phenyl 3-((2-(Qn)vinyl)) C=O 1,2-Ph CH 2 -0 2-thienyl 42 phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph C(CH 3 ) 2 -0 2-thienyl 43 phenyl 3-((2-(Qn)vinyl)) 0 1,2-Ph CHG 2 -0 2-thienyl 44 phenyl 2-naphthyl CH, 1,2-Ph 1,2-c-propyl 2-thienyl 45 2-(6-benzyloxy) CH 2 1,2-Ph CH=CH 2-methoxy-5- 46 naphthyl bromophenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3,4-dichloro 47 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-fluoro 48 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-chloro 49 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-propyl 50 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2,5-dichloro 51 thienyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl styryl 52 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-chloro-4- 53 fluorophenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-methoxy 54 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-bromo 55 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 56 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 57 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 58 I __phenyl -118- WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 9 Cpd 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2,4-difluoro 59 phenyl 2-naphthyl CH, 1,2-Ph 1,2-c-propyl 4-butyl-phenyl 60 2-naphthyl CH2 1,2-Ph 1,2-c-propyl butyl 61 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 62 ' phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-trifluoro 63 methylphenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3,5-difluoro 64 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3,5-dichloro 65 phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 66 methyl)ethyl) phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-(hydroxy 67 methyl)phenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 3-(hydroxy 68 " methyl)phenyl 2-naphthyl CH2 12-Ph 1,2-c-propyl 4-(methyl 69 sulfonyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-(methyl 70 sulfonyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(propyl 71 sulfonyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro- 72 methyl)-hydroxy methyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 73 phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 74 methyl) ethyl)phenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 4-dimethyl 75 aminophenyl 2-naphthyl CH2 1,2-Ph 1,2-c-propyl cyclohexyl 76 2-naphthyl _ _ , 1,2-Ph 1,2-c-propyL cyclopentyl 77 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 4-morpholinYL 78 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-naphthyl 79 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-thiazolyl 80 2-naphthyl ___ 1,2-Ph 1,2-c-propyl 1-imidazolyl 81 2-naphthyl CH2 1,2-Ph 1,2-c-propyl 2-furanyl 82 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 83 furanyl -119- WO 99/47497 PCT/CA99/00212 R 1 R 2 R 3 -Het A X B R 19 Cpdl 2-naphthyl CH 1,2-Ph 1,2-c-propyl 2-pyridinyl 84 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 85 ____ ____ ____ _ ______pyridinyl 2-naphthyl CH 1,2-Ph 1,2-c-propyl 3-indolyl 86 2-naphthyl CH 1,2-Ph 1,2-c-propyl 4-nitrophenyl 87 CHpthl 1,2-Ph 1,2-c-propyl 4-cyanophenyl 88 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 89 methyl)ethyl) ____ ____ ____ ______phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(hydroxy 90 _____________methyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(hydroxy 91 ____ ____ ___ _ __ ____ _ _ ____ ___ methyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 92 ____ ___ ____ _ _ ____ ___ phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 93 ____ ____ ___ _ __ ____ _ _ ____ ___ phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,4-difluoro 94 ____ ____ ___ _ __ ____ _ _ ____ ___ phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(methyl 95 ____________ _ ___ ___sulfonyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(methyl 96 ________sulfonyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(propyl 97 _________sulfonyl)phenyl 2-naphthyl S(0)2 1,2-Ph 1,2-c-propyl 4-butyl-phenyl 98 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 ) 99 _________phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro 100 methyl)-hydroxy _____ ________methyl)phenyl 2-naphthyl S(0)2 1,2-Ph 1,2-c-propyl 3-bromophenyl 101 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 102 ______ ________phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 103 ____ ___ ___ __ _ ___ ___phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-isopropyl 104 ____ ____ ____ ______phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 105 methyl) _____________ _ ____ ___ ethyl)phenyl 2-naphthyl S(O) 2 1,2-Ph 1,-c-propyl 4-methoxy 106 ___ ___ ___ ___ __ ___ __1,2 __ phenyl - 120 - WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B Cpd 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-dimethyl 107 aminophenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,4-dichloro 108 phenyl 2-naphthyl S(0) 2 1,2-Ph 1,2-c-propyl 3,4-difluoro 109 phenyl 2-naphthyl S(0), 1,2-Ph 1,2-c-propyl 4-fluorophenyl 110 2-naphthyl S 1,2-Ph 1,2-c-propyl cyclohexyl 111 2-naphthyl S(O)2 1,2-Ph 1,2-c-propyl cyclopentyl 112 2-naphthyl S(O)2 1,2-Ph 1,2-c-propyl 4-morpholinyl 113 2-naphthyl S( 1,2-Ph 1,2-c-propyl butyl 114 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-chlorophenyl 115 2-naphthyl S 1,2-Ph 1,2-c-propy 4-propylphenyl 116 2-naphthyl _ S(O 1,2-Ph 1,2-c-propyl 2-naphthyl 117 2-naphthyl S(O), 1,2-Ph 1,2-c-propyl 2-thiazolyl 118 2-naphthyl S( 1,2-Ph 1,2-c-propyl 1-imidazolyl 119 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 120 _phenyl 2-naphthyl S(0) 2 1,2-Ph 1,2-c-propyl 3-trifluoro 121 methylphenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 122 thienyl 2-naphthyl S(O) 1,2-Ph 1,2-c-propyl 2-furanyl 123 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 124 furanyl 2-naphthyl S(O)2 1,2-Ph 1,2-c-propyl 2-pyridinyl 125 2-naphthyl S(O), 1,2-Ph 1,2-c-propyl 2-styryl 126 2-naphthyl S(0) 2 1,2-Ph 1,2-c-propyl 3,5-difluoro- 127 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3,5-dichloro- 128 phenyl 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 129 pyridinyl 2-naphthyl S(0) 2 1,2-Ph 1,2-c-propyl 3-indolyl 130 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 4-nitrophenyl 131 2-naphthyl S(O) 1,2-Ph 1,2-c-propyl 4-cyanophenyl 132 2-naphthyl S(O) 2 1,2-Ph 1,2-c-propyl 3-chloro-4- 133 fluorophenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 )- 134 -1-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-isopropyl 135 -1-yl I I phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3,4-dichloro 136 -1-y1 phenyl -121- WO 99/47497 PCT/CA99/00212 Rl1R2R 3 -Het A X B R 19 Cpd 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3,4-difluoro 137 -1-yl phenyl 3-methylindol CH2 12-Ph 1,2-c-propyl 4-fluorophenyl 138 -1-y2 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-chlorophenyl 139 - 1 -y1 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-propylphenyl 140 -1-y2 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 141 -1-yl thienyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-styryl 142 - 1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3-chloro-4-fluorc 143 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-methoxy 144 -1-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3-bromophenyl 145 - 1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 146 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 147 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 148 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,4-difluoro 149 -1-yl phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-butylphenyl 150 - 1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl n-butyl 151 - 1 -yl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 152 -1-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3-trifluoro 153 -1-yl methylphenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 3,5-difluoro 154 -1-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3,5-dichloro 155 -1-yl _phenyl 3-methylindol CH2 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 156 -1-yl methyl)ethyl) I phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-(hydroxy 157 -1-yl I __methyl)phenyl - 122 - WO 99/47497 PCT/CA99/00212 R 1 R 2 R 3 -Het A X B Cpd 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3-(hydroxy 158 -1-yl methyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-(methyl 159 -1-y1 sulfonyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3-(methyl 160 -1-y1 sulfonyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-(propyl 161 -1-yl sulfonyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro 162 -1-yl methyl)hydroxy methyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 163 -1-yl phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 164 -1-y1 methyl) ethyl)phenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-dimethyl 165 -1-yl aminophenyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl cyclohexyl 166 -1-yl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl cyclopentyl 167 - 1 -y1 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-morpholinyl 168 - 1 -y1 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-naphthyl 169 - 1 -y_ 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-thiazolyl 170 - 1 -y1 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 1-imidazolyl 171 -1-y1 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-furanyl 172 - 1 -y1 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 173 -1-y1 furanyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-pyridinyl 174 -1-yl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 175 -1-y1 pyridinyl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 3-indolyl 176 -1-y1 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-nitrophenyl 177 - 1 -yl 3-methylindol CH 2 1,2-Ph 1,2-c-propyl 4-cyanophenyl 178 - 1 -y1 - I P- 1 1 -123- WO 99/47497 PCT/CA99/00212 RlR 2 R 3 -Het A X B R 9 Cpd 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3,5-di-(CF 3 ) 179 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-isopropyl 180 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3,4-dichloro 181 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3,4-difluoro 182 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-fluorophenyl 183 -1-y2 3-methylindol SO2 12-Ph 1,2-c-propyl 4-chlorophenyl 184 - 1 -y 1 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-propylphenyl 185 -1-y2 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2,5-dichloro-3- 186 -1-yl thienyl 3-methylindol SO2 12-Ph 1,2-c-propyl 2-styryl 187 -1-y2 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-chloro-4- 188 -1-y1 fluorophenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-methoxy 189 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3-bromo 190 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 2,5-dimethyl 191 -1-y1 phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-nitro-4-chloro 192 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-carbomethoxy 193 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 2,4-difluoro 194 -1-yl phenyl 3-methylindol SO2 12-Ph 1,2-c-propyl 4-butylphenyl 195 - 1 -y1 3-methylindol SO2 1,2-Ph 1,2-c-propyl n-butyl 196 -1-y2 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2,5-dimethoxy 197 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-trifluoromethy -198 -1-yl phenyl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3,5-difluoro 199 -1-yl phenyl 1-(3-methyl) SO 2 1,2-Ph 1,2-c-propyl 3,5-dichloro 200 indolyl phenyl - 124 - WO 9-9/47497 PCT/CA99/00212 RlR2R 3 -Het A X B Cpd 3-methylindol S02 1,2-Ph 1,2-c-propyl 4-((1-hydroxy-1- 201 -1-yl methyl)ethyl) phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(hydroxy 202 -1-yl methyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-(hydroxy 203 -1-y1 methyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(methyl 204 -1-y1 sulfonyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 3-(methyl 205 -1-yl sulfonyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(propyl 206 -1-yl sulfonyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-((bis-trifluoro 207 -1-yl methyl)hydroxy methyl)phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-(benzyloxy) 208 -1-yl phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-((1-methoxy-1- 209 -1-y1 methyl)ethyl) phenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-dimethyl 210 -1-yl aminophenyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl cyclohexyl 211 -1-yl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl cyclopentyl 212 -1-yi 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 4-morpholinyl 213 -1-yl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-naphthyl 214 - 1 -y 1 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-thiazolyl 215 -1-yl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 1-imidazolyl 216 - 1 -yl 3-methylindol S02 1,2-Ph 1,2-c-propyl 2-furanyl 217 -1-yl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3-(2-chloro)- 218 -1-yl furanyl 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-pyridinyl 219 -1-y l 3-methylindol SO 2 1,2-Ph 1,2-c-propyl 2-(4-chloro) 220 -1-yl pyridinyl - 125 - WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 9 Cpd 3-methylindol SO2 1,2-Ph 1,2-c-propyl 3-indolyl 221 - 1 -yl 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-nitrophenyl 222 -1-y1 3-methylindol SO2 1,2-Ph 1,2-c-propyl 4-cyanophenyl 223 -1-y2 2-naphthyl CH2 12-Ph CH=CH 3,5-di-(CF 3 ) 224 phenyl 2-naphthyl CH2 1,2-Ph CH=CH 4-isopropyl 225 phenyl 2-naphthyl CH 2 1,2-Ph CH=CH 2,3-dichloro 226 phenyl 2-naphthyl CH 2 1,2-Ph CH=CH 3,4-difluoro 227 phenyl 2-naphthyl CH 1,2-Ph CH=CH 4-chlorophenyl 228 2-naphthyl CH, 1,2-Ph CH=CH 4-fluorophenyl 229 2-naphthyl CH 2 1,2-Ph CH=CH 2,5-dichloro-3- 230 thienyl 2-naphthyl CH 2 1,2-Ph CH=CH 3-chloro-4-fluorc 231 phenyl 2-naphthyl CH2 12-Ph CH=CH 4-methoxy 232 phenyl 2-naphthyl CH2 1,2-Ph CH=CH butyl 233 2-naphthyl CH 2 1,2-Ph CH=CH 3-trifluoro 234 methylphenyl 2-naphthyl CH2 12-Ph CH=CH 4-((1-hydroxy-1- 235 methyl)ethyl) phenyl 2-naphthyl CH2 1,2-Ph CH=CH 4-(methyl 236 sufonyl)phenyl 2-naphthyl CH2 1,2-Ph CH=CH 4-(benzyloxy) 237 phenyl 2-naphthyl CH 1,2-Ph CH=CH cyclohexyl 238 2-naphthyl CH, 1,2-Ph CH=CH 4-morpholinyl 239 2-naphthyl CH 1,2-Ph CH=CH 2-thiazolyl 240 2-naphthyl CH 1,2-Ph CH=CH 2-furanyl 241 2-naphthyl CH 1,2-Ph CH=CH 2-pyridinyl 242 2-naphthyl CH, 1,2-Ph CH=CH 4-cyanophenyl 243 2-naphthyl SO2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 244 _ phenyl 2-naphthyl SO2 1,2-Ph CH=CH 4-isopropyl 245 I_ I_ I_ phenyl 2-naphthyl SO2 1,2-Ph CH=CH 2,3-dichloro 246 - phenyl -126- WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 9 Cpd 2-naphthyl SO 2 1,2-Ph CH=CH 3,4-difluoro 247 phenyl 2-naphthyl so, 1,2-Ph CH=CH 4-chlorophenyl 248 2-naphthyl SO, 1,2-Ph CH=CH 4-fluorophenyl 249 2-naphthyl S02 1,2-Ph CH=CH 2,5-dichloro-3- 250 thienyl 2-naphthyl SO 2 1,2-Ph CH=CH 3-chloro-4- 251 fluorophenyl 2-naphthyl SO 2 1,2-Ph CH=CH 4-methoxy 252 phenyl 2-naphthyl S2 1,2-Ph CH=CH butyl 253 2-naphthyl SO 2 1,2-Ph CH=CH 3-trifluoro 254 methylphenyl 2-naphthyl SO2 1,2-Ph CH=CH 4-((1-hydroxy-1- 255 methyl)ethyl) phenyl 2-naphthyl SO2 1,2-Ph CH=CH 4-(methyl 256 sufonyl)phenyl 2-naphthyl SO2 12-Ph CH=CH 4-(benzyloxy) 257 __ __ __ __ __ 1__ _ __ phenyl 2-naphthyl S 1,2-Ph CH=CH cyclohexyl 258 2-naphthyl so, 1,2-Ph CH=CH 4-morpholinyl 259 2-naphthyl S2 1,2-Ph CH=CH 2-thiazolyl 260 2-naphthyl S2 1,2-Ph CH=CH 2-furanyl 261 2-naphthyl SO, 1,2-Ph CH=CH 2-pyridinyl 262 2-naphthyl SO, 1,2-Ph CH=CH 4-cyanophenyl 263 2-naphthyl CH2-0 1,2-Ph CH=CH 3,5-di-(CF 3 ) 264 phenyl 2-naphthyl CH2-0 1,2-Ph CH=CH 4-isopropyl 265 phenyl 2-naphthyl CH 2 -0 1,2-Ph CH=CH 2,3-dichloro 266 _phenyl 2-naphthyl CH 2 -0 1,2-Ph CH=CH 3,4-difluoro 267 phenyl 2-naphthyl 0-CH2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 268 _phenyl 2-naphthyl O-CH 2 1,2-Ph CH=CH 4-isopropyl 269 phenyl 2-naphthyl O-CH 2 1,2-Ph CH=CH 2,3-dichloro 270 phenyl 2-naphthyl O-CH2 1,2-Ph CH=CH 3,4-difluoro 271 _ 1 _ iphenyl 2-naphthyl S 1,2-Ph CH=CH 3,5-di-(CF 3 ) 272 phenyl - 127 - WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B RCp 2-naphthyl S 1,2-Ph CH=CH 4-isopropyl 273 phenyl 2-naphthyl S 1,2-Ph CH=CH 2,3-dichloro 274 phenyl 2-naphthyl S 1,2-Ph CH=CH 3,4-difluoro 275 phenyl 2-(6-benzyloxy) SO2 1,2-Ph CH=CH 2-thienyl 276 naphthyl 2-(6-benzyloxy) S 1,2-Ph CH=CH 2-thienyl 277 naphthyl 2-(6-benzyloxy) SO2 1,2-Ph 1,2-c-propyl 2-thienyl 278 naphthyl 2-(6-benzyloxy) S 1,2-Ph 1,2-c-propyl 2-thienyl 279 naphthyl 2-(5-benzyloxy) SO2 1,2-Ph CH=CH 2-thienyl 280 naphthyl 2-(5-benzyloxy) S 1,2-Ph CH=CH 2-thienyl 281 naphthyl 2-(5-benzyloxy) SO2 1,2-Ph 1,2-c-propyl 2-thienyl 282 naphthyl 2-(5-benzyloxy) S 1,2-Ph 1,2-c-propyl 2-thienyl 283 naphthyl 2-(6-(4-trifluoro SO2 12-Ph CH=CH 2-thienyl 284 methyl)benzyloxy)) naphthyl 2-(6-(4-trifluoro CH2 1,2-Ph CH=CH 2-thienyl 285 methyl)benzyloxy)) naphthyl____ ________ ___ 2-(6-(4-trifluoro CH2 1,2-Ph 1,2-c-propyl 2-thienyl 286 methyl)benzyl oxy))naphthyl 2-(6-(4-trifluoro CH 2 1,2-Ph 1,2-c-propyl 2-thienyl 287 methyl)benzyl oxy))naphthyl 1-(6-benzyloxy) SO2 12-Ph CH=CH 2-thienyl 288 naphthyl 1-(6-benzyloxy) CH2 12-Ph CH=CH 2-thienyl 289 naphthyl 2-(6-(3,4-difluoro SO2 1,2-Ph CH=CH 2-thienyl 290 benzyloxy)) naphthyl 2-(6-(3,4-difluoro CH2 12-Ph CH=CH 2-thienyl 291 benzyloxy)) naphthyl -128- WO 99/47497 PCT/CA99/00212 R 1 R 2 R 3 -Het A X B R 9 Cpd 2-(6-(4-fluoro CH 2 1,2-Ph 1,2-c-propyl 2-thienyl 292 benzyloxy)) naphthyl 2-(7-benzyloxy) SO2 1,2-Ph CH=CH 2-thienyl 293 naphthyl 2-(6-(3,4-difluoro SO2 1,2-Ph CH=CH 3,4-difluoro 294 benzyloxy)) phenyl naphthyl 2-(6-(3,4-difluoro CH 2 1,2-Ph CH=CH 3,4-difluoro 295 benzyloxy)) phenyl naphthyl 2-(6-(4-fluoro CH 2 1,2-Ph 1,2-c-propyl 3,4-difluoro 296 benzyloxy)) phenyl naphthyl 2-(7-benzyloxy) SO2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 297 naphthyl phenyl 2-(6-(3,4-difluoro SO2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 298 benzyloxy)) phenyl naphthyl 2-(6-(3,4-difluoro CH2 1,2-Ph CH=CH 3,5-di-(CF 3 ) 299 benzyloxy)) phenyl naphthyl 2-(7-benzyloxy) SO2 1,2-Ph 1,2-c-propyl 3,4-difluoro 300 naphthyl phenyl 2-naphthyl CH2 1,2-Ph CH=CH 2-methoxy-5- 301 _ bromophenyl 2-naphthyl CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 302 bromophenyl 2-naphthyl CH, 4-Cl-1,2-Ph CH=CH 2-thienyl 303 2-naphthyl SO 1,2-Ph CH=CH 2-methoxy-5- 304 bromophenyl 2-naphthyl SO2 1,2-Ph CH=CH 2-methoxy-5- 305 bromophenyl 2-naphthyl 0 1,2-Ph CH=CH 2-methoxy-5- 306 bromophenyl 2-(5-benzyloxy) CH 2 1,2-Ph CH=CH 2-methoxy-5- 307 naphthyl bromophenyl 2-(5-benzyloxy) SO2 1,2-Ph CH=CH 2-methoxy-5- 308 naphthyl bromophenyl 2-(5-benzyloxy) S 1,2-Ph CH=CH 2-methoxy-5- 309 naphthyl bromophenyl 2-naphthyl CH 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 310 bromophenyl 1,2-Ph SO 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 311 _ 1__ 1_ bromophenyl - 129 - WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 9 Cpd 2-naphthyl S 1,2-Ph 1,2-c-propyl 2-methoxy-5- 312 bromophenyl 2-naphthyl CH2-0 1,2-Ph CH=CH 2-methoxy-5- 313 bromophenyl 2-naphthyl S 1,2-Ph CH=CH 2-methoxy-5- 314 bromophenyl 3-methyl SO 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 315 indol-1-yl bromophenyl 3-methyl S 1,2-Ph 1,2-c-propyl 2-methoxy-5- 316 indol-1-yl bromophenyl 3-methyl CH2-0 1,2-Ph CH=CH 2-methoxy-5- 317 indol-1-yl bromophenyl 3-methyl S 1,2-Ph CH=CH 2-methoxy-5- 318 indol-1-yl bromophenyl 3-methyl O-CH 2 1,2-Ph 1,2-c-propyl 2-methoxy-5- 319 indol-1-yl bromophenyl 3-methyl SO 1,2-Ph 1,2-c-propyl 2-methoxy-5- 320 indol-1-yl bromophenyl 3-methyl CH 2 -0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 321 indol-1-yl bromophenyl 3-methyl S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 322 indol-1-yl bromophenyl 3-methyl SO 2 4-Cl-1,2-Ph 1,2-c-propyl 2-methoxy-5- 323 indol-1-yl bromophenyl 2-(7-fluoro) SO 2 4-Cl-1,2-Ph CH=CH 2-thienyl 347 naphthyl 2-(7-fluoro) 0 4-Cl-1,2-Ph CH=CH 2-thienyl 348 naphthyl 2-(7-fluoro) S 4-Cl-1,2-Ph CH=CH 2-thienyl 349 naphthyl 2-(7-fluoro) CH 2 4-Cl-1,2-Ph CH=CH 2-thienyl 350 naphthyl 2-(7-fluoro) CH 2 6-Cl-1,2-Ph CH=CH 2-thienyl 351 naphthyl 2-(7-fluoro) CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-thienyl 352 naphthyl 2-(7-fluoro) CH 2 3-Cl-1,2-Ph CH=CH 2-thienyl 353 naphthyl 2-(7-fluoro) SO 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 354 naphthyl bromophenyl 2-(7-fluoro) 0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 355 naphthyl bromophenyl 2-(7-fluoro) S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 356 naphthyl 1 1 bromophenyl - 130 - WO 9-9/47497 PCT/CA99/00212 RlR2R 3 -Het A X B R 9 Cpd 2-naphthyl CH 2 4,5-C12- CH=CH 2-methoxy-5- 357 1,2-Ph bromophenyl 2-(7-fluoro) CH 2 6-Cl-1,2-Ph CH=CH 2-methoxy-5- 358 naphthyl bromophenyl 2-(7-fluoro) CH 2 4-01-1,2-Ph 1,2-c-Pr 2-methoxy-5- 359 naphthyl bromophenyl 2-(7-fluoro) CH 2 3-Cl-1,2-Ph CH=CH 2-methoxy-5- 360 naphthyl bromophenyl 2-(7-fluoro) SO 2 4-Cl-1,2-Ph CH=CH 2-trifluoro 361 naphthyl methoxy-5 chlorophenyl 2-(7-fluoro) 0 4-C-1,2-Ph CH=CH 2-trifluoro 362 naphthyl methoxy-5 chlorophenyl 2-(7-fluoro) S 4-Cl-1,2-Ph CH=CH 2-trifluoro 363 naphthyl methoxy-5 chlorophenyl 2-(7-fluoro) CH 2 4-Cl-1,2-Ph CH=CH 2-trifluoro 364 naphthyl methoxy-5 chlorophenyl 2-(7-fluoro) CH 2 6-C-1,2-Ph CH=CH 2-trifluoro 365 naphthyl methoxy-5 chlorophenyl 2-(7-fluoro) CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-trifluoro 366 naphthyl methoxy-5 chlorophenyl 2-(7-fluoro) CH 2 3-01-1,2-Ph CH=CH 2-trifluoro 367 naphthyl methoxy-5 chlorophenyl 2-(7-fluoro) SO 2 4-Cl-1,2-Ph CH=CH 2-thienyl 368 naphthyl 2-(7-fluoro) 0 4-C-1,2-Ph CH=CH 2-thienyl 369 naphthyl 2-(7-fluoro) S 4-C-1,2-Ph CH=CH 2-thienyl 370 naphthyl 2-(7-fluoro) CH 2 4-C-1,2-Ph CH=CH 2-thienyl 371 naphthyl 2-(7-fluoro) CH 2 6-Cl-1,2-Ph CH=CH 2-thienyl 372 naphthyl 2-(7-fluoro) CH 2 4-C-1,2-Ph 1,2-c-Pr 2-thienyl 373 naphthyl 2-(7-fluoro) CH 2 3-Cl-1,2-Ph CH=CH 2-thienyl 374 naphthyl -131- WO 99/47497 PCT/CA99/0021 2 Rlp.2R 3 -Het A x B R119 _ 2-(7-fluoro) S0 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 375 naphthyl bromophenyl 2-(6-fluoro) 0 4-C1-1,2-Ph CH=CR 2-methoxy-5- 376 naphthyl _____bromophenyl 2-(6-fluoro) S 4-C1-1,2-Ph CH=CH 2-methoxy-5- 377 naphthyl ______bromophenyl 2-(6-fluoro) CH 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 378 naphthyl _____bromophenyl 2-(6-fluoro) CH 2 6-C1-1,2-Ph CH=CH 2-methoxy-5- 379 naphthyl ______bromophenyl 2-(6-fluoro) CH 2 4-C1-1,2-Ph 1,2-c-Pr 2-methoxy-5- 380 naphthyl _____bromophenyl 2-(6-fluoro) CR 2 3-C1-1,2-Ph CR=CH 2-methoxy-5- 381 naphthyl _____bromophenyl 2-(7-chloro) S0 2 4-C1-1,2-Ph CH=CH 2-thienyl 382 naphthyl____ __ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(7-chloro) 0 4-C1-1,2-Ph CH=CH 2-thienyl 383 naphthyl____ __ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(7-chloro) S 4-C1-1,2-Ph CH=CH 2-thienyl 384 naphthyl__ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ 2-(7-chloro) CR 2 4-C1-1,2-Ph CH=CH 2-thienyl 385 naphthyl _____ _ _ _ _ _____ 2-(7-chloro) CH 2 6-C1-1,2-Ph CH=CH 2-thienyl 386 naphthyl____ __ _ _ _ ________ 2-(7-chloro) CR 2 4-C1-1,2-Ph 1,2-c-Pr 2-thienyl 387 naphthyl____ __ _ _ _ ________ 2-(7-chloro) CR 2 3 -C1-1,2-Ph CR=CR 2-thienyl 388 naphthyl _____ _ _ _ _ _____ 2-(6,7-difluoro) S0 2 4-C1-1,2-Ph CR=CR 2-thienyl 389 naphthyl _____ _ _ _ _ _____ 2-(6,7-difluoro) 0 4-C1-1,2-Ph CR=CR 2-thienyl 390 naphihyl _____ _ _ _ _ _____ 2-(6,7-difluoro) S 4-C1-1,2-Ph CR=CR 2-thienyl 391 naphthyl _____ _ _ _ _ _____ 2-(6,7-difluoro) CR 2 4-C1-1,2-Ph CR=CR 2-thienyl 392 naphthyl__ _ __ _ _ _ _ __ ___ 2-(6,7-difluoro) CR 2 6T-1-1,2-Ph CR=CR 2-thienyl 393 naphthyl______ _ _ _ __ _ _ _ _ _ _ 2-(6,7-difluoro) CR 2 4-C1-1,2-Ph 1,2-c-Pr 2-thienyl 394 naphthyl__ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ 2-(6,7-difluoro) CR 2 3-C1-1,2-Ph CR=CR 2-thienyl 395 naphthyl____ __ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ 2-(6,7-difluoro) SO 2 4-C1-1,2-Ph CR=CR 2-methoxy-5- 396 naphthyl I_____________ bromophenyl1 1 - 132 - WO 99/47497 PCT/CA99/00212 R1R 2 R 3 -Het A X B R 9 Cpd 2-(6,7-difluoro) 0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 397 naphthyl bromophenyl 2-(6,7-difluoro) S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 398 naphthyl bromophenyl 2-(6,7-difluoro) CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 399 naphthyl bromophenyl 2-(6,7-difluoro) CH 2 6-Cl-1,2-Ph CH=CH 2-methoxy-5- 400 naphthyl bromophenyl 2-(6,7-difluoro) CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-methoxy-5- 401 naphthyl bromophenyl 2-(6,7-difluoro) CH 2 3-Cl-1,2-Ph CH=CH 2-methoxy-5- 402 naphthyl bromophenyl 2-(5,7-difluoro) CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 403 naphthyl bromophenyl 2-(5,7-difluoro) S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 404 naphthyl bromophenyl 2-(5,7-difluoro) 0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 405 naphthyl bromophenyl 2-(5,7-difluoro) SO 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 406 naphthyl bromophenyl 2-(6-fluoro) SO 2 4-C1-1,2-Ph CH=CH 2-methoxy-5- 407 quinolinyl bromophenyl 2-(6-fluoro) S 4-C1-1,2-Ph CH=CH 2-methoxy-5- 408 quinolinyl bromophenyl 2-(6-fluoro) CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 409 quinolinyl bromophenyl 2-(6-fluoro) CH2 12-Ph CH=CH 2-methoxy-5- 410 quinolinyl bromophenyl 2-(6-fluoro) 0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 411 quinolinyl bromophenyl 2-(6-fluoro) CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-methoxy-5- 412 quinolinyl bromophenyl 2-(5,7-difluoro)- SO 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 413 quinolinyl bromophenyl 2-(5,7-difluoro)- S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 414 quinolinyl bromophenyl 2-(5,7-difluoro)- CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 415 quinolinyl bromophenyl 2-(5,7-difluoro)- CH2 1,2-Ph CH=CH 2-methoxy-5- 416 quinolinyl bromophenyl 2-(5,7-difluoro)- 0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 417 quinolinyl bromophenyl 2-(5,7-difluoro)- CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-methoxy-5- 418 quinolinyl I- I bromophenyl -133- WO 99/47497 PCT/CA99/00212 Rl 2 R 3 -Het A X B R 9 Cpd 3,4-dichloro SO 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 419 phenyl bromophenyl 3,4-dichloro S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 420 phenyl bromophenyl 3,4-dichloro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 421 phenyl bromophenyl 3,4-dichloro CH2 1,2-Ph CH=CH 2-methoxy-5- 422 phenyl bromophenyl 3,4-dichloro 0 4-C1-1,2-Ph CH=CH 2-methoxy-5- 423 phenyl bromophenyl 3,4-dichloro CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-methoxy-5- 424 phenyl bromophenyl 3,4-dichloro CH 2 5-Cl-1,2-Ph CH=CH 2-methoxy-5- 425 phenyl bromophenyl 4-chloro SO 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 426 phenyl bromophenyl 4-chloro S 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 427 phenyl bromophenyl 4-chloro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 428 phenyl bromophenyl 4-chloro CH2 1,2-Ph CH=CH 2-methoxy-5- 429 phenyl bromophenyl 4-chloro 0 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 430 phenyl _bromophenyl 4-chloro CH 2 4-Cl-1,2-Ph 1,2-c-Pr 2-methoxy-5- 431 phenyl bromophenyl 4-chloro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 432 phenyl bromophenyl 3,4-dichloro SO 2 4-Cl-1,2-Ph CH=CH 2-thienyl 433 phenyl 3,4-dichloro S 4-Cl-1,2-Ph CH=CH 2-thienyl 434 phenyl 3,4-dichloro CH 2 4-Cl-1,2-Ph CH=CH 2-thienyl 435 phenyl 3,4-dichloro CH2 1,2-Ph CH=CH 2-thienyl 436 phenyl 3,4-dichloro 0 4-Cl-1,2-Ph CH=CH 2-thienyl 437 phenyl 3,4-dichloro CH 2 4-Cl-1,2-Ph CH=CH 2-thienyl 438 phenyl 3,4-dichloro CH 2 5-Cl-1,2-Ph CH=CH 2-thienyl 439 phenyl 4-chloro SO 2 4-Cl-1,2-Ph CH=CH 2-thienyl 440 phenyl I I - 134 - WO 99/47497 PCT/CA99/00212 R 1 R2R 3 -Het A X B R 9 Cpd 4-chloro S 4-Cl-1,2-Ph CH=CH 2-thienyl 441 phenyl 4-chloro CH 2 4-Cl-1,2-Ph CH=CH 2-thienyl 442 phenyl 4-chloro CH2 1,2-Ph CH=CH 2-thienyl 443 phenyl 1-(5-chloro) CH 2 3,2-Pyr CH=CH 2,4-(Me)2- 444 indolyl thiazol-5-yl 1-(5-chloro) CH 2 3,2-Pyr CH=CH 2-thienyl 445 indolyl 1-(6-(4-chloro) CH 2 4-F-1,2-Ph CH=CH 3-chloro-4- 446 phenyl)indolyl fluorophenyl 2-(6-difluoro CH 2 4-C1-1,2-P CH=CH 2-methoxy-5- 447 methoxy) bromophenyl naphthyl 2-naphthyl CH2 4-MeO- CH=CH 2-methoxy-5- 448 1,2-Ph bromophenyl 2-naphthyl CH 2 5-Cl-1,2-Ph CH=CH 2-methoxy-5- 449 bromophenyl 2-(6-chloro CH 2 4-Cl-1,2-Ph CH=CH 2-methoxy-5- 450 naphthyl) bromophenyl 1-(5-phenyl CH 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 451 methoxy) bromophenyl indolyl 2-(benzo[b] CH 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 452 thiophenyl bromophenyl 5-(1-benzyl) CH 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 453 indolyl I bromophenyl 1-(6-(4-chloro) CH 2 4-F-1,2-Ph CH=CH 2-methoxy-5- 454 phenyl)indolyl - 1 bromophenyl 5 Table 11 R 1 R 2 R 3 -HET 0 A X-B OH 1-b (Compounds 324-346 and 455-542) - 135 - WO 99/47497 PCT/CA99/002 12 5 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ RlRMR-Het A X B Cpd S(0) -,-hnl H 2 2-naphthyl s() 1,2-phenyl CH=CH 324 4-methyithiophenyl CH, 1,2-phenyl CH=CH 326 3-methylindol-1-yl CR 9 1,2-phenyl CH=CH 327 3-chloro-4-fluorophenyl CR 2 1,2-phenyl CH=CH 328 -4-chlorophenyl CH 2 1,2-phenyl CH=CH 329 2-naphthyl CH, 1,2-phenyl CR=CR 330 2-naphthyl S(0)2 1,2-phenyl 1,2-c-propyl 331 2-naphthyl S(0)2 1,2-phenyl CH 2 -CH 2 332 -2-naphthyl S 1,2-phenyl CH=CH 333 3 ,4-dichlorophenyl S(0), 1,2-phenyl CH,-CH, 334 3,4-dichlorophenyl CR 2 1,2-phenyl CH=CH 335 2-(6-benzyloxy)naphthyl CR 2 1 ,2-phenyl CH=CH 336 2-(6-benzyloxy)naphthyl CR 2 1,2-phenyI 1,2-c-propyl 337 2-(6-benzyloxy)naphthyl s02 1,2-phenyl 1,2-c-propyl 338 2-(6-benzyloxy)naphthyl CH 2 -0 1,2-pheny 1,2-c-propyl 339 2-(6-benzyloxy)naphthyl 0-CR 9 1,2-phenyI 1,2-c-propyl 340 2-(6-benzyloxy)naphthyl so, 1,2-phenyl CH=CH 341 2-(6-benzyloxy)naphthyl CH 2 -0 1 ,2-phenyI CR=CR 342 2-(6-benzyloxy)naphthyl 0-CR 2 1 ,2-phen I CR=CR 343 2-(6-benzyloxy)naphthyl S 1,2-phenyl CR=CR 344 2-(-bnzyox~nphso,50 1,2-phenyl CR=CR 345 2-(6-4-trifluoromethyl) CR 2 1,2-phenyl CR=CR 346 benzyloxy))naphthyl______ 2-(6-fluoro)naphthyl SO 2 4-Cl- 1,2-Ph CR=CR 455 2-(6-fluoro)naphthyl S 4-Cl-1,2-Ph CH=CR 456 2-(6-fluoro)naphthyl CR 9 4-Cl-1,2-Ph CR=CR 457 2-(6-fluoro)naphthyl CR 2 1,2-Ph CR=CR 458 2-(6-fluoro)naphthyl 0- 4-C1-1,2-Ph CR=CR 459 2-(6-fluoro)naphthyl- CR, 4-Cl- 1,2-Ph 1,2-c-Pr 460 2-(7-fluoro)naphthyl SO2 4-Cl-1,2-Ph CR=CR 461 2-(7-fluoro)naphthyl S 4-Cl-1,2-Ph CR=CR 462 2-(7-fluoro)naphthyl CR 9 4-Cl-1,2-Ph CR=CR 463 2-(7-fluoro)naphthyl CRI? 1,2--Ph CR=CR 464 2-(7-fluoro)naphthyl 0 4-Cl-1,2-Ph -CR=CR 465 2-( 7-fluoro)naphthyl CR 2 4-Cl- 1,2-Ph 1,2-c-Pr 466 2-(6-chloro)naphthyl SO2 4-Cl-1,2-Ph CR=CR 467 2-(6-chloro)naphthyl S 4-C1-1,2-Ph CR=CR 468 2-(6-chloro)naphthyl CR 2 4-Cl-1,2-Ph CR=CR 469 2-(6-chlo o)naphthyl CR 2 1,2-Ph CH=CH 470 2-(6-chloro)naphthyl 0 4-Cl- 1,2-Ph CH=CH 471 - 136 - WO 99/47497 PCT/CA99/00212 RlR, 2 R 3 -Het A X B Cpd 2-(6-chloro)naphthyl CH, 4-Cl-1,2-Ph 1,2-c-Pr 472 2-(7-chloro)naphthyl SO, 4-Cl-1,2-Ph CH=CH 473 2-(7-chloro)naphthyl S 4-Cl-1,2-Ph CH=CH 474 2-(7-chloro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 475 2-(7-chloro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 476 2-(7-chloro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 477 2-(7-chloro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 478 2-(6,7-difluoro)naphthyl S02 4-Cl-1,2-Ph CH=CH 479 2-(6,7-difluoro)naphthyl S 4-Cl-1,2-Ph CH=CH 480 2-(6,7-difluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 481 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 482 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 483 2-(6,7-difluoro)naphthyl CH, 4-Cl-1,2-Ph 1,2-c-Pr 484 2-(6,7-difluoro)naphthyl CH 4-Cl-1,2-Ph CH=CH 485 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 486 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 487 2-(6,7-difluoro)naphthyl CH 1,2-Ph CH=CH 488 2-(6,7-difluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 489 2-(6,7-difluoro)naphthyl CH 2 4-Cl-1,2-Ph 1,2-c-Pr 490 3-methyl-5-fluoro SO 2 4-Cl-1,2-Ph CH=CH 491 indol-1-yl 3-methyl-5-fluoro S 4-Cl-1,2-Ph CH=CH 492 indol-1-yl 3-methyl-5-fluoro CH 2 4-Cl-1,2-Ph CH=CH 493 indol-1-yl 3-methyl-5-fluoro CH 2 1,2-Ph CH=CH 494 indol-1-yl 3-methyl-5-fluoro CH 2 4-Cl-1,2-Ph CH=CH 495 indol-1-yl 3-methyl-5-fluoro CH 2 4-Cl-1,2-Ph CH=CH 496 indol-1-yl 2-(6-fluoro)quinolinyl S0, 4-Cl-1,2-Ph CH=CH 497 2-(6-fluoro)quinolinyl S 4-Cl-1,2-Ph CH=CH 498 2-(6-fluoro)quinolinyl CH 2 4-Cl-1,2-Ph CH=CH 499 2-(6-fluoro)quinolinyl CH, 4-Cl-1,2-Ph CH=CH 500 2-(6-fluoro)quinolinyl 0 4-Cl-1,2-Ph CH=CH 501 2-(6-fluoro)quinolinyl CH, 4-Cl-1,2-Ph CH=CH 502 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 503 naphthyl 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 504 naphthyl 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 505 naphthyl 02 ___________ ______ 505 - 137 - WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B Cpd 2-(6-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 506 naphthyl 2-(6-difluoromethoxy)- S02 4-Cl-1,2-Ph CH=CH 507 naphthyl 2-(6-difluoromethoxy)- S02 4-Cl-1,2-Ph CH=CH 508 naphthyl 2-(7-difluoromethoxy)- SO 2 4-Cl-1,2-Ph CH=CH 509 naphthyl 2-(7-difluoromethoxy)- S 4-Cl-1,2-Ph CH=CH 510 naphthyl 2-(7-difluoromethoxy)- CH 2 4-Cl-1,2-Ph CH=CH 511 naphthyl 2-(7-difluoromethoxy)- CH 2 4-Cl-1,2-Ph CH=CH 512 naphthyl 2-(7-difluoromethoxy)- 0 4-Cl-1,2-Ph CH=CH 513 aphthyl 2-(7-difluoromethoxy)- CH 2 4-Cl-1,2-Ph CH=CH 514 naphthyl 2-(6-methoxy)naphthyl SO2 4-Cl-1,2-Ph CH=CH 515 2-(6-methoxy)naphthyl S 4-Cl-1,2-Ph CH=CH 516 2-(6-methoxy)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 517 2-(6-methoxy)naphthyl CH, 4-Cl-1,2-Ph CH=CH 518 2-(6-methoxy)naphthyl 0 4-Cl-1,2-Ph CH=CH 519 2-(6-methoxy)naphthyl CH2 4-Cl-1,2-Ph CH=CH 520 2-(6-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 521 2-(6-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 522 2-(6-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 523 2-(6-fluoro)naphthyl CH 9 4-Cl-1,2-Ph CH=CH 524 2-(6-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 525 2-(6-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 526 2-(7-fluoro)naphthyl CH9 4-Cl-1,2-Ph CH=CH 527 2-(7-fluoro)naphthyl CH2 4-Cl-1,2-Ph CH=CH 528 2-(7-fluoro)naphthyl CH, 4-Cl-1,2-Ph CH=CH 529 2-(7-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 530 2-(7-fluoro)naphthyl CH2 4-Cl-1,2-Ph CH=CH 531 2-(7-fluoro)naphthyl CH 2 4-Cl-1,2-Ph CH=CH 532 2-naphthyl CH 2 4,5-Cl2-1,2-Ph CH=CH 533 2-naphthyl CH 2 4-Cl-1,2-Ph CH=CH 534 3,4-dichlorophenyl CH 2 4-Cl-1,2-Ph CH=CH 535 2-naphthyl CH, 4-Cl-1,2-Ph CH=CH 536 4-chlorophenyl CH 2 4-Cl-1,2-Ph CH=CH 537 1-(5-phenylmethoxy) CH 2 4-F-1,2-Ph CH=CH 538 indolyl 1 _ - 138 - WO 99/47497 PCT/CA99/00212 RlR2R 3 -Het A X B Cpd 2-(benzo[b]thiophenyl) CH, 4-F-1,2-Ph CH=CH 539 5-(1-benzyl)indolyl CH 2 4-F-1,2-Ph CH=CH 540 1-(6-(4-chloro)phenyl) CH 2 4-F-1,2-Ph CH=CH 541 indolyl I 1-(5-chloro)indolyl CH 2 3,2-Pyr CH=CH 542 5 wherein D= -O(CH 2 ) 3 -0, Qn= 7-chloroquinolin-2-yl, 1,2-Ph = 1,2-benzenediyl, Rs = -CH2SCH2CH2Ph, Pyr = pyridinediyl, c-pr = cyclopropyl and Bn = benzyl.
19. A pharmaceutical composition which is 10 comprised of a compound in accordance with any one of claims 1 to 18 in combination with a pharmaceutically acceptable carrier.
20. A method of treating or preventing a prostaglandin mediated disease which is comprised of administering to a mammalian 15 patient in need of such treatment a compound in accordance with claim 1 in an amount which is effective for treating or preventing a prostaglandin mediated disease.
21. A method in accordance with claim 19 wherein the 20 prostaglandin mediated disease is selected from the group consisting of: pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, 25 synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, immune and autoimmune diseases; 30 cellular neoplastic transformations or metastic tumor growth; diabetic retinopathy, tumor angiogenesis; -139- WO 99/47497 PCT/CA99/00212 5 prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, asthma or eosinophil related disorders; Alzheimer's disease; glaucoma; 10 bone loss; osteoporosis; promotion of bone formation; Paget's disease; cytoprotection in peptic ulcers, gastritis, regional enteritis, 15 ulcerative colitis, diverticulitis or other gastrointestinal lesions; GI bleeding and patients undergoing chemotherapy; coagulation disorders selected from hypoprothrombinemia, haemophilia and other bleeding problems; kidney disease; 20 thrombosis; occlusive vascular disease; presurgery; and anti-coagulation. 25
22. A method in accordance with claim 20 wherein the prostaglandin mediated disease is selected from the group consisting of: pain, fever or inflammation.
23. A method in accordance with claim 20 wherein the 30 prostaglandin mediated disease is dysmenorrhea.
24. A method in accordance with claim 20, wherein the compound is co-administered with other agents or ingredients. 35
25. A method in accordance with claim 24 wherein the compound I is co-administered with another agent or ingredient selected from the group consisting of: an analgesic selected from acetaminophen, phenacetin, aspirin, a narcotic; - 140 - WO 99/47497 PCT/CA99/00212 5 a COX-2 selective NSAID and a conventional NSAID; caffeine; an H2-antagonist; aluminum or magnesium hydroxide; simethicone; 10 a decongestant selected from phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive selected from codeine, hydrocodone, caramiphen, carbetapentane and dextramethorphan; 15 another prostaglandin ligand selected from misoprostol, enprostil, rioprostil, ornoprostol and rosaprostol; a diuretic; and a sedating or non-sedating antihistamine.
26. Use of a compound, salt, hydrate or ester as defined in any one of claims 1 to 18 in the manufacture of a 20 medicament for treatment or prevention of a prostaglandin mediated disease.
27. A compound, salt, hydrate or ester as defined in any one of claims 1 to 18 for use in the treatment or prevention of a prostaglandin mediated disease. 25
28. A prostaglandin antagonist pharmaceutical composition comprising an acceptable prostaglandin antagonistic amount of a compound, salt, hydrate or ester as defined in any one of claims 1 to 18, in association with a pharmaceutically acceptable carrier. -141 -
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