[go: up one dir, main page]

CA2426430A1 - Biaryl compounds as serine protease inhibitors - Google Patents

Biaryl compounds as serine protease inhibitors Download PDF

Info

Publication number
CA2426430A1
CA2426430A1 CA002426430A CA2426430A CA2426430A1 CA 2426430 A1 CA2426430 A1 CA 2426430A1 CA 002426430 A CA002426430 A CA 002426430A CA 2426430 A CA2426430 A CA 2426430A CA 2426430 A1 CA2426430 A1 CA 2426430A1
Authority
CA
Canada
Prior art keywords
group
compound
alkyl
prodrugs
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002426430A
Other languages
French (fr)
Other versions
CA2426430C (en
Inventor
Yarlagadda S. Babu
Scott R. Rowland
Pooran Chand
Pravin L. Kotian
Yahya El-Kattan
Shri Niwas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biocryst Pharmaceuticals Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2426430A1 publication Critical patent/CA2426430A1/en
Application granted granted Critical
Publication of CA2426430C publication Critical patent/CA2426430C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/20—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines with at least one nitrogen atom of hydroxamidine groups bound to another nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
    • C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—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
    • 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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—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
    • C07D213/56—Amides
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • C07D213/78—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
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen 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
    • C07D307/38—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D333/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—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
    • 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
    • C07D333/38—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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Compounds of formula (I) are useful as inhibitors of trypsin like serine protease enzymes such as thrombin, factor VIIa, factor Xa, TF/FVIIa, and trypsin. These compounds could be useful to treat and/or prevent clotting disorders, and as anticoagulating agents. One example of a compound according to formula (I) is:
(see formula I) wherein R is -OSO2CF3; and R' is selected from the group consisting of -CHO, -CO2H, and (see formula II) ; and pharmaceutically acceptable salts thereof.

Description

BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS
DESCRIPTION
Cross-Reference to Related Applications This application is a continuation-in-part of copending U. S. applications S.N.
601241,848 Bled October 20, 2000 and entitled "Inhibitors for Activated Blood Coagulation Factor VIIa (FVIIa)" and S.N. (01281,'135 filed April 6, 2001 and entitled "Biaryl Compounds as Serine Protease Inhibitors"
Technical Field The present invention relates to the identification, through synthesis and testing, of heretofore unreported compounds which, in appropriate pharmaceutical compositions, exert a therapeutic effect through reversible inhibition of serine proteases.
Background of Invention Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well.
Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages.

While serine proteases are physiologically vital, they also can be hazardous.
Their proteolytic action, if uncontrolled, can destroy cells and tissues through degradation of proteins. As a natural safeguard in normal plasma, 10% of the protein matter is composed of protease inhibitors. The major natural plasma inhibitors are specific for serine proteinases. Diseases (associated protease given in the parentheses) such as pulmonary emphysema (cathepsin G), adult respiratory distress syndrome (chymases), and pancreatitis (trypsin, chymotrypsin, and others) are characterized by uncontrolled serine proteases, Other proteases appear to be involved in tumor invasion (plasmin, plasminogen activator), viral transformation, and inflammation (kallikrein).
Thus the design and synthesis of specific inhibitors for this class of proteinases could offer major therapeutic benefits.
Thrombus formation, that is blood coagulation, is normally initiated by tissue injury; its normal purpose is to slow or prevent blood loss and facilitate wound healing.
There are other conditions, however, not directly connected with tissue injury that may promote the coagulation process and lead instead to harmful consequences;
examples of such conditions are atherosclerosis and inflammation.
The complex pathways of blood coagulation involve a series of enzyme reactions 2o in which plasma coagulation factors, actually enzyme precursors or zymogens, are sequentially activated by limited proteolysis. Blood coagulation, or the coagulation cascade, is viewed mechanistically as two pathways, the extrinsic and the intrinsic (Fig.
1). Each pathway proceeds through a sequence of the Roman-numeral-designated factors until they converge at the activation of factor X after merger of the pathways. Thrombin generation proceeds stepwise through a common pathway. Thrombin then acts on the solution plasma protein, fibrinogen, to convert it to stable insoluble fibrin clots, thus completing the coagulation cascade.

The extrinsic pathway is vital to the initiation phase of blood coagulation while the intrinsic pathway provides necessary factors in the maintenance and growth of fibrin.
The initiation of the coagulation cascade involves the release of tissue factor (TF) from injured vessel endothelial cells and subendothelium. TF then acts upon factor VII to form the TF/FVIIa complex (where VIIa designates the activated factor rather than the zymogen form). This complex initiates coagulation by activating factors IX and X. The resulting factor Xa forms a pxothrombinase complex that activates prothrombin to produce the thrombin that converts fibrinogen to insoluble fibrin. In contrast, the intrinsic system is activated in vivo when certain coagulation proteins contact to subendothelial connective tissue. In the sequence that follows, contact factors XII and XI
are activated. The resulting factor XIa activates factor IX; then factor IXa activates factor X thereby intersecting with the extrinsic pathway.
With time, the TF/FVIIIa complex (of the extrinsic pathway) loses activity due to the action of tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor protein which, when complexed with factor Xa, can inhibit the proteolytic activity of TFlFVIIa. If the extrinsic system is inhibited, additional factor Xa is produced through the thrombin-mediated action in the intrinsic pathway. Thrombin, therefore, exerts a dual catalytic role in (a) the conversion of fibrinogen to fibrin and (b) mediating its own 2o production. The autocatalytic aspect of thrombin production affords an important safeguard against excessive blood loss, and, assuming presence of a threshold level of prothrombinase, ensures that the blood coagulation process will go to completion.
While the ability to form blood clots is vital to survival, there are disease states ~ wherein the formation of blood clots within the circulatory system can cause death.
When patients are afflicted with such disease states, it is not desirable to completely inhibit the clotting system because life-threatening hemorrhage would follow.
Thus, it is highly desirable to develop agents that inhibit coagulation by inhibition of factor VIIa without directly inhibiting thrombin.

Need for the prevention of intravascular blood clots or for anti-coagulant treatment in many clinical situations is well known. Drugs in use today are often not satisfactory. A high percentage of patients who suffer internal injuries or undergo certain surgical procedures develop intravascular blood clots which, if unchecked, cause death.
In total hip replacement surgery, for example, it is reported that 50% of the patients develop deep vein thrombosis (DVT). Current approved therapies involve administration of heparin in various forms, but results are not entirely satisfactory; 10-20%
of patients suffer DVT and 5-10% have bleeding complications. Alang these lines, see International to Publication No. WO 00/15658.
Other examples of clinical situations for which better anticoagulants would be of great value are when patients undergo transluminal coronary angioplasty and treatment .
fox myocardial infarction or crescendo angina. The present therapy for these conditions 15 is administration of heparin and aspirin, but this treatment is associated with a 6-8%
abrupt vessel closure rate within 24 hours of the procedure. Transfusion therapy due to bleeding complications is required in approximately 7% of cases following the use of heparin. Occurrences of delayed vessel closures are also significant, but administration of heparin after termination of the procedure affords little beneficial effect and can be 2o detrimental.
Heparin and certain derivatives thereof are the most commonly used anti-clotting agents. These substances exert their effects mainly through inactivation of thrombin, which is inactivated 100 times faster than factor Xa. Two other thrombin-specific 25 anticoagulants, hirudin and hirulog, are in clinical trials (as of September 1999).
However, bleeding complications are associated with these agents.
In preclinical studies in baboons and dogs, the targeting of enzymes involved in earlier stages of the coagulation cascade, such as factor VIIa or factor Xa, prevents clot formation and does not produce bleeding side effects observed with direct thrombin inhibitors.
Several preclinical studies reveal that inhibition of TF/FVIIa offers the widest window of therapeutic effectiveness and safety with respect to bleeding risk of any anticoagulant approach tested including thrombin, platelet, and factor Xa inhibition.
A specific inhibitor of factor VIIa would provide clinicians with a valuable and needed agent that would be safe and effective in situations where the present drugs of to choice, heparin and related sulfated polysaccharides, are no better than marginally effective.
There exists a need for a low molecular weight specific serine protease inhibitors specific toward various enzymes, particularly for factor VIIa that does not cause 15 unwanted side effects.
Figure 1. Pathways of Coagulation Extrinsic Pathway Intrinsic Pathway Release of TF Release of Contact Factors XII and XI
'VII XIIa-~-- XII
TF/FVIIa XIa XI
IXa IX
X
Common Pathway Prothrombin --~ Thrombin - Fibrinogen ---' Fibrin The ~ gore illustrates the extrinsic and intrinsic pathways of blood coagulation.
Summary of Invention An aspect of the present invention relates to compounds represented by the formula:
R
l0 ( R1 )~, E~ W E2 B
X (R2) ; pharmaceutically acceptable salts thereof;
is V~ L V
and prodrugs thereof.
X
l (I) Each El and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one ox more hetero groups selected from N, O, S, S(O), and S(OZ) which may be saturated or unsaturated. The bicyclic rings typically contain 7-13 atoms in the ring.
R is -CH=CH-R2, -CSC-R2, -C(R2)=CHZ, -C(R2)=C(R3), -CH--NR2, -C(R2)=N-R3, 4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from Rl, R2, or R3.

Rl is H, -R, -NOa, -CN, -halo, -N3, -C i_s alkyl, -(CHa)"COaRa, -Ca-s alkenyl-C02Ra, -O(CHa)"COaRa, -C(O)NRaR3, -P(O)(ORa)a, alkyl substituted tetrazol-5-yl, -(CHa)n0(CHa)n aryl, -NRaR3, -(CHa)" ORa, -(CHa)" SRa, N(Ra)C(O)R3, -S(0a)NR2R3, _N(Ra)S(Oa)R3, -(CHRa)" NRZR3, -C(O)R3~ (CHa)n N(R3)CCO)R3~ -N(Ra)CR R
substituted or unsubstituted (CHa)n cycloalkyl, substituted or unsubstituted (CHa)"
phenyl, or substituted or unsubstituted (CHa)"heterocycle which may be saturated or unsaturated.
m is 1 except that when EI is a cyclic ring of more than 5 atoms, then m is 1 or higher, 1o depending upon the size of the ring.
Ra is H, -halo, -alkyl, -haloalkyl, -(CHa)"-phenyl, -(CHa)i-3-biphenyl, -(CHa)1_4-Ph-N(SOa-C1_a-allcyl)a, -CO(CHRl)ri ORl, -(CHRI)"-heterocycle, -(CHRt)n NH-CO-Rl, -(CHRI)n-NH-SOaRI, -(CHRI)n-Ph-N(SOa-C1_z-alkyl)a, -(CHRI)"-C(O)(CHRt)-NHRI, is -(CHR~)"-C(S)(CHRI)-NHRI, -(CHa)"O(CHa)"CH3, -CF3, -Ca_5 acyl, -(CHR~)"OH, -(CHRt)"COaRI, -(CHRI)n O-alkyl, -(CHRI)"-O-(CHa)"O-alkyl, -(CHRI)n S-alkyl, -(CHRI)n-S(O)-alkyl, -(CHRI)"-S(Oa)-alkyl, -(CHRI)"S(Oa)-NHR3, -(CHR3)n N3, -(CHR3)"NHR4, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-20 (CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)" cycloalkyl which may be saturated or unsaturated.
When n is more than 1, the substitutions Rl and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -Ca_s alkenyl, substituted or unsubstituted 25 cycloalkyl, -N(RI)Ra, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NRzR3 may form a ring system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.

W is a direct bond, -CHRz-, -CH=CRZ-, -CR2=CH-, -CR2=CR2-, -C_--C-, -O-CHRa-, -CHR2-O-, _N(RZ)_C(O)_~ _C(p)_N(Ra)-~ _N(R2)_CH-(R3)-, -CHZ-N(R2)-, _CH(Rt)-N(Ra)-, -S-CHRZ-, -CHR2-S-, -S(Oa)-N(R2)-, -C(O)N(R2)-(CHR2)n-, -C(R1R2)n_NRZ_, -N(RZ)-S(Oa)-~ _RaC(O)~z_~ _R~NC(p)~2_~ -CONR2C0-, -C(_~Z)~2_~ _~ZC(-_~g2)NRZ-, -NR2O-, -N=NCHRZ-, Or -C(O)NR2SO2-.
E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, C1_8 alkyl, CZ_8 alkenyl, Cz-s alkynyl, 1o alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
each X individually is a direct bond, substituted or unsubstituted C1_~
methylene chain; O, S, NRz , S(O), S(O~), or N(O) containing one or two C1.~ substituted or unsubstituted methylene chains. X at different places may be same or different.

B is H, -halo, -CN, -NHz, -(CH2)n-C(--NR4)NHRS, -(CH2)n-NHR4, -(CHZ)"NHC( NR4)NRS, -(CH2)n OR4, Cl_8 substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B1 is selected from B; BI and B may be same or different.
There may be more than one similar or different Ra groups present on EZ, when EZ is a cyclic group of more than 5 atoms. In particular, p is 1 except that when EZ
is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring.
n is 0-4 A is selected from Ri.

o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring.
Each V and Vl individually is selected from Rl and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic;
N,N-disubstituted carboxamidyl (-CONRIRa where Rl and Ra may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (Soak or -SOZNRrR2); and methylene- or polymethylene chain-extended variants thereof.
l0 Each R4 and R5 individually is H, -(CHa)nOH, -C(O)OR6, -C(O)SR6, -(CHZ)"
C(O)NR7R8, -O-C(O)-O-R7, an amino acid or a peptide, Each R6 is H, R7, -C(R7)(R8)-(CH2)n O-C(O)-R9, -(CH2)"-C(R7)(R8)-O-C(O)R9, -(CH2)"_ 15 C(R7)(Rg)-O-C(O)-O-R9, or -C(R')(R$)-(CHa)"-O-C(O)-O-R9, Each R7, R$ and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, allcenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or 2o CH2COaalkyl.
The present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
2$ A further aspect of the present invention relates to a method for inhibiting trypsin-like serine protease enzymes, such as thrombin, factor xa, factor VIIa, TF/VIIa, and trypsin in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one of the above disclosed compounds.

Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, whexein it is shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be s realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
1o Best and Various Modes for Carrying Out Invention An aspect of the present invention relates to compounds represented by the formula:
i I
is ( R~ ) E~ W E2 B
pharmaceutically 2o p acceptable salts thereof;
L V and prodrugs thereof.
2s X (z) ( A) Each E' and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 3o to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-~ hydrocarbon chain which may be substituted with ane or more hetero groups selected from N, O, S, S(O), and S(Oz) which may be saturated or unsaturated.
1o R is -CH=CH-R2, -C C-R~', -C(RZ)=CHZ, -C(RZ)=C(R3), -CH--NR2, -C{R2)--N-R3, 4-membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from Rl, Ra, or R3. Preferably, these R, Rl, R2, or R3 do not include -(Cz_4 alkenyl)-COz-C1_s alkyl, -(C~_4 alkenyl)-COa-C~_8 alkyl-phenyl, and-(C2_4 alkenyl)-C02-C1_g alkyl-O-CI_4 alkyl.
R1 is H, -R, -NOz, -CN, -halo, -N3, -C i_$ alkyl, -(CH2)nC02R2, -C2_a alkenyl-C02R2, to -O(CH2)nCOaR2, -C(O)NR2R3, -P(O)(ORZ)a, alkyl substituted tetrazol-5-yl, -(CHa)n0(CH2)n ~'Yh -~ZR3a -(CHZ)n OR2, -(CH2)n SRa, -N(R2)C(O)R3, -S(O2)NR2R3~
-N(R2)S(OZ)R3, ~-(CHRa)n NR2R3, -C(O)RD, (CHa)n N(R3)C{O)R3, -N{R2)CR2R
substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CHZ)"
phenyl, or substituted or unsubstituted (CHZ)n-heterocycle which may be saturated or 15 unsaturated.
m is 1 except that when El is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring. For instance if the ring is 6 atoms, m can be 1 or 2.
2o R~ is H, -halo, -alkyl, -haloalkyl, -(CH2)n -phenyl, -(CHZ)1_s-biphenyl, -{CH2)m-Ph-N(SOZ-C1_z-alkyl)a, -CO(CHRI)n-ORI, -(CHR')"heterocycle, -(CHRI)n-NH-CO-Rl, -(CHRI)n-NH-S02R1, -{CHRi)n-Ph-N(S02-Ct-2-alkyl)2, -(CHRI)n C(O)(CHRt)-NHRI, -(CHRI)n-C(S)(CHRI)-NHRI, -(CHZ)n0(CH~)nCH3, -CF3, -C2_5 acyl, -(CHRi)"OH, -(CHRI)nCO2Rl, -(CHRI)p O-alkyl, -(CHRI)n-O-(CHZ)n-O-alkyl, -(CHRI)n-S-alkyl, 25 -(CHRI)"S(O)-alkyl, -(CHRI)n-S(02)-alkyl, -(CHRi)n-S(OZ) NHR~, -{CHR3)n-N3, -(CHR3)nNHR~, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated.
m When n is more than 1, the substitutions Rl and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -C2_8 alkenyl, substituted or unsubstituted cycloalkyl, -N(Ri)Ra, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NRZR3 may form a ring system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
1o W is a direct bond, -CHRa-, -CH=CRZ-, -CR2=CH-, -CRZ=CR2-, -C=C-, -O-CHRa-, -CHR2-O-, -N(RZ)-C(O)-, -C(O)-N(R2)-, -N(Ra)-CH-(R3)-, -CHZ-N(R2)-, -CH(Ri)-N(RZ)-, -S-CHRz-, -CHR2-S-, -S(Oa)-N(RZ)-a -C(O)N(RZ)-(CHR2)n-, -C(R~Rz)n-NRZ-, -N(R2)-S(Oa)-~ _RaC(O)~2_~ -R2NC(O)NR2-, -CONRzCO-, -C(-~tRa)NR2_, _NR2C(--NR2)NR2-, -NR20-, -N NCHRZ-, or -C(O)NRZSOZ-.
EZ is ~5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci_8 alkyl, C2_$ alkenyl, C2_s alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
2o each X individually is a direct bond, substituted or unsubstituted C1_4 methylene chain; O, S, NRZ , S(O), S(02), orN(O) containing one or two C1_4 substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CHz)n C(°NR4)NHRS, -(CH2)n-NHR4, (CH2)"NHC(=NR4)NRS, -(CH2)ri OR4, Ci-s substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B' is selected from B; B1 and B may be same or different.

There may be more than one similar or different RZ groups present on Ea, when E2 is a cyclic system of more than 5 atoms. p is 1 or higher if E~ is a cyclic ring of more than 5 atoms. For example, if the ring is 6 atoms, p can be 1 or 2.
n is 0-4 A is selected from Rl.
o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring. For instance, if the ring is 6 atoms, o can be 1 or 2.
to Each V and V z individually is selected from R1 and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic;
N,N-disubstituted carboxamidyl (-CONR1R2 where Rl and RZ may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted 15 sulfonamides (SO~NHR or -SOaNRIR2); and methylene- or polymethylene chain-extended variants thereof.
Each R4 and RS individually is H, -(CH2)"OH, -C(O)OR6, -C(O)SR6, -(CH2)"
C(O)NR7R8, -O-C(O)-O-R7, an amino acid or a dipeptide, Each R6 is H, R7, -C(R7)(R$)-(CH2)"-O-C(O)-R9, -(CHz)n-C(R7)(R8)-O-C(O)R9, -(CH2)n C(R7)(R$)-O-C(O)-O-R9, or -C(R7)(R8)-(CHz)n O-C(O)-O-R9, Each R7, R~ and R9 individually is H, allcyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted allcylaryl, cycloalkyl, substituted cycloalkyl, or CH2C02a1ky1.

R substituent groups employed pursuant to the present invention contribute to significantly enhanced activity of the compounds of the present invention.
Listed below are definitions of various terms used to describe this invention.
These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The expression "lower l0 alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The terms "alkenyl" and "alkynyl" refer to straight or branched chain unsubstituted hydrocarbon groups typically having 2 to 8 carbon atoms.
15 The terms "substituted alkyl", "substituted alkenyl" or substituted alkynyl" refer to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluorornethoxy, hydroxy, allcoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, axyloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 2o amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanolamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. S02NHa), substituted sulfonamido, nitro, cyano, carboxy, caxbamyl 25 (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH
aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.

Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl. ° ' The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
to The term "aralkyl" or "alkylaryl" refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.
The term "substituted aryl" or "substituted alkylaryl" refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl;
15 substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, aminoalkyl, azidoalkyl, alkenyl, alkynyl, allenyl, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, vitro, cyano, caxboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, 2o allcylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like.
The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or axalkyl. "Substituted benzyl" refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
25 The term "cycloalkyl" refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C~ carbocyclic ring.
Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term "cycloalkenyl" refers to optionally substituted, unsaturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3-7 carbons per ring.
Exemplary groups include cyclopentenyl and cyclohexenyl.
The terms "heterocycle", "heterocyclic" and "heterocyclo" refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaxomatic cyclic group, for example, which is 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have l, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atoms.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, dihydropyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane and tetrahydro-I, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl and triazolyl and the like.

Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, cournarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as faro[2,3-c]pyridinyl, faro[3,1-b]pyridinyl, or faro[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzothrasolyl, benzpyrasolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, to isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, theinofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
Within the above-described definitions, certain embodiments are preferred.
Preferred alkyl groups are louver alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. An example of a suitable alkylaryl group is phenethyl. Examples of suitable cycloalkyl groups typically contain 3-8 carbon atoms and include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C 1 _3 alkyl such as b enzyl.
The N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as N, S or O in the ring. Examples of suitable preferred heterocyclic ~.7 groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2-ethylpiperidino. In addition, the above substitutions can include halo such as F, CI, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
Examples of some preferred B groups include NHC(=NH)NHZ, -C(=NH)NH2, NH2, various N-substituted variants, and assorted prodrug derivatives.
Prodrug forms of the compounds bearing various nitrogen functions (amino, hydroxyamino, hydrazino, guanidino, amidino, amide, etc.) may include the following to types of derivatives where each R group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, allcynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl groups as defined begiruling on page 7.
(a) Carboxamides, -NHC(O)R
(b) Carbamates, -NHC(O)OR
(c) (Acyloxy)alkyl caxbamates, -NHC(O)OROC(O)R
(d) Enamines, -NHCR(=CHCROaR) or -NHCR(=CHCRONR.2) (e) Schiffbases, -N=CRz (f) Mannich bases (from carboximide compounds), RCONHCHzNR2 Preparations of such prodrug derivatives are discussed in various literature sources (examples axe: Alexander et al., 3. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO pp/41531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the invention.

Prodrug forms of carboxyl-bearing compounds of the invention include esters (-C02R) where the R group corresponds to any alcohol whose release in the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels.
Another prodrug derived from a carboxylic acid~form of the invention may be a quaternary salt type R~~_o)oC ~\ XO
. R
of structure described by Boder et al., J. Med. Chem. 190, 23, 469.
Examples of soma preferred groups for W are -CH2CH2=, -CH=CH-, -C=C-, -CH2CH2CH2-, -CHzCH=CH-, -CH2C=C-, -CONH, -CHzCONH-, -NHCONH-, -CONHCO-, -CONHCH2-, -C(--NH)NH-, -CHIC(--NH)NH-, -NHC(--NH)NH-, -NHNH-, -NHO-, -CONHSOa-, -S02NH-, -NHSOaCH2-, -S02NHCH2-, _CH20-, -CHzOCH2-, .
-OCHZCHz-, -CH2NH-, -CHaCHZNH-, -CH2NHCHa-, -CHZS-, -SCH2CH2, -CHaSCH2-, _ CH2SOzCHz-, -CHaSOCH2-, -CH(C02H)O and -CH(COzH)OCHz.
Examples of some preferred groups for V and Vl are N-alkyl substituted carboxarnidyl (-CONHR) where the alkyl group may be stxaight, branched, cyclic, or bicyclic, and typically containing up to ten carbons; N,N-disubstituted carboxamidyl (-CONR1R2 where Rl and R~ may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -S02NRIR2);
methylene- or polymethylene chain- extended variants thereof such as -(CH2)nCONHR~, -(CHa)nCONRIRa, -(CHa)"SO2NHR1, -(CH2)"SO2NR1R2 (where n =1-4), -NHC(O)R, N(Rl)C(O)R2, NHS02R, CH2NHR, CH2NR1R2.

Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, malefic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
Salts derived from appropriate bases include alkali such as sodium and ammonia.
to It is of course understood that the compounds of the present invention relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule.

The synthetic routes leading to the compounds in formula (I) are described in the following schemes.
Scheme 1 / COZCH3 p-1 or / COZCH3 B-1 or ~ COZCH3 COZH
1 0 H R O H_R

C
HsC CH3 H SOzCF' 2a, 3a, R-~ 2f, 3f, R= ~CF3 COZCH3 B-1 or COzCH3 CH
/ ~ B-2 /
2b, 3b, R=~CH 2g, 3g, R=
\ 3 C02MEM COZMEM 2c, 3c, R= CH3 2h, 3h, R
MEM = CHz-O-CHz-CHi O-CH3 2d, 3d, R \~ 2i, 3i, R= '-CHzCH3 \ CH3 - CH3 2e, 3e, R-~ / Zj, 3j, R
V CH3 . Cgs 3a H
6a R \ ~
~CH, 2l Scheme 2 Bn / D-1 or Bn0 \ CHO Bn0 ~ CO2H
+3a D-2_ / \ \
CHO H
H.~ ~ / H
H(OH)x H CO C / N v ' HxC02C
6 ~ O

~F
CF3SOz0 \ COZMEM HO \ COxMEM Bn0 \ COxMEM
' .E B-2 ~ E- G
/ I ' / \ / \
H CO C / N " ' H3COxC ( / N " ' H3COxC ~ / NV
a x I O O
O

Scheme 3 H OH SOZCF3 S02CF~
COZH / COZBn / COzBn ~ COZBn H ~- ~ ( B'2 - ~ ~ E

A-3 or SOiCF~
COZBn O N

Scheme 4 soZcF, , C02Bn p_1 or Bn0 / CHO Bn0 / COZH
\ I +6 p2 \ B \ I' \
H' ~ I / N
O N~ Bn0 C / N v \ Bn02C
O
16 O ,o i.
HO / I C02MEM HO / C02MEM Bn0 COZMEM
G /
\ \ \ \ \ \
/ N~ I / N~ / N\/
BnOZC ~ HOzC ''~ ~ BnOZC
O O

\. \
H
N
BnOzC
O

Scheme 5 COZMEM + R - X I ° D-2, D-3, D-4, D-5, D-10, D-11, or D-12 23 X = H, B-(OH)2, Sn(Bu)3, Sn(Me)3,or Si(Me)3 I-i J
E

I
2?
24, R =

°' / a' ~ ~ e°
H' S O O S
h, / i, / .1, g~ ~
/ H3C ~ ~ N
w N N \S~

OH
NCH p~ ! CH3 9, CH3 r' '~ /// l OH

CHZ
CHZ t~ ~ HZ u~ ~/OH v, _-_.~~ w, ~TMS
OH

24, R = (continued) CHO

x,~CH y~ ~OH z, ~ aa/=N ab, OHC a$
ac, ad, ae, CHO ~ OHC ~ ~ ~ N ~ ah, ~CHZ
S S~ S
Boc 25, R = H3C
a' ~ ~ b' ~ ~ °' ~ I H3C ~ S ~ a S . S .~ O O S

h, ~ , i~ ~'~.
N N S' N N
o ~H3 I
_ OH
~CHZ o~ Pa ~CH3 9> CH3.
s ~ ~/~oH

CHZ
~ /CH t' ~ u. ~OH v, _--.~~ w, CH

~iii~ 3 C~ OH
x, ~CH' y~ ~.OH z~ ~ aa~N ab' BnO2C HO C
ac, ad, ae, \ af, ~
~ HOHZC'~~
S~OH ~ N
S Boc H
ah, ai, ~ ' OH Na 26, R =

a' ~ ~ b> ~ ~ °' ,' d' S S ~ ~ H'C S 0 O S
h~ \ ~ i~ \ ~ J~ k~ 1~ ~ ~ m~

N N S~ N

n ~CHZ o r OH
CH3 q~ ~~CH3 ~

CH
s~ .- CHZ t~ /fCHz n, ~/OH v' --OH

x, ~ Y> ~~/OH z, ~ aa~N ab, S
BnO2C HOH C
z ag , ac, ad, ae, ~ ~ of HOHzC'~~
S OH
S S
Boc OH
ah, ~OH ai, ~/\N
a 27, R=

S

h~ ~ ~ '~ ~ j'/ k' ~ ~ l' ~ N
N N ' g I N

n~ ~CHz °~ ~ P~ ~CH3 4~ r, OH
~~%~CH3 OH

CHz s,' ~ CHz t> //CH2 n,'~OH ~ _--~~ w, ~CH
bH

27, R= (continued) CHZ OH
CH3 _ Y, ~/OH Z~ ~ aa/-i-N ab, ~CH3 OH
S
ac, ad, ae, ~ ~ a f HOHZC ag , , HOH2C'~~
S OH HOxC S/ H
S
H
ah, ~OH ai, of K' 2 i I b _ on 5a onvers 24ab K' I

24ac - 25ac -K'I

24ae - _ 25ae ' K' I

24ad ! 25af The reduction of the formyl group of 24ab, 24ac, 24ae, and 24ad was accomplished with NaBH4 to give corresponding alcohols 24ab-i, 24ac-i, 24ae-i, and 24ad-i, respectively.
Later, the MEM group was xemoved under acidic conditions to give 25ab, 25ac, 25ae, and 25af, respectively.
E, H, I-1 Conversion of 24ad ~ 25ad The aldehyde 24ad was oxidized to acid 24ad-i which was protected as benzyl ester to give 24ad-ii. MEM
deprotection under acidic conditions produced 25ad.
Conversion of 24ah L' I-1 ~, 25ah The vinyl compound 24ah was oxidized with Os04 to give diol Z4ah-i, followed by acidic hydrolysis of the MEM group to produce 25ah.
L, M, K, N, O, I-1 Conversion of 24ah -- 25ai The vinyl compound 24ah on dihydroxylation with Os04 gave diol 24ah-i.
Oxidative cleavage of the diol with NaI04 produced aldehyde 24ah-ii. The aldehyde on reduction gave alcohol 24ah-iii, which on further reaction with methane sulfonyl chloride yielded mesylate 24ah-iv. The mesylate on further reaction with sodium azide gave the corresponding azide 24ah-v, which on acidic hydrolysis produced 25ai.
Conversion of 24w I-1~Q-- 25w Scheme 6 CF D-I, D-2, D-3, D-4, or D-5 R-X
2g X = H, B-(OH)2, Sn(Bu)3, or Sn(Me)3 J

O

29, R =
b, ~ ' c, ~CHz d' ~ ~ e' ~ \ f~ ~CH2 CHa S
OHC CHO OHC
S° O 0 30, R =
O
a, b~ ~ c~ ~CHz d~ ~ \ , ~ e' ~ \ f' ~CHz CH3 CH3 S~ f N~HzC CHzOH HOHzC
\ h' ~ \ i' l \
o.
to 31, R=
a~ ~ b> ~ c> ~CHz d> e> ~ \ f~ / \ CHz CH CH' S
zs 3 f N3H2C CHzOH HOHzC
\ h, ~ \ i, l \
20 S ~ ~
32, R=
O
25 a' b' ~ c' ~C z d e~ \ f ~CHZ
~CH CH3 f N3H2C . CHzOH HOHzC
S~ O O
K, N, O, I-1 Conversion of 29g --~ 30g Aldehyde 29g was converted to alcohol 29g-i by reduchion with NaBHa, followed by the reaction of methanesulfonyl chloride to give mesylate 29g-ii. The mesyl group was displaced with azide to give 29g iii and finally, the MEM group was removed under acidic conditions to give 30g.
K, I-1 Conversion of 29h~ 30h K, I-1 29i ----~ 30i The reduction of the formyl group of 29h and 29i was accomplished with NaBH4 to give corresponding alcohols 29h-i and 29i-i, xespectively. Later, the MEM group was removed under acidic conditions to give 30h and 30i, respectively.
Compounds of the type 23 and 28, where X = -Sn(Bu)3, ara prepared using the methods AG-1 or AG-2 Scheme 7 P
35 O . 34 B(OH)2 CBz= i"p CH2C6Hs >> , Tff'S

TIPS = Tri-isopropylsilyl G _ n 40 3y Scheme 8A

+
10 B(O~z N

43 a2 \ I_2 NH
O
O ~ \ N \
H
/ \
~ / N
HOZC
O

Scheme 8B
/ ~ ~ / ~ NH
\ / ~ M3z \ O / ~ NHz O \ \
\ N \ N
g I-2 _ l H
/ \ ~ \
N~ ~ ~ N\/ \
H3COZC v ~ HOZC

Scheme 8C
Me0 ,~ CHO
+ 3a D-2 _ B(OH)z O

E
NHz J
N
O

2~

s1 Scheme 8D
G I_2 31g r Scheme 8E
26n G ' 27aj (R= ~./CH3 ) 32f C' - 27ak(R=~CH ) 26ai G " 27a1 (R = /~NHz ) 26u G -' 27am (R = ~~ CH

Scheme 9 r v / v / v / o /
O \ CHO ° \ C°aH ° \ N \
5+6- D2 ' E -- f - H
/ \ / ~ \ /
/ / /
H3CO2C C02MEM H3C02C C02MEM H~COZC C02M', 1 ~ 54 55 56 R
r ~ . N..
Boc ~ ~ O /
15 ° \ N \
c ~ H
. 1 /
H3COzC C02MEM
20 ~ ss s~

25 cF

t_ ..I
65 .-J ""

62, R =
a ~CH3 f ~~CH3 ~ ~CH3 b, ~\~\CH3 c, ~CHZ d' \ CH3 ' . CH3 CH3 OH
g yCH3 h\~y~ ~~~'C~ CH3 Y\CH3 /J\Of\ CH CH3 1~
m, \ 3 n,\/ CHs c, CH ~CH3 \ 1 P, .~CF~ Q, CH3 r' CH3 s, CH3 t, a OH y \\~CH3 ~OH

OH
w; ~N x, Y, ~CH Z ~CH3 aa, .,\~OH ab, ~/\/ ~
' ac ad, OH ae, NHR= -N~ af, NHR= -N~\''CH3 63, R =
3~ a~ ~,/~/CH3 b' ~\.~\CH3 c,\'~CHZ d, \ l e, CH3 f H H3 ~CH3 CH3 OH
g,~~CH3 h1\J~ i~~~~~~ CH3 ~CH3 O CH CH3 m, \ n, CH3 0 ~
CHI ~ l P, \~CF3 9, CH r CH3 ~CH3 \
CH

CH3 t, a OH y \~~CH3 ~OH

OH
w, ~N X, y ~CH Z ~CH3 aa, ~OH ab, ~N~
ac, ad, OH ae, NHR = -N' ) af, NHR = -N~CH3 O

64, R = CH
a CH3 f ~ s a' ~/CH' b' ~ c'~CH d' ' CH3 z .~ CHI

OH
g,~~CH3 h\\J~ ;~~~~~ CHs J, ~CH3 / \O CH " CH3 CH / I p' ~CF3 9, CH r, CH

C,H3 \ 3 3 O
CH3 t ~ OH
\1~CH3 OH

OH
N X, y, ~CH ~' ~CH3 aa, ~,~OH ab, .~,~/N~
ad, OH ae, NHR = -N' J af, NHR = -NCH' ac ~~//, O

es CH3 65, R =

Ccheme 10 59 + ~gU~3gn~ D-3 1_7 68, R=
S
CH
a, CH3 b~ CH3 ~, ~ a° '\/~CH e' ~CH3 f \ / s '~~--z _ CH3 CF3 h' ~ ~ ~~ .1> ~ k~ \CH I, .~CH3 / OH
CHI
~CH3 o CH3 P~ ~ 4~ CH
' ~H3 3 ~~~~~OH
r, NHBoc S~ ~ t' ~ u' ~ ~' w, x, .~~CH3 ~O '~ ~H

69, R =
d, ~ e, ~~s f, a' ~/~/CH3 b' \\~<~ CH' °' C \H
z _ CH3 a g ~ ~CF' h~ ~ ~ OH 1' ~ k' \CH 1> ~/CH3 n, ~~/ o, P~ ~~ q> CH3 "~n OH u, ~ v, ~z w, ~OH X, .~~CH3 ~CH3 70, R =
CH
a ~CH3 b, CH3 c, ~ d~ ~CH c' ~CH3 g ~ ~CF3 h, ~'~ i~ OH J, ~ k~ \CH 1, ~~CH3 n, ~/~3 0, CH3 P~ ~.~ q~ CH3 ~, . .. i OH u, ~ v, r, NHz w~ ~OH X ~~~CH3 ~CH3 71, R=
a, ----~ b, --~ c, ~'CH3 Scheme 11 CHO U_2 or ~ CHO
T a~nd~U-3 73 + 3a / /
Me0 Me0 B(OH)x D-2 V-1 or V-2 / i CHO and H or W
HO \ i \
R'O C / Nv \ N

75a, R' = Me 75 0 . .
75b, R' = Bn B_2 X
CHO
/ i D-2,D-3, or D-8 F3C02S0 \ \
I I H
/ N~ N
R O ''~~ ~~..C
76a, R' = Me 76 0 76b, R' = Bn NH
E E
0 / i '~z / i N \
H E J
R \ i \ R
v H~ ~
/ N~ N
R OZC
79 ~ 7g 0 T-2 or G

77a, 78a, 79a, SOa, R=-H=CHZ; R' = CH3 78b, 79b, R = OSOZCF3; R' = Bn; 80b, R = OH
77b, 78c, 79c, R = -O-CHZCOZCzHS; R' = Bn; 80c, R = -O-CHZCOZH
77c, 78d, 79d, 80d, R = -O-CHZCONHZ; R' = Bn 77d, 78e, 79e, 80e, R = ~ ~ ; R' = Bn S
77e, 78f, 79f, 80f, R = -O ~ ~ ; R' = Bn 74 E - 78g ~ J - 79g Z'2 _. _ 80g 78g, 79g, 80g, R = OGH3, R' = CH3 77f, 78h, 79h, 80h, R = ~O~CH3; R' = Bn O CH
77g, 78i, 79i, 80i, R = ~ ~ 3; R' = Bn 77h, 78j, 79j, 80j, R j0,~ ; R' = Bn 77i, 78k, 79k, R = OCHZ CHZ OAc; R' = Bn; 80k, R = -0-CHi CHZ OH

Scheme 12 R _ v'''°3 79a L
IE
S, I-2 82, 8d, 85-R
86a, R=CH(OH)CHZOH
86b, R= CH~OH
86c, R=COzH

Scheme 13 H OBn OBn T, U-1 CHO X ~ ~ CHO ~ ~ CHO 89 + 3a Br / B(OH
Br ~z F

IG
ys y~

y2f 7 ~ l..
95a, 96a, 97a, 98a, R=
l \ A-~ l \
9I 'I - 97b I-Z - 98b, R=-O-CHZC6H5 S Br S SnBu 98b G - 98c, R=-OH

Scheme 14 CHO CHO
T, U 3 ~B(OH)Z
OMe OMe 100 + 3a D'2 E

J

E

Scheme 15 CHO CHO CHO
T~ U-I
I I ~B(OH)z OH OBn OBn 107 + 3a CHO
OBn ~ / N

O

G
I-2 _ Scheme 16 ~ CHO HO ~ CHO ~ or Bn0 ~ CHO
Z 0~ X' V
/
O gr RO Br RO Br 6a T, U-I

Bn0 ~ CHO
cF,oslo RO / B(OH)2 / NHR' H,co2c 116 3a-j °

F
3n0 ( ~ COZMEM . HO ~ ~ C02MEM
G _ B_2 _ RO / ~ ~ RO /
/ NHR' / NHR' NHR' H3COZC H3COzC
O O
119 ~ 120 121 NHZ

NHR' O

O

O
114a,115a,116a, R = CH3;114b,115b,116b, R = CZHS; 114c,115c,116c, R = -CH(CH3)2; 115d, R = C-C(CH3)s 117a --125a, R = CH3; R' = .~
CHs I I7b --125b, R = CZHS, R' _ I I7c --125c, R = CH(CH3)2; R' -' CH3 117d --125d, R = CH3; R' 117e -- 125e, R = CH3; R' = -~~ CH3 117f --125f, R = CH3; R' = CH3 117g _- I25g, R = CH3; R' _ ~ CF3 117h --125h, R = CH3; R' _ %~CH

117i --125i, R = CHI; R' _ 117j --125j, R = CH3; R' =
117k -- 125k, R = CH3; R' _ ~ CH3 1171--1251, R = CH3; R' _ '~~ CH3 117m --124m, R = C-C(CH3)3; R~ _ ~ ; 125m, R = H; R' _ Scheme 16a 118b ~ I=-2 ,~

126,127, R = CzHs; R' = CH3 Scheme 16b 124a R S
H~
128,8=CH3;R'= ~CH
l Scheme 17 x CHO
+3a D-2 E
B(OH)Z

J, A-5, A-4, or ~R . I_2 \ ~ ~R
HOZC ~ ~ H3COZC
O ' O

133,134, R=
a' ' ~ ~ b' ~ ~ ~ c' \ ~ ~ d, ~ ~ ~ CF3 N

CF3 f \ ~ ~ g, ~ ~ ~ h' F
'-N/ \O.1'~~~ k~/ \N~~ i~~~~H
N
N-m' n' ~ ~~ ( ~ o' ~ P
S
OMe OH ~~N
9' ~~ ~ ~ ~ r~ \ ~ ~ ~ NHz S' ~ ~ ~ u, ~ N-/N
~N
OH

133,134, R= (continued) \N aa, ~ ~ ~ ab ~ ~ ~ OH ac ~ ~ \
~ I /
OH HOC
ad,,~ ~ ~ ~N ae~ \ ~~ I / ~ af,/~ ~ ~ OH
N
ag d~ ~ ~ OH ai i N~NH2/NHBoc ~H3 Scheme 17a A-3, A-4, A-5, or J I-2 3af ~ ---->

135,136, R =
N
N N / ~ NH /NHBoc a' ~~~ ~ b' \ ~~ c' ~ ~ d' ~~ \ NH
N d --j~ Z ~ N
CI

f,~~ ~ ~ NH g, ~~ ~ ~ CHZCN h° ~~ ~~~ CHzNHz/NHBoc z Scheme 18 COZH 02CHs OZCH3 , ~ COZCH3 HO \ HO \ HO \ 0 CP~OaSO \ O
W s ~ ~ ~ ~ / ~~~ I /
NHa NHa Bn0 / CHO E Bn0 / COaH
140+6 D2 \ \ I
I / '~ H CO C I /
H3COaC 3 2 F ', HO COZMEM Bn0 COzMEM
/ I <G / 1 I \ O \ I \ O
H3COZC'~~ H3COaC'' v F CO SO CO MEM R / COaMEM
3 a / I a D-2 or D-3 \ \ 0 \ \
OC I ~ ~\ HCOC
HSC a 3 z NH
It 2 ' COaH
\ I
H3COaC

I46a --149a, R= / \ 146b -- 1d96, R= / \ 146c --149c, R=-CH=CHa Scheme 19 CHO
+ 3a -D'9 N
Sn(Me)3 lsl E
~--J
t H
N
153 O Is~

1s4 Scheme 19a CHO
N I
+ 3a \ Sn(Me)3 E
J
COZH
N I
\ \
H
/ NN

15ri m 15y Scheme 20 NOZ OR
AB-1 or AB-2 +31f 0~0~
R , O

Ry ~ or O CI O
O
R~ ~ O NOR
O JZ H

160a, 161a, R=-CH3 160b, 161 b, R = -C2Hs 160c, 161c, R = -CHZC6Hs 160d, 161d, R = -C(CH3)s 162a, R = -CH3 162b, R = -CzHs 160e, 161 e, R = -CHi CC13 OMe 162c, R = -CHZC6Hs 160f, 161f, R=
160g, 161g, R= ~ ~ F 162d, R=-C(CH3)3 O
160h,161h,R= CHZ
/ ~O~CH3 O
160i, 161i, R= /CH2~0 CH3 ~ H3 160j, 161j, R =/CHI

Scheme 21 / CHO
Br \ \
+ 130 H3COZCHzC / H3COzCHZC

E
NHZ
/ COzH
J
\ \
H H3COzCH2C

Scheme 22 HO Hp HO
\ AC ~ ~ \ ~ ~ \
H3COZC / CHO H3COZC / / NOH ~3COZC '/ NHZ

AA
F3COZSO \ HO \

N / N

CHO COzH
172 + 130 D -~ \ I E \
\ . \
/ N ~ / N
H3COZC ~ H3COZC

. 1 .

I I
iio 175 O

Scheme 23 HO ,\ F3COZS0 168 . AEI _ H~ -~ . H
NN
H3COzC N H3C02C

R
F3COZS0 ~ Boc CHO ~ COZH
179 + I30 D-2-\ \ ~ oc \ ~ \ ~ oc N'u' H3COZC HsCOzC

J
E I-2, S

Scheme 24 z ~~R \ B~OH~z 0 .
3a, 3f, 3i, 3,j 6 lif4 AD
>-3 B-2 R R R
~' I ~ 7 O 186 iss 3a, 184a, i85a,186a,187a,188a, R=
3f,184b,185b, 186b,187b,188b, R=CHzCF3 3i, IBdc, I85c,186c, 187c, 188c, R=CHzCH~

3j,184d,185d, 186d,187d,188d, R ~~CH3 Scheme 25 AE-4, 74 ~ 189a 184a- AE-3 _ 189b ~ - 189c 189a, X = H, Y = OCH3 189b, X = OCHZC6H5, Y = H
189c, X = OH, Y = H
131 AE-3 _ 189d N ~ ~ (Prepared by method AJ-i, AJ-2, or AJ-3) HN NH, 189d, X=Y=H
CHO
AE-3 _ NHi l ~ N, W
H,COZC
HN NH, 131 189e 189a,189b,189c, 189d Scheme 26 NH
NH R ~ ~ NHBac / ~ Br , ~ ~ NHBoc X
Br HO Br 190 191 ~ 192 o .a .e CO~CH~
n 0 H I
6a R \ ~ ~NHZ R \ ~ ~NHBoc ~O S_2 -~ ~ ~O
N~ ~ /

p x-2 190a,192a -195a, R = H
190b, 192b -195b, R= CH5 Scheme 27 O N ~ ~ H R ~ OzN ~ ~ NH c' HzN ~ ~ NH B c z Ngz NHEoc NH v + 190b X

.,c 6a S

NHz Scheme 28 R
45--~
O O

/~
206 2u5 NH ~ ~ NH
/ ~ NHZ \ 0 ~ ~ NHZ
O
\ O / \
\ \ ~ \
/ ~t~ I-hN / N\ J\

p 0 O

Scheme 29 b.~ ~ .
lsz, sot- zoo Y
NH
NH
OH

E
211 iiu 209a, R = H
209b-211b,R=

Scheme 30 CN

\ /~
w urnr~
187a 212 Y

214 Lis Scheme 31 E-Z, HSC~H2C0 / CHO
F3C0xS0 HO
\ D \ \ H
/ N +6 / N / N
H3COxC N H3COxC N H3COZC N

~E
PhHZCO / COxH P1~C0 / C02MEM HO CO MEM
F _ I G _ / I x \ ~ \ \ \
/ N~ / N / N
HICOxC N ~ H3COyC N ~ H CO C N

~8-2 orFaCOxSO / C02MEM

N~ ~ / N
HyCOxC N
O

CJ
I-2 _ 228 Lt'l Me0%/~~ Me0 \ ~ Me0 H
/ / N /
Br N C02H Br N ~ ~N

Scheme 32 / ~ CHO AG-3 /
\ ~ Br + 6a ~
HO ~ ~Br O
OH O

R = H .n - ~. d~~
R = COzCH3 R = COZH
E
NH
/ ~ ~~2 \ r~ a E
\ \
R I
R = H 234 0 233 R=COZH R=H
R = COZH

NH
~i 231a, 232a, 233a, 23da, 235a, R = H
231b, R = COZCH3 232b, 233b, 234b, R = COZH

R=H

Scheme 33 NH
CN
~_1 \ ~ ~NHZ * 187a AE-2 HZN N HZN N

Scheme 34 L
161d ~ 140 'M
NH
~NHBoc NHBoc H
242 ~ am ~S

G~IJ GH4 Scheme 35 AD _- B-2 H~ N
N

Nti~

248 ~ N~4 222 - 'I I-2 ~
249 25~

NHi N~ I
HN NIi NH
/.'~ _ ___ Scheme 36 NH
H
/ ~ CHO AE_3 / ~ N ~ ~ NHz \ NH, \
Br , Br 2s3 2s4 HN NNi R
NH
H
H y_ i~~ E D-6 / N ~ ~ NHBoc NHBoc + 6a \
Br 25s I-2, S

O
NH
H
,N
NHz / N\
O

General Methods of Preparation The following abbreviations' have been used:
THF: Tetrahydrofuran; DMF: Dimethylformamide DME: 1,2-Dimethoxyethane; DMAP: 4-(Dimethylamino)pyridine Boc anhydride: Di-tert-butyl dicarbonate; TIPS: Triisopropylsilyl MEM: Methoxyethoxymethyl; Bn: Phenylmethyl or Benzyl to The organic extracts were dried over sodium sulfate or magnesium sulfate.
The general methods for the preparation of the compounds of formula (I) are given below:
A-1: Conversion of acid to amide To derivative (1 mmol), was added thionyl chloride (12.6 mmol) and a few drops of DMF. The reaction mixture was refluxed for 2 h and concentrated in vacuo to obtain an oily residue. The residue was dissolved in dichloromethane (3 mL); cooled with ice .water and amine (5 mmol) was added. The reaction mixture was stirred at room temperature overnight, washed with 1N HCI, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-2: Conversion of acid to amide To a solution of acid derivative (1 mmol) in dichloromethane (10 mL) at 0 °C
was added triethylamine (3 mmol) and ethyl chloroformate (3 mmol). The reaction mixture was stirred at the same temperature for 30 min and the corresponding amine (6 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with 1N HCI. The organic layer was separated, washed with water, brine, dried and concentrated in vacua. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-3: Conversion of acid to amide To a solution of acid (1 mmol) in dichloromethane (5 mL) was added 2M oxalyl chloride in diclaloromethane (2.5 mmol), followed by a drop of DMF. The reaction mixture was stirred for 2h at room temperature and concentrated in vacuo. The residue was co-evaporated once with dichloromethane (5 mL) and then dried in vacuo. To the residue in dichloromethane (10 mL) were further added triethylamine (3 mmol) and the corresponding amine (1.2 mmol). The reaction mixture was stixred for 16 h and washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-4: Conversion of acid to amide To a solution of acid (1 mmol) in dichloromethane or THF, (10 mL) cooled with an ice bath was added triethylamine (1.2 mmol) and ethyl chloroformate or isobutyl chioroformate (1.2 mmol). The reaction mixture was stirred at 0°C for 30 nvn and the corresponding amine (2.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with 1N HCl. The organic layer was separated, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
72 .

A-5: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1.l mmol), 1-hydroxybenzotxiazole (1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.l mmol) in pyridine (10 mL) was stirred overnight at room temperature and was concentrated ifa vacuo to dryness. The residue obtained was purified by column chromatography or used as such for the next step.
A-6: Reduction of acid to alcohol To a solution of acid (1 mmol) in dichloromethane or.THF (10 mL) at 0 °C was added triethylamine (1.2 mmol) and ethyl chloroformate or isobutyl chloroformate (1.2 mmol). The reaction mixture was stirred at 0 °C for 30 min and sodium borohydride (1.25 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with 1N HCI. The reaction mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish the desired alcohol. This can be purified further, if needed, by crystallization or column chromatography.
2o A-7: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1 mmol), and 4-dimethylaminopyridie (0.12 mmol) in xylene (10 mL) was stirred at ~0 °C
for 10 min.
Phosphorus trichloride (1 mmol) was added and the reaction mixture was heated with stirnng at 150 °C for 2 hr. After cooling, the product was extracted with EtOAc. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by flash column chromatography to furnish the desired amide.

B-1: Conversion of phenolic hydroxyl to triflate To a phenol (1 mmol) in dichloramethane (2.5 mL) was added pyridine (5 mmol) under a nitrogen atmosphere and cooled to -10 C. To the cold reaction mixture was added dropwise triflic anhydride (2 mmol) in dichloromethane (2.5 mL) over a period of mins and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and the organic layer was separated. The organic layer was washed with 1N HCl, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product to obtained was purified by crystallization or flash column chromatography to furnish the desired triflate.
B-2: Conversion of phenolic hydroxyl to triflate To a solution of substituted phenol (1 mmol) in DMF (10 mL) was added N-phenylbis(trifluoromethanesulphonimide) (1.1 mmol), and triethylamine (2 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated in vacuo.to furnish the desired triflate.
C: Conversion of acid to MEM ester To a solution of acid derivative (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and MEM-CI (1.05 mmol) and was stirred at room temperature for 24 h. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated iri vacuo to furnish crude product. Purification by flash column chromatography or crystallization gave the desired MEM ester.

D-1: Coupling of boronic acid with triflate A mixture of triflate (1 mmol), aryl boronic acid (1.5 mmol), potassium phosphate (3 mmol), potassium bromide (2.4 mmol) and tetrakis(triphenylphosphine)palladium (0.05 rnmol) in dioxane (10 mL) was heated at reflex overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water and was extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo.
Purification by flash column chromatography or crystallization gave the coupled product.
D-2: Coupling of boronic acid with triflate A mixture of triflate (1 mmol), aryl boronic acid (2 mmol), sodium hydrogen carbonate (3 mmol) and tetrakis(triphenylphosphine)palladium (0.05 mmol) or bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in DMElwater (9:1, 10 mL) was heated at reflex overnight. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo.
Purification by flash column chromatography or crystallization gave the coupled product.
D-3: Coupling of tributyltin derivative with triflate A mixture of triflate (1 mmol), tributyltin derivative (3 mmol), tetraethylammonium chloride (6 mmol), and bis(triphenylphosphine)palladium(II)-chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated i~x vacuo. Purification by flash column chromatography or crystallization gave the coupled product.

D-4: Coupling of trimethyltin derivative with triflate A mixture of triflate (1 mmol), trimethyltin derivative (3 mmol), and bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in THF (10 mL) was heated at 70 °C overnight undex an argon atmosphere. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
to D-5: Coupling of alkyne with triflate A mixture of triflate (1 mmol), triethylamine (4.5 mmol), substituted alkyne (3.5 mmol), and bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-6: Coupling of boronate ester with aryl bromides A mixture of boronate ester (2 mmol),' aryl bromide (1 mmol), potassium phosphate (3 mmol) and bis(diphenylphosphinoferrocene)palladium(II)chloride (0.05 mmol) in DMF (10 mL) was heated at 100 °G for overnight under an argon atmosphere.
The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl 2s acetate (2 X 10 mL). The organic layers were combined, dried and concentrated ifa vacuo. Purification by flash column chromatography or crystallization gave the desired product.

D-7: Coupling of boronate ester with aryl bromides A mixture of boronate ester (2 mmol), aryl bromide (1 mmol), sodium hydrogen carbonate (3 mmol) and bis(diphenylphosphinoferrocene)palladium(II)chloride (0.05 mmol) in DMElwater (9:1, 10 mL) was heated at 50-70 °C for overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and was extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated i~a vacuo. Purif canon by flash column chromatography or crystallization gave the coupled product.
D-8: Coupling of phenol with boronic acid A mixture of phenol (1 mmol), aryl boronic acid (3 mmol), molecular sieves (4A°), pyridine (5 mmol), copper(II)acetate (1 mmol) and bis(triphenylphosphine)-palladium(II)chlaride (0.05 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was cooled, filtered through a pad of Celite and concentrated in vacuo. Purification of the crude.by flash column chromatography gave the coupled aryl ether.
D-9: Coupling of trimethyltin derivative with triflate To a solution of triflate (1 mmol), LiCl (4 xnmol), PPh3 (0.15 mmol), CuBr (0.2 mmol), and bis(triphenylphosphine)palladium(II)chloride (0.07 g) in DMF (10 mL) under an atmosphere of argon was added trimethylstannyl compound (0.8 mrnol) and a crystal 2S of 2,6-di-t-butyl-4-methylphenol. After the mixture was stirred at 90 °C for 3 h, a second portion of aryl-trimethylstannyl compound (0.5 mmol) was added. The reaction mixture was stirred at 90 °C overnight. Water was added and extracted with ethyl acetate. The organic layer was dried (MgS04), concentrated and purified by flash column chromatography or crystallization to furnish the desired coupled product.

D-10: Coupling of amine with triflate A mixture of triflate (0.75 mmol), amine (0.9 mrnol), potassium phosphate (1.1 mmol), 2-(di-t-butylphosphino)biphenyl (0.015 mmol) and tris(dibenzylideneacetone) dipalladium(0) (10 mg) in DME (10 mL) was heated at reflux overnight under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography to furnish the desired coupled product.
D-11: Conversion of triflate to cyano compound To a solution of triflate (0.84 mmol), zinc cyanide (0.54 rnmol), Palladium acetate (0.016 mmol), 2-(di-tert-butylphosphine)biphenyl ( 0.016 mmol) and N-methyl pyrrolidine (10 mL) was heated under argon at 160 °C for 48 h. The reaction mixture was cooled to room temperature and quenched with water (50 mL). The reaction mixture was extracted with ethyl acetate (2 X 25 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired cyano compound.
2o D-12: Coupling of tetravinyltin with triflate or halide To a solution of aryl triflate or bromide (1 mmol) in DMF (5 mL) were added LiCl (5 mmol), tetravinyltin (2 mol), and dichlorbis(triphenylphosphine)palladium (II) (0.01 mmol). The reaction mixture was stirred at 70 °C under nitrogen for 5 h and then diluted with ethyl acetate and filtered. The organic layer was washed with water and brine and dried (MgS04). After evaporating the solvent ih vacuo, the compound was purified~by flash-column chromatography to give the desired product.

E: Oxidation of aryl aldehyde to acid A mixture of aldehyde (1 mmol), tart-butanol (5 mL), water (2 mL) and acetonitrile (1 mL, additional amount may be added until the reaction mixture was homogenous) was stirred at room temperature. The solution was cooled in ice-bath and 2-methyl-2 butane (1 mL), sodium chlorite (6 mmol) and sodium dihydrogenphosphate (1.6 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. If the solid separated out, the mixture was filtered to collect the solid, the desired product.
If no solid separated out, then the reaction mixture was concentrated in vacuo to remove acetonitrile, diluted with water (10 mL) and extracted with ethyl acetate (2 X
10 mL).
The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish crude acid. Purification was achieved, if needed, by crystallization or using flash column chromatography to obtain pure acid.
E-2: Oxidation of vinyl compound to acid To a solution of vinyl compound (1 mmol) in acetone (5 mL) was added KMnOa.
(4 mmol). The reaction mixture was stirred for 3 h (the reaction is exothennic, and refluxed on its own during the addition of KMn04). The reaction mixture was diluted with methanol and water and filtered. The organic solvents were evaporated ih vacuo and the aqueous layer was acidified to pH 1 and extracted several times with ethyl acetatelDME. The combined organic layers were dried (MgS04) to furnish the desired acid.
F: Conversion of aromatic acid to MEM ester To a solution of axomatic acid (1 mmol) in THF (10 mL) was added diisopropylethylamine (2 mnlol) and 2-methoxyethoxymethylchloride (1.1 mmol).
The reaction mixture was stirred a room temperature for 3 h and diluted with ether (25 mL,).

The reaction mixture was washed with water (10 mL), brine (10 mL), dried and concentrated in vacuo to obtain product as colorless oil. The product was purified by flash column chromatography to furnish desired product.
G: Conversion of aromatic benzyl ether to aromatic phenol, benzyl ester to acid, benzyl carbamate to amine, alkene to alkane; azide to amine, vitro to amine, and , oxime to amine To a solution of appropriate substrate (1 mmol) in ethanol (10 mL) was added l0 10% palladium on carbon (10-wt%). The reaction mixture was hydrogenated at 50 psi for 2 to 24 h (until all starting material disappeared as confirmed by MS and TLC
analysis). The catalyst was removed by filtration through a pad of Celite under nitrogen.
The filtrate was concentrated in vacuo to furnish the product, which was purified by flash column chromatography or crystallization.
H: Conversion of aromatic acid to benzyl ester To a solution of aromatic acid (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and benzyl bromide (1.05 mmol) and stirred at room 2o temperature for 24 h. The reaction mixture was quenched with ice water and extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried and concentrated in vacuo to furnish crude product. Purification by crystallization or flash column chromatography gave the desired ester.
I-1: hydrolysis of MEM ester to acid Ta a solution of MEM ester (I mmol) in DME (8 mL) was added 6 N HCl (2 mL) and stirred at room temperature overnight. The reaction mixture was neutralized with solid sodium hydrogen carbonate (18 mmol) and concentrated ifa vacuo. The reaction so mixture was acidified with 0.5 N HCl (20 mL) and extracted with ethyl acetate (2 X 20 mL). The organic layers were combined, washed with 'brine (20 mL), dried and concentrated in vacuo to furnish crude product. Purification of the crude by flash column chromatography gave the product. Alternatively the crude reaction mixture was diluted with water (10 mL) and concentrated in vacuo to remove DME. The solid obtained was collected by filtration and dried in vacuo to furnish pure acid.
I-2: Hydrolysis of ester to acid to To a solution of ester (1 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mmol). The reaction mixture was stirred at room temperature for 2-3 h, filtered through a plug of cotton, and concentrated iu vacuo to remove MeOH. The pH of the aqueous layer was adjusted to below 7. The solid that separated, was collected by filtration, washed with water and dried in vacuo to furnish the desired acid.
J: Coupling of acid with amino compounds To a solution of acid (1 mmol) in DMF (5 mL) was added corresponding amine (1.l mmol) and stirred at room temperature until homogenous. Pyridine (5 mL) was added to the reaction mixture followed by 1,3-dicyclohexylcarbodiimide (1.2 mmol) and stirred overnight at room temperature. The mixture was quenched with 6 N HCl (10 mL), diluted with ice cold water (10 mL) and extracted with chloroform (2 X 10 mL).
The organic layers were combined washed with brine (10 mL), dried and filtered.
Purification of the crude by flash column chromatography gave the product as a solid. If the product was soluble in water, then the reaction mixture was concentrated in vacuo to remove pyridine and DMF and purified by flash column chromatography.
8z K: Reduction of aldehyde to alcohol To a solution of aldehyde (1 mmol) in THF (10 mL) was added sodium borohydride (0.4 mmol). The reaction mixture was stirred for 30 mins and quenched with glacial acetic acid (0.3 mL). The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL)., The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo to obtain crude product which was purified by flash column chromatography.
1o L: Conversion of vinyl group to diol To a solution of vinyl compound (1 mmol) in THF/tert-butanol (1:I, 10 mL) and water (Z mL) was added 4-methylmorpholine N-oxide (2.5 rnmol) and osmium tetraoxide (1 mL, 2.5 wt% in test-butanol, 0.1 mmol). The reaction mixture was stirred at room temperature for 2 h and quenched with saturated aqueous solution of sodium sulfite (5 mL). The reaction was stirred at room temperature for 30 rains and diluted with brine (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was 2o purified by flash column chromatography to furnish the desired diol.
M: Conversion of diol to aldehyde To a solution of diol (I mmol) in DME/water (9:1, 10 mL) was added sodium metaperiodate (3 mmol) and stirred at room temperature for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 X
IO mL).
The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to furnish the desired aldehyde.

N: Conversion of alcohol to mesylate To a solution of alcohol (1 mmol) in DME (10 mL) was added dimethylaminopyridine (0.1 mmol), methane sulfonyl chloride (3 mmol) and diisopropylethylamine or triethylamine (5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The residue obtained, was purified 1o by column chromatography to furnish the desired mesylate.
O: Conversion of mesylate to azide To a solution of mesylate (1 mmol) in DMSO (10 mL) was added sodium azide (25 mmol) and heated at 100 °C overnight. The reaction mixture was cooled and diluted with cold water (25 mL). The reaction mixture was extracted with ethyl acetate (2 X 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried, filtered and concentrated i~a vacuo The residue obtained was purified by column chromatography to furnish the desired azido compound. .
P: Protection of amine as benzyl carbamate A mixture of amino compound (1 mmol), benzyl chloroformate (2 mmol) and triethylamine (10 mL) in pyridine (10 mL) was stirred at room temperature overnight.
The reaction mixture was concentrated ire vacuo to remove organic solvents and diluted with 0.1 N HCl (10 mL). The product was extracted with chloroform (2 X 10 mL), dried, filtered and concentrated ih vacuo. The residue obtained was purified by column chromatography to furnish the desired carbamate.

Q: Conversion of silyl protected amine to amine A mixture of silyl protected amine (1 mmol), tetrabutylammonium fluoride (1.0 M in THF, 2 mmol) in THF (10 mL) was stirred at room temperature for 1.5 h.
The reaction mixture was concentrated in vacuo and purified by column chromatography to obtain the desired product.
R: Protection of amine as tart-butyl carbamate to To a solution of amino compound (1 mmol) in acetonitrile (5 mL) was added triethylamine (2 mmol) and BOC anhydride (1.2 mmol). The reaction mixture was stirred for 2 h and.concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSOa.), and the solvent was evaporated ih vacuo to furnish tart-butyl carbamate. If needed, the product was purified by crystallization or column chromatography.
S: Conversion of tart-butyl carbamate to amine To a solution of tent-butyl carbamate (1 mmol) in dichloromethane (10 mL) was 2o added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 4 h and concentrated in vacuo. The residue was purified by column chromatography or crystallization to give the desired amine.
S-2: Conversion of tart-butyl carbamate to amine To a solution of tent-butyl carbamate (1 mmol) in methanol (13 mL) was added 6 N HCl (x.75 mL, 52 mmol) and water (4.25 mL). The reaction mixture was stirred at room temperature for 2 days. The pH was adjusted to 7 using conc. ammonium hydroxide and the solid that separated out, was collected by filtration, washed with ether, dried in vacuo to furnish the desired product. If no solid separated out, the product was isolated by extraction with chloroform and evaporating the organic layer.
T: Protection of aldehyde as acetal To a solution of aldehyde (1 mmol) in ethanol (5 mL) was added triethyl orthoformate (1.4 mmol), ammonium nitrate (0.2 mrnol) and stirred at room temperature overnight (if reaction was not complete by TLC and NMR analysis of an aliquot, the reaction mixture was heated at 50 °C until complete). After completion of the reaction, to the mixture was quenched with triethylamine (0.2 mmol) and concentrated in vacuo to remove ethanol. The residue was dissolved in ether, filtered to remove any insoluble inorganic impurities, and evaporated to dryness. The product obtained was used as such without further purification.
U-1: Conversion of bromide to boronic acid To a mixture of bromo compound (1 mmol) in ether (10 mL), cooled to -78 °C, n-butyl lithium (1.2 mmol) was added dropwise and the reaction mixture was stirred for 30 mires after the addition was completed. Tributyl borate (1.3 mrnol) in ether (10 mL) was 2o added to the reaction and stirred at -78 °C for 2 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (10 mL). The reaction mixture was stirred at room temperature for 1h and cooled with ice. The aqueous layer was separated and the organic layer was extracted twice with 1N NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product is obtained then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated ifa vacuo to furnish boronic acid.

U-2: Synthesis of boronic acid by ortho lithiation of aryl aldehyde To a solution of N,N,N'-trimethylethylenediamine (1 mmol) in THFlether (10 mL, 1:1) cooled to -20 °C was added dropwise, over a period of 15 mins, n-butyl lithium (1 mmol) and stirred at -20 °C for 15 minx. Aldehyde (1 mmol) at -20 °C was added dropwise over a period of 10 mins to this mixture. The reaction mixture was further stirred for 15 mins at -20 °C followed by the addition of n-butyl lithium (2.8 mmol) dropwise over a period of 15 minx and stirred at 4 °C overnight. The reaction mixture was cooled to --40 °C and tributyl borate (5.6 mmol) in ether (20 mL) was added to the to reaction and stirred at 4 °C for 12 h. The reaction mixture was allowed to warm to 0 °C
and quenched with 2 M HCl (3 mmol) and heated at reflux for 2 h and added to ice water (25 mL). The aqueous layer was separated and the organic layer extracted~twice with 1N
NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 rnL).
The basic layer was acidified to pH 3 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried ire vacuo to furnish boronic acid as a solid. If no solid product was obtained, then the basic layer was extracted with ether (2 X 10 mL). The oxganic layers were combined, dried and concentrated in vacuo to furnish boronie acid.
U-3: Synthesis of boronic acid by ortho lithiation of aryl acetal To a solution of aryl acetal compound (1 mmol) in ether (10 mL) at -7~
°C, tert-butyl lithium (1.1 mmol) was added dropwise and the reaction mixture was stirred for 3 h at -20 °C after the addition was completed. Tributyl borate (1.2 mmol) in ether (10 mL) was added to the reaction and stirred at -20 °C for l h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (10 mL). The reaction mixture was stirred at room temperature for 1h. The aqueous layer was separated and the organic layer was extracted twice with 1N NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HCl and the solid that separated out was collected by filtration, washed with Water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid' product was obtained then the mixture was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated iya vacuo to furnish boronic acid.
V-1: Demethylation of aryl methyl ether to phenol In a round bottom flask (50 mL), pyridine hydrochloride (10g) was heated in an oil bath at 180 °C. After the entire solid had melted, the corresponding aryl methyl ether (1 mmol) was added in small portions over a period of 20 min. The reaction mixture was heated at 180 °C for 4 h, cooled and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X lOmL). The combined organic layers were washed with brine, dried over MgSO~, concentrated to give phenol. This can be further purified if needed by crystallization or column chromatography.
V-2: Demethylation of aryl methyl ether to phenol To a solution of aryl ether (1 mmol) in dichloromethane (10 mL) cooled to -"78 °C
was added boron tribromide (3 mmol). The reaction mixture was allowed to warm to 2o room temperature overnight and quenched with water (10 mL). The solid obtained was collected by filtration to give the desired product. More product was obtained after evaporation of the organic layer and washing the residue with water.
Alternatively, if a homogenous biphasic mixture was obtained on addition of water, the organic layex was separated, washed with brine, dried over MgS04, and concentrated to give the desired phenol. This can be further purified if needed by crystallization or column chromatography.
s7 V-3: Demethylation of aryl methyl ether to phenol To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was added A1C13 (~.5 mmol). The reaction mixture was heated to xeflux for 12 h under nitrogen. To this mixture was added 12 mL of 1 N HCl slowly and the organic layer was separated.
The aqueous layer was re-extracted several times with ethyl acetate/DME. The combined organic layers were washed with brine, dried (MgS04), and evaporated in vacuo to furnish the desired phenol, which was purified by column chromatography.
to V-4: Demethylation of aryl methyl ether to phenol To a stirred slurry of NaH (2 mmol) in anhydrous toluene (5 mL) under nitrogen atmosphere was added pare-thiocresol (2 mmol) dissolved in toluene (40 mL).
The mixture was stirred at room temperature for 30 min and hexamethylphosphoric triamide (2 mmol) in toluene (5 mL) was added dropwise over a period of 30 min. A
solution of aryl ether (1 mmol) in toluene (5 mL) was added in one portion. The reaction mixture was stirred at reflux for 9.5 h, cooled to room temperature and diluted with ethyl acetate (40 rnL). The organic layer was extracted with 1 N aqueous NaOH solution (2 X
20 mL).
The basic layer was acidified to pH 5 and extracted with ethyl acetate (2 X 20 mL). The organic layers were combined, washed with water, dried (MgS04) and concentrated in vacuo. The residue obtained was purified by flash colwcrm chromatography to afford the desired phenol compound.
W: Conversion of acid to methyl ester A mixture of acid (1 mmol), cone. H2S04 or cone HC1 (0.5 mL) and methanol (10 rnL) was heated at reflux for 16 h. The mixture was concentrated to half of its volume and the residue poured into a saturated sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and dried to give the desired ester. If the ester did not come as solid, it was extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give the desired ester.
W-2: Conversion of acid to ester s A solution of methanolic HCl or ethanolic HCl was prepared by the addition of acetyl chloride (1 mL) to methanol/ethanol (9 mL) at 0 °C and stirred for 30 mins. To the solution of anhydrous methanolic HCl was added acid (1 mmol) and stirred at room temperature (or reflux if needed) overnight. The reaction mixture was concentrated to to dryness in vacuo and the residue was purified by column chromatography or crystallization to furnish the desired ester.
X: Conversion of phenol to alkyl aryl ethers or alkylatioa of amines 15 To a solution phenol or amine (1 mmol) in DMF (10 mL) was added cesium carbonate (1.25 mmol) and corresponding bromide (1.1 mmol). The reaction mixture was stirred at room temperature overnight and quenched with water (25 mL). The product was extracted with ether (2 X 25 mL), the organic layers were combined and washed with water (25 mL), brine (25 mL), dried and concentrated in vacuo to furnish 2o crude product. The crude was purified by crystallization or flash column chromatography.
Y: Conversion of nitrite to hydroxycarbamimidoyl 25 To a solution of nitrite compound (1 mmol) in ethyl alcohol (10 mL) was added hydroxylamine (50% aqueous solution, 5 mmol). The mixture was stirred at reflux for 2-h. The reaction mixture was concentrated in vacuo to furnish the desired hydroxycarbamimidoyl compound.

Z: Opening of aromatic methylene dioxy compound with alcohol A solution of potassium tert-butoxide (2.25 mmol) in DMSO (1.25 mL) was heated at 50 °C for 30 min. Methanol (1.25 mL) was added to it and continued heating at 50 °C for 30 min. To the reaction mixture was added 1,2-methylenedioxy aromatic compound (1 znmol) and continued heating at 50 °C for 30 min. The reaction mixture was cooled to room temperature and quenched with water (10 mL) and 1 N sodium hydroxide (16 mL). The reaction m mixture was washed with ether (2 X 10 mL) and acidified to. pH 4 using conc HCI. The solid obtained was collected by filtration to 1o furnish the desired product.
Z-1: Opening of aromatic methylene dioxy compound with alcohol To a mixture of methylene dioxy compound (1 mmol) in HMPA (2.5 mL) were added sodium methoxide (2.5 moral) and heated with stirring at 150 °C
for 12 min. The mixture was cooled and poured into ice water (20 mL), NaOH (30 mg) and stirred for 10 min. ' It was then extracted with ether and the aqueous layer was acidified to pH 4 with HCl and extracted with ether. The later ethereal extracts were combined, dried and concentrated. The residue was purified by crystallization or column chromatography.
AA: Conversion of amine to amide in the presence of a phenol To a solution of amino compound (1 mmol) in pyridine (5 mL) was added, dropwise, acid chloride (2 mmol) at 0 °C under Na. The mixture was stirred for 45 min and was then poured into ice water and acidified with 1 N HCI. The precipitated solid was collected by filtration, washed with 1N HCl, hexane, and then dried in vacuo to give crude product. The crude product was added to freshly prepared sodium methoxide solution (0.1 M, 10 mL) and stirred for 30 min at room temperature. The reaction mixture was quenched with acetic acid (1 mmol) and concentrated iyZ vacuo. The residue was dissolved in ethyl acetate and washed with water. The water layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgS04) and evaporated to yield a solid. The solid was washed with hexane and dried in vacuo to fiunish the desired amide.
AB-1: Conversion of amino of amidine to amino carbamate To amidine compound (1 mmol) was added O.1N NaOH (10 mL) and stirred at room temperature for 5 min. The reaction mixture was concentrated i~c vacuo and to the 14 residue was added allcyl or aryl 4-nitrophenyl carbonate (2 mmol) in 20 mL
of hexamethylphosphoramide and stirred at 45 °C for 24 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with water (I00 mL) and brine (I00 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired product.
AB-2: Conversion of amino of amidine to amino carbamate To a solution of amidine compo~.u~.d (1 mmol) in acetonitrile (25 mL) was added 2o triethylamine (5 mL) and aryl/alkyl chloroformate (~ mmol) or dialkyl/aryl carbonate.
The reaction mixture was stirred at room temperature for 16 h and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (2 X 100 mL).
The combined extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired product.

AC: Conversion of aldehyde to oxime To a stirred solution of aldehyde (1 mmol) in ethanol (10 mL) was added pyridine (10 mL) and hydroxylamine hydrochloride (1.25 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen and then concentrated in vacuo to one third of its original volume. Water (10 mL) was added and the precipitated solid was collected by filtration and dried in vacuo. The product was used as such for next step without further purification.
1o AD: Debenzylation in the presence of aldehyde To a solution of phenyl methoxyaryl aldehyde (1 mmol) in dichloromethane (10 mL) cooled to -78 °C was added dropwise under a nitrogen atmosphere boron tribromide (1M solution in dichloromethane, 1.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with chloroform (10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish crude product.
Purification of the crude by flash column chromatography furnished the desired phenolic 2o aldehyde AE-1: Reductive amination of aldehyde To a stirred solution of aldehyde (1 mmol) in methanol (40 mL) was added amine (3.3 mmol) followed by the addition of glacial acetic acid (0.3 mL). The reaction mixture was stirred for 30 min under nitrogen at room temperature, and then sodium cyanoborohydride (1.5 mmol) was added. After stirnng for 20 min, the solvent was evaporated ih vacuo, and the residue was taken in ethyl acetate. The organic layer was washed with water, and the insoluble material was removed from the organic layer by filtration. The pH of the aqueous phase was adjusted to 7 with 1N Na.OH and was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgS04). The solvent was evaporated in vacuo to furnish crude product. The crude product was purified by crystallization or flash column chromatography.
AE-2: Reductive amination of aldehyde To a mixture of aminoarylamidine (1.2 mmol), 4A° molecular sieves, and sodium hydroxide (1 N solution in anhydrous methanol, 1.2 mL, 1.2 mrnol) in methanol (10 mL) l0 was added a solution of aldehyde (1 mmol) in THF (10 mL). The reaction mixture was heated for 15 mins at reflux temperature and was cooled to room temperature.
Acetic' acid (1 %) and sodium cyanoborohydride (1 M solution in THF, 5 rnmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with I N NaOH (30 rn~mol) and stirred for additional 2 h and concentrated in vacuo to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 x 10 mL). The aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration, washed with ether, dried in vacuo to furnish product, which was purified by flash column chromatography, if needed.
2o AE-3: Reductive amination of aldehyde A mixture of aminoarylamidine (2 mmol), 4A° molecular sieves, pyridine (6 mL) in methanol (9 mL) was heated at 50 °C for one hour. A solution of aldehyde (1 mmol) in methanol (7.5 mL) containng acetic acid (1 %) was added and continued heating for 4 h to 12 h. The reaction mixture was cooled and sodium cyanoborohydride (1 M
solution in THF, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 5 N NaOH (30 mmol) and stirred for additional 2 h. The reaction mixture was filtered through Celite (to remove molecular sieves) and concentrated to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 X 10 mL). The aqueous layer was filtered and solid obtained was kept aside (mainly product). The aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration.
The combined solid materials were purified, if needed, by flash column chromatography.
AE-4: Reductive amination of aldehyde To a mixture of aldehyde (1 mmol) and aminoarylamidine (1.1 mmol) in MeOH
at room temperature was added triethyl amine (2.75 mmol), sodium cyanoborohydride (0.83 mmol) and zinc chloride (0.9 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to remove methanol. The reaction mixture was quenched with 1 N NaOH (10 mL), diluted with water (10 mL), and extracted with EtOAc (5 X 20 mL). The combined organic extracts were washed with brine (15 mL), dried (MgS04), filtered through Celite and concentrated to give the product.
Purification of the crude by flash column chromatography gave the desired product.
AE-5: Reductive amination of aldehyde To a solution of amine (1.2 mmol) in MeOH (10 mL) was added aldehyde (1 2o mmol) in THF (10 mL) containing acetic acid (0.1 mL) drop-wise. The mixture was stirred at 50 °C for 4-12 h and then cooled to room temperature. Sodium cyanoborohydride (I.5 mmol) was added to the reaction mixture and stirred at room temperature overnight. Water was added and pH of the solution was adjusted to 7. The solution was extracted with ethyl acetate. The organic layer was dried (MgS04) and evaporated ih vacuo. The residue was purifeid by flash column chromatography to furnish the desired amine.

AF-1: Synthesis of amidine from nitrite Acetyl chloride (5 mL) was added to methanol (5 mL) at 0 °C drop-wise and stirred at room temperature for 15 mins. To this solution of methanolic HCl was added nitrite compound (1 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and dried. The residue obtained of the resulting methyl imidate was dissolved in methanol (10 mL). Dry ammonia gas was bubbled into the reaction mixture at reflux temperature for 5 h. The reaction mixture was concentrated to furnish the required amidine.
AG: Addition of Grignard reagent to aryl aldehyde To a solution of aryl aldehyde (1 mmol) in THF (15 mL) cooled to -7~ °C
was added drop wise under a nitrogen atmosphere, vinyl magnesium bromide (1 M solution in THF, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4~ h. The reaction was quenched carefully with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried and concentrated i~c vacuo. The residue obtained was purified by flash column chromatography to obtain the desired addition 2o product.
AG-1: Synthesis of tributylvinyltin compounds from vinyl bromide containing hydroxyl To a solution of vinyl bromide with hydroxyl (1 mmol) in dichloromethane (20 mL) was added tart-butyldimethylsilyl chloride (1.5 mmol) and DMAP (1.5 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water (~0 mL) and the aqueous layer separated. The organic layer was washed with 0.1 N
aqueous HCl (10 mL), brine (20 mL), dried and concentrated in vacuo to furnish corresponding tent-butyldimethylsilyloxy compound as an oil which was used as such for the next step.
To a solution of the above oily residue (1 mmol) in diethyl ether (20 mL) cooled to -78 °C was added dropwise tent-butyllithium (1.7 M in pentane, 2 mmol) over a period of 15 mins. The reaction mixture was stirred at -78 °C for 3 h and quenched at -78 °C
with 2 N aqueous sulfuric acid (2 mL) and water (18 mL). The reaction mixture was neutralized using 2 N NaOH and the organic layer was separated. The organic layer was washed with water (20 mL), brine (20 mL), dried and concentrated in vacuo.
Purification 1o of the crude residue obtained by flash column chromatography furnished the desired tributyltin compound.
AG2: Synthesis of tributylmethyltin compounds from arylmethyl bromides or allyl bromides To lithium clippings (10 mmol) in THF (10 mL) cooled to -40 °C was added dropwise tributyltin chloride (0.27 mL, 1 mmol) in THF (5 mL) over a period of 15 min.
The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered through glass wool to remove insoluble impurities and 2o cooled to -40 °C. A freshly prepared solution of arylmethyl bromide or allyl bromide (1 mmol) was added dropwise over a period of 10 mins and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ether (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish desired tributyltinalkyl and was used as such without further purification.

AG-3: 4-Bramo-5-formyl-benzo[1,3]dioxole-2-carboxylic acid methyl ester To a mixture of 2-bromo-3,4-dihydroxy-benzaldehyde (2.17 g, 10.0 mmol) and KZC03 (5.56 g, 40.2 mmol) in h-propanol (25 mL) was added dibromoacetic acid (2.18, 10.0 mmol) and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature, another portion of dibromoacetic acid (1.7S g, 8.0 mmol) was added.
The mixture was stirred at reflux for 46 h. n-Propanol was evaporated and water (30 mL) was added. The resulting aqueous solution was acidified to pH 2 by adding 1 N
HCl and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried to (MgSOa) and evaporated in vacuo to afford crude 4-bromo-5-formyl-benzo[1,3]dioxole-2-carboxylic acid (1.34 g) as a brownish solid. This crude product was dissolved in anhydrous methanol (50 mL) and cons. H2SO4 (5 mL) was added drop by drop. The resulting mixture was refluxed overnight and cooled to room temperature. Water (50 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (100 mL X 3). The combined organic layers, were dried (MgS04) and evaporated ih vacuo.
The residue was purified by flash column chromatography (ethyl acetate:hexane = 5:95) to furnish 4-bromo-5-formyl-benzo[1,3]dioxole-2-carboxylic acid methyl ester as a white solid.
AH: Synthesis of tert-butyl ester of phenol To a solution of phenol (1 mmol) in pyridine (10 mL) was added 2,2-dirnethyl-propionyl chloride (1.2 mmol) dropwise. The mixture was stirred at room temperature for overnight and diluted with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X 50 mL). The organic layers were combined and washed with aqueous 0.5 N HCI (100 mL), water, brine, dried (MgS04) and concentrated in vacuo. The crude residue was purified by flash column chromatography to furnish the desired ester.

AI: Preparation of 2-bromo-5-hydroxy benzaldehyde To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), was added bromine (45 mL, 845 mmol) in chloroform (200 mL) drop wise over a period of 2 h at room temperature. The reaction mixture was stirred at room temperature overnight and filtered to collect crude 2-bromo-5-hydroxy benzaldehyde (32 g) as a dark brown solid. The filtrate was concentrated to 200 rnL, filtered through a pad of Celite and silica gel (40 g) and washed with ether (1000 mL).
The filtrate was concentrated in vacuo to give a second crop of the crude desired aldehyde (60 g) as a daxk brown solid. The above solids were combined and dissolved in glacial acetic acid {360 mL) by heating. Water {840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish brown crystalline solid, mp: 135 °C.
AJ-I: Amidine from nitrite A mixture of nitrite (1 rnmol) and hydroxylamine (aqueous 50%, 1.8 mL) in 2o EtOH (15 mL) was refluxed for 3 h anal concentrated ire vacuo. To the residue obtained was added EtOH (20 mL), acetic acid (2 mL) and a small amount of Raney nickel.
The reaction mixture was hydrogenated (50 psi) for 14-24 h, filtered and concentrated ih vacuo. The residue obtained, was purified by flash column chromatography to obtain the corresponding amidine.
AJ-Z: Amidine from nitrite A mixture of nitrite (1 mmol) and saturated methanolic HCl solution (freshly prepaxed by bubbling HCl gas or prepared in-situ by premixing methanol and acetyl chloride at ice cold temperature) was stirred at room temperature overnight.
The reaction mixture was concentrated ire vacuo to furnish methyl imidate. To the residue of methyl imidate was added MeOH (40 mL) and ammonia gas was bubbled at reflex temperature for 16 h or till the reaction was complete. The reaction mixture was concentrated i~z vacuo and dried to furnish the desired amidine. Alternatively, the methyl imidate was dissolved in methanol and ammonium acetate (10 mmol) was added. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine.
1o AJ-3: Amidine from nitrite To a solution of nitrite (1 mmol) dissolved in methanol (5 mL) was added N-acetyl cystein (0.1 or 1 mmol) and ammonium acetate (5 mmol) and heated at reflex till the reaction was complete. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine.
AK: Conversion of aryl triflates or halides to boronate ester To dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloro-2o methane adduct (0.75 mmol) under argon in dioxane (100 mL) was added aryl triftate (25 mmol), pinacolborane (31.5 mmol) and triethylamine (75 rnmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC
analysis. The reaction mixture was concentrated iya vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester.
Alternatively, the following method can be used.
To dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloro methane adduct (0.03 mmol), l,1'-bis(diphenylphosphino)ferrocene (0.03 mmol) under argon in dioxane (100 mL) was added aryl triflate (1 mmol), bis(pinacolata)diboron (1.1 mmol) and potassium acetate (3 xnmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated zn vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester.
The examples of the compounds pxepared are given in the following tables. The tables describe the compounds, their method of preparation, the starting material, and the analytical data. In some cases, where analytical data have not been given, those compounds were characterized at the later step in the synthesis.
to '-' N ~'~'~
o M ~O
~ ~ ~ h .~j ~ b c~ ~;~xo~
W o ~ cV O
A ~ a>
II
~ x "~, *-' ..
o x'> N
Z
~'~-~~o~a~N
'~? o ~o vo ~ ~
O M ~ II II N
II '~ '~ '~ + . N ~t o0 '' ~' ~C b ~ N N N
U
~ ~ N O ~ ~ C/~ C/~
.-: U ~ W
U x rte, ~ M ,-, ~
N
N N N N
U O '=J 'd O O O O
~~~ ~ ~ ~
b e-I r~ e-1 v--~
x. x.
M
x M M ~ x U ~ U
\ U
U ~U
~4 x /z xz ~o ~ xz o xz ~o Q' z N N N N
U

N
cC +~ C/~
A N
N
O N N ~ '~
z z z v U
°o ~ oho N
M N N N
U
v ~ '~-' W c~
U
cV cV N N N N
i~
O O O O O O
r1 v--~ ri '-I r1 v-I
w x x U ~ U
U U
U
xz xz xz xz xz 0 0 0 0 ~° xz Cdr Z N N N N N N
U

Q' z N N N N

O x x N
00 ,-. N ~: oo ~ N ~" II ~-: N
x x '_'' ~ ~ -r..~ '~ (w M
vi x ~ ~0~1. . x M '~ ~ O ~l' '~
l'e~
N 'b ~ ~ N ,L! ~
A
e~ ~ b t~ M ~ ,-~ b r' N
' N
00 ,--a ~ ,_, M 00 r., t~ ~D l~ ~~-' c~~~O~ x M x fl~ ~ N ~h M ('('1 C~1 ~, _c~ ~ _M x rs N "d U ~'l x N ~ U N
a~ A ;~ ~1 M ~ ,~ ~~ri ~~~, V~ ~O
+ +
a a v ~ ~ ~ ~ ~ M
xb~x N x~~w .wo N '~ .mo .~
o b P~ ~x1 ~4 ~ Pa 0.'1 0.1 P4 ~4 Pa 0.1 ' 0.~
N N N N N N
,N W
x M
UM U U x U . U U U
~U
xz xz xz xz xz o ~° xz w r~ r~ ~ w M M M M M M
U

r, x ~~'-'~ N ,-V ~O N V~ ,-W. ~ d' ~O N W
~xM~ ~x~ x~ II :-: ~~x~
°M x M M ~ x ~r' M ~ ~ II '~ x ~ N ~ II
I! p N ~+. N r~ '~ -c-. M rs ~ v _ x x ~, 1l N ~ x ~ N ~ x rN-~ x "C~ 00 a ,~ r-, b x x ~ M V x ~ M r" O v ~ l~
x~~'y '~ II ~~ ~ II ~~:. ci~M~
M ~ ~' 'P' '.~ N ~ '° ''~ N x II t~ ~: M x' ° o M ~ II ,~ ~ ~ II ro ~ ,~ ~''! ~ x .-: ~°. b 'h ~,:
'_~bMx '~bM ~, b~Mx ~~_Mx M x O ~M ~M ~~ ~ ~ m ~ ~N
_ ~n c-o x ,-i co x ~ ,-; ~
N ~ _v~ x 00 _~ ~ x 00 ~ r-, ~~t', C/~ 00 x o~0, x ~ ~ ,.~~ ~j v N
..
N v M ~T 'r a oo x ° ~ N '_° x x ~ '_.°. x x ~ ~ oo ,-; d' Z N ''' d-Wit: ~
r~
x ~O M~ ~ 0 x ~I ~ ~'rr-r I~ ~,''1 ~ O _v~ b_~' ~ ~ x VI
U M x ,-n ~ ~O C/~ M ~ ~ C/~ M ~ v x C/~ c'1 O d. M U ,~ x ,y.r N '"'' ~ C/~ O~ ~, N zj ~ ~ N ,~j ~ ~ ~ II ~n d: ~t ~ ~ ~ VI
M ~ II ''r ,-, ~ II v ,- .~., ~ ,> V7 M . . U 'n , N ~ ~ OIL s~ ~I ~ h. ~..~, O~O ..d ~.~~x ~b~x~~b~xW II N~x x n v ~ ~N ~ s~N O N '-' N 'J ~' ~O ,1~
'd M V~ x ~ d; x ~t x ~ M N N ~ 'b r~ x N
xb,~~N ~ x~~ ~ x~~, ~x x~xx~ ~ bxNx N N N N
O .d PG W Pa ~ ~1 N
O O O O
b0 C~
.' .., ~ CC~
yes., N N N N ~ M
U
U
U
tx xz xz xz o xz o xz ~ ~o r~ r~ rs; w w U U U U U
O O O O O O O
O O O O O 0.i M M M M ~ ~C

II II II M v~
N '~ x ,.N.., ~ '~ ~ N ~
"u x b b II O x_ x 00 i-~' N i~
ct M N . v0 .-Wt '~ ''~ M ~-' cd 0o NNO ~''~~'v xb~
"CS ,~ ~' W ~ Ox1 ~ ~ O N OV1 ,~b N~~- ~~x~ ~xM a ,~_M~
"~o,N~ ~-'~ N ~ bxx.~
~1 ~ ~ ~ n i-s ~ ~O Ov x O '~ 'b M ~'' .-y' ~ N
-~ x x M 00 ~ ~ tri ~ N N
x ~ N ~O ~ N M ~ ~ ~ M ~ ~ ''~ x ,x~ Cl~
'_' .b N N tip '~ ~ '~ is ~ N plJ tn ~': N
~' N 'h.-4' x . x + oo II .. oo °° va ,~x~a~o, ~b~ ~W(~~,o~M ,~'b I
OVJ~~O i ~ N~~ ss'C ~ ~~O
oMr,u a o~,xO~ ~b~ oMb~
II x '~ '> ~ t~ O N ~ U ,n ~ N .-~ M o '-'~ b b ~~ nn ws ~ x ~ II ~ ~ N
M ~x II x x u~ l~ ~ ~~ ~' x _ x '-, D1 "' ~ N ~ ~ '"'' 'L7 ~ N C/~
-, a1 N p N b N N 'C x vi _ ~x"xx ~~ a ~ ~_~, x,-:bxx x~~0.~ x NbW x~ N
x ~ M ~-~ N l~ L~ ~O x ~ ~ ~ x M
O 'C! N

CA
b yes'", ~ M M ~O ~O
~ w x U ~ U x ~ U
U U z ~ U
\ ~ o , 0 o v xz zx zx M
U
O O O O O
O
M 'e1' ~ l~ l~

N ~d N I I ~ ~ ~' N ,~~''~ . ,~ ' MO 1l N M II ~ ~ ~ ~ N ~ x ~ ~p M
x _ '~ '--' M .~
x M x 'v o°°o N O x' ~ ~ oo ~ II
°° N O ~ ,~ d. W II '> ~ ~ vi O
N ~ ~', ~-' pj ~ ~ ,.d ~ ~ ct3 M~x~' . xbrx'~"'x'~,~'° ''''~~~z b ~ ~ ~ u~ 01 ~ N
Ii x p ~_ _ _ v. l~ N ~ II N N O ~ ~ >~
l~ '> N ~ ~ x x ~ ~ ~ ~ xi M N N (vj O N N b x N ~
.V.W O r~ ~ O ~ '-' x ~ ~ ,x ~ r, l~ ~ ~ d' ~ O 1~ ~ N ,~ ~ 00 ~
ea N ~: II ~ O vo ~ ~ ~ ~ O ;-: ~t ~ W
yo x .-; '~ + : ~zi M '~ N I I r'~ M M ~ M 'n d' ,-~ ..r n? ~; s~. r~ ~ N ~ '~ ~ oo II . . ~ ~ ~ r~
Ubr"'~W~ ~ 1l °~~'~U ~x'~+, v~x'~~
M ~ ~ cC M
~M .~ N ~ q b x ~~ U N u~ V7 q rte', ~ nj Ov N II ~ ,_, ~ N ~ pj '~V~M~ ~l~~Mr~ ~~M~i-v ~l~N,~
~ N x ~;~ ~~ r~ "~d ~x r~ x rs ~ ~.O
r~i b x V t~ "~i o0 r~i ~ .w.s r~i N ~-~ ... ,.~i 's ~.O
b b N ii N
GA
M
U U U
x U U U U
U
O o ~-z xz x~ xz ~ w O O O o O O O
A, ° r ~ r ~z o !l r: ~o ~:
~~x ~x;~Nx x li ~~o~,, °'~'~:o~o.
d- N ''"'~', M ~ +
~:"~~'~z N x b ,.'~'' M N .+., w.s tn vi +j N N ~ ~ pp ~ ~, ~
!l7 ~ ~ M N II tn M
00 ,-r ~9 ~ + ~O
_N ~ tri r~ v v x°~~-~' z ~ vjd~
II
v; W -I- ,~; '~' l~ ~ c i W
M a ~ ~ p~ ~ .N ~' ~.r 00 .zj N Vj + ~, ~ ,,_., x ~ M Vj a~
m rØ N x ~ Z Z r ~~ ~ ,fir ~ M ,."'C, N
vi ~ + b v--. ~ ~" ~ ~ N
M ~ M r N ''J OO N
O ~ x ~ M N M ~ b d; N M "~
,~NM~D O~O~GO
d' ~ 'd' °p ~., ~ N II
O N ,-~ ~ ~ ~ ,_, ,..~
r~ b N ''° '~
~1 N 'd' O ~
~'',.l'-1 b ~ ° ,~' ~ ~ ~'~' ',-'G' t~ W-ri o U
o ~
w w c~
aio o + ~ 00 ov °
.~ w U O O O O
U U U U
0.! s~ ~ ~ w U
O O
O O O , ~ O
t~ 00 0, ° ''.' o~, N
v~

II
°~~b~~xM
II '"' p ~ r,r? ~ N
" N ~ II M II ~t ,., _.
'~ N
~ ~ ~-~ W
N l~ ~
b x ~n ~ N
r~i a o ~ ~, ,..~ N
II '"' ~ M "~
A ~ ~b ~ u0~"[~ N is II M .~ ~ N ~p W
Wr .~-; 1D
+' x r-C...C OO~~~~N'-.
0o a~
z z z ~.~~~x~o z "~ ~, oo .b ~ c~ O
N M M d; ~ b O ~p II
O CV N ~D ~ ~ op ~D "~
~ oo 1l .-: b :-: :-: :~ %-V~ ~ C/~ CAS ~ ~ b ,-~ N ~O ~ C/~
~x'~x~M~z ~~,~+
,~, ~ ~ ~ x r~' t~ ~ x M N
b O
A
bD
-~ ,.-~ r-~ r-~ r~~ H
H
~ w N N N N , U
x .
O
O N N
U ,~, ~ N N PV

A
.., M
U
M
i~
z N 'd; M ~ ,-~ ~ N
0o O ~ .zy N
M N m d' d' n +~ ~ ;-~
cad wr v ~ ~ y.r w.r ~ ~ ~ cUC
N cV ,~ r, .-~ r, ,--1-1 1-~ 1 1-~ 1 I-1 H
eet .c~ ~ b N N N N N
w w w ~ x x x x x o ~ 0 0 0 0 0 U U " 'U U U U U
U
U / ~ U v?
/ O W
U \.
x c ,. c~ "a ~ ~~ a~
N N M M ~'1 M M

N
A
~u z z ~ H

"" N ~O
H O o ~ M '~' t~~1 M
M ~ ~n d' d' N v»Y
in ~ ~ i~ ~ ~ n W W W W ~ W W W W
v ~ v v y~ 'r 'r 'r 'r U
''~ O H H
-. ,-~ ,!, ~1 ,-..~ °° , ~, N W
H H
H ~H
N N N
d' W x Q
O x O
E4 O O O O O ~ U U
U
\ \
U / cn x / ~ U ~ /
p: ~ U ~ N U U
' ~ ~ \ o x O o o O O
z x M M M M M ~!' ~Y ~1' 'd ~p " N
h N
b ~ II
d' 00 II
~h ~ M _ '-' " x Ctt N ~ x ~O
~ N N
A ~ ~:~r~
II r~ M 01 N '_~ II
m p 00 0o M b °.°.' II ~ ~
~d~',rrr:~
,~ V7 ~ v I~ W
N ~~
N 't ~1 00 "~"' O ' y,r ~ N 'r r''l~.i ~ N
'"' ~ N
v ~ ~ x~x o .o <C
N
ran ~ W O
r; e~
~w x"' U
x U
o x x o xz ~o r~ w r~
0.~' O O O
O O
'd o ~r .~

..

N f y n x, ~ b n N N N N

N '~ 00 x x x '~
M x ' ~ "

~ N -r ~ ~ ,~ II
~ -d r, ~ rs b _ xi v b V0 a WO r~ r- M ~

~ x ~ ~ ~ ~ ~ ~ ~ N b >~ ~
i m '~i ~ o ,~,~ ~ N''~
II w ~ f N ~ M ~.., op ,- oo N b N
~ N
m o0 , .-, ~ f b ' N ~ ~ ~ .
., d ri II CO
f N 'r x ~ f ~ ~ r.., ~

~ yp , O1 x n ~.rj ~ ~ r N ~ , ~N~ f ',.1~,N~'~,',~xb II
~iZixdy r vO f N o0 \O N -~ f .
N n N ,~, N ~D " ~ .-y' ~O
M

_ ~i ~ x N ~i M ~ .>~
~'' ~i ~ , f ~

l0 ,.--~ v0 N ~' ,~ ~O xi ~n r'.' t 1 f N ' M 00 C/~
x II ' II II II ,..., II M f f b W
x 'b ~ -~";

f _''a''C ~, ~ b b ~ ~D f >b ~ N '~ ~, '_'' 0~0 ~ f cat ~ ~ II 01 'J ~' ~ ~ 'WO N d' ,-~
II ~j oo , C ono p ~' o~o ~ II ~ vi II ~
'~' ~ ~''~ ,.~C~, ~i ~

, 'd l~ Y~ M
~ r ~

.b ~ M o O V'7 O
~

tØ ,..~ ~ ~ ~ r~-~ 'C1 ~
~ ~ ~ CV b N
~i ~

i-s r r~ N wr wr ~ N
M (S~ ~j f wr o l~ d' " o " o O N ~ ~. O '~' ~ '1' O r''~ II '~' ~ C/~ M 0~O '~' ~
~ f f N
' ''~ a x ~ ~ C/~ ~n h C/~ ~, ~ ~ ,-. _ h Q N c rv ~ lp "'~ n ~ ~D x " N N

t x .~y Cl' ~l~ Nx ~x~ x fl p f1 p bxxNoo ,, II ~
~, N ~M II N ~ 00 ~ M ~ O M ~-. 0v ~ ~ 00 d' ,~ ~.;
~ ~ ~; x .. M tW r M f l~ ~ ~
~ 01 ~ ,- M r~ v cc1 f 'b O
"C1 w w p ~O
~

do o x w ~ ~

U O

' U

O O O

~ ~ ~

aJ ~
Z

o II o ii ~ ~ cn ~ ~_' F-~ M ~N
~ mj ~ 'b ~M r~ ~ N .-. oo ~ ~'~' N '-' ~ '~, N N o~ W ~ M tn ~n ~-, ~ M oo t~ "vd N
v W .r ~ ,~, 00 N
~ II ~ x ~ ~~ II
-r ~ 00 N ~ ~ ~ ~i ~ ~' II
M vD x ,~,~ ~ ~ x '~ N t~ ~ N N t~' r~ N N ~, t-W~
v0 x '~' 'd ..-~ ~ N ~ t\ 'd ~-.~ ~ ~ '~ t\
N N N ~ V M _ II N l~ pp v II N d. ,~ II ~ II x m--, "1' I-a .-a ~ h M 00 N
ri ,.d x ~ ~ ,._, x x; d' m ~ x a vi b ,~ 'b ~ '~ ~ II "~ ~ oo ~ b vi, vo t~ ~t ''~
~ N
CI ~ M N 01 .-~ ~ pp N ~ ,~
~ m b o x, °° cfi ~ ii x x oo °° .-, "' II ~ 00 . ~D ~' I I . , x ~p -d N N r, ~ ~ N b x N
i1 ,_, V~ ~ ~ r", a '~"
b M ~ 4~ v 'U N m ~ ~' x W 'C N N d' N
x N ~ ~ O r~-i ,x~ ~ ~O ~ ~ O t 7 ~
N N ~ ~ ~ ~ ~p N ~ ~ WO N ~ M O N
yn t~ r.~~~~'~' ~ II ,°M ""'' ~ ~~~.,~ ~ ~ ,I~, ~' FL.I-, ~ o '° m ~ ,~ ~ ~ O ~ b II .-. ~ ~d >~ b ~ ~°
II .~'°'~~ ~
,~ h N N o , N ~ ,~ M ~ N N in .-~ N
x O ~ ~rr~ M h "W -~-i ~-~ O N ~O r,N~
.... a ~v ~ N ~ .~ cr1 W t~ h v ~O .. M ~P'7 l' (~ W
ro o ~u N
,N ~ N N
N
w i U rn O O w O
d' N N N

II ,.-. ,~ ~ N N
_ p~ ~, ~--, ,~. _ O " N
'~ ~.Mrj ~ lV b ~ ~ l~ ,.~, M p x ~ ~ 00 O ~N ~ ~~ ~ ~ b t~
~'r~Vj~~~xO rx~MII
~ N o0 00 ~O ~ N w r"~
~ ~ N
~--.I e-; t~ r~ CJ~ ~ .~~, nj ~ b ~ tar d' x' ~-' ~-~ ~ r~., ~ x M t' h N V~ .--U~ l~ T3 N rx d. ~ ~ ,~ n N ''~, r--, r~
M II ~ II .~ ~...r ~ x M ,~ '"~ N
0o r-' "~ d~ '_' oo ~ N N dN' A ~ ~ M ~ ~ ~ vl~ n b ~ ~ ~ N ~"' ~' v II ~ ,~ ~ ~ ",, ~ x II ~ Uj ~ x r, ~
II x N
~ t~ b N a ~ N N W r ~ r~ C+!1 p NNr~~~~~ O Nx,O~~d~W
~ ~ ~~x ~ ~ ~ ~ ~ ~ ~ ~ II
~M O o0 x ~ ~ ~ ~ b M .-~ ~ ~ ~'~' ~ ~O
N
'-~~b ~ b x ~~ ~ ~ b ~ N _~ V7 '"'' ~n N ~n M v0 ..-, h ,~~ N d; oo ~'~ .f.
N M b O II ~ ~-~S l~ l~ 00 t-~-i ~ C/~ C!~
N N ~~~ ,~ II
~ "d ~ .~ 00 .-a t~i rra ~ N ~' C/1 C/~
.. Mb~-W -~'d'~~~ .- M ~N~~.,x,u i~ ~ ~" ~ ~ ,.-n a ~ a a M M M M
N N N N
-f N N N N
W ~ W W
O O O
U L~ U U
p,,, ~ \~ ~ \~, w t~
x b o ,~ a Ts N N N N

A
.,.
.., can ~ N d; d;
+ ~v. ~ +~
+1 +
W W W
O ~d f1 ~ A X11 A
M M M M M M
N N N N N N
~ N N N N N N
W W
O O O O O O
U U U U U U
i ~ cn O r ~ ~ ~' ~ ~z ~ /z ~ /z o x p,, O ~4"" 'd d' N N N
U ,~L', N N N

A
,", U
.nr t Vi V~
u~ N
N ~ ~ ~ M ~-' d:
O M ~ ~_ n n V
N W W W ~ a U U ~ ~ ~ U
b .a ~ ~';' ~ m ~Y v~ ~ In a N N N N N N N
-~ -~ -~- -~- 'f' N
N N N N N N N
N N N N N N

x U O
V z U
~U
~ z' v ~z- \ C \ I x //
o ~.
N N N N
N

...
_~
_~
.~ .~ ~ W -~ d x z ' ~ z z z +~ +..' a +~ +~
d;
b Ti ~ ~ b ~ ~ ~ "ty N N ~ O N ~ '~ ~ N
'~ '~ ~ ~ ' +~ +r C!~ V1 ''-' C/~ C/~ C/~
a U U ~ ~ U ~ ~ ~ U
o b A ~-lf~~~~lrlA ' M M M M M M M M M
N N N N N N N N N
-~- +
N N N N N N N N , N
0 ~ ~ ~ ~ 0 U U U U U U U U U
' M M
x M x o ~ ~ ~ o U U ~ U O ~ O
U
' U
U
p~ ~ ~ ~ ~ ~ ~ d~' .d .d eC
U~,Z,N NNNNNNN

A
.., a~
a~
[~~- M ~, O d' O O N ,d ~ d ~O ~ N ~O
n sv n n +~' 'W,r ~W.r v ~ ~ v c~
U
~1 ~1 f~ ~.1 ~ A
N N N N N N
N N N N N N
O O O
U U U U U U
O
U U / / w U
/ v~ ~ /
/ \ ~~-0.1 \ ~ U \
O
O
d bA .C
O 'aN c~C c~C ca eet cei N N N N N N

V~ ~ N '~ ",~' l~ 01 ~ Tj N N
-.~, 'r ~ O N ~=. ~, N I~ N .-, II II M O ~ ,_, x ~ N '~v r, ~p ~ O~ x '~ N x .ty~ ~ ~ '"' x ~ M ~ ,--~ 00 l~ ~ O N 'd ~ ,-., b a ~ ,-, 00 .-r ~ b II II
'-' v ~ ~ II N ~ II ','~' O~ l~ N N ,.'~', x ~,N r 00 N N N 00 x ~' l~ "' ~O Qp x ~ N ~ N l\ '' .-n N N x t~ .-n N "~d II ~ ~ II ~ r-~ l~ r' x M II x OWE
w oo ~ N M ~"~ II N ,_, x '~, ~ N 'n p~, '-, l~ ~ ~ O ',, ~N,' ~ 'C ~ ~ r~ ~O ~ ~ ~ ,--, N II ~ ~ ~ v l~ .-, -n N II ~~,-~ ~ b ~ l~ ~ x y_; r~i F-~ ~ ~ °~ ~-Nr.~ r~ ~i n ~ vi w W.r x pp ~ '"' +~ + 00 ~ w M ~
x h x y.r tai h ~ t~ l~ ~ _ ~_ ~ d' N C/~
A ~ b ,-. II d°. °' ~ .b N ~ ~ N x II °'~ ~ x ~-' V
x II t~ ~ x M
v II ~ ~ pp ~ II ~ x x ,~ x lp ,-, h ~ ~ h M C/.7 .-r ~' o'~ N d' a "bd ~ ~ . f-, ~O rx C~ O v~ ,.d y~-t t~ .~ ~ ~ b tn ~ M N
I~ 'r x ~ ~ 0o N ..-a ~: .v " II I I ~i y. N II ~ ~--i b ~ t~ N .-.V -I- b ~ II ,."L', '-j II '~' ~,~ N "", N r-~ N ~ ~ V~ II ~ h N
~n Nx~'~M'.x~' ~~. Noo~l~~~x ~joo~'xb~N
N a I~ 'r W O~ N ~D
~W cp~M II ~~ N ~~'C7 N~N~
~xM~°~ ~0yn ~~o~~ xoo~~'?,-..~ ~~vx°' -I-~ II ~ ~ ~ ,-~ t~ ~ ~ II oo ~ ~ ~ ~ '° ~' W
TJ b ,x N x x 'C b N ~ "C.7 ~j ~ .~. ~.~, h lp b N l~ ~' x yr O ~ ~ '~ ,-, ~--~ O ~ ''~~; II ~ '~T~.,' :-: O '~ "'~ V7 ,-y b_ ,b Q i2'~, ~
II ~p C/~ ~ (V N vi V7 ~ ~, ''~ N .--~ x Cl~ t~ ~ N o0 ,-, ~ ~ ',2~' r-, N~ II
WO ~ ~ i"' ~O O .--, ~ "' N ~ rx O 01 ~ "'' ,-~ "d ~r' ~--~ i-s x, N ~ ~ CO ~ ~ N M O v ~O
t~ b_ ~ _.~.-P N l~ r~-~ .-~~ o ~' b "'' N ~ x x' ~ b ~ ~ l~ .-Nt N
M ~ V7 h ~' N l~ t'~ o0 [~ ',~"~ °~ tx ,~ N ~ CV nrr~ ~ M
~' ~i ~ ~ ~-~ r~ ~ N ~ N d; l~ 01 M II r~ r~i rs 00 M N l~ ~ ~ M xi x r~ ~ ~ ~ 00 h ~O w ~ ~ 00 ,~ .-., ,-, 'Eh., ~O
H 1-~1 1-~1 H
ECS ,.G U 'L~
N N ~'1 N
O O O O
' v v v v x, ~ ~ \ /
v x ~z - N N

11 ~ II ~o r' '-' r .-: ..~ ,-~ W 01 x [~ ~ x ~ b t~: N ,~ M ~ .-.
r~' ~ ,-~ II .-~ d. ~ N -i- M 'd x N 01 -I
.--v M ~ '-' °~ C/~ ~ ~ h ~ ~O W
~D
~b ~,, N ~ II ~ ,~ ,b ~ II r-: II r.~~ M ' .~.~ "~ x "' x '~ V~ ~ x N v x "d ~ V " .-a ~ ~p V ''wrG O '-' M_ ~p ~O x N ~-y0 .--yD ~ N N N ~ M _00 b ~ xi N
0o t~ ;.'l~ m x °° oo rx M ~ N ov 1l ~ ~: r °° .-:
~~x ~~ x~~~~ x~.~ °°
II b '-' '~ ~,' ~ "'' N p b a N x ''~ N ~--, b O x ~ V ~ ~ ~ b N O' ,~ N l~ ,.-~ b b ', ~D V1 ~ N ~p a x O ~, x I~ N ~
~I ~ ~ 00 0o N ~, h 0 M ~ ~ l~ ~
°° ~ II II oo "'' ~ °° ~ °° '~'' ~ '-' ~ t~ ~ II o c0 N r' ~ N
'-' . . II
,y x.o ~ N ,~ ,-,'b _s~ b M o x Vi ~ ~ ~ ~ b ~ O ~ d' ~ ap ,.~ ~ ~ ~T
_ .-V d; N
N ,'2', 00 ~ ~ ~ II ~ x x ~ x ~ b II
'fix ~~M Nxo,'~ ~Noo x N
O l~ N ~D ~ M N ~-~ N N l~ N r~ M O N O
.., w'~''.r t~ l~ x o0 ~ .. 00 ~ l~ N v1 .-. ,-~ xj x t~ l~ ~ V1 --i .-, ,--n H H r~ H
!~ O 'd '.G
N N N N
O O O O
U U U U
i \ _ \ O i O ~ \~
~Z
U
M
x c N N N N

N ~-,-. ~ +
~~ 1l t~ b ~ ~ x t~ ~ ,-~ W
h oo t~ ~ ~ ni ..r ~,~t',,~ 0 00 ~ x ~ x v~
.~~x~~~ ~Nx~~
CII oo ~ ~ i-''C, x °°
nj x .-y.r N ~TJ
'',~~ ~., M N yp rr.~ ~' x 'b x ~ N ~ N x ~ dy0 ~ x ~O o0 t~
01 N o'zj N ~ ~n .-yj ~ II II '_' +'~~' ~xyp~I~~~ xN~-'~
~ N pp II ~ 41 'G 'C 00 A x II II ~~-~~'~°m ~p~o~o~
+ II oM~x ~n b ~ II N ~ W ~' V~ ~ ~ '~
O ~ v ~-. x ~.rj ~ b ~. ~ ~ N Q.
xxx N
N
N ~ O ~ ~ x ~ ~ x ~ N
to ~ M II N ~ rA N N h N
. x x ~ ~ N x ~~ x x ~ F", a N _~ ~ x ~O ~~ ~ ~ b N
N N N Q ~ "C1 l~ d0'~ ~
C/~ o'~ N ~-" I~ II ~ ~ ~ M ~ ~ b .-~ N ~ ~ N O
M x 00 x x b ~ ~ ~ l~ N x h r~. ~ ~ ~~ b y-, rv N '-' 4; ~ C~/) vx ~' N O 01 vx x X01 x ~j O ~ .-. M N o0 d~ ~ wr ~ N ~ t~ ~ : ~ r; y0 .~ p .~ ~ VJ
~x~~xx _ M~.n ~~ U
y ~ H H H H 1 ~I
N N~ N N N
Q Q Q Q
U U U ° U U
/ ~.
U
M
x N N
N N

A
.., x k d' ~ ~ M d' ~ , .y-'., ~t d' V~ ~ ~ ~ ~ ~ °o N ~ N N
~.~.r a ~ ~ ~ ~ c~C
c~ c~ c~
U ~ ~ U U
b --. ,--a .-. ,-~ ,-.
H N 1 ~i 1~ V ~1 1 ~1 H H
pr ~ ~r VJ w ,h.
N N N N N N N
O O O ~ O O O O
U U U U U U U U
U p O V x x U ~ U N ~ O
U U U

N N N N N N N N

A
w ...
+~
b ~ . ~' d., + +' n x w ~.~r' M M M Fi . ~., 0~0 N ~ ~ ~ N
'~, ~ ,~ n '~ , ~ n N
cad ys v 'r cUG ~ ~ ~ U
~.
H
O
N ~ N N N N N
U~ .
0 0 ~ ~ ~ 0 U U U U U U U
M M
o ~ v o x o x o z U
x (; r-7-~ N N N N N N N.

II
II ~' '_' ..d .-. N
C~ s~ ~
_.. sv'~' O
xx~r~
N ~O
~r ~_~M_N
v N ..-a ,-v vi V N ~ ~D
~~ 00 ~ l~ N
~ l0 ~O d' t~ s~
z ~'','~x~ z ~xb~ n ~ , .r br,'JN~
N M ~ ~ ~ x 'T~ N f~
N l~ ~ ~ ~O h N ,d II °° ~ ~ ~ °' C!~ C!~
C/~ C/~ x N ~ ~ C/~ +.~
U
v W ~ x V7 ,--~
U
o .-" ,~ ,~ ,.~ ~ r.
H ~ ~ H H ~ H ~ H
c~
N
N N N N N N
U U U U U U U
O ~ ~ O "' / \v~
\
\ 'z ~ O
U U O
\ x .d c~ w wo .a N N N N N N N

WO 02/34711 PCT/USO1/32s82 Ov 00 ~ ~ o b ~ ~ ~. ~ ~n II II
I I M r ; d. ~ n I I ~'r? "'' "d "-' y-. '~
~-. l~ C. Q1 'b ~ h l~ II ~ ~ p~ ~"~ O~
~ r~ ~ l~ ~--~ +~ ~ ~ ~O N 01 ~ ~'"~ ~ 00 vi II ~ ~ ~ N M O
O d' ~ r~ ~ v O M ~ ,_.., r' 00 ~ N
.-a ~ ~ M ~ ~ f~ ~ i~
II o ~ ~ ~ ~ ~ ;~ ~ t~
r~i O ~y-~L", ~ '"' ~i O ~ ~ C j N N I~ r~
N m t~ b ~ ~ "! ~ oo W v x' II
II ,.Wr ,~, t~ ,~ ~ y-. c/' -~J ~ ~ .b ~O N 'v~," y0 x ~ 0~0 .-i .'d N ~ 01 ~-a o~o,Nb ~°°~ o~o.N ~~_. ~~M
~ ~ '~ V N x ~, l~ t'~ ,~
II x ~ ~ ~ ~ x ~' N II ~
W O ~~' N y0 ~O ~~ ~ ~~ x M x N II x b x N N II ~ ~ ~ °~ ,v N ~ ~O
01 Zj N pNp '~ ~ O~ b N ~v O
vx 'C O ux p ~O N
00 00 ~ ~ o'~ ~ v II ''~t~~'~ ~~ II N u~x~"~'~ -' ~ ~ ,-. N a ~ ~ h '~ ~ ~, t~ M °°
00 b ~' v-, '-' 00 .V M l~ ~ N II ~ s-; N
00 N a ~ N o0 N ~ .-, p r~ r-, l~ x O v~ M ~ b x' O vi M ~ 01 '.'' ~ II ~
~,p '-' d~ t~ V tA '-' d~ '~ ~ ~o ~ b f-, N
~ ~ ~ ~ II' ~ ~ ~ ~ x ~ II ~ "Ln _W
b V7 ,~~, ,~~ pp h 'd ~n i.~,~ 00 N 'C '"' 00 d' d. C/~
rr ~ r-s a O 0 ,.~~., .W-i ~ ~ 0 b l~ ~ O
~i p~ ,-~ N O\ ~ l\ V1 N N N ,--WO M N N ~-" o0 tx x ~ ~ x ~ N, x ~~,i~
N ~~ ~N N~ ~o0~r~x,r~
C~ M ,.~N, ~ -I- ,~,' ~ tai n V ~ N ~ N \O
~ r~r W ~ ~ ~ ,~, ~" rx ,~' ~ N N
~h~ ~ ~_~x~
b 'u ~ ~-," ~ ~ b ~ ~ ~ ~ 1l t~ ~ ~
o .o o ~ i~ ~n N N N
o ~z N N N .
h o 12s _ _ .~; x vo t1 00 ~ ~ x N .~ II ~.~ ~ N
x b ,-, M II ~ t~ b p~ II ~ N x N '-' x ~ CV
v~
.c... ~ c~ 1 ~ vi ~' ~ V~ rv o-'~ ~y 00 ~ ~ ~ r:
a yr _~..i ~ ~ N x _.~ M _~" .-~ t~ .--. N "~' x rr-~i t~ 01 d' t~ .-~ r~~ 00 N ~O ~ V 1 I I O v0 xi .-. N
N ~ ~O N p ~-~ .-, ~ ~ O ~ pp ~'_' ~ N ,,~,N N
M ~ N x ~ M ~ ~ b x ~ ~ x N b N x N x x °~ ~ ~ ,.~ ~ ,.~, cV N N _TJ C~ ~ N
'.x '~ ~ N II ~ ~ ~ ~~r ~ '~ ~,~t II III
~ M N N ~ I~ n ~ ,.~ ~ 00 ~~-a ~ 1p N ~ 1l ° "'C; ~ ~ x .~ .-~ x ~ N ~ x ~ ~ ~ 'v ~ +
~, t-, ~ l~ M 00 V 'd '-' M '~"r ~. .~-~ 00 ~ p1 C~J
s~ O1 _ M
~xy-xn~~
+~~~ N ~ ~ ~ +.e ~ x h ~ II N ~ IW .~~-~ ~ N N ~ ,~x~ .~ ~
uj N ~ ~ M C~l~ ~p ~ ~ ~' Wp i"~ ~., b ai yr ,-.~: ~ o W II b ~ "., x ~ ~ N
d~ °~ x '-' '~ N ~ _'d ~p l~ t 1 ,-, N h .~ o'~ N
V .-i ~ ~ ~ M CJ~ x b x N II ~ r~i x ,_, 00 O~ pp rWr ~O
N ~ 00 O ~-~ ~ ~ ~ ~ II 00 ~ I~ ~
'~,' ~ '0 00 .~.~ ~ '° II ,.~ '~' II ~ ~ 00 b '~' ~ oo "' N x; II o ~ ~ M -I- II ~ ~ ~ ~ .-. ~ b ~C "' ~ N~~ '''~ x~oW ''W-_d-_d.-. ~~~.-x~
vb "~'i,O b~~~oo~ 'vGrvNM N '~ "~d ~ V) N r~~ l~j~~ [~xd-O
l~ 00 x ~ x ~O 00 M
00 N ~ x r~-~ ~ 00 N l~ 00 ~ Q O~ ~ O\ 00 vi h vi r~ ~ ~ '"" ~ r~i Ov O
y-; "~' ~'_' x ~ rA ~ ~ r'' vj ~ tA ~ x r~ b ~
,~o "-~ b b N ~ ~ O M II M ,-i ,~p O '." '"' V~ ~ x vi ~ ~.x' .~, ~.r '~ ~ M .b tI~ s-s M -d Vj N rNr .-~ ..O ,--~ ...r ,~
0 "t~0~ N M O 0 n ~ b ~ v ~ rv x W ~p ~
Cf~ ~ ~ I~ II ~ x ~ N ~ ~ C/l x v0 N II -f' ~ ,_.., C~ a N ~ ~ ~' ~ N <'1 D1 ~i O ~' N o0 .--~ ,~ W ~ N
A 0o r~ ~ b ,~ ~ N t~ l~ ~ ~ ~ N II II ~ v ~ ~ r~ t~ ,..., ,~ ~' h c1~
x ~ ~j oho ~ ~1~ r~ ~ ~ x N b "rJ ~
~O ,~ tn ~ N ~O ~ " op ~ .-r ~.~. d. r~.a NL~oOrsl~ 'b N ~~ vi bMO~~~ Nl'; ~M
.-. x~~~~ .. ~xwsil 2 ._. ~~~x~ -. x~'.~
O TI
h h h h bJ~
too N N N
/ / \U /
v~ ~ U \
\ \
U
v x x '° o '° ~ Wo ~z N N N N

.~ o ~, ~ II
x d' '-' n °~ r~ ~O N N y--~ _ M
C/~ ~ ~ 'd~ ONO II ~ x x ~ ~ b W .fir x ~ ~ x v x x_ b h ~-~ .~ 'b ri o0 0 ,-h ~ N ~ N M h xj ~ H' ~' ..W.r ~ h N N
II h .~ ~ 11 x °~ '~ N o " "d rri x ~ x t~ '. ' II ~ N a'.
b ,b W,.; ~p b ~ ~ d: '~' ~ h b oo %~ .v II
ws N N h ~ s~ 'd _ ,-~., _ N ~-y N
V7 x ,,~Li N O ~ N ~ ~ ~ x d' x ~ 00 x b 00 '~ r : ,-~ x o~ II ~ x I I ~" M ~ r., vi ~ a, ...,mp ,p pp O~ ~ ~ H.-, ~ ~ h 00 II ~
~ M
r~i x ~ M ~ xi b 0 N a ~ ~ ~ ~ ~ r~ ~ h N h o ~ N 'b op xi ~ ~. ,-~ o0 r~ N O N ~ ~-~. ~ M 'd" ~ N vi 'r x h tA
2 ~ II ~ ~ ~,° .~ "~ d' M 'N x ~ N ~ ~ ,~ ~ r, OM
~ h x ~ ~ ~ ~ o'~ ~p ~D x ~n hj N .,,~ r, "~ ~ Op ~ N '~' l0 b N ,~ h x ~ i-:
CC o0 ~ 'b O 01 x x II N + rte., ~ II ~ a ~ ~ ~ ~i xt ~ c0 h v W O~ ~ ~ ~ M h x C~V ,-i x h ~ '"' ~ xi r-, "vd O C/~ M ~ ~ p~ '-' ~ 'v x ~.,.~ O h x ~ ~f' 00 ~f~ ~ ~ ~~ ~ V7 ~ ~ ~ h ~ ~ x O~M b O
h ~: ''_' ~ pip M ~p .~. h N ~ w ~, _ N N N ~ N
h o0 hj m ~ h II N ~ ~p 0h0 N x x ~ h d;
O~t~ ~. O~'~x ~ N~ O~C~t '-' N O v d- ".O d. ''-' ry-; N 'r tor,r~x ~o~x'~ox tomb ~ ~o,-~x boo N b ~ N ~ ~ ~ ~ h ~ ~ ~ ~O 00 ' ~ ~ dW.r O
"'C x ~ h N 'G o~ N ~ ~ ~ yn h II
O ~ r~ ~ ~ O ~ ''~~' ~ M 'b O ~ .-. ~' '.~, ~ oNO r h. '~' h N~ ~N'-'rW'o~0 ~N''xb ~-~' '~~h ~.r N 'r ~
A ~~ ~ ~ ~ V~ x ~ O ~ ~ N ~ O ~ ~ ,x~M
O h ~O b 'ct ~ 01 ~ ~ b N h x ~ O x o0 00 ~p ~ N ""' ~ OMO
~ IWo ~ '-°x ~,~ ~ h ~~h ~, ~ O s~~ ~' N ~' .~ N o0~ r~ ~ ~ ~ ~ r~i x N ~ ~ xi ~ r;
,- ~ 00 ~i a ~D .. x o0 ~ N ~ - cd .-i ~ ~p II d' (~ x O
h h GA
..n ~ ",!.
N N N
/~
_ _ ~ \
i U
M
x o ya so N N N N

h ~~~x~ v~~b~
o .".;
~. ~D a ~ ~ N N
~ x ~ N ~ ~ M N ~ x x '--~ '~G~
~ ~p d0., x r, ~ x ~ ~ oo t~ M ~ oho -1 l~ '~' O ,~ W rW~ ~ O
v0 v0 N ~ ~ ~ O
_ M _ N x ~ r~ ~', v~ t~ O ui II N ~ b l~ r~r r~ O W-. wr W II
vi II
N y.r ~ ~' x [~ O b h 00 r~
0~0 ~'~, v O 00 '-' ~ M ~ ~~j ~ M
UO N ~ N M N 00 '-~' tLi r~i O ~_o '~G r~i '~..r ONO
01 ~O rs r., r~ 00 ~' ~ ~ "~ x ~ tn ~ ~ x O ~ O .-i r. ,~ ~ N II '-' N ""
'~'' N~~xMv 'nH'O'~sx N~xi~x' vi as ~ II x N V
A N ~ ~ ~ ~ ~ ~ ~ II p~ ~ ~ N N
M . ~ ~ x r, l~
rv,~-~ 01 O ,~=~ r-~ r; s1 M b ,-~ ~ 01 b W ~O
~ ~ r~ N ~ x "'~ ~ ~ r~i x ~ O
vi h x v~ N vi ..-mph vi N W ~ o0 h '-'r~ M ..fl x " N N N ~x ry a Olp V~'7r~nxr~ 0~0~xM~D +
p N ~ ~ ~"' II O N x .-, ~D O ~ r' ~ Om r~-~ d' ~ II '-' N z N l N ~ ~ op ~ N ,~N., ~ 00 N '~' ~ ~ d: -I
'xt ~_ ' ' .~; ~ I I ~ is b ~, x rrrs~ ,--~ 00 ..-. b ~ ~ " 'O '"~ t' d' N M
~ N 00 41 O ~ m II O ~ ~ b ~ ~ vi ~ M
C/~ o0 t~ ~ M ~ C/~ ~ N r COr -~ Ov N x ~ <r ~ ~ ~ ~~:b ~~
~
b ~'b~'r~ ~av'~~~ r~'~~~~
OD h l~ M ~ ~D d: ~ ~ ~ N O l~ ~
N ~D
.. r~ r b ~O ~ ... II l~ T--~ II ~ -- s~ 00 l~ ~ ~O
.b O
r-, ~., h b4 w N N N N . N
U z U
w z_ ~ ~z-N N

V'1 N
~ ~

~NO~O ~ ~ ~D01~.
~x M ~.,~~ N~
x ~

N ~ ~x~ II
.~~ M ~ V ~ H
~
;x _ _ ~
~ ~ ~ M x ~

wr M N ~O x x ~ ~ ~
~ h ~' 00 a, ov M ~n ~ rn a ~O l~ N II p~ l~ .-, II '~ ~ N N ~ x N ~ ~ ry ~

~ l~; ~ "~ '-' v0 N ~ x M x (V x ,-, II ~ ~

,x ~ . ,-, .; x ~ b ~, ~: x x V ~ + ~~ x x NxMN ~,.~~ ~. N ~.:~~
x ~

~x ~ II x~
~ O

QO N C/~ s~ o~ ~ ""' N y ~D ~O v ~ ~-. ~ ~
r ~ ~p h b ~ ~

~ . + ~
~ p~ .N.r II ~' ,~ ,.~
M N II x ~' N " ry ~ C/~ ~' x~~~.
x ' ' N ~ x~, x ~ b O ~ ~ n II
N ~ ~j ~ ~
V

N o0 <n v1 N ~ h s-~ ~ N ~ d' ~

x +
N x ,--~ N " .b 01 ~ ~ ~ ~ ~ ~ V7 x ~;x~,~~ x~ ~ ~o ~~x.~ ~
NO
~w x ~~;M~ x b ~
~~~ ,~
O~xx~

.-~ ~ ~ ~
x ~ II N N , ~ ~ N
I~ "' ~-''~

.-, II ~ N II ~ l~ ~ II ~ ,.~
N , .-~ N
r-~ b x , vi vD ~--~
~ N
d' x N r~ O x b xb ~ .~~~ b ~~~x N

-, ~ 01 II wr v N b .r ~ ~ ~
M II y r~ ~j M .~
~ x ~M ~, p ~ x ~ x O [v ~' h 00 ~ N O .-i l~ M 's pip ""~ pp ry' O ~j x 00 '-' ~ ~
~ pp ~ O V~ .-~ ~
~ N

~~;x~ ~ .~~; ~x ~~,~x~~
~

'~x a x ~'~ ~ a II
x ~

.b .-~ N cV b N ~ .-. "d ~ ~ 'T~ ~ '~' l~ '.., ,-~ N x ~;

OV~x~~ o NbVN Oo~;x O

~~x M l~ N + ~ M M ~ x O

(N , ~ fl ~ oo 1l ~p ~ ~1 d' ~O II
D N W ~p ~ N
0 i ~
l~ C~

+ , II r.~, ,.
~ II v ~
~ p~ ""' ~

C t '' .~~ x O N "' x x b c f~ ' x b O ~ x .,-" G
~

-. ~ ~ II ~ ,~ ~ ~ ~, l~ N ,-., ~ o0 ~ ~ N Ov ~ ~ ~

N ~1 ri O N ~ ~O N ~ ~ N ~ M ~ ri ' i-v Mx ~xx II x x x~x~x .. ~,~
..~~

'b O
b h h h h GA

i~. m O N N
N N

U O U ~ p O

U
N U

U U

o . ~' ~o V N N N N N .
~, vb_v~ ~p N N ~' ~-' _ O ~ b ~~C/~
II p vo N ~ II ~ ~ ~ '. x ..: oo x; II M x N
h ~ ~D ~ ~: ~ ~ 00 M M x -~~ N ~"e ° r' ~ i;
+-" t~ r~ . ~ r~ o0 N ~ N '~' .,~ t~ N ~,'~' ~ N II 00 0 ~ v~ ~n ~ h ~ ,,x h ~ d- a a I~ ,x vi O N o~J
~'r Mr~'bx~ ~0 ~N M,~
II
N N N ~ ~ y~ '~C .-i N ~ ~ ~ n N h ~ l~
N O r~i '~ ~ ~ ~ rx ~ f r~i ~ .=j N O
II ~ '~ ,~ ~, ~ N ~° M x ~ ~ ~ II °' b rib ~ v ~ ~h ppN ~.wr,~ ~~-' ~ NN ~ N i-;~'pN
QO tn l~ vi o0 ~ ~ ~ ~ d- x ~ h ~ '~ '~ vj ,~ u~ '~ II ~ ~ °~ N II ~ .-. °° ~ ~ .-' d; x II
~°
,.~~, ~ o~p ~'' N 'r~ ~' ~ ~ x ~ nj ~b ~
A ~~~bo; ~N II ~_Wo-d~yo~x'bo;
c~ N N ~ O ".~ N N ~n ~ N ~ x '" ;~ N II
00 ~ ~ ~ N 00 x ~ p0 ~ 00 M ~ N 00 ~ ~' ~ N
II M .r, x .~ II II ~ ~ ~; II '~ M II II ~ r, ~
h N ~ N h h ~~ r, r-~ N N ~ r~ ~M
'~,~;1~ ~pp 'bbx,vN 'b,~N,l~~~ bN~~o0 N ~ ~ ~ O N ~ ~ ~ ~ ~ ~ ~ ~ N x ~ n o ,~N, N ~ x o ~n x c, II O II N oo -~
~ 00 h ~' _~ ~, W ~ N
~ r~
'b h l~ ,-i ~ ~C7 ~ h d- ~ ~M,'~ "y0 M .-i C/~ b ''~ ~-,~ "' O O
Q V II N II O ~ b v ~' tn O M h a ~' O "v.rd l~' ~ b N ~ d. ~ d; M h ~ ~ ~ x rx N x ~ ~ "~ ~ 'r d;
~1 M ~ ~~ 00 0~ ~ _d' c~ ~' ~ W r1 ,~ ,,_,, oo r., ~1 dv N II ~ M
--.. ,-. ...i r: ~' o ~oo~ xx~N~ ~ ~~'~ tx"~'xb00~_ N ~ t~ ~ + N M ~-' r~ ~ ~ ~ ~"' ~ N ~
N r~i r~ N N i-; ~ r' ~ ~'1 II
.. '~', N ~ ,-, a .-. ~ ~ '~i II '~ -- ,-. wi "C
O b h blo o ~ ~ ~1 ~n N N N N
M M
O U U
x U ~ N N N N

II II ~, ~ ~, II
.~ .-~ II ~' "' h ~ b N o0 II "I' h ,-, ,~ M N ,~ b ~n II '-' ~ " ~ .,-r II o x r~ II '-' b t-, ~ ,.~j W h ~ N N ~ h h 00 MO ,Lp r-, M~ N
bm~~ ~x'o~oN~?~t ~~II ~~_r '~t~,~l,~
'o m ~ ° ~ ~ '-' II II M ,-~ p x '-' ~ ~ ~ .-s ,.~ o M
°° °. ,1 M ~: r.~; ~ h h ,~~,~ ~ cry N b ~ s-: pp ~ M
~,x~r~-t N b'~N~ ~,.~',00 ,x ~, ON
'x ~ <t ~ vi N 'r ~" x, ~n M ~ N r~
.-m"~ '~ N ~ II d' o N C!~ '-' 1I ~_ v r' uNr~rx~ h~hh\OvW~r ~.'W-'x~~'.'~r Nhrxh h ~ b n rs ~ ~ ~ h ~ r~ ~ N 00 n~r~x~~ oMO~ NxOhO tn n r, II
N ,.~ r, .~: ~n II ~ N
.ice ,~ II 'ri ~ vi '~ '~ '~ 'n ~° x ~ II N .-.
~ b ~ ~ ~ \O O d: N ~O N r-~ ~ N ~ O ~
~-" t~ b d: ~t O V'1 ~N ~--, ~ ,-~ x N vi b I I x .-i 00 r~ O~
v ~ ~ h ~ ~ ~ t~ x rat ~ x ~.~--. ~ C~ ~ N d' of O ~ ~-"t.; ~ h b N ~ oo ~ m oo ~ N
°° ~ ~ N ~ II o~ M ~ II ~a Q ~ W-, ~
,~.~.; ~. N N x f-' ~ ~ "v .~'O" "~ ~ ~' '~'' N O~
N r~, ~ ~~y" ~ N d' 'r ri x h h ~ x ~. ~t x O~ ~ x N, '~ ~O ~ N M ~ QO
'r N ~ a' °° ~ ° o r., Wn oo h x ~ ~ x N h ° ~ ~ III ~ .~ ° ~° N ~ ~ o o ~ ~ '~ x ~ °' ~ N
'''' +
a0 .--n ~ "-' v-~' N ~O x N .-. .-i x c0 y N ,.~N, ,-~ t/~ ~ ,~ a s-s W
;., x b_ b ~ ;.~ .~ s-: a h ~ ~
b ~ ~ N ~ ,~~" b vi h ,~, x ~" ~ r' ~ b ~ N N C/~
00 ~ ' ,b .x II N ,:-:
N~ II II oNO ~~Nb~x ,~, 00 O W--. ,~ ,~ t~ ,.xN ~ ~ ~ ,"j', N N r~
r~h''~N .N~., ~r~~bv~ q~p~ ~"~'~ ~d. NM~O
N yt r~i ~ UN ~ x x ~ ~ N ~ N ~ h r~i ~ x x N x N r-, h h N
01 N ~ ~ p ..O ~ r~ ~ ~ r~ r~ ~ N ~ rW s=. V~ ('~
.. v7 v-~m-~t v0 vD V .. ~D v r~ trWO r~ ~ t~-c II v-~c .- N II r~' v0 O
h ~ h ~ .
W N N N N N
O
x o z U ~ /
?n O
W G
Pa b N N N N N

II ~ 'o o ~ x ~'? i1 II II '-' ~ ~ ,~ -rs ~ ~: If -, '~'-' x_ _~ ~~x~
r:~ ~ -~~~~ ~'P'xx"'~ °°xN'~
°° ~ ~n II
x ~ P-. ,~ Wit- 00 --i b -f- oo d; d; O ~ ~. oy--. d~.yd N
~ "~d v~ '° ~ ~ t~ x ~ .,~ ~ x o 0 N ,.., W oo _ _ ,--; oo _ 11 '~' ~ ~.. m ~ _ "~ ~ cr V~ ~ x r~ '~' "' N ~' ~ ~ c~/.1 N II
x ~. N N ~ r~.a 'b l~ °~ (~ W--, x ,-, '"' N x ~ ~ _ ~ r~i 'G M
r--, ,~ x :~ v ~ r~-i x O~ M ~Y r~ xi ~ N y0 ''' N N ~ tn ~n o1 00 ~ II ~ '-~ ,-, ~" t~ 'r ~
x x ~ ~ tn ~ ", ~-. ~ L~ N ~ ~ ~ 01 00 00 op ~ N oo l~ Ii et x ~ x ~ "' "' ' ,~ b x r., N,I!,~'vo .-~d.b.b M N '-'~ ~ xx ~~x _~_N
L~r ~ ~ ~' ~ ~ ~ \N ~ ~ ~ O ~ ~ N x ~ M 'n ~>~ rte., ,n ,~ ,~ x II b ~, '~ ~ ;.4 e~ ~ ~u ~ x ~ x N b ~ N ~~ 00 ~, ~~ x ~ ~ ~ x ~ ~ M b N ~ ~ x ~
II
~ ~ N ~ M 'd °° N '-' II
x x ~ ~ x x '-' N II O ~ r, ~ ~' N -N ~ ~ ,.~~ ~ ~ d, x ~ ~!i ~ ~D x ~ ~ x v \O x ~ ~ O x M ~ ~j .-~ 00 II ~ O
'-' N ~ O o0 ~ ~ N x O~ O h ~D
01 ~ .y. ,~ ay d- II O N ~ ~-~ ~ ~-~.O~x~ t0,-~ ~r-, tAyp N~rx~ oOb~r~
.~o~ ~~ ~~ ~ x'b N
~ N O~ ro ~ ~ ~ v~ ~, _ '-° C/~
O ~ M N O N ~ ~ O ~ x 'W O L° '° O ,.' G' "FL', '°
V7 v ~ C/~ 00 ~ M ~ p~ N II pp ~ 01 _ __ ~ O '~ __ ~n ~ ~x~x'~ ~~ ~bh~ ~ ~~~xx ø~"' N N '-' ~D f-' ,.-m1 b ~ ~ N H N ~O
x M N x N N .~ ,-~ ~ b rx W o0 ~ ~ N
~ rs ~ x ~ x ~ ~ I~ ~ ~ rr a ~ 's ~
N ~i 01 o0 01 O~ .-i ,--~ O N ~ x ~Y O o0 ..., ~ .''~' N .- ~ t' Sri ~ r. M x ~,' oo 'r~-i ~ .~ ,-. yri ~
o ~d h a~ c~.~ pJD .C ...
s~''. ~ tn ~ t~ ui N N N N N
x / \V~ / O
/~
x U '~ O
N O
x x UZ N N N N

~' ~ °°. °' °~ ~ II
N x OM1 _~ _~ _vh _~' __~' II x N
x ,~ yo x ,-: '~' '~' yo, -d o ~1 ~ '"~ ,.~ 00 d' b 'r ~ N d' N ~' I'~ m ~ l~ ~ N
a, .-~ N x V o ~ ,-... N ,-: ~ v yo .=, ~r v ~ ~r -d o~ ,'7.," + ~ x r; ,-; t~ ~ ....
~~~xoW oo,~xxd-ox ~v, °°~~a,'°~ °'~ex,~",-,.N:-:°_~ ~~,I! o _ b _x ~r~l~ Nr~CI~ rxN.Nb CCt ~ N rrrr ~ Ov ~ .-~ ~-W xi ~D v ,-, o0 N L~ x A
C yy..~ N 'C t0 y0 ~ x ~--., t~ b ~ ~ ~ l~ ~
N 'b d' .v. ~ II ~ ~ h N N N ~b II ~ N x ~ ~ o0 ~a d'1-' o~,lr, Ml/~~~'~~i M~--n~,.x c~ ~ b l~ rs ~-~ ~ ~-mC 1' b IWO ,-n ~ .~' N
o to ~ ~ x o II ro ~ ~ ° ~ ~ ~ ~ ~ x N d;
~D l~. ~ ~r N
'~ r- ~ ~ 'n II '~,' ~ a ~ "~ ~ ~ yn O b N O '-' ''' ~ '-' ~O O ~: ~, l~ N M
~x,~x~b ~~Vx~ II ~xx II ~~, r", M ~ N d' ~ ~ ~ ~ .-, ~ r., M
Ilox,°q~c;~xd~,.~N,~'.
~xx~~x ~xx~ N~ ~~~~~~
N c~ x x '_'' N °° '~., ~ x '-' .-: r; .-: x "' .-: x o :,~ r~i l~ 'e ....- ~: ..~~ x l~ x ~. ~ x ~ M
bn .~ W N N N
x x x U
U ~, U
U U
/
d N N N

1l ~ ;..~ II _ ov r: ~ ~ ~: ~ r: y0 r~ ~ x ~ M
~ b oNO x ,.-~ ,~ ~ '-~ x M ~ x 1l II ~p ~: b ,~ ~°
'-' ~ M 'O r~; _ 'n r' ~ '~ ~. it ~ 'e V1 M ~ ~ ~ N r~i ~ N ~ ~ ,~N, b V x ~t ~
N
N ~ ~ due', ~ ,~ v~ ,.,,~~ ~ b N ~~ O O ~D "'~Q ~ ~ N N _W
I ~ M II b. ~; ~. x ~ c~
00 0 '.. II ~O .-: ~=. ,~ C~ ,~ ~, 00 h O °~ "-' x x 00 N ,~, t~ N
°° ~ ~ N ~ ~ ~ ''' ,-: °° ._rj N ,~ ~ ~ x ,-~ l1 ~.Nr.~
~ ,~ N w x \O ro x ~ 01 ~O x N N '"' w W O ,~, x ~ '~ ~ ~ x " N ~ b ~D
00 ~ ,~ O ~ II x v V7 x~,~ vp ~ N ~ .~ N ~ h N ~ ~ N
_M _vi M W ~ II N ~ ~ rr ~~ [~ ~ ~ ~ ~ 00 ~ WD ~' 00 O .-, y-. x ~. v1 r,~ M O ~ x '~ M N r' ~ y0 "'i O~
O e.0'-~'~V~ tW-.J ~~ ~.O~~M ~ ~.0~ II x0~lb ,o O~ t-. ~ yr ~ N ,p O 'r ~, 00 ~° rx b a b ~ "C3 'G due' l~ N C~/1 "d 00 ~ 'C ,~ M b ,~ b ~ ~ O
O ,~~, ~t '~' o ~ oo '~' 1l x W 0 ,~,~i ~ "Vd ,x~" d; 0 N N "' ... ''~;
(s N x x N "d ~: ~ ~ x ~D ~ ~ 'p l~- ~ x' x~ix~ ~NxOhi-; vxN~~i+~ ~I'~~'i"[~,xoo t-~r ~ ~ ~ r~i O W ~ .-" ~O
II
h \D 01 ~ ~ N o0 M N 00 h rx~'xi l1 l~ r~O N "I\x ~~ 'd.r~M, a M ~v ~ x 00 b ~ M x x ~'' 00 N l~
O b H H H t-i b .~ G=t N N N N
M t~1 U U M U
U U U
U
/ / U /
i \
\ \
U U
x x N N N N

"' II ~n '° r, _ ~ x ~ a\ ~ p _ ~n~ ~r ~ o,"~~t N oo~_ xr''~,I~,~ II N~ ~y~t~"~~"o2jxoxo ~x'_~ Nx x N~~o N vo .-: ~ ti _ x _~
~~Ox'dxN '-' Nx~~~,vo N II xxN~ N~,'b~x .... O v II ~ .<j x ~-' ~ II II 'u ,~ "' ~-~ ~ ~ W ,~ II ~ ~ '-' p1 ~ N O1 C!J v N ''' s~ Q1 'Wr '~ "''~ O
00 x O h W ~ d; ~., ~ ~ N II O C/~ 00 ~ >~
O~ ~ ~ x ~ b O O ~ x F-.
-: oo ~.' t~ .,~ ~ crW o ~ ,.~ ~~ ~ r: ~ ~ N b II °° oo x ''~ 00 x ''' II xo,~ .~~p,~ N~d,~ .~:~'b~H,~ ,-;o,~x,,~o~
r, ~ N p~, ,~-a N _. x II °~ x ~D '_'' x x ~ .-i .,..~ '~-i l~ t~j N
.-, x +.~ N ~ ,~, N ~' ~ '"' ~ i-; ~' "_' N ~ t~ N N ~ x ~, ~-~I-i oM0 A OOU''~,r~i~ v~,~'~~jxyr vtj~rs0 N vixp~'J
~,'rroo~n"" N ~'b~ II v,~'oNO av;x~xcYi~ ..° r"'t~~
01 ~ II I~ N N h N r., s1 ,-WO ,1 d' vi II
. °'2~ x p ~n +r N ~ ~O O ~ ,-~ t!~
.= ~ II ''~oo'~'oo ~'o~bb ~x.-: ~ II ~rov- ~'~' II oW"~'x'~~
Go "'' 'd x ~ °° 'o ~.o °° N o, '~ ~ x ~ ~ "' "'~ ~ °° b ~r N cn ~-a l~ , ,-~ . v0 h N , ,-. ~t ~j , rs ~~o ~~ II b ~x°°r'~ II ~ ~~v,~x~ ~x~ ~x .
't1 tn y--~ ,-~ "b N ri ri ~ N 'C1 l~ t~ t~ 'C ..r ' v0 ~ ~ b oo ' x x ~ x °~ ' vp _ t~ O t .-. l~ N
pp ~ 01 "~ b O ~ V ,_., ,..., x 'b V1 N ~ 00 x ,.~ ~ O ~ N '~ ~O N. lp ~''~t~,d-O~ ~ N NNy II ~ ~'~=.NN~~ ~xx~'~''"['' N
x r'' ~ M ~ x, ~ ~ x rx N ,-' ,-~ ~ q x N x ~ ~O TWO x 's N V x l~ l0 ~ 00 ~, x N v W a N ~ x "~~ '-' ~ II ~ ~ I I pp N
~N Nxx ~' x~NfVrxO~ ~~~0~1 'I~V'M ~O~ Nyp O~ ~ x ~ ~ ~D N ~ ~ r~ °~ '~ M ~ ~ t~ ~, ~D N ~ ~ ~ l~ x M ~
l~ 00 ~ N l~ ~" x N l~ N ~ i-; ~ rs ri ~ M ~ r, Oy O
oO~l~u'~i~~ -~ xWr~l~x~ir~i xoOx~r~i~~1 xoO~i~OMw O
y ~ r~ r~ r~ f-H
.C ~ ~ .'~' c~~C W N N N N
x x U M U
U U
U U
-~ -~ ~ /z U
x U ~' N

b _ _ ~ ~ II rte, b ~ N x o ~
00 ~D W 0O ~ x M '~', r'~ ~ cri v0 00 V~ ~ II ~ ~ 'C~' ~ ~p ~ ~.
N ~ ~ ~ ~ O ~ N w.r x ~'~' Nxi~v~ N_,x~hxi _ujt~~~d',~ '-''-,M'-'pp II i.4 M ~' ~ N Q
~O O~ N O b ~ r' ',~ ~ x ~ ~ o0 b ~j ,~~, N ~ '~" II M ~ vi ~ O ~ ~ x pp x l~ O~O
°° ~~ x ~:"~~: o x~ ~ N~ r.,~ a o c~ rx~ M 00 x ~ b x O .-~ Ov ~ n x ~ x ,~N, l~ vi I~ 00 x O '~ ,~ b '~
n x 'i-Zi M 2i O ~ rte, 00 ~, ~ ''~,~,' II N , I~, N d' O
N ..~ M ~-' x ,.~r~ ~ .~yo N °~ ~ "''~ M N ~O ,.~N, 'd ~ ~ x C~/~
vi oo ~ ~ IW n O ~ 0~1 x x '~ .~o ~O
'b ~ ~ ~ n b II ~ ~ v~ II ~ b ~ ~ N n ~~~M''-' Vex p x~pp ~vx~x"i~ ~~M°~NN
~xr~t~ ~ ~'N ~'~'~ ~~~~~p' nj~~ ~~'lIl xh ~ ~ wr''.rM x'v ~ ~ ~ 'NCO ~~x N N N ~~ tai LV N ~-.~ ~ M C/~ s~ ~ ~ ~ ''~ lp V1 00 ~ ~-, W ~ ,x M x ~ ,."'C~, x vi O b ~D II y t~ ~: 'r ~ r' .-, N oo " oo V II a x N ~ l~ ~'' C/~
l~ N
x °° x ~ n ~ x ~ II '° x r;
II xN~ ~x~N~ ~:x~~x II ~x~~~
O b N N
y ~' H
Gp O
W N N N N
m m m m ~ m U m ~ m U
V U U
N
x U
x ~_ ~ ~ ~~-z-~
w O
at o ~ ~ r r.
U z c~~ N , N N

N
~ N " ~ ~ M N
~~~oo ~x Nxx v,~.~ goo "tx0 ~C~,~I,'ly~ pp ~y.~~r.,~ 000 nj r-s ~ ~ x n ~,"' ~ N l0 s; ~ W .-, n ~ ~ O lQ
v~ t~ r~' ~.r ~p x' II r~ II rx M 'r-~ ~ ~i N x I~ 'G O~
00 w.r i~ N N N N ~' W--. N ~ M ~ N _ ~ \O
rx N 01 n ~ v~ ~ . .
N N v; 'r~, ''' v; ~ " II .d vi r~ x vi ~ vi ,"~, v a V'1 pp v ,., ~ ~ ~ ,-, '.r+ 's vi ~O ~ .~; I~ ~ ,..~ d; 00 ~ ~ ,~; ~ pp '~' l~ C/a N ~.
~ x ~t .J o0 00 ,~ V oNV, W oo II b N O N ~ l\ op wr .-y, oo ~ ~, O O oo ~ ~ d' ~ C!~
CCW r ~ .~; P~ O~ .--s d' t~ ~ nj ' ~ ~ ~ N ~ ~ h +.~ 00 V t~ d- ,,~ ~D ,~ ~; "~ x M x x .r b ~
x ~ rv .-, . . N ~ ~ Ov N ~ N ~ ~ N ~ ,-, ~ N ~ N ~ O ss M
~' b x M ..s -I- ~ ~ ~ ~ V1 ~ ~ ~ N vi t'~ o x N ~D " '~ M x r~-~ yW... p ~' n 00 CIA p r~ O M~ N O ,~, ~ LV O N O ~' N ~ ~ ~ ~ ~ ~ ~ ~ ~ W 00 ~ ,r,i x x ~p ~ d1 te0 pp .~~.' ~ ~ ~ v~ C/~ ~ .-r x N ~ ~ ,~ ~ ~O ~ ~' 'r ~
'~Y ~ N
,~ M ~ ~; ~ ,~D O ~ N ~ a O .--~ ~-' x ~ ~ V x II ~ II ~ O O ,~ ~t ''~ iii f N ~' ~, ~ p ~ b ~ N °.~ N N v, O r ~' ~ "-' b °~ in ~

~pd~' ~~-~',~p~p'p ~xoo~x~ ~~..,~ II ~~~ O"~'',~~,M
'r .i-~ 00 -~, ,--~ x ~ ~ .-i ~p ~, ~ W ~ ~, ~O O~ ~ ~-n ~1 ~ ° ~ ~ _~ N ~ x ~ N II _o~ II '.' A r. _2i ~ ~ o ~ N _~ ..wn 'r~0.ø,~,-M~ ~\O N~\D ~~O~O~'C~J
~-"C, M x, ~ ~D v~ N C/~
,O ~ ~ O ~ II U N ~I, ~' II ~ cr1 ~ ~ ~ ~ '"' ~' V7 rv °° ' II x . ; ~
~ ,.~, y0 O "~ ''~ ~ l~ r~ CV v0 x h rx ~ ~ ~ Wr r.~i N
'C
O b N N CV
F-1 H t-i F-i F-1 ~I
N N N N N
.., U ~ U m U M U
U
V U U U U.
U p O -.U U
U x U
_x U
//

-' N N N N N

~O N i--. N ~O ~--. v0 rt~ ,-t i~
h ~' ~ h 00 ~ II ~; ~ oo ~ ~ II ~ oo ~ H ~ oo ~ b r-' v ~
~~HxOhO ~O,T,~'~ ~O''''~ ~ Nh ~-~ .-~ N
~i h b N O r~i h ,~ ~ ~ x h M o~'10, x ~p ,hue x ,~ ,.~i Nx~, ~' ~',x~ N,x~,~h~0 N~~.,~.-,M Nh II ~"x~,O~
~_ ~ ~ M M ~ ~ r, 'O ~D
~O N ~ M '-' N ~ ~ N N ~ h ~ x °~ d' r"L~' ~ N II
00 ~ ~ ~; ~ 00 ~ II ,x~ r~ 00 ~ t~i ~ O H ~ h N H
pp wr x ~ ~,_, ~O ~ ,-a N 01 pp ~ ~--n N ~ p1 ~ ~ ,r., tx "O
CC n M N x M n M .,.; ~ ~-~, N v! N C/~ ri h a CCt ~i v1 00 x \O v II "x ~O " rx W t"~i M O H l' d' N h v~" ~ '~ N h ~ ~ H N h M LWr _ (T yp H o0 j ~ l~ ~', ~ '~; ~ ~ d: O .b ~ ~ ~: II ~ vi ~ ,~d v '-' r~-t ~ ~' r~ ~ V r~ ~U ''~ ~ ,~, H ~ ~ ~ ~i ~
'~ ~ ~ ~ ~ N ~ O ,-~ ..d ~ O ~ ~~.~ ~ i-~ 00 x' h1 O~
-~ O
Ov ~ ~ 'd' N n O~ ~-'~ .-~ ~ O O~ ~, ~' ~ ~ '"'' N ~ y=. vi M '~ x O W ~ V7 ~ ~p x ~ M _~ N N ~ r~i ,-~
a O II O
~ ~-' N ,-, ~O ~ N ,-~ ~ Oy n ~ ~O ~O ~, d;
'b oo x "~y v~ 'n 00 ".; H 'd °° ~ x a~ b II
O ~ h ~,' ~ ~ O ~ ~ ~ O W O N ~O O H ,.~~, ''' ~ x ,~ ~'' ~"' ~ x _ II C/~ v ~ v1 x h ~-' H p~ ~ ,.~, ~ ~'' ~ p pNp ~ '"'' .~, ~ H-. ~ h ~-' M ~ M N
N b V7 ~ \O ~ N ~ M ~ ~ ~ N ,-, O .d ~ ~ V) II ~ ~!1 _ H
~ H ~ N
Mr~vt~ ~~~t~.ir~~ ~~xbphp II ~ ,-. ~ 11 ~ N N ~ II ~ ~ o h ~ ,-, tx~'~NO~O x~'~~', NW ~,~'I\~1n xNnN~i=.~
~ t~ r-~-i M II ~.'~"'r x v tai wr ~ II \O tai ~ x xi M ~i O Tj y ~ ~ ~ ~ H
a > ~ ~c N N N N
U U x ~ U
U
U U U U
i o x o U U U
a ~.
U ~ N N N N

V~ ~ ~ ~ in ~n ~ ~ N
0o b h II V~ ~ t~ ,~~~ rv 'rat ,-. pp b ~i N rW0 x N o0 d.
O ~'.-' ~ ,.~y ,1 ~ x, N ~ ,...., 00 xi l~ t~t ~-i ~O
t~~t ~ ~ ~ ~ N xj ~ .~ ~j ~ ~-~~ ~ N ,-, N ~ N V7 ~..~
N~,-a'~,~, vi~~p Nx~ N~"~'~~''~ vi''~x II xV1 ..fl _ ,~, O ~ ~i d' ~-1 N ;~
a \O ~ O ~O l~ -~u~ xi V1 ~O t/~ ~ x I~ N d' C~ a \O ~ N C!~
N ;.~ ~ M .-. II "b '~'', M '-' N °° V~ x W
-, ~ 00 y-, _ ~ vj ~ ~,.~ + ~ ~ ~ b N ~p wr CC 00 M l\ N ~O ~ I' x .,'~''-r Oy x 00 v 'b 'D W ~ I' .-i t~1 II
. x~ovcn'Wo xo'''II ~ N~~~~' .
A N ~ r" O vi ..-W~ ~ h N N pp tV +..~ ~ vi ,~ ,~ ' "
,D ~,~ II ~~ r~ ~,~~ ~~ ~ ~ ,x ~p \O
_ II " "-~ .~ o, x ~.; M ~ ..r .-, M
"d ° ~ °, ~ x ~ ~ °' ~ '° o ~° °' ° N ~ '~ oxo c.0 M ,~ M ~ ti0 ~ O a ~ t"'~ cep ~ ~ tx x ~ yD ~ N ~D
c'~1 ''~ ~,~~ x ~ M t~' b ~ ° ~'' ~ 00 ~ ,~, II ~-~' N II
b 0o d' 'd ~ ~~,~ v.i N o~p0 'C1 00 ~ N v0 b .~ ~-~ ~.-~ y--, r~ x ° O x ~ ~ ~"' ,~ .~ ,-~ oo d- ~ ~D W ,~ ~n '~~, ~ .--. ~ t~ b yo ~n t~ h o0 N ,-. M ~ II ~ v II ~, ~ Mni ~ II ~ ~ p t1 II ~~y O
V'7 ~ w N h pp ~/ r-~ ~ i"~ ~
gulf ~b ~ ~~r~'b0 ~y-~'btn ;L, ~ t-, 'n Oy .-a ,.' °~ ~ ~ ~ ~D M d' N ~ Wit' ~ M o0 l~ O~ rr-~ 'd:
x ~ II ~x a x ~ b x ~ ~ x a II ~
O
rN-' ~ H r~
bD
ca .a o ~ ~ ~ ~o w N N N N
M M M
M U M U U U
U U U U
i 0 ~ O
z U / cn O. O l~
(~ '~" N N N N

N
tn ~' ~.-~ x '~ ~ I~ s~ M O1 ~
rWD x N ~ x x x .~ ~ x ~ ~ '" N . . N ~, O ~"' N rW-, N
N N ~ vi ~ ~ ~ vi x ~ x V x ~ rv .-i ~ '-' M .-a ~
x ~!1 O '~ V7 ~ x ,1 N vo ~ II N CyD
W p V~ O ~ ~-~ x ~ O ~ ,~ rx M II
~,p ~' 'b ~' ~ ~ N N 'n ~ Ov ~~r~ + ~1~ ~ ~ x b_ y,~,r~royx x,~~ ~v~ x~~ II N~.o .N ~ ~: vo ~ ~ ~-' vo W x ' II N N ~ II o ~ ~ ~a ~.d x o ~w--,x ~rO~-.~r~~ ~rNrys~~
C~~rx~yr0~ ~00"~G
~D i-s ~D h .O ~ ,~-~ ~ ~ N ~ ~ II ~ ~ .Zj ~.
..
,~o p ..a O~ ~ b ~ ~' x, ~ N ~ a ~ x d; t .C7 pp '~-i ~O N d, 'b '"r ~ [~ ~ b ~ l~ N N ~, 0,x~~~~~~ ~oo~~~D ~oorx~~,x~~M
r~ xi ~-, ryn ~~,~ '~" x M ~ G N
O ~ v~ '-' ~ vi M
II N ,-. b ~ ~ b ~ '~ II ~ 11 ~
~ ~ M ,~ Cl~ V'I O~ O ~ ~ ~-r O f-, 'G C/~
~ l'~ t~ ~ x lW t ~ s~ r~
~ II x d- ,--, v~ oo ~ 'r~' "~, oo .J t~ a b O
N
~..;
GA
v b c~ c~
.iv W N N N N
x x x x U m U M U ~ U
U U U U
x o v v w w w ' U
U U
w x x x U ,~"' N N N N

M
~ N ~=, .~ h II N ~ ~ 'o ~ ~., b ~ ~ \O x 00 ~O II ~' x + 00 ~ '-' x ,WO N . r, ~ r-~ a l~ ~ x~ N
W s~
~ N i~
N x x ~ .=j v0 II " x .-. ~D O
-.xxt" d'~~-~'~v~
.9 v~ '-' '~ ~ N ~ x '_-' ~W.s .p ~ ~ ~ V _ _vi v.r M
O d' ~ b 01 ~ ~ ~-, O x l~ ~ ~ x N
01 O Ov ~ 00 x x v M ~O pip ~, r-r~N N
.-~ N ~ N ~ r : I~ WO
vo Nxx xx~~~'b ,~ x ~ II .~ M ~ ~O N v, N ~"' II ~ ~ ,-.
A ~ ~"~ N r--> N ~j Vj ~ nj ~p ~ M
'''.-:r~.'xx II ~~ N°°~
d'~.'x ~I,~ ~x II ,~~~ ~"".,'~~ II d.
~D M O ~ ~n O M ~ '' vi ~ x, II ~ ~ ~ ~ N ~W
~O r--~ t~ ~ f"~ 00 b ~ h ~ ~ ~ ~ ~ lW .r ~.'~-'.r~ ~ x b ~ ~ ~ II '~ O ~ x x o0 o C/~
b ~f'1 yO '~, ~ ~ h r, ~ i .-i \O
Mx d- Or~~',-~Nxi 'r A l~ ~O tV ~D x ~ ~ 'r l~ ~ N
N ~~ rx ~ ~ ~ + N v Ri ,..~ O v0 x ~ x x ~ V~ ~ ~ ~ x ~ ~ N W ~ ~ x M ~ 00 O 11 ,-~ ~n a 11 v~ ~ ,~ ~
x~ ~ ~ N x~rwN~x~ C/~ x~' ~x II
' x x V7 N ~n Ws N x h 00 wr ~ ~ V~ a 'i~
N N
H H
au .s~ '~ C1 N N ~ N
U U
U
U
U U
M
Q Z U
'zx o bo N N.

~-' ~ c~1 ~'' ~ _ n n d' ~ ~,p,'~ ~ r~ N ,"~., xi N M x N ~O
N ~ M x~ ~ '~ ono ~
0o x ~: t~ ~ r. N ~ ~ ~ ,I ~ 00 o ~ x ~ o .: ~ ~ o x ~ ~ ~
NN ~;x ~:~b ,I II
x +~ ~~~b N N .~ 'C
G~ ~ ~ ~ ~ ~ ~ ~ 00 .-, A ~ '. II O ~ vi W x p ~i "' .~. O oho CG ~~~'m ~ LOIN x ~u~t~Mpd' f3.
,.V" M ~ b ~, p~ l ; ~ d' In d' ~ .-w * rj v ~ ~ ~ ~ s-v ..--~
-, t-~-t ~ N ~ .-~ ~ ~ ~j 01 " ~.~," r, x ~ .,., . tp ~-~ o tA x ~' w.r ~O h ~ N ~"~ ~ ,k' ~ ~ ~ N o ~ r--a ~ 00 ~ ~ '~ r~-,i ~ Cl~ C.' ~a ~ x p ~~ r~ ~ ~ N
'tJ iP .-~ ~ Ov ~ b v N ~=. 'G ~i t~ M
N ~ ~p M Q ~ ~ x ~.,~ O ~ ~ t~ 00 ~
_ "'~i rx II oo ~ ..i N ~
''~~'~ N ''' _ ~ b ~N II b ,~ ~vrx'~v~'~ ~N ~br~~
h ~ -,- ,--~ r: ~O '~' M i ~'bino'DO W ~ xNW ~~MO~~W cUd N O~ ~ p ''' ~ .--n yr ~ 00 ~O ~ '~
l~ ~t s~ ,.~
x o0 l~ r~ r~ ~ x' CO x N ~ x 00 ~ ~i N ~ U
O b ,!, r~
bJ~
b ...
~ O N
~ G~ M N N M M
U x U ~ U x U U
U U U U U
O
U
U U
O
M M

1l ~ ~ ~x r-..
N ~ ''~ ~ ~ ~,~' x ..-a "~ N ~O ~i x r~ x ~ ~ n ~i N pp ''_' V1 ''i ,x N ~ ~ ~ N ,.~'C~, ~' d~
N II ~ N ~ _vi yr '-i .-~ rv '~ _ _.,.-,~
~ M N l0 01 ~ ~ ~ .~-n '"' d' -I-o~ b 'b ~ ~-: x ~ ~ ~ ~ II ~
N ~ '-' ~ x °~ ~ ,~ O d' N ,~, N ~ N ~ .-, ~ °~ x ~ cn oo ~ ~ n x ,~ ~ '"' ,d ~, ..: ~ ,.~ ,r~ ''' ' ,~ ~ "', '~ ~n I I
cd .-i W '~ ~-' 0o b . v~ ~ ~ N r~
r~ ~
''' "'' ~ oo ~ ~n M ~ ~. b ''.' N
~ 71 0 ~N,..d~,~~,~ bx.~Q ~i c/~ ~' ~
N N ~~ M ~ ~ N o0 ~~O
_ ~h ~D ~,2i n n '~ 00 O
~~~~o~
_ .r ....
t~ r~i p ~ M O ~ ~~ O r~i O +~ ~.~, ~ ~ N
II '~ N W M ~ 00 ~ M 00 C/Wr a tx~~ ~ N ~u ~ ~ ~~ ~l0 N ~ b N ~ ~~~~--~~JJ// N ~ N
v ~ v ~ 0l N Wit' ~D f-a x d' ~ x r~-i O ~ ~ ~' DO W ~ r~ 0o ~O O 0o ,~, ~ 01 O t,N~
~ ~i r~ ~.'~r ~O ~ ~ 00 l~ d' O v ~ t~ W
b O b y ~' ,-' ~ ,~ , '~ ,=
GD
t~
O rU-~ ~ H
M M M M M
U U x U U
U M M
f~ U U U U U
U / U /
,cn ~ v~
C
x M
z O N N N N N
M M M M ,M

-:
'° ~ ~ x ~~ r, ~ ~'N ~
~x~, x ~~~ ~+ x~.~~~ ~_~N~
N _ 'r ~ s~ N W ~, v) ~ MO ~ h ~ ~ ~ r~ x v~ N ''_' ~ op .-i ~r ~--~ ~.,.j ~ ~ W --, 'W n M
.,..:
~~~~x~ °~''~o~ ~~xc~
s-. ~ ~-. N a, o~ .... . ~ _ _ '"' rte' _ ~ r. M ~O ,.~., N
r, +O.m~ 00 ~ W x N N ,.'~ ~ ~ ~ ~ N N x '-' x a r-m.~-i ,.~ ~ T~-~ ~, "rT~, l~ x; x, N O N
v~ .-mp .~', V1 v~ ~ ~~-' ~ rfj ,..~ rW-" 00 ,fl ''i N ~ 'CJ l~ ~ ~ t~j r~ N ~O N
_ ~ ,~ ~ ~., x II
~' ~ ~D x M ~ y0 I~ x M ~ ~ ~ ~ ~ ~ N \O
~ ~ i~ ~~ ~ ~ h ~ h V ~ ~ ~ II
n N .-i "x ~ N M 00 , l~ h ~ x '~' '~' ~ 'r v~ "'' N "x ,~o ~ t~ b ~O .~o ,~ b '.O ~ ,~ ~ b ~D " ~, 00 b .-~ ~ ~p O 'C7 ~' '-' j ~D ~ ~. ~ N xW D ~ ~ d; 01 ~
~~H II ~~~xN II '~ ~oomo'~' rnVxo ~n ~~ ~ ~ ~ ~ ~ N ~ ~~~~ ~ ~ _ 00 ~ 'b ~ N ~ II ~ 'b ~ ~ x v~ ~
i-: O1 ' ' h d: O 'i" p-i ~ x ''' rr~i '~ O ~ ~ ~ ,b d' 0o W ~ .~O ~ ~ 000, O
~r~' ~. x~0\O~iri~
nN~O~ ~ r~O~O'~~' 'rr, ~.b 00 l~ t~ ~ r~ V~ ~ 01 t~ l~ 1x ~ v v ~~
O b H r~ H r~ ~~-t b~
'-~ M d' rh M M
M Nt rat c~
U ~ U x U ~ U ~ U
U U U U U
o i x ~o z ' /
U ~ ' O
O /O O
x <l' U ~ M M

v~ b ~ ~ II N .-N ,~, x ~ ~ ~ ~ ~ tn ,.y0 Vj I~ C/~
I~ ~ M~ r~ 11 II o ~ N ~ ~ "~" ',11, ~ ~ N
a a ~ ~~_N _N .-:
'-~-' b ''rLi, '~' ~ .V x N N Ov C!~ N ~ ~ ~ r~
rx x N W ~ N ~D
y~ N I~ N OD O 's y.r l~ ,-n ~ O ~ Oy. N Ov O~ r~i N
V> M ~D ~ l"r II ~ ~ x .~-~ O ~ ~ ~~., l~ N tx 00 Wr II ~"~ ~ ~''~ ~' x r' p~ ,~ ~ x ~ ~ ~ [~ x' N
°°. ,-, ~. ~ ~ II N :-; r, ''' °' ~
e~'~'e ~ ~ °~ Tj ~' ~ M ~ vi x II ~ ~ N x ~j _~ ~ ° II
d' M w.r Vi~ ri 00 i~ ~ ~ O ..vd x M i-yD
N ~ O ~ ~ x O L~ N 'b ~-' d. O N Lri pp O ~ +~
C~ V t~j x r-., O ~ M d' ~ I I M l~ ~ ~ 'r b ',~,' M~ ~. N ~ O \O N ~ ~ I~ ~ '~ V1 II M ~: v o~0 _'Ja d' l~ ~' M_ _ N
vi x ~ '~ C~ r, ~ ~ O O
'~ ~.~o'C n~M ~o~~ ~ II ,,~b~.ri II ~N 'f.n N ~ . . x ~ v~" ~ ~ x ~. ~ a. '> ~ ~ ,.bd ~ r~
l~ ~ 00 ~ ~ II ~ ~o ~ ~ pp N v ~c V ~ ~ 00 A N s-s ~ d' "C1 vi h o0 'LyD ~D
II r~i O .+ C~ ~ b ~ ~ ~ d; ~ ~ x ~ ~ Cj °N ~ ~-.
O" vi rv W ~ l~ O~ x ~p ~ rs l~ .-n '~ ~ ~ ~ ~ x x ,-s M
v's'-'x .. ~ ~\O N ~ ~ x l~ N II N ,~, q x N ~ ~ l~
oM0 N oho IZi x, ~-: N r~ N ~ ,.~i '~ N N
N ~h ~ r~ ,~2,' W ~ ~ x 01 '~ ~ vj r" ~' '~ II
rs s; x ~ N '-n pp 'J ~. '_" l~ M 01 ~ ~ M O ~ ~' C/.7 ~ x ,II ~ °' N II oy ,-.. o o, N
W ~"; x oo ~'' '> ~n cYi ~ x oo ~ b ~ W
o ~~ v~ tn era ~ a H N N
H H
p O N
", U M V U U U
U U
N
N N
O
O ~ M ~
V1 V7 ~ O

M
M r1 .-y1 ~-'n 00 pp "'~ II C/~ 00 ~ ~"'y ~ d. 00 N ~ II ~ 00 x 'C O '-' ~ ~O N ~ ~ n N r~ ~ x p1 ~ b d' ~~i.f;-~ x~r~~''~ x~ObN~
'-' I I N .~, ~ " x N ~ t~ N W N t~
II II
O O pp ~ x ~ ~ ~-~ v ,~ ~ r~
~ r-i pip ~",~ ~ ~~ O ~ ~ O ~ O vb rsx rte, ~M~: 00" x0 01M '~;~ p~~b',~N
x b V' "~ -~ ~ o r. ~n ~ °° ~o ~ x ~ °° ~ ~ ~
c~ ~ ~ " ~: ~n x t~ ,-~ I I x ~ r, '~ '~' h A '~" W ono x ~ N .=, II ~ ~ N ~ II ~ N N ~
~r a ..i '~' ~ p~ x v~ x x U d' 00 ~ N W.~.r ~ ~ ~ a ~ ,-~ M ~D W --i 00 '-~ ~ x ~ '-~ 'L7 V~ 00 ~ b W D ~ M ~"' ~-~~ M.
~ _i~t oo x ,-, '-' ~ "d '% '~ ~-.' '-' II
.r ~ , a ~ ~ " /'~ (I
tp~ ~~o~o ~ONo~o'r"~ up~o~ox'~ c0N ~~~ II
~ ~ ~ ~ x ~ ~ ~ 'b ~ 00 ~ 'b v, N ~ '~ ~ M 'b ~ N N "C1 ~ ~ N 'd ~ IW _ '~'.r r;
r~ ~ b ~ ~ ~ ~ M ~ ~ ~ ~ M ~ ~ ~ ,-, x U'1 M
~~xj~ '~~' f~ ~t~Nv '~v"~~N ~t~ ~v'~r~ ~r~j ~xr~, C ~ x M ~ ~ I~ b ~ ~ t~ 'b ~O I~ ~ ~ ~ ~ ~ 01 ~ ~ ~ ~ ~ 00 a1 ~ '~ ~ I~ Oy "~
M ~O N r~ n ~ O~ N r~i O~ O s~. ~O
00 l~ r~ ~ r~ ~ ~ t~ ~ ~ ~ ~ ~ ~O 4'W h ~ "v ~ r,, O l0 O ~b Cl1 V1 C/~ C/~
H H H H
V b ~ 4w U '~ M U
U
V U
N
U~ U U U
b o a b a~ u..

N ~~ N ~O
~ r xi 00 ~ x N x N ~ ,-, ~
x x ,.r., o, ~ o ~ ~ ~ x ~ ~ ° ° N x ~ ~ oo '° N x ~C o ~ Ov (~ ~ ~ ~ M ~ x x N ~ x x I ~r ~ ~ " II M ~ ,~ ~ x ~ ~-' ~ ~ x t~ ~j ~ ~ N ~'~' p O ~ ~O atll C' x _~ _vW_, ~~"' M
av ~ 'b O N x ~ o~ ~ v~ N + ~ ~ '~ r., ~ d- t' ~ II ~t ~xo~, ~W ~ob~d~o ~~b~
x ..: x x a1 ~ ~ ..J ,.; M II ~ v ~~~NN x~~ ~ ~o~ x~~"~x ~:~~b ~ II ~~ ~ ~x~;~ d.~0 ~ xxos,n A ~ ''~ pip x V~'~ vi '> ~ p~ ,.o v0 ~ ~ ~ ~ b N l~ t~ l~
..., ~ M .~ .~ -d o '. vo ~. _ x ~ x m ~ ~, 'G °N° °N° ~ x va M can ~ II ~ ~ x x ~t °° ~n '> Vi o oMO ~ oo x x i. ~~:x~w o~o~' ~x~ N ~ as ~'b~~~. as'° ~;~
~,oN'''~va roe.-;~2i ~o~~x'r ~oow ~+' ~o~
~~ ~ iI ~ ~x a ~ ~~b°'~ .~~°°~ w ~x~x wr ~-~ ~ M O .~ ~ N N 'r _ t~ 41 a 01 ~ b x O ~ b ~ O O ~ II ~ O x x x x ~ ~ vi b ~ N
IW ,r N C/~ ~ a ~ C/.1 ~ O ~ x C/~ ~ ~ " ~ II ' 00 M 01 ''' ~ x ~ ~ N ~ M I~ O i~ N M
d' r~-~ ~ (I ~ ~ ~ ' ~ d.
~NC~'no ~1~'°" N ~x'',~ ~ ~~~~,~N ~°°o~+.:
~~~x~ ~r~~xx ~~bVIN ~ooo'~~~ ~x~MW
N 00 ~ ~ ~ M I~ M ~p ~p n M _~ ~ ~ ~ ~ ~ V1 '.r ,~, ,-~ ~ N x i-~, ~ ~ o i-~, ~n o0 x ~'~' r~ x ~ O~ ~ N x ~ ~ ~ C/~
d1 l~ x ~ v a I) ~ 00 \D ,~ x ~ ~- ~ x V1 M O .-. a ~ x C/~ C/~ C/~ C/~
H H H ~ N
O 00 o~p ~ ~ Ox0 W ~ ~o ~o x O
U \
U
x.-J
U U U U U
0 bA .C~ ~ 0'~ .'t,' V ~ ~ r ~r _ _ m;~ N ~: ~, ~ x .:~ ~ NxN
N t\ 'r'~ x n x y.r I
~ tn M ~ rs 0~1, ~l1 ~ N N ~ N ~, t~ ~ m ~~b'~'t ~r.xm II ~°'~' ~'' xt~~x~
xOIN W ~ ~ Nx vx,-~l~ N ~~~p,~~ ~x~Op ~;~x _ ~ n M Cl~ ~ ~ l~ N tn ~ ~. ~ ~ M ~ D O I) , ~ ~ ~ ~, x x l~ ~ x N 00 wo ~ ~ l~ rx 00 ~ ~ W.r .-a x . '-' o, '~' ~: II '_'~ II °° r' x ' x~oo~°"'~
x ~ N cn r, ~ ~ ~. l~ 01 O ~ W yp . l~ x N v N 7-a ~ tn N ~ i~. .~j M ~ i~ ~'1 ~ l~ x O
mr. ~ ~iv_~i.~°~'x xro,,-;
r, v~ ~ O x M ~ ~ ~ ~[r x ~~ l~ x N X01 M '-rte ~
Q b '-~ N ~ '-' II w ~ p ~-' x O ~ "'' 00 x ~. N ~ ~ 'C
,..c ~-yr ~.,' II t~ ~ ~ ~ l~ i~v p~ ~ pj '"~ ~ .rN.., t!7 ~O v--i '~ ~.~, ~ a ~ II
'~ II ~ ~ .~ ~ x co O x N
. . b N . . l~ x '~ x x vD . ~ ~ ,b ~ 00 O b ~ ~ .-Wr ~ ,-, ~ h ~ p~ N ~ ~ N l~ N II ,.d ~ "~ ~ ~ M
bn ~D ~, Lj~x ~, ~,.~ x ~ N~ v ~II ~~01 x ~ ~ ~ 0 ~'~, ~ ~ ~ 0 x ..d ~ N ~ N ~ '~ x V ~ x ~ t~j ,-, ~1' -i ~ O1 N M ~ .-~ ~ II ~' ~ 00 II V7 ~ '~ .Lj . ..
N b ~~ ~ l~ ~x M ~ vi O~ ~ II m ~ ~~ WO ~ ~ N ''d,,~r.~.,~~
xx ~I) x~~ ~~Ob~,-r ~xl~b II O ~x~D,-,~CJ~
~ N ~ m ~ 00001 ~ '._' ~ Sf (~ N ~ ~ ~ ~ ~n ov yp ~ b ~ II ~-~ 00 ~ M ~~. V~01 ~x N
~ ~ t~ "x ~ 00 N_ '~ ~ ~ ~ ~ N ~ ~' 'n N ~' ~ ~ ,x~~ 1~ ~
'' i N ~ ~D x' oo t~ ~ x x x ~ x ~ ~ --'ri oo v~ x ri ~ x W. N ~ ,-~ x 'Z!
r~ r~ r1 r~-i r~
bA
b ro ~ oho o°0 00 U
'~ U
U U
U
x~ x~
U U U U U

~z ~ f N ~, N ~
~-~ ~ 1l t~ II ,~'~~ d~ " II t~ ~ ~ ~ x n x x 0o Ov '~ II %-~ ~ ~o ° '~ II x ~' .-:
'7 x x ~ ~ ~ "~ ~ N i,~~ l~ N x M M x M
b ~ r4 ~D a a:, ~.D d' ~ ~ '~' '-' ~. v ~ ~ x .v~, ~ '-' ~O
N x ~ r-, ~ ~ ~ Cy M N x ~ O N l~ vi ~~ ~ ~ N ~n N ~1 ~t v')00''' ~',nNp "oov~Nt~ 0'~~001~ oO~''~i-v N ~ ~ M ~ ~ tY1 O ~p ~ d' Ov ~ o p~ ~'~? N WO p1 00 ~ ~n op ~ '~' ,~ ~ M ~n x.;Q ~x~ .~x~.. x~o ~~ xx~.~
_ _ ,N ~~ Nxx xMx~ ~~:,'~ Nxv~ ,-~~ II bxv~ ,....~00 1~1 rm CCt x h x N d' ~ ~ N ~ x ~ x N W ~ ~ ~ 'n ~ ~ ~ _~ _ A N ~ l~ x vi O x V~ N '~ ~ x C!~ p~ N b in ~ C/~ Lfl .--. ~ x v x l~ 01 ~ ~_ ~ Q1 ~ ~ x l_~ U ,~., x ~ _ ~ ~O
~~ ~p '~ ~ ~ d' 00 ~ ~ % ~ O~ .b ~ '~ l~ ~ O~O x ~ n M [~
II v-i ~ x II x p~ ~ ~ II pp ~ ~ ~ "' M x .-i ~
~o o° ov '~ ~, ~o c~ '~ ~ ~o ~ oy '> ~o ~ ~; N ~ '~
~°°°b.~ .~o ~"~.ed ~ ~o0ob ~ 'o,.~~'~~',-a ~ ,~~N°
00 ~t t~ 00 0o x ov Ox's ;~ ~M O o";~ O''~~'"' ;'~ ON~~,"'-'xN~ Ooy r~ ~ ,~ ~ r~ ~ v~ ,.d . ~ ~ II
~xxN c~N~x~ ~x.~b~~ e~x~x n+ ~ n N ~ d.
x v ~ v~ ~ ~ II ~ ~ x ~ ~r-~ ~ b ~ ~'vC~
l~ l'~ I~ M '~ ~ l~ l~ ~ Ov O~ V' ~-~
x'~x~ Ncr~ x°'~~ x'dx~ N x°° ~~:'r'~ x~r;Q,oo ~ N ~ x ~ l'~ ~ N ~~ N ~ x o0 a x d' ~ a0 V7 N
O b C/~ C/~ C~ Cl~ C/~
N N N N N
i, r-1 H ' ~ ~, ~, GA
O Op 0~0 00 0~0 000 U O
x U
i x~ x~ x U U U U U

r r N N _p ~ ~ p ~ ~n N
~n x II °° M x ~ ,~ II ~ oo M ~ ',° x II oMO ~r .-: ~ '~ ~: O
V1 ~; x ~..\ ,.d '' 00 II Ii b C"~ ~ ~ 01 N x W .r C'~D
~ ~ ~' '~ vwn N ,~,~., ~ v II
~"v~~°.~1 0 ~~'~i' ~ V~ViN~
°'~~xN ~ ~x~~
00 l~ x x x l~ N ~ M 00 M ,--, x m _ .-~ _ x .-: _ ~ n .--~ ~ N vp N ,-, .--~
vi N .~ x x N x x l~ x N x ~ x N ~
A ~~xN ~, ~~, N~~xx_ ~ o ~ ° ~
~~ o ° ..d '~ ~ M °. ~ II t~ o ~ b ,-~ x ~~:
II ~ ,-. ~ o '' ~n o~ ~, ~o ~ ~. to ~ ~ b II ~.0 0 ov '~ t;
'~ II "'~ ~ oo O b II
b x r-' ~ d' ~Cj '_'~ ~ M ~" ..=j ~ 'w.r '~ rx' ~ II M
~ 'd .~; N ~ °° V~ x M ~ ni b .~: Q1 II
~ ~ ,~ N ~ II ~ N x M ~ ~mn r, '~ b i=. 00 N ~ ~ x r' ,~ Vj CO N ~ 00 ~~_x~ N~ ~ II ~xx~
"'' ,~; '_' N x + ,~ ~ N O
x Nx~ N x V7 ~..'~d'W rx xt~ Nn x N ~-~ x o0 'r II ~W r 'r N ~-~ r~i x 'b N N N
H H H
Q~Q 00 M M
U U
U--' U~ UN-' TJ . O > ~ DC
U ~ r '~o, x ~~ x II N ,~M '~ "' H i1 x ~ .~; ~ x .o +% r, d' ~ '-' ~n N N
t~ ~, x N xM~
~t d' II
oo t~ x x N ~ ~ ~ ~ ~ b N '.-' M N ...r '-' '"' x ,~ t', h 01 ~ ~ ~ M pp ~ ~. ~n N
N Il Il p~ .+
~ h h ~ ~ ~ x ~b V ~ M Ov M t/~ p~ II O o0 '.~, ~ N O rs ~' y~-~ ~ .--r r: 00 0o x x ,b '~ x x .:.~:. M ''' .-. v x ~ .~xx_~~ ~~o~N
~ '-.~ ~-r t\ N i,r o0 ~' N
'r x V~
N N N ~ x ~~., Ov ~ M
x M ~ ~ Q x M ~p ~
l~ ,1 00 +, ~ ,-, ~ II ~ Cl~
00 01 Q1 x ~ N t~0 _v~ rs t-, ~
r-v I~ ~I ~ w O ~ ,-a ~ +~ Ul ~~ h h N oo ~ ~ N M " W
x 00 ~ i ~ I~ "
O b b M M N ~ O ~ O M d_.
"" CJ7 ~ ~ M
~ '-, t~ ~ ,..~ N b '~'i r''~i 00 ~ ~O
N ,--~ l~ ~ ~ ~O
x ~ N ~ n1 00 0o II ~ ~ ~ ~ ~ ~ ~. ,.'-:
r~ "'_' + ~ lV ~ N v x x b ~ W ~ ~'~ '~ .:~W W
.-~ M ~ v ~ ~!1 ~ yr 'r N N V1 00 ~ ~U ~ ~ x M
xx~~
.b O ~~
h h bD
i~
'~'' O O O O O O
M M M M M
N
x ~ , I \
U ~ v w O
b O ~ ~ ~ ~ r~-~
M M M M M

WO 02/34711 PCT/USO1/32s82 II ,1~ II N ~ N
~n ~ x x , h N x ,-~ h ~ ,b ry0 N
x ~ O N a "~C M OO ~ d' x ~ x ,.., N ~ O pp 0o ~ ~n x M ~ pp ~ I~ , ~L, ~O
i .-: ~~~ ~~;xb II
N~'ty~W b~' xbdN,'~ vi M~ v~O W ho0 N N
vi ~-' '°~ ~ ~ x II ~ :-: C~ ~n ~ 00 N M ~O ~ N ~ x ,.~ N ~~ x O
o x t~ x °° N °° t~
O _ ~ ~ 00 ~ '~ ~ CO .-.
~x 01 x N x n ''~drv N N
~; O ~ x x l~ N ~ x x x x y ,-, N o0 N ~O ~ N ts. d' ~ N N N
q V ~ ~ ~ o~'o, .~ '-~ ~-: ,~~, II ~ h N ~' oho.
-, _.
~ N 'd y--.. ~ ~ "~C~ d' '-' ,.d ~ '~ ~ N s~
~ h b x O~ N " Oy ~ N x _ w.r N ri O ~ x ~ ~ ~O o0 tn N
~ '~~' o0o N p N x oo ~ ~ o '''.~ oo ~ x ~ ~ ~: ~° ~ r' x' t~. II ~
_ b M x l\ x ~O '~ ~W-; ~ rW.~.r ,~ "L,C N 'O 01 M x ~_.Cj t3, ~ 01 O x x N ~' Q x ,-, ,~ ~ can O x o0 00 r-, ~-.
~O 01 N x ~ '~ N N d. l~ k '.".' N ~ II ~; -}- x .-, x ° o M ~° I I x t~ oo a~ ~ I I ~ '-' 'J W a~
,..~ ,..., '~ N _ r, G x O .f b I I '~ ~ M av ~ r' I I x a~ ~ '-' ,~ b r' a~
i h .-r ~ ~ d. o b ~ ~ .-; ~ b ~ ~ M d; +'~
.,..,. ~ M
~~-I- C~f~N~t~N ~ ON~t'~x~ M ,d M
N II II Uj(~ ~OOOOI~ NM ~ 0000~M~
A oo ~.-~ ~ '-~ ~ ~ .-: ~ II x . ~ t=1 ~: ~ x ~i v5 . ~ . .
~ v~ x ,,.; ~ oo ° ~ " x r: ~ ~.' ~ ~ n~
x b 'o '~° ~ ' r' x x N h o~0 ~ x ~' x N ~t ~' ~ ,.~C, x N
x~~~,.~ .. ,~x~"v v ~x II xx Y" O~r M o C M
M M
x O
N r x W
U \n U ~ /

x ~~O x O
x ~° ~ ~ ~ ~ ~ ~
U z cn M M
1s2 c~
A
v .'., c~
+r a~
b a~
N
N
+.~
U
U
'b O b bA
b -r., O CAA
M
N
U

c~
A
..
U
.,.., M d; v h ~D
~'', cV cV ~n d;
.-i Vj 00 d' ;d N
n a U
b o ~a a, ~ C7 d nn a ~
M d' .~.' M M
M M
M
M
a O O
y'' x O/ O
v v Q'Z M M M M M
V
~n o b ~ "vd .~ 'b ~ II ~
N x N '~' h O~
~ x ~n II
ey~Nr~'tt~ n ~~NhN
.rj~01r~
d.

,, ~ ~ .tj N II
h N M ~ CO Ty N d: ~
00 x N

x V x W x b N ~ ~ N ~ ~i x ~ x ~ 01 N .~ ~ h ~ ,b N N ; -~ pp h wr y x ~D

M ~ ~
~ ~
~r~ ~ u~ ~ O ~'~ ~
~ N

. , A b II h x ~ II ~ b M 4 ~' ''7 ~ O x b ~ ~' " i-,. ~
~., ~O
M '"' ~ v ~ r' M ~ ~O II
01 ~ y' N M M N

h , ~xh o, 'b~... a .-.--i ~o~d~hN~~

"'~''~ N ~'~" .~o d' M rs ~ O rv ~ h Vh vi M W
N N

ett, ,~ h ryr ~
7, 'b _ v, nj"x,V1 N M ~ II ~O
M O~~ O
M~
i On~..~tx '~~x II ~
+ VI~x Mr-(/] " ~ ~ ~~
h ~ V~M bN,.;
~x~x~xz ~xM~,=. L,j ~~ xxN~;xm ~b N ~' N II _ _ N ~ ~ N ~ ~ x q ~ ~ N h h x r~ ~ t~ v sx ~ N ~!1 ~y 00 ~ M N
M d' ~ b b x x O x 01 V ~ ~
01 N O ~
N d' oo V ~''~ ~ ~
d- ~ cV t1 ~ ~ + ~
~ '-"
~ ~

~ d. ~
x~ II ~., M ~
II ~ II x II .~ O x x O d' N
p ~n '~' N ~n ~ W
M N~xM
~

~.~~M~~ ... ~xM .- ~
N 1l ~.

'b O c d V

.c1V W i-1 hi b~

O

U fs"
i m r g m x U
m U

~ ~ 0 zx l ~ U U

O O

O

~.
z '".' V

II . ~ a~ ~ t~ N .-.
M 'd r' N ~ ~ ~ ~ 00 ~ V7 ~ M ~ u~~N N
r-~ N lW.r '7 ~ oo ~C ~p i=. N ri ~ x x M N
M~
x~x~"' ~~ ~.~NxM'"~ x~
o ,-; ~ x ~ a N .--.
-i l~ ~t'7 I~ t~ N ~ .-~ r, ~ uj t.~~.~ ~ s-~ ~ ~ ~ ~ ~y p ~~ o ~' v~ II
N N ~ ~~ b N N N
00 ,..'Z', ~ N
M b m N ~ x ~ ,--i ,.~ ~ ~n ~ ~ ~ I1 ~ ~ ~ M V~
~h~ooN~ O'''bJ~r~dO'.x~ '-'y~xxM
II
+i f~ ~ r~ 00 '~ N \O ~ 000 r; N M N ~ ~ ~ N M ~ ~
,..~~ ~~N II .~ o, II ~t_~''x ~~ ~ ~.-:x ~ x' x C, O x xi 'C 01 ~ ~ O x ~' M M O N ~ N ~ ~ ~ ~ N
-, l~ '~-Zi O "'' ~ ~ N ,n a Oy y0 '~ ~ ~ N t' ~ II d~ ~ v 11 M ~ Ov N
~~~~~~t;
~M ~ ~Mwr~+ ~~~~n -y, N ~ N L!~ V~
b r~ ~ N x ~ II x ~ ~ N b z ~ ~ Oy ~ ~x ~ w -, ~ ,-~ N .-yj t~~ N
~ ~t ~ Ol rat N ~. x; 'G N M vi ~ ~ + x ~ ~ ~ d0', a l'W r 0o N ~i d' ... ..J r~-~ 00 a r~-i O wr x l~ d' "CS N (V
w w C7 aA
° r, ~ ~ ~ ~, M M M
U U U U U
M M M
U U U U
' O O O O O
/zx /zx ; x ~ x ,zx w w w N
O O O
U U U U
M
w x U ~o ~; O O
O O

V

a, t~ ~ II ~ N N ''~ d°~', ~ ~ ~ N v0 ~M~~,~N..,N NN ~b~,.~N II
I I
~; ,--.~ '7 b II ~ M tx V'1 '~~ ~ N o~
~b ~,~d.~~I~1"~DI~/~ ~II~O
v O °° N '> ~ II W v. ~ ~-. ''~ °~
~ _ I~ ~ N _ ~ ~ ~D ,b O
N
II
G O t~~tN~Mn~' N N~Nr ..n .-'' '7 _ rr~-~r d. r~ v + '"' r~ x N
',~ ~ b ~j ~ N M N ~' rx '-~~ ~ o~ N N N dM' b p~ ~° .~ x' x .~ ~ .b II ,.r 01 +
~ l~ ~ ~ M ~ ~ x 01 ~ ~ M M ~ ~ N
Cl1'1'C ~~N N N C/~b~ull a M
II N ~ o N . "~'; c~y.~.r~ ~ I I ~ ~, ~v ~ x M ~ . M
x N '7 r~ _ _ O II Ov ~j r''T~., M ~ -d W W ~' ,.~,., N ~., r, '~'' W
Go ~'' N M W r a ~' '~' M (~j ~D
'~ ~ ~ T~ r~i x ~ O ~ ~ W .~.r O ~ t~i ~i 't!
O
b4 H H
U U U ~ U
M M M
U U ~ U U
O O O O O
zx zx zx zx zx / / / /

O p U U U
i ~ ~ ~O i x x ~ ~ '~ x U U
U Z ,.~ ,-,, WO 02/34711 PCT/USO1/32s82 .,..~~ ~-, M M vp ~"' ~ I I ~ ~ N ,.~ ~j 00 'r M ~ V1 M ~ M a ~ _ .-~ _ N II +~ O v O~
00 ~o o '> ~ o x ,-~ ~ W,~, 'r Wo ~ c~ ~ II °° "' x r~ ~ t<1 "C ~ ~ ~. ~ M ~ N ~ d' ~ ~ 00 x~, ~.~~. N Cl~
x ~j ~ '~ N II ~; "~ M x ca vi ~ ~ N x -d L~r ~ "'~ ~ vi x N ~ ~ N x wr ~ ~ O ~ ~ N '-' N ~i '~ _~ ~ o0 M M tV ~ ~ ~ ~ N ~ ''' N x O o0 N W
+ oo ~-'., N rs ~ II ~' 'r'L", d1 x x ,~ rN,, ~ x b Ov ~"~ ~ '~~' b s1 p O ~ tp V1 II 's Z ~ ~D ~ x r.~0. h ~ ~ 00 '-' ~j N b ~ 00 ~O l~ . ~ ~ ~ tn GO. ~ .~ O~ x M
i-s O 'J V'7 i-v ~ s~ l~~ 00 -(" ~ l1 N N i-s 'C ".-y0 .o p~ r~i r~i op r~ p ~o ~ II ~ b M ~o O ~ p ~ 0l l~ M ,-. O 'O, ..~ '~~ O 'G ~ '~ ~ p 'O ~ M d. ~ O N M
p _ .-. ~ ~r ~~,; p ~ ..d ~ M p x N x ~ ~''? Q '-~ ..: err; 't p "' x .-;
(I rv ~ , C/~ ,--, 'r xi M C/~ '~' l\ M t~-~ pp C/~ N x .~ f"' V~ Q~ M ",,rC
~xt~+~ ~ NN~~n ~ ~'~_vi due' ~_~,"M~W ~,~,~ N
b b ~ N W ~ ~ ~ ~v~' ;~ ~ 01 x N ~' i=, ~ <t ~ x v ~ ~ op Ov _ ~O ~ ~ ~ r~
N QNO M N ~~-t ~ ~ ~ ~ M W ~ l~ N M d; ( a ~ l~ V7 N ~ II ~rj lpl~l~ ~ NN''r _x_~"'''' Mr~i ~~' '',M
II ~s~ ~ M i~ ~ ~ ~ w 01 w ~ ~ w ~O tr-i ~ b ~ ~O
x '~ i-4 rx °~ ~ ~i x ~ ~ ~ ~ x N I~ N x ~ x ~ ~ 1~ ~O x II b N ~ due' .b O b P~ W ~ W ~1 + o M + o o ~°
r~ ~ r~
.~ f~ ~ ~ M a m M
." U ~, U U ~, U U
U U V U U
O Q
xz xz ~z ~--z xz fx U O . U O . . U
U , U , x x x x x o ~z lss x ~x MN~x~ ~x M
vo n ~ N ~ %; ~''. ,~ os M
°' '-' ~ ~ ~ °~ ~' r--; .b ~: ~ Ii x~,~~~.~ x~~~°~
x M N b M II
CCt vi o0 x ~ N _~n yr ~ 00 n1 n c~d ,-y ~ ~D x +.
a oxbxxxz ~x~~:NN
--~ o ,-. ~ ~ .o + o ~ ~ M
II ~_ ~~ N .-, x N N ~' x N ~ 0 x N rs ~n ,., ~ b °° oo ~ oo N ~ x 'd M O ~ "d ~'": M o III N ~ vi O o0 O C/1 ,~ ~ x M "-' ~ p C!~ ~. O~
'"' ~ ~ +" b W 00 ~ _ l~- N
~M_°°xx~" _M ~~ II M II
M
V~ C/~ C!~ ~ ~ x ~ vi O ~ C/~ ~ 00 b l~
yr _ ,-. II '-' N W wr a ~, x N ~ ~ x ~ ~ ~ x N x due,' M ~ M ~ ~ ~ ~ M
O b an ~o 'o o + + +
~.
r~.r ~1 M M c'~ ~ , r-~ ri n U U ~ U x U ~ U
xz xz xz o xz xz o ~o xz o U U U U U U
O O O
O O O
,~ U
~z N h vi ~-' O II ~ ~D r-. ~ ,-, N
'r a a a I~ O~ ''J 00 ~' O l~ v l~ N M d' ~'.
'o ~' r-' ~''~ x ~ Wit' II 'r'. ~ II b d: II ~ II x ~M Wit; x O~ 00 ~ .-~ II ~. h M ~ h ~. M h ~ h ~ w '"' ~O
l~ ~ ~i7 M
'-' ~ b M vp ~ x ~ N x ~ r=. N ~ x ~ FII ~ ~' d.
\O 00 ~ ~ ~ x pj p ~ ~ y0 w.r ~ V7 x ~ O vi 'r ~.~r '"' x n ~ b M wr II
~p d. _ _ v r~ n '-' ~ 'r ~ x x ~ x ~ ~: x ,~, t~ N l~ x oho, x ~ _+."
oW' °' oo p N ov ~ N ov a0 O x ~ ~ W.O u~ WrN h x tp ~~ N X00 ~ x ,.~ x O
~Nx~~~ ~ ~~ ~ ~°° M a ~°° ~x '~ '--~ ONO C/~ ~: ~ ~: 'b ~ Ws ~ '. .-i -' x~r ~xa, ''-' ~xo vo ~~~'"xx r~ o a ~ r~ ~. x r~ ~ ~ M
~ 01 00 r' ~" i-s ~..r N ~ N N ~ N v DO
vD r-~ N + x ~ x rv .--~ ,--.. n x ~; N
0o b t~ ~ ~ W O x O x N M x O x ~ x .-.
~ N d. ' '~ ~ '~ ry ~ '-' x ~ M
r''~OxN'cYx ~ ~ Nx ~ No,x N ~ N.~:~x .-~ 00 ~--~ M ~ ~D II x M .-. II x l~ M x .- II ~-x x ~.. ~~
b O b Ga v ri r~ H ~~ r1 U U U
x U x x U U x U U
xz xz xz ~o xz xz o ~~ ~ ~o -O O O O O
U U U U U
w r.~ r~ u;
p; O O O O O
O O O O
o'~0 0 0~0 0 0 U ~ .-K ,.-~ ~ ~~ T., '-' ~ N ~ II 00 r-~ M
b O x M ~ v ~Q b T'~ N 'u t~ x ~' Cct ~ x O '"' ~~' b M ,~'-~, N
A d' N ~ N ,.~,N p V 01 h ~ N 00 ~D ~ ~ M
e~C t,0 N x ~ r-y.~' xr oo W
c/~
h N ~ ~ m tx M M M
N ~' x ,b 'J l0 + f'~ ~
z l~ N ~ ~ ~ rx ~ a v a ~: x ~bx~ iW~~~

M M M M
A
b .~ ~ ~ ~ ~ °°
x U ~ U
x U U
U
U
xz xz xz xz ~o ~o ~o / o O O O O
U U U U
x U U U U
U U U U
ono ono ono a~'o r-, ,-, 00 ro x o0 b ~ N V'1 Wit' M ~.~.o _. .
o N ~
x II ci .~
~: ,-~ 'o 'v~
x ~~M II
x~
~:x~:w NNwr ~ ~
.-ifV ~.-,Mwr II ~ x ~ II ro II
M
~ '~
N

c..o.. o ~~~ ~ M .
''' '~
~

o,b~, ob~
~ ~: ~
x l~ x O~ ~. M~~
ti x ,.-, N ~ ~ ..d ~D
d' ~
x :

c N ,-.
.~' d' ~
II ~ ~
N _v~
~ ~ ~ 00 M

M
'''xi ~
l~~ ~~xN~d ~

4l , '.'.' _ ' II

.. d: ,--y. ~
N n '~

~x x ~x x ~
x II

x x M M
a0 L~; '_' ' d up N

Q; N ~ N i~ nj .~j II
i~ O d ~ ~ a .b II ~ b II "'~ ~
'. M ~ II o M

~ro~~,~~ N_ ~b~~,x~~:
x M ~ ri h 00 ~ d; -, ~ W r--n a~xxM qNx~.
mN

~ ~ ~
,-;N w oo Nxo~~
x~, ~ ~
~ x x x N .., v x N ~ 01 O
N ~ ~
~ ' 01 t~ N .~ d M N x ~-,N
x v l~ x yr I~ ,.~
ly-~' t~i a II l~
M

O
b bA
b W W W

U U U

4.
~4 O O O

U

O1 N _ d~ vi II: N ~ ~ ~, r:~ O ~ M 01 y ~ ~ rx x, xr x xi xi xi h M N
C/,1 x ~ "~ ~' ~ x x N '-. ,--i 1p ul M ~ "_' OO N ,~ II N ''_' ,-~ M t~ ~D N o0 N II ~ ~n '"' t~ ~, vii-; u,~,h~~wj ~~~~ LUr"d'~-~ II ''~~xd'N
_ ''r a x d' ,-.i '~ .-i ~ \O ~ h N ~ M '7 ~w' 'O
N ~ ~ ~' h N ~ O~ ~ M N p ~ ~ ~ ~ ~ rN,~
00 00 N N 00 00 h M 01 d' w M _~ ~x N ~ N ~h ~~ ~'"~ II M II O h O x N ~~~ x a1 x x ~ N x ~r~' tai x' II W p ~
r., r~ t~ x d; r", h ~ '~ x ~i .--n ~' N ~-~ ,-, ~ '~d h "v ~ ~' dyr N~ "t~'ypj~Np~N '-~ "~O~N
h N~'r'[~, v~ IC vi~h '-'Nrxy.~r'~COxM
EC ~ b '~~' ,'1~ ~' d ~ ~ '-r II vp O '~' ~ h ~ ~D ~ h .-, h "" O OvOIM ~cV,tjh~''~ ~~pp~~ 0'-'~N~''~MM
~' v--r O oo d- a ,-~ II v II ~ ~-~ .r, h II ~ ~ ~"' °~ ~' rx ~' t~ d~
~s ~.oci-c~~ II ono ~o'~~~~Q,~~.luo~~~_;-:~o~Nco"',h~"'N ~:
s-sII ~~M ,:.:~'C~~r~~. ~ 'Lj~,C/~ ~~ NCO N..d~Md' '~ p _+-~ .o b M ~ ~ b_ ~ (J~ ~c xi b ~-x ~," d:
'G'CNy,n '001rvM,-f~~'OhM Nv'C NO ~M c~N
'G II h x ~ ,--, x h ~ r~' i~ ~ O ~ r~' ~ ~ ~ 01 00 h vi x n ~ ,,' M N . ~ 00 ~ ~ ~ M ~ ~ ~ h O ~ ~ ~ ~ ~ ,~ O ~ N M
n ~~~xx~ ~x ~x~v~ axx ii x ~u ,~~..~~~x ~.r N ~ ~n "y o~ oo ~. ~ ~ ~ ~ ~ .~ ~ ,n '.
h oo N .~: ~n ~h ~~ ~ vh ~i x M ~t~,' ~ ~ ~ b ~ ~ oho b O b x ~ N
h ~ ~ ~ ~ ~ N h ~n V7 V'1 h .-~ h 01 ~ ~ M
N .1 ~ +; W x M x h N r'~ rs x M o0 ~-a d: r~ M r~ h ~, 00 N
r~.i r~ Vi 's v.r.r op ,~ II '~.~ N i-~' r. o0 h I~ ,-~ .-. oo ,.~, t~ ~i v0 r~i a r~
b O
"C
(~
GA
»
y''''"~ O 00 01 O O~
w ' O O U O
U U U U
i i ~ i i U \O \O
~ ' ~ U
O U
U

II
II II

II ~ W

~b ~ ~ ~

~
Wit;

~~Mb~n "

00 ~ ~ v :-.

t~ ~ ~ M ,-~
N vs N ~ r~i ~i M

~ o~ r~' ~ ~'' d. ~.

M 'O

x II

'~ M

~b x ~ ~

'y.r N '>
M \O

O O ~ '' G

~
~ M
N ~' ~

r v N

l~ 01 N

b O
~O

H

bD
O

~D

i~

U

N

U

~
z v '~ ~ II ~ N
N
x v'd ~
~ d' b N N l~
II

~ N ~ ~ M
~

r ~i ~ M

N
v b '~ 'C7 ~ cr1 i W r tn ~-N wr .
p~ N ~O m O ~ M M

~ ~
rv Q~
~

A _ l x x ~,~ x av~

~ H
M M

(~
~
i :

~ ~ ~ i C~ "
, ~No~olW O'~' W
II l~ II
s N ~'' r bxro~

'~
~;
::

O N ~ ~ r"1~ ~n d; Wit' ~ ,''.C

00 t~ ~ '~ N N ot~o M
M

~ W O ~O
II
Gx ~ ~ . ~
~
p~

,- ~ N ''~ + + +
o o O

N ~-i N b D W a a ~ ,-, ~~

d~ N Q1 ~ ~
r~
' ~
"~'' ~i x oo t~
r N
~

b O

d GA
b x x . U

U U U

v v v v , N N
O

~z A
a d' V7 ~!7 M V1 M M d;
V~ M M I~ ~ l~ CJ
iv r~ i-s n s~ iv i~
O ~~/

n ~ M '~
U x ~ M U U
x U U U \O U
O
U U U U U U U U
, +~
Ca ..
...
M ~t d; ~ d: M V'S M M

n ~ ~ n ~ n v a a a yr v a .O
O b d ~ ~ ~ ~ ~ ~ d d nn r, ,H T, .~, H ,H H H ,~
~w x U U U U O
U ~ f.~ x U .
U U
U U U U U U U U U
.~r A
a N N .-~ ,~ ~ ~ M
l~ ~ N
n n i~ i~ ~ sv b O b p r1 r-1 ri e-~ r1 r1 r-I
o / z ~~ v x ~ \
cx ~ o x x x x x x x x U U U U U U U U
r CAS ..C U
13' r~ ~ N ~ ~ ~ O eC eC
U ~ ~ ~

A
..
c~
r~
M
n a a 'b O b nu r~
G~, rn x x p U
I
II
U U U
w b o UZ

.-; II _ ~ .~. ~ 1l N
~''~, ,-~ '> ~: rx l~ ,~ M vi ~ O
II N ~-° .J ~n ~~ II N vi ~'> ~ N
~, V1 - ~ 00 ~O ~ C/~
01 O~ t~ .~ v O 01 (Wr ~ .-~ l~ ~ ri ~
O l~ ~ ~ .--W~ ~ ~ ~ ~ xi '~' CJ~
~ 00 rv O~ ~ N x 0 01 ~ x ,r, ~ 01 t~ ~-' ~
N r~ ''~~ N ~ V~ ~ N 's N i-v N ~ ~ ~~( N .-i a.i ~-, ~.,1 N
O ~ d~ l~
W_ r .~n-~ N Ov r,~ '"~i N N N r~ ~ Ov ~ ~ N
'° oo n '~' M ~ ~ i~'' II
00 II d' C ~ O s~ N ~ N
CV ~ ~ ~ t~ M N ~ s-; ~p ~ ~ x ~j ~ II ~ ~ x "~ II ~. ~ ~ ~ 'b II
ro ,--y'~' '~ N "_' ~' '~ t\ .
_ ~ . ~ co .-.
'C ~ v N ~ b ~~" v ~ II 'b v0 N V'i wr O ~ ~ ~cV ~ O ~ ~ ~ ~ O
00 l~ x ~ W Vl 00 l~' M 'r CJ~ 00 x ~ M
~ ~ '-~ ,~ V7 ~ ~ ~ oleo ~ d' ~ ~~-~
N M x o ~ N ~. '~u' r' M r~i vi vi ~ ~ l~ 0~0.
~~Dr~M ~,~~~N ~,~1~V1 x~~x~x x~~~x x~xx°
H H H
r~
r~r U U
O O O
C

_ n rs l' M ~' _ _ n ~.' ~
N ~ ~ M rs ~ ~ ~ ~ x N M x M
M ~ ~ ~ r~ '-~, ~ ~ ~ V x vi '° 01 N ~ a N ~, ~ v n y.~r lp '_' N ~ t~, O N v ~ ~' lp \O
~ N vj r' 00 ~ ~ ~ p1 M v~ ~ Q1 r~i M ~
O
~,,~ ~D w.r v l~ O ~ 00 \O ~ ~ 00 ~O ~ O~ '-' l~ t~
00 ~D M d. I~ d' v p~ ~ ~ ~ o ~ ~ ~~ ~ ~ ~ N n .-: M N .~:.~: ~ ,.~ x ~ os .=, x ,~ x ~ ~ ~ ~i ~i ~ ,~i ~ N ~ ~i N ~, ~ x N '~~" I~ N
C~ .-~ ~ + ~ x r~i N vi ~ ~ '~ x ~ ~ ~ ~ vi ~ M M
'N '-'~ ~ C/~ r" ~ 'J ~ m ~ t~ M '_"' C~ vi ~ W '"' wr ~ ~O Z.., 'r ~ ~ ~ ~ l~ i-~ ~
A "'JO '.r a N d' l0 N ~ ~ O N M v0 O ~ ~ ssr~' N, N
00 OM1 ~ ~ N r.~ WO ~, 00 ~ l~ ~' ~ l' p [v r~ O ,-i Iy.~-i ~ M
I~ h ~ oo ~ t\ 01 N t~.. v ~ m 00 ~ xi ~, N
~ ~ i-s .N-n ~ ~ ~t ~D ~ ~ x ~ C/~ ~ xj x N N ~ x ~.,"~ ~ x C/~
h'CS tA x M x ~.O ~~ ,..r '-' ~~ tA ,_, ~ N a ~ ~ ~ ~ ~O '-' ~ ~ a N
b .-. M d' C/~ ' ' N i; C/~
vi ~ vi ~~a b ~ ~ b .'~o ~ ~ ,-. o ~, ~ N '~" ~ yo ~'~ x .ty'r..,iu bvv~~ b'sM~ 'C'~OMQ1 'Gr.,~~O~
N 01 l~ ~ O~ O .-n d' ~ ~ ~D ~ ~ ~ i~ ~O ~ M W-~r O N ~ N O M ~ ..-i ' oo t~ cV ~ o0 t~ ~ ,-, ~ oo ~ ~, ~ ~ ~ r~ ,~ m d. ,--.
rv rW ~ ~ rs r~ x x ~ x ~ x x ~ r~ x vi ~ ~ t~ vi ~r ~ ~v ~ d"
N d' N N ~-~ N ..-~ N N w..r v N N 'r ~ ~ M v ~ w,r sra.~r'r vv ~ N ~ ~ ~ O~0 ~ ~ ~ M ~ ~ ~ (y0 ~ Vl vo 00 ,-w0 ~ oo "'~ d' t~ ~ p d' ~ ~o '~ t~
x oo ~ ~r x o0 0~ rt ov x oo t~ .-:
~~x~
tn b a~ ~ w~ a U '~ U x U U
\O
U x \ 'U
l/yi O O O O O

O~ N _ _ N ~ xt~o00 00~'' II x N~ x i N '~ ~..-". N .-m;
N ~ ' N .~ ~ M O '-y .d N ,r~i '~-'-' -~'"r b x Vx~'~ xMvb v.-r ~ u~~M
M ~ ~ C/~ ~ r' x x x N l~ d- I~ O ~ t .-~ ~ ~ O vi ' " vi ~ '~ O, ~ ~ O 00 ~D
x 'r ~ N a '-' d' M M ,~, O~ .-n C/~ O~ M ~ ~', ~ ,-~ ~ ~ Op ~ ~ M ~ ,[~ r~ t~
-: ~.: x ~:
xx ~~ x«~~.~V ~~~x x~~, ~ xxN II
N ,-: ~ .d ~-; ,-' ,-: ,-, W r' .-, ~x~ o xx ~ ~ ~x ~ ~~ ~~~b RS ~. 'r l~ .--i s~ .--~ ~ ,~~, ~ N N ~p ~ ~ '~ d. ~ C/~ ~ p wr ~,'~ ~ N x ,...., x t!a ~',~ ~D y.r N ~D ~ y.r ~ ~-' M
x .W t' x' N ,~ W . v0 N .--~ x I~ ~ t~ t~
c~ oo l~ h N M O~ Cl1 0 x ~ '~' 01 ~ n N M pp x ,.x~ ~ M rs ~ n x ~ O r' N ~ a '~ 01 ~ x y~ .--, r, x ea Lo N ~,r ~ to II °~ O M zo ~''~ .. ~ II N ,.~ ~ ~ ~ x .~x~~W
a ' ~O ,~ ' N x ~ ~+ ' .~-i l~ v ' O~ ~ ~ ' Do NO~x~ Oo~o~.,~N~ O ~~M~ OoNO~~II ~ ~~l,~pN
~ x ~ ~ p ~ ty0 x ~ q oo d. ''~' ''~'' ~ x ~ b r, ~ x N x pi N ~ N ~ O ~ ,~ ~ M ~., N ~ N ~ N ,~ +
M ~ a II x II x ~ x ~ N N ~ ~ ~ O~ 00 ~ ~ C7 W
0~0 ~ x ~ ~ ~ M ~ N ~ ~ V7 O ~ O~O rv ~ ~ O~
x~x,~~ x~b ~v~ x ~~~t~ xoo~xx xoor-~~
b .a ~ '~ vwn v~ ~ v~
H H H 1~n H
b ..
U U
øC, ~ U
o ~ o o ~ o \ \~ \ \
ro o .. ~ x op ~ Ov b x ~ ~i N ~ N M V~'' d' ~'O ~ ~ ~N d- ~N ~ N
x~M°~ x ~' x N t\ ~ ,--~ ~ N .~~, ~ N v~" ~O N N O_v 0 N ~ ~-' vp ~C/~ ~pMpx "oNod' ~~M
t j ~~.,-~ p~ n ~ ' p\ r~-,..WI ~ 0N0 ~.i 00 ,--~ V7 x w ~ ~ lp rW ~.-~ 00 I~ ,-r y o0 M ~ C/~
C~ ~ ~ ~ 01 M rx '"~ ~O N rx ,--~ n n I~ r~. M
N _~ ~ ~ x N ~ ~ V~'7 N V ~ N x ~ ~ N ~ ~ i~
n ~D .~-WO _ _ x '~ N ~ ~ r~i + . ~ 0~1 ~ v v 'O rryr ~ x ~0 c~ 00 "" ~ 01 ~ ~ L/7 N ~ O M d' ~ II ~ ~ W N ,"~~,~ ~ ~ o a ~,o o a ~ V ~,o x o ~ ~,o x ~ rA ~ M
00 r: '~ v'~ i-s ~ ., s~ ~ ~ N i-s x ~ N i~. vi ~ O
'Z7 ~ ,.~ rv 00 ,rj '-' ~ N "O ~ N b "~ ~ M b ~O ~
01 M ~ O l~
cra mn N ~ ~ ~ r. N ~ ~ r- ~n r~ ~ ~ x ~ v~ ~ ~ ~r ~x ~oM ~x~ '~ ~x~~ ~o~~ox ~v~ ~x ~ ~
t~ l~ N N d' l~ N d' ~ Ayr ~ N wr 1n I~~~pN v 'v~' ~ 'v'~"''~ ~x '~~"~~ ~~ri ~O ~-' ~ s~
x b x ~.n' ~~ ~ x 00 ~ ~ x ~ ~ ~M ~ ~", ~ ~r.,-~ it,-~W x ~ ~~-,-~ t~
.~ N .~ '> N 00 l~ ~'.i 00 t~ w a t~ W ''rl~, 00 w d' O b c1~ v~ v~ C/~ v~
.~1 d t~ r~ ~ ~ ~ r~
bD
p ~ , O b O t3, a" a..
V U
U U U U
O O O O O

~z '-' ~ x ~ O ~ ~ r~~~" II N N "~ ~; r~ ,y0 ,.x~ ~ vi N ~ l~ d~ ,~ N ~ ~ ~, ~t ~ ~ N N ~ x '~ '>
V
~ ~ n ~ 'vC wr ~ ~ ~ lD t~
N ~ ~~ ~
N ~O p~ ~ r~i ~-i ''~ '~ N ~ M .d- ~ ~ ~ ~ v~ vi O p"
'r ~' ~ p O ~ N '"_' N O ~ M ~ ,~, ,.~, d- ..r wr dW
01 l~ ~ ~+ ~ x d. ~-~ 01 ~ N M
~ ,~ v M .~ ~ ~; '~ W d' ~ + ~ x oo t~ ,.., ~' _ ~ N .--WO '.O ~ N x "~ ~ '-'' ~ ~ Vl o ~
A _N ~ N ~r ~ ~ ~ ~ i-; ~-' .-~ l~ M ~ ~ rs ~ ~ ~,j ~D N
vi N + ~ ~ ~p ,n 00 rs ~ ~ ~ ~D r~
o ~ N NNW ~oo~ II yo~xx ~a Qv ~ x ~ .-M~ V1 ~ r~ ~ ~ N ~ ~ ~ M N ~ ~ ~ x ~O ~
~ co r N ~ ao II ~ ~ M ~ ~ ~ x V ~ ~ ~ ~ N ~o II _~ N II ~
M
~ ~ M ~~o ~ ~ d' ~' ~ 00 ~ 41 .Zy .-a (\7 r-~ .b ."' ~ ~ ~ ~ "d v v dw--~ 'C ~O TJ ~ M O
O "' O~xbxN Ov~,oo~~ O~~I~I O°r ~'"NV~
CJ~ ~ l~ d~ ~ ~ ~" v ~ N V1 ~ ~ r~ rat C/~ ~ x ~ C/~ y.r l~ M
M N ~ ,~, N O x ~ '-'~ N ~ ~ ~ ~ ~ C/~
b rv 0o x oo~N~ N~t~ ~ ~Nr~t ~~., .~~, vV~N ~N~NNi~
~~?? ~ ,-, ~ ~ ~D N ~ M V1 d' ~ r.~
r~ _~ N W ~ 'n II x' ~ ~ y_n N ~ N 01 ~ ~t ~ vi ~r.~ ~ N
M ~ O '~ N II ,..: r '~' v0 M t~ l~ ~ ~ N ~ ,.~C, N
x ~'°'~~ x°'v ~.~ a' x~°~~~ x~~x x°~ ~~'!o, MN
'. l~ O~ v w..r .r wr 00 .~ .-~ 00 v l~ ~O W
o ~~ rm v? v~ ~n va N N N N N
r~ » ri r~
GA
W
z U U O O
v ~ z O
O O O O O
~I

z WO 02/34711 PCT/USO1/32s82 'O ~ N v ~ ~ ~ pOp M C/J N ~-~ ~ v ~ x ~
a II ~ ~ ~ ~ i'~ x f~ ~ ~ vi a o0 ~O ~ N
M ~ x ~~-.i ~, ~~Pf p ~ x N ~ x ~ ~ p 01 N rs v ~ \O
b N .--~ M ~ ~ i.~H .-, v..~r xj '".'' x ~ d1 ~D d' t~ pOp ~D
O ~.' N d; ~ ~ W~ ~ l~ ~ ~ M ~ l~ ~ ~ O n O'-x~W ,~, ..r ~ ~.~nj ~xx ~ a,''x 00 ~ N .~ -~.,' O o0 'r ~ x, ,!'r, x N '-~ ~"' ,,~''~~'' c/
.N vi x ~ p .--~ .~-~' ~ ~ M
.
~ ,~~, ,x~' oho t'~ ~ N ,,..~ ~ II ~ v p ~~., N
_ _vi v h, "~ ~ N N vo '~-~ N O .-~ 'r .,.~ .-~ oo ~ II ~rj ~r [w N ~O N ,.~ N ,.~ ~ ~, ~ l~ rv V~ x ~O x ~ ~ ~ U~ ''r ~ ~ '-a ~ x b x ~ ~=. ~i t,p ~ ~ ~ ~ ~O ~ ~ a0 ~ .-, ~ r, ~ O r, rA r~i N
ri II ~ ~ r~ O d' i~ pp l~ s-v n ~ OO ~
~c ~ N II ~0 00 ~o x .o ~ v ~; ~ ~c ~ ~ N
N O ~ '.D ~ O
Vj ~ ~ ~ ._,i M ~ ,~, ,--~ ~ .~ d' N V1 ~ t~ x M (/~ ~ l~ ~n n n -.r ~', N ~ ~ ~ O N A ~ ,.~., ~ ~ N
N ~~r-;~ ~~~ p ~~ ~ ~ ~ N M '''.- dM' N d' v a, ~ "' ~ ~ ~ II d' vi '-' ,-y, ~, y" ~ ~ II ~ ~ yr ~...r ~ ,~, ~ v v O ~' ~ N ~i '~ x W x ~ x ~ ~ ~ ~ ~ ~ ~ ~ n 01 's .", ,-~ ~ Vyr ~ M ~ ~~.r x 00 C~ r~ ~ ~ x 00 t~ x b r~ r~ H ~ H
bA
b ~ ~ .r~
ea b v x ~I ~l ~l ~1 ~I
~z 17s ~r ~ r-~ m m tn ~ N ~' N r~ ~ ~ ~ ~ x x '-' r' v, II ''' ,,~ ~ N N ~ ~ ~ '~ N
~, ~ ~ ~ ~ ~i N x ~ rW
N ,~ N ,'I,' '~,' ~p M ~p °° +
.-, vD ~ ~ ~ ~ ~ N N ~ ~ "'' (y0 ~ C/~
II ~ W
i~ 01 N ~".,~ x .-a ~ N n ~ C/~
00 'ct x ,-~ CJ~ 00 x v r~ N ~ n x r~i -i ~ Uj b v W ~ I~ N N .-~ x r~ ~ N
~ (~ '~ " ~ ~ 00 N t~ N '-' N i~
N Q~ O~ ~ ~ x II l~ N ~ vi ~' r~i ~ .~.~" ~ ~O cV ~ . N ~ ~ ~.. ~ ~ ~ M ~ d' Q1 ~~i~
~.,..~ ~ b ~ ~ M .~ ~ ~ N-t ~i W r ~ ~ r~ ~r-n 00 (~ yr N'~M M x N N N ~ O ~ ~ N N t~ ~~ ~O
01 ~ ~ ' '~ ~", ~ ~,' Wr ~ ,-m=. WO N
a0 ~ '"' \O t.0 ~ wr 'r cp _~ 0o tn ~ op r~ N ~ O
.. rs ~ ~ 00 00 01 00 _' x ~ O O i-W _~' x ~O
r .tj ,~ ~ + b ~ cri ,--i .d N .-~ rs M 'G ~ 01 d' o W ~ ~ ~ 'r''m~i ~' ~ N
a ~O v C/~ x x x x Va a N '"" r~i ~ ~ l~ -~~, 'r~
~ox~ ~,-~N,~~t' ~ oxxNO ~1'-~x~M
.
t~ ~,x ~WO~~t ~~ N ~'d~',001 " N . . II II ,~
'"~ ,~ '-" 00 l'~ 1p .-n ,~ ,~ ,~ M + N ~.,~ M O
x " ~ ~ ~,x' x '~' '~' '~.' xi .~.~ b -r~ ~ W ,"'.C, °°, d; .-:.-;
wr v v o0 h ~i r~
O "~ C/7 C!~ C/~ C!~
r~ ~ r~
bD
+~ ~ CMG ~ ~ CMG
'~'', O 'x U
II
II
O O O O
O CvC
V Z ~ ~ ~

~~x x ~x o~o x .~' ~' °° ~-' N ~ r, v~ ~ x ~ ~ ~° II
~: °° ~p b_ h .-, ~~,' d' N l1 tV
O ~ ''~' x ~ h '"'' ~j O , ~- ~ x ~
~ x wr ~' M a eet vi ,~,~
'ice n ~ ~ m M Od'1 d' A ~ x p~ 00o r'' ~,.~ d. d. ,..~ ~ ~ N
.. h O ~ vi ~ ,~ h x N .~ ~' h ~, ~ h x N
~a 00 x N ~ ~O h x N
x ~ Nxw 'u~" d' ~p 's ~ C/~ tip x ~ p ~~Wr 00 ~ h ~ ~ , , ~-' C/~
.o"viWr bOll~ .~ou~ll~"
yr ('h .V pp ,~ ~ "C7 h ~ d' i-; d,--~ ~ r~ ~ O
~~xM ~x~~
M ~ ~ N ~t ~M
.~, x ~ ~ ~~.j ~ ~ x 0 Vj ~.r x_00 ~t°°', ~ ~~x,'_; ~ ~ II xo h ~ ~. 00 M
x~x.~~ xx ~N x~~x0 H
a .~ w M M
x x U U
/ \O U U
x x U U
ea .a Uyo .., N

O
~

M
~
~, N ~ ~ ~~

.-; ~ h,~' V' xx ~

~, ~

.~~x~~

xx ~~~

'"' 01 N N
~

...yi NOr r ~. rte, ~ Ov N

~ II o II
~' ' a II
a n ~
N II b ~ ~

Wr ,L~
a rA VSO
~
O

~ ~D M

N
~i r ,~

N
i~
~

~N ,~, N

~
~ ~

h II

x ~ ~ a 'b V~

O
b ~ d~

r CA

O C' W

U

N

U

~C U

U
~

A
b d d' d; M M M d' 01 d' N oMO o0 Ov N N
i-v iv i~ !'~
'L'~
O '~
i bA
m n x U U x N
M U
U , U U U
U U U U U U
zi o c~ .c~ v b V, o .:~ Q, e~ a~
b 'd k a~
a~
+~
N N m m c<1 d; d: ~ 'P?
~i ~ rte" O~~ ~ l M 'd ~O ~O 'n V't ~ ~ N ~O
v W wW.r a W a U
b d an b p t~ k~ I~ I~ I~ h t~ l~ I~
~D ~D ~G ~D ~o ~D ~o ~G ~D
w O U
V \ ~ U U
U
' > r U U U U U U U U U
' . . . . ' ' pa ~ 00 0'~0 ~ ~ o'~o ~ ~ oho o°o VZ

c A
U
.,., i O
W ~P7 V'1 d' 'cY M d' d' M ~ Ch ~r-i ~ M l~ l~ M
r--n dW--~ ~ d' 00 01 00 n ~ ~ ~ ~ + n ~ ~ ~ ~ v ~ v b O
bA
b p t~ I~ l~ t~ k~ l~ I~ L~ I~
W
U
U ~ ~ U U
U
U U U U U U U U U
2t a c4 a' ~. ~ .~.~ p > ~ ~S
VZ

t~ a.
a; ~ °.~,' ~+
w rr~
y W ~ Z
A ~ ~ ~ ~
v ., oo ,~
+~ N ,--, N '"' M M G' M ~ ~ M
~.~ cd C~C ~ ~ ~ ~~N~ ~p~p~ ~ ~M
M M d' ~ tn ~ M N d' + LV ~ M
n ~ i~ ~ ~ ~ ~ ~ Cue, n ~D
C/~ C/~ C/~ C/~ C/~ C/~ V C/~ ~ V C/~ O
W W wW.. W M wW.. ~ W M ~.~~. W in U ~ n U
G N x 0.1 ~ G x x ~1 G
ap ,a ea .Q .a .c .c + r r ~
O
x x ~ x U U ~ U ~ U ~
U U ~ U U U U U U U
, , , , , , , --, ~ ~. r.
v M ij ..., C1 ~, n n ,'.ye a .L1 n a M ~, r~ M
o '; ~ ~ U U x U O i o ~i~ U O O O O ~ o U w O O U U O O
. ~°',, O , o ~r UZ ~r~r '.~r° r~ r ~r~

,~N ~ _ '' N
"
' ?
, II ~
~n N ,~
~, ~ ~

.-~ .'' ~ N c~j II ~ ~ +
i "., ~ M M oo ~ .N n M l~
II ~"~
r-~ i.~ 'C ~ ~ ~ cd cat N cd ~ O x ~
yi I~
f'_' 'C ~
~i ~
0o .-y z z z N
+ + ~- Q~
r ~ ~b~- ~N~~
~

A ~x ~ ,~cy,b~~d. ~N.r~ a U __ _ ~ ,.-~ 01 ~
~O ~' ~i M ~ O

O~
~D ~~N '-' ~r N t~
~N~' N~xM ~~x, o ,~ O

~ M
U
~

+, 11 +1 ""~ ~ ~ N +, x'Nx~pNo~~

a x ~ N
~ ~ ~

~

~b ~' ~ ~ ' ~ U U ~' t ~
~
~ x' ' ~

,-.. ~
oo c c r- ~
~

~C ~C ~C W W W W

.a ,a .c .c ca.Q .Q
r ~ r r ~ r ~ r U

O O O O

>x x x x x O O O O

U U U U U U U U

v .., .-. ~ m r-, ~a ~ ~. M y .r b '~' n v v w ~
v U U U O

.,., ~ O U U
a p p U O
/

~ f~" ~ p O

~ ~

p, r ~ r ~ o'~oo'~oonoobo ~

UZ ~ ~ ~ ~
a a, v~ h ~ M h ~i o0 0~
+~ ~ _ N N b_ r~.~ c~d ~ d' r~ x l\ 00 N N \O .-, ~ .
eCt ~ ~ p~ ,~ N ~ h x xi ~-' ~ W N
A N x x 'C N ,~-r .
rp x C ; V7 ~ ~ 'yr ~ ~ d' M .-n M d' d' S.~.' ,.=~ N ,.r.~ '~~"f '-' ~ ~ ~ M ,-r ~
h ~ ,_, M ~ i M N ~t oo d' N .~ U
N o0 00 h O N ~ r--, ~ ~ ~ Zj ~' rs '~', ~
n M d' d' ~n .~ v,.d N, h ,~, M ~~ r~i ~ x, W
N
n ~ rv r~
V7 C/~ V7 L/~ iI~ ~ ~ N ~ '"' h ~ M ~ ~p v v a ~ v ~ 00 ~'.' N ,,'~ ~ ~ wr ~ N cd z U '~', b ~ 11 x vi ri N ~
b N
W W W W W W W
nn "d ~ 4-i t~A ,.t~ ~, M
w h r h r ~ h h Ov W P~ U Pa Pa W P.~ U
~ x ~ x x p i~ O O O O O O O U
i~ j, M a ~ ~M'' 'M'~
,r, y.
n x m tx p ~ ~ ~ V U x U O
'n ~ ~ ~ ~ U U U
p a, ~ ~ o % ~ % %
~,~ ~ ~ ~ ~ ~ ~ ~ o Uz ~ h ~ h h ~ h ~

vi oo ~ N
W r ~ "d '~ ~O
.-. d' ~ ~ l l " d' 00 M ~i ~ ~--, ~ ~ M
N ~ ~ ~ ~ O '.~" cad + ~ cad N
NxxxN~W z ~ z z z W
tA ~ M
. N ~ N ~
~y,~~,, ~ r~ ~I xi r~ ~ ~ N V M M .-. ~ N, ~-i (~ N ~"~. d' M tn n N N ~t N N O N ~ O
p A r' ~b I~ ~ oo ~ ~n d- ~D m d- M ~ ~'. d' V ~'~' O ~' \O ~ N +~.~ + n ~ n .+ -I- -I. ~ ,~
b M r~ x ~ ~ L/~ Cl1 Cl~ Vl I/~ ~l1 Ci~
~ ,~.~ 'J ~ N 00 z ~,W.s v yr v ~ ~,W.s ~ W ~.~r pMp "~ ~ x N ~p + Cf~ C/~ C/~ C/~ C!~ C/~ CI~ C/~ C/1 t~ oo vo N '~ 1i ,~
0 2s w w c7 N '~' '~ N w N w p M M
O ~ N M ~I' ~ H p -I- p C71 C~ o~ 01 M M M M M M M M M M
U U U U U . U U U U U
f~ O ~ ~ O x O x O
N N N N
U O O O O U U U U U
U U U U
.,.
_ _ n M V a / /
°a Pa ~ N w. w. U U ~ Pa O O Q ~ O O O O
O
C .-~ N M '~t ~ ~ p O O O
O~ O~ 01 O~ ~ Q1 r-W -I

'r II v O x ,~ 00 ,w,s ~ NO M N x ~, x ~ 11 N 'l° 00 ~
l~ .--W~ "'' ~ _.,~ -, ' ' C'.j o0 h ~i r-, o M
01 ~ N'~~O ~C+!~ t,0 x h x x ~ l~ ~~C%~
A ~ ~ x x x M r~i W M ~h ,-v N N ~i W
o, "-' M ,.,., ~ o "Cj l~ ,~ 11 ~ ,-, a v b o0 l~ ~~ ~ "d v0 v l~ N ~ ''' N V~
_~, ~-~ x II ~ x ~ ~ p II o~°o II x ~ b ~ ~ ~ ~n n ~ v~ 'b ~ ,~ ~ ~ b ,-:, b Do ~-~ o, M vo ~ ", v, U ~ p ~ II N ~ N "'~i ~, II N ~ a "' ~ ,.~ n M ~' l~ s~ N ~!1 '-' l~ ~ x n n N + +
M .N l~ b M x r~ ~ O~ vi l~ -rr O~ x M r~ ,x ~ C/~
00 N ~..~ N ,-~ N pp ~ N ~ ~ [y ,--' M N d~ W
~ O i.~, N r~ N ~ ~' x ~ r~ d; II N ~; N ~ C/~ C/~
'~ oo N ~ ~ rte' II ~ ,-i oo ,-~ ~ ~ ~ x ~' n b .sJ ~ N t~ I
~1 r~
+ +
a o + can N ~p N \p M
U U U U
U U
O O
U U
o 0 . U
~ ~t ~-.
x x x x.

x~
M M
M
~ z ,~ ,~ °~

vi ~NNo~O
N I~ ~, r, ~O n ~D x ~
,;, ~ II N "' ~y0 b N
N ~ N
A t0 V~ b r~ x ~i IV M
b ~D 0~0 00 ~ ~N~, .b d' ',H, M M O II
o ~: cn ,~ h II ~ II o~ n dh" n v W-' O ~ ~O C!~
GM "~ b h r~ N ~ ~ ,~ a 00 ~ ~D ~i O r~i wr ~ ~ h V1 M ~-~
C/~ C/a x M ~ ~-i ~~x ~x ~x~
N N ~y C/~ V~
CA
QM1 OM1 O~1 M M
N N N
O
U
d t~ p., ,..
.~ b '~' x O
~ C ~ Wn .~~-, ,-~H .~-~

~~~~~~vv"~~ b b w ~ '~ ~ x yo, x ~ Wit' ~o .b ~ ~ ~ ~ ~ r, ,~ N o Uos~,r~,""~"'~ ~~~~W
e~'~~x~~°~'Nx~~
V b x x ~ pp ~ N ~ N ~O .--i _ _ N~hV~r~~~~x0 M
N x ,--y ~ ~D ,v ~O LO d' V~
N N
~ x C~l~ Cl~
~ b ,-r b ~n W
M
~ ~x~ ~~~~xN~ ~
wr l~ 00 ~ a ~D r~ N ~ ~ h O b H i bA Cet GIs ,-H
U
U
zx U
~7 b P~ n O v R, O ~ O
vz lss b N a N o0 00 F--~ ~ ~ xr _ r~
tA o0 N 0o r~ ~
t~ i-v "u I~ ~.~ N o0 N ,~ ~D N x I~ " ~o ~' .., .~ v~ ~,~Nb x c~ v ~ ~-' .-mo ... II ~
:~ O ~ ~ N .ri ~ ~-~ .-, ~ ~o r.., <t.
~ro II ~ ~ m N ~ ~ r ~-~, 0~~, ~i ~ "'"~ ~t v0 ~lx~_~ II ~-'M'-'xo~_dos 'r Wr V1 ..-~ M r, N n N 0~ ~-r L~ ~ + 1 + n N N b tai x ~ V~~ i-. W W W
~ N tn ~ pp M x O 'I- ~ W r '-' Ov ~ 00 ~ N '~ N N ~ W V~ C/~ C/a yr ~D x ~O I
.b O
~ ~ N
r~
GA
b 0 o O. ~ o N N N
M
x U
U
zx zx zx x~
U ~x U~ O~ O
,.t1 o W ~-.
',~,'' o ~ ~ O O
R~~' V ~ N c°~1 c°a H.

.. N
yr ~ II x rW ~ ~ . Wp x b x ~ x x N x "~ h ,~ ;.>~ .-. '~' ~ ~ N II ,~ '~ os II .-,W. M cO '~ ~~ '-' N ~ C~ ~' N
CC ~ N ~ ~ II N ~ vi ~ ~ ~ W -'fit l~ ~, ~ rte, ~ ~ M ~
II O
y.' M t-, x ~, 'r ~ N o0 ~ ..-i pp ~' (y M ~' ~ .b N x'' ~ t-~ ~,x ~ ~Y ~ ~, 'b N N ,.~ N ~ ~ N
~. ,~oOro '°'.r''~ NCO .000 II 01~ II v~M'~rx C~ 'O l0 ~ ~' ,--~ N M lp 'O ~ d, ,~ ~' d' ,~ M N 00 '.N M o II O ~ ~ II r~ ~ x II M p ~ v ~ r' r~ '~C °° x ,..; N
~: r~ ~ oo ~ ~n ~ ~ p W ~ ~ ~r.~ d~ o ~-' x ,~', II
CCf v~ ~ .~ ~ -~.,. ~ d; !~ ~ ~ ~~ 00 ,.~.1 O ~ r~' vi ~ ~p "' O
d' ws W .s v d' '~ lW r ~ r~r ~r '~ d:
~ '~' ~n ~ oo II ~ II ~ . . A ~ °~ II W p ~ ~ O ~ II '~ ~n yp '"~ l~ N 00 r-' ~ ~ 00 ~ ~ M ~ ~ N M n 1p ~' r, ~1 pp ~ !~ ,~.a ~D 'b ~ ~ O W OV x '~ r~ t~ ~ ~ ~n d- ~ l'~
r~ N r~ O~ ~ O II ~-., x ~ ~ tic t~N 00 ~ r~ t~N..1 ~ ~i ~I ~ n W
r-1 Oa ,~ l~ .--~ lp h M ~ ~ T'~ r4 t~ r~> ~-~ W ~D .-~ h N ~ a "O
O
bA
O M p O
N
M M M
U U U
x zx \ / .
zx zx zx o~
a.. ~.
'.
a~ w b U U
o ~
ar U U
~d a a o UZ N N N

v~ ~ ~ II
'r N '~ I I ~ ' _' ~ N "VO~
N~~~,.~x~'~ ~ ~~~~' Nx~,~x II
~,.~,~ ~x~x ~ ,,'rte, rx~0">
-~ 00 ,-, oo ~ N O ~ ~ ~ ~ ~ ~ O
cp ~ ~ N ~ ~ l\ ~O ~ ~ ~ ,.~ "~d ~ ~ N ~ II ~ n x N~N~ ~ ~~, N ~~x A ~x~~~b~~xxx~~b~o,~~~~~M,~
._ ~_ _ ~ N ~ W O M ~ /~ U II ~ '_' d: x ~ ~
II x II '~ ~ ~ x '~ II N M 'p x p .-, O~ b r~ ~ pp ~"'' ~p ~' ~ ~ b ~ O ,.d '~ x x~, vi ~ ~D
l~ 'r r", q ni II o x b vi b II b .-~ ~ x ~. ~ ~ "~d ~ ~ ,.-~ N N
xv,b~ Voxcy"~'~~ ood;x~d; II x''''x'D
.-WO ~ ",1 ~ ~ ,-mn M p -I- ~ ~; h "' ~ ~ ~ ~ r~ N ~O
vi ~ 00 x d' .-~ 01 ~ ~ ~O x n N i-; ~ p x N II
'~~I,~t,.~~xcVxW-''~Yi.-~,~,''xxxi~r-.N~''>
O ~
H a~
a ~w o z zx U
zx zx .3 ~ ~, .-.
a w ,-, ,'r0"'r .0 b U U
Ix Q~ U U
b o ~ N
U ~-, N N

<t' M N ~,~
M .-, ~ o II II N .-: 'w~" ~ vp II et N ~p d' II ~ :=. o0 ~ ~, "C~ I I t j .-: 'd ~ x x ~ ~~ '-' hj ~ 00 ~~:,b~,xx~b~~~~°~x v_~x".
xob~N~p~ ~ ~~~N~ ~,"Z',M~-~x~~~'700 N oo ~ I! x ~n '° ~ ~ ~rS x N II °° ~ ~ ;~~., N ~n -V x .r x i-' l~ 'r N x M ~ "~: x ,~ N ~O
~
.~ o~~~~~xxM I~ N ~~~°oMx~~x~ ~~~N
xa II ~'~ ~~~, II o'~ ~ ~ II ,~M~~,_'. ~
C~ ~, ~ N ~ ~~ '~ N N ~ ,~ ~ ~ ,~ 01 ~, ~ ~, ,~.,~~ N ~ ~ N r.~~.i 01 ~, W,'~'.r 01 N ~ ~ pv x x 00 x M a ~ W ~ x x "~d l~ ~ ,.-~ M N O
x ~ N l'~ ~ N l~ ~ ~r~ ~ ~~.~ '~ 00 ~D OD ~j ~ N ~ Cl~
M II ~ x rv~~ M ~ ~ ~ x II ~ ~ II x '>
~.,.~01 NrI,~~V7xll7 Nr;~ ~ x~,b~,bu. ,.~~~ N~ N
x"~xx.~~~~~xx,~x~ ~..~x.~,~,~x a x~
ro o ro nn o .N-, ,.~°', N N
x x U
o zx zx zx zx ~ a, ~ ~
a ~s, ~ x °b U U
'~ .,,.~
II II
U U

UZ

O N vp i ~i ~rin~ b x O
00 N ~ ~ ~'~" ~i ~i N p ~ N W -.
f~1 ~ cP?
~"' N N N '~ ~ ~ ~ rs ~~ ,--i A x N~ ~'x~rxt~ONIOMNN~r~
V 'b ~' ~ ~ C~ t~ t' ~ O ~., N O *C!l _ O~'~ ~l~ ii a ii ~.-,~d:ox~w M O
O ~D r-.' ~--. ~--~ 'L~ V1 N ~.O ~ C/~ ~ d' V~ b b b "d s~ 'd' ~ t~ . ~ . .
00 l~ '-i wr v uj i O ~ dN", N O t~ ~' x ~ h ~ 'y.-,.t~ ~ C~l~
N ~.r a ~ x o0 0 0 0 ~ '"~' ~ 0 00 '~
~t,~ .~'., '~; M O~ st,1~ ~ xi ,-1 00 N
wr r.4 v 1'~ 1~ I~ ~O r4~ ~ ,-~ M .-, r~t O ~ N
N
H
b ~ -I- cd ~D
M ~ ~ N
w N '~ V7 C/~ N
U
U
x x z ~ z \ / \ / \ /
zx zx zx '"
f~ /S( N
°~ ~ ~ x x x ~. U
d V ~ N N N

A
r"' s~, s~., d; Q, t~.
a~ a~
cV ~ ~ ° '"'v, p N
t'~,' ~ G7 p a~ a~ W a> a~
a Y
p ~
W cVd N W cVd '-' s~ c~
U U ~ U U
b o .o h wo o'~o o'~o o"o oho ono owo ~ r~ r r r r U U U U U
U x ~ ~ ~ x U U U U U
~ ~
.-.
~ ~; V . a (.r1 ~ ~ N
V
N m N
U U O ~ W n II O U ~ ~ \
U p U
O O o\

~j II ~' r"
~h ~ '~ b ~ ~ N
r~

_ +' ~ O N ~ x x ~ II l~ 'b x N
x x b ~ y0 Vj ~ ~ ~
~ N O

~n ~ ~ xN

~o~

~M~nd'o lxx M~m.-' M NM x'-'", 'W ~ II x i M vi M " , N W D ~ N N

O~ r-r~~ l~ O~ 'r ri O N a ~ w OMO ~ ~ M
~
~ N p . ~ N ,~x x r. ~
-~ ~ x ,-~ V7 l~
N

EC , ~ 01 x tn Vy ~ N ~ ~ ~ 00 ~ ~ x ~
~

n x x ,~, N 00 x II y0 N \p VI ~ x A ~ ~ '-' ~ d' ~ ~ ~ N '-' N w ~ ~

r x ~ N x _ 01 N x ~ N W -, ' N ~ u'1 b +u x C17 V

~ ~ x N ~ 00 "d I) v0 ~

y-. ~': )I ~' a ~ ~' ~ ~ ~
II N i-:

i ~-"VU ~x ~-r~ ~~ QnOMx V

I ~x~~.~

t 0 l~ O ~ d ~O x w ~O '~ ~ x ' nj j _ ~~b~.~ ~~x~x ~ M
~~b~~
x M a r., b i--. ~P7 'Tj p tp~j ~, N
x x O o0 0o x cr? d: err; d;O N ~ p O oo N ' x t /

C/7 '" M II l~ M ~ .-iC/~ O ~O n N ~ "-' ~ ~ ~ ~Dx C
~ ~ ~ ~
~ ~ x '-' x N

~ ,.~
x x ., b ~ ~

b ~ s~ i-s ~ N '""' v v ~ v N
M M ~, + + + ~ x x L~ N
N C/~ C/~C/~ C/~

r, b O
~ N ~ ~ ~ ~ ~ ~?
2,x ~

~ N x ~ M ~O ~ O
~ ~
~

0 0 ~ v~ r~ v~x ~. ,-, a ,-: ~ ,-;
0, II ~ ~ o ~ x x .. 01 ~ ~, 00 ~ .. ~p l~ ~O
M --~ II ~ h O
~b h h h h h ~ r1 bD

O 00 ~ ~ ~ ~ ~ l~

x ~ ~ ~ ~ ~x x f~ ~4 Pa 0.~ Pa U

M

U ~
x n -. x ~
V O M
U

'~ "' ,-~ .
U U .r U U

x O O O U

o ~ ~ ~ ~

~ o o ~z o o h x ~
~

o M_ ~'-'v ~ ~"x h00 ~

( 'O
N 'r N M ~x ~ N M ~ o M d i'' ~
~ r II i y . 00 t M ~
x ~ ~~ m d' ~ N
~O ~i ~ oo t~ ~.. ,-yO N
OW ~

_ 00 ' ~ _ vp M o0 +-" r~ N -~ d. ~ ~
rs ~ r~-, C~ ~ ~ t~ DO
~p 01 ry _ _ ~ o lp M d1 x ~ ~
~ N N v ~ r '~ ~ N
~

x ~ ~. ~ ~ t~ ~ p ~ ., v~ ~ U ,~
~ yo : ~ ~ ~ II
~

ce :-; ~ t~ .-: ,~ .-. .r .,.,~ ~ II ~. ~ ''' ~ x 'd ~ N -I- ' ,~ A _ II N d" ~, N
.~. ,~ ,.fl .-:
~ : ~ O xi d M N .~ x h '~ h ~ o~ oo M _ -, x ~ ~

ai~ ~~~-.O~ ~tV 'dri C~rl~~~i x O ~D
~ x ~., ~
N ~

x N ~ M ~ ~O v r, ~ M ~
~ ~., 'TJ M ~ ~. ~ N ,~, ~ N
x N ~~r~ .
~r~i ~ - p ~~~0 ~ ~
te vi d' r ~O , ~ ~.0 00 ~ ~ '" ''' .r M ~-. I x'~ ~ O
W ~~ON N I ~ ~
; ~' - I~ v x .. ~p , ~ ~
t~j ~ a ~ O ry, ,~ a ' O ,~p~
b M 00 'C "~
~ V

b ~ --W J l .~j ~
~ O ' p , O N ,x ~ ~ r, M
O V~ oo l~

h ~ ~ N (~ N o~0 N
~
~

N 'b A '~ ~ ~ D ~ oo ~ N ~ ~ ~, ~
b ~ d; ~ d; ~
'~
' ~ ~ ~ C
~ N N

vD ~ 0 ~ rx /~
M b O l~ N o ~ x M ~ N ~ ~p ~ 00 II x ~ x r w' II a O

h V1 d' ~ \p '~ n ~O t ~ ~ ~O N ~' N L/~
te ,~, r r-~' x b O r . II t~
, ~ x N x x' , a ~ ~ N h v ~' -:

~ ~ . ~ r. .
te r .CI CV Ur N C i1 CV

r~ ~ H

GD

x x x x x ~
M a M

a O
O ~ ~

U ~ \ U

O

O o O

\

fl" o o ~

~ c o V ~ ~ o o ~ .

Ij x ~ ~ '~ ~~ N

M x .~ _. x _ ,~ a '., ,--~ ~
~
"

rx ,Zy V1 x M vp s~ x s d' r '--' N [
x N ~ -~
~ ~ ,.-, oo oo n o ~
O x N ~O v N ,.-.
x r x '~ '-~
x ;x~~~x~ n ~-.~~ N'~bN

~ ~-, N
ji r ~ II ~ ' ~ '"' x o ~
,~ b ' o~

.,- ~
~ 1l ~ ~ W t N x o o o ~ ov a~ ~ ~ II

b ~ V~ oo v0 O_ ~ i--. C!~
~

'~'~~'t'n ~~~ix ~~N~~
,~~, , v A d d' ~ ~ b x h '" ~ ~
M ~ pp N

CCt ; 01 ~ ~ ~ e-~ ~, M vj ~ ~ N
.-~ ~.,~ M ~ ~ x N ~
x O N ~ ~ ~ ~ x r' ..o V1 V't ,- y 00 ~t N n iv ~

.: in i~ N r ~p ~
~ p 1 ~ 'y p N "~' ~O
t v x r~i '-' N x ~D o0 ~

n _ ~
' ~~II
'~~~

W W 'N ~ oo ~~" x N N

b II xx~ ~ ~~ ~~;~xx ,~o II ~ ~' ,~o ~ '-~ ~,o '~ N
N N M ~ ~n o0 0 'L
. i ' ~D
x 0 b N ,~ p b N N p~ ~ y p L1 r-~ ~
~ oo II
II

d: d. s ~ oo x x ~n ,~ O t O ~

' O ~: ~n oo v~ t~ v? ~ II
~ ~ ~ ~ '~~' ~ 'dW0~ ~ ~ ~ ~ '-~
~ x '~ b b W ~ r.~..~ ~ .-.~ b II I ~ ,, A ~ ~p I .-~
~

i~ ~ ~ O ~
., N O~ .
~ y- ~ nj ~ d;
h ~W W ~ ~ '-' 'r ~ C/ y x N d O
d. ~

. N r .r ~O N O ~l1 ~ N

x O~ ~ ,.-~ x ~~xoo~ x ~~~~Mx N

n v M x x ..

x x o 0 ~' x x N x x U U U U O

O .U

b ~ o o x o ~ ' ' ~ o o o o o o N ~O ~ 0~1 " ,~~, ~ ~ ~ N vi o0 v0 h W ~ ~ r~L', Vj ~ Ov yr ~p ~ M I~ 00 ~ 00 ~ ~ h "" '-' + x 'o ~ II r, ,~ ~-: b hj ~-~' ~-' n C/~ l~ N i--, N ~O ,.<y" x t~
N (V ~ N x N N ~i W N d' vi tW r r' 00 Mrs 'nN~O'~''Nv a ~~ ~r,l~n NO
°° ;~ '° ~ II '~ ~ N N ~o ,~ x ~ o~ x '~ x .,:
rs ~-~ N V1 ~ b ~, x l~ O ~. ~ O r '"' ~ II pp ~ a, '. o ~ ~ ~ t~. .-a p~ b CC ~ x ~ a00 ~ ~ n rrr~sO~ ~ ~ ~~~ II N
vi O ~ ~ ~ 00 ..d C/~ w ~ ~ xj x d' W-.
I~ ~rl~ II xN a.b C~'~ ~1~01~ .-X01 b0 V~
..n h ~ ~ v ~ ~ ~ ~p N ~ t~ ~ ~ pp ~
~ M_ ~ b ~ x ~O ~O ~ ~ ~ x ~ ~ ~ ~ r~i M ~
..,~~ tA ~ ~ ~ '-'~ ~ ~ II ~ d: nj x 00 ~ ~ '~ l~ ~ r~
O N ~ x ~' x M ,~-'i, N ,~ .+ M N ~ ~ N N
r~j ~ M a ~p ''~ ~!1 ~ C!~ ~ ~ ~ ~ pj M
'~ r~r x M ~O ~."~ 00 N ~ "C1 ~ a ~ ~ '-' p N '-' Q ,'1", ~,~~ c~ M N ,~~ II ~ N oo ~
b b r~ x ~ M o0 b ~ l~ N M 'b r"' vp ~ ~ tl~
p ~ ~ N ~ ~-' N ~'? '~ '° O 11 ~ x ~ O ~ ~t II II W
C/~ I~ '~ p~ t/~ ~ b ~ ''~ II V~ ~, r~i pp '~ C/~ ~ l~ h ,.' v ~.0 ~ x M r'. ,~~ ~-~ ~p ~; rs 'b ~M
yp n ~' ~ ~~,-~ pp M ~ b ~ ~ ~ rIy [~ rte, W r~ II ~ M o0 00 d: ~ ~ h M
N N wr , N "'~ ,d, ,~ O I~ N ~ N ~ r; s~ ~
~i N M Vl v~ ''b ~t x n ~ ~ n ~ ~ d; r~ r~ N
.-, ~., o ~ ~ 'b l~: N rx .. N r~ M r~i '~ t~ ~ N ~i b ~' r.' H H
V,1 Gp i~
.N W
M M
U U
~
~
/ ~
v V7 \ /Ya \ W
O
U p O

V z oo a o~ o, a N _+-" _~ O
M ~ ' C/

v.~r .~ N ~ ,~ ~. ~ ~
000 pip _ r'~ 00 N O
~ ~
x x o0 N N M

xi _~, ~ n ~ r~' t~
Q1 00 r~ V7 N O \

o0 N O~ x O ~ N
. V
N s-s r1 x ~ N ~ N N

N ~ t-, tn ,~ V~ 0o Cdr ~ N
I1 d' N M M '~ ,~~, ~ xi ~ ~ ~ ~ o0 N OW .r " ~
G

o0 Cl~ O ~ o0 ~ l i ~ \O M
v I) ~ O 01 ~O
~ 00 x ~ x tn d' 00 V7 ~t ~ O v0 (~ ~ N N

't~, ~; ~ ~ N ,-' ~p ~' v x, b b 'r ~ -~-~ ~ --~ ~
l~ i-v Cy ~, uj '-' wr C!~ 0 N ~ '' v N r~ ~ \D 0 p; 01 0 ; ~ ~ ~ ~ ~
M ~ ~ -r wr ~ ,x ~
x ~ ~
O

N ~ M ~ ~ ~ V> a ~ i ~ ~

Ri 00 O ,.~'[~, ~ O ~ ~ v~ ~
~ x, x ~ ~O l~ MO r~
~ ~.

Q1 x II 01 r, y5 tA [1 ~ p~ ~
.-~ pp ' N ~' ~ M M
t.- M ~
~O

, t,~ ~ ,_, . . ~ ~, tn N ~O ~ vi w ~i ~ -, 00 N
~' "~ V ~ ~ a ,~,~
~y II Oo ~ h,., ~

~C O N ~ b p dw0 .~ v, ~ M ~, ~ O
' ~ ~ M N p "~C ,--rO Oo ~ M M ~', 0 ~ ~
II ' r~
'' 0 N

t/~ I I M ~ ~ Oy 'd r y ~'' ~ m II ~ ~ ~ C/~ t~ oo~~ ,~' oo ~' 00 ~ ~ ~ ~
t-- 'L7 , ~ r~' . x ~O
~ N ~ ~ tW r~i M .~j ~ ' r M
~

"YIbQ _~ v +-,r ~ ~,~T-' ~~'r N~ ~

~d:,~, ~ N ~ ~ V ~ '~"~b ~~ ~,"r~iM
~''x ~'O ..

00 wr a 00 ~D ,~ ~ ~ ''' ~ ~ ~ M ~ II c,,' N ~ ~ ,-mn ..-~ ,-.
l\

y o ,'T',rn v~ .~ x ~,, ~-~, ~
~'' ~ ~ ~ ~ U O o 00 oo ~ -~
' ~ w ' o ~
O
~

.~ ~t ,-. ..,r .-. ,~ r l~ r. ~ t M '.
~ ~

o ~n ~

.O ~ ,~ N ~ 'U h N N
~

i~ H

by O
.C N M Cv O ~ ~O ~0 O O O

~

M M M M
U x U U U

' ~' ~
~' w , ~ ~ ~ ~
~ N N ~ ~ M ~
~ M ~

~ N
v M M

M M ~ ~ ~ ~y U U ~ ~y ~

p O U U
~ ~ o ' ~ Q ' O O . x ' ~ O
'.

x U

d ~

V ~ , ~
~ -s c~
A
..
U
.,r ~a M M ~ M
'""' Vj Q1 i-s ~ n n C~
a ~~.r ~ a b O 2f ra ,~ ~ W ~-t GO
0'~0 ONO Om0 OMO N

n ,D
v N ~ ~ ~ ~.~J a N
. .s~ ~.. U U O O O U U
U U U O x U . ~ U
s .
U
V ° o oNO o'~'o cd'o ono ~

l~ O N
xx~ x ,-...~

ov p ~ r~
~ II

-. N .-~ v ~

, ~ ~' y,-,N d: ~,, ~; II x ~ .-,' +

~ ~~~ 01 ~ O OO~O o OO
' -~ x ~ N
N
~

Z . ~ r ~ M l'~
00 ~.., ~ N c0 h ~ NN N M MM
M ~
i~

O ~ ~ u0 n ~ ~
fl t,0 . ~ 'O
o N ~

v ~ ~ x d; O ~ O OO~O o OO
~ 00 ~ n O . U l~. C/~ ~ OvN t~r'V'iOi -~ v0 l~ 'ria ' ' N c,-~

l~ O ~ i.~C, ~ oo Nd'vW'~Md ~ ~ ~ ~ ~ ~ NN N M MM
xx r~
x ~~,; UN N ~ ,:,~ " :.:~:-;
~~ " ~ ~ a ~ . + ++
-, N

~. , ~ r ~ a VlC/~VlVlC/~C/1 a ~ ,~ R; W
M ~

N ~ x x ~ ~ 'W-'v v . Wv i i~ N ~ '~ N O~ M -a c~1 CI~C/~C/~f!~Cl~C/~
~ ~ ~
'n W i1.d "G ~
~
~

I x~~ .-. 'r ~ 0 ~

M r"
~

NN N ~C~CPC

O ~ N E-~ H
"~

U

'.G~ oo ~ o ~~ ;=;d'~t'~'d' o rw .N oo a~ ,-s r,r.,.-~~ ~,.~., W

0 o x x xx x x xx xx x ~,~,~, x x x x 0 0 o 0 00 xx U x xU

x x x x oo x o Nx o ' o ' 'o , .

~a xx x x xx x x x o Q .. . . ..

x x x ~ ~ ~~.

~ 0 0 o ~,. ~ , ,~
mr~aaaaa~

as Uz ~ ~ ~o A

a~ ~ a~a~

~ Y

.N.H.H

N N N N

. ~, N N N N
~ ~ ~

+ .v.+ .~-cUd ~ N ~

U U U U

b a .

H H H

ago T, ~w G

G

. < <

x U

O~

~

O ~ . U
O

x x x x N N N
!1/'~r1 r1 riv-Iri ~

U ,.-r ,-~r.,.-, N _ x O
M '"' ~ V7 N ~N

II ~

N

N
~ h N
>~

"d N ~O
r~

'" II
N
N ~ ~
~ r~-~

'rry ~
~D
~O
O x a O~ '"' ~ O II

h ~

M

No~o, Nxoo c~ ~ ~ x .-~ 00 M II ,~
N O
~,~~-x~

b N ~
,~3'~, ~ II ~
N

r~ N h r, op II

,.._, N

N p0 b~

O II
~h ~ b 00 ~' QO

~ ',n II

~d, h M
~

O ~

-~ oo a II

,. CV
~C
d ~ H
y ~

b N
~

~z N
~ pp ~ ~j ~ O ..
CC ~D .-, O~
~" r~ W_ 01 Nhr~~MC/~
N
II h ~
h c.~ . . ~ ~ ~n '.G N N M ,~ ~' b ~r x N tx ~ co ~y U II '-' ~ N M ~
d' d' ~ ~ ~ O ~ ~ ~ N
f'~ f~ f~ ''r °° ~ '~ M "~'~
M
M
O h x~uxxM'~~
o .o ~ cV N N N
~ +~ +~ +~ +~
~ M ~ M H M H M ~
m m U U U m M m m U U U
U
U ~ U U
O O O O
N
n M
U x ~ U
U x , U
A. o U '~ ,~ ,-i ~ ,-r 00 ~ ~ N O '~ ~ ~ '1 M
00 t~i M ~ r, 00 I~- ~!1 r~ C/~ ,r, ~ ~ d1 N
M _ h II ~y ''' ~''.' ~ x, ~p M ~ r~ l~- ~ O ~ ~-; '-' ";~ ~ r: ~ ~ t~ M O~
CCI o0 01 b ~ N x w ~ N II d' O ,-i ~ pp ~..' l\j x ~ O '~ ~j x ~O II ~
oOb~~'r3v0 MCV ~--,~D y M~rrx~;d~~ 'n Nr~N_'> N' A ~ ~ ~"~ d~ p~ II ~ ~ ~ ~ ~ ~ ~'' l~ ~
ca b M II [v ,-. h ~ ~ x ~n ~ +, (A N ~ ~ °'. ,-.. ~ x tA ~ N v ~ "~~
''' M .J
V i 00 h l~ b II N M ~ oho ~ M ~ ~ ~'' '-' l~ l\ M _M CV _ °~ ~ b ~ C/~
y~y~~ 'C ,~ '~ h Wit; "~ O W (~ N ,-.Wn ~ ~ ~ , fi a U ll pp l~ ~ v1 N N
~ ~ ~ ~ x ° b M ~ d. ~ v~ (~ ~' ~'! ~ r~ II vo P~ '~
N v~ '-' N ~C n~-r~ ,-.~ _ b ~rr~ U II ~r,~ v0 ~ N i-:
hj~'~N~v~M~M~ V~ OOv"~~f~Y7 w.rb~~~r~~ ~xi 00 00 ." ~ M
,~~QVx~OVM~O O ~.l~N't5 ~ p~ty ~'~~l'M
O~ ~ M ax N ~~" x ~ d. II y0 "~C .V~. d; 'vvr~ b x V7 ~'~' M
~_ n n d' M s-: ~ ~ ~ ~ ~ N M M Op ~ 'd' t~ M p ~ \O
N N O1 N N n xi rs ~ N ~ ~ x i=. O N ~ ~ N ~ ~O
II x x ~ ~ x M ~ M ~ ~ ~ xi ~ '~-~ ~ ~ ~!1 d' ~ d' -- x 00 I~ w.s ~ ~ M

-I- vo + ~D + ~D
~.. yes" v ,.., ~C ,-, '~ .-, .;r F'~ ~'' ~ M ,-~ M ,-i U
U
M
x U
U
U U U
>~ s~
O O O
M M M
U U U
~ d . t~' UZ

"~ ~O N M N x M ~ N ..-~ O M
r' ~N~wM ~~ '"' ~x~ II ~"Nx~'d' '-' 'y.
d' ~ ~ ~ ~ ~ x N ~ ~ ,~ tn N N l~ v ~ t~j l'~ '~ d' C!~
" x .-~ II ~ '" x .o .r x ,-~ t~ .J II '° x ~. ~n x x '°
'°. ~
~O '~ ~N ~ ~ M ~ a l' '"'~ N II 00 b ~ M M ~ ~ ~ ~"~ ~ ~O ~ M
A ~ cax..dx~,~,-;~ ate; Nx~~N.b~'"~°oW ~.~ox.~x'txx ,b ~,Nxo x~,.b .
z CCI ..l';~ ~ p~N ~_Q~~~,~~,~'~M~~C/a ~~ r,..~MWI-U II °~ o ~ o .-: ~ x U II °~ ~ M x '~' " II x ~ U !l °~
n II ~, ,P, II ~ x b ;.4 (~ II M ~~ M
~ x ~ ~ N M ~, v b ~ x ~ ~ ~, M b ~,' N v b '~ h ~ ~''~ r, O_ d' 'tj ~ ~ N N ~ ~ ~ ~ .d M O N ~ t~ 01 N 'd Q1 M r~i~ ~ V7 M 'v ~ ~O x x d; x M ''vC V l~ ~ x M O, ~ ~ M "~d V~ N N
00 ~ ~ N~ oo M ~ M oo M ~ ~ M ~ ~ M '-' N ~ O ~' ~n N
~O V'1 Vl ~N ~ ~ s~0 ~ x M ~, N ~~M ~O ~~ N ~i~
xx~~~ml...xx~xx~~N~~xxxoxx~xxxx~
.C y A
bA
+ \O
O
MH Mx Mr~-~
M
x U
i U U U
s~
O O O
U U , U
'o o ~ ~ i~

.-. o ,-. o' ,-. N II o0 ,.-r ~ ~1 cf, , , r, ~ .-: Do N ~ ~? ~, "' "'' ~x ~ ~ '-' ~r~ ~i N v00 ~ ~ ~"' II -0"J II
~~~,~~cnxW ~s.~~''xN~r~x n ~"~~.~-~,-.,n~.,c"~os,.~d;
.;d ~ ,~ ~ ,,p v '-' ~n r, ~ ~ v O~ ,.~ N _vi h _a: 'yp .:
N h ~N N ~ 01 N h ~N N C~/~ ~ N op 01'1~n vx'-' V1 A c.0 x .b x Oy, ~ <.O x 'C s-~ Oy' W ~ x h x m O N O i-~.
h M ~r i-; h M 'r n ,~ . h V i-W ~ \D i'W_ ~ ~ O C/> ~ h x h ~ M N C/~
_ x ~, U ~ °_' ~xMM+~Lj 1l ~ ~xM~
~ II M N ~ ~ Z ~ '~ II M N ~ ~ ~ ~, ~ ~ oo ~ ~ ~ ~ v~
v.s'V'~~ ~mN -I- u'd'~~ ~M~~~~V't N~~N I
'r h V7 b 00 'd' ai ~.., ~O ,-i x N x ~' M '1 Cf~
Mb~N_vi ~ ~M_'C V~N_vi_~,'Z o0 II N_bNh_~~x 0o N h rn ~ ,' O o0 N N ~ d' -1- °~ ''' ~ O h ~ M ~ ~ C%
~O i-;~~D h x ~O ~.~~0 O\ ~ ~~ ~D ~ N xi N
x~xxM~~-~ x~xxMO.~.. x,~~~x ~M,~x °b N cV ~O
p ~-1 ~1 Gl aA
h M ~.., x U
x U U U U
N
U U U U
~ >~ t~ s~
O O O O
x U
R~ U U . U U
A. o U ~ ,r,-, ,-, ~ ,.., v y N cf1 '.G N N ,~ M M .~ p o0 o ~ ''~ m ~o ~d ov o0 p ~ ".~ N V~ ~n N d' d' .. .. ~ ~ ~ ~~ n n n n W W ~ W W ~ W W
'r a ~ ~ ~.s ~ v 'r U ~ ~ U
o~
W W~ ~ W W W W W W
ago p ..
a ~ ~ ~ ~,.~ nu .s~
,~
~ w U ~ x U
U U x x U
U U '" U U
x, U
,Y OU OU O OU O O OU O
~ . ~
O O O O ~ O O O
N
.~'1 M
M M M M M M
U U U U U U
r U
b a~ w 0A
0 0"00 00 00 00 00 00 00 U Z ,-, ~-V ,~ ,.-. ,-. ,-r r, .~-.

,~ ~-~ d~ M II ~ N
N i=. ~ b I~ x ~ M
~ ~r x x ~ '~ '~'. O II ~' ~ '1;. M ~ .N
.N o0 l~ "" ~ ~O ~ M M '~ ~ N N M
I I N t~ ~ ,~ .-. oo ~
A e'~x'C''~'NWrr-t a0y_O~O~,.x~r~i b 01 l~ ~. M 00 ~ ~ l~ r~ N M ~
U l~ x ~ '_~ a ~ '~ oo N
'~ ~/~ 00 ~ II N N o0 y0 A ~ ~" rW O ~
~~M~, ~ a Nv,-,~.rj0 ~~ _.. _..
x .--~ b o0 I~ ~ f~ ~j N ~ N ~ ~ ~ V C/1 C/~
~ M 'b V'7 ~ ~ 01 a a N ~ ~ N 01 M ~: N
-.a x ~ c~ t~ ~O ~ r'~t o U -~, r-S, b O
W W W W W W
'.,.~, p t~" ~-'~. I ~'1~' o'~0 0~0 ~ w ~ ~ ~"
U
x '-~~ U U U
W W
~Y, O O O O
U U~ U U O O
U U
r~
O O O O O O
x N
U U U U U
' U
~ . , Zc ~ oxo ~ ~ a a U ,.-~ ,~., ,--~ ,.~'', M ~1 '7 01 ~ ''' ~ t~ ~ O
b ~ ~ ~ CM M
~ iii ~
M yr N
+' N
pp b ,~, ~ ~ v ~ d' x M M
v +~
M N ~ M .~', WO ~ tn v x ,~ M
U t~ r~
.: ~o ~t O cV ..d ~ ~~ oo vo ~
In ~ ~ ~ ~ ~ ~ M
i~ ~ '~ ~tx r~i l~ ~~v~." N M
W ~ W W ~ N~M~~t;
'mr v ~ ~ ~ ~,~y N \O d' M M
D\
U
b o ~o w w w w w w wo U ~CS Cu W bn .~S

~1 ~ ~ ~ ~ ~ ~i M M
x x M
U U x w U
M M U
_ M U M U U
U U
U U U U U U
O O O O O O
N

M
f1; U x x x U U U U U
U
a b a~ 4, bD
r-, r, UZ

II ~ d- ~ .v oy: ~: ~ ;.~ V os ~. ~: O
'> o; ~ '-' ~ ~ ,.-~ ~ ~ "' 'b x .yo ~ x O '"' "d x ~ 'f: ,-..
~ ~ M .... ;.>1 0 ~ II ~ ~ ~ ~ II ~ ~''~ v~
ci0 b_ Wr w.r ~ a wr o0 _'C .-r A ~ ~C x ~ ~ d' ~ '~ :~ o, II M ~ x M vM,, z %-: ~n II ~ ~ M
co "~ ~ d~ x vo ~ N ..~ M '> ~ ~i M ,-, ~ ~ M ~ r, "~ ~ o0 ,~ O ~O ~ ~ ~r,-~ M ~ 1 ~ ~ M ~ N ~ M i 00 .~ ~ .-~ 00 M .i-O "cW O N r~i ~ ~ O "tJ ~n N ~n U 00 l~ ~ cad w M 0~0 ~ x o_ l~ ~ d' M ,r, ~_' ~ ~ ~ f 1t1 M ~ M
~t A~~~'o ~xo ~N~xx~ ='x;~°. ~ No~o~xx~x~
--~_~~''M_ x,l,-,~~~M~ x,l.--,r-'M N
r~ dN'. 0~0, vr~ ~'~ ~ N v ~M vW ~ ~ x N v~ ~ ~ '°
N \O M ~ ~-'' r~ l~ '-'' x r", r., n M ~ V1 r~-~ ~ N Q\ II M
r~ O~ ,-~ ~ ~ ~ d: ~ r~ rx II N O~ 00 M x N ~ rx II N O~ l~ 00 N ~
N wr xj ~ M a N .-. ~ x t~ ~O d' M M ~ .- ~ ~ l~ ~O M M a V'1 O"
w w w ~w x U
N

M
U U U
,b ., n , "~.

os ~, ~: ~ ~O ,--. ,--., 'r N o0 l~ d' M '-' ~ N "'' ~ l~ O N M II
,x~ x N ~ 00 ~ ~ x V~i ~ x ~ 'C O
a0 b .-, M ~ .f. ''~ a M 'r V7 M 00 M i-v n ~ b ~~ n ~ _ l0 ,~~~oc~~l~MO Viv~tx ~ i~V~_vixM~'~O'i-s x z ~ oo 'C M N oo ~ N ~ -I- ~ ~ b .-. ~ M ~ ~ O C+/~
b v0 N p ~ ~,'~ O CO "~C l~ V .~ ~,~ rv W + .--~ N
l~ vi M ,~N, ~ ~ ~ ~ t~ x N '~., " ~~ o~J N
~.: ~o~M ~x°~~M~ N°''i'z ~ o _ _ ~ _ _~
xx M ~~';~~° xx Nx°' ~'°Nx w w ~ ~ v ~ ~ ~ .~ x ~O M v II r, ~O M
I~ N N ~.~ r N ov ~ oo N a., .-: W '~ N '" ~ ~' 'n x x vo ~ v~
xI~~DMM~r~iwr.- II x~u Mu O
w w C7 C7 o ~ ~ ~ a r~
M
U '~ x x U x U ~ U
U ' U U
W W W
O O O
U U U U
x x m m x m U m N
U O U U U
-. ~ ~r .a N N
U

z z +~ M M d: M ~' ~' M M N
~D ~ O O ~ ~ o0 N
V~ d' ~n ,n ~ N ~ ~n d' ' ~, ' ~ i~~ n r~ ~ ; 'n ~ ~ ~~"~, ~ Cl~ C!~
~~.r U
o ~
C7 C~ , C7 C7 C7 O C7 O C7 an .ice w ~' ~-~ ~ ~ ~ ~ ~"i .-, r"
U U
U
U x U U U U
~., U U
W W W W W W W W W
' O O O O O O O O O
~ , ~ . , , , O O O O O O O O. O
, . , N
/'1 I~~1 U ,~' '',-~; r.~ '~' '~' '~ "~' 't.Zi , U U U U U U U U
U
N N N N N N N N~ N
z N N yx~ I~
~r ~.; n x M °~ %-: v~
-N-m-; ,-~ h M ~: N ~
O ~ ~ x~ 00 p: v r'7~-~ LV ~ ~+ ~ ~ ~ c~d I I " N x c~d C~ ~ N ~ N ~ ~ ~ N ~ ~ z z z z N
. o ~ ~ x b ~ M ~ ~O ~ ~ '~' + 'I-U ~~ N ""~~MhM
x °° d; x ~' M p II ,.~ x M ~; .-m0 d; '-' N N
~, N C/1 ,~, o0 ~ .~ N a N
q ~'' II ~ x '.~-' N ~ ~ r~ r~ t<7 ~ ~ ~O
i~ V r' t-. ,-i ,-..~ M x N~ M '~ ~ TJ
00 '~ ~ v ~O b ~ t~, ~ II ~ d: Wr a a x dN.' ~ ~ x ~ d; ~ ~ ,.~ ~ ~ ~ V~ C/~
~ oo v t~ ,~ N M ..r wr ~n in O b ..C! a7 ~ ,U. cV CV N
m r~ as nn a ~ ~ ~ ~ ,r~
e°~~ e°~~
M
M
U
U U U
_ M M x Ix U ~ U U U
W W W
O ~ O O
U U U U U
c1 M cn O O O O O
' . . rn v~ cn O O O
..
N
U U U x U
o , U
U
~. ~ c~ .a O N ~ N N N
U ~ ~." Nr, ~ ~ .-a WO 02/34711 PCT/USO1/32s82 N ov ~ r.., ~ ~ N ~ N
~'! x ~ ~_~ _cn x x "~'~~ II
d: xi ~i 01 M ~ + d: x 'r N N M ~ ~ ~ .-~ N I~ N vi 00 ,.-~ o, .-r M ~; '~' W oo ,-. ~ ~ ','1", ~ x oo I~ 'r~', II ~n ~ ~ ~ 'D ~
~ y. N ~r ~p N Ov O rx ~ ~ ~O ,~ 00 ~--~ ,~ p ~,, ~, dN'. ~"~ ~ s1 r~ l\ ~ ''~ M ~l1 .~.,~ ~ b ~ b x' d' ~, ~ ~ M
"t7 m r~, ~ N M '"~ ~ 'O o0 ~ ,-i w.r ,.b ~r .-, ,~ 'J ,~, N N
O ~ V~ ~ IL M d' d: ,,.~' O 00 '"~ 00 ~ ri V1 ,~~ O ~-'' ~ ~ ~ l0 ~ 00 O V~ h ~ ~ N M M .--a O~
V~ ri~,.~ N IL ~ t~i N ~ II M p W ~, ~ O M ~ ~ y--. N o0 LI ~ M ~ M ~ ~ b ~ N N ~ ix' ~ 10 ~,j~~~_,~M~ ~~~~v~3"MNd'~ qxNx~xN~N
II d. x °~ :.~ II ''' II. .b N ~ M ~ r. ~ °° '. N
Qy ~ I~ ~ M ~ ,~ M o0 yr Vl 'r n a 'I' ~; n ~ '~ ~ ,.-y1 01 Q rv d; ~-; O r~ M ~ ~ ~ ~ N II
II b ~i a r-~ M W O ~. x, b I~ rr-~ d' d' ~ ~.- LI ~ 00 i~ ~-, M a ~D O W
'b N N
ap a ~ "c a~ o x x U U
M
x U
U U
W W W
O O O .
U U U
~; w w U
O O O
O O
M M ~ .
U U U
~~ o ~~,O
~z 21s II ~ ~ M °° ~ ~~ M II N II N ~-;M
01 ~ O~ M ~ ~ ~ v M x ~. '~ p~ M ,~ r~-i r~ M
,~ ~ r~-r I~ N ~ ~ ~ ~ ch vj ~p ,-i N "b ~ i~ O M ~ ~ L!~
x ~ ~ M ~ x M wr x ~ II ~ ~~"° ~O Uj A °° ,b OO x ~ 'rrN,~ ~ ''~~.,'~ ~ "'~N,~ rte' M ~ N II ~ b v! ~ 3' M
b ..a W ~ M ~O ,.~ ~ i."~ ~ W .r ~ a ~ ~' n M 00 N ~ fV O'~f'1, d' ~ i~. M '~, M ~. . O i~ M O r~ O ~ d; xi r~ tai b ~ ~ ,~ ~ ~ ~ ~ ~ N ,~ O O ,-, M r~ M ~ N
U oo x' ~ '-' 1l '~ ~ ~,° U 1l " N x r.., '"' ~ U o0 00 ~i M
C~C A,..\''"il~N''''~~ ~ ~,_,~ ~,M~~~.~rs~Nrsvi~
~nbNMf~ ~'v~Nv''~OW ~xxi~r~~N~",-, ''" b x N ~ ~ ~ 01 x ~ ~O x ~ N N N M ~ x O
j N ~ N vri ~ M ~ l~ ~ ~ M a N ~ ~ r~-i r~' ~ tai i-: ~ ~ ~ 00 Oy N M ~ ~ i~ ~ r~ ~ d~ ;-., ~ Oy1 xi ~'; x r., ~., l~ ~ r~-i d- ~ x x x ~ ~ r~i M ~ x x N ~ ~ d' N M ~'.r" N ~O
'i~
O b y cV N cV
P~ PG 0.1 ao '.b~ ~ o o c ~ w M
x U
w U
' O O O
U U U
m m m U U U
O O O
O O O
m m m ' U U U
"J p ,~;o ~
U ~ ,-c~~, ,.N-~

.-", d' ~ , o, ,--~ +
!~~x~:xxx ~~. ~ N ~ ~. x ~~'~M~r~
b _ ~ v ~ l~ M N ~~" ~ ~ t~ M f/~
n x, l~ N d- ~ ~ ~ 'yo 'r ~ II
A °° ~ ~O ~ ri ~ ~ ~ rA M ~ ~ ~M', ~ ~ ~ c ~ ~ ~~1, W .r ~. ~ s~-,--=1 M '-' ~ I~,- ,r, M M ~ ~ ~ ~ ~ .-~ M
V iv O t~ N ~i l~ 01 ,~ ~ ,-~ 41 00 ~ ~ i=. ~ xi ,.~ o r., ,<i ,-, vy. M U ,~, ~ rte, '°' c~1 U oo M N ~ ~ N op N _M ~ ~ U N ~ N _M ~
NON r~
~rx~r~xx~~~ V ~.,~~p ~x~W ~ ~,~0 .~-i ~ ~ c'<1 M + ~ ~ r~ ~ M M C/.~ ~ ,~ ~ M
N II ~ II :~: W °. x ~? ~'.~ ~ ° x ~! '.o ''~ '~ t'~ '~ ~O V7 ~ ~ ~p V'7 ~ 00 V7 ~ ~' 01 N ~O M ~ x ~ N s~ ~ M r~ ~ N s~ ~D l~
x .-a y0 ~ M M ~ , r~ x ~ M M M x ~ r~-i r~i c~1 ~
"b O ~1~
N N N
as ; as nn x .
O N ~ N
-'~w f~ '"i r"' '"i M
x r-~ U
U
U
W W
O O
U U U
M M M
U U U
O O O
O O O
M M M
U U U
..
° i z ~, l~ x M ~-' N
.-r ~ M
t~ II ~ .~ ~ N x ~ x' 'o '+~ °° ~' ~ x .--~ N N M 1l z z z A ~v~,"II ~~x ..
~ OO b O ~ ~ ~Y _tn ~ 0~ ~ ~ c~ , M N
NNM_~'~~V7 ~ M ~ o~0 ~-' v~ ~n d' ~.-~oo,'~,''d. II xMNxIW N ..
x ~j ~ O" vi x ~ v~ ~ U C/~ G~ C!~ t!~
~~xx~~
N v~
N ~ ~ N ~ ~ ~ M ,~, ~ C/~ C/~ C/~ C/~
II x ~ ~ ~ ri .~ 1l wo U
o zi G N M M M M M
Pa ~1~1~1 ~1~1 aA
C!t ,.G G ~O d ri r~ ~ H
W ~ H
x U
x x x x x U U , U ~' U x U U U U U~ U
0 0 ~ ~ 0 0 w x x x x x U
O U U U v U
p U U U U U
N
..
U U x U U U
~ x O U
ca ,a G b Ow O ~ N N N N N
~z 21s a ca cps +~
A
N
_~ d_' ' ~ ' ~ "" d' d' N N N
N N N
U U U
o ~
nn 4, an ,s~ .., o ,~ , m x M
U U ~~ U
U
O O O O O ~ O
U U U U U U U
x x U U U C~ U U U
x x x x x x x U U U U U U U
, x x x U U U U U U U
, , , . . , , b ~ ~o a - ..~ x N N N N N N N
H

Va~., M ~
~N
II oo ~ ~ x ~ ~j ~
~ h _ co ~v II '_". oo ~ ~ x n M ~' r-i ~-~, n--n '° M ~'' a II "d ~ "' r~i M ~ ~ ~O W
-, h ~ l~ LV N m x N
oo "~C v0 .tj ~ A x r'~ N M ~ ~ ~ ~ d' o0 r4xx N~bob ~ i v~~Wi vwi rr, .D ~ yo ,-. M
~ ,-~ N N ~ rx ~ C/~ V1 ~ C/~ C/1 r~ 00 WD r~-i v'i ~ ~ M N O

c~ .a v ~tS
x x x U ~ C) M U ~ U
U U U U
W
x x x x ~x o 0 0 0 0 U
x U U U U U
U U U U U
N
U x U U
U U
b N N N N N
,.., ..~ ,.~ ,-., ~ W "~'' N
r'' ~
~ x ~

vi ~ '~
., x I'~ .-i M II
W ~
b ~ ~ ~
''-' ~ b ~ ~ ~ ~ M
~ ~
u ' ~
~ ~ x ~' ~

. ~ II
M ''~ .b ~ ~ b '~ II M M
O p '-' ''~'' '~
'>

N ~ ~ '> ~ d' II ~ vD
~ N b ' 0~0 ~ M N
N

A ~ rp b oo M '~ x n?
o0 M ~ ~ rx ,-'~ ~ b b ~ x c0 '~' V ~ i ~
~ O x O
~ ~ ~ b ~ O
~ M

.~ t v M M 0 x 0. M M
O vp ,~ ~ ~ M w ~ ,-~ ~,., ~.. r~
N

~t ~ ~ 11 N II ~ ~n ~ ~ ~"'' oo ~n ,~ ..-.
~f .r M II

'~xi',-~,.~iM IO~D~
~Q1 "r,M
~x~

~ , ~ N
.-n ~
.-a ~ ~ .-, O n r~ M In W W ~ N ~ ~ x x ~ ,~ vi O b ~ O~
M II N d' b v N ~ '~
N ~ ~

p n 'r ~ ~ , r~-t ,..~ ~ ~ ,-W
x ~ 00 l'~ x x M ., ~--, M O ~ C/a M

C/~ V~ ~.:, ~ ,-~ O1 l' ,~ ~ r~ ~ N N I I
; M M M ~, ~ ~ W
-; a d' ~l1 -V o0 ~i ~ '~
' r' M N rW s ~ ~
0 ~ ~O 1D
-i . ,~
E-~

~ -' .t~~ ,--~ ,- m H H H

b a~ ~+, bn ~

N N N N
H

U

U x U

M
U U

O O O O

U U U U

U U

U

x U U U U

M M M
U U U

. U
, N N N

~.-r M ~ ~ ~ M ~ ,x~ ~ "G o0 ~ M V~ V ~ '~ N
00 ~ 00 ~O ~ ,--~ ~ '-' N 01 ~ c<1 ~ W l~ M ~ ~ N ,~~ N
N M i-~ . W r N N xi o0 O 'r N l~. ~ ,~ ~ ~ O ~ N o0 ~, ~ ~ x M
aj .-~ M x; ~ II ,~ " V?
yes,, M x ~ ~ ~C x I_~ o ~rj p ~ ~O ~ ~ ~ ~ r., M ~ M ~ tip ~ I~ ~ II r, vi n A oOt'~y~_O~N II ~''~,'.-1N ~~o'~r~ib~ '~~ ~~r'~, ~x~~~_II ~W_ yr 'r ~ a a b 00 Nx~bM,~o ~..~~Mb~xNM~ ~ ~~~~O~MC/~
Q vp ,_, ~ r~ r,, ~ b "N ~ C' O N II 1~ ~ ~ nj ~ v ~ ~ 00 N r~ ~ ~ r.~~
v ,~ ,~N, x ~ ~ ~ M o~.o ~ N ~ ~ pp '~ ,.~~, ~ ~ r~ ~ oho. 0 ~ op ~ '~ .~ N M
A +.: N II ~ ~ M ~ ~ , b ~ ~ M ~ ~ x ~ v~
W r0\ V) ~~ ' ~~.rN ~ ~ ~-~ ~(y w vM
O~ ~ II ~ ~ r= ~ ~ ~ ~ ray ~, ~ rv N ~ N r-~ ~ ~ ,~ 01 N '-~ b ~ r~L', x '~i ..-~ W ,'-, rr~ V'~ xi II r~' x ~ ~r l~ N ~ x l' ;
~--~ M Wr ~j 00 tn '~ 01 ~ ~n ~ ~ N ~ ~ ~ M ~ M N
00 M 'b 'N N rv s; ~ ~ ~ O N ~ r, N ~ N 1-.i x ,1 ~O N rv O
xx'~~;~b~xxxx~x~x~x~'~~xx~-x-~~x.~xx~
a ~ ,~ ,~ ~, bA
N N
x U
'~s U U U
M M M
U U U
N N
r-i ,..., ~ II f '-' ,-: ~ aw-, o N -d 00 yn ~ ~ M II x II
M 01 ~ V1 M w.r ~ ~ ~ ~-. b ..-m--W D
f '~ ~-, 00 d ~ f 'r r, ~-. _ II ri r~ ~''~ ~ ~ ~., N x ~ x '~ b O~
~D ''' M ~ v ~"'' ~ '" ,~, wo 01 II N~ ~ ~~Mn"' t.0xx N~
A a '~ r~ ~ ~ ~-.~, ~ x, '~'. i~ ~ tai ~j ~ ~ M
~ ~ ~ M i~ ~ N ~-, b '° ~, .~ ~ x ~ ..~ II
b l~ 00 W ~ f ~ ,-~ d; ~ I1 '~', ~ N f 'b ~ ~ M ~ ;2; ~ II 'n x, v-, x °°. .~ M
N a ~ Cl7 ~ 00 ~ f ~ N M ~ ~r p M ~ ~ '~ ,-i _ r~ ~ ,--~ 00 w l0 x ~ x ,-i ~" x ~ v II ~ ~ N ~ ~ 'r ~.~t p~ f 's N _ '-' ~ '-' M a ~ ~..r N ~ ,~ ~ x f '~ f N O i~;
M ~ ~ ~ II rr-rr ~ M ~ 00 b ~ ~ ~ 'C x M N r~ _W
00 .-~ ~ .-W r O ,r .--~ 00 a f 'r ~ ~--~ ~ ~O wo r ~t r~
bA
N
H
M
U
U
M
'-F.ie U U
x o. o N N
U U
M
U
M V
U
O
M
~z A Q, a~
...
M M cr1 ~ ~D
b V~1 ~ ~ N 47 rn Cl~ t/~ ~ W
a U
O
b o b b ~'~, CSI 1~
o M M
+~.~ w r"
M
x U
x U U M U
U U U U
r~' rat 'rTt' ~'', U U U U U
N
f~
M
M M
U x U U U
U x , U
~z ~ N N N
V

WO 02/34711 PCT/USO1/32s82 v0 M ~ V7 ~p II ~O ~ r~-t ~ M rs M
II ~ °° _ _ ~ M "' Sri x N
'~ ~ 't~ x _vi ~ n N '~
~ l~ ~
N ~ II ~? o0 ~ N O II
M 00 N ~ 0.x.1 ~ M ~ M
00 ~p W ~ yr t~ '~O~ M ~ ~!7 +.~
n i~' II ~: N M
~N,-,~x~ vi Ny ~I MO
n '-~ o vo ~O O, ~ OVA r~ x M M rw "V t\ N
l~ tn '-' n ~ '~ p M
~O r~ ~ ~ .-, M r~ ~ vi V1 's r~ '"' N
~O O ~ ~ ~ ~ ~ ~ O p ~ x ~ d; d: M M
wj ~ O 00 ~ ~ rte., ~ ~ 00 '~"~ ~ ~ l~ .~ .~ M
c/~ ~. b ~ ~ '-' N rJ~ C~l~ C!~ C/~
v..r b x ~ .b ~p r., x x d' ~ ~ O ~ ~ ~ v W ~r v u~ ~O x x'~rN'~~ r-~~
o ~d h h ~ ~ ~ h b ~ ~., ~ ,~ .. ,~ x --M M M
.i~ W
U M x U
U ~ U
U
x' '~', '~', '~' 'rt~-i U U U U U U U
U U U U U U U
b .. ~ x .-, en a ~z 22s - N ~~ ~ ~ oho N
N ~n ~ x N N v ~ p ~ ~ ~ ls. l~ O p 'r ~ Vj ~D
vi N x x ~ ~, ~ ~ M x ~ ~D ~ l~ O ~O ~ LV x ~' n ~ ~ x .vc0,.~~~ ~~ 'Cy.rMN pprx~lppOx M~x~'.~s 01 ~ ~ II [s x ~ v ~ ~ ~' N '"' x ~ ~ 00 00 vi x '~ x ~ 00 r, x "d h ,-, I I r-v ~ N ~O ,.~ v r~i x ~ x d' ~ a '~ ~ '"~ l~ \O
01~ b"dr'N~ N~Ox~pp M ~ ~j~'~~ II ~~"N~
N o0 O ~ '~.dr ~ ~ ~ M ,~, 'r 00 ~ pp p~ ~ x o0 x ~x ,-, V1 .-.~ p~ N ~ ~ ~ N N II 41 ~ N ~ ~~~ b ~O ~ tn ~
'-' ~ p W-' "~: x ~ x x x x O ''' oN,, ~ ai ~ x' r-; ~o ~"~~~~"'~ II ~ N~~Mb oo~~~ NNoo ~~~,~x n x0 A h I I Tj x ~ ,..., ~ ..V x ~. '-' ~ ct b l~ .b ~ x p ~ ,-, N '~ N
o~~ ~bx~~~ ~o'I°~'~MO ~.-:~x~!~~ ~r_~_>~'b_~x :C ~ IW ,.~ -~ ~n b vW0 "" x N N '"' oo M crj ~ ~., N p ~ N a ~ ~ h ~ a ~ ~ l~ x ~.O nj .-~ ~ 01 M O~ N
x t0 l~ ~O N
~D~OOC1~ rp~r'-'0~0~0 oOu~M'~~.rII ~ ~ ~ ~ x..r l~ M ~ W ~ ~ t~' 00 x ,-, pp ~ OeJ N ' ri \O '~ M
Qx"~'~,~'~-'r:x .~b O't~~MxM p~'?'r''~M ~~'r', Ox~xO~V~
C/~ N ~ ,~, ,-~ II x O1 ~ V~ ~ ~ '~' ~ '-' V1 ~ ~ ~ N N d' ~ ~ ~ ~ ~ N M ~ ~
N V1 r-~ frl uj M ~ .-, .~ ,..., ~",~ ~ , ,~.., ~, M x r; O ~ ~
tn x 's a x ~ [~ x M
y..mr ~
~r00 ~ ~ wul~ ~ ~ N a N ~yr~ ~ ~ '-' ~ ~ ~ v~, ~O l~ ~ N Cl~
00 ~ M ~. M \D M V7 ~ x ~!1 x C'~ V7 I~ ~ ,--m-..i M ~ C/' ~ ~ ~ N
0o II n t~ o ~n r..~ ;~' oyp dy-, W ~ x , I> ,~, c~i ,~ ~ ~ v II
00 l~ ~ ~D M ~ ~~t~ d' N N ~ ~ M .--i .~ ~ ~ r~-, x ~ ~ ~ ~ x r~
~ ~ ri x ri rv x x v,r r-~ ~-i x r.~ ~ W v ~ N '~ ~ ~ .. oo W.e ~v .--i N ~ ~O .. o0 I~ vv d~
b O b V7 ~ N H H
w x "' U U
U ~ M
x U U
x x x x U.
x x O U U U
U
O d' N
N N
V H r~ rH ry .

II ~~ N o ~ ~', x x M ;-~ ~ O vi N ~ N ~p x M n yDxxO ~Nrx ~O Vlr~i ~-; v~
"~ 00 x ~j \O l~ N M wr .v OMO N ~ "-Wr I~ ~ ~ M
II n O 'x~,, ~ ~ a h ~ 41 n ~ x 01 l~ .-.i ~t v~ r.~ ~ ~n O ~n O~ x '~ N _ N ~ pj o0 M WN NO x ujNd;~~W x NM~M~ ~~'~I~xi II r., vi ,~, N ~r I~ ~ r-, ~i ~ vi ~ ~ ~ .-i N 'b °~ '"' N
~at ~--~ ~ ~ '~, ~; oo ~. ~rj ~' ~ ~~ ~, ~-: v~ o ~ b II
A ~Lj~M.--rM ~00~~'.rV ~ II Nx~.. ~~v~
-, ~D .-~ vi V~ l~ x ~ ,-, _ "'' '--~ x ~ ,~ x O 'r "V, ~~nII '~ ~ri N~Mx ~-nv~~N W N~~~O
x t"~ ~O x ~ W ~ ~
-, ~~ rv~~ ~M (yes 01 wr~01 r-, ~ M ~ N o0 r~ x ~ oo "' ~ ~ ~O oo ~i V'i 'b x v ~ ~ b ,.~N
II vi °o x ~
i-s o ,-i y!j x M ~ d' ,..~ v ~ ~ O x ~ n O v ,-, N
vaoy N~; v~ox~N'~o ~ ~~~x'"' ~x'_° xo;
N
°i N vb~, ~ II x q '~ ~ ~i ~ ~ ~1 '~ ~ o °, "' ~ +
b ~',~,N' o W ~ b oo '° ~ 'b a ~ ~ oo ~ x can o ~ oQ'o ,d '~ ~ W
O d' ~ N ~ ~ ~ r~ N ~O O ~ ~ r-; N n ~ r~
00 ~ ~ ~ ~ t~ II .--. x ui ,.~ ~ x N x x ~ ~ ;2; x O "C
y ~ H H
Cf ~ .d y w GA
M
U x' U
M
U U U
x x x x x x x x U U U U
N N N N
e~1 r1 r~

e-; L~j 0l N M II ~ + 1 v M ~ N
~ 'r v~ 11 ,~ ~n '~' 'n x ~ 4~i x N ~-~' '~~'' d' ,~ d' W ,~ ~ r, N ~ ~p ~
r~i M rs M N t~ l~ ~ ~ '~ ~ LW r ~ C/~ .~-. II N II
~' N ~ x N uj N '~ ,_I~, r~y O o0 ~ v0 M ~ ~ ~ ~ r~ N '~ r~ ~ ~n ~ ~ N ~ v II p M o °° x ~ ~. ~ -ry N h v N
M ~ ~v' '~ ,7 vi r~~~ ,-V ~ '~" ;~ pp '~' ~-. ~D ~ oo ~ ~ ~~n, 01 ',.., .~ ~' pp M "C ~ ~ vi ~ "'' W ~ ~ II M '-~~ o n ~b~~,x ~.~x ~D N N ~ ~ ~ ~ r, ~n N ~ off, ,-.~ ~ ~ 'r ~n W O ~ M ~ ~ ~ ~ ~, M v~ x ,-.
CW.r r., 00 wr n N d' x M ~ ~ ~ ,n .V., M MO ~D vjr~~'-' ~'~~O II O N~N 'r .~.,~~i~
00 ~ ,-, O c~i ~ '~; M ~ .., _ ~a 01 Wr''~ ~ n 00 01 ~-, x ~ ~-~ N ~ ~D 01 ~ ~ ~ ~y o0 M l~ N
tO~Db~x ~0~~~,-,~" ~~x"~.-' ~p ~i~xM ~~
y.r t~ N ~' ~D d' ~ '"" M ~ M N O ~ ,~ ~ ~ M
~ ~ °~~. .~ ~ Wit; ~ x ~ ~o ~I ~ n ~ ~ ~ '~ M o oNO '~ ~~ x O x '' u'N
p~ N V~ r, 'V
r~xi~h~ ~~~x ~ ~~'C7 Mh yr~~.~
wr ~ vi ~,r,'~OW ~b~D ~. vx~p~'~ qtO~nM~
n ,~ W ~ L~ ~ x <h x C!~ ~ N i~ ~-i cri ~ N yO x' +j tT _ ~, v~
~_~'~4x~
~; '~' ~~ ~
.WO ~"~ N C/1 due' dM', rM', ~ N i-. ~ ~ x N ty-~' N N rte, ',S~' ~ N i~
v b H H H H H
n ~~
~1 .N r-f 'e-~ r1 H
n U U
x U
U
U U U U U
b Z i° in in f3a N N N N
U

N
~ ~~ ~ x .~ ~ x Il O~.--~~~ N
r"'.4'' vi a x N o0 O vp vi~Dn~,x~~'M
~LV;xx b A l'~ II ~' ~, v O W.~r N
yp r~l.i .-n ~ ~i i~ d~ h ,--~ ~~ v Ci b op ~ b ~ r, b ~ Ox~ ~ d'~ ~
C/~ N .-r \O ~
v' ~ II N oo ~t ~~brs~;'~
o,r.bxxW
op ~ ~, ~-i N
~x O~ N N
x~~xx~
~I ~ N
bA
O
F., N
w M
x U
M
x --~~ U
Gw x d z c A
M
N N N
U U U
xz M M M M M
w U U U U U
x x x x x z~ x v xz ~ z /
/ \ /
\ ~ v \
zx z / xz zx x\ ~ /
M M M M M
U Z ..., T-, ~.., ,..; ,-, +., A
k ~ ~ k a~ a~ a>
M
." .~ N
N N N N N
N N
cUC N ~ N cVd c~ c~ c~ c~ N~
U U U U U
b o .d d d ago N N N N N N
O
U U U U U U
, , . , . , x x x x x x w U / ~ U / w / / z\ 'z YIO
fx \ w \
\ \
z xz zx xz~ xz~ ~ ~ z M M
U~ M M ~ M M x M M
H ~ ~ rH H H

N
ran V C/1 +~
N
N M N M ,._, ,..., c~ O
d' d' ~n ~n .~- ~t.
i~ i-v iv N
v 'r v v ..r v cCU
b o 'd ,n h N N N N N N N
M M M M M t~ M
.~ w t~ U U U U U U
x x x x x x x o I ~ ~.. ~ xz- ~
z / ~ zx ~ /
x / ~ z ~ r ~ r W ~ x zw xz ~ z xz\ xz~ zx \ xz\ t /
O M M M M (~ M M
~z c A
G
CV N N N ~ cn N
M lV N h ;.d d' rY d' ~ N d' d' v ~ W a U

.a a~ '!~ ~n p ~n ~, v, ~, p ~ ~ d ~ ~ ~ d ago N N N N N N N
O
U U U U U U U
, , , , , , z ~ \ ,- ~ ° ~ ( z~ y \
\ ~ z / ~.~ \ , zw \
x[ xz xz xz zx zx zx \ \ \ \ ~ ~
O M M M M M M M
~z M
d' N N N
,N iri Vi vi c~ 00 Q\ o0 A ~' ~t ~d' i~ n W
's ~' ..
C ~ v1 ~ C/~ '~' i M M
~i a1 rj C~ <,y _,-~
<I' d' ~ th .°~~ Vl n i=n i~
+ ~ +
v W a a b O
b~
O ~ N N N N N N
O
~W
U U U U U U
x x x x x x x ° ° ° ~ ~ ~ ~ °
z ~ I xz ~ z z \ z~" ~
x zx x~ xz~ \ x~ ~ xz\
\ \

~z M M M M M M
r1 ri r1 ri r1 H

h x N h f.., N V7 ~-Wr o0 II v~ M
~~Nx ~.~~.~x~ x~b~~.~
o ~ ~ o~, ~ ~ ~--' -d o °° ~~~; II
°° 'b ~n x II '-' r, ~ ~ II ~ N o Wit; t~ ~ h ~-".'~~'~".h nj '~oo~~~,Nb x x '~
~ ,-: x ,~ o N ~ ~ N °° p N
.O x d' ~ ~ 01 .S~ n1 ~ ~ O ~O ~'' .-w N N
vN ~O d' "x tW sM II ~, v ,ri N x A M ~_ ~~ N ~ ~M ~~ _ ...ix ..-r d' x a M ~NMxrm M ~xoxvV~ c~o~ II x.~M
~ M ~ ~ N W ~ ~ .-, ~ d' ~ ~ ~ po ~ '"'~
N ~ M ~ ~ M N Ov O ~ ~ x "~, ~ "~' Oy ~
"~ ri x "' ~ ~ 'b r-~ 00 00 ~ W '~ '"'' M N ~ ,-.n C%
O r~i .~-i d' O +S ~ ~, M C!1 ~ N ~O ~ rv W
d' ,-~ N ~ '_' ~ '-s ~ '-' ~ x wr C/a ~ W/7 rs rv C/~ x l~ r~
v1 O~O ~, N,r.,OV~-~C/l'~~'x~x ~ ~M~''~~'NC/~
d' ~ ~ x ,~ ~ W (a 00 ,.-~ ~ ,-~ '~ cal q V'1 ',~i d' i~ ~ ~..r M ..-~ a e-i M a I~ '.s N
00 ~ C/~ ~ N ~ N 00 00 t-. ~i N
'O ~ ~ ~ N ~n d. o~ ~ v N x OV ~ x ~r M ~ ~ ~ i~ O x d; ~p ~ ~O
C!~ C/WO Oy ~ o~ x N "'' ~," r x W d; 00 ~ n II
-, ,-,-S-,, II ~ x ~-mD .. Lfls II ~ II N ..i.- o0 I~ ~ x t--. x 'C!
O ~d b ',N ~ N N M M
i.~~ ~1 ~ ~ T-1 T-1 x x x x x U U
x x x x x z ~ z ~ zx /
'x' xz xz ~ z / ~ M
z I v zx xz~
...
O M M ~e~t' 'd N
~ rr l~ N ~ ~ ~ N 00 ~ N N p °~ N r~-i Wo ~ x .~ '. t1 jj II ~° x ~ M ~ ~ °' N M \°
... x II
~ ~ x ~ M ~ ~' ~' ~ '~ ~ ~'~ oo I1' .oo ~ '-~ ~ ~ ~ °a ~ M ~ M x b "~ N ~, x V7 H II ~.r .-'' ~
°° x '-' M .-; °° v~ ~ N °° x ~ N 'V
~ .~ '-~ d' '~ °° ~ N ~ V7 .~. N 00 x ,~ O ,.~ ~D ,~ ~ ~ W
~ ,~ x ~ II ~ ~ N D1 ~ 00 ~ ~ ~ x b [~. x ~
N ,-, ~ ~ N ~ ~ x rx ~ ~ Ov O N p ~-~ 00 rs N V~
v~~'~(3~ "~~ N~nx~ib W DO ~ x '~ N x ~ ~ N _ ~ ~ ~ ~ t~ ~ .-, '~Y r~l, x N ~ ~ N ~ N ~ ~D x r-, '~ ~' x- . C x ~ '~ M x _~' ~O x N ~ ~ ~ x v x p ~ ~ b ~' N .-Mr ~ N r, ~ N o ~ M
c0 ~'' ~ 'O x ~p h '-' o0 N .~; c0 ,-, N ~- cp '-' N ~ ~O ~l1 ~-.
~N i-yell ~O iWu~~~x '~bm~~ ~Nxx00d' ~~~~00 ''d l~ V1 ~'' N 'b ~h o0 n ~' N b ~ ~ '-' ~ 'd CO N O ~' ~i 'C M ~ O~ 1p p .~ ~ ~, ~; p Do ~ x 'V ~ ~ O o, x ~ W O ~ j' ~ ~ W O °° x °m II
Cl~ x ~ ~ ~ ~ II '-' N 00 '~' ~' ~ M '~° v~ x ~' II ~ C/~ .-, h x O ~p '~ ~ r, N ~.ri pp ~ ',~ ~ N Cla '~ ,_.., ,.d r-, N ~ ~ ,~, ~ r~~~ b v N M II ~ ,-i "vd" ,.~'Ci, d' r-~ f/.7 ~ x ~", N ~ A ~ ~ Tj N ra ~ ~=~ ~ ~ '-' 00 ~ ~ ~t1 ~ N p-rrt x ~ 00 Nxxb xo~.;~~~ ~;,...~~x Wow,-.a'° ~ ~o op oo N ~ oo ~ III N c1 ~' ~ ~ II v0 ~ op ,~ ~ II vD N ~ ~ ,1 r-, r~ ~ ~ c0 ~ ~ N N i-; N r~ ~' N rv x n ~' N ~ x ~ rx x~~.,o.. ,'! xbxxx _ ~x~x x~x~x~ ~~..~~~-b ob N fV N (V CV
d ~ H-1 1-I H I-1 H
b M M M M M
W
x x x x x x 'x x x x wM
U ~ ~ w / U / ~ U / ~ w /
xz xz xz\ fzx % x \ \
o ~ v~
UZ

~' b -~-.: x h N V N v N ~ v II v 00 t~ ~ ~' II v ri ~O
ri \O x 01 ~ ~ b tn ~ x y~ 0~0 ~ ~. ~ ~ ~ N ~ ~ ~ ~ r; N
O '~dl~.-'~rx ~ ~'UM
n 00 ~"~ N V~ ~ ~ n II ~ ~ ~ ~O ~ vi pp n ~ ~ ~ '~ 00 v r x °° x ~ b ~ 'I° vo 'o x ~ m x - x ~: x a\ 11 ~ ~ x oo x V7~M.-y_ ~~~, IAN
N M ~ ~ ~ x ~ "'~ ~ v \p M ~ .fl ~ ~ ~ Zj ~' ,.~., .fl ~ ~, 00 t~1 .N ~ ~ M vi l~ N ~ +~ 00 ~ a ~ rW r ~ 'C +.~
A V x ~ ~p ~ " ~ O pp w.s r, ~p x ,~ N ~., N x a v 00 O r, ~ ~ O N
'_" r ~ ~ oo O v0 r~ ~ ,~ ~O ~ oo ~ N °o O~ ~D ~n dwD ~'? O x oo M
~ I~ ,~ 'J cri 1l ~ x~ ~-' O a ~ '_'' o~ O II M ~ I~ ~ N
:G I I '-' ~~: y1~ h tn ~ ~ "' ~. N ~O M ,' ' '' ~ N d..
up ~ <j~ r~ ~ ~O _vi ~ ~.~~ t.0 x 'J r~ up ~ ,.~~ x n n ~ ~-~1 x~, t~j ~ n to ~ "~d ~ N ~ ~ N d. ~ ,~o N ~ ~ tN~ ,~p ~ ~~, v0 ~i r~i b ~.r~ ~ 00 M ,~Ti, x C/~
'C -. N C!~ "C~ M ~ Q1 'L~ N ~ ~.r~ N 'b ~, N N ~~ ~O ~p 'O ~ ~ v ~xM~M~tri ~x ~ II ~,'ysOd~ Ox_~~_~,' C/~ 00 ~ ~ ,~ ~/] ~ N er p ~ ~ [~ W 00 ~ ~ '~ pp ~' V pp ~ ~ ~ ~ N ~ Q1 ~
rv N ~p r~ ~ _~', O ~ ,~ n ,-Wp ~i ,.~~., N ~D ~ O_ N r~ ~ ~ N ~t O N
II ~ q x ~ d. ~ ~ r, W ~ x l~ ~ ~-~ s~~~
'~ ~ N N I~ ~ 'b ~ ~ ~ N ~ V~ ~.,~ N ~ ~ ~7 ~ ,~ ~ i vi M ~ rr-~ x t~ x ~ c'1 M N O +~ rx b x ~ ~ x ~ M b r~ M r~ W
00 ~ ,~ ~ ~ M 00 ~ d~ ~ 00 ,-, ~ ~ '~-~ N ~f' ''~ ~ d' v M ,r.~, ~ ~U ~ r~-i N ~ ~ ~, ~ ~ O ~O ~ ~O N ~ N 09 ~ ~D t~j t~ ~ C/~
00 ',I,' M II ~ h ~ '~' ~-~ .-.~ '-~.~'' II '~' M II (I "~' N u'~' ~ .-..- II
'~
b N N N N N
I ~1 f-~i F ~~1 H H
M t~ M M
~N f~
x x x x x x x x x x z l w xz \ i xz\ \
M M ~ M
V

r' ~ oo "~ 'rj ~' h ,._., "' -" ~ ~° ~~ ~' ~ b " b ~ b ~'. II '" N o0 n '° ~; 1 xN~°~ ~~rn ~~'~ ~~~t~~-, Nxo..
V7 N O ~--, N ~O ~-, ~ ~ O ~ O o0 00 II N ~ O ~ ~ x l~ r, -00 ~ c~ .,..; x oo .=j ~ ~ M II .-. ~ II ~ ,~ x ~t ,-. ~ x ~ ~ oo ;~ ~
rvv~ ~ ~v'~~~~ M ~ ~' .~~~ z n N ~ II b ~
x~xo~° xo~xx'~oo x~~~~'D+ x~ ~;~~"' ~
~--i ~ ~' ('<j II ~--~ 00 h ~ pp ~ ~ r-~ ~ II ~ .-w ~"r -~~
~ ,.O ~ ~,' '~ ~ M ~ ~ rs N 00 ~ rri N ~ N O ~' N ~ N ~ x 01 ~-i M
"x,.~xb~:.vxxx ~o~-~x~ ~~bo;.~xc;r.,c~ II °°~
~ ~ f~ ~' O ~- M a N II M x M N ~ N h ~ O 'I ~ ~ x ~ ,~, b x yr ~~ '"a ~ ~ l~ Cl~ ""~ 1Q W-. ~ ' ~ c~ ~' C!~ td ~ '-' N Cf7 ~ O x M ~ ~ ~ N ~ ,~ x ~ pp '°° ~ ~ ~ '-' ~ W oo 'p _~ '~D. N N
N
oo r-.~ ~ ~ ~ 00 II ... ,-. N ~ ,~~ II ~ ~ N ,-~ ~j ~.o II ~ ~ ~ ~ ,."L,, 'G ~ ~j 'G ~ ~-", N N pp ~ "U ~-, p~ C; "C7 r-, Q y.~, oxxx ~oox~~x.~~o~:~ ~
N a ~ ~ ~.r ~D v 'r v ~~,~ v d. ~"r ~ '~
,.~~ N~ ~00 i ,~, N~~~Ox~ ~~x~ON~ ~ ~~xx~~~r~iZ
~x a ~~W_~x~xbN~~~~~. ~_w~°_°~ x ~
~"i _ ~ 's N ~ r., v a 00 M l~ ~D
bb,~x~ .~x ~ ~xx ~xxxMx~ xx N
II
N r' ~ ~ pp ~D r., V'~ r, r. N ~, ~-, ~? ~ ~' ~ M ~ M
x N i-s ~ N N II ~D nj ~ vi ~ ~j rs N i-s ~ l° s1 ~
II ~~xx~ o x~~ II x ~n xxxx.. III b~xx'~
b 1-~1 H H H
n ~'" ~ M M M M
~ W
a~
° \ xz-z z ~ .- \ \
zx I \
x z I /
z~
z xz xz\
xz~ ~ \
~, o ~z ,..., ~ ,-~ N N N ~ ~O
O
~: M '~~" N a x ~ N ,x ~ ,.~~ x '~-'~' x ,.~~'~, ,n M h ~' r N r ~ ~ yp V1 a1 ~ ~ x V'1 ri ~--i ~ Yj x ,-, ~ V7 n O ~ N ~ ~ ~ ~ 00 ~ ~O l~- ~ N ~p ~'' ~ N ~ FII r.~ M N ~ r MN ,n ,~, x '~r oo II '~',' op .-, o0 111 II 'j1' II ~ '',,L,' '~' ~ ~ "r~,' t~ ~ M vo W l~ M Op ~ ~ ~, N 'r-1 ~ ~ ,-~ y--, ~ N o 'd. ~ a ~ ~-' ~p xi ~' 00 V1 ~D r~ ~-, "d t~ x "rT~ b ,~; 00 ~ p~ d' ~ ,..., v O
~ N W ,-' O~ L~'~ '~ ~ j1' Ih N ~ OMO ~ Ih '~, N
cCt 1..., 01 ''.'' N O1 N ,.~, C/~ O;, ~ M N 1~ ~O ~ V~ r-, ~ .,-~ N r' 'b ~ r~' .O r ~ M N ,~ CO' ~, r N ~ +~ b '~~," ~ ~ _.1.-" _ui x t~ir~Mpp M~l~ ~ .-;,~rM II ~d'MxxC/~ p~~~ N
~ ,-, ~ M .-~ ~p ,n ;~i ,-; ~ ~ '~ N r~ x .~ ~ '-' v~, oy ~O N N
0o t~ x '~ M II ~ ~ x N vo ~-~ ~ ~' x' ~-1 "~ oo r ~ v~ ~ oo ~ N M ~
tp ,I~, N ~ .~ h rA ~ ,--~ M ~ N tPJ N N .-~ tp n ~ ~ ~ rx~ u0 r~ "~ rj 00 ~.., .. x x, l~ Ix ~ "x N r~ p\ t~ r~ r~ x ,-i VI
N N ~ b cNn x ~ v oo TJ can ~ ''~ ,n p ~O N ,-~ .C N
O °r° ~t ~ x o Q °° vo x o ~° p oo ~ ~
~ x 0 ~ x ~-: ~ x O x r ~ cxy v~ is v~ ~". c~i II v~ .-: ~ II v~
~~'v'oFl1 r, ~ b"~"~b ~1 Nvor ~Q ~~~'~'~' II '-rte N~'~,mo p '"' ~ N O ,-i N Ov N p~ d' ,-~ o0 'et ~ ,-~ O w-~ dy0 ~d;~~ ~ xr,-.boo xr~~ooM bbcyi.~
r II ~ ,.; ~ ~ c~ _ II
~O ~ N r O ~: ~ "~ M O ~ ,~~.~ s~ s~ _ ~ ~ ~ ~ x 0~0 M r ~ ~' 00 00 'r M ~ .- h r~ ~ d' rr-t, .- h ~ ~ .-i ,.~, ~ ~ o0 l~ x .-, O .~ 00 rll, N
WD
'd O Zy ' ,~ ~. N (V CV N N
H r ~t r-r r-a r~
b~
M M M M M
w w ~ r"
x x x x x x x x x x N
~ z o ~ o x, ~ ~ , ~ ~ z ,~ W
xz~
f~ O M . M M M M
U '~ ,-, ,.-.

'd ~ °~ V? ~ N ~ _ v M wr O l\ \D ~ ~ v t~ rs ~ O~O ~ a v I\ ~ O~ ~- d' ~ l~ n ~ ~O
CT1 d; ~ rl~, h N ~ ° ~ x ~ ~ C+/~ N ~ ~ pip i/WD O
~,'2', ~~'r~' M~: ~O~x ~W goo h ,~ b ~-" x ~ ~ ~ x w ~ .o x .r ~ ~:
vVCO ~~; ~~ ~~ ~ ~~ N x ,b N
~ r~i N ~ ~ ~ ~i r~i ~.' ~_ _ N ~ ~ t~i N ~ N '~ r~i x ~~ ~ .-, v O
'' ~ '"' x ~ ~ II '-' ''' M ~ x N ~ ~ .~ x M ~N"~ ~ ,-... N _ uj '-' N O r-~ vi N y~ ~--i x ~ N .-mr~.~ ~ N V~ II ~ O ,~~
'~'°Nx~xx'd °x~x ~~ ~xcf~i ~~'x° '~'°x~-~..ro~v~
O m II ,-.i o0 ~ L~r ~n ~ N ,1 ~ ~,~' W
A .-a 00 ,y-. ~' O N ~: ~ r' O II N 01 ~ '-' o II N ~ ~j r~ ~. 'd~ ~ ..i v °xr'~r.~'['N,''rN.,° ~~''-'r~~"oxo ~'II'~~"oxo o''II''''~x -~,~ri 'G ~ ~o .~ ~ ~ w w N
tip ~-, ~ N 0 ~ ,~, 60 '~ N t0 ~ N y0 , , ~ [y x M , , a s~
N ~ x ~ x ~ ~ .-. ~ ~ II ~ ,.~ x x ov .~.
"rJ r~ ~ ~ ~ ~. ~ 'C7 M ~ h N M ~ N "G M ,..~ N M ~-. M 'C N
OL~I~ ~~~ DoO~ +-" N~ O O~r~i ~'~''C70 ~~~ ~d'~W
'jI' ~ x ~ ~ ~n .-a ~ ~ ~ M '~~' x ~ ~ 'n ~ v ~ N o ~
+' II v~ ..., oo va ,-. N
~~ N N ~ ~~~ ~ N ONO r~~' ~~W N O ~~~W N 00 ~N x i~
~ ~i ~ ~rr~ r~ r~ ~ r~' l~ r~.a b rN-~ ,~ 'J ~ 00 x o 'r>1 '~ x t~ rx .
pp'_'1~~"''<y~ M~N~.f.-~M O~,-y:,-~M U~(~y~~~0 h r~ ~ ~ ~ N N ~ ~ r~i ~ O n ~ M ~ x ~" ~ ~' M tII x ~ ~O ~--, N
r.'Zi v-. N v r~ ~ ~ .. f-., ~ v I~ rW r d' .-. f-. r-~ ~ d' .. i-, r~
O
~;
bA
'~'' O M
M M M
-N W eM-~ ,-~ rw-~~
x x x x x x x x O ~ zi i i zw ~ W ~ W
x w xz~ . /zx ~ x /zx o. o c~ z b N N N ~ ,~ ~-~ ',.f; N C/~ ~-, d' h N t0 '-' a x '-' ~ ~ r II N v0 N N M +." 00 ~xn?N~,~~ ~;oo~~:ni~ ~~r~x~ x~.yo ~ c~ Y? o ~~: Wit; ~ ~:..d ~n ~ ~ °° ~n . :. 0 1!
°° t~ ~ ~ dy ~ N t~ x t~ '~' .~' O ~ .~ ~ 'I° ~ b '~-~' M
h M
ao ~ ,-.~ N ~ c~ ~; ,-.
,~bN'"'NOV ~'r x~x~~~ ~ N.-:=rx I~x~'~~°'~' ~ ~ '~~-1 ~°o'no,ci~'"'~''? ~o,~~ hx~o~ icy ~°°.~
O N ~ t!7 ~ x ~ ~ W V W r 00 V~ r., _ ~, N ''~ ~.e~ II Wr l~ ~ O C/~
O ~ ~ ~ ~ t~ ,~~ ~ O ~ ~ h ~ ~ .-i ~ ~ N ~ t-' ~ x ,I~, ~ N N ~ ,.~ l~ b b ~ ~ ~ ~ x x b M o0 b ,~''7, c0 .--~ b _~ N cA _vi ~ ~ ~ ~ ~ V i~ M O~ ~"'' ~.O ~ ~ ~, 00 ~ N p~ ~ ,~ t~ ~D a ~O ~ ~ M ,_, ~ ~ 0~0 II ~.~J ~ ~ ~ ~ t~ a ~
'O N r~It' CV O ~W p ~~ WD ~t ~ "O (~ ~ C~ O ~ 'd t~ ~ oNp i1 ~ o0 00 ~ ~ M VO ~ Q °° ~ x 'x x v~ 0 ..:.b ''' '~ ~ Q ~=, ~ ~ W
Vj yn ~ ~ ~ ~ ~ C/~ rs ~ N ~ N ~, V~ ",.'L~, ~ M ~i W Cl~ x ~ ~ v x r~' ~i ~"; v0 ~ x I~ N r; ~ N M ~ N ~ N <t; r~
~T,bcy~~-~~ If ~~~' ~~,r.C~'~"~x ~ ~1 ~~n"t~N~
~r.~r~r~i~j~ r~i,x0~'~D~ ,..M..,ir~i ~-,'o~od~' ~rx,.~'L",~~.-i N
l~ h ~; ~ O ,~ o l~ N C~ ~ II ,.~'L'~., 00 d' Q ~ ~ 00 d' 00 h I I tit t-m--> h N O .. t-wr ,'~m.r W O .. tW .r (~ t~ ~ .~ ,'Ii 'r I I tai O b H H H H

~ f~
x o z z / ~I ' /
w ~ w zw z~~ w x xz xz xz\ \ \ xz\

~z M M M M

II o~ -~j ~; N ,d .-..
O ,~ ~ ,-~ .-.~ 'J t~i .-a v ~ N ~ N
~ M ~ ~ ~ N N O ~ V Qv ry x pV~p '~t ~ ''~' x _~ "'. _t~ ~ oo N _''' ~ ~p t~ x n7 ~ r, ~
b NN~d~' 01,.~,~~x~' ~xN
r~ ~ b_ ~' "'' '~ ~ ~, ~ op "C1 M a ''' ~ ,yp O W x '-~J ~ ~ rx 0~0 x ~ O h ~ ~ O
+~ vi c~ ,D ~ ~ ~ x vi N l~ ~'1, 01 O vi N ~ b v0 ~ ~ l~
A ~ ~ ~ ~ ~ QO ~ ~' ~ n ~ 00 ~ O ~ ~.j iv, l0 N II x ~ ~ t~ ~ x ~ ~--. x tp ,-.~ r, ~ x ~"~ ~D Cl~
,~C~" Oy~ h d' ~ d' 01 'x .--~ ,~,, ~ ~ ~ x ~ .-, rx N c~d W
,~, tA v b 00 ~ tA .-i vj N wr ~." ti0 ~ ~, ~ N x -~-~ 'J
a .i-s ~ '~ ~ ,-, V~ ~ N ~ N O ..r N ~ N ~ r~ ~~ ~ -j- C/~
.b oo ~ o ~ W Ti '~", ~ x ~ o'no. c°-'n 'b "x 'M° '"' o ,~N, 'o V1 ~ O (~ ''~ ~ r, d' O lp t~ ~ ~ II M N M
,x~C%~ ~V~x.-~~I~ h~ ~ d' N '-' x x r~ A '-' x N V1 ~ yr a N ~ ~ N ~ v N ~ '~'~ a ~ ~ n ~x°N,..~~~~~xb ~oo~' v~ vi "C1 N ~ II x 00 ~ h tW0 i-: ~ 'T ~ ,~ M ~ W WW.r c~ ~d~',~'°o ~"',~~I rW 11 x ~~~N"-'~'~i,~~, ~O I~ a ~D '. x h r~ x ~--. ~O .. ,~ r-, l'~ l~ r~
d N cV cV N d' H
O M M M M O
i, M
,N W
x y ~ ~ x x U

x x x x U
z x °
U xz-~ z /I z x, xz , y x \ xz~ ~z ~ x ~, o ~ ~ ~ ~
z M M M M ,..r U r,..i ,.-m,.., r-.~

c~1 M
,N M
A ~' ~
v v c~1 ~n N .~ ,--~ M ' N
'd 'P d~-.~' ~ ~ 1:.:, i~ i~
v b O
h h bA .
p O C 4 C O O O O
M M M M M M M
r~
p; U U U U U U U
x ~ x U U . U U U U U
U U U U U U U
(] N
x ~_ o xz''~z z z ~ ° z v z ~ /~ x z/ \z i xz zx xz \
f ~z\ ~ xZ\ xz\ xz a ~ 4n yn ~ ~n -W' ~ ~ N~.
M m '-' V~ vi ~ x x V ~ N ~ x x "-' x' N ~ ~ ~ ~ _ yr N ~ oo ~ oo ~_C ,-~r~ ~ V) ~~ N ~1. ~ ~~ ~' x r' ~7 01 x N ~ ~ ~p r~, ~ o N ~D x ~ ,b ~ yr due' ~!7 ~ ,-~ n N x II ~ _ 00 x x_ ~ N r~i _~ ~ r~ N ~ ~ x x ~ ~ ~O ~ ~ ~~ -I-.
00 N 00 b x ~ tai r~ '-' r~ ~~., r~ N ~ ~ N I~ '~ ~-. rs W
ly0 ,F; 00 ~C~ N x ~ d~ v II 'b N °° ~ N ....~ 11 ~° ~-~, D '~., N m-. oo ~ ,II, ~D V~ ~ LD ~ h ~ c0 j~ ''~ ~ x' cy Cl~
°° y ~ II 'o h _~ r?
-~ ~G ~ vW. oo N
LO N ~ ~ ~ ~ v ~ ~ ~!j tA '~ ~ ~ ~ ~ ~ ~ b ~ x ~, x i-v V7 n ~ ,~j .-~ n ~O r '-a e~'C ' D d, ~ N '~, '~ I'~ N ~'' ~ a O ' vl~ r~ v ~ ~ ~ N ~ '~ b ~WO
~ l~ ~ ~ ~ O ~W'' "C1 ~ l~ ~ 0 ~ N
'C7 ~--. W n ~ x O VI O x N ~ ~ ~ O ~ n O .,.5 t~Ii d~ b N ~ ~ x N _ W Va ~x~ ~ ,~, _t°1 x ~, V1 ,~'r, x ~ ~p ~ 00 'o r~i hj N r~ ~:rj W .r ~ r~ N~ ~ ~ ~ O ~O
~~,-,tx~NM A~~~N ~,.-i ~,.~N, ~''b",NM
~D rs R~ ~ ~ ~ x ~ V~'. 'o ~ ~ N ~ b ~ o~'o, ~ ~''~ ~ ° ~ ~' b ,~ ~, ~ N ~ r, ~ ~ i °~ .-; 0 00 "'' + h t~ l~ ~ ~-y ~' M t~i .M--v ,-, CI ~ ~ ~ x 01 ~ ,.~-~ ~ ~ ~ 00 N o0 00~~, ~~hu.-~W ~.~Li~V'lMr~v.-. br~xt~Dr.~iO
O 'O C/~
v~ r~, r~ CV
r~
bA
V7 n!1 ~%
~W
N N N
U U U
/ xz~z -,.
z z~
xz~
zx d ~o .~QO ~o U Z ~ ~ ',-;

r" ~ X11 p ~ ~ ~,, ~G o0 00 a ,~ ~~., ~ II .~' N N ~ ~ O 'p ~ .zy x ~ os ~''~ II '-' w,. vo ,~, :-:
x N ,.d p~ O ~ ~ tW-= ~-~ N ~ _ x °~Nxb~~M~,° ~~,~x~xb_ N M ~ ~ ~ r-, c~G ~ b M x ~ ~O O ~ '~ "'~ ~ N
~x r~ ~,' 00 ~ N b ~:,~°~.~~M'nx'°~~ rt.o ~~ax,,o "oo rr~ x vi N ~ O wr N ~ ~ .r-i N C~ ~ O
n O~OCO~~ N~~iO~ ~~x~~~x ~x~~Mh (V N N " ~ ,~ ~ ~ ~b "~ b ~xbxx~°°x~ ~~ x~~.~ II ~ x.~
00 ,~ '-' ~ oo ~ II '"'' W ~ ~ ~ '"' ~ ,i~ ~ r '° ~, p~ '"' r' t~
N~~~x~ ~ci ~x~~~~,--'.1, noo N~ooo x U ~ .~ ~ _-c~ N b o'°o, ~ O N ~ °~ a~ ~ ~ W O av ~ 000 ~ ~
a xrd'~xn,'~:~~~x~h~''"'NV~~_~'~'_'',~I,,--.
~VVx~~~xW_~~'-'b~x~~~x~~b~dN., N C/~ ~ x rs ~ ~D ~ ,-, 00 N ~ ,-and x ,~, N O N o0 vi m wfi oo d' ~ II ~
__ _ ~ ~ h _ xx~x°~~x.. ~~x ~~~x~ ~x ~x~xW
o ~
a ~ b ~, o ,n ~ f~ ~ ~ ~ , U U U
r N
z U
z/ 1z \ , \ \
xz xz~ \ ' xz\
o ~ ~o ~;

N ~
rs r' ~ °° x x cr x o0 v0 N N ~ N N ~
pp ~ 'y0 x ~ ,..-, x '"' ~ p h ~ ~b ~ ~ M b ~n 1l xoo ~v'r~',~r~~,~
~-~ aW~ ~"' ~, N oo ~ .~-~ ,~ N
r~ vi l~ ~ N Tj O ,-, ~j O
a .~rrv '~'-'N x ~ ~ri A M rx N ~ O°°1 00 ~' ~ ~ oo ~
tet p ~ '~ l~ ~ Oy ,~
""' v II M N ~ r'~ II 'n M
~ N ~ ~ ~-' x ~D ~ ~ ~' ~ x WO
.--n o0 ~ 'G ~ ~ M
~ O N C/~ ' O M N
xt 1~ x x ~ W Q LD \O x x n O ~ tr-~ CIA '~ ~ ~ O .-Wi ~ ~ N ~ ~ ~ x ~ y N
o'~ ~"' N i~ '"' N o'~ ~ N
~O l~ ~ p~ b r~ r~ vi ~'' ~ b x r~
O 'J ~ M ~p ~ ~ " M ~D
O O
N '-' ~Y ~ N O 0~1, '-' M ~ N
.-, t~ h Vi ~ "~'' .~ o0 vo h ~i ~ ~, "d O ~~ N
.~C ~ N
H
nn :a W
x N N
U U
U
x z U x c~
/ ~ /
\ \
xz xz~
o ~o Uz N
~ 01 ~
. .-, rx d; .-v x ~ N l~ l vJ 00 ~r" yr x b x I~ ~ N l~
.-~, x '> ~ ~ O NO O ~ Ov °'-'b~D° ° II Nix'~~~
'-' ''~ II
(V b ~ N ~ ~ ~ m pj i-~f'~, '~
~ x ~ x V1 CG x ~ m ~' x '"' O b I~ Ov N ~ W
+., _ t' N ~j r.., r, '~ l~ rx ~D
A ~O~t~i N ~~~"C ~~ 01OCl~
-W1 .~ ~ x ~ s-W ~ ~ M N
O ~ ~ M O O ~i ~~ ~ I~ nn r/J' ~, '-° ,~ II ' cp rri N ~-~ N ~O ''-' N ~ ,~ '',.1y , ~.., N i=. M a ~~o vW'~b~ .~ooMOr~'xl~p~xrx >~
'U, v ~ i N 'J t~j v, o0 O ~ ~ ~ 01 Ov N ~i ~ ~N
~ ~ N ~O ~ x '~ ~ ~ x '~ '~ b ~,~x x x a N~~",M~ ~vb~01 Nbb ~'~
n x N
C~ V1 d' ~ 01 ~ U
~~~x~~ ~~~x a 01 N ~ M et ~ ~ N '~ ~ N O
01 ~,,~ t!7 01 ~ ss N II n n .ti x o; ~ N cYi o x x x ~ ~ '> ~ x U
o b h tiu b ~.
w H
x x x U m U ~ U
U U
' O O O
/zx ~ x /zx x x x U U U
'p 'v~ U
U
Uz II II p p iO N M ,x~ ~ ~ x Ov ~ 2y p b O ~ N x ~ N O~ oo N
~ l~ M x p M M M ~ v '-~' ~ ~-: r'' x v CV l~ O ~ N ~
_ N O\
II °'~x~
N x ~ N ~ ~ 'C '~" ~ M C/~
x~ox~o~o ~v~ ~'~~w ~x~~, CC ~ N N l~ '~ ~ ~ O ~ ~-' V N N
'~t d; b~ V~1 ~ d' ~-' Lfl C\ M ~ ~ x ~ C/7 00 'y n ~ ~ ,~~ 01 ~ ,,~ ~ V ~. 00 V ~ I~ ~ II M C/~ p~p ~ ~ ~ V~ x x y--n '~ iv '.N ,.M-~ ,~~ ~ ~ ~ W pp ~ ~ m N ~ pp ~ n op x ~ TJ ~ Vj ~O c0 ~ vi N c0 x \O
~'-' . . ~ ~x ,nN N
~t~.~oo ~~vx ~c~ '~ ..:-: b M . 'b ~ o ~p 'b o0 O ~O 'x ~ M x ~ N N M ' ' II I~
M r: O ~p ~O O ~ ~ due. O ~-: N II O ~, Q, N ~ is x N N oV7o ~ d' '~-~ ~ x' r~'~ '~ .b "-' x ~ N x M n ~ W .'nr W ~ ~ x O ~ O~
~ x N ~D ~ ,~~, ,~ '! fZi ~ p N M 'C7 v l'~ N II ~ ~ 'n ~ ~ N ~ .-r ~ I'~ ~ DO
l~ t-~t ~ M c0 p\ ~: r: p O
00 .-~ II O N .~ :~: s~; ~ x x .:
x o0 N ~ t~ b ~ x x x x x x v0 ..-i x O~ M x 'b O b H H H ~ H
ono o'~o ono 'd' '~ °°
M M
U U ~ U U U U
U U U U U U
O O
0 0 o zx zx z-~
/zx /zx ~zx x x x ~ x x w~ U
x x U
a o o~, ~ ~ r r ono dr', ,.~., ,-r ,-, ,.-.

N Tl 's ~O
O _ cti d. ~ ~ N
'et ~ °o ""' ~i A '~ I~ ~ d~t-ec N ..
N ~ N ~ W
b ~N~
N vp v N
b .C d y '~ N
GD
N
it O prJ
,N
M
U
x U
i zx x x U Z °°

~ ~N
~.x~~ ~:b~xx ~ N ~ N x '~' x N x ..-i N O '.~ v ~
"" t~ x ~-~ ~ N oo ~ II
b N ~ 01 00 v x y..r \O
x II '-' II c- ~xaM~j 01 ~ ~ d' ~ ~~ ~
b t~ b ~"' II ~j I~ x O~
~x~:~0 A ~ M ~ M ~ b ~ ~ N r~
~,~Mxx "
~x.~xNx r. o .,~ ,~ ~ ~o ..d ~ II ~ ~r d' N ~ N M N
Mx~x~x o~.~.b°''t ~~,x~x~ x~~~~
M ~ d' ~ ~ M ~ ~ ~ "'a V'1 ~ C/~
~' U II ~; 1! ~; 1l Ux~~xv r. ~~~~~~ ",~r.~NV~
b N b ~n b ~ v ..~ x ~~VM'1M01 V1~ NNx x oo x l~ ~ O x o0 ~--, x M ~O
O"
nn o ~ M n w r, x U U U
x z x z O
U
zx nn o a~~..
M M M

vr~

WO 02/34711 PCT/USO1/32s82 _ _ _ _N~ II Nr~r~v ,>b~~~' N°~°~x ~Vl ~ ~ .'t7~- ,.-; 'r~'' N ~ ~ p~ ~ N ~ .zj 0 II vi ~D ~ II o ~ =..
'r '~ a 'W.r M i;
C'1 x ~' x N ° ~O ~p II ~, tn ~ ~ °° '~ ~ ~, ~'! 'd ~ ~ xi p~ O r~-~ ~ ~ '~ .-~ x °.'~ ~ ~ l~ x ~O
~ ~j oo tN ~ II N ~ "v ~, ~p ,'~ ~ r' b ~, ~ ~ M ~ ~ ~ .-i ~ ° n N ,~ ~ l~ ~ ~ r~ CO x N N
II 'r ~
~-~' ~n o ~.~, x r, N r, °1 "~ ~, ~ ~-~, II
I ,~ 00 N M ~ x ~ ° vi x W
A ~r II nj II '"'' '~ ~ ~ ~ ~ ,D ~ Oy N .-~ a N N I~
0o '~ '~,~' '~ b M ~--r r~ ~ ,<y ,.-~ '~' x ~ l~ r~ b b ° ~ ,-~ N II oo II vi ~ ,-. ~ ~ ~ II
:N ~ ~ ~ ~ ~ ~ ~ o0 ~ ~Y ~ pp ~"~ '-i ~ O 'r ~ ~ o0 c ro oN, II o~~, ~ .~ °° '~ ~ x '''' b uo ,.d ~ II ~ 'r ~
°~' II b o ;~ oo '~ t~ ~ N ° ''.~°. ~ o. ~ o .-:
~ '~~' ro x N ~ x' ,~ U oNo III N ° ~ oho x ~ '" ; ~ ~ ',~,~' ~ ~ r.
N M .-. N ~ '"' d- ~ ,~ vi n ~ ,-~ ~ .-: C!~ ~ M O ~ '~,'' M ~ ~ ., ~~00 N x II ~, O ~~b ~x ~r~Li ~ l~ N ~ la ~~0 x ~ O
r~ '7 ~ ~ ~ rr N C/~ lp b o~0 ~ ~ pj ~ ~O ~ ~ ~ N r-i x ~v,' ~ ~ 0~1 x1 ~~"' ~ <h Oi N ~ ° ~ + rat ~' r~s ~. ery ~'t o0 '~ ,~ :-: 00 '-" N ~
n ~ 01 ~ V7 ~ W ~ trt ~' ~ Y-vv QJ M ~ M II N r~ ~ r~ N V1 t~-v W
x'.~~.,~x ~ ~4~;x~~,:~~ ~;~x~M~ xx~N.~
V7 H ~ W ~ H
M M ~D I~ 00 N H
r~
m m m U U U
z z z U V
zx zx zx o~ o~ o~
an o p '~ ~, b M .~' ~' ~' d.
z ~
O
~z 2s1 WO 02/34711 PCT/USO1/32s82 00 ~ '~N' ro ~ N N y--. O~O
x ~ b ~ O M ~ ~ ~ M x ~ b II "d p II r, II ~ ~ ~ II ~ ~ ~ II N ''~ N x h ~ '--~ ,1 '"" h O~ b d~
..~"''.r M ~--. O a l~ b '° x p N .: N ~ ~ ~ ~ vo x oo x d' OO '~ d' x x x Op 'r M x pp "a ~O "-' 00 xx~OM~ ~~~M xx~x~
n '""i uj ~D
N ,-i x '-' ~ II d' ~ ,1 ~ N r.. l~ ''r~
vi o0 M t~ ~ ~ ui ~ x V7 vW p ~ ~ N
~rll _~l-Mb 'Lx'-"M 'III ~'-~ N
r..mr ~p O~l~ II ~~ Nt~~i.~~M OhM
O~ 'Vd ~O r"o x ~ O~ ~ ~ M ,-~ 01 ~ ~ .b ~O
t~0 ~~ ~ ~ N ~~ p ~ h ~M ~
t~ x 0 '~ x ~ ,.~j ~ ~ v x ~ dx' p ~, M
-i 00 ~ x .-r x ~O iv .-a 00 frj ,y, ~ O p ~' N M VyI- yp ~ M
01 ~ ~ v I'~ M C/a vi ~ ~p G~
b ~"x~'°~.... rr~'-'~:'., err.-,ooxo;-:
v~ ~: II "~ v~ II x ~ v~ ~ N M -,-p N M x, ,..., 00 O ~ r-~ ~ p N (~ vi ~x~~ ~ ~n ~ ~.x td0 d> " N b ~ a0 x b ~ n tA 01 i-y ,-i h x N x ,%~ ~ xi i1 r, ,-n ..'n° II Tl ~ ~. N b N pip p ~ ..'~d II ~
o ~ ..... o, ~b~ II xx o°°~II o ~b~xM~
~~~~ N II ~ r~~~bx a~~xxx x ~ ~. N N ~O
N N l~ +-~ U7 N t\ d~ ~, A.i ~ N r-i N ~.O
.; " ~ ~ ~., ~ N ~ x II
r: '~ o ~' .-: ~ .~: ~n ~' '-~ t~ rt r~
xx~x~~i~ xxxx ° xx~~~b O ~ CV N (V
~, w M M M
M M M
U U U
tY, x U U
U
U
ca .Q
A. ° ~ o 2s2 O N r, N II N r-, ~;
"' ~p t~ l~ ~ i--, ~ ,.~ ~' r, vi 00 ~ ~ d: b ,~' ~ l~ b o0 n x ~ cry b e-' Vj ,n II ~
Ii °~'.x~~x II °~'."'~rq h ~b _ '~, "~' N ~ ~n N '' b W. x ~r~'~~x~D ~~x~ N ~~~F'."'~~O
d; ~; CV ~ ~ .~ p II ~ ~ 00 v-w-W; b ~O
~ ~ vi II ~ N ~ H ~ ~
00 x r~ v r-a ~ ~' II N ~ ~ ~ ,~~ ~
.;o~ M ~ oo b ~oy''' ~ x II M ~~ M ,-. b .-. b m ~ h o~
vi .--~ O ~O ~ ''''''' ~D vi ,~ 00 0~ '"~ '~~" o ,r oo ~ ,-; II ° + ~ ~ ~ d' '~'' o N a ~b .: ,~ a ~x~~~, ~ n ~ fib,-:
~~'t~'~xx p~,,xN.bn~ ~ uNx v x b t~ 0o r; ~", r~ ~ M ~-i M M ~ '~'~, b x ON, trj ,_, '-r ''"' lp ~ ~ ,ys O yr ~ ~.~
00 ~ ~ M N ~ v.r viO~riII ~ vO~00~~~ VOM~xV~
00 ~ p ~ oo W '~ ~ ~
~ ~_ ~ ~ ~ r' ~ x ~ ~ N ~, ~ ~
II ~ N N ° x' ~ 'b ~ .-: x ° x II ~ ov N
p~ a0~ N ~' p d~ N ~'O~ N '~ ~ M v0 c0 N h 01 x ~ ,--~ N
y0 "~d ~ op ~ '~ ~ ~ "d OO ~ F"~ 00 ~ Y~ ~ ~ ' ~ II t~ b ~' II ~: ~ II ~ '~~' ~ M b ~ II ~ b b II
. O~ h f--, ~ h ,~ '~ ~' r~ ~, h ~b ~N r ~'~ A b i~ ;~ II ~ ono A b N N p ~~
N I~ i~ ~ N p ~ .-~ o " f~ ~
v~ O
N N s-s ~ ~ + ~r N N o0 b nj ~ P~.~~ N N ~ ~ ,-WO
W ~ ~ '~' x II M W ~ ~ '~' II ~ '~" x ~ oo ~ "~~' ''~~i cri xt ~ M ~ x ~ ~ b 1p '-.~ ~ x ~--~ ~ ~ x c~t v ro ro N , , p a ~, w ~, ~.
M M M M
w U U U U
w O
~ U
'~ \
x v x W ~ /
U V /
~d a~ w ap .~ ,~

H ,~N, b ~ N y-. ~ O ~D ~ p~ ~n 'v 1l II ~'i ~ti "G ~ o M 'fl 0l b t~ ~ ~ II W .
r-~ pp ~ h V1 ~O '"~

..~ oo ~n II ~ II b '~' II 'D ~ II a~, "-~ x '~~.
,~i ro , ~ ~ b N M ~ i ~
x y-, " ~

v b rx, a . ~ eY
~, ~ ~
v O
N M ~~
d~.,' ~xx~~, N ~ N" Ov ~
D ~

~ N ~ O O ~ x y pp , ~~ x ,~
II ~

vi ~r N
x r~~O~ ~ ~ O~
M I~ ~ h x x ~ ~~ ~x ~M
"..' N ~ ~ '~' II w0 00 ~ O

~1~,~ V'~'-r~ II r; ~~Oxr~~i=.

N II ~ b ~ N
~' I~
I ~
' ~

o y-, l~ C b ,x , oo I , II r,-, ~
~ 'b ~O r-, f-- ~ ~
oo O~
~l i ~

CSC. ,b 'x O~O d: _ ... N r.
~ o ~ ,.bd "d .
,-~ M C/a ~ d. ~ 00 t _~G'x o0 xi ''' N 'r ,-y0 ~ ~ !1 ~ a x O M l~

,- ~ _ oo " o x -, oo ~
~

s. , oo .
N ~ II
,n ~ ~
x x ~
~
~

-i N "'' l~ ~ l~ h QO ~ N
x l ,~ ' n t!7 n ~ \O N
O N ~ r~i N O a N O ~ l~ ,.bd ~, O r~i ~ x N

~ .-n N ~ -v yr ~ N x ~ .-i [[ M N t~ ~

c0 O~ II ~ _ c0 ~ 01 l~ ~ O I
~ i0' ~O
' x~

xtr? i-s,~,"pt~~x ~
'"
~N
~

..~d II ~j ,-. b ~ " Il ~ n II ~ II
~ N ~_n - ~ ~ v~
V ~
~ ~ ~ ~ ~

i ~ ' r" I~ ' ' pp ' ~O + .
N ~p ~ ' ~p ~x ~ y x~x ~ o ~~ b a ~
~~ n a w ~, l~ ~"~ x CV o-'~ r-v ~ N ~-. ~, ~ N M ~' O~
-I- x N

N s~ 'LS ~ ~ .~~ V7 ~ x O -F: 00 O "C x N ~0"O
~ ~~'J~ qx~
t vN
'~~
q a o , p~
, I N
T 0 ~
, ~
II
N
~

~ a ~ rv Ntn i-v ~
'~ N rv,- t t~ t~ a , II M ~ ~-' !l N II x ~ M M
~ '-'~' _ _ ~'V1 Nx N
N0lr r r II Ox o0 N
~ x N
r x "~ x , xx Wr l~ b t -i II y ~
- M M

~

~ t . t , M r i p ,-, ..~ ,-i .d CA

4w W W
~

c M M
h w M M M
U U U

U

U O U

O V O

O O
O

.ct n A.
p U '-, ,-, ~
~

~oSN 'WNO, .1 "~ C.r; 'I' .,; ~ p ~ x ~ ~ ~ N ~: ~ °° ~, II ~ 1p 00 x N W x l~ h x d' ~ N t~ x ~ N ~ v H' N ~O
r~ ~ N ~ x N t~
~ v~ O '~' C/~ ui ~ b N N ~ °~ ~ N N ~ b O II
M ~p ~, N x ,I~, .r~r W ,r ~ M N yD ~ h ~; '~ ~ ~ ~" "Cb 01 v ~ '-'' 00 I I '~-W .r II OW-, 00 M ~ ~ ~ x II ~ ,-, r~~, ~ N ~ ~ ~ ~ ~ ~ 'b (p II ~-. r~" r' N b ~ '~ N II II ~ ,-, r-, l~ N d, '~' ~ '-r ~D ~j ~ rte, ~ ~ ~' ~ h O + ~ t~ ~T
"PVC N ~ '~, x ,--r p N 0 ~ "~C x ,.C M j7a ~ ~ O ~ _vi .i~ ~ l . t~ x r, ~ t~j ~ ~ rv ~ p N ~ ~ v O M 00 rx d.
°. O II ,~ O o, x o W ~ ..-~ II '-' Wit;
~_ ~ ~ ~ ,..~_, ~ ~ 01 ~'_' tt~i [s. M ~ ~ 'r v0 N ~ r-i ~~" F-. N .-~
N ~ ~ II l~ ..-~ 'b '-' II N ~ ~ s~ ~ ~ ~ ~O 'G x ~~~
U x 'b N ,,' oo x II ~ N ~ x x' x II x ~ ~ x o0 O ~'~" ,,' .--i O ~ O
vi I~ ~ 'b x vi '-' N ~ ~ N r~ rri Vj N vi N
2 t~ t~ ~° b ~ ,-mn ~ ~ .:° b ~N-, .~ x .~ ~ t~ II
o .~ o cn ~ ~ ~. ~ ~ o ~ ~ ~ o p x 'n ~ ,-, ~ "~ ~r Ov N ~ ~ ~ N N M ~ d' N N ~f' ~ w0 ~y ~ r~' ,b o0 11 ~ v ~ °~ ~ ~ ~ '~" °° ~ ~ N II ~' ~d' No~d;
N r-~ x ~ , n ~ N ' sy O
~.o ~.o ~r,~;"~ toy~~~xb ~~x~x~n b V7 ~ N '~ b x ~ h N '~ ~ x ~ .-~~ ~ V ~ti N ~ N
~ i.>~ ~ b d; x N o h l~ 01 ~ tn 00 V7 W--s N M -I
'zj x, ~ ~1 x o0 '~ ~, ~ ~ b_ b_ ~ ~ ,.~~ b x~ C/~
M h ~ ~ II LV ~D ~ ~ ~ ~../ ~ M l N ~ '~t d' O ~ W
pp ~' ~ ~ 00 ~ W ~' ~t o0 d: ~ ~ tn N '-'i ~' (/
~ II M '~ '~ .-~ b r' v ~ t~ ~D U7 v II ~ ~ ~' ~ 00 t~ ,..' ' 00 '-' N ..~ M ~ ~. ~ V7 ,-, s-: N t~ r~
'' x t~ ~n ~ h ~'''"['' oo h 'r~ ~i N
b O ~ , N
f~/! a 1-1 1 ~1 1-.y H
)~
cet .C~ v 'b ~ w x x x x M ~ ~ M
V U ~ U
U U
U 'C7 O N N ~O . ~O

M ,.~ r'v ~ n M ~ -I
~~ x ~-' '~~' v~ x x r, N V~ CI~ ~j ~ I~ W r i-s v x 00 V i-s O\ ~ x vi O~ M n~ N x l~"d~,~~ v n~i vi xOr~ NN
r~ h y.~
M ~' x N N ~ M t~ d: v? r y~ I
~~M z° x _ h 00 r--. ~t ~ x ~ M x ,.~C
,' N .~, _ ~C
N ''~ ~ ~ N b ~0.~ ~ ~ x N ~O ~ N o0 ~t N O
..~x .,~~ M
~ N N U> ~ !~ O '~ (~ ,1 ~ co x ~ ~ ~ ~ ~ °~ ~ ~ ~ ~ r~
~ L~ N N N
n N "p ~~ V7 N ~ r~-~ ~~ ~ A ~ x x ~,1-~1 ~~ v~~ '~" "N~00 w~s~DC~'x ~'' N N w ~ o~ 00 M
v M ~~" i~ ~
_~N~ c~ NO~ ~'",y0dv ~-~ t~ ,x' cYi ~ U r. oo cri W x '~ ~ ~ can b x U
N
M
'~", '~ d' ~ \O
H
m m m U U U
U
zx zx o~
c "~N ~ .v ii ~h +
x~x.~~x ~
pp ~ ~ N Co b + ~ a x ~'~'~~~

~

A o bV
x :
~x o ~
~
n ~~M .-.~x~x "_, b i v tj d; x ~; ~. .~
O o0 s~ x ~

, ~ x M
, , N
~~x~

~x~ N~~~, ~~~x,~b~." ,-:

N ~ ~ ,b ~ x ~
x x ~D ~~ v ~ ...-n b .-.~ M

a N l~ h d' .-~
M l~
' ' ~
~
~
' M ,.
~

i1 W ~
~,~~
'~
~
x , ~
~.
~

O M M
z "d ~w ix x , x U U

i U

N N
x x z z ~

Z z ., N N

U U

x x U U

~ coo o"~o o ~ ~

N
r-c O ~D ~ ~--~ 00 M O II ~ ~ ~ ~-a ~ N ~D
l1 ~'''~M N~~.,~~,~M.-..-. "''~xx'~ ~x 1l _ Vj _ _ _ _ tp b 0o '~' ~' °° ~ N x ~ r~-'' ~ '~' ~ 'r~i ~ xi o 0o N i-; 'n cC~ ~ Q1 ~ ,--~ b II x ~' p2j ~ N tn ~--~ 00 N l~ ~ ~ ~ ri ~ ,~, ''~ ~rj '~
W .r ~ ,yr 'I ~ C ~ x ~ 00 M ~ v M to ~ ~ ~ ~ ~ ~ 'v~" er to N ~ M ~,~ x ~ ~ ~r ,o x 'L7 .-~ ~ x M ,~ ,~c d' x (V x ~ x M ~ ~ vi N ~.G'' ~ "_.' n v 'ocY,~t~y0~,~~,~~~'tJppNI~Ndv~-~'-:~'d..v,.~~~x~ ~'''xv~
'''' ' b. ' W
II ,~ ~ ~ ~ ~ ~ ~ ~ ~ ~ x ~ ~ M '" yo o x '~ .~
M .~ M N ,-~ '_' N ~ '-I' ,~ ,-. ~O ,-. ~O ,-, N ,~ Vl ~,~' ~o ~ II x '-' ~'-' 'u~" C/~
oa x ~ x N b "~' N W ~ ~ ~ ~ ~ ~ M ~ ~ ~ ~ oo "'_' N ~ ~ O
r~ r'' wr p~ x l~ r~", ~ yr rW s a ~ n x l'~ ~rj ~ O 00 i~;
x N m II o0 ~1 II v~"' ~ I~ x M ~ M ~ ~D x r'' I~ 'VC ~ x l~ ,-i x M x l~ H, N ~ ~.-, 00 ~ l~ r'' ~ ~ .-a ~ nj ,~ ~"' M ~ ~O
~ r~ b x N i: ~' i=. ..~ ~ . : x rx' dM', ~ ~ rs x N
~r~x'~~N"~..dMx.- x ~x ~x ~x ~.. ~~t~t~-...°xNx O ~d M M
w w v Zt ~ n x x x x v v U x V U
N N N
z ~Z z M
x x U U ' o°°o a°°o ono -, ,-1 ,-, d' N ~ ,--n .-W
~ o'~, x ° x 'n N x b x °° ~. ~' ~ cry M
~ ~ Wo N II ~ ,I~, b .n ~ N ~ .~ ~ 'r ~ x ~D ~ M II ~' ~''~ °° ,.~ ~ v '',°, ro cn x; x _cr ~ b N ,_~ ~ "V° t~ II ....
~N Do~p~~'~~p"~~p~pd~' t~'r''~~'~.-rOd'r'~'d~

1l d°'- o ° "' ~~ °° x ~ ~° V'r II ~ ~ tn V 'd ~ M ~ ~ ~.,~ ~ ~ "t7 00 ~ LV O ~ \p x ~ N 00 "~ ~, °° .d ''~' r~ W O ~ N 'x, t~ '~' ~ .-.~ 'C ~ ,yt ~ C/~ ~ v n ~ N ~ ~ ~- C/~ x l~ ri N ,..yr a ~ ~ ~a ~ ~ vN ~ ~
~ h b v0 M N ~D ~ ~ l~ ~I N ~ N N M I~ 'b 01 ,...,, ~ 1p ~=~ O ,,.~, 00 i~ y~ ~ N ~' N l~ N pp W-a N v~ +
~i N ,~, tai ,_, ,-~ r~i ~ ~ O o0 b xi ~ r~ I~ ~i +~ 00 ~ V~
"'' l~ M ,1 N ~ ~O .~. 01 ~ ~ tn ~ N ~, ~ ~ p b M
nn .a r, ">
x v v v M M M
U U U
N N N
z z ~Z
~Z ~Z z \ / \ / \ /
.. ~
x, ~ x x O O
A" o A
so *:-;
~O M
bA
b O
i U
M
hT~IU
N
~z x w U ~ °~°

N ~ N N
N O pp 00 x II ~ h O
~ ~ d. ~

x oo II M '-' h ~, d' ': vo ~ II .

-:~~~,~: ~.~ II -;~
H x x :

~ n ~ ~
~' '~ x vD
N

.-~ c ,-~ ,~
/~ b w '~
xbo O h ~ ,~, _ 'n ~ x v~
,~ b h a N ~~y~M ~ p ~M L9rx V7 d. ~ ~ v N o0 x ~ ~ ~.~" 0 Cf 00 O

d' x ~ ~ 0 'C1 .., ~ ~ ~- 0 ~O ~.~ x v p N o0 ~ ~ ~
vi II
' o ~ W-, N O ~ N O~
,~
' ~
~ '~

M t1 ~-r N ~ 00 trt H W-' W
x N i ' "
vi ~Y N ~~ C~
x II b _ r ,-d. ~ ~ 0o v , ~ N ' ~
t~' ~.,j N H M
v M

,-, ~' ~ II ~ 'O ~ N
O r-~a O ~ Ov h '-' r' ..vb ~ip ~ t~
~xo GO 0 hH ~ h ~ ~ '""i ~ ~ o ~~ 2u'bxx ~NO~~tx hx,-.~

A s O ~-. ~D ~ 00 '-' N 00 'J ,-~ II
w--~

-; ~ '.'' ~ ~ ~ "'' W ~

V a ~
+~ s v'~ .-~
.~ ~ WD
.
~'-~ pp N ~p .-d N r p~ t~
xN ~~~ x~x~~ ~ NM~

cC t0 ~ ~ r,., oo V ~ II ~
N x O v0 cV ,-.
~-' O ~ II ~ ~ 't1 ~ N ~-.
~ 00 ~ rv ~
~.ox x ~ ~x xx x ~ ~ o II b H '-' p V7 '-i ,-r d' x LV N N
~ .-~

O O ~ N ~ H
x M ~ tV M ~
oo N -h ~ N N

Nv~N N Nx~; II , x~: -~'~~xx 'J ~D x ~ ~ ~ H ~ ~ ~ ~n II ~ N ,~ v1 ~ v0 W "
' tD h o O N
.. a ~, h -c7 ~
~

H ~ ~ II b ~
b II x II b II
~ ~ II 'U b ''' ~ ~ ~' ~ ~ "' ~' j ; , ,~, Ohd.x r 0 "~ O~ ~~n .
' o ~f ,.~
~
.W

M ~ vp ~ ~ N oM0 ~ ~ CIJ ~
~

01 ~ pp M h H M e-x v i ~

. r~
N ~ xt ~ x ~'' 'n x ~ b x~h~x ~~:xN~ r ~ II ~.~N~, l0 ~=.
N ~O xVINN H~~
O
~W

O~xxM ~ 2~.~xx .y , _ ~~..~.~~

O
"~1 N

CA

'.G
O O O

N N N

N
z U U

N N N

N

N
yr ~~x h .' N O b ~ Vj '"' d N ~ ~ h ~
n ~n v O
r, ~

_ a1 II ~D
O ~,~r s'~
W
~

o~~,x~

x ' N ~N
o0 r:

O ~ N '""
~ N '~' '~'x v~_)) ~
~ N

+~.~~ N
iG L~ x h CO b ~
y0 N

A N
o .'-~ o N
I~ N h x Cti ;. v) -~ vi ,-~
~ O

.~O 00 x ~. v ~O

ONO O

O~"',.xN'NMb ~

's ~

N M b N
O
N
oo ~ N

.-.
~

~~x ;; ~xx ~

' ~D
d. h r.~
N

~ O Tj d, ~p M

0o N ro ~
~~ x h ~

C!~ ~ t0 ~ O
~-~ vo O )~

i r-~ ~ ~
M

v ,~p ~'x~.:b L
r 'r , O ~r ~ 00 M x p N ~ N Ov O~ 00 x ~--~ O

',s C

. N
~

bD
b ,'''O
~ N

N
x z x ~z x~~ box ~~x~
r-. cn ~ N ~ '-' ~ .~ M vp x x .. ; W o ,~ ni I~ ~ ~ I~
N oo C!~ N ~~~ ~~' ~ N
N ~ ~ '~ b 'r~i ,-, ~ rte, II ~ ~ ~ ,-~ M '.'~ ,-~ <w0 ~ x N ~ ~ ~ N .~
N x ~ p ur~i m II
N ~'MO~ Ooprx~'~
ea ~ I~ ~ x " ~ ~h '~' ~ II c~ b +
~ ~O pOp ~ ~ ~ c~ ~ cW0 ~N
.. w ~ a' ~O ~ b ~ ~ O "I' ~ N M '~ i~ N x ~ ~ O M
O 'r.~ .-;'~ ,~ I~ ~ ,-. O oa ~ ~ N ,-.
~ooxQ, ~~°x ~xx ~N ~ M
'b ~ N ~ N ~n ~M11 i~ %v ~ ~ N N ,.~., 00 N
b0'~' ~MOt~i ~r~,tn.-. .. W W
"'' v0 N ~ ~ N oo ~+ ~ w..
x oo ',7~'~ ~~"'' N x r~ '~ ~ vp x ~ '~ N ~
~ N
M ~ '~ ~ CV ~i WM
A
b4 H H M
N N N N N
x x O O
U U U
x M U ~ U U
U U U U
xz xz xz xz ' ~o ~o ~o z z P; U U
O O

N N N N N

II ~ ~ ~ ~ ..
M .-.

M s~ ~
M

~
x TJ N ~ x ~ ~ N II M C/~

~

~ 00 l A ~,-:n x.~N~~ z z ~
~,x~ + +
~
x ~
~
t0 -' "v.
M
l0 N l~ ~
_~
M
~
~

t~ M M 00 tn~!1 O
O
~ ~
N

A oo ,- mrjr;, UO~~~xN ,n l~ N N ~D d, ~ d~_ 0000 v x w0 ~ Ii x II ~ . . M M
i1 . .

~ .
, N
~~ ~ w W W W W
Ih ~

O x ~

~ ~ ili N

O
~O w w N M r1'W O

N N N N N N

N

U U U U U U U

I 1 1 . 1 N N

x U
as a n n O O ~ o ~ U U

P~,~ p N N N N

O

N N N N N N N

A
M M d' ~ dN', M d;
~n ~h M ~ M d' N
a a ~
~ U
ro a1 a dW '' l~ 00 H ~ ~O I~ N
N N N N N N N
U ~ U U U x U
wN
U
O O ~ ~ o U U p U U
N
N
o p o U U U
zx zx xz zx a V z N N N N N N N

A
U
d' ~; M M N d, .t d' ~ C' ~''~ r-i v~D~ d' d' dyl' i~ ~ ~ ~ n W W ~ W
.s1 ~ N
47 y--~ 'U
C~
O~ O l~
O
N N N
x x x N
x 0 o x ' ~ ~ ~ ~ /z zx zx x o~ o~
c ~z N N N

.-~
o N
M

O

C~ I
~
b M
~' ~
va ,.d A d' ~

~~
O

~
~O

,~U,~' ~
M
O

n r~
vi O

v U

c U
II
~o b ~

O
~

O
p~

b ~p M
~

b4 , O
N

+~
w r, x U
N

O

U

',~

UZ N

II ' ~ ~ '-' N " M '"_' ~ u N
x d'-' x .-, ~~ ~o~
II ~z O II
~

,_'C~ ~ x ~ tW p 0o ~ N ~
~ r' ~ + v ~ N ~' ~O
'-' ~ ~
' ~ ~
II ~

' .~ N .r oo ~ sr d' .-, ' ~ ,-r N I!
~ ~r ~ r~
M ~xbo x ~M
d; N

~~ M ~, ~ 'ti M ~ N ~ b M ~r ~

O ~ .--~ v pp vi N II ,1 O ., pp C/~ ..fl x '~, - ,~ O ~ -r t~ w '-II ~

~ ~~.., N~Ox A ~b~:.x~ ~m N II '~ ~
~'' ~ v~ M O
~ ~ ~ '' ,--.
.-, N ~ ~ ,-., ~
~ ~ M r~ oo ~, ~t7 .-; vi ~
~ M ~ ~; x ~ N
x ., wr v ~
f x ~.i~ ' .-y .. ~ ~~ x d iU ~ II d ~ M due' v b N o ~'-x~
oho 1 N ,, ~ ~ ~
>-.o~ t~ x M . ~t a~ N - oo ,-~
~ "~ M x ~ M
M ~ ~' N l~ ~ M N M

rip ~O ro~ Nx~
n rox ~~ N
~
..'vx"-'~M'~

_ ONxx'~~x O,-:'xxW
C/]
-~N,~Nxasw U O x N .-. n II r", v~ x N II
w w II ~a N .-. v N

vi ,~ ~ ~' ,~ ~ vi ~
~~M II ~x~ ~ x~
ab~ ~ A
'I b v N
N

h h x O N ;-~ ~ ~ '',~ O
-' ~ N i-v x ~ II M
O x ' ~ c ~
b ~D nj r1 Oy ~p pj N ,-~ ~p b ~ V7 ~' l~
,-~ x ~ ~ 00 ,-, ~ x (~ N M ,~

x ,~ ~, x .; ,~ .; II b .; x ~ N r; ~: ~ ~ N
N,J~~~x x. , xxxo ~
.x ~.~x ~ ~
r ~
.

o a d .~

' o o w ~

q b o -I- -I-C~ N
H ~
~

~~ \ ~ N N

0.i M H1 c.1 U U U

U U

U

x x o x O N N e~

U N N N
''~-' M
x Vi r;
wr ~ "~~N x N oa ~N,.~ ~ ~ ~ O ~ ~ ~ b 'G ~ x m x ~N.t v0 ~ M ~ ~ OO ~ ~ ~ ~ M ~ OO N
h tf' ~p ~ '_' ~ ~ N N M V7 ~ " ~O '-~' "' "'-' ~ O
~ x oho, ,_, x ~ ~ t~ 00 x pip .:~ N °~ b II 'b '~ '~' v, f, ~ N ~ r: II '~' .-~ o ~d ~ .-. oMO, va CO ~ O ~ ~-y-: '~O. Vi b s-~ x ~--~ ~--n ~ ,~'~' p ~ v ~O o0 N ~x "y ~'i''~ '"' b. .Jx a) 00 ~ ~ riC/~
~ ~ x p N Wit' N M N N ~ ~ N
v 't7 N M x '~ p~ ~ x ~ '."' M x ~ U ~' n ""' N
~x 1°°~'b.b~,",x ~.~:~oo.bt~.:~x qb'v Nix N o, ~ x ~ '° ~ x ,~ II ~ x ,ri '~ ~ ~ ~ ;-~ ,yo b x '~ ~ ~n II N ~° ~ ~' oo ~ ~ II
O d' ~ II ° ~ x Wit; O ~ ~ b ~~~ II
va !I ~~: ~ vi .,~ ~ t~ r1~ ~ p d. 1-, N ,~ _,.; oo c/~ ,~ iI ,-, 00 ~~'x,zy o o'° n ~os~o,.~xoo~ ~x~h II . . 0 00 ' ' ''' v1 b "vd ~ o ~ ~1 ~ °o b ~mD ,-~ II q ,-. ~ ~ ~ II M
t0 M ''' + r, e-; N ~; cn ~' Q
°..:,-;b '~ ~xx~bx,.1'd ~,.'~"N., ~"oMV'~
~~~~xx~ ~ ~N~~ ~~xo ~N~~~:~+~
x ~xo~o ~ ~~xx~x~o~ ~"~xNO~
.~
w h tin a M ~ M M
.~ (ry N N N N
x x x U U U
x x x z z z x N
zx zx zx o~ o~ o~
x x N N

~ O M <f' '~d' If V Z' N N N N

~D ""' b ~ N N N
vi N ~ r'~i ~ ~ II h h~ ~~NCOI~~o~O
00 ~ r~~ II ~ ~
O
of II v r~bWDx NMO ,~~x,- viwN
N
00 ~i n ~ II , ea ~ ~ II II ~
yrN h V1 ~ ~~ V7 b ~ ~_~ ~D
A ~~xb.d II Vv ~ II ~~~x~ II
eei O ~ nj N .~ ~ M O p h II l~
.v. ~-~ x x ~ M v ~ ~ ~-~ ~"; ~, O ~'--~ N b cp N l~ h M ~-, cp ~ op .N
N Ov .. N
r~'O"~~'~~t'r~-,,'~ ~~N"x~~.-.00 'C f~ 00 N .-.~ ,~ ,~ .-~ 'G °~ N ~ ~ II ~.rj O
p '~ II ~ O ~ °° ~ '~ r, ,-; ov oo ~
C/~ II ~. ~ x '~' 'r ~ '~t N ri x r~-~ M M M
''' 'O " iV ~ ,~ ~ N ~ x x ~ M 01 N
~ 00 jZi N O~ ~ vi ..-a 00 ~-~ ~ V v ~O ~t1 II d~ ~ ~ N b ~; ..
yn ~ 2 ..~ t~
N 0o h _ rx T~-' l~ d' o, ~n d:
00 0~ ,~'~ b ~ r~ ,~.,' N ~ ~ m ~? °~ '~', M. '-' W W W
ri ri ~--y0 ~ ~ N ~ O~ ~ .~ f' ,~ ~ ,..~ ~ wr N h ~~,.y: II II ~ x x ~ v~ v~
N r~ a l~ '~ ~ ~ ~D ~ W h h '~ a ~ .-~ ,~, O "d a nn "CS
O r-~ N M
N N N N
x U U U U
N N N
O U U U
N x U O
U
O ' x x x U
UUU
d N N N N N
p A

ca a ...

N

O
N

m N

M tf' 4, f~ ~ n Pa v ,a O M
~~

bA
O

O tM(~ I~(~
N N

U
N O

z z z xz xz ~z The following non-limiting examples are presented to further illustrate the present invention.
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-thien-2-yl-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-thien-3-yl-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-I, I':4',1 "-terphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(3-furyl)-4-[(isobutylamino)carbonyl]-I,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-pyridin-4-yl-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-(1H-pyrrol-2-yl)-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-[2-(hydroxymethyl)thien-3-yl]-4-[(isobutylamino)carbonyl]-I,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-[3-(hydroxymethyl)thien-2-yl]-4-[(isobutylamino)carbonyl]-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-vinyl-l,l'-biphenyl-2-carboxylic acid 4'-Allyl-2'-[( f 4-[amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-l, l'-biphenyl-2-carboxylate 2,'-[( f 4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-(1,3-thiazol-2-yl)-l,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-[3-(hydroxymethyl)-2-furyl]-4-[(isobutylamino)carbonyl]-l,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)caxbonyl]-4-[(isobutylamino)carbonyl]-4'-prop-1-ynyl-1,1'-biphenyl-2-carboxylic acid 2'-[( ~4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(3-hydroxy-3-methylbut-1-ynyl)-4-[(isobutylamino)carbonyl]-l,l'-biphenyl-2-carboxylic acid 2'-[( f4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4-[(3-methylbutanoyl)amino]-4'-vinyl-1,1'-biphenyl-2-carboxylic acid 2'-[( ~4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(4-hydroxybut-1-ynyl)-[(isobutylamino)carbonyl]-1,1'-biphenyl-Z-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-[(1 E)-3-methylbuta-1,3-dienyl]-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(3-hydroxyprop-1-ynyl)-4-[(isobutylamino)carbonyl]-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(2-furyl)-4-[(propylamino)carbonyl]-l,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(sec-butylamino)carbonyl]-4'-(2-furyl)-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(2-furyl)-4- { [(2,2,2-trifluoroethyl)amino]carbonyl}-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)caxbonyl]-4'-(2-furyl)-4- {[(4-hydroxybutyl)amino]carbonyl}-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(ethylamino)carbonyl]-4'-(2-furyl)-l, l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-5'-methoxy-4'-vinyl-l,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-(thien-2-ylmethyl)-1,1'-biphenyl-2-carboxylic acid 2- {3-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]pyridin-4-yl}-5-[(isobutylamino)carbonyl]benzoic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(cyclopentylamino)carbonyl]-4'-vinyl-1,1'-biphenyl-2-carboxylic acid 2'-[( f 4-[Amino(imino)methyl]phenyl} amino)carbonyl]-5'-ethoxy-4-[(isobutylamino)carbonyl]-4'-vinyl-l,l'-biphenyl-2-carboxylic acid Methyl 2'-[( {4-[( { [(acetyloxy)methoxy]carbonyl} amino)(imino)methyl]phenyl}
amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-vinyl-1,1'-biphenyl-2-carboxylate Methyl 2'-[ ( {4-[ { [(benzyloxy)carbonyl] amino } (imino)methyl] phenyl }
amino) carbonyl]-4-[(isobutylamino)carbonyl]-4'-vinyl-1,1'-biphenyl-2-carboxylate Nl- f 4-[Amino(imino)methyl]phenyl}-N8-isobutyl-6-oxo-6H-benzo[c]chromene-1,8-dicarboxamide 2'-[( f 4-[Amino(imino)methyl]phenyl) amino)methyl]-4-[(isobutylamino)carbonyl]-4'-vinyl-l,l'-biphenyl-2-carboxylic acid 2'-( { [4-(4, 5-Dihydro-1 H-imidazol-2-yl)phenyl] amino } c arbonyl)-4-[(isobutylamino)carbonyl]-l,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-5'-thien-2-yl-l,l'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-5'-(2-amino-2-oxoethoxy)-[(isobutylamino)carbonyl]-1,1'-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-ethoxy-4-[(isobutylamino)carbonyl]-l,l'-biphenyl-2-carboxylic acid ' 2-{5-[( {4-[Amino(imino)methyl]phenyl; amino)carbonyl]-1,3-benzodioxol-4-yl}-5-[(isobutylamino)carbonyl]benzoic acid 2'-[ 1-( {4-[Amino(imino)methyl]phenyl} amino)ethyl]-4-[(isobutylamino)carbonyl]-1,1'-biphenyl-2-carboxylic acid 3-[2-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-(benzyloxy)phenyl]-6-[(isobutylamino)carbonyl]pyridine-2-carboxylic acid 3-[2-(4-Carbamimidoyl-phenylcarbamoyl)-4-vinyl-phenyl]-6-isobutylcarbamoyl-pyridine-2-carboxylic acid 2'-[(5-Carbamimidoyl-pyridin-2-ylamino)-methyl]-4-isobutylcarbamoyl-4'-vinyl-biphenyl-2-carboxylic acid 2'- {[4-(N-Hydroxycarbamimidoyl)-phenylamino]-methyl}-4-isobutylcarbamoyl-4'-vinyl-biphenyl-2-carboxylic acid 2'- { [4-(N-Hydroxycarbamimidoyl)-phenylamino]-methyl} -4-isobutylcarbamoyl-4'-vinyl-biphenyl-2-carboxylic acid methyl ester 3- {2-[(4-Carbamimidoyl-phenylamino)-methyl]-4-vinyl-phenyl} -6-isobutylcarbamoyl-pyridine-2-carboxylic acid Biological Assay Methods In Vitro Assay for Inhibition of TF/FVIIa To assess the inhibition of the test compounds against the target enzyme, TF/FVIIa, an amidolytic assay based upon the absorbance of p-Nitroanalide (pNA) at OD4o5 was utilized. The ICSO of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
l0 TF/FVIIa assay reactions were performed in a 200 ~,L mixture containing 4 nM
FVIIa, I O nM lipidated tissue factor, in an assay buffer containing 100 mM
Tris, pH 7.2, 150 mM NaCI, 5 mM calcium chloride, 0.1 % bovine serum albumin (BSA), and 10%
dimethyl sulfoxide (DMSO). TF and FVIIa were allowed to equilibrate at room temperature for 15 minutes. Test compounds dissolved in DMSO were incubated at varied concentrations with TF/FVIIa for 10 minutes, followed by addition of substrate Spectrozyme-FVIIa. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD4os nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Thrombin This colorimetric assay was used to assess the ability of the test compounds to inhibit the human thrombin enzyme. ICSO of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
Thrombin assay reactions were performed in a 200 p.L mixture containing human thrombin at (1 U/mL) in an assay buffer containing 100 mM HEPES, 10 mM calcium chloride, and 10 % DMSO, pH 7.5. Test compounds dissolved in DMSO were added to thrombin enzyme reactions at varied concentrations, followed by the addition of substrate Na-Benzoyl-Phe-Val-Arg p-Nitroanilide at a final concentration of 1 mM.
Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD4os nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Trypsin This enzymatic assay was employed to evaluate the ability of the test compounds to inhibit human pancreatic trypsin. ICso of the test compounds was determined by using I~C4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
Trypsin assay reactions were performed in a 200 ~,L mixture containing human pancreatic trypsin at 1 ~,g/mL in an assay buffer containing 200 mM
triethanolamine (TEA), 10 mM calcium chloride, 10 % DMSO, pH 7.~. Test compounds dissolved in DMSO were added to trypsin enzyme reactions at varied concentrations, followed by the addition of substrate Na-Benzoyl-L-Arginine p-Nitroanilide (L-BAPNA) at a final concentration of (0.25 mg/mL). Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD4os nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
27~

Biological Data IS
ICSO Values of Some Selected Compounds on Different Serine Protease Enzymes R (With Respect to R. TFIFVIIa Trypsin Thrombin Phen 1 Rin CH3 ,.
N (4) ++ + +

~ \ ~3 OH (4) ++ + +
S CHs '~\ ~ (4) ++ + +
N CHs OH (4) ~ .~+ _ _ CH3 ' _ -o ~ ~ (3) ~ + _ _ ~ (3) ++ _ _ O
CH +++ ++ +

~CHZ ~q,~

+++ ++ +

O
C0 +
H ++ +

~CHZ ~q~

+++ ++ +

ICSO values: + means >1 ~M; ++ means >100 nM; +++ means <100 nM
zso A comparison of Examples with R group and without R group illustrates the greatly-enhanced activity achieved pursuant to the present invention.
Compounds of the present invention are useful as inhibitors of trypsin-like serine protease enzymes such as thrombin, factor VIIa, TF/FVIIa, and trypsin.
These compounds may be employed to inhibit the coagulation cascade and prevent or limit coagulation.
to These compounds may be used to inhibit the formation of emboli or thromboli in blood vessels.
These compounds may be used to treat thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thromboarteritis.
These compounds may be used to inhibit thrombus formation following angioplasty. These may be used in combination with other antithrombolytic agents such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
These compounds may also be used in matastatic diseases, or for any disease where inhibition of coagulation is indicated.
These compounds may be used as diagnostic reagents in vitro for inhibiting clotting of blood in the tubes.
These compounds may be used alone or in combination with other compounds such as heparin, aspirin, or warfarin and any other anticoagulant agents.
zsi These compounds may be used as anti-inflammatory agents.
According to a fiu-ther aspect of the invention, compounds may be employed in preventing ex vivo coagulation such as that encountered in the extracorporeal perfusion of blood through for example artificial valves, prothesis, stems or catheters.
According to this aspect of the invention the extracorporeal device may be coated with the compositions of the invention resulting in a lower risk of clot formation due to extrinsic pathway activation.
Dosage and Formulation The compounds of this invention can be administered by any means that produces contact of the active agent's site of action with factor VIIa and other serine proteases in the body of a human, mammal, bird, or other animal. They can be administered by any conventional means, such as oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. Parenteral infusion includes intramuscular, intravenous, and intraarterial. They can be administered alone, but generally administered with a pharmaceutical carrier elected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, or course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment;
and the effect desired. A daily dosage of active ingredient can be expected to be about 0.0001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg.

Dosage forms (compositions suitable for administration) contain from about mg to about 500 mg of compound per unit. In these pharmaceutical compositions, the compound of the present invention will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The daily dose of the compounds of the invention that is to be administered can be a single daily dose or can be divided into several, for example, two, three or four, part administrations. The pharmaceutical compositions or medicaments of the invention can 1o be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion 15 solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
Gelatin capsules contain a compound of the present invention and powdered 2o carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours.
Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet 25 from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms fox oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and preservatives. Liquid oral products can be developed to have sustained-release properties. They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents. Antioxidizing agents such as sodium bisulfate, sodium l0 sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company and in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association, both standard reference texts in this field.
2o Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows:
Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared sand injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
The capsules are washed and dried. The prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 rng of microcystalline cellulose, 11 mg of starch, and 9.98 rng of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes.
These units are taken orally without water for immediate dissolution and delivery of the medication. The drug is mixed containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Moreover, the compounds of the present invention can be administered in the form of nose drops, metered dose nasal or buccal inhalers. The drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.

In another embodiment of the invention, a compound of the invention can be used in an assay to identify the presence of factor VIIa and other serine protease or to isolate factor VIIa and other serine protease in a substantially purified form. For example, the compound of the invention can be labeled with, for example, a radioisotope, and the labeled compound is detected using a routine method useful for detecting the particular label. In addition, a compound the invention can be used advantageously as a probe to detect the location or amount of factor VIIa and other serine protease activity in vivo, in vitro or ex vivo.
1o Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
The foregoing disclosure includes all the information deemed essential to enable 15 those skilled in the art to practice the claimed invention. The foregoing description of the invention illustrates and describes the present invention. Additionally, the disclosure shows and describes only the preferred embodiments of the invention but, as mentioned above, it is to be understood that the invention is capable of use in various other combinations, modifications, and environments and is capable of changes or 20 modifications within the scope of the inventive concept as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art.
The embodiments described hereinabove are further intended to explain best modes known of practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with the various modifications required by 25 the particular applications or uses of the invention. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended that the appended claims be construed to include alternative embodiments:

Claims (63)

1. Compound having the structure (I) shown below:

pharmaceutically acceptable salts thereof;
and prodrugs thereof;
Each E1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(O2) which may be saturated or unsaturated;

R is -CH=CH-R2, -C.ident.C-R2, -C(R2)=CH2, -C(R2)=C(R3), -CH=NR2, -C(R2)=N-R3, membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1, R2, or R3. Preferably, these R, R1, R2, or R3 do not include -(C2-4 alkenyl)-CO2-C1-8 alkyl, -(C2-4 alkenyl)-CO2-C1-8 alkyl-phenyl, and-(C2-4 alkenyl)-CO2-C1-8 alkyl-O-C1-4 alkyl;

R1 is H, -R, -NO2, -CN, -halo, -N3, -C 1-8 alkyl, -(CH2)n CO2R2, -C2-8 alkenyl-CO2R2, -O(CH2)n CO2R2, -C(O)NR2R3, -P(O)(OR2)2, alkyl substituted tetrazol-5-yl, -(CH2)n O(CH2)n aryl, -NR2R3, -(CH2)n OR2, -(CH2)n SR2, -N(R2)C(O)R3, -S(O2)NR2R3, -N(R2)S(O2)R3, -(CHR2)n NR2R3, -C(O)R3, (CH2)n N(R3)C(O)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CH2)n-phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated;
m is 1 except that when E1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring;
R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n-phenyl, -(CH2)1-3-biphenyl, -(CH2)1-4-Ph-N(SO2-C1-2-alkyl)2, -CO(CHR1)n-OR1, -(CHR1)n-heterocycle, -(CHR1)n NH-CO-R1, -(CHR1)n-NH-SO2R1, -(CHR1)n-Ph-N(SO2-C1-2-alkyl)2, -(CHR1)n-C(O)(CHR1)-NHR1, -(CHR1)n-C(S)(CHR1)-NHR1, -(CH2)n O(CH2)n CH3, -CF3, -C2-5 acyl, -(CHR1)n OH, -(CHR1)n CO2R1, -(CHR1)n-O-alkyl, -(CHR1)n-O-(CH2)n-O-alkyl, -(CHR2)n-S-alkyl, -(CHR1)n-S(O)-alkyl, -(CHR1)n-S(O2)-alkyl, -(CHR1)n-S(O2)-NHR3, -(CHR3)n-N3, -(CHR3)n NHR4, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated;
When n is more than 1, the substitutions R1 and R3 may be same or different;
R3 is H, -OH, -CN, substituted alkyl, -C2-8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R1)R2, or 5-6 membered saturated substituted or unsubstituted hetero ring;
-NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring;
wherein said ring system comprises carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted;

W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C=C-, -O-CHR2-, -CHR2-O-, -N(R2)-C(O)-, -C(O)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-, -CH(R1)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(O2)-N(R2)-, -C(O)N(R2)-(CHR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(O2)-, -R2C(O)NR2-, -R2NC(O)NR2-, -CONR2CO-, -C(=NR2)NR2-, -NR2C(=NR2)NR2-, -NR2O-, -N=NCHR2-, or -C(O)NR2SO2-;

E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino;

each X individually is a direct bond, substituted or unsubstituted C1-4 methylene chain, O, S, NR2 , S(O), S(O2), or N(O) containing one or two C1-4 substituted or unsubstituted methylene chains; X at different places may be same or different;

B is H, -halo, -CN, -NH2, -(CH2)n-C(=NR4)NHR5, -(CH2)n-NHR4, -(CH2)n NHC(=NR4)NR5, -(CH2)n-OR4, C1-8 substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated;
B1 is selected from B; B1 and B may be same or different;
There may be more than one similar or different R2 groups present on E2, when E2 is a cyclic group of more than 5 atoms; p is 1 except that when E2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring;

n is 0-4;

A is selected from R1;
o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring;

Each V and V1 individually is selected from R1 and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic;
N,N-disubstituted carboxamidyl of the formula -CONR1R2 where R1 and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different;
mono- or disubstituted sulfonamides of the formula SO2NHR or -SO2NR1R2; and methylene-or polymethylene chain-extended variants thereof;

Each R4 and R5 individually is H, -(CH2)n OH, -C(O)OR6, -C(O)SR6, -(CH2)n C(O)NR7R8, -O-C(O)-O-R7, an amino acid or a dipeptide;

Each R6 is H, R7, -C(R7)(R8)-(CH2)n-O-C(O)-R9, -(CH2)n-C(R7)(R8)-O-C(O)R9, -(CH2)n-C(R7)(R8)-O-C(O)-O-R9, or -C(R7)(R8)-(CH2)n-O-C(O)-O-R9; and Each R7, R8 and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2CO2alkyl.
2. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OH, -OSO2CF3, and and R' is selected from the group consisting of , CO2MEM, and -CH2NH2; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
3. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, , and -OCH3;
and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
4. The compound of claim 1 represented by the structure wherein R is -OSO2CF3; and R' is selected from the group consisting of -CHO, -CO2H, ; and pharmaceutically acceptable salts thereof;
and prodrugs thereof.
5. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
6. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of and ; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
7. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof; and prodrugs thereof.
8. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OBn, -OCH3, and - ; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
9. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of and R' is -H or ; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
10. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, , -CH=CH2, and -H;
R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM;

and R" is selected from the group consisting of -CO2MEM, and pharmaceutically acceptable salts thereof; and prodrugs thereof.
11. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, , -CH=CH2;
R' is -H or -Boc; and R" is -CO2MEM or -CO2H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
12. The compound of claim 1 represented by the structure wherein R is -CH3 and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof; and prodrugs thereof.
13. The compound of claim 1 represented by the structure wherein R is ; and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof; and prodrugs thereof.
14. The compound of claim 1 represented by the structure wherein R is and -CH=CH2 and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof; and prodrugs thereof.
15. The compound of claim 1 represented by the structure wherein R is -CH3 and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof; and prodrugs thereof.
16. The compound of claim 1 represented by the structure wherein at least one R is selected from the group consisting of -OCH3, -OH, -OSO2CF3, -CH=CH2, -OCH2CO2C2H5, -OCH2CONH2, , -OBn , -OH, -OSO2CF3, , -OCH3, -OBn, -H, -OBn, and -CH=CH2;
R' is selected from the group consisting of -CHO, -CO2H, -CO2MEM, and R" is selected from the group consisting of-H, -CH3 and -Bn; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
17. The compound of claim 1 represented by the structure wherein at least one R is selected from the group consisting of -CH=CH2, -OSO2CF3, -OCH2CO2C2H5, -OCH2CONH2, -OCH2CO2H, -O-CH2-CH2-OH, -CH(OH)CH2OH, -CH2OH, -CO2H, , -OBn, -OH, -OCH3, -OBn, -OH, -OC2H5, -OBn, -OCH3, and -CH(OH)CH3; and R' is selected from the group consisting of -CH3, -CH2C6H5, -Bn, -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
18. The compound of claim 1 represented by the structure wherein at least one R is selected from the group consisting of -CH=CH2, -CH(OH)CH2OH, -CH=O, -CH2OH, -CO2H, -OCH3, -CH=CH2; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
19. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of halo and -B(OH)2; R1 is selected from the group consisting of -H, -OCH3, -OBn; R2 is selected from the group consisting of -H, -OCH3, -OC2H5, -OCH(CH3)2, and R3 is selected from the group consisting of -H, -OH, -OBn; and R4 is -OBn or -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
20. The compound of claim 19 wherein said halo is -Br.
21. The compound of claim 1 represented by the structure and pharmaceutically acceptable salts thereof; and prodrugs thereof.
22. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CH3, -C2H5, -CH(CH3)2, ;
R' is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH=CH2;
R" is selected from the group consisting of -CO2H, -CO2MEM, or -CHO;
and R"' is selected from the group consisting of ;and pharmaceutically acceptable salts thereof;
and prodrugs thereof.
23. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CH3, -C2H5, -CH(CH3)2, , and -H;

R' is -H or alkyl; and R" is selected from the group consisting of ; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
24. The compound of claim 23 wherein said alkyl is -CH3.
25. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of R' is -H, -CH=CH2; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof;
and prodrugs thereof.
26. The compound of claim 25 wherein said alkyl is -CH3.
27. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CH=CH2, and -H; R' is -H or alkyl; and R" is selected from the group consisting of and ; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
28. The compound of claim 27 wherein said alkyl is -CH3.
29. The compound of claim 1 represented by the structure wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of -CHO, -CO2H, and and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
30. The compound of claim 29 wherein said alkyl is -CH3.
31. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CH3, -C2H5, -CH2C6H5, -C(CH3)3, -CH2-CCl3, and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
32. The compound of claim 31 wherein alkyl is CH3.
33. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CHO, -CO2H, and ; and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
34. The compound of claim 33 wherein said alkyl is -CH3.
35. The compound of claim 1 represented by the structure wherein at least one R is selected from the group consisting of -CH=CH2, -OCH3, -OBn, -OH, and -H; R' is R" is selected from the group consisting of ; and R"' is -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
36. The compound of claim 1 represented by the structure wherein R is -CH2OH or and R' is -Boc, or -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
37. The compound of claim 1 represented by the structure wherein R is -OCH3, -OH, -OSO2CF3, -C(=NH)NH2, and -H;
R' is or NH2;
and R" is halo, -CH=CH2, -CO2CH3, and and pharmaceutically acceptable salts thereof; and prodrugs thereof.
38. The compound of claim 37 wherein said halo is -Br.
39. The compound of claim 1 represented by the structure wherein R' is selected from the group consisting of -CHO, -CO2H, -CO2MEM, R' is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH=CH2;
and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
40. The compound of claim 39 wherein said alkyl is -CH3.
41. The compound of claim 1 represented by the structure wherein R is -CO2CH3; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
42. The compound of claim 1 represented by the structure wherein R is -H or -CO2H;

R' is selected from the group consisting of -CHO, -CO2H, and and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
43. The compound of claim 42 wherein said alkyl is -CH3.
44. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CH(OH)-CH2OH,-CHO, and -CH(OH)-CH=CH2;

R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
45. The compound of claim 44 wherein said alkyl is -CH3.
46. The compound of claim 1 represented by the structure wherein R is and pharmaceutically acceptable salts thereof; and prodrugs thereof.
47. A pharmaceutical composition containing at least one compound according to claim 1.
48. A method for inhibiting serine protease in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one compound according to claim 1.
49. A method for inhibiting the coagulation cascade and preventing or limiting coagulation by administering to a patient an effective amount of at least one compound according to claim 1.
50. A method for inhibiting the formation of emboli or thromboli in blood vessels by administering to a patient an effective amount of at least one compound according to claim 1.
51. A method for treating at least one condition selected from the group consisting of thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thromboarteritis which comprises administering to a patient an effective amount of at least one compound according to claim 1.
52. A method for inhibiting thrombus formation following angioplasty which comprises administering to a patient an effective amount of at least one compound according to claim 1.
53. A method for preventing arteria occlusion following thrombolytic therapy which comprises administering to a patient an effective amount of at least one compound according to claim 1 and an effective amount of at least another antithrombolytic agent.
54. The method of claim 53 wherein said other antithrombolytic agent is selected from the group consisting of tissue plasminogen activators, streptokinase and urokinase, and functional derivatives thereof.
55. A method for treating metastatic diseases which comprises administering to a patient an effective amount of at least one compound according to claim 1.
56. A method of claim 49 which further comprises administering a further anticoagulant agent to said patient.
57. The method of claim 56 wherein said further anticoagulant agent is selected from the group consisting of heparin, aspirin, and warfarin.
58. A methof for treating a patient in need of an anti-inflammatory agent which comprises administering to said patient an effective amount of at least one of the compounds according to claim 1.
59. A method for inhibiting in vitro clotting of blood which comprises contacting said blood with at least one compound according to claim 1.
60. The method of claim 59 which comprises inhibiting said blood in tubes.
61. An extraarpereal device having a coating therein which comprises a compound according to claim 1.
62. A method for detecting future presence of a serine protease which comprises contacting a sample with a compound according to claim 1.
63. The compound of claim 1 represented by the structure wherein R is alkyl and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof; and prodrugs thereof.
CA2426430A 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors Expired - Lifetime CA2426430C (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US24184800P 2000-10-20 2000-10-20
US60/241,848 2000-10-20
US28173501P 2001-04-06 2001-04-06
US60/281,735 2001-04-06
PCT/US2001/032582 WO2002034711A1 (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors

Publications (2)

Publication Number Publication Date
CA2426430A1 true CA2426430A1 (en) 2002-05-02
CA2426430C CA2426430C (en) 2014-10-07

Family

ID=26934639

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2426430A Expired - Lifetime CA2426430C (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors

Country Status (8)

Country Link
AU (2) AU2002213393B2 (en)
CA (1) CA2426430C (en)
DK (1) DK1383731T3 (en)
HK (1) HK1062676A1 (en)
IL (1) IL155202A0 (en)
MX (1) MXPA03009130A (en)
NZ (1) NZ526003A (en)
WO (1) WO2002034711A1 (en)

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6906192B2 (en) 2000-11-07 2005-06-14 Bristol Myers Squibb Company Processes for the preparation of acid derivatives useful as serine protease inhibitors
AU2002227269A1 (en) 2000-11-07 2002-06-03 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
US6713467B2 (en) 2000-11-07 2004-03-30 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
TWI311133B (en) 2001-04-20 2009-06-21 Eisai R&D Man Co Ltd Carboxylic acid derivativeand the salt thereof
US7687664B2 (en) 2001-06-04 2010-03-30 Eisai R&D Management Co., Ltd. Carboxylic acid derivative, a salt thereof or an ester of them, and medicament comprising it
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
NZ567711A (en) * 2001-06-11 2009-10-30 Xenoport Inc Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
DE10137163A1 (en) 2001-07-30 2003-02-13 Bayer Ag New thiophenecarboxamido-substituted isoindole derivatives, useful as Factor XIa inhibitors for treatment or prophylaxis of, e.g. thromboembolic diseases, atherosclerosis, arthritis, Alzheimer's disease or cancer
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
GB0128996D0 (en) 2001-12-04 2002-01-23 Novartis Ag Organic compounds
US20030181488A1 (en) 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
US6924285B2 (en) 2002-03-30 2005-08-02 Boehringer Ingelheim Pharma Gmbh & Co. Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US7338956B2 (en) 2002-08-07 2008-03-04 Sanofi-Aventis Deutschland Gmbh Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
EP1388341A1 (en) * 2002-08-07 2004-02-11 Aventis Pharma Deutschland GmbH Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
TW200410921A (en) * 2002-11-25 2004-07-01 Hoffmann La Roche Mandelic acid derivatives
EP1594505A4 (en) 2003-02-11 2008-08-13 Bristol Myers Squibb Co Phenylglycine derivatives useful as serine protease inhibitors
WO2004072102A2 (en) 2003-02-11 2004-08-26 Bristol-Myers Squibb Company Benzene acetamide compounds useful as serine protease inhibitors
GB0317665D0 (en) 2003-07-29 2003-09-03 Astrazeneca Ab Qinazoline derivatives
US7371743B2 (en) 2004-02-28 2008-05-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
US8673889B2 (en) * 2004-04-26 2014-03-18 Ono Pharmaceutical Co., Ltd. BLT2-mediated disease, BLT2 binding agent and the compound
FR2871157A1 (en) * 2004-06-04 2005-12-09 Aventis Pharma Sa BIARYL AROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF
US7459468B2 (en) 2004-10-28 2008-12-02 Medicure International, Inc. Aryl sulfonic pyridoxines as antiplatelet agents
CA2584338C (en) 2004-11-04 2013-08-06 Xenoport, Inc. Gabapentin prodrug sustained release oral dosage forms
TW200637843A (en) 2005-01-10 2006-11-01 Bristol Myers Squibb Co Phenylglycinamide derivatives useful as anticoagulants
US7754717B2 (en) 2005-08-15 2010-07-13 Amgen Inc. Bis-aryl amide compounds and methods of use
TW200806290A (en) 2006-01-25 2008-02-01 Synta Pharmaceuticals Corp Substituted biaryl compounds for inflammation and immune-related uses
TW200827346A (en) 2006-11-03 2008-07-01 Astrazeneca Ab Chemical compounds
EP1921070A1 (en) 2006-11-10 2008-05-14 Boehringer Ingelheim Pharma GmbH & Co. KG Bicyclic heterocycles, medicaments comprising them, their use and process for their preparation
US7998949B2 (en) 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
TW200836719A (en) 2007-02-12 2008-09-16 Astrazeneca Ab Chemical compounds
PE20090236A1 (en) 2007-04-06 2009-03-13 Neurocrine Biosciences Inc GONADOTROPIN RELEASING HORMONE RECEPTORS ANTAGONISTS AND PROCEDURES RELATED TO THEM
JP5735799B2 (en) 2007-04-06 2015-06-17 ニューロクライン バイオサイエンシーズ，インコーポレイテッド Gonadotropin releasing hormone receptor antagonists and related methods
MY150290A (en) 2008-02-07 2013-12-31 Boehringer Ingelheim Int Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
JP5539351B2 (en) 2008-08-08 2014-07-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Cyclohexyloxy-substituted heterocycles, medicaments containing these compounds, and methods for producing them
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
AU2015305214B2 (en) 2014-08-22 2020-04-23 Biocryst Pharmaceuticals, Inc. Compositions and uses of amidine derivatives
AU2017348305B2 (en) 2016-10-31 2022-04-21 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
AU2018300150A1 (en) 2017-07-11 2020-01-30 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
TW202322824A (en) 2020-02-18 2023-06-16 美商基利科學股份有限公司 Antiviral compounds
AU2021224588B2 (en) 2020-02-18 2024-07-18 Gilead Sciences, Inc. Antiviral compounds
TWI775313B (en) 2020-02-18 2022-08-21 美商基利科學股份有限公司 Antiviral compounds
AU2022256476A1 (en) 2021-04-16 2023-10-12 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
EP4387977A1 (en) 2021-08-18 2024-06-26 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4551279A (en) * 1984-01-09 1985-11-05 G. D. Searle & Co. Protease inhibitors
US6358960B1 (en) * 1998-02-17 2002-03-19 Ono Pharmaceutical Co., Ltd. Amidino derivatives and drugs containing the same as the active ingredient
EP0987274A1 (en) 1998-09-15 2000-03-22 Hoechst Marion Roussel Deutschland GmbH Factor VIIa Inhibitors
KR100838418B1 (en) 1999-01-13 2008-06-13 제넨테크, 인크. Serine Protease Inhibitors

Also Published As

Publication number Publication date
CA2426430C (en) 2014-10-07
IL155202A0 (en) 2003-11-23
WO2002034711A1 (en) 2002-05-02
MXPA03009130A (en) 2004-02-26
NZ526003A (en) 2005-09-30
DK1383731T3 (en) 2009-12-07
HK1062676A1 (en) 2004-11-19
AU1339302A (en) 2002-05-06
AU2002213393B2 (en) 2007-02-15

Similar Documents

Publication Publication Date Title
CA2426430A1 (en) Biaryl compounds as serine protease inhibitors
EP1383731A1 (en) Biaryl compounds as serine protease inhibitors
AU2002213393A1 (en) Biaryl compounds as serine protease inhibitors
US6399644B1 (en) Aryl sulfonyls as factor XA inhibitors
US6369227B1 (en) Thrombin or factor Xa inhibitors
US6436925B1 (en) Substituted benzamides, their production and their use as cysteine protease inhibitors
JP2003500383A (en) Factor Xa inhibitor
WO2001032628A1 (en) Cyano compounds as factor xa inhibitors
JP2013121919A (en) Plasma kallikrein inhibitor
JP2002509924A (en) Disubstituted pyrazolines and triazolines as factor Xa inhibitors
US20040077635A1 (en) Lactam-containing diaminoalkyl, beta-aminoacids, alpha-aminoacids and derivatives thereof as factor Xa inhibitors
JPWO2003011812A1 (en) Novel amine derivative having human-β-tryptase inhibitory activity and medicament containing the same
WO2002050039A1 (en) Urea and urethane derivatives as integrin inhibitors
KR20030090739A (en) LIGANDS OF THE αvβ6 INTEGRIN
CN113512025B (en) A kind of indazole ester compound and its pharmaceutical application
CZ2003835A3 (en) Method for efficient preparation of Xa factor inhibitor
US6407256B1 (en) Cyano-pyrrole, cyano-imidazole, cyano-pyrazole, and cyano-triazole compounds as factor Xa inhibitors
US11732007B2 (en) Therapeutic compounds and methods
CN113735787A (en) Naproxen triazolethione derivatives and their application in the preparation of novel coronavirus inhibitors
KR20000053122A (en) 1-(3-aminoindazol-5-yl)-3-phenylmethyl-cyclic ureas useful as hiv protease inhibitors
CN117534661A (en) Methyl Ophiopogon japonicus flavonoid A derivatives and their preparation and application
CN118993944A (en) Guanidine-substituted aromatic ester derivative, preparation method and medical application thereof
SK2952003A3 (en) Biphenyl derivatives and the use thereof as integrin inhibitors

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20211022