AU2002213393B2 - Biaryl compounds as serine protease inhibitors - Google Patents

Biaryl compounds as serine protease inhibitors Download PDF

Info

Publication number
AU2002213393B2
AU2002213393B2 AU2002213393A AU2002213393A AU2002213393B2 AU 2002213393 B2 AU2002213393 B2 AU 2002213393B2 AU 2002213393 A AU2002213393 A AU 2002213393A AU 2002213393 A AU2002213393 A AU 2002213393A AU 2002213393 B2 AU2002213393 B2 AU 2002213393B2
Authority
AU
Australia
Prior art keywords
compound
group
dmso
alkyl
0234711pct
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.)
Expired
Application number
AU2002213393A
Other versions
AU2002213393A1 (en
Inventor
Yarlagadda S. Babu
Pooran Chand
Yahya El-Kattan
Pravin L. Kotian
Shri Niwas
Scott R. Rowland
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
Biocryst Pharmaceuticals Inc
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 Biocryst Pharmaceuticals Inc filed Critical Biocryst Pharmaceuticals Inc
Publication of AU2002213393A1 publication Critical patent/AU2002213393A1/en
Application granted granted Critical
Publication of AU2002213393B2 publication Critical patent/AU2002213393B2/en
Anticipated expiration legal-status Critical
Expired 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)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (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)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

WO 02/34711 PCT/US01/32582 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.
60(241,848 filed October 20, 2000 and entitled "Inhibitors for Activated Blood Coagulation Factor VIIa (FVIIa)" and S.N. 60/281,735 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.
WO 02/34711 PCT/US01/32582 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 ofprotease inhibitors. The major natural plasma inhibitors are specific for serine proteinases. Diseases (associated protease given in the parentheses) such as pulmonary emphysema (cathepsin 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 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.
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.
WO 02/34711 PCT/US01/32582 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 prothrombinase 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 TF/FVIIa. 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 the conversion of fibrinogen to fibrin and mediating its own 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.
WO 02/34711 PCT/US01/32582 Need for the prevention ofintravascular 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. Along these lines, see International 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 for myocardial infarction or crescendo angina. The present therapy for these conditions 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 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 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 Vila or factor Xa, prevents clot WO 02/34711 PCT/US01/32582 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 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 VIIla that does not cause unwanted side effects.
Figure 1. Pathways of Coagulation Extrinsic Pathway Intrinsic Pathway Release of TF Release of Contact Factors XII and XI I VII XIIa-
XII
TF/FVIIa 1 XIa XI IXa
IX
X
Common Pathway Prothrombin Thrombin--- Fibrinogen Fibrin WO 02/34711 PCT/US01/32582 The figure 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
B
I
E
1 E2
B
m X
(R
2 )p
V
i
L-V
pharmaceutically acceptable salts thereof; and prodrugs thereof.
(A)
Each E' and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 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 maybe substituted with one or more hetero groups selected from N, O, S, and S(0 2 which may be saturated or unsaturated. The bicyclic rings typically contain 7-13 atoms in the ring.
R is -CH=CH-R 2
-C=C-R
2
-C(R
2 C H 2
-C(R)=C(R
3
-CH=NR
2 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 R 1
R
2 or R 3 WO 02/34711 WO 0234711PCT/USOI/32582 R, is H, -NO 2 -CN, -halo, -N3, -C 1-8g alkyl, -(CHA 2
)CO
2
R
2 -C2-8 alkenyl-C0 2
A
2
-O(CH
2 )nCO2R 2 -C(O)NRR, -P(O)(0R 2 alkyl substituted
-(CH
2
).O(CH
2 aryl, -NRR, -(CH 2
OR
2
SR
2
-N(R
2 -S(0 2
)NRR,
-N(R
2 )S(0 2
)R
3
-(CHIR
2 )n WW 2 R, (Cli 2
N(R
3
-N(R
2
)CR
2
R
substituted or unsubstituted (CH 2 )n-CYCIakyl, substituted or unsubstituted (CH 2 *phenyl, or substituted or unsubstituted (CH 2 ),-heterocycle which may be saturated or unsaturated.
m is I except that when E t is a cyclic ring of more than 5 atoms, then mn is 1 or higher, depending upon the size of the ring.
W? is H, -halo, -alkyl, -haloalkyl, -(CIH 2 -phenyl, -(CH 2 13 -biphenyl, -(CH 2 1 4 -Ph- N(S0 2
-CI-.
2 -alkyl)2, -(GH-R'),,-heterocycle, o-RI,
-(CHR
1 )n-NH-SO 2
-(CHR
1 ),,-Ph-N(SO2-Cz 2 -alkyl) 2 -(CHRl).-C(O)(CHR')-NFIR', -(CHR')n-C(S)(CHiJR')-NHR 1
-(CH
2
),,O(CH
2 )nCIs, -CFI, -C 2 5 acyl, -(CHR 1
),OH,
-(CUR
3 ),NUR, 2 to 8 carbon atom alkene chain having I to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-
(GER
3 )n heterocycle, or substituted or unsubstituted-(CHR 3 )n cycloalkyl which may be saturated or unsaturated.
When n is more than 1, the substitutions R1 and R 3 may be same or different.
R
3 is H, -OH, -CN, substituted alkyl, -C2-8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R')R 2 or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR R 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 fuirther it may saturated or unsaturated and also may be substituted or unsubstituted.
WO 02/34711 WO 0234711PCT/USOI/32582 W is a direct bond, -CHR 2
-CH=CR
2
-CR
2
-CR
2 =CR 2 -O-CHR 2CWO,-()CO-
-C(O)-N(R
2 -R)C-W H 2-NR-
-CH(R')-N(R
2
-S-CUR
2
-CIIR
2 -S(0 2
)-N(R
2
-C(O)N(R
2
)-(CHR
2
-C(R'R
2 )n-NR 2 -N(R)-S(0 2
-R
2 C(O)NR-, -R 2 NC(0)NR-, -CONR 2
CO-,-
C&NR
2
)NR
2 -1\l{C(-NICk,
-NR
2
-N=NCHR
2 or -C(O)NR 2 S0 2 E 2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, C 1 s alkyl, C 2 8 alkenyl, C 2 -9 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
each X individually is a direct bond, substituted or unsubstituted C14 methylene chain; 0, S, NR 2 S(02), or N(0) containing one or two C 14 substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -Nil 2
-(CH
2 4 )NIIR, -(CH 2
).-NI{R
4
(CH
2 ).,N1C(=NR 4 YNRW, -(CH 2 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 1 is selected from B; B 1 and B maybe same or different.
There may be more than one similar or different W 2 groups present on E2, when E2 is a cyclic group of more than 5 atoms. i particular, p is I except that when E 2 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 R'.
WO 02/34711 PCT/US01/32582 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 V 1 individually is selected from R' and N-alkyl substituted carboxamidyl CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N,Ndisubstituted carboxamidyl (-CONR 1
R
2 where R 1 and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO 2 NHR or -SOzNRIR 2 and methylene- or polymethylene chainextended variants thereof.
Each R 4 and R s individually is H, -(CH 2 )nOH, -C(O)OR 6
-C(O)SR
6 -(CH2)n
C(O)NR
7
R
8
-O-C(O)-O-R
7 an amino acid or a cpeptide, Each R 6 is H, R 7
-C(R)(RW)-(CH
2
-(CH
2 )n-C(RW)(R)-O-C
O
-(CH
2 )nor -C(R7)(R )-(CH 2 )n-O-C(O)-O-R 9 Each R 7
R
s and R 9 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 CH2CO 2 alkyl.
The present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
A further aspect of the present invention relates to a method for inhibiting trypsinlike serine protease enzymes, such as thrombin, factor Xa, factor Vila, 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.
WO 02/34711 PCT/US01/32582 Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein 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 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.
Best and Various Modes for Carrying Out Invention An aspect of the present invention relates to compounds represented by the formula: R B 1 W E 2
B
X
(R
2 ;pharmaceutically acceptable salts thereof;
V
1 L- V and prodrugs thereof.
(I
(A)
Each E 1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 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 maybe substituted with one or more hetero groups selected from N, O, S, and S(Oz) which may be saturated or unsaturated.
WO 02/34711 WO 0234711PCT/USOI/32582 R is -CH=CH-R 2
-C=C-R
2
-C(R
2
)=CH
2
-C(R
2 -CH=NR2, -C(R 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 R 1 R2, or W2. Preferably, these R, R1, R2, or R' do not include -(C 2 4 alkenYl)-02-C 1-9 alkyl, -(C 24 alkenyl)-C02-Cl -8 alkyl-phanyl, and -(C 2 4 alkenyl)-C02- R' is H, -N0 2 -CN, -halo, -N 3 -C 1 alkyl, -(CH 2
).CO
2
R
2
-C
2 -9 alkenyl-C0 2
R
2
-O(CH
2
),CO
2
R
2
-C(O)NR
2
R
3 -P(O)(0R 2 2 alkyl substituted -(CL1 2 )nO(CH 2 arYl, -WW, -(CH 2 )n OR 2
-(CH
2 SR', -N(R 2
)C(O)R
3 -S(0 2 )NR 2
R',
-N(R
2 )S(0 2
)R
3
-(CHR
2
NR
2 R, -C(O)W 3
(CH
2
N(R
3
)C(O)R
3
-N(R
2
)CR
2
R
3 substituted or unsubstituted
(CH
2 ),-cycloallcyl, substituted or unsubstituted
(CH
2 phenyl, or substituted or unsubstituted (CH 2 ),-heterocycle which may be saturated or 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.
W? is H, -halo, -alkyl, -haloalkyl, -(CH 2 -phenyl, -(CLI 2 1 3 -bipheflyl, -(CH 2 )14~-Ph- -(CHR1).-C(SX(CH1~)-NIIR,
-(CH
2
).O(CH
2 ).CH3, -CF 3
-C
25 acyl, -(CHR 1 0H, _(CHjR 3 )nNIIR, 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-
(CHR
3 )n hetero cycle, or substituted or unsubstituted-(CHR 3 )n cycloalkyl which may be saturated or unsaturated, WO 02/34711 WO 0234711PCT/USOI/32582 When n is more than 1, the substitutions R' and W 3 may be same or different,
R
3 is H, -OH, -CN, substituted alkyl, -C 2 8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R')R 2 or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR K 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, -CHR 2
-CH=CR
2
-CR
2
-CR
2
=CR
2 -0-CUR 2
-CUR
2
-N(R
2
-N(R
2
)-CH-(R
3
-CH,-N(R
2
-CH(R')-N(R
2
-S-CUR
2
-CHR
2 -S(0 2
)-N(R
2
-C(O)N(R
2 )-(CHR 2
-C(R
1
'R
2 )n-NR.
2
-N(R
2 )-S(0 2
-R
2 C(O)N11 2
-R
2 NC(O)NR-, -COWRCO-,-
C(=NR
2
)NR
2
N
2 -N'NC1R-, or -C(0)NRS0 2
E
2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero, ring, bicyclic ring system, Cl-g alkyl, C 2 -9 8 alkenyl, C 2 8 alkynyl, alkcylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
each X individually is a direct bond, substituted or unsubstituted C1..
4 methylene chain; 0, S, N7R 2 S(0 2 or N(0) containing one or two C 1- 4 substituted or unsubstituted methylene chains. X at different places may be same or different.
B is -halo, -CN, -NH 2
-(CU
2 4
)NIR
5
-(CH
2
),,-NHR
4 2-S (CH 2
),NI{C(-NR
4
)NR
5
-(CU
2 4
CI-
8 substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B 1 is selected from B; B 1 and B may be same or different.
12 WO 02/34711 PCT/US01/32582 There may be more than one similar or different R 2 groups present on E 2 when E 2 is a cyclic system of more than 5 atoms. p is 1 or higher if E 2 is a cyclic ring of more than atoms. For example, if the ring is 6 atoms, p can be 1 or 2.
n is 0-4 A is selected from R'.
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.
Each V and V' individually is selected from R' and N-alkyl substituted carboxamidyl CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N,Ndisubstituted carboxamidyl
(-CONRIR
2 where R 1 and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides
(SO
2 NHR or -SO 2 NRiR 2 and methylene- or polymethylene chainextended variants thereof.
Each R 4 and R 5 individually is H, -(CH 2 )nOH, -C(O)OR 6
-C(O)SR
6 -(CHz)n
C(O)NRR
8 -0-C(O)-O-R 7 an amino acid or a dipeptide, Each R 6 is H, R 7 2 )n-O-C(O)-R 9
-(CH
2 )n-C(R 7
-(CH
2 )n- C(R 9 or 9 Each R 7
R
8 and R 9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted hcterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or
CH
2 COzalkyl.
WO 02/34711 PCT/US01/32582 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 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.
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, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 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
SO
2
NH
2 substituted sulfonamido, nitro, cyano, carboxy, carbamyl
CONH
2 substituted carbamyl 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.
WO 02/34711 PCT/US01/32582 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.
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; 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, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl. "Substituted benzyl" refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
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 C 3
-C
7 carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more WO 02/34711 PCT/US01/32582 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 nonaromatic cyclic group, for example, which is 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 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 1, 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, 1,3dixolane and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl and triazolyl and the like.
WO 02/34711 WO 0234711PCT/USOI/32582 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, fnropyridinlyl (such as furo[2,3-c]pyridinyl, fbro[3,lI-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazoliflyl (such as 3,4-dihydro-4-oxo-quinazolilyl), beuzisothiazolyl, beuzisoxazolyl, benzodiazinyl, beuzofurazanyl, benzothiopyranyl, beuzotlirasolyl, benzpyrasolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfonie, dihiydrobenzopyranyl, indolinyl, isoebronianyl, isoindolinyl, naplithyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyriclyl, quinazolinyl, tetrahydroquinoliflyl, 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 sub stituents.
Within the above-described definitions, certain embodiments are preferred.
Preferred alkyl groups are lower alkyl groups containing I to about 8 carbon, and more preferably I 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. Tile aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phtnyl CI- 3 alkyl such as benzyl.
The N-heterocyclic rings preferably contain 3 -7 atoms in the ring and a heteroatom such as N, S or 0 in the ring. Examplos of suitable preferred heterocyclic 17 WO 02/34711 PCT/US01/32582 groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2methylpiperidino and 2-ethylpiperidino. In addition, the above substitutions can include halo such as F, Cl, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
Examples of some preferred B groups include -NHC(=NH)NH 2
-C(=NH)NH
2 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 types of derivatives where each R group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl groups as defined begirmnning on page 7.
Carboxamides, -NHC(O)R Carbamates, -NHC(O)OR (Acyloxy)alkyl carbamates, -NHC(O)OROC(O)R Enamines, -NHCR(=CHCRO2R) or -NHCR(=CHCRONR 2 Schiff bases, -N=CR 2 Mannich bases (from carboximide compounds), RCONHCH 2
NR
2 Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO pp/ 4 1 5 3 1, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the invention.
18 WO 02/34711 PCT/USO1/32582 Prodrug forms of carboxyl-bearing compounds of the invention include esters
(-CO
2 R) 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 quatemary salt type 0/ O RC(=O)OCHN- X 1 io
R
of structure described by Boder et al., J. Med. Chem. 1980, 23, 469.
Is Examples of some preferred groups for W are -CH 2
CH
2 -CH=CH-,
CH
2
CH
2
CH
2
-CH
2 CH=CH-, -CH 2 -CONH, -CH 2 CONH-, -NHCONH-, -CONHCO-, -CONEHCH 2
-CH
2 C(=NH)NH4-, -NHC(=NH)N-, -NHNH-, -NTO-, -CONHSO 2
-SO
2 NI-, -NHS0 2
CH
2
-SO
2
NHCH
2
-CH
2 -CH20CH 2
-OCH
2
CH
2
-CH
2 NH-, -CH 2
CH
2 NI-, -CH 2
NHCH
2
-CH
2
-SCH
2
CH
2
-CI
2
SCH
2
CH
2
SO
2
CH
2
-CH
2
SOCH
2
-CU(CO
2 H)O and -CH(C0 2 I1)OCH 2 Examples of some preferred groups for V and V 1 are N-alkyl substituted carboxamidyl (-CONLR) where the alkyl group may be straight, branched, cyclic, or bicyclic, and typically containing up to ten carbons; N,N-disubstituted carboxamidyl
CONR
1
R
2 where R 1 and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO 2 NJR or -SO 2 NRiR 2 methylene- or polymethylene chain- extended variants thereof such as -(CH2),CONHR 2
-(CH
2 ),CONRlR2, -(CH 2
).SO
2 NHRI, -(CH 2 )oSO 2
NRIR
2 (where n -NHC(O)R,
N(RI)C(O)R
2
NHSO
2 R, CL 2 NTR, CH 2
NRTR
2 WO 02/34711 PCT/US01/32582 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, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-psulphonic, 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.
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.
WO 02/34711 WO 0234711PCT/USOI/32582 The synthetic routes leading to the compounds in formula are described in the following schemes.
Scheme 1 A-1 or A-2 H SO 2
CF,
1013B-1 or COCH,
COC
3 13-2 COMEM
COME-M
4 5 MEM CH 2
-O-CH
2 -CfH 2 -0-CH, 2 k-i 3 B-I or B3-2
~N-R
H 3 C -,CH, 2a, 3a, RD 2b, 3b, R
CH
2e, 3c, R= CH, 2d, 3d, R 2e, 3e, R =CH 3 2f, 3f, R= 2g, 3g, R= 2h, 3h,R 21, 3i, R -C 2
CHI,
CH 3 2j, 3j, R
COCH
3 0 N-R 6a
CHI
R
CH-I
WO 02/34711 PCT/USOI/32582 Scheme 2 1 3n
CHO
B(OH),
BoO CHO D-1 or +3a D-2
H
0 BnO COY
H
HCOC
0 8
F
H-
3 C0 2
C
9 CF~SOO copsm H3Co2H 0 HO CO 2
MEM
R
3 CO 2
C
WO 02/34711 PCT/USOI/32582 Scheme 3
OOQCF
3 sO 2
CF
1 B2CO 2 Bn 0A CHO C0 2 ~1 14 i 4 A-3 or WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 4
H-
17 U18 1 ~B-2
F
3 CO,SO CO 2
MEM
H
BU02 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme P'Co 2 SO Co'.MEM D-1, D-2, D-3, D-4, D-5,0D-10, D-11, or U-12 23 X Sn(Bu) 3 Sn(Me) 3 ,or S(Me) 3 1o2C 0 BnOC
U
0 24 R CO 2
H
BnO 2
C
0 i 24,R= a
.N
b, c, 7 C/ f 0 0
H'C
rn,
N
H
3 C \s
N
'I
IN
ell, n, xH a,
CH-
2
CE,
0,
H,
C14,
H
3
C
CH,
v 01 10 W, -:TMS CH-I 2lI U- Cl, WO 02/34711 WO 0234711PCT/USOI/32582 24, R =(continued)
OH
3
CH~I
ac,
CHO
ad, ad S11~
H
2
OH
aa>, N ab. s aah N CH, ae,
OHCO
R
s
H
3 CIIt N N 0
N
HOc 0 0S
S
CB,\
M,
n,
CH
C14
CH,
CH
3 ac,
H
OH
ah, OH4 S N
CH,
u OH
OH
HC
CH 2 r, K on w, Y, OH
Z'OH
ad, BnO 2 C ae,/ HOHZ s
S
S
OH
af, HOH 2 O ag,/ s N3
SL
ai, WO 02/34711 WO 0234711PCT/USOI/32582 26, R
HC
rI 3HG N N N 0 0, f, fl-\\ 0/ 0 oS\
N
Gil 3
N
AV,
-CH
CH,
ac/ OHl o, T h il 3 C
OH
CH;
CH
Gil 3
OH
CH,
2
OHH
ad, ae,
\,J
sO 2
OH
a, N ab, af, ilOHl 2 ag F Boc
OH
ah, O ai, 27,R= a, C, d, k, N N
'N'
N
0 0 0S sN N
H
3 G
OH
CH
,Oi n, Gi 2
CH,
olGil 3 GiH,
U,,
WO 02/34711 WO 0234711PCT/USOI/32582 27, R (continued)
CH,
ac,~ ah,
OH
OH
ad, /0C
CH,
OH
/e \4H S aa, 2N a, af, HOH1 2 C~dag
S
N
H
ai, Conversion of 24ab 24ae 24ad K,11 The reduction of the formyl group of 24ab, 24ae, 24ae, and 24ad was accomplished with NaBH 4 to give corresponding alcohols 24ab-i, 24ac-i, 24ae-i, and 24ad-i, respectively. Later, the MEM group was removed under acidic conditions to give 25ab, 25ac, 25ae, and 25af, respectively.
E, I-.
24ad 3, Conversion of The aldchyde 24ad was oxidized to acid 24ad-i which was protected as benzyl ester to give 24ad-ii. MEM deprotection under acidic conditions produced Conversion of 24ah L, The vinyl compound 24ah was oxidized with OSO4 to give diol 24ah-i, followed by acidic hydrolysis of the MEM group to produce L, M, K, N, 0, 1-1 24ah Conversion of The vinyl compound 24ah on dihydroxylation with 0S0 4 gave diol 24ah-i, Oxidative cleavage of the diol with NaIO 4 produced aldehyde 24ah-ii. The aldehyde on reduction gave alcohol 24ah-iii, which on futher 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 Conversion of ConversionQof WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 6 D-1, D-2, D-3, D-4, or D-5 28 X H, B-O),Sn(Bu) 3 or Sn(Me)s IA~t
H
C0 2
MEM
H
2
COC
0 29 R C0 2 1- 1H 2
CO
2
C
0 a, 0 b, OHC CHO 91 h, d, fS f,
H
WO 02/34711 WO 0234711PCT/USOI/32582
R
0 a, A
H
OH
3 1,
N
3 1 b,3 CH701
C,~~~CH
2 d, C CH 2 22 1,
C,
31, R= 0 CH 3
NI-IC_
32 b, C2H b, h, C, d, CH d, fS HOHf 1, /t
CH
32,R= 0 a,A
CH,
9 N
AH
2 C K, N, 0, 1-1 29g Conversion of Aldehyde 29g was converted to alcohol 29g-i by reduction with NaBH 4 followed by the reaction of mnethanesulfonyl chloride to give mesylate 29g-ii. The mesyl group was displaced with azide to give 29giii and finally, the MEM group was removed under acidic conditions to give Conversion of K, 1-1 29h-~ K, I-1 29i Thle reduction of the formnyl group of 29h and 29i was accomplished with NaBH 4 to give corresponding alcohols 29h-i and 29W-, respectively, Later, the MEM group was removed under acidic conditions to give 30h and 301i, respectively.
Compounds of the type 23 and 28, where X =-Sn(Bu) 3 are prepared using the methods AG-i or AG-2 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 7 11 1-1
CF
3
SO
2 O COH
H
3 Co,C 0
.P
35
B(OH)
2
TIPS
TIPS Tri-isopropylsilyl 0 CBZ O CH 2
C
6
H
H
WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 8A
B(OH),
D-8 -9 3 Scheme 8B
N
2 1-2 8 1 WO 02/34711 WO 0234711PCT/USOI/32582 MOO CH-O 47 Scheme 8C 3a D-2 MoD CHO
H
3 CO 2
CH
0 48 Schem Nl s 52
NH
53 WO 02/34711 PCTUSOI/32582 Scheme 8E 26G 27ai (R C3) 32f G .27ak(R=,
'CH
3 26.1 2a N WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 9 6 D- 54 s 3 64 0 WO 02/34711 WO 0234711PCT/USOI/32582 62, R=
CHH
CH
3 CH j CH, H H
C
3 0 CH, CH 3 CH
CH
3
ON
3
CHH
N a a, O o-ab, aad, OH ae,N4R-No afNHR= 0 63,R c' CR2
CN
011 91CM 3 C IL-3 1 CH, 0 Cu 1 H,~1 CH, 31 CH P' ~CF 3 "CliC
CCH,
CH
3 ON- 0 v, 0 CH,
OH
NV, rx, y, ,CH 3 OH ab, ad, ae, NTJR N af0II WO 02/34711 WO 0234711PCT/USOI/32582 64, R= a,, g, CH,
CH,
3
CH,
C,
NCH,
ac, -0 ad, d, CH, CH, CH,CH CM, k, OH CH, C3 uC,
OH
aa, O b OH- ae, NHR NMR H 0
CH
R
CII,
WO 02/34711 WO 0234711PCT/USOI/32582 Scheme D-3 59 (Bu)Snz L69 170 11 68, R= ab, C -I 3 c d, Ce, CH 3
CH
3
CH
3 CH, ,C H CH, 0, CH3 s, H U, w, x, CM 3 04 CH, 38 WO 02/34711 WO 0234711PCT/USOI/32582 69, R= a, 3 b CR c, d, eCHC 3
C
g F 3 b C H ,C R CH ,~CH H, ,O
CCH,
7 0 R H d CC
H
CH
3 R" ,q R 3
C
3 CRC 3
H
-0 111 ~1~CI
CCR
3
CHNH
HN
SNHR
H0 2
C
71, R= 7 a, C" H WO 02/34711 WO 0234711PCT/USOI/32582 CHO U-2 or T and U3-3 MeO 72 Scheme 11 CHOb 17j BO) 73 3a MeO BOH) 2 D-2 V-1 or V-2CH and Hor WCH
H
3
CO
1
C
0 74 0 D-2,D-3, or D-8
E
WO 02/34711 WO 0234711PCT/USOI/32582 77a, 78a, 79a, 80a, R C= CHR'CH H 2 R=C1 78b,79b,R=OS0 2 CR=n8bRO 77b, 78c, 79c, R =-0-cH 2
CO
2
C
2
H
5 R!=Bn; 80c, R -0-CHICO 2
II
77c, 78d, 79d, 80d, R =-0-CH 2 CONH 2 n 77d, 78e, 79e, 80e, R ;R=Bn 77e, 78f, 79f, 80f, R -oT ~;'Bf 74 E 78g 79g1-2. 8Og 78g, 79g, 80g, R =0GB 3 R' CH 3 77,78,79,80,R H3 0=B 77, 78i, 79, 80i, R 0 C 3 R' Bn CH 3 7'7h, 78j, 79j, 80j, R 0" K H3;R' Bn 77i, 78k, 79k, R OCH 2
-CH
2 -OAc; R' Bn; 80k, R =-O-CH,-CH 2
-OH
WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 12
NH
O NH,
N
00
OC]-
3 79a 0
NH
o0 NHBoc: 'N 'N.HO 83 NH K
NN
H
0 0 86 0 86a, R- CH(OH)CR4 2
H
86b, R- CHOH 96c, R=CO 2
,H
WO 02/34711 PCTIUSOl/32582 Scheme 13 HOBn OBn HCHO xCHO T,-1 CH-O 89 3a Br Br D(OH), 87 88 89 o~nBn OBn
CO
2 MEM BnCOH C4 K~4H 3
CO
2 C' 'o 92 0 10900
CGMMC
2 MEM C2MEM B-2 C2F
H
3
CO
2 C H 3
CO
2 C H 3 CO7C 93 0 94 0 95 0 NH NH 0 NH R 0 NH 02 1-2H HOC H ,C0 2 C 2 3C0 2
C
98 097 0 96 96s, 97a, 98a, R~ s 91 7 9b R =-O-CHC 6
H
5 S r S nu 9b G 98c, R=-OH WO 02/34711 WO 0234711PCT/USOI/32582 CHO0 OMe 99 T, U-3 Scheme 14
B(OH),
OMe 100 CHO0 100 3a D-IE
H
2
COC
0 101 0
OR
OMe 1-55 K L: 4,C020 102 0 0 0 NH NH Ci1-2
NH
NH
2 NH
HO
2 C H 3
CO
2
C
0 0 104 103 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 0X oT, U-1 1 H OH- O~n O~n 105 106 107 107 3a
NH-
4D-2 0) N H ,I 0C
H
N& OH E HH
H
OBn D OB. O~n N Co C H 3 COC HCO 2
C
0 0 0 110 109 108 NH NH 0 N20 ~NH N N H 12, H WO 02/34711 PCTUSOI/32582 Scheme 16 K CHO Ho CHO z or*Z- 0 Br RODIa5 Br 113 114 BnO C0 2 o H nO CHO RO NH'RO HCOC HC0 2
C
0 0 118 117 BrnO C0,MEM HO CD 2 MEh RO I H' RoI 119 0,120 X or X, V4,Al Iln O C H O RO: Br 115 T,
U-I
cro 0-D2L Bno
CHO
RD
HCO,C 116 3a-j 0 40.3
SCO
2
IMEM
R O NH R
H
3
CO
2
C
0 122 WO 02/34711 WO 0234711PCT/USOI/32582 0I 114a, 115a, 116a, R=CH 3 ;114b, 115b, 116b, R= C 2
,H
5 114c, 115, 116c, R= -CH(Cr 3 2 115d, R= C C(CH 3 3
CH
3 117a--125a, R CH 3
;RW
CH,
C
3 117b--125b, R =CAI 5 R!
CH,
CH 3 117c 125c, R =CH-(CH 2
R'=
3 21
CH
3
CH
3
CH
3
CCH
117f-- 125f, R =C14- 3 R=
CH
3 117g--125g,R=CH 3 CF 3 117h 125h, R =CH 3 R! Cr1 3 11'7j 125j, R R'= 117k 125k, R CH) R! CH 3
CE
3 117--125,R=CH 3
CH
3 0CH 3 Cr1 3 117m 12m C(CH) 3 H 125m, R H I; WR' CH WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 16a 18 3 1-2.,
CH
3 126, 1I7, R C 2 R'
CH,
Scheme 16b 124a
R
128, R
CH,
WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 17
B(OH)
2 130
H
3
CO
2
C
0 131
IR
HOC
0 134 '91- 132 A-4, ur A-3 133, 134, R
CF
3 OF3 CF 3
F
CF3 91
F
/K k, NH 2
S
0
N-N
OOH
WO 02/34711 WO 0234711PCT/USOI/32582 133, 134, R (continued) Z'N aOH OH ac N
I
Nl N/ ag,~ O ai,~ M NH
H
CH
3 H/Ho Scheme 17a 2000 A-3, A-4,R1-/R or 12Y g'N 1 e) 'N
HCO
2 C 0 03 13513 135,136, R~ a, N N b, /j N, 1 K NH 2 N NN
NH-
2 fNH~oc C 0, f4 9, h, CH2Cn,/NH N~l CI-1NH 2 /Ho WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 18 137 138 139 140 140 6 D-2 BnO CHO 0 HC0,C 141 HO C0 2
MEM
KD
H
3
CD
2
C
E
TBnO C0 2 11 0.
1-1 3 C0 2
C
0 B110 C0 2
MEM
143 F3CO2S C02MEMD-orD- 1~ 0
H
3
CO
2
C
145 146a-- 149a,R= 146b 149b, R
S
52.
146c 149c, R -CI-1C-1 2 WO 02/34711 WO 0234711PCT/USOI/32582
CHO
150 Scheme 19 3aD-
JR
151 0 S C0 2
H
N-
152 0 WO 02/34711 PCTIUSO1/32582 Scheme 19a CHO CHO N
N~
H
2 CO 2
C
1560
NH
JE
o NH, N& CO ,H
H
H
H
H
3 C0 2 C
H
3 Co 2
C
I 0 1570 159 0 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme
NO
2 +31f 0o 0 0 R~l 0) Clor 0 160 160a, 161a, R. -CH 3 160b, 161b, R =-C)JH 160c, 161c, R =-CH 2
CAH
160d, 161d, R. -G(CH 3 3 160e, 161c, R. -CH 2 -CC1 3 160f, 161f, R -O 160g, 161g, R F 160h, 161h, R= I CHO
H
0 160i, 161j, R CH2- CE 3 CH
CH
3 160j, 161j, CHl 0'J 162a,R =-CH 3 162b, R -CH, 162c,R =-CH 2
C
6 Hs 162d, R -C(CH 3 3 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 21 13 D-2
H
3 Co 2
CH
2
C
163
CHO
H 3 CO 2 CI- 2 C
K
164
.F
166 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 22
HO
H
3 CO 2 C CHO 168 110 HCOC
-NOH
169 GHO l FfICO 2
C
170
I~AA
F
3
CO
2 SO N
N
HC
2 C l 172 0 172 130 -2 1-2 176 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 23 168 A- HOH
N
177
F
3
CO
2
SO
B-2~
H
I1 CO C
N,
178
F
3
CO
2 sO Boo
R
3 C0 2 c 179
CHO
179 -130G
D-
Boo H- N O, i{ 3
CISC
Boo
NH
0 N iI 2 x~ N
H
N
HO
2
C
183 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 24
H
D-2 6 3u, 3f, 3i, 3j B-2 188 3a, 184a, 185a, 186a, 187a, 188a, R=~ 3f, 184b, 185b, 186b, 187b, 188b, CH 2
CF
3 3i, 184c, 185c, 186c, 187c, 1 88c, R Cl1 2
CH
3
CH
3 184d, 185d, 186d, 187d, 188d, R =CR1 3 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme
NH
NH
2 x I
HOC
0 189a, 189b, 189c, 189d AEA4, 1-2 74 -~-189a 189a, X H, Y =OCH 3 189b, X OCHCHs, Y H 189c, X Y =H N14 N (Prepared by method AJ-1, AJ-2, or AJ-3) EN NH, 189d,X=Y=B Clio AE-3N N14 Hf CO C HO 2C 131 N NH, WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 26
NII
NHNo 191 x SS-2 190a, 192a 195a, H 190b, 192b 195b, R= CH, WO 02/34711 WO 0234711PCT/USOI/32582
NH
196 Scheme 27
NH
R 2 N C NRBoc 197 NH~o Ve NI13oo D-7 6a
NH
G
2 H N-Hoc 198 190b X y 200 1 1-2
NH
H, NH 2 HO 2
C
0 202 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 28 4'R 1-2 205 4 S -2 OH 0 207 WO 02/34711 WO 0234711PCTUSOI/32582 Scheme 29
CO
2
H
132, A-7 1-2 210 209a,R H 209b -211 b, R=- WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 0
H
H, C0 2
C
0 181a 1-2
CN
H
3
CO
2
C
212 0 47y
R'
WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 31 MeO MeG MeG N- N Br N CQ 2 14 N N 216 270 280 21-2 HCHCO CHO F C O SO H D-2 j B-2
H
3
CO
2 C N
H
3 COC N' 221 0220 Ho
H
H,CoC
N
219 0 225
NH
0 NH,
H
1-OC N- 229 WO 02/34711 WO 0234711PCT/USOI/32582 ,CO AG-3 'Br Scheme 32 CHO D-6 or D-7 Br +6q -0 231
R=H
R C0 2 C11 3
NH
NH
2 R=H 232 R C0 2 R= C02H k 233 R=14 R =C0 2
H
235
R=H
231 a, 232a, 233a, 234a, 235a, R =1H 231b, R =C0 2
CH
3 232b2, 233b, 234b, R =C0 2
H
WO 02/34711 PCT/USOI/32582 Scheme 33
CN
H
2
N
236 137a
A-
WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 34
L
AG
1-2 WO 02/34711 WO 0234711PCT/USOI/32582 Scheme Ho1 CHO 221 A K- H
H-
3 C0 2 C N r 0 3-2
F
3
CO
2 So CHO
H
3
CO
2 C N 0 246 1 -3 AE-3 NH, 2
H
222-
NH
0 NH4, BnO
N&
1-2 I H
HO
2 C N 250 NH A 247 4N WO 02/34711 WO 0234711PCT/USOI/32582 Scheme 36
CHO
253 AE-3 N12 HN Nfl, D-6 6a 256 112S WO 02/34711 PCT/US01/32582 General Methods of Preparation The following abbreviations have been used: THF: Tetrahydrofuran; DMF: Dimethylformamide DME: 1,2-Dimethoxyethanc; DMAP: 4-(Dimethylamino)pyridine Boc anhydride: Di-tert-butyl dicarbonate; TIPS: Triisopropylsilyl MEM: Methoxyethoxymethyl; Bn: Phenylmethyl or Benzyl The organic extracts were dried over sodium sulfate or magnesium sulfate.
The general methods for the preparation of the compounds of formula are given below: A-i: 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 HC1, 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 71 WO 02/34711 PCT/US01/32582 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with 1N HC1. 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.
A-3: Conversion of acid to amide To a solution of acid (1 mmol) in dichloromethane (5 mL) was added 2M oxalyl chloride in dichloromethane (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 stirred 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 chloroformate (1.2 mmol). The reaction mixture was stirred at 0°C for 30 min and the corresponding amine (2.5 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 vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
72 WO 02/34711 PCT/US01/32582 Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1.1 nmiol), 1hydroxybenzotriazole (1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.1 mmol) in pyridine (10 mL) was stirred overnight at room temperature and was concentrated in 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 HC1. 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.
A-7: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1 mmol), and 4dimethylaminopyridie (0.12 mmol) in xylene (10 mL) was stirred at 80 °C for 10 min.
Phosphorus trichloride (1 mmol) was added and the reaction mixture was heated with stirring 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.
WO 02/34711 PCT/US01/32582 B-l: Conversion of phenolic hydroxyl to triflate To a phenol (1 mmol) in dichloromethane (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 HC1, 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 triflate.
B-2: Conversion of phenolic hydroxyl to triflate To a solution of substituted phenol (1 mmol) in DMF (10 mL) was added Nphenylbis(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 in vacuo to furnish crude product. Purification by flash column chromatography or crystallization gave the desired MEM ester.
WO 02/34711 PCT/US01/32582 D-l: Coupling of boronic acid with triflate A mixture oftriflate (1 mmol), aryl boronic acid (1.5 mmol), potassium phosphate (3 mmol), potassium bromide (2.4 mmol) and tetrakis(triphenylphosphine)palladium (0.05 mmol) in dioxane (10 mL) was heated at reflux 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 DME/water 10 mL) was heated at reflux 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 in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
WO 02/34711 PCT/US01/32582 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 oC overnight under 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.
D-5: Coupling of alkyne with triflate A mixture of triflate (1 mmol), triethylamine (4.5 mmol), substituted alkyne 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 °C for 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 desired product.
WO 02/34711 PCT/US01/32582 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 DME/water 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 in vacuo. Purification 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 pyridine (5 mmol), copper(II)acetate (1 mmol) and bis(triphenylphosphine)palladium(II)chloride (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), LiC1 (4 mmol), PPh 3 (0.15 mmol), CuBr (0.2 rmnol), and bis(triphenylphosphine)palladium(II)chloride (0.07 g) in DMF (10 mL) under an atmosphere of argon was added trimethylstannyl compound (0.8 mmol) and a crystal 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 OC overnight. Water was added and extracted with ethyl acetate. The organic layer was dried (MgSO4), concentrated and purified by flash colunm chromatography or crystallization to furnish the desired coupled product.
77 WO 02/34711 PCT/US01/32582 Coupling of amine with triflate A mixture of triflate (0.75 mmol), amine (0.9 mmol), 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 mmol), 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 oC 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.
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 LiC1 (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 (MgSO 4 After evaporating the solvent in vacuo, the compound was purified by flash-column chromatography to give the desired product.
WO 02/34711 PCT/US01/32582 E: Oxidation of aryl aldehyde to acid A mixture of aldehyde (1 mmol), tert-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-butene (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 KMnO 4 (4 mmol). The reaction mixture was stirred for 3 h (the reaction is exothermic, and refluxed on its own during the addition of KMnO 4 The reaction mixture was diluted with methanol and water and filtered. The organic solvents were evaporated in vacuo and the aqueous layer was acidified to pH 1 and extracted several times with ethyl acetate/DME. The combined organic layers were dried (MgSO4) to furnish the desired acid.
F: Conversion of aromatic acid to MEM ester To a solution of aromatic acid (1 mmol) in THF (10 mL) was added diisopropylethylamine (2 mmol) and 2-methoxyethoxymethylchloride (1.1 mmol). The reaction mixture was stirred a room temperature for 3 h and diluted with ether (25 mL).
WO 02/34711 PCT/US01/32582 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, nitro to amine, and oxime to amine To a solution of appropriate substrate (1 mmol) in ethanol (10 mL) was added 10% palladium on carbon 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 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 To a solution of MEM ester (1 mmol) in DME (8 mL) was added 6 N HCI (2 mL) and stirred at room temperature overnight. The reaction mixture was neutralized with solid sodium hydrogen carbonate (18 mmol) and concentrated in vacuo. The reaction WO 02/34711 PCT/US01/32582 mixture was acidified with 0.5 N HC1 (20 mL) and extracted with ethyl acetate (2 X 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 a solution of ester (1 mmol) in MeOH (10 mL) was added 1 N NaOH mmol). The reaction mixture was stirred at room temperature for 2-3 h, filtered through a plug of cotton, and concentrated in 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 (1.1 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 HC1 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.
WO 02/34711 PCT/US01/32582 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 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.
L: Conversion of vinyl group to diol To a solution of vinyl compound (1 mmol) in THF/tert-butanol 10 mL) and water (2 mL) was added 4-methylmorpholine N-oxide (2.5 mmol) and osmium tetraoxide (1 mL, 2.5 wt% in tert-butanol, 0.1 nunol). The reaction mixture was stirred at room temperature for 2 h and quenched with saturated aqueous solution of sodium sulfite mL). The reaction was stirred at room temperature for 30 mins and diluted with brine 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 purified by flash column chromatography to furnish the desired diol.
M: Conversion of diol to aldehyde To a solution of diol (1 mmol) in DME/water 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 10 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.
WO 02/34711 PCT/US01/32582 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 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 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried, filtered and concentrated in 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 in vacuo to remove organic solvents and diluted with 0.1 N HC1 (10 mL). The product was extracted with chloroform (2 X 10 mL), dried, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography to furnish the desired carbamate.
WO 02/34711 PCT/US01/32582 Q: Conversion of silyl protected amine to amine A mixture of silyl protected amine (1 mmol), tetrabutylammonium fluoride 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 tert-butyl carbamate 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 (MgSO4), and the solvent was evaporated in vacuo to furnish tert-butyl carbamate. If needed, the product was purified by crystallization or column chromatography.
S: Conversion of tert-butyl carbamate to amine To a solution of tert-butyl carbamate (1 mmol) in dichloromethane (10 mL) was 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 tert-butyl carbamate to amine To a solution of tert-butyl carbamate (1 mmol) in methanol (13 mL) was added 6 N HC1 (8.75 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, 84 WO 02/34711 PCT/US01/32582 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 mmol) 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 OC until complete). After completion of the reaction, 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-l: Conversion of bromide to boronic acid To a mixture ofbromo compound (1 mmol) in ether (10 mL), cooled to -78 nbutyl lithium (1.2 mmol) was added dropwise and the reaction mixture was stirred for rins after the addition was completed. Tributyl borate (1.3 mmol) in ether (10 mL) was 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 HC1 (10 mL). The reaction mixture was stirred at *room temperature for Ih 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 HC1 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 in vacuo to furnish boronic acid.
WO 02/34711 PCT/US01/32582 U-2: Synthesis of boronic acid by ortho lithiation of aryl aldehyde To a solution of N,N,N'-trimethylethylenediamine (1 mmol) in THF/ether mL, 1:1) cooled to -20 OC was added dropwise, over a period of 15 mins, n-butyl lithium (1 mmol) and stirred at -20 oC for 15 mins. Aldehyde (1 mmol) at -20 OC 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 mins 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 reaction and stirred at 4 °C for 12 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCI (3 rmnol) and heated at reflux for 2 h and added to ice water mL). The aqueous layer was separated and the organic layer extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL).
The basic layer was acidified to pH 3 using 6 N HC1 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 basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic 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 -78 OC, tertbutyl 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 1 h. The reaction mixture was allowed to warm to 0 OC and quenched with 2 M HC1 (10 mL). The reaction mixture was stirred at room temperature for lh. 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 HC1 and the 86 WO 02/34711 PCT/US01/32582 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 in vacuo to furnish boronic acid.
V-l: 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 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 10mL). The combined organic layers were washed with brine, dried over MgSO 4 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 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 layer was separated, washed with brine, dried over MgSO4, and concentrated to give the desired phenol. This can be further purified if needed by crystallization or column chromatography.
WO 02/34711 PCT/US01/32582 V-3: Demethylation of aryl methyl ether to phenol To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was added A1C1 3 (8.5 mmol). The reaction mixture was heated to reflux for 12 h under nitrogen. To this mixture was added 12 mL of 1 N HC1 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 (MgSO4), and evaporated in vacuo to furnish the desired phenol, which was purified by column chromatography.
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 para-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 mL). 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 (MgSO4) and concentrated in vacuo. The residue obtained was purified by flash column chromatography to afford the desired phenol compound.
W: Conversion of acid to methyl ester A mixture of acid (1 mmol), cone. HzSO4 or cone HC1 (0.5 mL) and methanol mL) 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 88 WO 02/34711 PCT/US01/32582 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 A solution of methanolic HC1 or ethanolic HC1 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 HCI was added acid (1 mmol) and stirred at room temperature (or reflux if needed) overnight. The reaction mixture was concentrated 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 alkylation of amines 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 crude product. The crude was purified by crystallization or flash column chromatography.
Y: Conversion of nitrile to hydroxycarbamimidoyl To a solution ofnitrile compound (1 mmol) in ethyl alcohol (10 mL) was added hydroxylamine (50% aqueous solution, 5 mmol). The mixture was stirred at reflux for 2h. The reaction mixture was concentrated in vacuo to furnish the desired hydroxycarbamimidoyl compound.
WO 02/34711 PCT/US01/32582 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 mmol) and continued heating at 50 OC 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 cone HC1. The solid obtained was collected by filtration to 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 mmol) and heated with stirring at 150 OC for 12 min. The mixture was cooled and poured into ice water (20 mL), NaOH (30 mg) and stirred for min. It was then extracted with ether and the aqueous layer was acidified to pH 4 with HC1 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 OC under N 2 The mixture was stirred for 45 min and was then poured into ice water and acidified with 1 N HC1. The precipitated solid was collected by filtration, washed with IN HC1, 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 in vacuo. The residue WO 02/34711 PCT/US01/32582 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 (MgSO 4 and evaporated to yield a solid. The solid was washed with hexane and dried in vacuo to furnish the desired amide.
AB-1: Conversion of amino of amidine to amino carbamate To amidine compound (1 mmol) was added 0.1N NaOH (10 mL) and stirred at room temperature for 5 min. The reaction mixture was concentrated in vacuo and to the residue was added alkyl or aryl 4-nitrophenyl carbonate (2 mmol) in 20 mL of hexamethylphosphoramide and stirred at 45 OC 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 (100 mL) and 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.
AB-2: Conversion of amino of amidine to amino carbamate To a solution of amidine compound (1 mmol) in acetonitrile (25 mL) was added triethylamine (5 mL) and aryl/alkyl chloroformate (2 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.
WO 02/34711 PCT/US01/32582 AC: Conversion of aldehyde to oxime To a stirred solution of aldehyde (1 mmol) in ethanol (10 mL) was added pyridine 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.
AD: Debenzylation in the presence of aldehyde To a solution of phenyl methoxyaryl aldehyde (1 mmol) in dichloromethane 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 aldehyde AE-1: Reductive amination of aldehyde To a stirred solution ofaldehyde (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 stirring for 20 min, the solvent was evaporated in 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 92 WO 02/34711 PCT/US01/32582 filtration. The pH of the aqueous phase was adjusted to 7 with 1N NaOH and was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO 4 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 mmol) in methanol (10 mL) 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 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 1 N NaOH (30 mmol) 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 HC1 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.
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 OC for one hour. A solution of aldehyde (1 mmol) in methanol (7.5 mL) containing 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 nunol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 5 N NaOH (30 mnnol) 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 93 WO 02/34711 PCT/US01/32582 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 HC1 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 nunol), 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 (MgSO4), filtered through Celite and concentrated to give the product. Purification of the crude by flash column chromatography gave the desired product.
Reductive amination of aldehyde To a solution of amine (1.2 mmol) in MeOH (10 mL) was added aldehyde (1 mmol) in THF (10 mL) containing acetic acid (0.1 mL) drop-wise. The mixture was stirred at 50 OC for 4-12 h and then cooled to room temperature. Sodium cyanoborohydride (1.5 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 (MgSO 4 and evaporated in vacuo. The residue was purifcid by flash column chromatography to furnish the desired amine.
WO 02/34711 PCT/US01/32582 AF-1: Synthesis of amidine from nitrile Acetyl chloride (5 mL) was added to methanol (5 mL) at 0 OC drop-wise and stirred at room temperature for 15 mins. To this solution of methanolic HCI was added nitrile 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 -78 °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 48 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 in vacuo. The residue obtained was purified by flash column chromatography to obtain the desired addition product.
AG-1: Synthesis of tributylvinyltin compounds from vinyl bromide containing hydroxyl To a solution of vinyl bromide with hydroxyl (1 mmol) in dichloromethane mL) was added tert-butyldimethylsilyl chloride (1.5 mmol) and DMAP (1.5 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water mL) and the aqueous layer separated. The organic layer was washed with 0.1 N aqueous HC1 (10 mL), brine (20 mL), dried and concentrated in vacuo to furnish WO 02/34711 PCT/US01/32582 corresponding tert-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 tert-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 of the crude residue obtained by flash column chromatography furnished the desired tributyltin compound.
AG-2: Synthesis of tributylmethyltin compounds from arylmethyl bromides or allyl bromides To lithium clippings (10 mmol) in THF (10 mL) cooled to -40 OC 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 cooled to -40 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.
WO 02/34711 PCT/US01/32582 AG-3: 4-Bromo-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
K
2 C0 3 (5.56 g, 40.2 mmol) in n-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 (1.75 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 HC1 and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried (MgSO4) 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 cone. H 2 S0 4 (5 mL) was added drop by drop. The resulting mixture was refluxed overnight and cooled to room temperature. Water mL) was added and the resulting aqueous solution was extracted with ethyl acetate (100 mL X The combined organic layers were dried (MgSO 4 and evaporated in 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-dimethylpropionyl 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 N HCI (100 mL), water, brine, dried (MgSO 4 and concentrated in vacuo. The crude residue was purified by flash column chromatography to furnish the desired ester.
WO 02/34711 PCT/US01/32582 AI: Preparation of 2-bromo-5-hydroxy benzaldehyde To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), wvas 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 benzaldehyde (32 g) as a dark brown solid. The filtrate was concentrated to 200 mL, 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 dark 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 OC.
AJ-1: Amidine from nitrile A mixture of nitrile (1 mmol) and hydroxylamine (aqueous 50%, 1.8 mL) in EtOH (15 mL) was refluxed for 3 h and concentrated in 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 in vacuo. The residue obtained, was purified by flash column chromatography to obtain the corresponding amidine.
AJ-2: Amidine from nitrile A mixture of nitrile (1 mmol) and saturated methanolic HC1 solution (freshly prepared by bubbling HCI gas or prepared in-situ by premixing methanol and acetyl 98 WO 02/34711 PCT/US01/32582 chloride at ice cold temperature) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to furnish methyl imidate. To the residue of methyl imidate was added MeOH (40 mL) and ammonia gas was bubbled at reflux temperature for 16 h or till the reaction was complete. The reaction mixture was concentrated in 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.
AJ-3: Amidine from nitrile To a solution of nitrile (1 mmol) dissolved in methanol (5 mL) was added Nacetyl cystein (0.1 or 1 mmol) and ammonium acetate (5 mmol) and heated at reflux 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) dichloromethane adduct (0.75 mmol) under argon in dioxane (100 mL) was added aryl triflate mmol), pinacolborane (31.5 mmol) and triethylamine (75 mmol). The reaction mixture was heated under argon at 100 OC for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in 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) dichloromethane adduct (0.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.03 mmol) under argon in dioxane (100 mL) was added aryl triflate (1 mmol), bis(pinacolata)diboron (1.1 99 WO 02/34711 PCT/US01/32582 mmol) and potassium acetate (3 mmol). The reaction mixture was heated under argon at 100 OC for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester.
The examples of the compounds prepared 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.
R'
Cpd. -R R'Starting MethodAnltclDa No. -'IFrom UsedAaytalDa CH3 'H NMR (DMSO-d,): 6 10.26 11H), 9.84 1 H 8.15 J1 3.0 Hz, 1 7.64 (dd, J= 2.0 Hz 2a -HN "KC3 1 A-or-2and 8.9 Hz, 1 6.94 J =8.9 Hz, 1 3.90 (s, 2a OH H 3 A- orA-23 2.15 J1=6.9 Hz, 2 2.06 (in, J -6.9 Hz, 01 0.93 J= 6.9 Hz;* 1 0.93 J 6 Hz, 611; MS 252.12
H
2b -OH CH, I A-i or A-2 Characterized in the next step
H
N CH 3 2c -OH C I A-i or A-2 MS 294.54 0
H
N C 2d -OH 1 A-i or A-2 MS 288.49 (M1-+Na)+ Cpd. -R R'Starting Method Analytical Data No. IFrom I Used
H
2e -OH 1H A- I or A-2 Characterized in the next step
H
2g -OH1 1YN-" A-i or A-2 MS 300.40 S(S-:286 0
H
2g -OHz NY 1) A- I or A-2 MS (ES 272.48 E}286 0
H
2i -OH 1) l- n A-i or A-2 MS (ES):26.4(Na 0 ~1Jt
-OH
CH
3
H
N
CH,
A- I or A-2 Characterized in the next step 102 Cpd. -R Statin Method Analytical Data No. From J Used
CH,
H
3a -OSO 2
CF
3 Y N CH., 2a B3-ior B-2 MS (ES 4 384.37 0
H
3b -OSO 2
CF
3 2h B-i or B3-2 MS (ES 4 370.36 0 CH,
H
N CH 3 3c -OSO 2
C
3 OHY 2c B-i or B-2 MS (ES 4 426.37 0
H
3d -OSO 2 CF3 EC 3 2d B-I or B-2 Characterized in the next step 0 Hy,, 1 H NMR (CDC1) 8 8.41 J= 2.3 Hz, 1 8. (dd, J 8.5, 2.4 Hz, 7.37 J= 8.5 Hiz, 1 H), 3e -050 2
CF
3 02e B-i or B-2 6.48 (broad, I 3.98 3 3.46 7.2 Hz, 2 1.62 (in, 2 1.42 (in, 2H), 0.96 J= 7.2 Hz, 3 MS (ES 4 384.1 N CFH HNMR (CDC1 3 3 8.45 J 2.4 Hz, I 8.14 3f -050 2 CF, 217 B-i or B-2 (dd, J= 8 2.4 Hz, 1 7.42 J 8.7 Hz, 1 H), 3f -O02CF36.52 (broad, I 4.14 (in, 2 4.00 3 MS.
0 410.2 Cpd. -R 1R Starting JMethod Analytical Data No. From Used I 'H-INM!R (CDCI 3 6 8.42 J 2.3 Hz, I 8.12 H (dd, J= 8.5, 2.3 Hz, 1 7.39 J= 8.7 Hz, 1 H), 3 g -OSO 2
CE
3 N 2g B-I or B-2 6.31 (broad, 1 4.00 3 3.34 (dd, J= 7.2, Hz, 2 1.07 (in, 1 0.59 (in, 2 0.30 (in, 0 ~2 MS (ES 4 382.2
H
3h -050 2
CF
3 Ny 2h B- I or B-2 MS (ESt): 396.36 'H NAIR(DMSO-d 6 868.85 J= 5.5 Hz, 1 H), 3i~ 9OOC 3 N C1 i BIo .49 J= 2.3 Hz, I 8.23 (dd, J= 8.7, 2.3 Hz, 1 7.70 J 8.7 Hz, 1 3.92 3 3.31 (in, 2 1. 14 J 7.2 Hz, 3 MS (ES 356.1 'H NMR (DMSO-d 6 568.81 J =6.0 Hz, 1 H), G~9 .49 J 2.3 Hz, 1 8.24 (dd, J1=8.7, 2.4 Hz, 3j -oSO 2 cF 3 N CH, 3 2j B-I or B-2 1 7.71 J= 8.7 Hz, 1 3.92 3 3.15 (mn, 2 1.64 (in, 1 1.41 (in, I 1.12 (in, I 0.88 (in, 6 MS 398.2 'H NMR (DMSO-d 6 6 8.52 J= 2.0 Hz, 1 H), 8.32 (dd, 1= 2.0 and 8.9 Hz, I 7.72 J= 7.9
-OSO
2
CF
3
-CO
2 MEM 4 B-2 Hz, 1 5.50 2 3. 88 3 3.-78 J =4.9 Hz, 2 3.44 J 4.9 Hz, 2 3.17 3 H); MS (ES 4 439.1 (M+Na) 4 0o CH 3 'HTNMR (CDC1.
3 6 8.29 J3 1.6 Hz, 1 7.96 /H (dd, 3=7.5 1.6 1z 7.58 =7.5 H,1 -B -NC1 3 3a AK 6.24 (bs, I 3.94 3 3.3 0 J 6.5 H-z, 21H), 1.92 I 1.43 12 0.99 J= 0 Hz, 6 MS 362.2 Cpd. 1 -R Starting Method fAnalytical Data No. j tjFrom Used 0 CH 3 'H NMR (DMSO-d 6 8 10.26 1 9.84 I Hl), 8.15 J =3.0 Hz, 1 7.64 (dd, J 139 -OH N H 138 AA and 8.9 Hz, I 6.94 J= 8.9 Hz, 1 3.90 (s, H 3 2.15 J= 6.9 H~z, 2 2.06 (in, J= 6.9 Hz, 1 0.93 J= 6.9 11z, 6 MS 252.12 0 CH 3 1 HTNMR(DMSO-d 6 5 10.38 I 8.36 (d,J" 2. 8 Hz, 1 7.99 (dd, J 2.6 and 8.9 Hz, 1 H), 140 -OSO 2
CF
3 N CH 3 139 13-2 7.52 J 9. 0 Hz, 1 3.89 3 2.23 J~ H 7.0 Hz, 2 2.09 (in, J= 6.6 Hz, 1 0.94 J 6.6 Hz, 6 MS 384.0 'H NMR (CDC 3 5 8.08 I11H), 8.00 2.3 169 168 AC Hz, 1 7.75 (dd, J =2.3 and 8.7 Hz, I 7. 01 -O X OH J='8.7 Hz, 1 3.97 3 3.50 1 MS 196.1 'H NMvR(DMSO-d 6 5 7.79 J 2.0 H-z, 1 H), 170 -OH -CH 2
NII
2 169 G 7.51 (dd, J 2.3 and 8.5 Hz, I1-H), 6.95 J= Hz, I 7.01 J= 8.7 Hz, I 3.90 3 3.72 2 3.50 (bs, 2H); MS 182.12
H
CH
3
D
MS 250.50; MS 274.50 (M+Na)+ Cpd.
Starting From Method Used Analytical Data No CH, 1 H NMR (CDCI 3 5 7.96 J= 2.3 Hz, 1 7.55 H J 2.3 and 8.3 Hz, 1 7.26 J1=8.3 Hz, 1 172 -OSO 2
CF
3 N, CH3 1 71 B-2 5.90 (br s, 1 4.50 J= 4.1 Hz, 2 3.97 3 2.44 (sep, J= 7.0 Hz, 1 1.20 J' 0 Hz, 6 MS 384.1 CH 3 'H NMR (DMSO-da,): 5 10.62 1 8.88 (in, 2 177 -OH H 16 Ej 7.99 J =2.3 Hz, I 7.70 2.3 and N 16 A~l 8.5 Hz, 1 7.06 (di, J= 8.7 Hz, 1 4.09 (mn, 2 CH 3 3.91 3 2.70 (in, 2 1.98 (in, 1 H, J= 6.8 Hz), 0.93 J= 6.8 Hz, 6 MS 238.1 CH NMR (CDCI 3 8 8.05 J =2.3 Hz, I 7.63 H CI 3 (dd, J- 2.3 and 8.3 Hz, I 7.25 (di, 8.3 Hz, 1 178 -OSO 2
CF
3 N177 B-2 3.96 3 3.85 2 2.43 J= 6.8 Hz, CH 3 2 1.77 (in, J1= 6.6 Hz, 1 0.93 J1= 6.6 Hz, 1 MS 370.2 Boc H 3 'H INMR (DMSO-da): 6 7.93 (mn, 1 7.47 (in, 1 179 -OSO 2
CF
3 CH3178 R 7.26 (ri, I 4.48 (mn, 2 3.96 3 N (in, 2 1.91 (mn, 1 1.52 (in, 9 0.89 J= 3 Hz, 6 MS 492.2 (M+Na)+ 106
R
H 3 c0 2 c 0 No. -R R romng Method Analytical Data 'HNVMR (DMSO-d6): 89.79 11H), 8.85 J 5.7 H-z, 114), 8.50 J 2.0 Hz, 111), 8.20 (cid, J 1.9 Hz, 111), 7.55 (in, 9H), '7 -OBn -CHO 6 +3a D-2 5.35 2H), 3.69 3H), 3.23 J 6.5 Hz, 2H), 1.98 (it, 1H), 1.02 J 6.8 H-z, 6H); MS 446.3 8 -OBn -CO 2 H 7 E MS (ES 4 484.33 (M±Na) 4 9 -OBn -CO 2 MEM 8 F MS (ES 4 572.2 (M+Na) 4 1n -OH -CO 2 MEM 9 G MS (ES 4 482.33 Nal- 'H NMR (DMSO-d6): 88.75 J 5.6 Hz, 114), 8.44 J 1.6 Hz, 1H), 8. 11 (dd, J 1.9 Hz, 1H1), 8.01 J =2.9 Hz, 1H), 7.84 (dd, J 8.4, 2.6 Hz, 111), 7.47 3 8.5 Hz, 1H), 7.41 3 11 -0S0 2
CF
3
-CO
2 MEM 10 B-2 8.0 Hz, 114), 5.23 AD system, 2H4), 3.59 311), 3.44 (in, 211), 3.30 (mn, 2H), 3.18 311), 3.13(t, J 6.6 Hz, 211), 1.88 (in, 1H), 0.91 (ci, J 6-7 H7, MS 614.3 (M±Na) 4 0
ACH
3
I
D-3
-COMEM
Characterized in the next step 107 Cpd. -R 1R Starting MethodAnltclDa No. -R R From Used ]AaytalDa 29b -CH, -CO 2 MEM 11 D-3 MS 520.2 (M+Na)+ 29c -~-CH 2 CO2MEM 11 D-3 MS 482.3 29d -CO 2 MEM 11 D-3 MS 562.3 29
CO
2 MEM 11 D-3 MS 556.4 (M+Na)+ 'H NMR (DMSO-d6): p8.50 J 5.61Hz, 8.18 J 1.9 Hz, 111), 7.86 (dd, J 7.9, 1.9 Hz, IH), 7.78 J =1.7 Hz, IH), 7.56 (dd, J 8.0, 1.8 Hz, 1H), 7.13 J 8.0 Hz, 1IM, 7.00 J 29f 'CH 2
-CO
2 MEM 11 D-3 7.9 Hz, 11H), 6-67 (dd, J =17.6, 11.1 Hz, 1H), 5.76 J 17.6 Hz, 2~1 5.19 J 11. 1 Hz, 1 4.99 AB system, 211), 3.37 (s, 3H1), 3.20 (in, 2H), 3.11 (mn, 2H), 2.97 3H), 2.91 J 6.7 Hz, 211), 1.67 (mn, 1H), 0.70 J 6.6 H~z, 6H); MS 492.3 (M+Na)+ O1HC 29g -CO 2 MEM 11 D-2 MS 576.2 MS 552.2 Cpd. -7 R Starti=ng Method1 No. I m Used Analytical Data
CHO
29h -CO 2 MEM 11 D-2 MS 538.2 29i -CO 2 MEM 11 D-2 MS 560.4 (M+Na)+ 0 0
-CO
2 H 29a 1-1 MS (ES 398.3 ;MS 396.3
CH
3
H
3 -00211 29b I-i Characterized in the next step 3c CH, -CO 2 H 29c I-1 MS 392.1 S C0 2 H 29d I-1 MS 452.1 -00211 29e 1-1 MS (ES 446.2 109 Cpd. -R -t Starting Method Analytical Data
'-CO
2 H 29f 1-1 MS (ES-3: 380.1
N
3 H 2
C
C0 2 H 29g KN ,MS 515.3 (M+Na) MS 491.2
CH
2
OH
CO
2 H 29h K, 1-1 MS 450.1 0
HOH
2
C\
-CO
2 H 29i K, I-I MS 450.3 33 -OSO 2
CF
3
-CO
2 H 11 1-1 Characterized in the next step 41 ~O -CO 2 MEM 10 D-8 MS 534.30 42 0 -CO 2 H 41 1-I MS 446.30 48 -OCH 3 -CHO 47 3a D-2 MS 392.2 (M+Na) 49 -OCH 3
-CO
2
H
48 SMS 386.1; 408.1 (M+Na) I I. 4 110
CO
2 Bn Cpd.] [RR Starting MethodAnltclD a No. I- From Used AnalytclDt 14 -OSO 2
CF
3 -CHO 13 B-2 Characterized in the next step
-OSO
2
CF
3
-CO
2 H 14 IE MS 403.58 CH 3 'HNMR (DMSO-d 6 6 8.83 J 6 Hz, 1 H1), 8.49 J 2.6 16 -OO 2
F
3 N 5 -3orA- Hz, I 8.23 (dd, J =8.6 Hz, 1 7.72 J =8.6 Hz, 1 H), 1 OOC3CH 3 1 A-or-47.49 (in, 2 7.41 (in, 3 5.43 2 3.1 J 6.9 Hfz, 2 0 2.29 (mn, 1 0.89 J 6.9 Hz, 6 H).
R R BnO C 0 Cpd. -R -RI ~Starting MethodAnltclDa No. I From UsedAnltclDa 1 1{NWvR (DMS0-l 6 60.88 J =6.0 Hz, 6 1.85 (in, 1 H), 3.1 J =6.0 Hz, 2 5.02 J 13 and 2.5 Hz, 2 5. 18 2 17 -OBn -CHO 16 +6 D-2 6.88 (in, 2 7.17 J 8.6 Hz, 1 7.26 (in, 411), 7.35 (in, I 7.40 (in, 41H), 7.49 J =7.7 Hz, 2 8.07 (dd, J =7.7 and 1.7 Hz, 1 8.38 J =1.7 Hz, 1 8.72 J =6 Hz, 1 H), 9.63 1 MS (ES+):522.89 I1{NMR (DMSO-d 6 6 0.86 J =6.9 Hz, 611), 1. 85 (in, 1 H), 3.09 J =6.9 Hz, 21H), 5.01 J 5.01 Hz, 2 5.14 2 H), 18 -013n -CO 2 H 17 E 7.08 (mn, 3 7.14 (dd, J =8.6 and 2.6 Hz, 1 7.27 (in, 4 H), 7.34 (in, 1 7.41 (mn, 3 7.48 (in, 2 7.99 (dcl, J 6.9 and 1.8 Hz, 1 8.32 I 8.64(t, J 6 Hz, 1 12.57 1 H); MS (ES±):538.86 I HNM4PR (DMSO-d 6 0.90 J 6.8 Hz, 611), 1.86 (mn, 1 H), 3. 10 J 6.5 Hz, 211), 3.16 31H), 3.28 (dd, J 3 and 6 Hz, 2 19 -OBn -CO 2 MEM 18 F 3.36 (dcl, J 3 and 6HT-z, 2 5.02 J =3.8 Hz, 211), 5.12 J 15HI-z, 211), 5.64 2 7.11 (in, 311), 7.24 (dd, J =8.25 and 2.75 Hz, I 7.29 (in, 4 7.35 (in, I 7.42 (in, 3 H), 7.49 (in, 211), 8.02 (dd, J 1.7 and 8.2 Hz, 1 8.36 1.7 Hz, 8.68 J 6 Hz, 11I-); MS 626.44 112 Cpd. R -Rv Starting MethodAnltclDa No.1 From jUsedAnltclDa 'HNMR (DMSO-d,): 3 0.88 J 6 Hz, 6 1.85 (in, 1 H) 3.10 J =6 Hz, 2 H) 3.16 3 3.28 (m 2 3.35 (in, 2 5.04 21 -OH -CO 2 MEM 19 G, H J=3.5 Hz, 21H) 5.11 J= 14 Hz, 211), 6.98 2H), 7.11 mn, 2 7.29 (mn, 5 8.03 (dd, J 8 and 2 Hz, 1 8.32 J 2 Hz, 1 8.67 J 6 Hz, I 9.9 I MS 536.30 (100%: 'JHNMRp (DMSO-d 6 830-89 J 6. 8 Hz, 6 1.86 (in, I H), 3.12 J 6.5 Hz, 2 3.16 3 3.29 (in, 21-1), 3.40 (in, 2 22 -OSO 2
C.F
3
-CO
2 MEM 21 B-2 5.04 2s 21), 5.16 (dd, J 18 and 6 Hz, 2 7.15 (in, 2 H), 7.31 (in, 3 7.36 J 8.95 Hz, 1 7.41 J 8.5 Hz, 1 H), 7.73 (dd, J1-8.6 and 2.6 Hz, 1 7.85 J 2.6 lHz, I 11), 8.07 (dd, J 7.7and 1.7 Hz, 1 8.45 J 1.7 Hz, 1 8.73 J 6 Hz, 1 MS 668.15 ISz 1 1PN4MR (DMSO-d 6 8 0.89 J 6.8 Hz, 6 1.87 (in, 1 H), 3.12 J 6HI-z, 211), 3.16 3 3.29 (in, 211), 3.39 (in, 211), 5.05 J 2.6 Hz, 211), 5.16 J 17 Hz, 2 7.08 (in, 2 H), 7.21 (in, 4 7.24 3 7.7 Hz, 1 7.35 J3 7.7 Hz, 1 H), 7.62 J 3.5 Hz, 1 7.64 J3 5 Hz, 1 7.86 J 8.6 Hz, 1 8.06 (in, 2 8.42 1 8.73 J 6 Hz, 1 MS 602.52
-CO
2
MEM
22+23 rCjT.
Starting Method Analytical Data No Fro Used 'HNMR (DMSO-d 6 3 0.89 J 6.8 Hz, 6 1.87 (in, 1 H), 3.12 J 6 and 6.8 Hz, 2 3.16 3 3.30 (in, 2 3.39 (dd, J 5.2 and 3.4 Hz, 2 5.04 J 4.3 Hz, 2 5. 16 J 24b \-CO 2 MEM 22 23 D-I 16 Hz, 2 7.08 (m,2 7.20 (mn, 3 7.24 J1 8.6 Hz, I b S 7.35 J =8.6 Hz, 1 7.61 J3=5 Hz, 1 7.71 (dd, J 4.8 and 3 Hz, 1 7.91 (dd, J3 1.7 and 7.7 Hz, I 8.00 (in, 1 8.06 (dd, 3 =2 and 8 Hz, 1 8.14 J 1.7 Hz, 1 8.41 J 1.7 Hz, 1 8.68 J 6 Hz, 1 MS 602.27 'IINMR (DMS0-l 6 5 0.89 J3 6.8 Hz, 6 1.87 (mn, I H), 3.12 J3=6 and 6.8 Hz, 2 3.16 3 3.30 (mn, 2 3.40 I(in, 2 5.05 J 5 Hz, 2 5.17 J 17 Hz, 2 7.09 (mn, 24c -CO 2 MEM 22 23 D-I 2 7.21 (in, 3 7.30 J 7.7 Hz, 1 7.37 J 7.7 Hz, 1 7.44 (in, I 7.54 J 7.7 Hz, 2 7.73 J 6.8 Hz, 2 H1), 7.88 (dd, J3=1.7 and 7.7 Hz, 11H), 8.07 (dd, J3=7.7 and 1.7 Hz, 1I-I), 8. 11 J =1.7 Hz, 1 8.42 J=1. 7Hz, I1H), 8.72 J 6 Hz, 1 MS 596.45 24d \-CO 2 MEM 22 23 D-1 MS 616 H 3
C-
24e I C0 2 MEM 22 +23 D-1 MS 586.4 0 Cpd. Starting 1Method 1nltclDt No. j R ~From UsedAnltclDa 24f CO 2 MEM 22+±23 D-I MS 586.39 0
H
3
C
24g CO 2 MEM 22+±23 D-1 MS 616.63 24h 2 MEM 22 +23 D-1 MS 597.25
N
24i -CO 2 MEM 22 23 D-1 MS 597.4
N
24j -CQ 2 MEM 22 23 D-1 MS 597.4
N
24k H.
3 C -CO 2 MEM 22+23 D-1 MS 644.3 0 Cpd. W Starting Method No. -R R' From Used 1Analytical Data 241 N -C0 2 MEM 22 23 D-3 Characterized at the next step
IR
24m N-CO 2 MEM 22 23 D-10 Characterized at the next step 24 R 2 CMM 22 D3 M (S)N507 24on 7
-CO
2 MEM 22 23 D-4 MS 560.72 4pC, -CO 2 MEM 22 23 D-5 MS 558.3 24q 24r CH 3
OH
HC
OH
-CO
2
MEM
22+23 D-5 Characterized in the next step I. 1 -I-
-CO
2
MEM
22+23 D-5 MS 610.4 (M+Na)' I Cpd -R Starting TMethod Analytical Data No. j -R jFrom jUsed 24s C2 -C0 2 MEM 22 23 D-3 Characterized in the next step
CH
3
CH
2 24t -CO 2 MEM 22 23 D-3 Characterized in the next step CH 3 24u -CO 2 MEM 22 23 D-3 MS 598.4 (M+Na)+ 24v -CO 2 MEM 22 23 D-3 MS 500.4 [(M-MEM)-1Y- 24w :TMS -CO 2 NMM 22 23 D-5 Characterized in the next step C14 3 24y -CO 2 MEM 22 23 D-5 MS 56.5 (M+Na)+
CH
3 24z OH -CO0 2 MEM 22 23 D-3 MS 576.4 (M+Na)+ 24aa -CO 2 MEM 22 +23 D- 11 Characterized in the next step 11-7 Cpd. I -R I Starting Method A ayiclDt No.j 1 [1From] Used
CHO
24ab /\.C0 2 MEM 22 23 D-2 MS 630.55
/S
24ac /\.C0 2 MEM 22 23 D-2 MS 630-74 s
CHO
24ad O/ -CO 2 MEM 22 23 D-2 MS 652.3
S
24ae oiqc -CO 2 MBM 22 23 D-2 Characterized in the next step 24ag N-CO 2 MEM 22 23 D-1 MS 685.01 24ah CH2 -CO 2 MVEM 22 +23 D-3 MS (ES 4 546.49 118 Cpd. -R 1R Starting [Method AnltclDt No. J From UsedAnltclDa 1 HNMR (DMSO-d 6 5 0.91 J 6.9 Hz, 6 1.88 (in, 1 H), /3.13 J =6.9 and 6 Hz, 2 5.07 J 11.2 Hz, 2 7.09 (in, C0H 24\- 2 7.22 (in, 5 7.35 7.7 Hz, 1 7.63 2.6 Hz, 1 H),
O
2 H 24a7.65 J =5.2 Hz, 1 7.82 (dd, J 7.7 and 1.7 Hz, I 8.05 J 1.7 Hz, 1 8.07 1 8.40 I 8.72 J 6Hz, 1 12.77 (brs, I MS 514.19 1 111iM{R (DMSO-d 6 8 0.92 J 6.9 Hz, 6 1.88 (in, I H), 3.12 J 6.9 and 6 Hz, 2 5.07 J 13 H4z, 2 7.09 (in, 2 7.22 (in, 4 7.35 J 8.6 Hz, 1 7.63 J 5.2 Hz, 1 /\C0 2 H 24b 1-1 7.70 (dd, J =2.6 and 4.3 Hz, 1 M, 7.88 (dd, J =7.2 andl1.7 b/S ~Hz, 1 8.02 J =1.7 Hz, 1 8.07 (dd, J =1.7 and 7.7 Hz, 1 8.15 (in, 1 8.39 J 1.7 Hz, I 8.72 J =6 Hz, 1 H), 12.70 (brs, 1 MS 514.06 'HNMR (DMSO-d 6 6 12.73 (bs, 1 8.73 J 6 Hz, 1 H), 8.41 J1=1.7 Hz, 1 8.12 J 1.7 Hz, 1 8.07 (dd, J 7.7 1.7 Hz, 1 7.83 (dd, J =7.7 1.7 Hz, 1 7.72 J C0 2 H 24c 1-1 6.9 Hz, 2 7.54 J 2 7.44 J1 7.7 Hz, I 7.37 J 7.7 Hz, 1 7.28 J 7.7 Hz, I 7.21 (in, 3 7.09 (in, 2 5.08 J 14 Hz, 2 3.13 J1 6.5 Hz, 2 1.88 (in, I 0.91 6.8 Hz, 6 MS 507.93 1 HNMR (DMS0-l 6 6 12.75 (bs, 1 8.71 J 6 Hz, 1 H), 8.39 J 1.7 Hz, 1 8.05 (dd, J 1.7 7.7 Hz, I 8.01 (d, J 2.5 Hz, 1 7.75 (dd, J1=2.5 7.7 Hz, 1 7.42 3.4 Hz, /\C0 2 H 24d 1-1 1 7.34 J 7.7 Hz, -1 7.22 (in, 3 7.19 J 8.6 Hz, 1 7.09 (in, 2 6.95 TJ 3.4 Hz, I 5.06 J1=11 Hz, 2 3.12 J 6.5 Hz, 2 2.52 3 1.89 (in, 1 0.81 (d, 6.8 Hz, 6 MS 528.51 Cpd. 1 -R Starting IMethod AnltclDt No. j R From UsedAaltia Dt IHNNVR (DMSO-d 6 8 0.89 J =6 Hz, 6 1.86 (in, 1 3.12 J 6.8 and 6.0 Hz, 2 5.03 J 10 Hz, 2 7.02 1 H), /\C0 2 H 24e 7.06 (in, 211), 7.16 J =8.6 Hz, 1 7.21 (mn, 3 7.31 JT 7.7 Hz, 1 7.75 (dd, J =8.5 and 1.7 Hz, 1 7.78 J 1.7 0 Hz, 1 8.04 (in, 2 8.29 1 8.36 JT 1.7 Hz, I H), 8.66 J =6 and 5.2 Hz, I 12.58 (bs, 1 MS 498.49 /\C0 2 H 24f 1-1 MS 498.36
H
3 C IHNMR (DMSO-d 6 5 12.72 (bs, I H1), 8.69 J 6 Hz, I H), 8.39 J =1.7 Hz, 1 8.06 2 7.79 (dd, J 1.7 7.7 02H 24g 1-1 Hz, 1 7.45 1 H1), 7.35 J 7.7 Hz, 1 7.21 (mn, 511),
\C
2 H 2g7.1 (m,2 M, 5.07 J =8.6 Hz, 2H), 3.12 J 6.5 Hz, 2H), S 2.29 3 1.89 (in, 1 0.91 6.8 Hz, 6 MS (ES+) 528.38 a N C0 2 H1 I HNMR (DMS0-l 6 5 12.74 (bs, I 8.73 (in, 2 8.63 J 1.7 Hz, 1 8.41 J 1.7 Hz, 1 8.23 (dd, J 1.7 and 7.7 Hz, 1 H1), 8.08 (dd, J 1.7 7.7 Hz, I 8.05 (di, J =7.7 Hz, 1 7.96 (cit, J 7.7 1.7 Hz, 1 7.43 (dd, J 6 7 Hz, 1 H), 7.37 (di, J =7.7 Hz, I fH), 7.29 (di, J =8.6 H-z, 1 7.18 (in, 311), 7.08 (mn, 2 H1), 5.01 J 10 25 Hz, 2 3.13 J 6.9 and 6 Hz, 211), 1.89 (in, 1 0.92 1 6.9 Hz, 6 MS (ES+) 509.58 Cpd. -R Starting MeUsed ]Analytical Data '1{NMR (DMSO-d 6 612.70 (bs, I 8.91 3= 2.6 Hz, I H), 8.68 J 6 Hz, 1 8.62 J =2 Hz, 1 8.4 J 1.7 Hz, 1 8.12 (in, 2 8.05 (dd, J =8.6 1.7 Hz, 1 7.88 (d, IC0 2 H 24i 1-1 8.5 1. 7 Hz, 1 7.53 (dd, J =8.6 5.2 Hz, I 7.34 J N 7.7 Hz, 1 7.28 J 8.6 Hz, 1 7.18 (in, 3 7.08 (in, 2 5.04 J 12 Hz, 2 3.11 J1=6.5 Hz, 2 1.87 (in, 1 0.9 6.8 Hz, 6 MS 509.11 'HNMR (DMSO-d 6 6 0.90 J 6.9 Hz, 6 1.88 (mn, 1 H), 3.11 J 6.9 and 6 Hz, 2 5.03 2 7.06 (in, 2 7. 18 02H 24j 1_1 (in, 3 7.33 8.4 Hz, 1 7.30 J 8.4 Hz, 1 7.75 J
O
2 H 4j 6.2 Hz, 2 7.85 (in, 1 8.05 (dd, J =7.6 and 1.7 Hz, 1 H), N 8. 18 1 8.40 J =2 Hz, 1 8.71 (in, 4 MS (ES±) 509.49 C0 2 H 24K 1-1 Characterized in the next step 251 N C0 2 H 241 I-1 MS (E+:511.54 NC0 2 H 24m 1-1 MS 501.66 Cpd. -R R 1 Starting Method AnltclDt No. j RJFrom UsedAaltclDa
-C
2 C0 2 H1 24n 1-1 MS (ES t 472.4 S Z C0 2 H 24o I-I MS 515.65 2 5 p CH 3 C0 2 H 24p 1-1. Characterized in the next step
CH
3 2q ,OH C0 2 H 24q 1-1 MS 536.3 OH C0 2 H 24r 1-1 MS 500.4 CH, C 2 H 24s 1-1 Characterized in the next step
CH
3
CH
2 C0 2 H 24t 1-1 Characterized in the next step
CH,
C0 2 H 24ui 1-1 MS 486.4 22 2 Cpd.
No.
Starting From' Method Used Analytical Data
CH
2 C0 2 H 24v I-1 MS 524.3 (M+Na)h
H
CH0G 2 H 24w I-1, Q Characterized in the next step
CH
3 CH C0 2 H 24x I-i MS (ES7J: 498.3 OHy01 C0 2 H1 24y 1-1 MS 484.3
CH
2 C0 2 H 24z I-i MS (ES 488.3
OH
C0 2 H 24aa 1-1 Characterized in the next step OH\ C0 2 H 24ab K, 1-1 MS 544.27 Cpd. -R 1 -RI Starting Mto nltclDt No. jFrom_ LUMed I ~ayiclDt C0 2 H 24ae K, I-I MS 544.2 s
-OH
BnOC \C0 2 H 24ad EH MS 670.3 (M+Na)+ jS\ 'HNMR (DMSO-d 6 8 9.1 (bs, 2 8.8 (bs, 211), 8.5 J =6 Hz, I 8.02 1 7.68 1 7.62 (in, 6 7.53 J HOHC- C0 2 H 24ae K, 1-1 5.8 Hz, 1 7.15 J 6 Hz, 1 7.13 (mn, I 7.01 1 S 5.5 J 5 Hz, I 4.7 J 5 5Hz, 2 H4), 3.01 (mn, 2 1.8 1 0.85 J1 6.8 Hz, 6 H) IIOH1 2
C\
C0 2 H 24ad K, I-i MS 566.2 (M+Na)+
S
N C0 2 H 24ag I-1 MS 597.7 Boc
OH
OH C0 2 11 24ah L, 1-1 MS 492.54
M,
Xi C0 2 H 24ai K, N, Characterized in the next step
R
N
H
H-
BnO 2
C
0 Cpd. -RStarting 1nltia Metho No. -RjFrom JUsedAnltclDa 'HNMR (DM50-l 6 6 0.88 J =6.9 Hz, 6 1.84 (in, 1 3.07 J =6.9 and 6.0 Hz, 2 5.05 2 7.04 J 6.9 Hz, 2 7.20 (in, 4 7.35 I 7.7 Hz, 11-H), 7.43 J1 7.7 Hz, I 7.66 3 =5.2 Hz, I 7.70 26a "25a i J 4.3 Hz, 1 7.75 (mn, 4 7.82 (dd, J 7.7 and 1.7 Hz, I 7.94 (d, J 1 1.7 Hz, I 8.03 (dd, J 7.7 and 1.7 Hz, I 8.26 (dd, J 7.7. and 1.7 Hz, I 8.69 J -6 Hz, 1 8.80 2 9.17 2 10.76 1 H); MS 631.05 'HNMR (DMSO-d 6 3 0.88 J=-6.9 Hz, 6 1.84 (in, 1 3.07 J 6.8 and 6.0 Hz, 2 5.04 2 7.02 J =6.8 Hz, 2 7.20 (in, 3 7.34 26b /\25b f 1 7.7 Hz, 1 7.43 J =8.6 Hz, 1 7.72 (in, 6 7.90 (dd, J 1.7 and 7.7 Hz, I 8.05 (in, 3 8.23 (di, S 1.7 Hz, 1 8.68 J 6 and 5.2 Hz, 1 8.82 2 9.17 2 10.73 1 MS 631.82 'HNMR (DMSO-d 6 8 10.75 1 9.19 2 8.89 2 8.69 J 6 Hz, 1 8.29 J 1.7 Hz, 1 HM, 8.07 (dd, J1=7.7 1.7 H-z, 1 7.99 J 26c 25C 1.7 Hz, 1 7.87 (dcl, J =7.7 1.7 Hz, 1 7.83 J3 7.7 Hz, 2 H), 26c 25c 1 7.77 (mn5 7.54 J 7.7,2 7.43 (in, 3 7.19 (mn, 3 7.03 J 6.9 Hz, 2 5.04 (bs, 2 3.09 J1 6.5 l1z, 2 1.84 (in, I M, 0.89 (d, Hz,_6_H);_MS_(ES+)_625.81 Cpd.
No.
Starting From Method Used Analytical Data 'HNMvR (DMSO-d 6 8 10.7 I 9.14 2 8.82 2 8.64 J 6 Hz, 1 8.21 1 7.98 (dd, J =7.8 2 Hz, 1 7.8 J =2 Hz, 1 H), 26d /\25d j 7.7 (mn, 4 7-68 (dd, J 2 7.8 Hz, 1 7.44 J 3Hz, 1 7.37 (d, Hf' 7.8 Hz, 1 7.27 J 7.7 Hz, 1 7.16 (in, 3 7.0 1 6.99 1 6.96 J1=3 Hz, 11H), 5.0 2 3.03 J 6.5 Hz, 2 2.46 3 H), 1.78 (in, 11-H), 0.83 6.8 Hz, 6 MS 645.77 1 EpNyR (DMS0-cl 6 8 0.87 J 6.2 Hz, 6 1.73 (in, 1 3.07 J 6.7 and 6.2 Hz, 2 5.05 2 7.03 (dd, J =1.7 and 8 Hz, 21H), 7.11 J 1.7 26e /\25e Hz, 1 7.21 3H), 7.31 J =8Hz, IH), 7.42 (d,J 8Hz, 1 7.78 (in, 5 7.92 J1 1.7 Hz, I 8.02 (dd, J 8 and 1.7 Hz, 1 8.25 J 0 1.9 Hz, 1 8.33 1 8.63 J1 6 and 5 Hz, 1 8.80 (bs, 2 9.14 (bs, 2 10.67 1 H);I MS 615.75 'HNMR (DMSO-d 6 8 0.87 J 6.7 Hz, 6 1.83 (mn, 1 3.06 J1 6.7 and 6.2 Hz, 2 5.04 2 6.67 (in, 11-H), 7.03 (in, 2 7.16 (in, 3 H), 26f /\25f 1 7.35 J =8.6 Hz, 1 7.42 J 8Hz, 1 7.74 (in, 4 7.85 (mn, 2 H), 7.98 J1 1.2 Hz, 1 8.03 (dd, 3 =1.7 and 8 Hz, 1 8.25 J= 1.8 Hz, I 0 8.67 J 6.2 and 5.5 Hz, 1 8.88 (bs, 2 9.12 (bs, 2 10.772 (bs, 1 MS 615.75
HGC
26g 25g 1 IINMR (DMSO-d 6 8 10.67 1 9.12 2 8.78 2 8.61 J 6 Hz, 1 8.21 1 7.98 (dd, J1=7.8 2 Hz, 1 7.84 J1=2 Hz, 1 H), 7.7 (mn, 5 7.46 1 7.39 7.8 Hz, 1 7.29(d, J 7.7 Hz, 1 7.16 (in, 411), 7.01(s, 1 6.99 1 5.0 2 3.03 J 6.5 Hz, 2 2.23 3 1.79 (in, 1 0.83 6.8 Hz, 6 MS 645.77 Analytical Data 1 IINMR (DMSO-d 6 6 10.77 (bs, 1 8.95 (bs, 4 8.76 J 4.3 Hz, 1 8.69 J 6 Hz, 1 8.4 1 8.29 (in, 2 8.15 J =7.7 Hz, 1 H), 8.07 (dd, J3 1-7 and 7-7 Hz, I 7.99 (dt, J 1.7 7.7 Hz, 1 7.76 (in, 4 7.46 (in, 2 7.18 (mn, 3 7.05 1 7.03 1 5.06 2 3. J 6.9 and 6 Hz, 2 1.86 (in, 1 0.89 J 6.9 Hz, 6 MS (ES+) 626.69 'H-NMR (DMSO-d6): 6 10.73 (bs, 1 9.16 (bs, 2 9.05 J 1.9 Hz, 1 8.79 2H), 8.69 J 6 Hz,1I 8.64 (dd, J 1.2 5Hz, I H), 8-29 3 1.7 Hz, 1 8.24 J1 8 Hz, 1 8.05 (mn, 2 7.93 (dd, 8 1.8 Hz, 1 7.76 (in, 5 7.56 (dd, J 8 4.3 Hz, 1 7.44 J 7.4 Hz, 2 7. 18 (mn, 3 7.0 (in, 2 5.0 2 3.08 J 6.5 Hz, 2 1.82 (in, 1 0.88 6.8 Hz, 6 MS (ESI) 626.44 1 HNMR (DMSO-d 6 0.87 J3 6.9 Hz, 6 1.75 (mn, 1 3.08 J 6.9 and 6.0 Hz, 2 5.03 2 7.03 (mn, 1 7.18 (in, 3 7.45 J 7.8 and 7 Hz, 2 7.76 4 7.87 J1 6 Hz, 2 7.94 (dd, J1 8 and 2 Hz, 1 8.05 (dd, J1 8 and 2 Hz, 1 8.08 J =2 Hz, 1 8.29 J3=2 Hz, 1 8.70 (in, 3 8.84 2 9.11 2 10.76 1 MS (ESI) 626.76 1 1{NMR (DMSO-d,): 6 10.72 (bs, 1 9.15 (bs, 2 8.81 (bs, 2 8.86 J =6 Hz, 1 8.28 1 8.03 (in, 3 7.91 J1 7.9 Hz, 1 7.81 J 4 Hz, I 7.74 4 7.42 S 7.9 Hz, 1 7.38 J 7.9 Hz, I H), 7.18 (mn, 3 7.04 (in, 2 5.04 (bs, 2 3.07 1 6 Hz, 2 2.57 3 1.83 (in, 11-H), 0.87 J1 6.8 Hz, 6 MS 673.7 Cpd. R[Starting Method Analytical Data 'HNNMfR (DMSO-d,): 8 10.66 I 9.20 2 8.86 2 &66 J 6 \Hz, 1 8.24 J =2 Hz, 1 8.15'(dd, J 7.8 2 Hz, 1 7.69 (in, 4 H), 261 N 251 1 7.68 J Hz, 1 7.63 J 7.9 Hz, I 7.43 J =7.9 Hz, 1 7.37 1 J 7.9 Hz, 1 7.24 (in, 3 7.09 (in, 2 6.92 1 6.40 1 H), CHi 6.17 J 4 Hz, 1 5.10 (bs, 2 3.74 3 3.09 (t,5J 6 Hz, 2 H), 1.83 (in, 1 0.88 J 6.8 Hz, 6 MS 628.65 26m N25m S MS 618.91 'ITNIVR (T)MSO-d 6 6 10.56 I 9.15 (bs, 2 8.84 (bs, 2 8.64 J S6 Hz, 1 8.19 (d2 J 2 Hz, 1 7.99 J 7 Hz, 1 7.70 (in, 4 H), 26n 25n 1 7.46 1 7.36 (in, 2 7.24 (mn, 3 7.05 1 7.00 1 6.0 (in, 1 5.18P 16 Hz, 1 5.10 J =11 Hz, I 5.0 2 3.47 (d,J =6 Hz, 1 3.03 J 6 Hz, 2 H4), 1.79 (in, 1 0.83 J 6.8 Hz, 6 H); MS (ES-f) 589.5 'HNMvR (DMSO-d 6 8 10.84 1 9.16 211), 8.78 2 8.69 J5 6 Hz, 1 8.27 J 2 Hz, 1 8.19 1 8.09 (dd, J =2 7.7 Hz, 1 H), S6 8.04 (dd,J =2 7.7 Hz, 1H), 8.01 J =4HIz, 1 7.89 J '3 Hz, 1 H), 26o Z50 1 7.73 (in, 4 7.44 (dd, J 3 7.8 Hz, 2 7.16 (ifn, 3 7.30 I 7.05 I 5.03 (bs, 2 3.06 J 6.5 Hz, 2 1.82 (in, 1 0.86 6.8 Hz, 6 MS 632.4 26p -2 5 p i MS CBS+) 609.3 (M+Na)+ Cpd. -R Starting Method AnltclDt No. -RFrom UsedAnltclDa CH 3 26q OH 25q 3 MS 631.5
H
3
C
'HNTIR (DMSO-d 6 5 10.71 1 9.16 2 8.81 2 8.68 J =6 OH Hz, 11H), 8.25 I 8.03 J 7.8 Hz, I HI), 7.73 (in, 5 7.69 1 H), 26r 25r 1 7.55 J =7.8 Hz, 1 7.39 J 8.9 Hz, 1 7.26 (in, 3 7.03 (ra, 2 5.02 (bs, 2 4.95 J 5 Hz, 1 3.62 J3 6 12.8 Hz, 2 3.07 J 6 Hz, 2 2.62 J 6 Hz, 2 1.83 (in, 1 0.88 J3 6.8 Hz, 6 MS 617.4 1 HNMR (DMSO-d 6 5 0.89 J3=6.8 Hz, 6 1.84 (in, 1 1.99 3 H), H, 3.09 J 6HIz, 2 HM, 5.04 2 5. 18 1 5.28 1 6.73 J =16 26s 25S 3 Hz, 1 7.04 J 6 Hz, 2 7.23 (in, 5 7.42 J 9 Hz, 1 7.73 CH 3 5 7.85 11E), 8.03 (dd, J =9and 2Hz, IH), 8.26 J= 2 Hz, I1H), 8.69 J 6 Hz, 1 8.87 (bs, 4 10.91 1 MIS 615.4 'HNMR (DMSO-d 6 6 10.8 (br s, 1 9.1 and 8.9 (2 br s, 4 8.6 (mn, 1 H), 26t CH2 25t 1 8.2 I 8.0 (mn, I 7.8-7.6 (mn, 6 7.40 J 6.9 Hz, I H) 7.3 (in, 4 7.0 1 5.6 (in, 1 5.2 (mn, 1 5.0 (br s, 1 3.1 J 6.8 Hz, 2 CH, H 2.2 s, 3 1.8 (in, 1 0.95 6 MS 589.4, MIS 5 87.5 '1{NMR (DMSO-d 6 8 0.88 J 6.8 Hz, 6 1.84 (mn, I 3.09 J1 6 Hz, 2 4.33 J3 5.5 Hz, 2 5.02 2 5.01 J 5.5 Hz, 11-1), 5.95 26u O 25u j (in, 1 6.57 J3 11.5 Hz, 1 7.04 3 6.7 Hz, 2 7.25 (in, 3 H), 7.31 J 7.8 Hz, 1 7.43 (mn, 2 7.54 1 7.74 4 8.05 (dd, J =7.8 and 2 Hz, 1 8.23 J3 2 Hz, 1 8.69 J3 6 Hz, 1 8.83 (bs, 2 9. 18 (bs, 2 10.66 1 MS 605.3 129 Cpd. T Starting MethodAnltclDa No. J RJFrom UsedAaytalDa 'HNMR (DMSCO-d 6 0.88 (di, J 6.8 Hz, 6 1.84 (in, 1 2.75 J =7 CHl Hz, 2 3.09 J =6 Hz, 2 3.60 (in, 2 4.65 J 5 Hz, 1 5.05 (s, 26v 25v f. 2 7.05 J 7 Hz, 2 7.29 (in, 5 7.42 J 7.8 Hz, 1 7.66 (dcl, OH 7-8 and 2 Hz, 1I-H), 7-75 (in, 6 8.03 (dci, J3 7.8 and 2 Hz, 1 8.25 (s, 1 8.68 J3 6 Hz, 11-H), 8.82 (bs, 2 9.18 (bs, 2 10.68 I MS 619.4 'HNMIR (DMSO-d 6 860.88 J 6.8 Hz, 6 1.84 (in, 1 3.09 J 6 li-z, 2 4.41 1 5.04 J I11 Hz, 2 7.05 J 5.5 Hz, 2 7.29 26w H25w i (in, 3 7.34 J3 8 Hz, 1 7.40 J 8Hz, 1 7-65 (dd, J =8 and 2 Hz, 11-H), 7.75 4 7.79 I 8.05 (dci, J and 2 Hz, I 8.28 J =2 Hz, 1 8.71 J 6 Hz, 1 8.82 (bs, 2 9.17 (bs, 2 10.73 1 MS 573.3 l'p.4NA (D)MSO-d 6 830.86 (di, J 6.8 Hz, 6 1.47 3 1.74 3 H), CH 3 1.85 (in, 1 3.06 J 6Hz, 2 3.43 (di, J 8 Hz, 1 5.04 2 H), 26x .25x J 5.11 (in, I 7.03 (mn, 2 7.23 (in, 5 7.52 (in, 2 7.72 (ra, 5 8.02
CH
3 (in, 11H), 8.21 1 8.66 J3 6 Hz, I 8.81 (bs, 2 9.23 (bs, 2 H), 10.52 1 MS 617.6 'HNMIR (DMSO-d 6 3 0.87 (di, J3 6. 8 Hz, 6 11), 1.72 (in, 11-H), 3.07 J 6 2 4.36 J 6 Hz, 2 5.0 (mn, 2 5.42 J 6 Hz, 1 7.03 (d, -6 5 OH I=7Hz, 2H), 7.25 3H), 7.31 J =8Hz,lIH), 7.39 (d,J =8 Hz,1IH), 26~ 7.58 (di, J 8 Hz, 1 7.73 (mn, 5 8.02 (dd, J3 10 and 2 Hz, 11I), 8.23 (s, 1 8.68 J3 6 Hz, 1 8.76 (bs, 2 9.15 (bs, 2 10.71 1 MS (ESI) 603.4 130 Cpd.
-R
S tartiug Method Analytical Data CH,'HNMR (DMSO-c13: 8 10.6 1 9.17 1 8.85 1 8.6 8 J CII,5.9 Hz, 2 8.25 1.98 Hz, 1 8.05 J3 1.96 Hz, I 8.03 J 1.9 26z 25z Hz, 1 7.75 (in, 4 7.65 (in, 4 HI), 7.41 J 7.87 Hz, 4 7.25 (mn, 1 OH H) 5.4 I 5.2 J 5.9 Hz, 2 4.44 J 5.9 Hz, 1 3.09 J= 6.89 Hz, 2 1.89 I 6.89 Hz, 2 H) 0.88 J3 5.9 Hz, 6 MS (ES+) 605.69 26na N 25aa 3 Characterized in the next step OH 1 HNMR (DMSO-d,): IS 10.70 1 H) 9.15 (bs, 2 8.77 (bs, 2 8.67 J 6 Hz, 1 8,25 11H), 8.04 J =7 Hz, I 7.77 J Hz, I 7.71 26ab /\25ab (m 4H), 7.70 J =2 Hz, I1H), 7.59 J =6Hz,1IH), 7.46 J= 8 Hz, 1 7.41 J3 8 Hz, 1 7.22 (in, 3 7.05 I 7.03 J =2 Hz, 1 SH), 5.31 J3=6 Hz, 1 5.04 (bs, 2 4.51 3 =6 Hz, 2 3.07 S= 6 Hz, 2 1.82,(in, 1 0.86 J 6.8 Hz, 6 MS 661.74 'HNMR (DMSO-d 6 8 0.87 J 6.9 Hz, 6 1.83 (mn, I 3.07 J =6 Hz, 2 4.71 J 5 Hz, 2 5.04 (bs, 2 5.69 J1 5 Hz, I 7.03 26ac /\25ac i J =5.8 Hz, 2H), 7.21 (m,3 7.3 5(d, J 5Hz, 1IH), 7.3 8(d,J =8 Hz, 1 s -OH 7.44 (in, d, S 8 Hz, I 7.58 J 5 Hz, I 7.74 (in, 6 8.03 J =8 Hz, 1 8,24 1 8.67 J 6 Hz, 1 8.79 (bs, 2 9.14 (bs, 2 10.64 1 MIS 661.74 BnCO 2\ H1NNM (DMSO-d 6 8S 9.65 I 8.71 J 5.15 Hz, I H) 8.39 J BnO 2 2.57 Hz, 4 8.09 J3 1.79 Hz, 4 8.05 J 1.79 Hz, 4 7.43 J -26ad 25ad J 7.77 Hz, 2 7.29 2 7.19 (in, 2 7.08 (in, 2 5.03 J3 2.58 Hz, 2 H) 3.29 (in, 2 3.12 4 2.49 (in, 2 1.87 (in, 2 0.90 J S 6.87 Hz, 6 MS 765.4 Cpd. Starting Method Analytical Data No. From Used HOH 2 C- 26ae 25ae i 26af
HOHC
25af 'HNMR (DMSO-d 6 6 9.1 (bs, 2 8.8 (bs, 2 8.5 J 6 Hz, 1 8A-02 1 7.68 1 7.62 (in, 6 7.53 J 5.8 Hz, 1 7.15 J 6 Hiz, I 7.13 (in, I 7.01 I 5.5 J 5 Hz, I 4.7 1 5 Hz, 2 3.01 (mn, 2 1.8 (mn, I 0.85 I 6.8 Hz, 6 MS 571.2 'HN4R (DMSO-d 6 6 10.6 1 9.17 I 8.85 1iH), 8.68 J 5.9 Hz, 2 8.25 1.98 Hz, 1 7.75 (in, 4 7.65 (in, 4 7.41 J 7.87 Hz, 4 7.25 (in, 4 5.4 1 5.2 J 5.9 Hz, 2 4.44 J 5.9 Hz, 1 3.09 J1=6.89 Hz, 2 1.89 J 6.89 Hz, 2 0. 88 J1 5.9 Hz, 6 H).
1 ImiMR (DMSO-d,): 6 0.90 J 6.9 Hz, 6 1.41 9 1.87 (in, I H), 3.11 J1=6.9 and 6 Hz, 2 5.07 2 6.37 J 3.4 Hz, 1 6.51 1 Hf), 7.11 (in, 2 7.26 (mn, 3 7.33 7.7 Hz, 1 7.41 J 8.6 Hz, 1 7.45 J 1.7 Hz, 1 7.61 (dd, J 1.7 and 7.7, 1 7.74 (mn, 5 H), 8.05 (dd, J 8.6 and 1.7 Hz, 1 8.26 J 1.7 Hz, 1 8.66 J1 5 and 6 Hiz, I 8.77 (bs, 2 9.15 (bs, 2 10.58 I MIS 714.78 26ag Dc I 25ag
OH
26ah OH 25ah J MS 609.6 'HPNMR (DMSO-d 6 8 10. 8 1 6.2 and 8.9 (2 br s, 2 H each, 4H), 8.7 (t, I 8.2 I 8. 0 J 6 Hz, 1 7.7 (in, 5 7.6 J 5 Hz, 1 H), 26ai 25ai 1 7.4 S1- 5.8 Hz, I 7.35 1 6.9 Hz, I 7.29 (in, 3 7.0 (in, 2 H),
N
3 5.0 (in, 2 4.6 2 3.01 J 6.8 Hz, 2 1.81 (in, I 0.95 J 6.8 Hz, 6 MIS (ESI) 604.3 Cpd. -R Strtin] Method Analytical Data '11 NMAR (DMSO-d 6 8 14.95 1 8.97 4 J =6 Hz, I 7.97 J 2 Hz, I 7.80 J1 2 2aCH 3 2a 12 Hz, 1 7.73 (dd, J 7.9 and 2 Hz, I 7.61 (in, 7 H), 27a/ \26a 1-2 7.18 J3 3.9 Hz, 1 7.05 J 7.9 Hz, 1 6.93 Cs C 3 (d,J =7-9 Hz, 11H), 3.01 J =6.9 and 6.0 Hz, 2 1.81 1 0.84 J3 6.9 Hz, 6 MS 541.17 'H NMR (DMSO-d 6 5 13.24 1 9.05 2 8.9 2 8.49 J 6 and 5.2 Hz, I 7.97 1 7.99 2bCl! 3 2b 12 I 7.87 lIH), 7.75 (di, J 7.7 Hz, I1H), 7.65 (in, I 27b 26 1-2 7.62 (in, 6 7.05 J 7.7 Hz, 1 6.93 J CH 3 7.7 Hz, 1 3.01 J 6.9 and 6.0 Hz, 2 1.81 (in, 1 0.85 J 6.9 Hz, 6 MS 541.42 'H NMVR (DMSO-d 6 8 13.28 1 9.04 4
CH,
1 J3 6 Hz, I 7.97 I 7.82 1 7.74 (in, 3 27c 26c 1-2 7.62 (in, 5 7.5 J3 7.7 Hz, 2 7.4 J 7.7, CH 3 1 7.1 J =7.7 Hz, 2H), 6.97 J Hz, 1H), 3.01 J 6.5 Hz, 2 1.8 (in, 1 0.85 6.8 Hz, 6 MS_(ES+):_535.48 Cpd. j -R j -Rf Starting Method Anialytical Data I H NMR (DMSO-d 6 8 9.03 2 8.89 2 8.49
/\C
3 J 6Hz, 1 7.99 1 7.65 8H), 7.37 (d,iJ 27d H 3 C- s c 26d 1-2 3 Hz, 1 7.04 J 7.7 Hz, 1 6.98 1 6.82
CH
3 J =3 Hz, 1 2.98 J =6.5 Hz, 2 2.46 3 H), 1.76 (in, I 0.81 6.8 Hz, 6 MS (ES):555.61 'H NIVR (DMSO-d,): 8 14.10 1 9.05 (bs, 2 H),
CGB
3 8.79 (bs, 2 8.47 J =5.6 Hz, 1 8.3 1 7.96 27e 26e 1-2 J 2 Hz, 1 7.78 Csn, I 7.63 (in, 7 7.05 (in,
G
3 I1H), 7.01 J .7Hz, IH), 6.92 (d,J=7.7 Hz,1IH), Hz, 6 MS 525.36 'H NMR (DMSO-d 6 8 9.07 2 8.86 2 8.53 C H, J =5 Hz, 1 8.03 1 7.89 J 1.4'Hz, I H), 27f 0 6f 1-2 7.78 (mn, 2 7.65 (in, 6 7.1 (mn, 2 7.08 J =7
ZB
3 H H 6 z, 1 6.64 (dd, J 3.5 and 2 Hz, 1 3.03 J =6.9 and 6.0 Hz, 2 1.81 (in, 1 0.86 J 6.9 Hz, 6 H); MS 525.43
H
3 C CH 3 'HNMR -(DMSO-d 6 5 13.81 1 8.74 (bs, 4 H), 8.43 J 6 Hz, 1 7.92 J =2 Hz, 1 7.69 J 27g CH 26g 1 2 2Hz, 1 7.62 (dd, J 7.7 2 Hz, 1 7.54 (mn, 5 H), 27g \CH 3 26g 1-2 7.38 1 7.15 1 6.99 J =7.8 H~z, 1 6.89 S f 6.8 Hz, 1 2.97 J =6.5 Hz, 2 W, 2.20 3 1.76 (in, 1 0.8 6.8 Hz, 6 MS 555.67 Cpd. -R Starting Method1AnltalDt No. [IFrom jUsedAnltclDa 'H NMR (DMSO-d 6 8 13-95 (bs, I 8.99 (bs, 2 8.79 (bs, 2 8.65 J 5 Hz, 1 8.43 J 6 I-Iz, 1 CH 3 8.25 1 8.09 J 7.8 Hz, 1 8.00 J 27hi 26h 1-2 7.8 Hz, 1 7.94 1 7.87 J 7.8 Hz, 1 7.58 CH 3 5 7.34 (dd, J 7.8 5 Hz, I1H), 7.09 (dd, J 7.7 N Hz, 1 6.90 J 7.8 Hz, 1 2.97 J 5Hz, 2 H), 1.76 (mn, 1 0.81 6.8 Hz, 6 MS 268.64 (m/2) 'H NMR (DMSO-d 6 8 9.05 (bs, 2 8.95 J 2.1 Hz, 1 8.-75 2 8. 65 (dd, J 5 1.4 Hz, 1 CH 3 J 5.6 Hz, 1 8.2 (dt, J1 1.8 7.7 Hz, 1 7.99 27i26i 1-2 J 2.1 Hz, 1 7.9 J 2.1 Hz, 1 7.85 (dd, J= cn 3 26i 7.7 &2.2 Hz, 2 7.65 (mn, 5 7.55 (dd, J 7.7 Cm7i Hz, I 7.15 J 7.7 lIz, 111), 6.95 J 7.7 Hz, 1 3.08 J 5 Hz, 2 1.82 (in, 1 0.9 6.8 Hz, 6 MS 268.85 (ml/ 2) 'H NMR (DMSO-d,): 8 14.19 1 9.06 (bs, 2 H), CH 8.67 (bs, 2 8.67 J 6 Hz, 2 8.50 J1 6 Hz, 1
CE
3 7.97 (in, 2 7.91 (dd, J 7.7 and 2 Hz, 1 7.80 27j CH 26j 1-2 J1=6 Hz, 2 7.64 (mn, 6 7.18 J1=7.7 Hz, 1
CE
3 6.95 J 7.7 Hz, 1 3.02 J 5.0 Hz, 2 H), N1.82 (mn, 1 0.80 J 6.9 Hz, 6 MS 536.43 'H NMvR (DMSO-d 6 8 9.04 (bs, 2 8.78 (bs, 2 H), HC 8.55 J =6Hz, I 8.1 I 7.98 (d,J =4 Hz, I 27k HC26k 1-2 7.95 1 7.87 J 7.9 Hz, 1 7.75 J S CE 3 6.9 Hz, 11H), 7.66 (mn, 4 7.2 (mn, 2 7.09 1 H), 0 3,03 J 6 Hz, 2 2.55 3 1.81 (in, I 0.85 J 6.8 Hz, 6 MS 583.59 StrigIehl Cpd.
Startng TT~~r1 Analytical Data In1 NMR (DMSO-d 6 8 9.1 2 8.84 2 8.56 (t, CH,. J 6 Hz, 1 8.08 (bs, 1 7.67 (in, J =7 7.5 8 J 271 F/ 26 1- 7.9 Hz, 1 7.11 (in, 2 6.91 (bs, 1 6.31 (bs, 1 N6 1-2 HM,6.11 J=3 Hz, 1 3.74 3H), 3.05 J =6Hz, 1B 2 1.83 (mn, I 0.88 J 6.8 Hz, 6 MS GBh 3 538.64 'B NTVR (DMSO-d 6 5 9.04 2 8o.94 2 8.46
CH
3 J 6 Hz, 1 7.96 1 7.63 (in, 6 6.94 I 2mN 2m 12 6.83 J1 7.7 Hz, I 6.7 J 1 6.62 (dcl, 2mjCH 3 J6 J7.7 and 2Hz,I1H), 3.28 4H), 3.02 J =6.5 Hz, 2 1.98 (mn, 41H), 1.82 0.82 6.8 Hz, 6 H); MS 528.76
CH
3 'H NM (DMSO-d6): 8 13.96 1 9.02 2 8.85 CH 2 8.46 J =6 Hz, 1 7.91 1 7.58 4 CHCH3 7.39 1 7.25 J =7.8 Hz, I 6.92 J 27H 26n 1-2 7-7, 1 6.87 J =7.7 Hz, I 6.01 (mn, 1 5.17 (d, J 16.7 Hz, 1 5.08 J 10 Hz, 1 3.45 J 6 Hz, 2H), 2.99 J 6 Hz, 2 HM, 1.78 (in, 1 0.83 J 6.8 H~z, 6 MS (ES7): 499.3 S
GB
3
CH,
IH iNMR (DMS0-l 6 8 14.08 (bs, 1 9.06 2 H), 8.79 2H), &.51 J1=6 Hz, 1 8.11 J1=2 Hz, 1 8.01 (in, 3 7.85 J1 3 Hz, 1 7.63 (in, 6 H), 7.17 J 7.8 Hz, 1 6.97 J 7.8 Hz, 1 3.02 J 6.5 Hz, 2 1.81 (mn, 1 0.86 6.8 Hz, 6 H); MS 542.2) I 136 Analytical Data 'H NMR (DMS0-l 6 3 9.1 and 9.2 (2 br s, 4 H, NHl proton), 8.6 (in, I 8.3 (in, 1 8.0-7.6 (in, 8 H, aromatic proton), 7.3 (in, 2 3.1 2 2.2 3 H), 1.8 (in, I II), 0.9 (2s, 6 IR (K!Br Pellets) 2957, 1676, 1480, 1324, 844 MS :497 'H NMR (DMSO-d 6 6 9.06 2 8.77 2 8.53 J =6 Hz, 11-H), 8.03 (in, 1 7.64 (in, 6 7.46 J =6.9 Hz, 1 7.05 2 6.96 1 5.52 1 H), 3.02 J 6.8 Hz, 2 1.81 (mn, 1 1.48 6 H),0.85 J= 6.8 Hz, 6 MS 539.4 'H NMR (DMSO-d6): 8 9.06 2 8.78 2 8.52 J 6 Hz, 1 8.01 3 6.8 Hz, 11-H), 7.62 (mn, 7 H), 7.46 1 6.8 Hz, 1 7.0 (in, 2 4.94 J 6 Hz, 1 Hf), 3.60 J 6 12.8 Hz, 2 3.01 J1 6 Hz, 2 H), 2.58 J 6 Hz, 2 1.82 (in, 1 0.85 J 6.8 Hz, 6 MS 525.4 'H NMR (DMSO-d 6 3 9.01 2 8.88 2 8.5 (t, J 6 Hz, 1 8.07 (in, 1 7.73 (mn, I 7.63 (in, 7 7.11 J =17 Hz, 1 7.01 J 17 Hz, 1 6-97 (in, 1 6.69 J 17 Hz, 1 5.24 1H), 5.14 (s, 111), 3.03 JI 6.9 and 6.0 Hz, 2 1.92 3 1.81 (in, 1 0.84 J =6.9 Hz, 6 MS (ES 4 525.4 'H1 NIVR (DMSO-d 6 3 9.08 2 8.82 2 8.53 JI 6 Hz I 8.04 (in, 11H), 7.67 (mn, 7 14), 7.04 (in, 2 5.55 11H), 5.20 111), 3.04 J 6.9 and 6.0 Hz, 2 HM, 2.19 3 1.81 (in, 1 0.87 J1 6.9 Hz, 6 MS 499.4 Cpd.
-R
Starting Method Analytical Data 'H NMR (DMSO-d 6 8 9.11 2 8.86 2 8.5 7 CH, J =6 Hz, 1 8. 13 (in, 1 7.53 (in, 2 7.74 (in, 6 27u -26u 1-2 HM, 7.37 J 7Hz, 1 7.17 (in, 2 6.54 J 12 CHI Hz, I 5-91 (in, 1 4.99 (mn, 1 4.31 (mn, 2 H), 3.06 J 6.9 and 6.0 Hz, 2 1.83 (mn, 1 0.87 J 6.9 Hz, 6 MS 515.4 CH, 'H NMR (DMSO-d 6 5 9.08 2 8.82 2 8.54
CH
2 6 Hz, 1H), 8.05 1H), 7.63 (mn,8 7.06 2 27v CH 3 26v 1-2 5.52 1 5.2 1 4.63 J 5 Hz, 1 3.56 OH 2H), 3.05 J =6.9 and 6.0Hz, 2H), 2.71 (t,J =7 Hz, 2 1.82 (in, 1 0.87 J 6.9 Hz, 6 MS 529.4 C11,'H- NMR (DMSO-d 6 8 9.08 2 8.86 2 8.54
CH
2 J 6 H-z, I 8.03 (in, 1 7.62 (in, 7 7.08 J 27w 26w 1-2 7.5S Hz, 1 HI), 6.99 (in, 1 4.32 I 3.03 J
CH
3 6.9 and 6.0 Hz, 2 2.71 J =7 Hz, 2 1.82 (in, 1 0.87 J 6.9 Hz, 6 MIS 483.3 _CH 3 CH 3
CH
3
CH
3 1 H NMIR (DMSO-d 6 8 13.8 1 9.04 2 8.96 2 8.47 J 6 Hz, 1 7.93 1 7.61 (mn, 6 7.42 (in, 1 6.91 (mn, 2 6.07 (dd, J 17 and 9 H-z, 1 5.35 (in, 1 5.09 (dd, J 17 and 11 Hz, 1 H), 3.38 J 6.5 Hz, 1 3.0 J 7 Hz, 2 1.78 (in, 1 1.72 3 1.41 3 0.84 J 6.9 Hz, 6 H); MS 527.5 138 Cpd.]L -R -R Starting Method [Analytical Data No.] From JUsed CH, H NMvR (DMSO-d 6 6 8.99 2 8.86 2 8.52
CR
3 O J1 6 Hz, 1 8.03 1 7.63 (in, 6 7.50 J OH H, 2y 7Hz, I 7.07 J1= 7 Hz, I 7.12 (in, 1 5.40 27yCR 3 26 Y 1-2 J 6 Hz, 1 4.33 J 6.0-Hz, 2 3.01 J1 7 Hz, 2 1.80 (mn, 1 H,0.84 J1 6.9 Hz, 6 MIS 513.4
CHR
2 'HNMR (DMSO-d 6 6 9.50 (bs, 1 8.77 (bs, 2 H), CH, 8.49 J1 6 Hz, 1 7.98 (mn, 1 7.63 (mn, 6 7.55 27z OH26z 1-2 J 1 6.9 Hz, 1 7.01 J 1 7.9 Hz, 1 6.99 (in, 1 CH, 5.55 1 5.38 1 5:13 J 5 Hz, I H), 4.3 9 J1 5 Hz, 2 3.02 J1 6.9 and 6. 0 Hz, 2 H), 1.81 (in, 1 0.86 J11-6.9 Hz, 6 MS 515.4
CR
3 IH NN4R (DMSO-d 6 6 9.08 2 8.73 2 8.53 J 1 6 Hz, 1 8.06 1 8.02 (bs, 1 7.94 J 27aa C3 26aa 1-2 =7.8 Hz, 1 7.62 (in, 6 7.24 J 7. 8 Hz, 1 H),
CR
3 6.95 J 7.8 Hz, 1 3.03 J1 6 Hz, 2 1.82 (in, 1 0.87 J1 6.8 Hz, 6 MS 484.3 27ab
CCOH
CIR
3
CH
3 26ab 'H NM-R (DMSO-d 6 6 9.05 (bs, 2 8.81 (bs, 2 H), 8.49 J1 6 Hz, 1 8.02 1 7.68 I 7.62 (mn, 6 7.53 J1 6 Hz, I 7.21 J 6 Hz, 1 H), 7.13 J 7 Hz, 1 7.01 I 5.25 J 5 Hz, 1 4.51 J 5HRz, 2 3.01 J 6 Hz, 2 1.81 (mn, 1 0.85 J1 6.8 Hz, 6 MS 571.64 I .1 L .1 1.39 Cpd. -R StFromnT Method 1Analytical Data I1H NMR (DMSO-d 6 5 9.05 (bs, 2 8.78 2 8.52 CH3 J =6 Hz, 1 8.02 (bs, 1 7.65 (in, 6 7.53 J OH 5H Hz, IH), 7.54 J =5Hz, 1H), 7.26 (d,J=5 Hz, I 27ac s H26ac 1-2 7. 10 (in, I 6.99 (in, 1 5.64 J =5 Hz, I1H), CH 3 4.71 J 5 Hz, 211), 3.07 J 6.9 and 6.0 Hz, 2 1) 1.73 (in, 1 0.84 J 6.9 Hz, 6 MS 571.56 27ad CI{ 3 26ad 1-2 MS (ES 4 585.4
HO
2 C S
C
I H NVIR (DMSO-d 6 5 14.11 (1s, 1 9.05 (bs, 211),
CH
3 8.75 (bs, 2 8.5 (mn, I 8.0 I 7.8-7.6 (mn, 8 H), 27ae /\26ae 1-2 7.49 J 3 Hz, 1 7.1 J 6.9 Hz, 1 7.0 (mn, I
HOH
2 C CH 3 5.5 1 4.7 (in, 2 3.09 (in, 21H), 1.74 1 H) 0.86 J =6.9 Hz, 6 MS 571.2 27af HOH
C
CE
3
,-KCH
3 26af 'H NMR (DMSO-d 6 8 14.11 (bs, I 9.05 (bs, 211), 8.75 (bs, 2 8.49 J 6 Hz, 1 7.97 I 7.67 J 3 Hz, 1 7.61 (in, 711), 7.54 J 3 Hz, 1 H), 7.06 J 6-9 Hz, 1 6.89 J 6.9 Hz, I 5.23 J1 5 Hz, I 5.42 J1 5 Hz, 211), 3.09 J 6.9 and 6.0 Hz, 2 1.74 (mn, 1 H) 0.86 J 6.9 Hz, 6 H); MS 571-3 140 T r Method Cpd.
Starting Met o Analytical Data INO. I Irf-
CH
3 'H NMvR (DMSO-d 6 8 11.45 1 9.08 (bs, 2 H), \8.88 (bs, 2 8.75 J 6 Hz, I 8.04 (bs, I 7.88 12 (in, I 7.7 (in, 7 7.03 (in, 2 6.9 (in, 1 HM, 6.62 27g
C
3 Ha (mn, I 6.17 (in, I 3.07 J 6.9 and 6.0 Hz, 2 H), 1.84 (in, 1 0.86 J =6.9 Hz, 6 MS 524.65 OH 'H NMR (DMSO-d 6 6 13.83 1 8.9 (bs, 4 8.47 CH 3 J 6 Hz, 1 7.95 1 5.3 1 7.61 (in, 6 OH 7.4 (mn, 1 6.95 J3 7.7 Hz, 1 6.85 J3 7.7 27ah CH, 26ahi 1-2 Hz, 1 6.64 J 9 Hz, 1 6.22 I 4.6 J 5.1 Hz, 1 3.51 J =5.6 Hz, 2 3.01 J 7 Hz, 2 1.8 1 0.85 J =6.9 Hz, 6 MS 519.2 I,-N-1 CH 3 27ai Z6ai MS (ES+I) 514.25 CH3 27aj
CH
3
CH,
1 H NMR (DMSO-1 6 8 9.05 2 8.67 2 8.47 J 6and 5Hz, 1H), 7.95 (mn, 1 7.95 (in, I 7.63 (in, 5H), 7.40 1 7.3 8 J 7.7 Hz, 1 6.92 (in, 2 3.02 J 6.8 Hz, 2 2.64 (in, 2 1.80 (in, 1 1.66 (in, 2 0.96 J 8 and 6.5 Hz, 3 0.85 (d, I 6-8 Hz, 6 MS 499.31 I_ I Cpd. -R [Starting Method Analytical Data
CH
3 'H NMR (DMSO-d 6 8 14.3 (bs, 1 9.05 (bs, 2 CH38.75 (bs, 2 8.5 (mn, I 8.0 1 7.8-7.6 (in, 8 H), 27ak CU 3
C
3 32f G 7.49 J=3 Hz, I1H), 7.1 J =6.9 Hz,1IH), 7-0 1 5.5 1 4.7 (in, 2 3.09 (in, 2 1. 74 (in, 1 0.86 J =6.9 Hz, 6 MS 487.2
CH
3 27a1 H 26ai G MS 488.3 (100%: M- 1 CH, 'H NMR (DMSO-d,): 5 13.9 (bs, 1 9.05 (2 bs, 4 H), (in, I 7.9 I 7.7-7.5 (in, 8 7.3 J 3 27am OH26u G Hz, 1 6.9 (in, 2 4.6 (mn, lIH), 3.5 (in, 2 3.09 (in,
CH
3 2 2.6 (in, 211), 1.8 (in, 1 H) 0.85 J 6.9 Hz, 6 H); MS (EiS+) 517.3 'IH KMR (DMSO-d 6 5 9.84 (bs, I 9.07 (bs, 2 H), 0 C14 3 8.87 (bs, 2 8.51 J 6 and 5 Hz, 111), 8.13 (in, 1 32a 31a. 1-2 8.03 (mn, 2 7.65 (in, 5 7.20 J3 7.7 Hz, 1 "K C3CH 3 6.94 J 7.7.Hz, 1 3.04 J 6.8 Hz, 211),
CU
3 2.66 3 1.83 (in, 1 0.86 J 6.8 Hz, 611); MS 499.4, (ESI) 501.4 32b CH 3 32 CH 3 31b 1-2 Characterized in the next step
CH
3 142 Cpd. -R Starting 1Method Analytical Data No. IIFrom ]Used 'H NMR (DMSO-d6): 3 14.24 1 9.29 (bs, 2 H),
CH
3 9.01 (bs, 2H), 8.73 J =6Hz, 1 8.2 J 2Hz, .1 CH2H), 7.85 (in, 5 7.74 2 Hz, 1 7.4 J =8 Hz, I 732c CHCH 3u 31c 1-2 7.22 J 7.4 Hz, 1 7.13 J 1 6.73 3 -6.8 Hz, 11-1), 5.59 J =6.8 Hz, 2H), 3.25 J= 6.8 Hz, 2 2.04 1 1.08 J =6.8 Hz, 6 MS 495. 1, 497.2 32d /H 31d 1-2 MS 553.3 CH, I'H NMR (D)MSO-d6): 6 13.642 (bs, 1 9.06 2 H), 8.9(s, 2H), 8.50 J= 6and 5Hz, 1 7.98 I H), 32e CH3 31c 1-2 7.62 (in, 7 7.43 1 7.33 (in, 4 6.95 (in, 2 H), 4.04 2 3.02 J 6.8 Hz, 2 1.80 (in, 1 H), 0.86 J 6.8 H4z, 6 MS 547.4 'H NMR (DMSO-d6): 8 0.85 J 6.9 Hz, 6 1.81 32f CH 3 3f (in, 1 3.03 J 7Hz, 2H), 5.35 J 11 Hz, 1 H), 32f CH 2 33f -2 5.94 J= 17 Hz, 1 6.84 (dd, J =17 and I11Hz, 2 H), 7.0 (in, 2 7.64 (in, 8 8.01 1 8.54 J 6
CH-
3 Hz, 1 8.77 2 9.06 2 MS :485.57
N
3 H 2 C 3 32g H 31g 1-2 MS 596..2 143 Cpd. -R IR Starting IMethod [Analytical Data No.1I From Used CH3'H NMIR 5 14.2 (bs, 1 9.1 4 8.6 32h 31h 1-2 (in, 1 8. 15 1 7.9-7.6 (in, 8 7.2 (in, 2 6.7 1 5.3 (br s, I 4.6 (in, 2 3.1 (in, 2 1.9 (in, 0 1 0.9 J =6.7 Hz, 6 MS (ESI) 555.1 1H KNMR (DMSO-d 6 5 13.84 (bs, I 9.01 (bs, 2 H), 8-80 (bs, 2 8.46 J 6 and 5 Hz, 1 8.03 1 H),
HOH
2 C CH 3 7.95 1 7.77 I 7.67 (mn, 2 7.61 (in, 5 H), 32i 31i 1-2 7.02 J 7.7 Hz, 1 6.94 (in, 1 5.13 J 5 Hz, CH 3 E 11-),447 2 297(t, J= 6.8Hz, 2H), 1.78 1 NH39 1-2 MS 524.3
CH,
'H NMR (DMSO-d 6 5 13.82 1 9.20 (bs, 1 H), 0113 9.10 (bs, I 8.51 J1 6 Hz, I 7.97 111), 7.73- 44 3 7.45 (in, 5 7.43-7.3 9 (in, 2 7.20 J =8 Hz, 1 H), C43 3- 7.10(m, 6H), 6.96 (d,J =8 Hz,1IH),3.0 (t,J 6 Hz,2 Hl), 1.80 (mn, 1 0.68 J =6.8 Hz, 6 MS 551.30 CR3. 'H NMR (DMSO-d 6 9.21 (2 bs, 2 H each, 4 8.61 46 C3 45 1-2 (in, 1 8.1 111), 7.8-7.4 10 7.3 1 7.2 46\ H04 J= 7Hz, 1 7.1 2H), 5.2 2H), 3.1 2H), 0 1.8 (mn, 1 0.91 J =6.8 Hz, 6 MIS (ES 4 565.27 Cpd. r -R Starting [Method Analytical Data No. FromI Used I 1H NMvR (CF 3
CO
2 5 8.43 1 8.01 (d,J 7.5 Hz, CH31 7.67 J 24 and 8.4 Hz, 4 7.56 J =7.7 Hz, 51 CR 3 H 50 1-2 1 7.38 1 7.23 2 3.98 3 3.43 J 7Hz, 2H), 2.01 (in, 11H), 1.01 J =6.8 Hz, 6H); MS CH 3 487., 489.3 CH11NMR (DMSO-d 6 8 14.00 (bs, 1 8.52 J 6 and Hz, 1H), 7.98 1H), 7.63 (in, 8II), 7.07 J =7.7 53 52 1-2 Hz, 1 6.96 I 7.7 Hz, I 3.83 2 3.02 J
CR
3 6.8 Hz, 2 1.81 (in, 1 0.86 J 6.8 Hz, 6 H); NH2 MS 568.1 'H NMvR (DMSO-d6): 8 13-84 (br s, 1 9.05 2 H), 8.94 2 8.48 J 5.7 Hz, 1 7.97 J =1.9 CH, Hz, 1 7.70 (mn, 7 7.00 J= 7.9 Hz, 1 6.92 (d,
IC
3 68a 1-2, S J 7.9 Hz, 1 6.84 (dd, J =10.9 and 17.7 Hz, I H), 5.93 J 17.7 Hz, 1 5.34 J 10.9 lIz, I IH), 3.19 (in, 2 1.46 (qui, J= 7.0 Hz, 2 1.29 (sex, J=" Hz, 2 0.87 J1=7.3 Hz, 3 MS 485.2 'H NMR (DMSO-d6): 6 12.71 (hr s, I 9.12 2 H), CR CH, 8.93 2 8.20 (in, 2 7.86 (in, 1 7.70 (in, 6 H), IH 68b 1-2, s 7.20 (in, 2 6.87 (dd, J= 10.9 and 17.7 Hz, 1 5.99 CR, J1= 17.7 Hz, I 5.40 J1= 10.9 Hz, I 3.97 (in, I1-H), 1.50-1.20 (in, 8 H) 0.86 7.2 Hz, 6 H1); MS 145~ Cpd.] -R R' 1Starting IMethod TAnalytical Data No.] From [Used I H MAR (DMSO-d 6 8 12',84 (br s, I 9.08 (in, 3 H), CR 8.36 7.7 Hz, 1 8.18 1 7.83 (in, 1 H), CH2 68c I-2, S 7.67 (in, 6 7.15 (in, 3 6.86 (dd, J= 10-9 and 17.7 -0 ~Hz, 1 5.98 J= 17.7 H-z, 1 5-39 J1= 10.9 Hz, 1 3.74 (in, 1 1.84-1.55 (mn, 5 1.38-1.04 (in, MS 511.3 CH 2 H'MIR (DMSO-d 6 869.11 2 8.89 2 8.81
CR
2 J 5.7 Hfz, 1 8.21 1 7.85 (in, 1 7.68 (mn, 68d 1-2, S 7 7.17 (in, 3 6.87 (dd, 10.9 and 17.7 Hz, 1 H), CH2 6d 12,S 5.99 J= 17.7 Hz, 111-), 5.88 (in, 1 5.39 J= 10.9 Hz, 1 5.12 (in, 2 3.88 J= 5.0 Hz, 1 MS 469.2 'H NUvR (DMSO-d 6 6 9.11 2 9.01 2 8.3 8
CH
2
CH
3 J= 7.5 Hz, 1 8.18 1 7.83 (mn, 1 7.67 (in, I68e 1-2, S 6 7.16 (in, 3 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H),
CH
3 5.98 J= 17.7 Hz, 1 5.39 10.9 Hz, 1 H), 4.09 (mn, I 1.15 J= 6.6 Hz, 6 MS 471.3 'H NMR (DMSO-d 6 8 9.11 2 9.05 2 8.31 CH, CR 3 J= 8.1 Hz, 1 8.20 I 7.85 .J 7.7 Hz, 1 68f 1-2,SCR 7.69 (mn, 6 7.17 (mn, 3 6.86 (dd, J= 10.9 and CH, 17.7 Hz, 1 5.98 J 17.7 Hz, 11-H), 5.3 9 J=" 10.9 Hz, 1H), 3.91 1H), 1.50 2H), 1.12 (d,J= 6.6 Hz, 3 0.85 J= 7.3 Hz, 3 MS 485.3 Cpd.-R trigAnalytical Data 'Hf N'R (DMSO-d 6 8 12.82 (br s, 1 9.25 (in, I H),
CHR
2 9.12 2 8.91 2 8.23 1 7.87 (in, 1 H),
C
3 68g 1-2, S 7.68 (in, 7 7.18 (in, 3 6.87 (dd, J= 10.9 and 17.7 Hz, 1 5.99 J= 17.7 Hz, 1 5.40 JI= 10.9 Hz, I 4-07 (in, 2 MS 511.2 'H NMR (DMSO-d 6 8 10.34 1 9.05 (mn, 4 H) 8.18 CH 2 1 7.71 (mn, 11 7.34 J 7.8 Hz, 2 7.09 68h 1-2, S (in, 3 6.86 (dd, J= 10.9 and 17.7 Hz, 1 5.98 J 17.7 Hz, 1 5.39 J 10.9 Hz, 1 MS 505.3 H NMR (DMSO-d 6 8 12.64 (br s, 1 9.09 (in, 4 H), CH? 8-56 (mn, 1 8.09 1 7.66 (in, 9 7.08 (in, 3 H), 68i 1-2, S 6.86 (dd, J 10.9 and 17.7 Hz, 1 5.96 J= 17.7 Hz, 1 5.-37 J 10.9 Hz, 1 4.40 (mn, 2 H) 3.3 9 (mn, 2 3.22 (in, 2 1.48 (in, 4 HI); MS 5 01.3 (100%: 'H NIVR (DMSO-d 6 5 9.08 41-H), 8.69 J 6.0 Hz, CR2 1 8.16 1 7.69 (in, 5 7.13 J= 7.7 Hz, 2 68j 1-2, S 7.09 (in, 3 1H), 6.86 (dd, 10.9 and 17.7 Hz, 1 H), 5.97 17.7 Hz, 1 5.38 J 10.9 Hz, 1 H), 3.11 J= 6.0 Hz, 2H), 1.01 (in, I H)I, 0.41 2 H), 0.21 (mn, 2 MS 483.3 CH 'H NMvR (DMSO-d 6 8 9.11 2 8.97 2 8.54 70k(, 1 8.12 1 7.68 7 7.17 (rn, 4 6.86 CH, 68k 1-2, S (dd, J= 10.9 and 17.7 H~z, I 5.97 17.7 Hz, 1 5.38. J= 10,9 Hz, 1 2.75 J= 4.3 Hz, 1 H); MS 443.26 147 Cpd. f -R Ftromn Method Analytical Data 'H NMR (DMSO-cts): 8 9 .07 2 8.92 2 8.53 CH, J 5.5 Hfz, 1 8.02 I 7.62 (in, 7 7.01 (in, 701 C 3 681 1-2, S 2 6.85 (dd, J= 10.9 and 17.7 Hz, 1 5.95 J= I 17.7 Hz, 1 5.36 10.9 Hz, 11H), 3.24 (qui, J= 6.7 Hz, 2 1.08 J= 7.2 Hz, 3 MS 457.2 'H NMR (DMSO-d 6 6 12.53 (br s, 1 9.10 (in, 3 H),
CH
2 8.38 7.9 Hz, 1 8.11 11H), 7.68 (in, 7 68m 1-2, S 7.12 (in, 3 6.86 (dd, J= 10.9 and 17.7 Hz, 1 5.96 J= 17.7 Hz, 1 5.37 J= 10.9 Hz, I 3.94 (in, 1 1.88-1.33 (in, 12 MS 525.3 'TH NMR (DMSO-d 6 8 9.09 (mn, 4 8.59 J 5.2 Hz, CH2I_2 1 8.17 1 7.70 (in, 7 7.16 (mn, 4 6.87 I68n 1-,S (dd, 10.9 and 17.7 Hz, 1 5.98 J= 17.7 Hz, 1 5.39 10.9 H-z, 1 3.20 6.7 Hz, 2 H), 1.52 (sex, J= 7.2 Hz, 2 0.87 7.3 Hz, 3 MS 471.3 'H NMR (DMSO-d 6 6 12.97 (br s, I 9.08 2 H),
CH
2 C,8.99 2 8.53 J= 5.1 Hz, 1 8.06 1 7.64 68o 1-2, S (in, 7 7.06 (in, 2 6.85 (dd, J= 10.9 and 17.7 Hz, 1 5.96 J= 17.7 Hz, 1 5.36 J= 10.9 Hz, 1 H), 3.20 J 6.5 Hz, 2 1.49 (qui, J 6.6 Hz, 2 1.27 (in, 4 0. 86 J =6.6 Hz, 3 MS (ES 499.3 'H NMR (DMSO-d,): 6 9. 10 2 8.91 2 8.55 CH, CH 3 J 5.5 Hz, 1 8. 13 1 7.68 (in, 7 7.12 (mn, I CE tSp S 2 6.86 (dd, J 10. 9 and 17.7 Hz, 1 5.98 Ji= CH 3 68 1-2,S 17.7 Hz, 1 5.3 8 J 10. 9 Hz, 1 3. 10 (in, 2 H), 1.62 (in, 1 1.39 (in, 1 1.10 (mn, 1 0.86 (in, 6 MS 499.3 148 Cpd. ISatg Mehd[Analytical Data No. -R R'From Used 'H NMR (DMSO-d 6 8 9.06 2 8.82 2 8.11 CH2
CH
3 J= 7.9 Hz, 1 8.00 1 7.62 (in, 7 6.99 (mn, 68q 1-2, s 2 6.85 (dd, J 10.9 and 17.7 Hz, 1 5.95 J=
CH
3 17.7 Hz, 1 5-35 J= 10.9 Hz, 1 3.81 J= Hz, 1 1.45 (in, 4 1.24 (in, 4 0.82 (mn, 6 H); MS 527.3 CH 2 'H NMvR(DMSO-d 6 8 13.81 1 8.44 4 H), 68r 1-2,S~ 7.97 1 7.61 (mn, 7 6.90 (mn, 3 5.93 J= 17.7 Hz, 1. 5.34 J =10.9 Hz, 1 3.22 (in, 5 H), 2.73 (mn, 2 1.52 (mn, 4 MS 500.3 CH I'H N-vIR (D--MSO-d 6 8 9.09 2 8.86 2 8.42 2 (dl,J= 7.5 Hz, 1 MI, 8.11 I. 7.68 (in, 8 7.10 (in, 68s 1-2, S 2 6.86 (dd, 10.9 and 17.7 Hz, I 5.97 J= 17.7 Hz, 1 5.3 8 J =10.9 Hz, 1 4.20 Ji= 7.2 Hz, I 1.93-1.44 (in, 8 MS 497.2 I H NMR (DMSO-d 6 6 13.78 (br s, 1 9.07 2 H), CH 2 OH8.87 2 8.25 J 8.1 Hz, 1 8.00 1 7.62 68t 1-2, S (in, 7 6.98 (in, 2 6.85 (dd, J= 10.9 and 17.7 Hz, 1 5.94 J =17.7 Hz, 1 5.3 5 J 10.9 Hz, 1 H), 5 J =4.1 Hz, 1 3.68 (in, 1 3.3 9 (mn, 1 H), 1.79 (in, 4 1.28 (in, 4 Hr); MS (ES 527.2
CH
2 'HI NMR (DMSO-d 6 6 13.36 (br s, 1 9.05 (in, 3 H), 68u 1-2,S5 8.49 I 7.98 1 7.61 (in, 8 6.92 (mn, 3 H), 5.94 Ji= 17.7 Hz, 1 5.3 5 J 10.9 Hz, 1 H), 2.81 (in, 1 0.69-0.48 (mn, 4 MS 469.3 149 No. -R f -Rp Ftrtim Method Analytical Data 'H NMR (DMSO-1 6 8 9.05 (in, 4 8.75 J= CHi Hz, 1 8.15 11-H), 7.70 (in, 7 7.14 J 7.9 Hz, 268v 1-2, S 2 6.86 (dd, J= 10.9 and 17.7 Hz, I 5.97 J= 17.7 Hz, 1 5.39 J =10.9 Hz, 1 4-40 J 9- Hz, 1 2.12 (in, 4 H) 1.65 (in, 2 MS 483.3_ CH IHNIM (DMSO-d 6 8 13.17 (hr s, 1 HI), 9.05 (in, 4 H), 8.51 J= 5.8 Hz, 1 8.06 I 7.64 (mn, 7 7.03 H 68w 1_2, S (in, 2 6.85 (dd, J= 10.9 and 17.7 Hz, 1 5.95 J =17.7 Hz, 1 5.36 J= 10.9 Hz, 1 4.72 J= 5.4 Hz, 1 H)'3.47 J= 5.7 Hz, 2 3.28 (in, 2 MS 473.2 CH CH, 'H NMR (DMSO-d 6 8 9.07 2 8.90 2 8.50 C2 J1 5.5 Hz, 1 8.04 1 7.63 (in, 7 H1), 7.03 (in, CH, 68x 1-2, S 2 6.85 (dd, J 10.9 and 17.7 Hz, 1 5.96 J= 17.7 Hz, 1 5.36 J 10.9 Hz, 1 3.23 J= Hz, 2 1.59 (mn,J= 7.0 Hz, I 1.39 J= 6.8 Hz, 2 0.8 8 (di, J =6.6 Hz, 6 H).
150 Cpd. I -R Starting [Method Analytical Data No. Fro Used 'HNMR (DMSO-d 6 5 10.85 I 9.21 2 8.91 2 8.71 J 9 0 Hz, 1 8.21 J =1.96 Hz, 1 8.23 J 1.96 Hz, 1 8.19 J 2.19 31a 30a 1 Hz, 1 8. 17 J1 1.97 Hz, 1 8.09 J 91 Hz, 1 7.77 4HT-), A CH 3 7.53 J =7.53 Hz, 1 3.57 3 3.11 J=6.89 Hz, 1 2.71 3H), 1.86 (in, 1 3.88 6.87 Hz, 611); MS 515.3 31b 30b J MS 527.2 31c C 2 30c .1 Chiaracterized in the next step 'HINMR (DMSO-d 6 8 10.59 (bs, 1 9.16 2 8.85 2 8.69 J1 6 and 5 Hz, 1 8.21 1 8.04 J 1.5 Hz, 1 7.73 (in, 4 7.58 t 31d /30d i 7.50-7.38 (in, 3 7.32 (mn, 1 7.03 J 7.5 Hz, 2 4.31 2 H), 3.55 2 3.07 J 6.8 Hz, 2 1.85 (in, 1 0.87 J1 6.8 Hz, 6 MS 567.3, 569.3 31e 30e i MS 561.4; MS 563.4 151 Cpd. -R Starting MethodAnltclDa No. I R [From 1UsedAnltalDa 'H NMR (DMSO-d6): 8 10.73 1H), 9.24 2H), 9.00 211), 8.71 J 5.7 Hz, IN), 8.24 J 1.9 Hz, 1H), 8.05 (dd, J 1.9 Hz, iH), 7.77 (in, 31f C 30f 1 7.71 (dd, J1=7.9, 1.5 H-z, I 7.42 J1=7.9 Hz, 7.31 J =7.9 Hz, I H), ~CH 6U9 (dd, J 17.6, 11.0 Hz, 1H), 6.04 (d,J 17.6 Hz, 1H), 5.42 J 11.0 Hz, IN), 3.56 3H), 3.10 J 6.4 Hz, 2H), 1.85 (in, 1H), 0.89 1 6.7 Hz, 6H); MS 499.3 'HNMR (DMSO-d 6 6 10.73 1 9.19 (bs, 2 8.88 (bs, 2 8.71 J
N
3
H
2 C 6 Hz, 1 8.27 1= 2 Hz, 1 8.07 (dd, J1 7.7 and 2 Hz, 1 7.88 2 31g 30g Hz, 1 7.8 J 2 Hz, 1 7.83 (in, 4 7.72 (dd, J1 2 and 7.7 Hz, I H), \7.46 J 1 7.41 J 7.7 Hz, 1 4.56 2 3.56 3 3.11 s J1 6.8 Hz, 2 1.87 (in, 1 0.92 J 6.8 Hz, 6 MIS 608.2, 610.3 31h /\30h i Characterized at the next step HOH 1 INM.R (DMSO-d 6 5 10.68 1 9.17 (bs, 2 8.82 (bs, 2 8.68 J 2C\ 6HEz, 1 8.25 J1=2 Hz, 1 8.16 J1=2 Hz, 1 8.05 (dd, J =8 and2 31i 30i1 Hz, I1H), 7.87 1 7.89 (dd,J 8and 2Hz, I1H), 7.75 (mn,5 7.44 f 9 Hz, I 7.36 J 8 Hz, I 5.22 J 5 Hz, I 4.54 J 5 Hz, 2 0 3.57 3 3.10 J =6.8 Hz, 2 1.84 (in, 1 0.88 J 6.8 Hz, 6 H; MIS 567.4, 569.4 43 -o ~2 1 MS 563.4 -Obn 8 J Characterized in the next step
-OCH
3 49 1 MS 503.1 2 Cpd. -R Statin Uehd _Analytical Data 52 -31g G Characterized in the inext step NH2 Cpd. 1 -R R No.I Starting From Method Used Analytical Data 34 -OSO 2
CF
3 -H33 J MS 621.2 0
-OSO
2
CF
3 34 P MS 755.2; (ES) 753.3 AOBn Trips 0 37 N~ 35+t36 D-2 MS 828.5
TIPS
/8 N -H 37 G MS 694.4; 692.4 39 -H 38 Q Characterized in the next step 154 R R
H
3 C0 2 C R Cpd. -R -R R" ]Starting Method1AnltalDa No.1 J From UsedAnltclDa 'H NMR (DMSO-d,): 6 9.69 1 MI, 8.49 (d, J =2.0 Hz, 1 8.22 J= 6.9 Hz, I 7.53 (in, 4 7.43 (in, 2 7.3 7 (in, 2 11), 7.24 (d, 54 -OBn -CHO -CO 2 MEM 5+ 6 D-2 J= 8.9 Hz, 1 5.57 2 5.26 2 H), 3.85 J= 4.9 Hz, 2 3.60(s, 3 3.51 (t, J 4.9 Hz 2 3.32 3 MS (ES): 501.02 (M-fNa)+ 1 H NNM (DMSO-d 6 8 12.65 1 8.41 (d, J= 2.0 Hz 1 8.14 (dd, 2.0 and 7.9 Hz, 1 7.50 (in, 3 7.3 8 (in, 4 7.24 (dd, .J= -OBn -CO 2 H -CO 2 MEM 54 E 3.0 and 8.9 Hz, 1 7.11 J= 8.9 Hz, 1 H), 5.54 2 5.20 2 3.82 J =4.9 Hz, 2 3.57 3 3.49 J =4.9 Hz, 2 H), 3.23 3 MS (ES 493.2 'H NMR (DMSO-d 6 6 10.2 1 9.65 (s, 1 8.25 J= 2.0 Hz, I 7.85 (dd, J 0 CH3 2.0 and 8.9 Hz, 111), 7.51 J 7.9 Hz, 2 H), 04 GOn CH 406 7.45 2 7.35 3 H),7.29 J= 7.9- 141 O~n CHO N40 +6 D- Hz, 1 H) 7.2 J= 7.9 H1z, 111I), 5.24 2 H), H 3.5 5 3 2.3 (rI, J 6.9 Hz, 2 11) 2.1 (in, J 6.9 Hz, 1 1.0 J= 6.9 Hz, 6 MIS 446.31 Cpd. T R 1 R "Starting] Method Analytical Data No. -R -R FR From ]Used 'HIIR (DMSO-d 6 8 12.38 I 10.01 1 8.05 1 7.68 J= 7.9 Hz, 1 H), 7.41 J= 7.9 Hz, 2 7.35 (in, 5 7.27 142 OBn -CO2H 141 E 1 7.11 J= 8.9 Hz, 1 7-04 J= 0 Cli, 8.9 Hz, 1 6.99 J 8.9 Hz, 1 5.11 (s, 2 2.13 J =6.9 Hz, 2 2.02 (in, J 6.9 N CH 3 Hz, 1 0. 852 J 6.9 Hz, 6 MS H 460.2 'H NMR (DMSO-d 6 6 10.12 1 8.16 J= 1.9 Liz, 1 7.80 (dd, J= 1.9 and 8.3 o CH 3 Hz, I 7.42 (in, 6 7.26 (dd, J= 2.8 and 14 -~nF 8.3 Hz, 1 7.13 (in, 2 HI), 5.21 2 5.17 14 On -CO 2 MEM ~N CH, 142 r 2 3.54 3 3.40 (in, 2 3.32 (in, 2 H 2.22 7.0 Hz, 2 2.10 (in, 4H1), 0.95 6.4 Hz, 6H); MS 572.3 (M-iNa) 4 'H NMIR (DMSO-d 6 3 12.7 (br s, I 9.09 o CH 3 2 8.91 2 8.57 (in, 1 8.11 1 144 -OH -CO 2 MEM 143 G 7.92 J 1.9 Hz, I 7.81 (in, 3 H), N CH 37.67 (mn, 5 7.14 (in, 3 6-66 (in, 1 H), H 4.40 J= 5.3 Hz, 1 3.39 (in, 2 3.22 2 1.48 (in, 4 MS 592.2.
o CH 3 14 -SOCF -O 2 EM144 B-2 MS 592.2
H
0 CHi, 146a -CO,MEM -,_Njt CH, 145 D-2 MS (ES 4 532.5 (M+Na)+ 0 H Cpd.
No.
Starting Method From IUsed I Analytical Data 146b
S-
0 CH, NA ICHl
H
-CO
2 MEM 145 'H NMR (DMS0-l 6 6 10.1 1 B1), 8.21 (d, J= 2.0 Hz, 1 8.10 2.0 Hz, I 7.89 (dd, J= 2.0 and 7.9 Hz, 1 7.84 J and 8.9 Hz, 1 7.63 (in, 2 7.25 J= 7.9 Hz, 1 7.19 (in, 2 5.22 J 14.8 Hz, 2 3.57 3 3.43 J 4.9 Hz, 2 3.34 J 4.9 Hz, 2 3.20 3H), 2.23 J= 6.9 Hz, 2 2.11 (in, J= 6.9 Hz, I H), 0.96 5.9 Hz, 6 MS 526.48 MS (ES4): 470.2 (-M-fNa)+ I- 4- i I 146c -CH=CH 2
-CO
2
MFM
0 OH 3 N'KH
OH
H
147a -C0 2 H 0 CH 146a 1-1 MS 420.29 0 N OH, 'H NMR (DMSO-1 6 8 12.65 1 10. 12 0 OH 3 1 8.18 J= 1.9 Hz, 11-H), 8.07 J= 147b I C0 2 H 146b 11 3.0 Hz, 1 7.83 (in, 2 7.61 (in, 2 7.19 N CH4 (in, 3 3.56 3 2.22 J= 6.9 Hz, 2 S H 2.11 (mn, J= 6.9 Hz, 1 0.96 6.9 6 MS 438.52 0 CH 3 147c -CH=CH 2
-CQ
2 H N OH3 146c I-1 MS 380.32
HII
Analytical Data 'H N R( M O d) 8 1 8 42 (t, 6.2 Hz, 1 7.90 (dd, J= 1.1 6.6 Hz, 1 7.82 J 1.9 H4z, 11-H), 7.72-7.5 0 (mn, 3 7.34 J= 7.7 Hz, 1 7.27 (dci, J= 1.3 6.2 Hz, I 4.38 (di, J= 6.0 Hz, 2 3.53 3 2.47 (in, 1 1.07 (ci, J 7.0 Hz, 6 MS (ES 340.05 'H NMR (DMS0-l 6 6 12.35 (br s, I 8.31 J= 7.5 Hz, 1 7.80-7.31 (in, 5 7.06 (in, 211), 4.25 6.0 Hz, 2 3.41 3 H4), 2.37 (mn, 1 0.97 (di, J 7.0 Hz, 6 H); MS 353.83 'H NM (DMS0-l 6 8 9.70 1 7.87 (in, 2 7.69 (in, I 7.55 (in, 211I), 7.35 (di, J= 7.9 Hz, 1 7.27 J 7.5 Hz, I 4.51 (s, 2 3.52 3 3.05 (mn, 2 HI), 1.92 (in, I 1.40 (mn, 9 0.85 J= 6.8 Hz, 6 H); MS 448.3 (M+Na) 4 'H NMR (DMS0-l 6 5 7.81 (in, 2 7.56 (mn, 1 7.44 (in, 2 7.16 (in, 2 4.47 2 3.51 3 3.02 (in, 2 1.92 (in, J= Hz, 1 H1), 1.41 (in, 9 0.85 J= 6 Hz, 6 MS 440.2 'H NMR (DMSO-d6): 59.78 11H), 8.85 J =5.7 Hz, I1H), 8.50 (di, J 2.0 Hz, I 8.20 (dd, J 8 1.9 Hz, 111), 7.55 (mn, 9H), 5.35 (s, 2H), 3.69 3H), 3.23 J 6.5 Hz, 211), 1.98 (in, 111), 1.02 J1 6.8 Hz, 6H); MS 446.3 Analytical Data 1470.2 418.3 460.3 'TINMvR (DMSO-d,): 6 10.06 1 9.63 (s, 1 8.73 J 6.5 Hz, 1 8.36 J 2 Hz, 1 8.09 (dd, J 2 anid 8 Hz, 1 7.45 J 8 Hz, 1 7.28 1 7. 11 2 H), 3.58 3 H1), 3.13 J 7 Hz, 2 1.87 (in, 1 0.91 J 6.8 Hz, 6 MS 354.2 and 378.2 (MI-Na)) 380.1 'HNMR (DMSO-d 6 3 10.21 I 9.78 (s, 1 8.87 J 5.80 Hz, 8.51 1 H), 8.23 J 7.92 Hz, I 7.60 J 7.9 Hz, 1 7.43 I 7.25 2 3.74 3 11), 3.46 J1 5.65, 2 1 .32(t, J 7.8 Hz, 3 H) Cpd. Starting 1Method From IUsed I Analytical Data 'ITN.IVR (DMSO-d 6 6 10.06 1 9.62 (s, CH, 1 8.69 J 5.90 Hz, 1 8.36 1 H), 'y N C 3 8.08 J 7.92 Hz, 1 7.45 J 8.1 Hz, 185d -OH -CHO 184d AD 1 7.28 1 7. 10 2 3.5 8 3 H), o 3.22 (in, 11H), 3.11 (in, 1 1.66 (mn, I H), 1.44 (mn, 1 1.18R (in, 1 0- 89(t, J 6.4 Hz, 6 H).
CH
3
H
186a -OSO 2
CF
3 -CHO N CH3 185a B-2 MS (FS').488.24 0 H 'HNMR (DMSO-d 6 6 9.74 1 9.44 J N CF3 15 B- 5.90 Hz, 1 8. 51 1H), 8. 11 (d,J =7.91 186b -OSO 2
CF
3 -CHO 15b B- Hz, 11H), 7.54 (in, 4 4.18 (mn, 2 3.59 (s, 0 3 H).
'HNMR (DMSO-16): 6 9-45 11H), 8.59 3 H 5.90 Hz, 1 8.28 1 7.94 J 8.10 N86 -OO 2 FH-H 185c B-2 Hz, IH), 7.79 J 2.8 Hz, IH), 7.67 (d,J 186c OS02F3 -CO "Y7.9 Hz, .1 7.32 J 7.9 Hz, 2 3.40 (s, 0 3 3.12 J 7.1 Hz, 2 0.97 J 7.16 Hz, 3 H).
'HNMvR (DMSO-d,): 8 9.71 1 8.78 J CH, 5.90 Hz, 1 8.49 1 8.18 J 7.92 18d -S2F CO15 Hz, 1 8.00 1 7.88 J1 8.51 Hz, 1 186d -OS 2
CF
3 c~ N IA 3 85d B-2 7.52 J 8.1 Hz, 21H), 3.67 3 3.22 0 m1 3.16 I1H), 1.68 IBH), 1.44(mn, H, 118 I, I 0.89(t, J 6.4 Hz, 6 H).
160 Cpd.
-R
Starting [Method [Analytical Data Fro Used r I T r I
CH
3
H
_Y
CH
3 0 187a -CH=IICH 2 -CHO 1 86a 'HNMR (DMSO-d 6 5 9.74 1 8.76 J Hz, 1 8.42 (d,J 2Hz, 1 8.11 (dd, J 2 and 8 Hz, 1 8.00 J 1.7 Hz, 1 7.84 (dd, J =8 and 2 Hz, 1 7.47 J 8 Hz, 1 7.27 J =8 Hz, I 6.90 (dd, 3 11 and 17.7 Hz, I 6.01 J 17.7 Hz, 1 5.42 J 11I Hz, 11H), 3.59 3 3.14 J 7 Hz, 2 1.88 (in, 1 0.92 J= 6.8 Hz, 6 MS 364.2 anid (ES 4 388.2 (M+Na) 4 MS 390.1 187b -CH=CH 2
-CHO
H
,CF3 0 186b 187c 187d -CH=CH2
-CH=CH
2
-CHO
H
0 186c MS 336.2 MS 378.2
-CHO
CH
3
H
N O, H 3 186d D-3 161 Cpd. 1 -R I -R t 1 IStarting] Method IAnalytical Data No. rom sed H NMR (DMSO-d): 8 10.67 11H), 9.2 2 887 2 8.33 J= 2.0 Hz, 1 8. 17 (dd, J= 2.0 and 56 -OBn -H -CO 2 MEM 55 1 7.9 Hz, 1 7.77 41H), 7.49 (in, 4 7.39 (in, 2 H), 7.30 2 5.54 2 5.27 2 3.83 J= 4.9 Hz, 2 3.57 3 3.49 4.9 Hz, 2 3.23 (s.
3 MS 612.4 57 -OBn -Boc -CO 2 MEM 56 R MS 712.4 1 H NMR (DMSO-d 6 5 10.4 1 WI, 10.0 1 8.9 1H), 8.28 J =2.0Hz, I 8.12 (dd, J =2.1 and 7.7 Hz, 1 7.89 J= 8.4 Hz, 2 7.61 J 8.4 58-H-Boc
-CO
2 MEM 57 G Hz, 2H), 7.45 J=7.7 Hz, I 7.13 J= 8.4 Hz,I 58 -OHH), 7.06 I 6.98 (dd, J= 2.8 and 8.4 Hz, I 5.52 2 3.81 J 4.9 Hz, 2 3.56 3 3.46 J 4.9 Hz, 2 3.20 3 1.43 9 MS (ESD: 620.5 1 ;2 Cpd.
No.
Starting From Method Used Analytical Data 'H NMR (DMSO-d,): 5 10.55 1 8.38 J Hz, 1 8.18 (dcl, J= 2.0 and 7.9 Hz, 1 7.86 (mn, 4 59 -OSO 2
CF
3 -Boo -CO 2 MEM 58 B-2 7.75 (dd, J1=2.0 and 8.9 Hz, 1 7.54 (mn, 5 H), 5.51 2 3.77 J 4.9 Hz, 2 3.55 3 3.46 J =4.9 Hz, 2 3.18 3 H) 1.41 9 MS 754.3 'H NMR (DMSO-d 6 6 10.61 1 8.94 1 H), 8.37 11H), 8.19 (dd, J= 2.0 and 7.9 Hz, 1 8.02 (s, 1 7.89 5 7.65 J 8.9 Hz, 2 7.54 J -Boc -CO 2 MEM 59 D-2 7.9 Hz, 1 7.3 9 J 7.9 Hz, 1 7.17 J1=3.9 0 Hz, 1 6.68 (in, 1 5.54 2 3.82 J= 4.9 Hz, 2 3.58 3 3.49 J =4.9 Hz, 2 3.22 3 1.45 MS 672.5 'H NMR (DMSO-d 6 8 10.50 111I), 8.96 1 H), 8.32 1 8.07 J= 7.9 Hz, I 7.98 1 H), 61 -Boo -CO 2 H 60 1-1 7.87 (in, 5 7.63 J= 8.9 Hz, 2 7.38 (in, 2 H), 0 7.15 1=3.0 lIz,1Il, 6.67 (in-il), 3.57 3H), 1.45 9H); MS 582.4 'H NMR (DMS0-l 6 8 10.56 1 9.02 (hr s, 1 H), 8.35 J= 1.7 Hz, 1 8.18 (dd, J= 1.9 and 6.0 Hz, 1 7.88 J= 9.0 Hz, 2 7.80 J 1.3 Hz, I H), 7.71 (dd, J= 1.7 and 6.2 Hz, 1 7.63 J= 8.9 Hz, 2 66 -CH CH 2 -Boo -CO 2 MEM 59 D-3 7.50 J1=8.3 Hz, 1 7.32 J1=8.1 Hz, 1 H), 6.89 (dd, J 10.7 and 17.7 Hz, I 6.04 17.4 Hz, 1 5.54 2 5.43 J= 11.7 Hz, 1 3.82 J= 4.5 Hz, 2 3.57 3 3.48 1= 4.5 Hz, 2 3.22 3 1.44 9 MS 632.1 Cpd.- R [WR trigMethod trta Use Analytical Data -CH'=CHz -BOC -COH 'H NMR (DMSO-d 6 5 10.49 1 8.99 (br s, 1 H), 8.31 I 8.07 J 8.3 Hz, 1 7.87 J Hz, 2 77 (in, 2 7.66 (rn, 3 7.38 J= 7.7 Hz, 1 7.29 7.7 Hz, 1 6.88 (dd, J =10.7 and 17.7 Hz, 1 6.03 J =17.4fl-z, I 5.41 J= 10.9 Hz, 1 3.56 3 1.43 9 MS (ES): 542.1 I Cpd.
_R
Starting Method Fro I u Analytical Data 'LI NINR (DMSO-1 6 8 10.57 1 8.92 1 8.64 J= 5.4 Hz, 1 8.24 J= 2.0 Hz, 1 8.02 (dd, J= 2.0 and 7.9 Hz, 1 7.98 1 7.88 (in, 3 H) 7.84 I 7.64 J 8.9 Hz, 2 7.42 J= 7.9 Hz, I 7.36 7.9 Hz, 1 H), 7.14 J =3.0 Hz, I 6.67 (in, 1 3.5 5 3 3.26 (in, 2 1.50 (in, J= 7.4 Hz, 2 1.43 9 1.32 (in, J= 7.4 Hz, 2 0.89 3 MS 639.5
-CH
3 3 4
-CH
3
-CH
3
-CH
3 MS 625.5 I II
CH
2 I eli 3 61 61 MIS 623.4
I
MS 687.4 J I Cpd.
Starting Method Analytical Data 62 -H 3 61 A-4 MS 625.4 62e -CH3CH, 62f -CIT 3 '4 CH 61 A-4 MS 653.5
CH,
62g -CIT 3 C,61 A-4 MS 653.5
CH
3 62h -CH 3 61 A-4 MS 667.3 0 CH 3 02i -CIT 3 61 A-4 MS 681.5 CH 3 62j -CIT 3 61 A-4 MS 637.3
OH
62k -CIT 3 61 A-4 MS 640.3 621 -CH 3 -061 A-4 MS 665.4 Cpd. I Starting MethodTAaltalDa No. R From Used AnltclDt 62ma -CH B 3 61 A-4 IMS 597.
CH 3 62n -CH 3 61 A-4 MS 639.4 62o -GB 3 61 A-4 MS 695.4 (M+Na)+ 62p -CH 3
C
3 61 A-4 MS 665.4 62q -GB 3
GH
3 61 A-4 MS 653.4 62r -CH 3
CH
3 61 A-4 MIS (E-S 4 567.3 62 G 3 CH, 61 A-4 MS 667.5
CH
3 62t -GB4 3 OH61 A-4 MS 641.3 62u -CIT 3 61 A-4 MS 655.3 Cpd.
_R
Starting Method Used Analytical Data No. Fr0 62v -Gil 3 61 A-4 MS 663.1 62 -H 3 N N61 A-4 MS 577.2 62x -Gil 3 61 A-4 MS (ES 4 679.2 62y -CH 3 61 A-4 MS (E 62 1.1 62z -CH 3
H
3 61 A-4 MS 611.1
OH
62aa -CH 3 -"OH 61 A-4 MS 657.1 62ah -Gil 3 /61 A-4 MS (ES 4 659.1 62ac -CH 3 61 A-4 MS 679.3 Cpd. _R [R [Starting 1Method Analytical Data No.1 RR From JUsed
OH
0 62ae -CH 3 NHR No 61 A-4 MS 651.3 62af -CE 61 A-4 MS (ES 4 679.4 Cpd. -R ~Starting [Method AnltclDt No. -R-']From UsedAaltalDa 'H NMR 6 12.80 1 9.09 2 H), 7 o 8.91 2 8.57 (in, 1 8.15 1 7.91 1 H), 64a -62a 1-2, S 7.80 (in, 3 7.67 (in, 4 7.20 (mn, 2 7.07 1 C QO 6.63 1 H) 3.21 J =5.9 Hz, 2 1.46 J= 7.4 Hz, 2 1.28 (in, J 7.4 Hz, 2 H) 0.86 J 7.4 H1z, 3 MS 525.3 1H NMR (DMSO-d 6 6 12.76 I 9.10 2 H), 7 0 8.82 2 8.59 (mn, 1 8.20 1 7.95 I H), 64b -C 3 62b 1-2, S 7.83 (mn, 3 7.70 4 7.25 (mn, 2 7.10 I 6.6S 1 3.20 J 6.0 Hz, 2 1.51 J =7.4 Hz, 2 0.87 J= 7.4 11z, 3 MS 511.2 'H NMR (DMSO-d 6 8 12.84 1 9.11 2 H), 7 0 8.84 (mn, 2 8.26 (in, 1 7.94 (mn, 2 7.83 (in, 3 64c "C 62c I-2, S 1H), 7.71 4 7.28 (in, 2 7.12 11H), 6.65 1 0" 5.87 (in, 1 5.15 J 17.2 Hz, 1 5.07 J= 10.3 Hz, 1 H) 3.88 J 5.2 Hz, 2 MS 509.2 -IStarting Method fAnalytical Data From UsedL 'H NJR (DMSO-d 6 5 12.78 I HI), 9.11 (in, 2 H), 62d 1-2, S 8.85 2 8.22 1 7.93 1 7.83 (in, 3 H), 7.68 4 7.19 (in, 3 7. 10 (mn, 5 6.65 1 H), CH 3 4.41 2 2.27 3 MS 573.3 'H NM (DMSO-d 6 8 12.82 1 9. 11 2 H), CH 3 8.86 2 8.3 9 J 7.7 Hz, 1 8.24 1 14), 62e 1-2, 5 7.95 1 7.90 (mn, 1 7.84 (mn, 2 7.71 4 H), Gil 3 7.28 (in, 2 7.11 (in, 1 6.65 1 4.08 J= 6.9 Hz, 1 1. 14 J 6.9 Hz, 6 MS 511.3 CH 3 NMR (DMSO-d 6 5 13.28 (br s, 1 9.05 (in, 2 H), 8.84 2 8.46 (in, 1 7.99 I 7.88 I H), H,62f 1-2, 5 7.77 (in, 2 7.63 (in, 5 7.07 (mn, 2 6.96 (in, 1 6.63 1 3.16-2.96 (mn, 2 1.65-1.03 (in, 3 0.85 (mn, 6 MIS 539.3 'H NM'R(DMSO-d,): 6 13.37 1 9.06 2 H),
GH
3 8.84 2 8.47 (in, 1 8.00 I 7.88 1 H), 62g 1-2,S~ 7.78 (in, 2 7.70 (in, 5 7.08 (in, 2 6.97 1 Gil 3 HI), 6.63 1 3.22 (mn, 2 1.58 (mn, 6.0 Hz, 1 1.38 (in, J= 6.9 Hz, 2 0.87 J= 6.9 Hz, 6 H); MS 539.3 1H NMR (DMSO-d 6 5 12.71 (hr s, 1 9.13 1 H), 8.75 (in, 3 8.31 (in, 1 7.97 (in, 2 7.86 (in, 2 62h 1-2,S 1 7.73 (in, 4 7.64 (mn, 2 7.33 (in, 2 HI), 7.13 (in, I 6.67 (mn, 1 3.98 (in, I 3.77 J= 6.9 Hz, 1 3.62 J 6.9 Hz, I 3.29 (in, 2 1.86 (in, 3 1.59 (in, 1 MS 553.3 171 Cjxl. -R Starting ethod Analytical Data 'H NMR (DMSO-d 6 6 12.81 (br s, 1 9.13 2 H), 641~C 3 2 12 8.85 2 8.26 (in, 2 7.96 (in, 2 7.86 (in, 2 64i O 6i 121S 7.74 (in, 5 7.32 (in, 1 7.13 (in, 1 6.67 (in, CH3 1 3-99 (in, 1 1.5-0.85 (mn, 14 MS (ESI): 567.3 'H NMR (DMSO-dr,): 6 13.74 (hr s, I 9.07 2 H), 8.92 2 8.62 J 5.6 Hz, I 8.03 I 7.89 64j 062j 1-2, S J 7 Hz, 1 7.79 (mn, 2 7.64 (in, 4 7. (in, 3 6.99 J 8.5 Hz, 1 6.64 (in, 1 3.08 J 6.0 Hz, 2 1.00 (in, 1 0.40 (mn, 2 0.20 (mn, 2 MS 523.4 OH R NMR (DMSO-dG): 8 9.12 2 8.8 8 2 8.52 64k I 8.12 I1H), 7.92 (mn,2H), 7.81 3H), 64k 62k 1-2, S 7.67 (mn, 4 7.14 (in, 3 6.66 (in, 1 4.75 J=~ Hz, 1 3.77 (mn, 111), 3.17 (mn, 1 1.04 J Hz, 3 MIS 527.2 'H NMR (DMSO-d6): 6 13.91 (hr s, 1 9.07 2 H), 8.90 2 8.29 J 8. 1 Hz, I 8.00 1 H), 641 -621 1-2,S5 7.89 (in, I 7.78 (in, 2 7.64 (in, 5 7.08 (in, 2 6.96 J 7.7 Hlz I 6.64 (in, 1 3.71 (in, 1 1.82-1.03 (in, 10 H)p; MS 551.33 7o' 'NMR (DMSO-d 6 8 13.87 (br s, I 9.07 2 H), 8.90 2 8.48 (in, 1 7.99 1 7.89 (in, 1 H), .64m -62m 1-2, S 7.79 (in, 211), 7.62 (mn, 5 7. 10 (in, 2 6.97 J" CH, 7.9 Hz 1 6.64 (in, 1 2.73 J Hz, 3H); MS 483.2 [Cpd. -'Starting 1Method AmItclDt No. -RRFrom jUsedAnltclDa 'H NMR (DMSO-d 6 8 9-08 2 8.85 2 8.26
GB
3 J= 8.7 Hz, 1 8.07 1 7.91 1 7.80 (in, 64n CH362n 1-2,S~ 2 7.67 (in, 5 7.09 (in, 3 6.65 (in, I 3.89 cn 3 (mn, J= 7.0 Hz, 1 1.49 (in, .J 6.9 H-z, 2 1.10 (d, J= 6.6 Hz, 3 0.85 J= 7.2 Hz, 3 MS 525.2 Yo 'H NMR (DMSO-d 6 6 9.19 (mn, 2 9.10 2 H), 64o 62o 1-2,S 8.82 2 8.19 (in, I 7.94 1 7.83 (in, 2 7.68 (in, 4 7.33 10 (mn, 8 6.66 (in, t 4.45 J= 5.71Hz, 2 Hz); MS (ES 4 559.2 'H NMR (DMSO-d 6 8 9.22 (mn, 2 9.09 2 H), 741 0 CFp 1-2,S~ 8.81 2 8.17 (in, 1 7.95 1 7.82 (in, 2 H), 7.68 4 7.16 4H), 6.66 (in, I 4.06 2 MS (ES 551.22 'H NMv~R (DMSO-1 6 5 9.10 2 8.86 2 8.56 7o(in, 1 8. 13 (in, 1 7.93 1 7.82 (in, 2 H), 64 G 3 62q 1-2,S 7.67 5 7.15 (mn,3 6.66 (in, 1 3-19 2 C 1.50 (in, 2 1.28 (mn, 4 0.87 J 7.0 Hz, 3 MS 539.3 C HH 3 1-2, S 1H NMR (DMSO-d,): 8 9.09 2 8.90 (mn, 2 H), 8.15 (in, 2 7.93 1 7.81 (in, 3 7.68 (in, 4 7.13 (in, 3 6.66 (in, 1 3.83 (in, I 1.47 (in, 4 1.25 (mn, 4 0.83 (mn, 6 MS (ES 4 567.3 173 Cpd.
No.
Starting Met hod From .1Used Analytical Data 0 CH 3
CH
3
CH,
1-2, S 'H NMR (DMSO-d 6 8 9.08 2 8.86 2 8.48 (in, I 8.03 (mn, 1 7.90 1 7.79 (in, 2 H), 7.65 (mn, 5 7.12 (mn, 2 7.02 (mn, 1 6.65 (in, 1 3.22 (mn, 2 1.42 J 8.2 Hz, 2 0.91 9 H); MS (ES 4 -553.4 H NMR (DMSO-d 6 5 13.61 (br s, I 9.07 2 H), 9.00 2 8.52 J= 5.5 Hz, I 8.02 1 7.90 J 1.9 Hz, 1 7.79 (in, 2 7.64 (mn, 5 7.10 (in, 2 7.00 J 7.7 Hz, 1 6.64 (mn, 1 4.47 J= 5.3 Hz, 1 3.43 (in, 2 3.27 (in, 2 1.64 (qui, J= 6.8 Hz, 2 MS (ES 4 527.23
OH
62t 1-2, S 'H NMR (DMSO-d 6 8 12.7 (br s, 1 9.09 2 H), 8.91 2 8.57 (in, 1 8.11 1 7.92 J= 64u O 62u 1-2,S 1.9 Hz, 1 7.81 (in, 3 7.67 (in, 5 7.14 (in, 2 6.66 (mn, 1 4.40 J 5.3 Hz, I 3.39 (in, 2 3.22 (mn, 2 1.48 (in, 4 MIS 541.34 0 'H NMR (DMSO-d 6 8 9.16-8.89 (in, 4 8-16 (in, 1 64v 62v 1-2, S 7.93 1 7.81 (in, 3 7.67 (in, 4 7.56 1 7.15 (in, 5SH), 6.65 (in, 1 6.38 (mn, 1 6.26 (mn, 1 4.42 J= 4.9 Hz, 2 MS (ES 4 549.27 'H NM!R(DMSO-d 6 8 11.59 (br s, 1 9.14 2H), Yo N 8.98 2 8.70 J= 5.7 Hz, I 8.24 1 7.99 64w /62w 1-2, S (mn, 2 7.87 (mn, 3 7.71 (in, 3 7.36 1 H), 7.27 (in, 2 7.10 (mn, 2 6.67 (in, 1 4.07 J= 6.9 Hz, 2 3.24 J 6.5 Hz, 2 1.98 (qui, J 6.7 Hz, 2 MIS (ES 4 577.17 174 Cpd.
No.
Starting From Method Used Analytical Data 'H NMR (DMSO-d6):. 5 13.72 (br s, 1 9.13 2 H), 9.06 2 8.50 J= 5.7 Hz, 1 8.00 J= 1.3 64x 62x 1-2, S 1Tz,1I 7.89 1.9 Hz, 1 7.78 (in, 2 7.62 C 0 4 7.08 (in, 2 6.96 J 7.9 Hz, 1 6.64 I 3.04 J 6.5 Hz, 2 1.72-1.43 6 H), 1.25-1.08 (in, 3 0.88 (in, 2 MS (ES J: 565.25 Yo' HNMR (DMSO-d6): 5 9.16-8.87 (in, 4 8.09 1 64y I 1-S 7.91 I 7.80 2H), 7.6S (in, 5 7.12 (i, 64y 5 6.65 (m,1IH), 4.01 2H), 3.10 (m,1IH); MS
(ES
4 507.2 y 'H NMR (DMSO-d 6 59.10 2H), 8.97 2H), 8.59 (t,iJ 5.7 Hz, I 8.13 1 7.93 1 7.80 (in, 64z C O62z 1-2, S 3 7.68 (in, 4 7.16 (mn, 4H1-), 6.65 (in, 1 3.26 (qui, J 6.0 Hz, 2 1. 10 J =7.2 Hz, 3 MS
(ES
4 497.2 oOH 'H NMR (DMSO-d 6 5 14.1 (br s, 1 9.08 H), OH 8.79 2 8.45 (in, 1 8.01 1 7.90 H), 64aa 62aa 1-2, S 7.79 (in, 3 7.63 (in, 5 7.09 (in, 2 6.98 (in, 1 6.65 (in, 1 4.80 J= 4.7 Hz, 1 4.56 J= 6.8 Hz, I 3.60 (mn, I 11), 3.32-2.90 (in, 3 MS 543.2 'H NMR (DMSO-d 6 8 10.34 1 9.07 2 H), 64ab 0 2b I2S 8.85 2 8.18 1 7.93 I 7.80 (in, 6 H), \4a /2b 12 7.66 (in, 4 7.34 (in, 2 7.11 (in, 4 6.65 (in, 1 MIS (ES 4 545.2 4Jvu. j -R -R IO;lI- nltclDt No. Frm Used jAaytclDa tH NUR (DMSO-d 6 8 9.07 (in, 411), 8.38 J= 64ac 2ac 12, S Hz, 1 8. 10 1 7.92 I 7.84-7.62 (mn, 7 C 0 0 -0 7-11 (m,3 6.66 (mn, 1 3.94 1 1.88-1.35 (in, 12 MS 565 -3- 'H NMvR (DMSO-d 6 8 13.71 (mn, 2 9.36-8.57 (in, 4 8.50 (in, I 7.98 1 7.89 1 7-78 (2 64ad H 62nd 1-2, S 7.61 (in, 5 7.08 (mn, 2 6.95 J= 7-9 Hz, 1 6.63 (in, 1 3.19 (in, 2 2.16 J 7.2 Hz, 2 0 1.48 (mn, 4 1.28 (in, 2 MS 581.2 'H N'MR (DMSO-d6): 6 9.12 2 8.89 2 7.91 (mn, I 7.81 (in, 2 7.70 J 8.7 Hz, 2 7.62 64ae MI 0-RNo 62ae 1-2,S J= 8.9 Hz, 2H), 7.48 1H), 7.22 2H), 7-11 J= 3.4 Hz, I 7.05 J= 7.2 Hz, I 6.65 (in, 1 3.53 (in, 2 3.08 (in, 2 1.62-1.21 (mn, 6 MS 537.20 'H NMR (DMSO-d 6 5 12.81 (br s, 1 9.13 2 H), 8.82 2 7.95 1 7.85 (in, 2 7.71 (mn, 5 64af NHR -N Gi 3 62af 1-2, S 7.43 (mn, 1 7.29 (mn, 21H) 7.13 (i,1 6.67 (i,1 3.49-2.97 (mn, 4 1.67-1.37 (i,2 1O ,0 1 0.90 (in, 3 0.61-0.26 (mn, 4 MS 565.3 NEl
-~~NHR
.11NCM
I
Cpd. -R 1Starting IMethod Analytical Data No. JFrom Used
CH
3 1 H NMR (DMSO-d 6
D
2 8 13.87 (br s, 1 9.56 (in, 2 H) 9.21 1 8.74 1 8.47 (in, 11-1), 7.97 (in, 1 7.88 (s, 61 A-4, 1-2, S 7.78 (in, 3 7.58 (in, 7 7.09 (in, 3 6.96 (in, I H), 0 CH, 3 6.65 (mn, 1 3.14 (in, 4 t.77-0.80 (in, 18 MS (ES): 609.4 'H NMR (DMSO-d 6 6 13.80 (hr s, 1 9.91 I 9.41 1 ha CH~'H 2 67 A-4,1I 2, S H1), 8.63 (in, 2 8.07 1 7.98 1 7.60 (in, 8 6.90 71a -H=CH2(in, 3 5.94 J 17.7 Hz, 1 4.3 7 (in, 1 4.16 (in, 1 H), 2.41-1.58 (mn, 12 MS 537.4 'H NM4R (DMSO-d 6 5 9.76 I 9.41 1 8.95 1 H), 8.53 (mn, 1 8.07 1 7.65 (in, 8 7.08 (mn, 2 6.85 71 b CH'CH 2 67 A-4, 1-2, S (dd, J =10,9 and 17.7 Hz, I 6,92 (mn, 3 5.97 J 17.7 Hz, 1 5.37 10.9 Hz, 1 2.84 (in, 1 2.70 (in, 1 H), 0.98-0.51 (in, 8H); MIS 509.4 1177 Cpd. 1 -R 1R Starting Method AnltclDt No. JFrom UsedAaltalDt 'H NMR (DMSO-d 6 5 12.51 (br s, I 9.59 I 9.22 1 Cl-13 8.79 1 8.58 J=5.5 Hz, I 8.17 I 7.67 (in, 71C -CH=CH 2 67 A-4, 1-2, S 8 7.12 (mn, 2 6.86 (dd, J= 10.9 and 17.7 Hz, I 5.98 (d, J= 17.7 Hz, 1 5.38 10.9 Hz, 1 3.27 (in, 4 1.20 J= 7.2 Hz, I 1.09 J= 7.2 Hz, 1 MS 485.3 Cpd, [R Starting MethodAnltclDa No. j- R From UsedAnltclDa 68a -CT 3 7 -4 MS 599.4
CHH
3 68b -CIT 3 67 A-4 MS 641.4 Cl' 3 68c -CH 3 -067 A-4 MS 625.3 68d -Gil 3 XCH2 67 A-4 MS 583.3 68e 68f
-CIT
3 -CIT1 3 Cl 3
CRH
CH
3 MS 585.3 MS 599.4
ISO
Cpd. -R Starting rMethod AnltclDt No. -RRFrom UsedAaltclDa
C
3 6 8 p -CH 3 CE 67 A-4 MS 613.5
C
3 68q -CH 3 67 A-4 MS (ES 4 641.5 68r -CE NB 67 A-4 MS (ES 4 714.5 68s -CE 3 67 A-4 MS 611.4 68t -CEJ 3 67 A-A MS (ES 4 641.4 68u -CH 3 67 A-4 MS 583.3 68v -CH 3 67 A-4 MIS 597.4 68w -CH 3 OH67 A-4 MS 587.4
CE
3 68x -CH 3 3 67 A-4 MIS 613.5
CHJ
13 Cpd. -R (Position wvith f Starting Method No. Respect to Phenyl -Rvt From Used iAnalytical Data Ring)____ 74 -OCR 3 -CHO -CH 3 73 3a D-2 MS 368.2 -OH -CHO -CH 3 74 V-2,W MS 354.1 -OH -CH0 -Bn 74 V-I, H MS 430.2 76a -OSO 2
CF
3 -CH0 -CH 3 75a B-2 MS 488.1 76 O0C3()-CH0 -Bn 75b B-2 MS (ElS-) 562.3 MS 76b -SO 2 CF (3)586.3 (M±Na)+ 77a -CH=CH 2 -CH0 -CH 3 76a D-3 MS 366.38 77b -0CH 2 C0 2
C
2
H.
5 -CO-Bn 75b X Characterized in the next step 77c -OCH 2
CONT{
2 -CO-n 7b x MS 487.3; MS 511.35 (M-lNa)+ 77d S -Bn 76b D-2 Characterized in the next step *O0/0 (3) -CH0 MS 530.3 (M±Na) MS Sf(ES-): 506.3 Cd -R (Position with StriMto Cp. Respect to Phenyl -R R1 From UsedAnltclDa 77f 0 H -CHO -Bn 75b X MS 496.3 (M+Naf+ (3) F77g -CO-Bn 75b X MS 482.4 (M+Na)+ 77h 0-,Y -CHO -Bn 75b X MS 510.4 (M±Na)+
CH,
1 IHpIVIR (CDCI 3 8 9.59 111), 8.39 J 2 Hz, 1 8.03 (in, 2 7.84 J3 8.9 Hz, 11H), 7.35 J 8 Hz, 1 7728 (mn, 2 H), O~c7.12 (in, 2 62.93 (dd, J 77i 0(3) -CHO -Bn 75b X and 8. 8Hz, 1 6.64 J Hz, 1. 6.31 J =6and 5 Hz, 1 5.06 (in, 2 4.42 J Hz, 2 4.13 (in, 2 3.34 J =6.8 Hz, 2 2.11 3 H), 1.94 (in, 1 1.01 J 6.8 Hz, 6H) 78a -CH=CH 2
-CO
2 H -CH 3 77a E MS 380.1 78b -OSO 5
CF
3
-CO
2 H -Bn 76b E Characterized in the next step 78c -OCH 2
CC
2
C
2
H
5
-CO
2 H -Bn 77b E Characterized in the next step 78d -OCH 2
CONH
2 -C0 2 H1 -Bn 77c E IMS 527235 (M+Na)+ 183 Cpd. -R (Position with Starting Method N. Respect to Phenyl rm Ue ultclDt No. Ring)Frm UeAnltclDa 78e ()-CO 2 H -Ba 77d E MS 536.4 (M+Na)+ 78f -CO 2 H -Bn 77e E MS 522.3 78g -OCH 3 -C0 2 11 -CH 3 74 E MS 384.1 78h -CO 2 H -Bn 77f E MS (ESD: 488.3 78i 0' o CH 3
-CO
2 H -Ba 77g E MS (ES-J: 474.4 78j 0 -CO 2 H -Ba 77h IS MS 502.4
CH
3 78k 01 -CO2H -Ba 77i E Characterized in the next step 1 1{N1\R (CDC1 3 8 10.47 1 8.36 J =2Hz, 1 7.96 (dd, J =2.2 and 7.7 Hz, I 7.68 (in, 2 7.46 (in, 5 7.23 J 8 Hz, I 7.12 J =8.7 Hz.
-OBn -CHO -CH 3 89 3a D-2 1 6.73 J =7.2 Hz, I H), 5.23 J 11I and 15 Hz, 2 H), 3.67 3 3.31 J 6.8 Hz, 2 1.94 1H), 1.01 J 6.8 Hz, 6 MS 468.2 444.2 Cp. -R (Position with] Startn Meho Cp. Respect to Phenyl I R' F R trtim Mehd Analytical Data No. Rimg) Frm Ud 'HNNM4 (CDC1 3 6 8.22 1 H), 7.83 J =7.2 Hz, I 7.34 (n 8 7.02 J 1 Hz, I H), 91 -OBn -en11 C- 3 90) E 6.75 J =7.4 Hz, 1 5.16(s 2 3.66 3 3.21 J =6.8 Hz, 2 1.85 (in, 1 0.94 J =6.8 Hz, 6 MS (ES-i) 484.1 (M+Na)+ 92 -OBn -CO 2 MEM -CH 3 91 F MS 572.2 (M-iNa)+ 93 -OH -CO 2 MEM -CH 3 92 G MS 482. (M+Na) t 94 -OSO 2
CF
3
-CO
2 MEM -CIT 3 93 _B-2 MS 614.3 (M+Na)+
-CO
2 MEM -CH 3 94 D-3 MS 562.3 (M+Na)+ 96a C H H3 9a 11 M (E+45. MN)
S
101 -OCIT 3 -CHO -CIT 3 100 3a D-2 MS 370.1 102 -OCT 3
-CO
2 H -CIT 3 101 B MS 384.2; MS 386.2 108 -OBn -CHO -CIT 3 107 3a D-2 MS 446.2 -OBn (2)
-CO
2
H
-CIT
3 MS 460.1 I I .1 Cp. -R (Position withStrigM ho CNo. Respect to Phenyl From UsedAnltclDa 'T{NMR (CDC13-di): 5 9.79 1 8.39 J 188 Hz, 1 H), 8.02 J =6.0 Hz, 2 7.59 (n 131 -H -CHO
-CH
3 130 ±3a D-2 2 1I), 7.3 8 J 7.9 Hz, 1 H), 7.22 J =8.1 Hz, 1 6.30 (b, 1 3.72 3 3.36 J 6.6 Hz, 2 1.96 (in, 1 HM, 1.02 J =6.8 Hz, 6 MS 340.1 1 HNMR (DMSO-d 6 8 12.28 (b, 1 8.52 J 6.03 Hz, I H), 8.12 1 7.86 IJ 8. 1 Hz, I 7.74 J 7.74 Hz, 1 H), 132 -H
-CO
2 H -CH 3 131 E 7.41 J 8.67 Hz, 1 7.31 (t, J 7.9 Hz, 1 7.12 J =8.1 Hz, I 6.97 J 7.5 Hz, 1 3.39 3 2.92 J Hz, 2 1.66 (in, 1 0.78 J =7.4 Hz, 6 MS 354.1
NH
193a -H NHBoc 3 19a+ D-7 MS 560.5 6a
NH
193b -HCH, NEBoc -CH 192b D7 M E :545 ~~6a D7 M E~:545 Cpd.
No.
-R (Position with Respect to Phenyl Starting From Method Used Analytical Data'
NH
194a -H NHI 2
-CH
3 193a S-2 MS 460.3
NH
194b -H CH 3
NH
2
-CH
3 193b S-2 MS 474.3 'HNMR (DMSO-d 6 6 8.79 (bs, 4 8.63 J 6.5 Hz, 1 H), NH ~8.35 I 7.85 J =6 Hz, 1 7.62 J =8.2 Hz, 2 7.26 195a -H NH7 -H 194a 1-2 (in, 5 7.06 (in, 1 5.0 (in, 2 3.09 J -6.2 Hz, 2 1.86 0(in, I 0.89 J Hz, 6 MS 444.3 and (ES+) 446.3 Cpd. -(PstowihStarting Method Analytical Data No. Respect to Phenyl From Used Ring-) INWM~ (DMSO-d 6 IDCl): 5 8.24 (d,J 1.6 Hz, I 7.91 (dd, J 7.7 and 1.6 Hz, 1 7.56 (di, J3 8.7 Hz, I 7.48 (di, J 8.7 Hz, NH I~ 7.32 J 8 Hz, I 7.16 A~(in, 3 6.91 J =7.5 Hz, 1 H), 195b -H CHi, NH 2 -H 194b 1-2 6.76 J 8.5 Hz, 1 6.66 (di, J =8.5 Hz, 1 4.99 (in, 1 H), 0,0 2.92 (di, J 6.9 Hz, 2 1.68 (in, 1 1.33 J =6 Hz, 1.2 H), 1.27 J3 6 Hz, 1.8 0.71 (d, J =6.5 Hz, 6 MS 458.2 and 460.3 Ni-l 200 -H CH, NHBOC CH 3 199 6a D-7 MS 573.5
N&
1E88 Cpd- R (Position with -"Starting MethodAnltclDa N. Respect to Phenyl -R'Frm Ue No.g From______Used___ Ring)_JINMR (DMSO-d 6 /DCI): 6 8.49 J =5.6HIz, 1 8.18 J NH 6.9 Hz, 1 HW, 7.84 J =7.8 Hz, 1 7.23 (in, 4 7.01 (in, 2 H), CH NH13oc6.82 J 7 Hz, I 6.22 J 201-H 3 -H 200BO 1-2 8.5Hz, 1 6.15 201 H ~I -H 200 1-2 Hz, 1 3.95 (mn, 1 2.85 I H ~1.23 9H), 1. 1 (d,J =6.7 Hz, 1-2H), 1-05 J =6.7 Hz, 1.8 0.67 J Hz, 611); MS 559.4
NH
-HM4 H 0. S NS (ES 4 459.3
H
NH
203 -OBn 0 NHBoc -CH 3 45 R MS (ES 4 679.4
AN&
HN
204 -OIBn 0 NHBoc -H 203 1-2 MIS 663.4
N
Cpd.
No.
-R (Position with Respect to Phenyl Starting From Method Used Analytical Data 209a -H
-CIT
3 132 A-7 MS 454.3 'HINMvR (DMSO-d 6 5 10.72 (s, 1 8-65 I 6.03 Hz, I H), C N 8.24 1l-1), 8.03 (d,J =8.1 Hz, 0 1 7.75 (in, 6 7.40 3 7.90 Hz, 1 7.34 J3 8.1 Hz, 209b -CH-CH 2 N -CIT 3 30f A-7 I 6.88 J 11.2 Hz, 1 H), H 6.04 J 7.5 Hz, 1 5.41 (d, J 11.1 Hz, 1 3.55 3 H), 3.10 J -6.6 Hz, 2H), 1.86 (i, 1 0.88 J1 6.6 Hz, 6 H); 480.3 210b -CIT=CH 2 (4) NI-l 0 N-OH
H
AN&
H
-CHI 209b 'HNMR (DMSO-d 6 6 10.12 (s, 1 9.37 1 8.48 J=6.1 Hz, 1 8.05 J=1.9 Hz, 1 H), 7.85 1=7.9 Hz, 1 7.56 (d, 3=7.9 Hz, I 7.49 J=7.9 Hz, 1 7.36 4 7.21 J=7.9 Hz, 1 7. 10 J=-2.8 Hz, 1 H), 6.69 (in, 1 5.84 J=1 5.5 Hz, 1 5.60 1 5.22 (d, J=1 1.4 Hz, 1 3.38 3 H), 2.91 J 6 Hz, 2 1.66 (in, 1 0.71 3 =6.8 Hz, 6 MS (ES+I) 515.40 I 1 FCpd.
INo.1 -R (Position. with Respect to Phenyl Starting From Method Used Analytical Data C C 'HNMIR(DMSO-d 6 6 12.62 (bs, 10.24 1 8.48 (t, J=5.65 Hz, 1 8.15 1 H), 7.81 J=,10.9 Hz, 1 7.61 (s, NHI I 7.50 J='7.9 Hz, 1 H), 211b -CH=I-1 1 Ob 1-2 7.49 6 7.16 J=8.1 Hz, 1 21T -H=C 2 4) -0 N-OH H 21b -2 7.08 J=-8.1 Hz, 6.72 (in 1 5.85 J=13.7 Hz, 1 N 5.24 J3=11.5 Hz, 1 H), H 2.93 J =6 Hz, 2 1.68 (in, 1 0.72 J 6.8 Hz, 6 MS 501.40, 499.2
__N
-CH=CH
2 (4)
-CH
3 187a A.E-5 'H NMR (DMSO): 6 8.70 J 5.6 Hz, I 8.36 J= 1.7 Hz, I 8.07 (dd, J 1.9 Hz, 1 7.42 (in, 4H), 7.09 J' Hz, I 7.04 J =7.7 Hz, 1 6.74 (dd, J 17.5, 10.9 Hz, I 6.49 J1=8.8 Hz, 2 5.79 J= 17.7 Hz, 1 5.27 J= 10.9 Hz, 1 4.0 J= 6.0 Hz, 2 3.62 3 3.11 J 6.2, 2 HI), 1.86 (in, I 0.90 (d, J= 6.6 Hz, 6H) J Cpd. -R (Position with Starting MethodAaltclDa No. IRespect to Phenyl -R From Used nticlDa Ring) 1 'H-INM (DMS0): 5 9.23(s 8.71 J= 6.2 Hz, 1 8.36 J= 1.9 Hz, I 8.09 (dd, J 7.9, 1.7 Hz, 1 7.49 J 7 .9 Hz, 2 7.40 J 8.3 Hz, 1 NH 7.32 8. 8 Hz, 2 7.*04 J 7.9 Hz, I 6.73 (dd, J= 213 -CH=CH 2 N-OH -CH 3 212 Y 17.7, 11.1 Hz, 1 6.40 (d,J H ~8.5 Hz, 2 6.33 J= 7.0 Hz, 1-N& 1 5.78 J= 17.7 Hz, 1 H), H 5.58 1 5.26 J= 11. 1 H4z, I1H), 3.96 (in. 2 3.64 3 3.11 J= 6.4 Hz, 2 1.86 (mn, i 0.90 (di, J 6. 8 Hz, 6 MS 501.3 1 HNMR (DMSO): 5 8.76 J1= 5.8 Hz, 1 8.37 I 8.04 NH J= 8.7 Hz, I 7.39 (in, 7.06 J 8.3 Hz, 1 6.72 (dd, J= 17.9, 11.3 Hz, I 6.43 214 -CH=CH 2 N-OH -H 213 1-2 J= 8.5 Hz, 3 5.76 J= H 17.9 Hz, I 5.24 J= 11. 1 N Hz, 1 3.98 (in. 2 3.11 J H 6.6 Hz, 21H), 1.86 J =6.8 Hiz, I 0.90 J= 6.8, 6 H); MS 487.2 '192 Cpd.
No.
-R (Position with Respect to Phenyl Ring) Analytical Data 'H7NMR (DMSO-d 6 6 8.68-8.60 (in, 1 8.50 J 2.4 Hz, 1 7.90-7.80 (in, 1 7.76-7.70 (in, 1 7.56-7.50 (mn, I H), 7.48-7.42 J 7.7 Hz, I H), 7.30-7.22 .1 7.9 liz, 1 H), 7.10-7.02 J1 7.7 Hz, I H), 6.90-6.75 (dd, J =17, 11 Hz, 1 6.5 (bs, 1 5.92-5.80 J1 17 Hz, 1 5.40-5 -30 11 Hz, 1 4.50-4.20 (in, 2 3.20- 3110 S 6.6 Hz, 2 2.10- 1-88 (in, 1 1.2-0.94 J 6.6 Hz, 6H) -IMS 471.3 238 -CH=CH 2 (4) 573.3 459.1 Cpd.1 -R Starting Method Analytical Data 79a -CH=CH 2
-CH
3 78a J MS 499.2 79b -OSO 2
CF
3
-CH
2
C
6
H
5 78b J Characterized in the next step 79c -OCH 2
CO
2
ZC
2
H
5 -CL-1 2
C
6
H
5 78c J Characterized in the next step 79d -OCH 2
CONII
2
-CH
2
C
6
H
5 78d j MS 622.4; (ES) 620.4 79e (3 -C11 2
C
6 11 5 78e 3 Characterized in the next step 79f o 0/3) -CH 2
C
6 H5 78f 3 Characterized in the next step 194 Cpd. f-R StFromn Method jAnalytical Data I'HNMR4 (DMSO-d 6 8 10.6 (bs, 1 9.29-9-32 (bs, I Hn), 9.06 (bs, 1 8.82-8.75 J =5.84 Hz, 1 8.32 J
-OCH
3 1. 88 Hz, 1 8. 13 J1 1.7 Hz, 1 7.83 4 7.78 (d, 79g
-CH
3 78g j J 8.67 Hz, 1 7.50 J =7.9 Hz, I 7.20-7.15 (dd, J 8.67, 2.3 Hz, 1 6.92 J 2.4 Hz, 1 3.94 3 H), 3.64 3 3.21-3.14 J 6 Hz, 2 2.0-1.86 (in, 1 H), 1.0-0.94 J1 6.5 Hz, 6 MS (ES 4 503.3 79h N CH 3 -Bn 78h J MS (ES 4 607.3 79i 0o -cH, -Bn 78i i MS (ES 4 593.4 79j 0(3) -Bn. 78i J MIS (ES 4 621.4
CH,
79k -0-CH 2
-CH
2 -OAc -Bn 78k i MS (ES 4 651.4 1 IitNMR (DMSO-d,): 5 9.1 2 8.87 2 8.53 J -CH=C2 (3)6 Hz, I 8.02 11H), 7.64 (in, 7 7.1 1 6.98 (d, 4C=CH 79a 1-2 7.4 Hz, 1 6.80 (dd, T =11 Hz, J 17.6 Hz, 1 5.90 J =17.6 Hz, 1 5.35 J 12 Hz, 1 3.03 6 Hz, 2 H), 1.83 (in, 1 0.86 J1 6.7 Hz, 6 MS (ES 4 485.2 'HNMR (DMSO-d 6 5 10.3 7 1 9.20 (mn, 3 8.72 (t, -OH 6 Hz, 1 8.2 1 8.85 (in, 6 7.65 J 8 Hz, I 79b 1-2 7.12 8 Hz, 1 7.02 (dd, J 2.5 Hz, J 8 Hz, 1 H), 6.60 J =2.5 Hz, 1 3.25 J 6.5 Hz, 2 2.0 (in, 1 1.07 J 6.8 Hz, 6 MS (ES 4 475.2 I I Cpd.
Starting Method
TT.,
Analytical Data [NO0. 1 I
-OCH
2
CO
2 H (3) 'H NMIR(DMSO-d 6 6 12.7 (2H, bs, 1 9.01, 8.87 (2 bs, 4 11), 8.36 (in, 111), 7.83 1H), 7.44 (mn, 6 6.75 (mn, 2H), 6.31 J=2.2 Hz, 111), 4.42 2H), 2.84 (in, 2H), 1.63 (mn, 1H), 0U7 J=6.5 Hz, 611); MS(ES+): 533.4 I_ -I I -OCH2CONH2 (3) 1 H NMR (DMSO-d 6 5 9.13 (bs, 5H), 8.59 J=6.28 Hz, IH), 8.14 J 1.7 Hz, 1H), 7.63 (in, 9H1), 7.42 1H1), 7.09 J =7.5 Hz, 111), 7.03 (dd, J 12.7 Hz, 11H), 6.70 J H, 11H), 4.48 2H), 3.05 J= 6.6 Hz, 211, 1.83 (in, 1H1), 0.87 J=6.8 Hz, 6H); MS(ES+): 532.4 111 NMR (DMSO-d 6 5 12.6 (111, bs, COOH), 8.98, 8.67 (2 bs, 4H), 8.46 (mn, 1H1), 8.08 (ni,1H), 7.76 (in, 1H), 7.53 (in, 6 7.39 (in, 2H), 7.06 (in; 111), 7.04 (in, 1H1), 2.89 (in, 2H), 1.66 (mn, 111), 0.69 1=6.5 Hz, 6H); MS(ES+I): 541.4
I
Sl- 1 4 1 4 (3) 'KNMR (DMSO-d 6 6 9.14 J 10 Hz, 41H), 8.60 J 6 Hz, 1 8.22 (bs, 11H), 7.87-7.62 (in, 7 H4), 7.47 J 8 Hz, 2 7.26 7 Hz, 1 7.22 (mn, 411), 6.70 (bs, 1 3.09 (t, J =6 Hz, 2H), 1.83(mn, IH), 0.91 (d,J =6.8 Hz, 6H); MS
(ES
4 551.4 I I 4.
sg-OCH 3
-H
1-2 =6 Hz, 1 8.25 (bs, 1 7.78 (mn, 1 7.76 (mn, 5 H), 7.25 I 7.17 (mn, 1 6.73 (bs, 1 3.83 3 H1), 3.10 J 6 Hz, 211), 1.80 (mn, 1 0.88 J 6.8 Hz, 6 H); MS 489.3 196 Cpd. -R 1 R 1Starting fMethod Analytical Data No. From Used-I 0.H -H 79h 1-2 MIS 517.7 0. H -H 79i 1-2 MIS (E--:503.4 MS 501.4 0" H -H 79i 1-2 MS 531.4; MS 529.4 C14 3 'HNMR (DMSO-d 6 5 13.52 (bs, 1 9.16 (bs, 2 9.03 (bs, 2 8.50 J 6 Hz, 1 7.96 J =1.7 Hz, 1 H), 7.56 (in, 6 7.00 (dd, J 2.5 and 8.5 Hz, 1 6.90 J _OCH2CH2OH -H 79k 1-2 8 Hz, 1 6.48 J1 2.5 Hz, I 4.91 J =5.5 Hz, 1 H), 4.00 J 4.5 Hz, 2 3.69 J 5.5 and 10 Hz, 2 H), 3.05 J1 6.8 Hz, 2 1.80 (mn, 1 0.84 J 6.8 Hz, 6 MS (ES 519.3, 517.3 'HNMvR (DMSO-d 6 5 9. 15 (bs, 3 8.65 J1 6 Hz, 1 H), 8a -CH(OH)CH2OH -82 S12 8.12 2 7. 82-7.56 (in, 7 7.55-6.96 (mn, 4 5.5 (bs, 86a H 8 S. -2 I 4.90 (bs, 1 4.65 (bs, 1 3.10 J 6 Hz, 2 1.90 (in, I 0.92 J1 6.8 Hz, 6 MS 519.3 'HNMR (DMSO-d 6 6 8.82 (bs, 2 8.68 (bs, 2 8.40 (t, -CHO0H J 6 Hz, 1 7.88 (bs, 1 7.53 (in, 5 7.45 8 Hz, I 86b 2 -H 84 S,1-2 7.25 J 8 Hz, 1 6.81 (in, 2 5.22 J =5.5 Hz, I 4.41 J3 5.5 Hz, 2 2.88 (tj= 6 Hz, 2 1.65 (mn, 11H), 0.71 J 6.8 Hz, 6 MS (ES+ 489.2 Cpd. -R -R Starting Method Analytical Data No. LFrom JUsed lipTiva3 (DMSO-d 6
.D
2 6 13.7 (bs, 1 8.32 J =6 Hz, 86c -CO 2 H -H 85 S, 1-2 1 7.63 -7.17 (in, 7 14), 6.72 7.0 Hz, 1 2.81 J =6 Hz, 2 1.53 (in, 1 0.64 J 6.8 H-z, 6 HM; MS (ES"' 503.2 97a CH 3 96a J MS 569.2 ljfHN.MR (DMSO-d 6 3 10.62 I 9.15 (bs, 2 8.82 (bs, 2 8.67 J =6 Hz, I 8.25 J 2 Hz, 1 7.99 97b -OBn -CH 3 91 1 (dd, J 8 1 and 2 Hz, I 7.69 8.8 and 16.2 Hz, 4 H), 7.44 (in, 3 7.28 (mn, 3 11), 6.89 J 7.7 Hz, 1 5.5 (s, 2 3.6 3 3.08 J 5.8 and 6.8 Hz, 2 1.83 (in, 1 0.87 J 6.8 Hz, 6 MS 577.2, 579.3 1 HNMR (DMSO-d 6 3 13.45 (bs, 1 9.06 2 8.99 (s, \2 8.51 J 6 and 5 Hz, 1 7.99 I1-H), 7.62 (mn, 98a -H 97a 1-2 7.47 11-H), 7.36 (in, 2 6.99 (mn, 4 4.26 2 H), S 3.02 J =6.8 Hz, 2 1.80 (mn, 1 0.86 J 6.8 Hz, 6 MIS 553.2, 555.2 .98b -OBn (5) 'HNMR (DMSO-d 6 3 13.52 (bs, 1 9.09 (bs, 2 H1), 9.04 (bs, 2 8.48 J 6Hlz, 1 7.94 I 7.61 (in, 4 H), 7.49 1 M, 7.46 I 7.34 (mn, 5 7.15 J 8.2 Hz, 11-H), 7.00 J 8.2, 1 6.02 J 7.4 Hz, I 5.21 (s, 2 3.01 J 6.8 Hz, 2 1.80 (in, 1 0.85 J 6.8 H-z, 6 MS 563.2, 565.2 I_ I 1_ l_ 198 Cpd. -R r R1 Starting iMethod Analytical Data No. -From 1 Used 'HNN.R (DMSO-d 6 6 9.85 I 9.07 8.98 2 8.50 J 6 and 5 Hz, 1 7.99 J 1.7 Hz, 1 H), 98c OH 5) H 9b G 7.63 (in, 5 7.20 J 8 Hz, 2 6.90 J1 7.9 Hz, 1 98C -O 98b G 6.49 J 7.2 Hz, 1 3.-21 J =6.8 Hz, 2 1H), 1.8 0 (in, 1 0.85 J1 6.8 Hz, 6 MS 475.2; (ES-) 103 -OCH 3
-CH
3 102 1 MS 503.1 1 HINMR (DMSO-d 6 6 9.08 (bs, 2 8.80 (bs, 2 8.52 (t, 104 OCH3(2)-H 13 1- J 6 Hz, 1 8. 02 1 7.64 (in, 5 7.16 (in, 2 H), 104 OCH 3 H 10 1-2 7.03 (mn, 2 3.84 3 3.03 J 6.8 Hz, 2 1.81 (in, 1 0.86 J3 6.8 Hz, 6 MS 487.3, 489.3 110 -OBa. -CH 3 109 1 MS 579.3 ill -OH -CIT 3 110 G MS 489.3 126 -0C 2
H
5 both -CIT 3 118b i Characterized in the next step -OBn J H NMR (DMSO-d6): 6 9.06-9.09 (in, 3H), 8.5 6-8.50 (in, IH), 8.05 11-1), 7.711-7.58 (in, 6H), 7.55-7.28 (in, 6H1), 7.10- 127 -0C 2
H
5 -H 126 1-2 7.01 (mn, 1H), 6.63 IH), 5.19 2H), 4.05-3.97 (in, 2H), -OBn 4 )j .both 3.05-3.01 (mn, 2H), 1.86-1.77 (mn, lIT), 1.29 J6.7 Hz, 3H), 0.87 J=6.8 Hz, 6H) lboth IH NMR (DMS0-/ 6 13.64 (br s, 1 8.99 (br s, 2 8.49 J= 5.1 Hz, 1 7.99 1 7.73-7.56 (in, 5 7.32- 129 -OCH 3 -H 128 I-2, S 6.83 (mn, 5 6.50 1 5.17 J= 4.3 Hz, 1 5.01
-CH(OH)CH
3 (in, 1 3.75 3 3.03 J= 6.0 Hz, I 1.81 (in, 1 1.32 J1=6.2 Hz, 3 0.86 J =6.6 Hz, 6 MS 533.4 (100% Cpd. -R (With Respect to Starting Method Analytical Data 81 -CH=CH 2 79a R MS 597.2 82 -CH(OH)CH 2 OH 81 L MS (E5S 1 631.3 83 -CH=~O 82 M MS 601.3 84 -CH 2 OH 83 K MS 601.4
-CO
2 H 83 E MS 615.3 128 OC3()]both 124a R MS 629.4
-CH=CH
2 J Cpd. T Starting TMethod No. j -Rj R I R R3 [R From Used Analytical Data 'HNMR (CDC1 3 6 10.48 1 7.42 7.25 (in, 7 7.00 (dd, J =2 and 7.4 88 -Br -H -H -H -OBnl 87 X Hz, 1 5.19 2 IR (K.Br) 170 1, 1585, 1452, 1262, 1009 cm 4
MS
313.0, 315.0 (M+Na)+ IHNMR (CDC1 3 5 10.61 I 7.65 J 7.2 Hz, 1 11), 7.60 J 7.9 and 89 -B(OH) 2 -H -H -H -OBn 88 T, U-i 7.2 Hz, 11-1), 7.41 (in, 5 1H), 7.19 J 7.9 Hz, 1 6.81 bs, 2 5.20 2
H)
'HNM\R (DMSO-d 6 8 10.2 1 H), 100 -B(OH) 2
-OCH
3 -H -H 99 T, U-3 8.34 2 7.92 J 9.4 Hz, 1 H), 7.13 (mn, 211), 3.92 3 MS (ES-) 179.0 107 -B(OH) 2 -OBn -H -H -H 106 T, U- 'HNMR (DMSO-d6): 8 10.1 I H), (in, 8 (mn, 2 H) 114a -1Br -H -OCH 3 -O)H -H 113 Z MS 229.0 and 23 1. 0) 1l4b -Br -H -0C 2
H
5 -OH -H 113 Z-1 MS 242.9 and 244.9 1l4c -Br -H -OGH(CH 3 2 -OH -H 113 Z-1 MS 257.0 and 259.0 115a -B3r -H OCH 3 -O6Bn -H 114a X MS (ES 1 321.0 and 323.0 115b 1 15C -14 -flC.,T-T~ MS (ESA 335.0 and 337.0 -Br -H-OCI(CR) -OBn 114b S(S:390adI.
-Br -OCHWH-A) -OBn 114c msj S,):349.Oand351.0 Cpd. _R -RIl R2 -113 R4 Starting Method altc Da 1 15d -Dr -H -OBn -H 115a X 4,Characterized in the next step 0 C(CH 3 3
A
116a -B(OH) 2 -H -OCH 3 -OBn -H 115a IT, U-1 Characterized in the next step 1 16b -B(OH) 2 -H -0C 2
H
5 -OBn -H 1 15b T, 1 Characterized in the next step 116c -IB(OH) 2 -H -OCH(CH 3 2 OBn -H 115c T, U-i Characterized in the next step
H
00 Cpd. TStarting 1MethodAnltclDa No. From UsedAnltalDa 'HNIMiR(DMSO-d 6 5 11.28 I 9.31 2H), 9.0 2H), 8.88 J 11.30 Hz, 1 8.82 J =1.88 Hz, 1 8.25 J 1.88 Hz, 1 8.18 (di, J 1.88 Hz, 1 H), 112 111-.2 8.04 (di, 3 8.47 Hiz, 1H), 7.92 (in, J =24.48 Hz, 2 7.75 (in, J 15.82, 1 7.75 J 8.28 Hz, 1 7.55 J =8.66 Hz, 1 3.10 J =12.6 Hz, inH), 2.5 J Hz, I 1.8 (in, J 19.9 Hz, 2 0.88 (in, J 6.6 Hz, 6 H).
203 Cpd. -R R" -R"Starting Method Analytical Data No. I From Used
CH
3 117a -CH 3 -OBri -CHO 3l 1a+ D-2 MS 474.2
CH
3 117b -C 2
H
5 -OBn -CHO 3a D-2 MS 488.2 CH, 116b
CH
3 117c -CH(CH 3 2 -OBn -CHO 3a+ S(S 0.
C
3 116c D2 M ED 0.
'H NMR (CDC1 3 8 9.56 1 8.34 J 1.7 H~z, 1 8 1 8.01 (dd, iT =7.9 and 1.9 117d -CH 3 -OBn -CHO CH 3 3b D-2 Hz, 1 7.40 (in, 7 6.9 I 116a 5.24 (mn, 211), 4.2 (mn, 1 H), CH, 3.80 3 3.52 3 1.02 J =7 Hz, 6 MS (M+Na)' CIpd. -R I Starting 1Method Analytical Data No. JFrom JUsed I1{NM\R (DMSO-d 6 8 8.43 J =1.65 Hz, 1 8.31 J =8.66 Hz, 8. 12 (dd, J =1.69 Hz, 1H), 7.98 111), 7.41 J 8 CH~and 10 Hz, 11H), 7.19 (d,J =8.1 117e -CH 3 -OBn -CHO 3c D2 Hz, 11), 5.20 (dd, J 6.2 Hz, C'3116a D- 1H), 3.98 (dd, J 7.75 Hz, 3H1), 3.94 311), 3.42 (in, 3H), 3.32 (in, 311), 3.19 3H), 2.5 (mn, 3H), 2.0 411), 1.5 (mn, 2H1), 1.28 (mn, 311), 0.88 J =6.59 Hz, 311); MS 664.3 1H NVR (CDCI 3 6 9.50 1 8.40 J =2.1 Hz, I 8.04 (dd, J 2.1 Hz, I 7.57 (s, 1 7.48 (in, 5 7.38 (in, 11fCH 3 -03 -H 3d D2 6.67 1 6.50 (broad, 1 117f -el 3 CHO116a D2 5.27 J 11.9 Hz, 1 H), 5.22 (dd, J= 11.7, 1 H), 4.63,(in,3H) 4.17 (in, 41H), 3.92 3 3.66 3 MS (ES): 488.3 'H NMR (CDC1 3 6 9.5 0 1 8.40 J 2.1 Hz, 1 H), 8.04 (dd, J 8. 1, 2.1 Hz, 111), 3f +7.57 1 7.48 (mn, 2 7.38 117g -CH 3 -OBn -CHO 11a D-2 (in, 3 6.67 1 6.50 116a (broad, 11H), 5.27 J= 11.9 Hz, I 5.22 (dd, J= 11.7,2 4.17 (in, 2 3.92 3 H), (s,_3_H);_MS(ES5):_500 205 Cpd. -R Starting 1Method [Analytical Data No. ____IFrom jUsed 1H NMR (CDC1 3 5 9.56 I 8.34 1.7 Hz, I H), 8.01 (dd, 7.9, 1.9 Hz;, 11H), 7.57 1 7.50 (dd, J= 7.2, 11h _H On -CHO 3e D2 1.5, 2 H4), 7.40 (mn, 4 6.67 (s, 117k -CH 3 -O~n116a D- 1 6.21 (broad, 1 5.24 J CH 3 =2.8 Hz, 2 3.92 3 3.65 3 3.52 (in, 2 1.65 (mn, 2 1.46 (in, 2 0.99 J 7.3 Hz, 3 H).
1 H NMR~ (CDCI 3 8 9.57 I 8.3 7 J 1.9 Hz, 1 H), 8.03 (dd, J= 7.9, 1.9 Hz, I H), 8 1 7.50 J 7.2 Hz, 3g+ 2 7.3 8 (in, 3 6.68 1 H), 117i -CH 3 -OBn -CHO 116a D-2 6.33 (broad, 1 5.26 J 116a11.5 Hz, 111), 5.21 J=11.9 Hz, I 3.92 3 3.65 3 3.37 (dd, J= 7.2, 5.3 Hz, 2 1.09 (in, I 0.60 (in, 2 H), 0.32 (in, 2 MS 4-74.2 'H NMR (CDC1 3 3 9.55 1 8.32 J= 1.9 Hz, I H), 8.00 (dd, 1.9 and 7.9 Hz, 1 11j -H On -CHO 3b D2 7.59-7.30 (in, 7 6.67 (s,1 117j CIT 3 -O~n116a D2 5.23 (in, 2 4.45 J= Hz, 1 3.91 3 3.64 3 2.21-1.46 (in, 8 MIS 510.3 (M +Na) t Cpd. _R 1R Rt_1 Starting Method 1Analytical Data No. From JUsed 'H NMR (CDC1 3 8 9.56 I 8.35 J- 1.9 Hz, 1 H), 8.02 (dd, J= 1.9 and 7.9 Hz, 1 117k -CH 3 -OBn -CHO 3i D-2 7.58-7.33 (in, 7 6.68 1 C-3 116a 5.24 (mn, 2 3.92 3 H), 3.65 3 3.56 (in, 2 1.30 J= 7.2 Hz, 3 MS 470.3 Na) 'H NM4R (CDCb-): 8 9.56 1 8.35 J= 1.9-Hz, 1 H), 8.02 (dd, J= 1.9 and 7.9 Hz, 1 1171 -CH 3 -OBn -CHO CH 3 D-2 7.58-7.33 (in, 7 6.68 I
CI
3 116a 5.24 (in, 2 3.92 3 H), 3.65 3 3.40 (in, 2 1.80- 0.94 (in, 9 MS (ES 1 512.2 Na)+ 'HNMR (DMSO-d 6 6 9.73 1 8.86 I 5.7 Hz, I 8.52 J 1.5 Hz, 1 8.22 (dd, J 0 CH, 3 8and 2 Hz, 1 7.79 1 H), 117m -OBn -CHO 6a D-6 7.60 J 8 Hz, 1 7.5 (mn,
CH
3 115d 7.22 1 5.35 J I11 (CHAand 17 Hz, 1 3.70 3 H), 3.23 J 6.5 Hz, 2 1.98 (in, 1 1.3 9 1.01 J =6.8 6 MS 546.4
CH
3 118a -CH 3 -Q~n -CO 2 H C3 117a E MS 490.2 Cpd. -R1' R Starting Method AnltclDt No. L RRRR[From [UsedAnytclDa
CH,
118b -C 2
H
5 -OBn -CO 2 H 117b E MS (ES7): 504.2
CH
3 118c -CFI(CH,) 2 -OBn -CO 2 H 117c E MS 518.2
CH
3 1 18d -CH- 3 -OBn -C0 2 H 1,CH 17d E Characterized in the next step Cu 3 118e -CH 3 -OBn -C0 2 TH H 117e E MS 534.3 118f -CH 3 -OBn -CO 2 H C 117f E MS 506.3 118g -CH 3 -OBn -CO 2 H C 117g B Characterized in the next step 11811 -CH 3 -OBn -CO 2 H C3 117h E MS 490.2 118i -CmH -OBn -CO 2 H 117i E MIS 488.3 Cpd.
-R"v Starting From Method Used Analytical Data No.. j- 'U1 NMR (DMSO-d 6 6 12.19 (br s, 1 8.50 (di, J= 7.4 Hz, 1 8.31 J= 1.9 Hz, 1 H), 118j -GCl 3 -OBn -CO 2 H 117j E 8.02 (dd, J= 1.7 and 7.9 Hz, I 7.58-7.29 (in, 7 6.71 1 5.17 2 4.27 J= 6.4 Hz, 1 3. 80 3 1H), 3.5 7 3 1.97-1.51 8H) 118k -GCl 3 -OBn -CO 2 H C, 117k E MS (ESD: 462.3 'H NMR (CDCI 3 8 8.3 0 (di, J= 1. 9 Hz, 111), 7.95 (dd, J =1.7 and 7.9 Hz, I 7.66 1 1181 -eli 3 -OBn -CO 2 H CH 3 1171 E 7.52-7.27 (in, 6 6.62 1 H),
GB
3 6.49 (in, 1 5.21 2 3.88 3 3.61 3 3.38 (in, 2 1.79-0.94 (mn, 9 MS 504.4 0
CH.I
118M (H -OBn -COzH C3 117m E Characterized in the next step Gil 3 119a -GCl 3 -OBn -CO 2 MEM H 118a F MS 578.3
CH
3 119b -C 2
H
5 -OBn -CO 2 MEM IH 118b F MS 592.3 209 No.T R -R I -R -R Ftrtin UsMehd Analytical Data
CH,
119C -CH(CH 3 2 -OBn -CO 2 MEM H3 118C F MS 606.3 119d -CH 3 -OBni -CO 2 MEM "I C3 118d F MS 564.2
CH
3 119e -CH 3 -OBn -CO 2 MEM C H3 118e F MS 620.1 119f -CH 3 -OBn -CO 2 MEM
CH
3 118f F MS 592.3 119g -CH 3 -OBn -CO 2 MEM 3~C 118g F Characterized in the next step 'H NMR (CDC1 3 5 8.32 J 1.9 Hz, 1 7.96 (dd, J= 7.9, 1.9 Hz, 1 7.68 1 7.50 (in, 2 7.35 (in, 4 6.62 1 119h -eli 3 -013n -CO 2 MEM 118h F 6.33 J =5.4 Hiz, 1I1M, 5.24 (mn, 4 3.88 3 3.63 3 3.46 (in, 6 3.34 3 H), 1.63 (mn, 2 1.44 (mn, 2 0.98 J= 7.3 Hz, 3 H) 210 Cpd. 1 R 1 R I Starting Method Analytical Data No.] -R -R -R-I From [Used 'HNMR (CDC1 3 5 8.34 J= 1.9 Hz, 1 8.00 (dd, J=7.9, 2.1 Hz, 1 Hf), 7.68 1 7.50 (mn, 2 7.36 (in, 4 6.63 1 119i -CH 3 -O~n -CO 2 MEM 118i F 6.42 (broad, 1 5.24 (in, 4 3.89 3 H1), 3.64 3 H), 3.45 3 3.3 5 (in, 5 1.07 (in, I 0.58 (in, 2 0.30 (mn, 21) 'H NMR (DMSO-d 6 8 8.55 (d, J= 7.4 Hz, 11H), 8.39 1.9 Hz, 111), 8.10 (dd, J =1.7 and 7.9 Hz, 1 7.63-7.35 (mn, 7 H), 119j -Clii -OiBn -CO 2 MEM 118j F 6.81 1 5.25-5.12 (in, 4 H), 4.31 J=6.4 Hz, I1H), 3.86 (s, 3 3.62 3 3.3 3 H), 3.23 3 H) 1.99-1.53 (mn, 8 H); MS 614.3 Na)+.
'H NMR (DMSO)-d 6 8 8.70 (t, J 5.5 Hz, 1 8.35 J= 1.9 Hz, I 8.05 (dd, J= 1.7 and 7.9 Hiz, I 7.59-7.30 (in, 7 H), 11 9k -CH 3 -OBn -CO 2 MEM 118k F 6.77 1 5.21-5.08 (mn, 4 H),
GB
2 3.82 3 3.58 3 3.40- 3.29 (in, 611), 3.18 3 1. 14 J 7.2 Hz, 3 MS (ES): 574-3 Na)+ Cpd. I Starting MethodAnltclDa No. J RR From JUsedAnltclDa 'H NMR (DMSO-d 6 8 8.68 (t, J= 5.8 Hz, 1 8.35 J= 1.9 CH, FHz, 1 8.05 (dd, J= 1.7 and
CR
3 7.9 Hz, 1 7.63-7.33 (in, 7 H), 1191 -CH 3 -OBn -CO 2 MEM CH, 1181 F 6.77 1 5.22-5.08 (in, 4 H), 3.82 3 3.58 3 3.39- 3.22 (in, 6 3.18 3 1.56 (qui, J= 7.0 Hz, 2 1.27 (mn, 1 0.94-0.75 (in, 6 MS 616.3 Na)+ 'H~I (DMSO0-d 6 8 8.72 J 5.6 Hz, 1 8.38 J =1.8 Hz, I 8.70 (dd, J =1.8 and 8- Hz, 1 HI), 7-71 11H), 7.40 0 elI 3 (mn, 6 7.02 11-H), 5.20 (in, 4 119M -OBn -CO 2 AffM 118m F 3.59 3 3.37 (in, 2 H), C(CHA) C11 3 3.31 (in, 2 3.17 3 3.12 J =6.5 H~z, 2 11), 1.87 (mn, 1 1.21 9 0.91 J =6.8 Hz, 6 MS 650.4 and 672.3 Na)+
CR
3 120a -CH 3 -OH -CO 2 MEM 119a G MS 488.1
CH
3 120b -C 2
H
5 -OH -CO 2 MEM C3 119b G MS 502.2 Cp. R 1 -Rw-Rf R''Starting Method Analytical Data 120c -CH(CH 3 2 -OH -CO 2 MEM 119C G MS 516.3
CH
3 120d -Gil 3 -OH -CO 2 MEM H3 119d G MS 474.3
CH
3 120e -CH 3 -OH -CO 2 MEM CCH3119e G MS 530.4 120f -Gil 3 -OH -CO 2 MEM G~ 3 119f G MS 502.3 120g -Gil 3 -OH -CO 2 MEM C, 119g G Characterized in the next step 120h -Gil 3 -OH -CO 2 MEM H 3 11911 G Characterized in the next step 120i -Gil 3 -OH -CO 2 MEM 119i U MIS 486.3 120j -Gil 3 -OH -CO 2 MEM 119j G MS 524.3 Na) 4 120k -en 3 -OH -CO 2 MEM 119k G MS 484.2 Na) 4 Cpd. -R 1 I -R"f Starting Method Analytical Data No. [J From JUsed CH 3 1201 -CH 3 -OH -CO 2 MEM -,C3 1191 G MS 502.3 l'iNMf (DMSO-d 6 5 10.83 (bs, 1I-H), 8.77 J =5.6 Hz, I H), 8.42 (d,J 1.8 Hz, 1 8.12 (dd, J =1.8 and 8.1 Hz,1I H), 0CH 3 7.68 1 7.41 J 8.1 Hz, 1 6.73 1 5.21 J 120m (H -OH -CO 2 MEM Cfl 3 I 19m G 21 and 6 Hz, 2 3.65 3 H),
CC
3 3.48 (in, 2 3.37 (mn, 2 3.24 3 3.18 Ji 6.5 Hz, 2 H), 1.94 (mn, 1 1.39 9 0.97 J 6.8 Hz, 6 MS 560.5 and 582.4 (M+I (ES-) 558.4 121a -CH 3
-OSO
2
CF
3
-CO
2 MEfM CH3120a B-2 MS (ES 4 644.1 Na) 4
CH,
121b -C 2 11 5 -080 2
CF
3
-CO
2 MEM CH 3 120b B-2 MS 658.2 Na) 4 121c -CH(CH 3 2 -050 2
CF
3
-CO
2 MEM H3120C B-2 MS (ES 4 672.2 Na) 4 Cpd. Starting [Method. Analytical Data No. From
CH
3 011H3 121 d -Cl' 3
-O)SO
2
CF
3
-CO
2 MEM 120d I t 1~ I 121 e cH 3
-OSO
2
CF
3 I -CO 2
MEIM
CHI
OH
3 120e 1.9 Hz, I H1), 9.31 I 8.12 J 1.69 Hz, 1I 7.98 1 7.41 J 8.1 Hz, I 7.19 1 5.20 (in, 2 3.98 (in, 1 3.94 3 3.42 3 H), 3.19 3 2.50 2 1.08 J 6.59, 6 MS (ES+) 608.3 1 1{NMvR (DMSO-d 6 8 8.49 I 8.34 J =1.8 Hz, I 8.2 J 1.8 Hz, I1-H), 7.97 1 H), 7.4 J 7.8 Hz, 1 7.2 1 5.2 J 6 and 10 Hz, 2 H), 4.0 (in, 3 3.6 3 3.4 (in, 4 3.2 3 1.5 (in, 4 H), 1.3 (in, 4 0.85 (in, 6 MS 'HNMR (DMSO-d 6 6 8.83 J =5.46, 1 8.55 J 1.88 Hz, 1 8.23 (dd, J 1.88 Hz, 1 H), 8.19 1 7.73 J =7.93 Hz, 1 7.29 1 5.29 (dd, J 6.217 Hz, 2 4.06 3 H), 3.71 2 3.54 (mn, 5 2.62 J 3.57 Hz, 3 1.66 J 6.59 Hz, 2 1.42 (in, 6 0.99 J 6.79 Hz, 3 MS 636.6 i 1 4- t Cl-I, 121f -CH3 -OSO 2
CF
3 1 -CO 2
MEM
120f 215 Cpd.j -R f -Re -Rf" Satn Method Analytical Data 'H NMR (CDC 3 8 8.43 J 1.9 Hz, 1 8.03 (dd, J= 7.9 Hz, 2.1 Hz, 1 8.00 1 H), 7.3 5 J1=7.9 Hz, 1 6.79 1 2 1g -CHf 3
-OSO
2
CF
3
-CO
2 NEM 120g B-2 (in, 2 5.29 J 6.2 Hz, 1 5.26 J 6.2 Hz, 1 H), 4.16 (in, 2 3.94 3 3.67 3 3.48 (in, 4 3.36 3 MS 646.3 1 HNMR (CDC1 3 8 8.41 I 7.96 J 8.3 Hz, 2 7.8 1m (in, 3 121h -CH 3
-OSO
2
CF
3
-CO
2 MEM 120h B-2 I 3.6 3.9 63)
CH
3 3.4 s, 3 1.7 (in,.2 1.45 (in, 2 H4), 0-98 t, J 7.3 Hz, 3 MS 620 1H NMR (CDC1 3 6 8.41 J 2.1 Hz, I 8.03 (dd, J= 7.9, 1.9 Hz, 1 8.00 1 7.32 J= 7.9 Hz, I 6.43 J 121i -CH 3
-OSO
2
CF
3
-CO
2 MEM 120i B-2 4.9 Hz, 1 5.30 J= 6.0 Hz, 2 3.94 3 3.67 3 H), 3-55 (mn, 2 3.48 (mn, 2 3.35 5 1.09 (in, 11-H), 0.59 (in, 2 0.31 (mn, 2 MS (ES-) 618-4 Cpd. -R -RI -R1' 1Starting Method Analytical Data No. IJFrom-- Used- 'H NMR (CDCI 3 8 8.3 5 J= 1.9 Hz, 1 8.00 (in, 2 7.31 J= 7.9 Hz, 1 6.77 1 H), 121j -en 3
-O)SO
2
CF
3
-CO
2 MEM 120j B-2 6.27 (in, 1 5.28 (in, 2 4.44 J- 7.0 Hz, 1 3.94 3 H), 3.66 3 3.57-3.45 (mn, 4 H), 3.35 3 2.19-1.45 (in, 8 H); MS 65 6.3 Na)+ NIVR (CDC1 3 8 8.3 8 I 8.00 (in, 2 7.31 J 7.9 Hz, 1 6.78 1 6.37 (in, 1 121k -CH 3
-OSO
2
CF
3
-CO
2 MEM 120k B-2 5.27 (in, 2 3.94 3 H),
CIT
3 3.66 31H), 3.59-3.43 (in, 6 H), 3.3 5 3 1.28 J 7.2 Hz, 3 MS 616.3 Na) t 'H N-MR (CDC13): 6 8.3 8 1 C113H), 8.00 (in, 2 7.31 (di, J= 7.9 Hz, 1 6.78 1 6.37 (in, 1 1211 7.CH 3
-OSO
2
CF
3
-CO
2 MEM CH 3 1201 B-2 5.27 (in, 2 HI), 3.94 3 H), 3.66 3 3.57-3.25 (in, 9 H), 1.78-0.92 (in, 9 MS Na)' 21-7 No. -R T R -R Sta' romn Method JAnalytical Data 'HNMIR (DMSO-d 6 6 8.75 J =5.6 Hz, 1 8.45 J 1.8 Hz, 1 8.11 (dd, J 1.8 and 0 CH38.1 Hz, 11-H), 8.04 1 7.57 0 CR 3 1 7.42 J 8.1 H, 1 H), 121m -OSO 2
CF
3
-CO
2 MEM 121m B-2 5.23 J =21 and 6 Hz, 2 H),
C(CH
3 3 CH 3 3.60 3 3.41 (in, 2 3.32 (in, 2 3.17 31H), 3. 13 J Hz, 2 1.87 (in, 1 H), 1.37 9 0.91 J1 6.8 Hz, 6 MS 690.4 CH 3 122a -CH 3
-CH=CH
2
-CO
2 MEM CH3 121a D-3 Characterized in the next step
CR
3 CH 3 122c -C(CH 5 -CHfrCH 2
-CO
2 MEMCH 121c D-3 MS 536.3 (M+Na)+ C 3 122d -CH3 -CH=CH 2
-CO
2 MEM H 121d D-3 MS 550.32M-N~
CH
3 122e -CIT 3
-CH=CH
2
-CO
2 MEM CJ121e D-3 MIS (ES t 564.5 Na)+ 218 Cpd. 1 R -R 1Rf 1R Starting [Method AnltclDt -No. RRRRJFrom- UsedAaltalDa 122f -CH 3
-CB=CH
2
-CO
2 MEM 121f D-3 MS (E-S t 514 .4 (M-I Na) t 122g -Gil 3
-CH=CH
2
-CO
2 MEM l__CF, 121g D-3 Characterized in the next step 122h -GCl 3 -CH CH 2
-CO
2 MEM CH 3 121h D-3 Characterized in the next step 122i -CH 3
-CH-=CH
2
-CO
2 MEM 121i D-3 Characterized in the next step 122j -CH 3
-CH=CH
2 -CO7MEM 121j D-3 MS (ESD: 422.3 122k -Gil 3
-CH'=CH
2
-CO
2 MEM 3 121K MS (FS t 494.2 Na) t MS (ES t 536.42 Na) t I* A- CH 3 CH 3 -Gil 3 1221 -CB=CH2 -C02MEM 1211 Cpd. 1R 111TStarting [Method] No. -R -R R" I ro Usd JAnalytical Data 'HNMR (DMSO-d 6 8 8.73 J ~5.6 Hz, 1 8.43 J =1.8 H~z, 1 14), 8.11 (dd, J 1.8 and 8.1 Hz, 1 7.61 1 7.57 0
CH
3 1 7.42 J 8.1 Hz, 1 H), 6.72 (dd, J3 11 and 17.5 Hz, 1 122m
-CH"'CH
2
-CO
2 MEM CH 3 121m D-3 6.03 J3 17.5 Hz, I H),
C(CH
3 3 5.52 J =11 Hz, 1 5.19 (q, J3=18 and 6llz, 2H), 3.60 3 3.41 (in, 2 3.32 (in, 2 H), 3.18 3 3.13 J 6.5 Hz, 2 1.89 (mn, 1 1.38 9 H), 0.91 J= 6.8 Hz, 6 MS 480.4 fRM-MEM)-1]
CH
3 123a -CH 3
-CH=CH
2 C0 2 H 122a I-1 MS 410.2
CH
3 123b -C 2
H
5
-CH=CH
2 C0 2 H 122b I-1 MS 424.2
CH
3 123c -CH(CH3) 2
-GH=CH
2 C0 2 H C3 122c 1-1 MS 438.2
GH
3 123d -CH 3
-CH=CH
2 C0 2 H KC, 122d I-i MS 396.2 Cpd. 1 -R I R t Starting [Method Analytical Data No. I Used
CH
3 12e -C 3
-CH=CH
2 C021 122c MS 454.3 123f -CH3 -CH=CH 2 C0 2 14 3 122f 1-1 MS (ES 4 426.3 IHNNKR (DMSO): 5 12.37 1 9.35 J= 6.0 Hz, 1 8.42 J- 1.7 Hz, 1 8.10 (dd, J= 8.1 Hz, 1.9 Hz, 1 8.06 1 7.40 J =7.9 Hz, 1 H), 123g -CH 3
-CH=CH
2 CO2H 122g 1-1 6.98 (dd, J= 17.9, 11.5 Hz, 1 H),
F
3 6.77 I 5.89 (dd, J 17.7, 1.3 Hz, 1 5.37 (dd, J =11. 1, 1.3 Hz, 1 4.14 (in, 2 3.84 3 3.61 3 MS 436.3 'HNMR (DMSO): 8 8.66 J= Hz, 1 8.35 J= 1.7 Hz, 1 8.05 1 8.03 (dd, J= 8.1, 1.9 Hz, 1 7.34 J 7.9 Hz, 1iii), 6.98 (dd, J =17.9, 11.3 123h -CH3 -CHCH2 02H122h 1-1 Hz, 1 6.75 1 5.88 (dd, 123h H JC 3 -HC 2 CO 2h 1 =17.7, 1.3, 1H), 5.36 (dd, J=
CH
3 11-3,1.3 Hz, I 3.84 3 H), 3.60 3 3.3 0 J 5.6 Hz, 2 1.52 2H), 1.33 2 0. 96 J =7.3 Hz, 3 MS 410-4 Cpd. -R RR"Starting Method Analytical Data No. From Used 'H NMR (DMSO): 6 12.34 1 8.80 J 6.1 Hz, 1 8.3 7 J 1.9 Hz, 1 8.06 (dd, J= 9. 8, 7.9 Hz, 1 8.05 1 H), 7.36 J= 7.9 Hz, 1 6.98 123i -CH3 -CHCH2 02H122i 1-1 (dd, 17.9,11.3 Hz, 1 6.76 123 -C 3
-H=C
2
C
2 H 221(s, I 5.89 (dd, J=17.9, Hz, 1 5.36 (dd,J= 10.9, Hz, 1 3.84 3 3.60 3 3.18 6.2,2 1.06 (in, 1 0.45 (in, 2 0.25 (in, 2 H); MS 408.4 1 1NMR (DMSO04 6 8 12.31 (br s, 1 8.52 J 7.3 Hz, I 8.34 J 1.7 Hz, 1 H), 8.05 (in, 2 7.34 J= 7.9 Hz, 1 6.97 (dd, J= 11.5 and 123j -CH 3 -CH=C11 2 C0 2 H 122j 1-1 17.9 Hz, 1 6.74 1 5.89 J 17.9 H-z, 1 5.37 J 11.5 Hz, 1 4.27 J= 7.3 Hz, 1 3.84 3 H1), 3.60 3 1.98-1 .50 (mn, 8 MS (ES): 422.3 'H NMR (DMSO-d 6 6 12.27 (br s, 1 8.58 (in, I 8.23 (s, 1 7.92 2 7.47 (in, 1 123 -H 3 -CHCH C 2 H122k 1- 7.22 (in, 1 6.84 (in, 1 H), 12kCH3 3 C=H2 C2 6.63 1 5.76 J= 17.9 Hz, 1 5.24 J= 11.5 Hz, 1 3.71 3 3.47 3 H), 1.0 (In,3_)_MES38.
222 Cpd. -R 1 R Starting Method AnltclDt No. I R R' jFrom UsedAaytclDt 'H NMR (DMS0-l 6 5 12.30 (br s, 1 8.52 J= 6.0 Hz, 1 8.33 J= 1.7 Hz, 1 H),
CH
3 8.02 (mn, 2 7.31 J= 7-9 CH 3 ~Hz, I 6.95 (dd, J=11.5 and 1231 -CH 3
-CH=CH
2 C0 2 H CH 3 1221 I-1 17.9 Hz, 1 6.73 I 5.86 J= 17.9 Hz, 1 5.33 J= 11.5 Hz, 1 3.81 3 3.57 3 3.14 2H1), 1.65 1 1.39 (in, I 1. 11 (in, I H), (mn, 6 H) 123m -CH'=CH 2
-CO
2
H
CE
3
CH~
122m 'ITNMR (DMSO-d 6 512.81 (bs, 1 8.72 I1 5.6 Hz, 1 H), 8.38 J 1 1.8 LIZ, 1 8.08 (dd, J 1.8 and 8.1 Hz, 1 H), 7.61 1 7.57 I 7.39 J 1 8 Hz, I11), 6.72 (dd, 21 11 and 17.5 Hz, I 5.99 J 17.5 Hz, 1 HI), 5.49 J =11 Hz, 1 3.57 3H), 3.13 (t,J Hz, 2 1.87 (in, 1 1.37 9 0.91 21 6.8 Hz, 6 H); MS 480.3 0 "K C(CHA)
NH
0 NH,2
N&-
HHR
CO
Cpd. R r l "starting 1Method A-ualytica1 Data No. -R -RI R From IUsed 124a -CH 3
-CH
3 C,123a j MS 529.3 124b -C 2
H
5 -CIT 3 123b j MS (ES4): 543.3
CH
3 124c -CH(CH 3 )7 -CH 3 123c j MS 557.3
C
3 124d -Gil 3
-CH
3 123d J Characterized in the next step
C
3 12e CH -U 3 123e 3 MS 571.6
CH,
224 Cpd. 1 -R -Rv R" JStarting Method fAnalytical Data No. [-From jUsed 124f -CH 3
CH
3 C, 123f J MS (ES 4 543.6 1 H NR (DMS0): 6 10. 62 1 9.3 5 J 6.6 Hz, 1 9.20 2 8.90 211), 8.30 J= CF3 ~1.9 Hz, 111), 8.11 (dd, J= 8.1, 1.9 Hz, I1H), 7.86 124g -CH 3
-CH
3
C
3 123g J 1 7.76 4 7.50 J 8.1 Hz, I H), 7.04 (dd, J= 17.9, 11.5 Hz, 1 6.94 1 H), 6. 01 (dd, J 17.7, 1.3, 1 5.42 (dd, J 11.3, 1.3 Hz, 1 H) ,4.11 (in, 2 3.89 311), 3.57 3 H) 1 HNMR (DMSO): 8 9.03 (broad, 3 8.49 (broad, 1 8.04 I H1), 7.65 (in, 6 6.99 (in, 14 C3 -CH 3 GB"- C 3 123h 1 2 6.61 1 HM, 5.90 17.5 Hz, 1 5.35 124h -CH 3 11.5 Hz, I 3.78 311), 3.20 (in, 2 H), 1.46 (in, 2 1.28 (in, 2 0.87 J= 7.3 Hz, 3
H)
124i -C3 CH 3 123i 3 MIS (ES 4 527.4 124j -CIT 3
-CH
3 123j 3 MS 541.4 124k -CH 3
-CH
3
'CH
3 123K 3 MS (ES 4 501.3
CH
3 1241 -CH 3
-CH
3 CH, 1231 1 MS (ES 4 543.3 225 Cpd. -R -R R Starting Method Analytical Data No. jJFrom Used 'HNMIR (DMSO-d 6 8 10.67 IH), 9.19 (bs, 2 8.88 (bs, 2 8.71 J 5.6 Hz, 1 8.25 J =1.8 Hz, 1 8.07 (dd, J =1.8 and 8.1 Hz, 1 124m -C3CH 7.73 (in, 4 7.65 I 7.50 J 8 Hz, 02n CH, 312m i IH), 7.45 1 H,}6-73(dd, J 11 andl17.51Hz, 1 6.03 3 =17.5 Hz, 1 5.49 J II1 Hz, 1 CH 3 3.56 3 3.09 IJ=6.5 Hz, 2 1.85 (in,
C(CH
3 )A 1 1.37 9 0.89 J 6.8 Hz, 6 MS 597.3 and 599.5 1 JpNMfl (DMS0): 6 13.40 (bs, 111), 9.26 and 9.03 CH 3 (2s, 4H), 8.53-8.49 J 6 Hz, 1H), 8.02 (d, J='1.28 Hz, 1H), 7.71-7.53 (in, 6H), 7.0-6.9 (in, 125a -CH 3 -H CH3 124a 1-2 2H1), 6.5 111), 5.89 J1I7.6 Hz, 11H), 5.3 3 (d,
CH
3 Jf12.4 Hz, 111), 3.77 3H), 3.04-2.99 (in, 2H), 1.85-1.75 (in, 111), 0.86-0.84 J='76.8 Hz, 611); MS 515.3 'HNMR (DMSO):. 5 9.17 and 8.92 3H), 8.67- 8.63 (mn, 1H), 8.28 lH), 7.95-7.93 (in, 111), 7.83 CH 3 1H1), 7.73 5H), 7.29 J=8.1 Hz, 1H1), 7.02 125b -C 2 H -H124h 1-2 (dd, J=17.7 Hz, 11.3 Hz, In), 6.82 IH), 6.00 (d, 12be2H Hn- H 3 12b 12 17.7 Hz, 1H1), 5.38 11.3 Hz, IH), 4.14-4.06 (in, 2H1), 3.11-3.04 1=6.8 Hz, 2H), 1.89-1.80 (mn, 111), 1.35 J=6.8 Hz, 3H), 0.88 J=6.8 Hz, 611); MS 529.2 HBNVM (DMSO): 8 13.74 111), 8.99 311),
CH
3 8.59-8.41 (in, 111), 7.95 111), 7.69 111), 7.65- 7.53 (in, 611), 7.06-6.91 (in, 211), 6.53 1M1, 5.89 .125c -CH(CH 3 2 -H 124c 1-2 J=17.7 Hz, 111), 5.32 J=1 1.5 Hz, 1H), 4.62- CH 3 4.54 (mn, 111), 3.03-2.99 (mn, 1.87-1.71 (mn, in), 1.25 J=6.1 Hz, 6H), 0.85 J6.8 Hz, MS 541.2 Cpd. -RStarting Method Analytical Data 'HNMR (DMSO-d 6 6 8.9 J 33.74, 4 H), CH 3 8.08 J 7.9 1, 1 7.81 1 7.51 I H), 125d -CH 3 -H 124d 1-2 7.41 4 6.78 1 6.3 2 5.70 J 7.78 Hz, 1 5.15 J= 11.8 Hz, 3.82 (m, CH 3 J 20.34 Hz, 2 3.56 (bs, 3 H) 0.92 6H); MS 501.3 1 HNMR (DMSO-d 6 6 9.05 2 8.85 2 H), 7.96 J =9.04 Hz, 1 7.88 1 6,86 (in, J CHI 17.8 Hz, 3 7.62 (mn, 1 7.24 J 7.8 Hz, 125e -CH 3 -H 124e 1-.2 1 6.95 J 7.8 Hz, 1 7.45 (in, J 28.63 CHHz, 5 7.55 1 5.75 J 17.5 Hz, 1 H);
CH
3 5.61 J= 11. 11, 1 H) 3,61 311) 1.30 (bs, 3 H) 1.05 4 H) 0.66 (in, 6 MS (ES+i) 555.3(100% Me) 'H NMIR (DMSO-d 6 6 12.7 (bs, 1 9. 01 (bs, 2H), 8.87 (bs, 2H1), 8.36 J 6 Hz, 1H), 7.83 (s, 125f -CHr 3
CH-
3 124f 1-2 1H), 7.44 (in, 611), 6.75 (in, 2H), 6.31 J =2.2 Hz, 1H), 5.7 J =17 Hz, 1H), 5.1 J =11 Hz, 1H), 3.5 3H), 2.84 (mn, 2H), 1.3 (mn, 2H1), 1.1 (mn, 4H4), 0.7 (mn, 3H); MS 529.4 1 HNMR (DMS0): 5 9.22 (broad, 1 9.09 2 8.9 2 HI), 8.18 I 7.80 (in, 2 7.66 12g CI 3 H124g 1-2 (in, 4 7.16 I 7.00 (dd, J= 17.7, 11.1 Hz, 125g CH3 H CF31 6.70 1 5.94 J =17.7 Hz, 1 5.37 J= 10.9 Hz, 1 4.07 (mn, 2 3.81 3 H); MS(ES-)_539.3 227 Nod. -R jR R" StFromng Method Analytical Data 'H NMR (DMSO): 6 9.03 bs, 4 8.49 (bs, 1 8.04 1 7.65 (mn-6 6.99 (in, 2 H), 125h -CIT 3 -H C 3 124h 1-2 6.61 11H), 5.90 J 17.5 Hz, 11H), 5.35 J S11.5 Hz, 1 3.78 3 3.20 (in, 2 1.46 (in, 2 1.28 (in, 2 0.87 J= 7.3 Hz, 3 H); 515.4 1H NMR (DMSO): 8 8.86 2 8.7 8 2 H), 8.44 (broad, 1 7.89 11-H), 7.53 (in, 2 H), 7.43 (in, 4 6.86 1 6.78 (dd, J= 17.5, 125i -CIT 3 -H 124i 1-2 11.3 Hz, 1 6.44 I 5.71 J =17.5 Hz, 1 5. 14 J= 11.1 Hz, 1 3.59 3 2.89 (in, 2H), 0.79 (mn, 1 0.20 (mn, 2 0.01 (mn, 2 MS (ES- 513.4 1 INM\R (DMSO): 8 13.14 (hr s, 1 8.84 3 8.12 J= 7.3 Hz, 1 7.79 1 7.40 1241 1-2 (in, 9 6.74 (in, 2 6.33 1 5.66 J 1251 -IT 3 -H 19.2 Hz, I 5. 10 J 11.7 Hz, 1 3.94 (mn, 1 3.54 3 1.66-0.93 (in, 8 MIS (ES) 'H NMR (DMS0): 869.25 (mn,4 8.73 J 5.7 Hz, 1 8.28 I 7.86 (in, 7 6.84 (s, 125k -CH 3 -H 124k 1-2 1 6. 10 J= 17.7 Hz, 1 5.55 J= 11.3
CH
2 Hz, 1 3.99 3 3.43 (qui, J 6.2 Hz, 2 IT), J= 7.2 Hz, 3 MS 487.2 'H NMR (DMSO): 5 8.91 (in, 41H), 8.38 J 5.5 Hz, CH3 I 7.96 I 7.53 (in1, 5 6.86 (in, 2 B1), 6.52 1251 -CH 3 -H 1241 1-2 I 5.77 J= 17.7 Hz, 1 5.21 (d,J 11.5 CH, Hz, I 3.65 3 2.94 (in, I 1.57-0.56 (in, 11I MS 529.3 228 Starting Mto Method Used Analytical Data 'IMR (DMSO-d 6 8 10.07 (bs, IH), 9.05 (bs, 2 8.98 (bs, 2 8.49 J =5.6 Hz, 1 7.96 (s,
CH
3 1 7.62 (in, 5 7.06 I 7.03 I H), 124m 1-2 6.94 (dd, J=I1I and18 Hz, 1 5.78 J=18
CH
3 Hz, 1 5.26 J =11 IHz, 1 3.02 J =5.7 Hz, 2 1.81 (in, 1 0.85 J =6.8 Hz, 6 H); 499.2 and 501.3 229 0R
R'
2 0 Cpd. -R -R -R Starting Method AnltclDt No. J R -R From UsedAaltclaa
H
X-x N 133a -N N -CH 3 132 A-5 MS 506.4
N
133b N"Ii -H -CH 3 132 3 MS 499.3 133c N H -CI4 3 132 A-5 Characterized in the next step
H
CF
3 13d NqF H -H312 A- hrctrzd ntenetse 133e CF -H -CIT 3 132 A-S Characterized in the next step
H
230 Cpd.
No.
Starting From Method Used Analytical Data
CF,
133f \6 -H -GCl 3 132 A-5 Characterized in the next step
H
CF
3 133g H -GCl 3 132 A-5 Characterized in the next step
N
F
133hi H -GCl 3 132 A-5 Characterized in the next step 133i -N 0 -H -CH 3 132 A- 5 Characterized in the next step 133j /H -H -CH 3 132 A-5 Characterized in the next step
N
N
133k N N4 -H -CH 3 132 J MS 502.3
N
Cpd. -R -R"T Starting MehdAnalytical Data 1331 H H-H -CR 3 132 J MS (ES 4 470.2 /N-d 133m -N -H -CH 3 132 J MS 437.3 H 133n -H -CR 3 132 .T MS (ES 4 518.2 133o -N N -H -CR 3 132 J MS (ES 4 501.3
H
N
13p -H -CR 3 132 1 MS 469.1
H
N
H
133q N -H -R 3 S 469. 1; MS (S':471.2 13q_ C3 3 S(ES):(S) 133r -CR 3 132 A-5 Characterized ini the next step
H
232 Cpd.
No.
Starting From Method UsedI Analytical Data
OH
H33/ -H -CIT 3 132 A-5 MS 483.2 (M+Na)
N-
H
H3u /N0 H -C312 A5 M (ES):43- 133,v N -H -CIT 3 132 A-S MS (S).432.2
H/\
133w /NP -H -CIT 3 132 A-5 MS 432.2 133x -H -CH 3 132 A-5 MSratrie in~) 447.2 t te
HO
N
13yN -C -H -CIT 3 132 A-5 MS 446.3
H
133z
N
H
-CIT
3 MS 446.2 Cpd. IR1-R Starting MethodAaltalDa No. R! Fromj UsedAnltclDa 133aa N -H -CH 3 132 A-4 M(E+:475.3 133ab O -H -CH 3 132 f MS 499.3 (M+Na) HIL :oil
N
li33ac N -H -CH 3 132 A-4 MS 483.2; MIS 485.2
H
3
C
133ad N -N -H -CH 3 132 A-4 MIS 497.2; MS 495.2
H
133ae H -CH 3 132 A-4 MS 483.2; MS 485.2 N N 133af
H/
N Ac -CH3 133af-CENIS 511.3 (M+Na) t MIS 487.3 Cpd.
-WI
Starting Method Used Analytical Data No.
I -Rvt From 133ag
H
N -q OH N NHBoc
-H
-H
-CH
3 MS 451.3 1- -4- 133ai
-CH
3 132 133a MS (ES-D: 584.4 134a -N
N\\
N
'UNMR (DMSO-d 6 5 13.13 (bs, 11H), 8.76 J =6 and 5 Hz, I 8.32 (in, 2 11), 8.02 (dd, J 1-2 1.9 and 8.1 Hz, 1 7.42 (in, 4 7.25 (in, 1 3.62-3.19 12 3.11 J 6.8 Hz, 2 H), 1.87 (in, 11H), 1.76 (in, 2 0.90 J 6.8 Hz, 611); MS 490.3; (ES-I) 492.3 4- 4 4- .4 I- 134b~
N\
HH
HH
CF
3 133b 133c (bs, 2 8.50 J 6 and 5 Hz, 1 7.99 J Hz, 1 7.83 1 7.8 1 11), 7.59 (in, 4 7.46 (in, 2 7.03 (in, 1 6.92 J =7.9 Hz, 1 3.89 4 3.02 J 6.8 Hz, 2 H4), 1.81 (mn, 1 0. 8 J 6. 8 Hz, 6 H);MS 483.3; MIS 485.4 134c 'I{NMR (DMSO-d 6 5 8.71-(t, J=5.5 Hz, 1 H), 8.40 J-=5.3 Hz, 111), 8.30 I 9.00(d, J= T.8 Hz, 1 7.63 J=z43 H-z, 2 7.40 (d, J=7.4 Hz, 4 HM, 7.27(d, J='8.1 Hz, 1 7.18 1 6.91 J=7.1 Hz, 1 4.42 211), 3.13 (t, J Hz, 2 1.93 (in, 1 0.91 J 6.8 Hz, 6 MS 497.3 235 Cpd.
No.
Starting From Method Used Analytical Data 1 HfNMIR (DMSO-d 6 8 10.45 1 8.63 I H3d N F 8.27 1 7.93 J=8.IHz, 1 7.67 (t, 13d ,N 3 -H4 7133d 1-2 J=6.8 Hz, 2 7.55 (in, 2 7.27 (m 3 7.12 (in, 21H), 3.06 J 6 H-z, 21H), 1. 82 (in, I H), 0-86 J 6.8 Hz, 6 H1); MS(ES-) 483.3 'HNMRp (DMSO-d 6 8 12.92 (bs, 1 8.71 (t, 1=5.8Hz, 1 8.49(t, J=6.2 Hz, 1 8.32 1 CF 1H), 8.01 1= 7.8 Hz, I 7.52 (in, 5 7.27 134e ~N -H -H 133e 1-2 J=~7.9 Hz, 1 7.18 (mn, 1 7.08 J=8.2 H Hz, 211), 4.32 J=4.2 Hz, 2 3.12 J Hz, 2H), 1.88 (m,1IHf), 0.91 (d,J =6.8 Hz, 6 MS(ES-) 498.2 CF 3 'HNMR (DMSO-d 6 6 8.66 J=5.7 Hz, 1 H), 8.27 1 7.92 J=8.1 Hz, 1 7.45 (in, 7 134f 133f 1-2 7. 18 3H), 4.32 (d,J=5 -9 Hz, 2H), 3.12 J =6 Hz, 2 1.89 (in, 1 0.91 J 6.8 H Hz, 6 MS(ES-) 497.2
CF
3 'HINMR (DMSO-d 6 8 13.1 1 Hf), 9.58 (,1 8.65 1 8.29 I 7.98 J=5.9Hz, 134g -H 133g 1-2 1 7.75 J=5.2 Hz, 2 7.30 J=9 Hz, 2 N 7.12 1k12.0 Hz, I 7.12 (in, 4 3.06 J =6 Hz, 2 1.85 (in, 1 0.86 J 6.8 Hz, 6 MS 483.2 'HNMR (DMSO-d 6 5 10.31 I 8.65 (t, F J=6.2 Hz, 1 8.31 1 7.98 J= 7.9 Hz, 134h H -H -H 133ha 1-2 1 7.66 (in, 1 7.53 (in, 3 7.27 (in, 4 H), N 6.85 (in, 1 3.09 J 6.5 Hz, 2 1.86 (in, I1 0.89 J1=6.8HI-z, 611); MS (ES-) 236 Cpd. -R F R' 1-R" Starting 1Method FAnalytical Data No. [From jUsed 'HNMR (DMSO-d,): 6 8.71 J=5.7 Hz, I H), 8.31 1 8.01 f= 7.9 Hz, 1 7.46 (in, 2 134i -H -H 1331 1-2 7.39 (in, 2 7.24 I 3.38 8 H), 3.11 J 6.5 Hz, 2 1.86 (in, 1 0.91(d, J 6.8 Hz, 6 MS(BS-) 409.3 F 'HNMR (DMSO-d 6 6 9.61 1 8.67 (t, Hz, 1 8.32 1 7.98 J= 7.9 Hz, H \1 7.71 2 7.54 (mn, 2 7.29 J=7.9 134 -H 13 12 Hz, 1 HM, 7.04 (mn, 411M, 3.10 fJ 6.5 Hz, 2 H), 1.86 (in, 1 0.89 J =6.8 Hz, 6 MS (ES- 433.3 1 BNMR (DMSO-d 6 5 8.59 J 6 and 5 Hz, 1 N 8.3 f 5 Hz, 2 8.18 1 7.86 J 134k -N-11 -I-I 133k 1-2 8 Hz, 1 7.36 (mn, 5 6.6 J 4.7 Hz, 1 4.0 (mn, I 3.75 (mn,2H), 3.37 N 30 t z .1(,IH,08 d 6.8 Hz, 6 H) 'HN MR (DMSO-d 6 6 10.92 (bs, 1 8.55 f =6 and 5 Hz, I 8.14 I 7.76 f 7 Hz, 11-1), 7.68 (in, 1 7.62 (in, 1 7.45 (in, 1341 -H -H 1331 1-2 21H), 7.24 fJ=2.61Hz, I 7.19 1 7.15 H I 7. 10 (mn, 2 6.95 (dd, J 1.5 and 8.7 N-d Hz, 1 6.28 1 3.04 J 6.8 Hz, 2 H), 1.82 (in, 1 0.86 J 6.8 Hz, 6 MS (ES- 454.3; (ESH-) 456.3 'HNMP. (DMSO-d 6 6 13.30 (bs, 1 8.62 J 6 and 5 Hz, 1 8.18 I 7.87 f 7.9.
134m H -H -H 133m 1-2 Hz, 1 7.42 (in, 3 7.09 (mn, 2 3.03 (in, N 0 1 3.1 J 6.8 Hz, 2 1.86 (in, 1 1.4 (mn, 4 1.09 (in, 1 0.89 J =6.8 Hz, 6 H); 421.2; 423.2 Cpd. 1-R f -R T Starting 1Method TAnalytical Data No. From Usedj 1 1TNMR1 (DMSO-dj): 6 15.89 (bs, 1 8.56 J N a 6 and 5 Hz, 1 8.06 1 7.67 (in, 2 H), -H 3n 12 7.54 J 8.8 Hz, 1 7.48 (in, 4 7.05 (in, 134n N H 13n -2 11-1), 6.96 (in, 2 3.77 3 3.03 J 6.8 S OMe Hz, 2 1.81 (in, 1 0.84 J =6.8 Hz, 6 MS 502.3; 504.3 'HN1VR (DMS0-l 6 8 13.07 (bs, 1 8.63 J 6 and 5 Hz, 1 8.26 1 8.05 3 4 N- Hz, 1 7.94 J3 8 Hz, 1 7.43 (in, 5 H), 134o -N N- -H -H 133o 1-2 7.28 (in, 1 6.72 J 8.8 Hz, 1 6.62 (dd, J 5.5 and 6.5 Hz, 1 3.34 (mn, 8 3.07 J 6.8 Hz, 2 1.82 (in, 1 0.85 J 6.8 6 H-1; MS 486.3; 488.3 1 IINMR (DMSO-d 6 6 12.94 (bs, 1 10.20 (bs, 1 8.63 f1 6 and 5 Hz, 1 8.28 J Hz, I 7.96 (in, 2 7.92 J =8.3 134p /N -H -H 133p 1-2 Hz, 1 7.68 (in, 1 14), 7.52 (mn, 2 7.4 (in, I jN 7.3 (in, 2 7.24 (mn, 1 3.08 J 6.8 H Hz, 2 1.84 (mn, 1 0.88 J3 6.8 Hz, 6 MS 455.2; 479.2 (M+Na) 134q
H-
N N 133q 'HNMR (DMSO-d 6 6 12.84 (bs, I 10.45 (bs, 1 8.62 J 6 and 5 Hz, 1 8.27 I ,1.5 HL, 1 8.01 1 7.93 2 7.9 J 1.5 Hz, 1 7.69 (mn, 1 7.57 J3 8.7 Hz, I 7.52 (in, 2 H1), 7.29 J 8 Hz; I 7.23 (mn, 1 7.02 (dd, f 1.5 and 8.7 Hz, 1 3.07 J 6.8 Hz, 2 1.83 (mn, 1 0.87 J 6.8 Hz, 6 MS 455.2; (ES+) 479.3 (M+Na) 238 Cpd.
Na- Starting Method From Used Analytical Data 'HNMR (DMSO-d 6 5 8.64 J=5.5 Hz, 1 H), 8.16 11H), 7.87 J=7-1 Hz, 1H), 7.50 (in, 1 134r H -H 133r 1-2 7.40 J=4.1 Hz, 21), 719 3 7.07 H 3.97 1=5.6 Hz, 211), 3.13 3 =6.5 Hz, 211), (mn, 1 0.91 J 6.8 Hz, 6 H) OH 1 J{N3\4 (DMSO-d 6 6 9.53 (bs, I 11), 8.67 (t, J=4.7 Hz, 1 8.32 1 7.99 d, 1=8.1 Hz, I 1 34s -H -H 133s 1-2 7.70 J=7.6 Hz, I H1), 7.52 (in, 2 7.46 H J=1 1.5 Hz, 1 7.32 (in, 3 7.18 (mn, 3 H), N 4.33 2 3.10 J 6.5 Hz, 211), 1.86 (mn, 1 0. 89 J 6.8 Hz, 611); MS 445.2 'HNMRp (DMSO-d 6 8 12.57 1 8.69 (t, J-5.6 Hz, I 8.36 I 7.99 1= 7.9 Hz, 1 7.92 J=7.7 Hz, 1 7.57(t, 1=7.5 Hz, 134t -OH -H -H 132 1-2 111), 7.46 J=7.7 Hz, 111), 7.23 J=5.2 Hz, 1H1), 7.17 (di, J-7.5 Hz, 111), 3.12 J 6.5 Hz, 2 1.88 (in, 1 0.91 J 6.8 Hz, 6 MS 340.2 1 HNMR (DMSO-d 6 5 8.56 J=5.0 Hz, I H), 8.16 1=7.0 Hz, 2 7.94 J=8S.4 Hz, 1 H), 134u -H -H 133u 1-2 7.75 J=7.4 Hz, 1 7.63 (mn, 211), 7.46 (mn, 2 Hi 7.21 1 7.07 2 6.99 J=5.1 Hz, IN-O 11H), 3.05 (t,1J=6.5 Hz, 2 1.83 (in, 1 H), J 6.8 Hz, 611); MS _416.3 1 IINMVR (DMSO-d 6 6 8.60 J=5.6 Hz, 1 H), 8.32 J=5.3 Hz, 211), 8.1 1(s, I 7.78 (d, 134v /H -H -H 133,v 1-2 J=7.7 H-z, I 7.65 3=5.5 Hz, I 7.55 (MI, H 2 7.43 J=4.5 Hz, 2 7.14 (mn, 3 3.06 N N J =6.5 Hz, 211), 1.83 (mn, 1 0.86 J Hz, 6 MS 416.2 Cpd. -R -R JStarting 1 Method[AnltclDa No. From jUsedAnltclDa 'HNMv~R (DMSO-d,): 8 10.10 (bs, 1 9,31 1 8.65 J=5.7 Hz, 1 8.27 1 7.93 (d, H J=8.1 Hz, 1 7.62 J=5.3 Hz, 1 7.48 (in, 13wN H 13w -2 2 7.28(s, 1 7.20 J=12-0 Hz, 1 7.09 134w/ H -H 133w 1-2 1 6.98 J=7.0 Hz, 1 6.81 J=7.3 OH Hz, 1 6.37 1=7.6 Hz, 1 3.09 J Hz, 2 1.85 (in, 1 0.90(d, J1=6.8 Hz, 6 H); MS 43 1.1 'HNMR QJMSO-d 6 8 10.28 (bs, 1 8.63 (t, 1=5.3 Hz, 11-H), 8.34 1=4.7 Hz, 1 8.06 (s, N 1 7.82 1=6.6 Hz, 1 7.53 (in, I 7.42 134x -H-/33 (mn, 2 7.34 J=8.6 Hz, 1 7.18 1 H), H 13 7.07 1=2.7Hz, 2 6.10 1 4.43 1 H 4.12 1 3.12 J =6.5 Hz, 2 1.89 (in, 1 0.90(d, J 6.8 Hz, 6 MS (ES+) 432.3, 430.2 'HNMR (DMSO-d 6 8 9.79 (bs, 1 8.62 (t, 1=6.0 Hz, 1 8.31 1=4.5 Hz, 1 8.20 (s, /N 1 8.08 1 7.78 1=2.1 Hz, 1 7.51 134 -H -H 133y 1-2 (mn, 1 7.42 (in, 2 7.06 (in, 3 6.88 (in, 1 NI 4.02 2 H4), 3.13 J1=6.5 Hz, 2 1. H (mn, 1 0.93 J 6.8 Hz, 6 MS (ES+) 430.3 134z N -N
H
133z 1 HNIVIR (DMSO-d 6 8 10.71 (bs, 1 8.64 (t, J=5.9 Hz, 1 8.21 1=5.2 Hz, 2 8.05 (s, 1 7.81 J=7.7 Hz, 1 7.51 (in, 1 7.42 (in, 2 7.18 1 7.04 1=1.4Hz, 2 H), 6.51 2H), 4.41 1 4.01 1 3.13 (t, J1 6.5 Hz, 2 1.91 (in, 1 0.91 1 6.8 Hiz, 6 MS 432.2, 430.2 Cpd. Starting Method Anlytical Data No From I Use 1 1flN1vR (DMSO-d,): 6 10.02 (bs, 1 8.65 J -5.7 Hz, 1 8.26(s, 1 7.94(d, J= 7.7 Hz, 1 H 766(d, J=5.8 Hz, I 7.51(m, 21-1), 7.36 (d, N3n H 13a h=8.4 Hz, 2 7.29 J=7.9 H1z, I 7.22 (d, 134a -OH -11 -H 13aa -2 =5.5 Hz, I 7.07(d, J=8.3 Hz, 2 4.57 (t, 3=9.0 Hz, 1 3.51 (in, 211), 3.09 I '6.5 H~z, 2 2.62 1=6.6 Hz, 2 1.85 (in, 1 H), ~0.90(d, J1 6.8 Hz, 6 MS(ES-) 459.2 1 1{NIVR (DMSO-d 6 5 9.05 1 8.70 (t, H 3=5.7 Hz, I 8.56 1 8.36 1 8.12 N OH (mn, 211), 7.79 (in, 1 HE), 7.60 (in, 1 7.44 2 134ab H -H 133ab 1-2 7.09 (mi, 211), 6.56 J='8.9 Hz, I 4.89 OH J=4.4 Hz, 1 4.38 J=5.6 Hz, 211), 3.11 J 6.5 Hz, 2 1.84 (in, 1 0.90 J Hz, 6 MS(ES-) 461.1 1 1{NMRJ (DMSO-d 6 3 8.60 J 6 and 5 Hz, 1 N 8.13 211), 7.85 J1=2 Hz, 11II), 7.46 13ac/-H i3H (in, 4 7.36 J 7.7 Hz, 1 7.16 (in, 411), 134a -H -H 13ac 1-2 7.10 (in, 1 3.17 311), 3.08 J 6.8 Hz, 2 NH), 1. 85 (in, 11H), 0. 89 J =6.8 Hz, 611), MS HC 469.2; 471.3 'HNMR (DMSO-d 6 3 8.55 J1 6 and 5 Hz, 1 H 8. 10 211), 7.73 J 7.2 Hz, 1 7.34 134ad NH -H 133ad 1-2 (mn, 4 7.46 (mn, 5 7.08 (in, 3 3.04 J =6.8 Hz, 2 HM, 1.82 (in, 111), 0.86 J3=6.8 611), MS 48 1. 1; 483.3 241 Cd.
T
Starting Method ad 134ae 134af
H
N
H
133ae Analytical Data 'I3NMR (DMSO-d 6 5 9.66 (bs, 111), 8.54 J 6 and 5 Hz, 1 8.12 2 7.77 (dd, J 8 and 2 Hz, 1 7.6 (dd, J 7 and 2.Hz, I H), 7.45 (in, 5 7.10 (mn, 4 4.36 (bs, 2 3.09 J -6.8 Hz, 2 1.86 (in, 1 0.89 J 6.8 Hz, 6 MS 469.2; 471.3 'HNMR (DMSO-d 6 8 9.76 1 9.17 1 8.63 J=5.0 Hz, I 8.29 I 7.90 (d, J=1.6 Hz, 1 7.60 1 7.51 J=8 Hz 1 7.30 J=3.6 Hz, 2 7.28 J=8.2Hz, 1 7.22 3 6.60 1=8.9 Hz, I 3.06 (t, J 6Hz, 2 1.85 (in, 1 0.86 J 6.8 Hz, 6 1f); MS 431.2 L I I. 4 I- N OH 133af 'HNMR (DMSO-d,): 5 9.64 1 9.06 1 8.66 f=5.6 Hz, 1 8.29 1 7.95 (d, H J=7.9 Hz, 1 7.63 (in, 11-I), 7.50 (mn, 2 H), 134ag N OH -H -H 133ag 1-2 7.29 J=3.1 Hz, 1 7.20 J'=8.9 Hz, I H), 7,11 (in, 1 7.03 (in, 1 6.60 1=8-9 Hz, 1 CHI 3.08 J 6 Hz, 2 2.05 3 1.85 (in, 1 0.86 J 6.8 Hz, 6 MS 445.2, 469.3 (M±Na) N Na -H -H 133ai 1-2, S MS 472.2; MS 470.2 N NH 2 135a
H
-CH=CH
2 IMS 489.3 242 Cpd. 1 r- 1 1starting ehd]Analytical Data No.] R -R From Used
H
N
135b -CH=C11 2
-CH
3 30f A-4 MS 475.3; MS 473.3 N N
H
135c
N
13c NiBoc -CH-CH 2
-CH
3 30f J MS 573.5; MS 571.3 H k 135d 7 N- -NH, -CH=CH 2
-CH
3 30f A-4 MS 472.2
N
Cl 135e H \-CH=CH 2
-GB
3 30f J MS 489.1 0 135f N -CH'CH 2
-CH
3 30f I MS 498.1 135g N CH 2 CN -CH"'C 2
-CIT
3 30f J MS 494.3 135h JMIJ CH- 2 NHBoc -CH=CH 2
-GB
3 30f J MS 584.2 243 Cpd. -R 1 Starting [Method JAnalytical Data No. Used 'HNMR (DMSO-d 6 6 8.66 J .55 Hz, 1 H), 8.35 J =4 and 6.4 Hz,1I 8.28 J 2 Hz, 1 7.95 (dd, J 7.9 and 2 Hz, 1 7.69 1 7.59 (in, 2 7.25 J 8 .1I Hz, 2 7.15 N N N (in, 2 6.93 1 6.88 (dd, J 17.7 and 136a -CHCH2 135 1-2 11.5 Hz, 1 5.95 J 17.7 Hz, 1 5.37 (d, J 11.5 Hz, I 3.76 J 6.8 Hz, 2 3.10 J 6.4 Hz, 2 2.96 (in, 2 1.86 (in, 1 H), 1.67 (in, 2 0.89 J 6,8 Hz, 6 MS 473.3; (ESI- 475.3 'HNMR (DMSO-d 6 8 8.64 1 8.51 1 H 8.21(s, 1 7.88 J=~7.8 Hz, 1 7.74 (s, N 1 7.56 2 7.15 (in, 2 6.80 2 H), 136b I -CH=CH 2 -B 135b 1-2 5.90 J 17 Hz, 1 5.36 1=11.0Hz, 1 H), N N3.18 (in, 2 3.06 6 Hz, 21-1), 2.43 (in, 2 H 1.85 (in, I 0.86 J 6.8 Hz, 6 MS (ES-f) 461.2, MS 459.2 'ITNMR (DMSO-dd/D 2 5 8.71 1 8.27 1= 3 Hz, 1 8.21(d, J=3 Hz, 1 7.96 1 N 7.79 1 7.72 1 7.63 J='8 Hz I 136c N NH 2
-CH=CH
2 -H 135c 1-2,85 7.30 1=6 Hz, 1 7.24 1=7 Hz, 1 H), 6.87 2 6.00 J=8 Hz, I 5.41 J"8 Hz, 1 3.06 1 6 Hz, 2 1.85 (in, 1 H), 0.86 J 6.8 Hz, 6 MS 459.2 Cpd.
INo.
Starting Method From Used Analytical Data 'HNMR (DMSO-d 6 5 12.86 (bs, I 9.17 1 8.65 J 6 Hz, 11H), 8.29 J 2 Hz, 1 8.26 2 7.97 (dd, J =8 and 2 Hz, 1 H), N 7.76 I 7.63 8 Hz, 1 7.31 J =8 136d H C \N H -CH=CH 2 -H 135d 1-2 Hz, 1 7.24 J 8 Hz, I 6.86 (dd, J1 N -NH10.7 and 17.5 Hz, I 6.49 1 5.99 J N 17.5, 1 5.40 J 10.7 Hz, I 3. 10 21= 6.8 Hz, 2 1.86 (in, 1 0.89 J 6.8 Hz, 6 MS 458.2, 460-3 }TNMVR (DMSO0-d 6 5 12.72 broad, 1 H), 8.65(t, J' 5.7 Hz, 1 8.29 1 W, 7.93 (d, J=7.9 Hz, 1 7.74 (mn, 2 7.65 1=6 Hz I 136e H CH=CH 2 -H 135e 1-2 7.42 J=7.9 Hz, I 7.24 (mn, 3 7.11 N (in, 1 6.84 1= 1. 1, 17.8 Hz, 1 5.97 (d, J=18 Hz, 1 5.58 1 5.41 I 3.08 (t J =6 Hz, 2 1.85 (in, 1 0.86 J1 6.8 Hz, 6 MS 475.1 136f 0
NH,
-CH=CH
2 135f 'ITNMvR (DMSO-d 6 6 8.67 iz, 111), 8.28 I 7.90 2=7.7Hz, 1 7.67 (mn, 4 7.32 (in, 5 7.09 2=7.9 Hz 1 6.89 2h10.9 18.0 Hz, 1 5.99 J=17.5Hz, 1 5.42 J=11I Hz, I 3.08.(t, J=6.3 Hz, 2 1.88 (in, 1 0.87 J21 6.8 H4z, 6 MS 484.2 245 1 1Starting Method -R From JUsed Analytical Data IjTNMR (DMSO-d,): 8 10.38 1 H,8.66 (t, J=6.06 Hz, I1-H), 8.29 1 7.95 J=6.1 Hz, I 7.75 1 7.63 2 H1), 7.43 2 H), H -CH'CH 2 -H 1 3 5g 1-2 7.26 (in, 3 7.00 J=7.7 Hz, 1 6.85 (q, H CHC J=10.9 18.0 Hz, I 5.98 J=17.5Hz, 1 H), CHCN5.40 J=1 I Hz, I 3.98 2 3.08 (t, J=6.3 Hz, 2 1.86 (mn, 1 0.88 (di, J3 6.8 6 MS 480.2 'HNMR (DMSO-d 6 5 8.5 5 J=6.06 H-z, 1 H), 8.02 1 7.60(mf, 4H), 7.21 J=7.1, 2 H), 6.99(m, 2 6,83 J 6.8 Hz, 1H), 6.81 (q, N 0 CH 2 NH1 2
-CH=CH
2 -H 135h S,1-2 J=10.9 13.0 Hz, 111), 5.92 J'47.5Hz, 1 H), 5.35 J1=11 Hz, 1 3.89 2H), 3.03 (t, 1=6.3 Hz, 2 1.36 (in, I 0.86 J =6.8 Hz, 6 H) Cpd.
Nn
-R
Starting Method Fr 148a 0
S
-CH
3 0 CH, NA -CH,
H
147a 1 4 4 Analytical Data 'H NMVR (DMSO-d 6 10. 65 I 10.15 I H), 9.19 2 8.88 2 8-10 J= 2.1 Hz, 1 H), 7.92 I1-H), 7.93-7.75 (in, 6 7.31 (dd, J= 8.4 and 23.9 Hz, I 7.12 J= 3.5 Hz, 1 6.67 (in, 1 H), 3.53 3 2.20 J= 7T0 Hz, 2 2.07 (in, 1 H), 0.94 J= 6.3 Hz, 6 H).
'H NMR (DMSO-d 6 5 10.65 1 10.09 1 9.17 I 8.83 I 8. 10 J 2.0 Hz, 1 7.85 J =2.0 Hz, 2 7.81 J 2.0 and 7.9 Hz, 2 7.76 (mn, 5 7.66 J 3.9 Hz, 1 7.62 J =4.9 Hz, 1 7.31 (d,J 7.9 Hz, 1 7.26 (d, J 7.9 Hz, 1 7.19 J= 3.9 Hz, 1 3.53 1 2.19 J= 6.9 Hz, 2 2.06 (in, J= 6.9 Hz, I 0.92 J= 6.9 Hz, 6 MS(ES-): 555.6 7 Characterized in the next step 0 CH 3 N CH 3
H
148b 147b 4 I 4 1- I 148c -CH=CH 2
-CH
3 0 CH, 3 N 01 147c 2 2.47 Cpd. -R RI J Starting JMethod Analytical Data No. I From Used o CH 3 149a -H 148a 1-2 MS 525.3 0
NCH
3 1 H NMR (DMSO)-d 6 8 13.95 1 9.79 I H), o CH, 8.87 4 7.76 1 7.65 (in, 8 7.46 (dd, J=~ -H 48b 1-2 2.1 and 8.4 Hz, I 7.16 J= 4.2 Hz, I 7.04 (d, 140b -H Nj C14 48 3 J= 7.7 Hz, 1 6.76 J= 8.4 Hz, 1 2.13 J= H 7.0 Hz, 2 2.03 (in, J= 6.3 and 7.0 Hz, I 0.90 (dJ= .3 z,6 MS 541.62 o CH 3 149c -CH=CH, -H ~N CH 148c 1-2 MS 485.6
H
'H INR (DMSO-d 6 6 8.81 (in, 4 8.37 J= 175 -H -CH 3 N7 jM Hz, 1 7.74-7.23 (mn, I I 4.31 J =6.2 Hz, 2 H H,3.51 2.44 (in, 1 1.04 J =7.0 Hz, 6 CH, H4); MS (ES 4 473.3 0 'H NMR (DMSO-d 6 6 13.79 (br s, 1 9.03 (in, 3 16 -H -H NC 3 175 12 8.25 (in, I 7.78-7.35 (in, 7 6.99 (mn, 2 H), 176H 6.79 (mn, I 4.20 (br s, 2 3.51 3 2.39 (mn, CH, 1 1.00 J= 6.8 Hz, 6 MS (ES 4 459.3 CH 3 'H N-MR (.DMSO-d 6 8 8.96 (in, 2 7.79-7.38 (mn, 182 -H -GCl 3 N178 1 9 7.29 (dd, J= 7.5 and 1.7 Hz, 2 4.42 2 H), I CHi, 3.50 3 2.97 2 1.87 (in, 1 1.36 (mn, 9 Boc 0.81 J= 6.8 Hz, 6 MS (ES54): 559.5 Cpd- -R -RW Startingj Method Analytical Data No. _J om se
GH
3 I-i
CH,
1-2, S 7.66 (in, 5 7-49 (in, 2 7.38 (in, 1 7.08 (in, 2 4.12 2 2.59 (in, 2 1.87 (in, 1 0.81 (d, J= 6.6 Hz, 6 MS 445.32 3 2 0 Cpd.
No.
N (in Ring with Respect to Starting From Method Used Analytical Data 151 3 -CHO -CH 3 15+ D-9 MS 33.
1 NMR (CDCI 3 8 8.69 J~ 5.8 Hz, 1 H), 8.50 J= 4.9 Hz, 1 8.33 J= 1.7Hz, I 152 3 -CO 2 H -CH, 151 1 E 8.24 1 8.01 (dd, J= 7.9, 1.9 Hz, 1 H), 7.53 J= 5.1 Hz, I 7.34 J= 8.1 Hz, I 3.56 3 3.12 (in, 2 1.87 (in, 1 H), J =6.6 Hz, 6H) NHi 0 NH,
AN&
H
1 H NMR (CD 3 0D): 5 8.75 J 4.7 Hz, 2 H), 8.55 1 8.42 J= 1.9 Hz, 1 8.07 (dd, J 8.1, 1.9, 1 7.74 3 7.70 J= 5.1 Hz, 1 7.51 J= 8.1 Hz, 1 3.69 3 H), 3.21 (mn, 2 1.94 (in, 1 0.98 6.6 Hz, 6 MS 474 250 1 7 1 Cpd.
No.
N (in Ring With Respect to Starting From Method Used Analytical Data 1 L 1 H NMR (TMSO): 8 11. 18 I11), 9.31 2 NH 9.10 2 8.92 J 5.1 Hz, 1 8.78 (in, 2 8.43 J= 1.5 Hz, I 8.07 (dd, J= 154 3 0 NH 2 -H 153 1-2 7.9, 1.3 Hz, 11-H), 7.97 J 5.3 Hz, 1 7.82 A N J= 8.7 Hz, 2 7.72 J 8. 8 Hz, 2 H), N 7.50 J= 7.9 Hz, 1 3.10 J= 6.0 Hz, 2 H 1.86 (in, I 0.89 J=6.6 Hz, 6 MS 1 460 156 4 -CHO -Gil 3 155+ 3a D-9 MS 341.4 'HINMR (CDC 3 5 8.80 11-H), 8.46 J= 5.1 Hz, 1 8-29 1 7.85 7.9 Hz, 1 157 4 -C0 2 H{ -Gil 3 156 E 7.13 J 7.9 Hz, 11H), 7.00 J= 5.1 Hz, 1 6.83 (bs, 2 3.45 3 3.15 (in, 2 H), 1.84 (in, 1 0.90 J= 6.6 Hz, 6 MS (ES- 355.2 NH4 'H NM (CD 3 OD): 6 8.85 1 8.75 J' 5.3 Hz, 1 8.41 I1 1.9 Hz, 1 8.07 (dd, 58 4 0 NH-, -CH 3 157 1 8.1, 2. 1, 1 7.74 4 7.48 J 8.1 I lHz, 1 7.45 J 5.1 Hz, 1 3.69 3 H), A N& 3.21 2 1.94 I 0.97 J=6.8 Hz, H 6 MS 472.4 4
NH
0 NH 2
AN&
H
HNMR (DMSO): 6 10.97 I 9.24 2 8.96 3 8.79 (in, 2 8.40 J 1. 8 Hz, I 8.06 7.7 H~z, 1 7.77 4 H), 7.52 (in, 1 7.3 8 J =7.5 Hz, 1 3. 10 (mn, 211), 1. 85 (mn, I 0. 89 J 5.3, 6 MS (ES1) 460.2 Cpd. -R Starting Method TAnalytical Data No. From [Used 1H NVR (DMSO-d6): 5 10.55 111), 9.00 (bs, 2H), 8.68 J 5.8 Hz, 111), 8.24 J =1.9 Hz, 111), 8.04 J 8.1 Hz, 1H), 7.91 J 8.8 Hz, 211), 7.77 J =1.3 Hz, 1H1), 7.67 (in, 311), 7.40 J 7.9 Hz, 161 a -CH 3 -C11 3 31f? AB-2 1H), 7.29 J =7.9 Hz, 1H), 6.90 (dd,J =17.7, 11.0 Hz, 1H), 6.03 (d, J1 17.7 Hz, 111), 5.42 J 11.0 Hz, 1H), 3.61 3H), 3.56 311), 3. 10 J 6.4 H-z, 2H), 1.8 5 (in, I1H), 0. 90 J1 6.5 Hz, 611); MS 557.3 H N4R (DMSO-d6): 5 10.54 111), 9.20 (bs, 4H1), 8.67 J='6 Hz, 111), 8.24 (111), 8.02 (111), 7.91 7.77 7.66 (in, 3H), 7.40 161b -C 2
H
5
-CH
3 31f AB-2 (11H), 7.29 (1 6.8 8 (dd, J 17.3, 10.7 Hz, 111), 6.03 J 17.3 Hz, 111), 5.42 J 10.7 Hz, 111), 3.56 311), 3.5 (mn, 311), 3.09 (211), 1.85 (mn, 111), 0.89 (611); MS (ESI): 571.3 'H N.MR (DMSO-d6): 8 10.54 1H1), 9.20 (bs, 211), 8.68 J 5.8 Hz, 1M1, 8.24 J 1.9 Hz, 1H), 8.03 J1=8.1 Hz, 111), 7.92 J 8.8 Hz, 2H), 7.77 IR), 7.68 (in, 4H), 7.36(m, 6H1), 6.89 (dd, J 161c -CH 2
C
6
H
5
-CH
3 31f AB-2 17.7, 11.2 Hz, I 5.05 211), 6.03 J 17.7 Hz, 111), 5.42 J 11.2 Hz, 111), 3.56 3H), 3.09 J =6.6 Hz, 2H), 1.84 111), 0.89 J 6.6 Hz, 611; MS 633.3 2 Cpd. 1R -R1 Starting MethodAnltclDa No. IRJFrom- Used LAnltclDa 161d -C(CH 3 3
-CH
3 31f AB-2 MS 599.3 and 499.3 'H NMR (DMSO-d6): 6 10.59 114), 9.24(s, 2H1), 8.68 J 5.6 Hz, 111), 8.24 J =1.8 Hz, 111), 8.03 (dd, J =8.9,1.9 Hz, 111), 7.96 J =8.9 Hz, 211), 7.79 J 1.5 Hz, 111), 7.69 (in, 3H1), 7.41 J 8.1 161e -C11 2 -CC1 3 -C11 3 31f AB-2 Hz, 1H1), 7.29 J =8.0 Hz, 1H1), 6.89 (dd, J 17.7, 11.1 Hz, 111), 6.03 J 17.7 Hz, 111), 5.42 J 11. 1 Hz, 111), 4.88 2H), 3.56 (s, 3H1), 3. 10 J=6.6 Hz, 2H), 1.85 (in, 111), 0.89 S =6.6 Hz, 611); MS 674.97 I'HNMR (DMSO-d6): 5 10.58 111), 9.15 2H), 8.69 J 5.4 Hz, 111), 8.25 J 1.8 Hz, 111), 8.04 (dd, J 8.1- 1.9 Hz, 111), 7.95 J S8.9 Hz, 2H1), 7.78 1H4), 7.68 (in, 311), 7.40 J 8.0 Hz, 111), 7.29 161f OMe -CH 3 31f AB-2 J 8.0 Hz, 111), 7.07 J1 8.8 Hz, 211), 6.93 J3 8.8 Hz, 211), 6.89 (dd, J 17.7, 11.1 Hz, 111), 6.03 J 17.7 Hz, 1H), 5.42 J 11.1 Hz, 111), 3.75 3H1), 3.57 311), 3. 10 J3 6.6 Hz, 211), 1.85 (in, 111), 0.89 J 6.6 Hz, 611); MS 649.3 'H NMR (DMSO-d6); 6 10.59 1 9.19 2H1), 8.68 J 5.7 Hz, 111), 8.25 J 1.8 Hz, 111), 8.03 (dd, J3 8.1, 1.9 Hz, 1H1), 7.95 J 161gF =8.9 Hz, 211), 7.78 J 1.7 Hz, 1H1), 7.70 31), 7.41 J3 8.1 16g F -eli 3 31f AB-2 Hz, 111), 7.29 J 7.9 Hz, 111), 7.20 (in, 411), 6.90 (dd, J 17.9, 11.1 Hz, IH), 6.03 J 17.9 Hiz, 11-1), 5.42 J 11. 1 Hz, 111), 3.57 (s, 3H), 3. 10 J 6.8Hz, 211), 1.85 (in, 111), 0.89 J 6.6 Hz, 611); MS 637.5 253 Cpd.
Starting Method Analytical Data No Used_ 0 0 "LKCH, 161h
-CH
3
A-B-
1 Hf NUR (DMSO-d6): 8 10.58 111), 9.00 (bs, 2H), 8.68 J =5.9 Hz, 1H1), 8.24 J 1.9 Hz, 111), 8.03 J 8 91 Hz, 1Ff), 7.94 J 8.9 Hz, 2Hf), 7.78 J1 1.5 Hz, 1Hf), 7.68 (in, 3H1), 7.40 J 8. 1 Hz, 111), 7.29 J 8.1 H~z, 1Ff), 6.89 (dd, J =17.5, 11.0 Hz, 1Ff), 6.03 (d, J 17.5 H-z, 1H1), 5.71 2H1), 5.42 J =11.0 Hz, 1Ff), 3.56 3H1), 3. 10 J 6.2 Hz, 2H1), 2.07 3H), 1.85 (in, 1H), 0.89 J 6.6 Hz, 6H1); MS 615.3 'H NMR (DMSO-c16): 8 10.57 1Hf), 9.22 2Ff), 8.67 J 5.9 Hz, 1Ff), 8.24 (di, J1 1.9 Hz, 1H), 8.03 (cid, J 1.9 Hz, 1H1), 7.94 J S8.9 Hz, 211), 7.78 J1 1.5 Hz, 111), 7.69 (in, 311), 7.41 J 7.9 Hz, 111), 7.29 J 7.9 Hz, 1H1), 6.89 (dci, J 17.7, 11.1 Hz, IH), 6.03 J 17.7 Hz, 1FH), 5.73 2H), 5.42 1 11. 1 Hz, 111), 3.56 (s, 3H), 3.09 J1 6.6 Hz, 211), 1.85 (mn, 1Ff), 1. 14 9H1), 0.89 J1 6.7 Hz, 611); MS 657.52 0
CH
3
CH
-CH
3 AB-1 3 -I -l CR 0 0H CR0 1161j
-CH
3 'Hf NMR (DMSO-d6): 6 10.57 1H), 9.24 1 9.17 1Ff), 8.68 J1 6.2 Hz, 1Ff), 8.25 1Ff), 8.04 J 8.2Hz, 1Ff), 7.94 J 7.5 Hz, 211), 7.67 1Ff), 7.67 (mn, 311), 7.40 J 7.9 Hz, 1Ff), 7.29 J1 7.9 Hz, 1Ff), 6.90 (dci, J1 17.8, 11.1 Hz, 1H1), 6.71 J Hz, 1H), 6.03 J 17.7 Hz, 1Ff), 5.42 J 11. 1 Hz, 1Ff), 3.56 (s, 311, 3.10 J 6.6 Hz, 211), 2.00 3Ff), 1.85 (in, 1Ff), 1.43 J1 Hz, 3Ff), 0.89 J 6.7 Hz, 611); MS 629.4
AB-I
254 I Cp~d -R -R Starting Method AnltclDt N o. -RFrom [Used AnltclDt 'HIPVIR (DMSO-d6j: 6 9.04 (bs,311), 8.57(t,J =5.4 Hz,IH), 8.16 (s, 16a-Cl 3 -H 161a 12 7.58 3H), 7.12 J 8.0 Hz, 2H1), 6.87 (dd, J 17.7, 11.0 Hz, IH),- 16a5.97 J =17.7 Hz, 1H), 5.37 J= 11.0Hz, 1H), 3.59 3H), 3.05 J1 6.6 H4z, 21-1), 1.83 (in, 111), 0.87 J 6.6 Hz, 611); MS (ESI): 543.38 1 H NMR (DMSO-d6): 3 12-8 (bs, 1H), 10.8 (bs, 111), 9.20 (bs, 2H4), 8.68 J 5.9 Hz, I 8.24 J 1.9 Hz, I 7.91 (mn, 3H1), 7.77 (d, J 1.5 Hz, 1H), 7.64 (in, 3H), 7.28 (di, J 8.1 liz, IH), 7.22 (di, J 8.1 162b -C 2 .Hs H 161b 1-2 Hz, IH), 6-87 (dd, J= 17.7, 11.4 Hz, IH), 6.01 J =17.7 Hz, IH), 5.42 (ci, J1 11.4 Hz, 111), 4.05 J 7.2 Hz, 211, 3.08 J 6.4 Hz, 2H1), 1.84 (in, In), 1.21 J 7.2 Hz, 311), 0.88 J 6.6 Hz, 6H); MS 555.2 'H1 NMvR (DMSO-d6): 6 12.7 (bs, 1H1), 10.75 (bs, 111), 9.15 211), 8.63 J 5.8 Hz, 111), 8.27 (bs, 111), 7.90 J 8.3 Hz, 211), 7.77 (s, 12 C CH5 -H 161 c 1-2 111), 7.43-7.15 (in, 811), 7.40 J 8.1 Hz, 111), 7.29 J =8.1 Hz, 162c CH 2
C
6 5 11), 6.87 (dci, J 17.4, 11.0 Hz, 1H), 6.03 (di, J1 17.5 Hz, 111), 5.71 (s, 211), 5.42 J 11.0 Hz, 1H1), 5.09 2H1), 3.08 J1 6.4 Hz, 2H), 1.85 (in, 111), 0.88 J 6.6 Hz, 611); MS 619.2 1 1INMR (DMSO-d6): 612.6 (bs, 111), 11.0 (bs, 111), 9.04 2H), 8.62 J1 5.4 Hz, 111), 8.24 111), 7.86 (in, 3H), 7.77 in), 7.62 (in, 162d -C(CH 3 3 -H 161 d 1-2 311), 7.24 J1 8.2 Hz, 111), 7.20 (di, J 8.0 Hz, ili), 6.87 (dd, J 17.2, 11.0 Hz, 111), 6.00 (di, J 17.7 Hz, 111), 5.40 (di, J 11.0 Hz, 111), 3.07 J 6.3 Hz, 2M1, 1.84 (in, 111), 1.44 9H1), 0.88 J 6.6 Hz, 6H); MS 585.4
R
R!O CH 2C Cpd. -R -W Starting Method Analytical Data 'HNMJR (DMSO-d 6 5 9.58 1 7.91 (dd, J= 1.2, 8.0 Hz, 1 7.71 (dt, J 1.2 and 7.4 Hz, 1 H), 164 -CHO -CH 3 163 +130 D-2 7.58 J =7.4 Hz, 1 7.41 (in, 2 7.38 (in, 1 7.32 J 8 Hz, 11H), 7.24 J 7.4 Hz, 1 H), 3.52 J 16 and 26 Hz, 2 3.35 MS 255.32_ 165 -C0 2 H -CH 3 164 E Characterized in the next step
NE
'HNMR (DMSO-d 6 8 10.34 1 9.18 2 H), 166 0 NH -CH; 165 1 8.92 2 7.72-7-5 (mn, 7 7.34-7.14 (in, 5 H), 1 3.60 J3=17 40 Hz, 2 3.48 3 MS AN& 388.67 NH 1 'flQ~fl (DMS0-l 6 6 11.74 (bs, 1 9.90 1 8.79 (bs, 2 7.64 (mn, 1 7.50 (in, 7 7.33 16 NH 2 -16 2 J=8.6 Hz,1IH), 7.26 J =7.4 Hz,1IH), 7.12 167 2 1661-2 J 7.4 Hz, 11-H), 7.02 J 7.4 Hz, 1 6.89 (d, N J 6.8 Hz, 1 3.83 J3=15 Hz, 2 MS (ES+) H 374.79 256 4
R-
2 R W"OOC Cpd.
No.
IStarting From Method Used Analytical Data NH
C
188a -CH==CH 2 N2C, -H 187a AE-3 MS 485.4 (100% NH '}HNMR (DMSO-d 6
/D
2 8 8.5 (d, J 2 Hz, I 8.17 (dd, J1 8 Hz, 2 7.65 1 7.63 1 7.54
NH
2 d, J =8 Hz, I 7.49 (bs, 2 Hl), 188b -CH=CH 2
-_,CF
3 -H 1 87b AE-3 7.14 J 7.7 Hz, 1 6.78 (dd, J1 11 and 17 Hz, 1 6.62 (d,J1= 9 hz, I 5.93 J=l17hz, I H), 5.33 J =11hz, 1 4.17 J 9 hz, 1I), 4.12 2H); MS (ES+) 497.3 257 No rm UeCpd. -R f-R' 1 1 1I Starting Method Analytical Data NH- HNMR (DMSO-d 6
/D
2 0):5 8.6 (in, 3 8.3 (in, 3 7.9 J 7.9 Hz, I 7.45 J 8 8 Hz, 1 Nil 2 7.3 (in, 3 7.1 (mn, 1 11), 188C -CH C]7 2
,,CH
3 -H 187c AE- I 8.1 Hz, 1 6.6 (dd, J1 6 aind 29 Hz, 1 6.4 J 8.8 Hz, 2 5.7 J 17 Hz, 1 5.15 J =11 Hz, 1 3.9 (in, 2 H), 3-25 2H), 1.1 J 3 MS :443.3 'HNMR (DMSO-d,): 6 8.8 (in, 2 NH 8.7 (in, I 8.4 (in, 2 8.1 CII, I1H), 7.6 (mn, 2H), 7.5 (mn,3 CH, 187dH), 7.3 (mn, I 7.2 (in, 1 6.8 188d -CH=CH4 2 N11 2 C3 H 17 E3 (in, 1 6.6 (in, 2 5.8 (in, 1 5.3 (mn, 11-1), 4.1 2H), 3.31 (mn, I 3.2 (in, t 1.7 (in, I 1.6 (in, 1 1.3 (mn, I (in, 6 MS 485 'IINMR (DMSO-d,): 8 8.60 J N14 6 Hz, 1 8.39 (bs, 2 8.28 (bs, CH, 1 7.78 (in, 1 7.5 6 (in, 11-H), 18a -C3()NH CH AE-4 7.43 (dcl, J =5.8 Hz, 3.8 Hz, 2 H), 189 .OCH -H 74 12 7.18 2H), 6.80 3H), 6.51 (bs, 1 4. 10 (in, 1 3.85 (mn, 1 3.70 3 3.17 J 6 Hz, 2 1.80 (in, 1 0.89 (ci, J1 6.8 6H); MS(ES+) 475.2- Analytical Data 1 HNTq~mR(DMSO-d 5
/D
2 5 8.24 J .5 Hz,1I 7.86 J =7 Hz, I 7.49 (in, 2 7.36 (in, 4 7.26 J =8.3 Hz, 1 6.94 (in, 3 6.66 J 8.7 Hz, 2 Hz, 2 5.03 2 4.06 J 16 and 21 Hz, 2 3.02 J 7 Hz, 2 1.86 (in, 1 0.89 J 6.8 Hz, 6 MS 549.2 and 551.4 'HNMR (DMSO-d 6 5 11.3 (bs, 1 9.07 1 8.46 J =6 Hz, 1 8.27 (bs, 2 8.15 (bs, 2 H), 7.66 J 7.7 Hz, 1 7.36 J Hz, 2 7.03 J 8.1 Hz, 11-H), 6.77 (in, 2 6.68 J 8.3 Hz, 2 Hz, 2 6.6 I 6.47 9d, J 8.2 Hz, 1 4.05 J 14 Hz, 1 3.09 J5=14 Hz, 1 H), 3.01 J= 7Hz, 2 1.79 I 0.82 J 6.8 Hz, 6 MS 459.2 and (ES 4 461.4 MS (ES 4 445.4; MS 443.3 259 WO 02/34711 PCT/USOI/32582 Cpd.
No.
Starting From Method Used Analytical Data '1 7 HNMRJ (DMSO-d,): 6 11.04 0.6 10.97 (bs, 0.4 11), 8.66 J 5.6 H-z, 0 0.6 8.56 J 5.6 Hz, 0.4 8.22 1 8.11 J 2 Hz, 0.6 8.03 205 Bo, 204 A-4 J 2 Hz, 0.4 7.94 (dd, J 2 and 8 Hz, I 7.82 (in, 4 7.40 (in, 8 205-Bc 24 -4 7.18 2H), 7.04 (mn,2 5.21 0.8 5.11 1.2 3.11 (t,Jf=6.2
NH
2 Hz, 1.2 3.06 J Hz, 0.8 1.84 (in, 1 1.43 5.4 1.42 (s, 0.91 J =6.8 Hz, 3.6 0.88 J =6.8 Hz, 2.4 MS 665.5 'H1NMvR (DMSO-d,): 8 12.15 (bs, 1 11.07 (bs, 1 10.69 I 10.38 (bs, 1 8.68 J =5.6 Hz, 1 8.12 J= 1.7 Hz, I 8.00 1. 8, 8 Hz, 206 -CH 2 OH -IBoc 204 A-6 1 7.68 (in, 4 7.46-7.30 (in, 6 7.16 J 2.8 Hz, 1 7.01 J 8.5 Hz, 1 6.86 (dd, J 8.5 and 2.8 Hz, 1 5.07 2 4.30 J =7.4 Hz, 2 3.15 J =6.2 Hz, 2 1.86 (in, 1 1.53 9 0.89 J1 6.8 6 MS 649.4 'HNMRfl (DMSO-d,/D) 2 5 1 0.66 1 9.19 (bs, 2 8.86 (bs, 2 8.69 J 5.5 Hz, 1 8.13 J 2 Hz, 1 8.02 (dd, J1 8 and 2 Hz, 1 7.72 C2H -H 206 S-2 (mn, 4 7.3 8 (mn, 6 7,17 J =2.6 Hz, 1 7.03 J =8.5 Hz, 1 H), 207 -H 2 OH6.87 (dd, I 8.5 and 2.5 Hz, 11-H), 5.39 J 4.7 Hz, 1 5.08 2 4.30 (mn, 2 3.13 J 6.5 Hz, 2 1.87 (in, 1 0.91 J 6.5 Hz, 6 MS 551.4 261 7Cpd- No.
Starting From Method Used Anal ytical Data 'HNMR (DMSO-d,): 6 11.26 0.6 11.20 (bs, 0.4 9.15 (bs, 1.2 H), 0 9.11 (bs, 0.8 8.84 (bs, 1.2 8.82 (bs, 0.8 8.67 J 5.6 Hz, 0.6 H), 8.58 J 5.6 Hz, 0.4 8.3 1 8.12 J 2 Hz, 0.6 8.04 J3 2 208 -H 205 S-2 Hz, 0.4 7.96 (dd, J 2 and 8 Hz, 1 7.84 (in, 1 7.70 (in, 2 7.57
NH
2 (rn, 3 7.40 (mn, 4 7.22 (in, 2 7.02 (in, 2 5.21 0.8 5.11 (s, 1.2 3.12 f =6.5 Hz, 1.2 3.06 J =6.5 Hz, 0.8 1.84 (in, 1 H), J 6.5 Hz, 3.6 0.86 J 6.5 Hz, 2.4 MS 564.5 2G2
R
R" N R' Cpd. -R -R1R Starting jMethod AnltclDt No. From JUsedAnltclDa CR,3 'HNMR(DMSO-d 6 6 8.48 J= 6.2 Hz, I1H), 27 OC3H 8.06 J 8.3 Hz, 1 7.69 J1=8.5 Hz, 1 21 OC 3 N-Br 216 A-3 4.01 3 3.15 J= 6.5 Hz, 2 1.91 CRH (in, I 0.91 J= 6.6 Hz, 6 MS (ES o 287.1 1 NMR (CDC1 3 8 8.08 (in, 2 7.20 (mn, 2 H CH 3 6.39 (dd, 1= 2.0 and 17.3 Hz, 1 5.53 (dd, 218 -OCR 3 N -CH=~CH 2 217 D-12 J= 2.0 and 10,9HI-z, 1 4.01 3 3.15 J YCH 6.5 Hz, 2 1.91 (in, 1 0. 91 J =6.6 Hz, o 61H)
CH
3 'H NMR (DMSO-d 6 6 11.05 1 8.48 J NH-2~ 6.2 Hz, 1 8.06 J1=8.7 Hz, 1 7.53 (d, 219. -OH CV- J=CH 21 2 8.5 Hz, 1 3.90 3H), 3.12 J= 6.6 Hz, 219 OH CH _C2C3 218 -2 2 1.85 (in, 1 0.86 J= 6.6 Hz, 6 MS 0 253.2 CR 3
H
22 O0C3CR 3 -CO2CH 3 219 B-2 MS 407.2 (M+Na)+ 0
NH
237 -NH 2 -H 236 AF-1 MS 137.1 NH4, R' R
H
Cpd.- R Starting Method No. j From j Used 1Analytical Data 'H NMR (CDC1 3 8 9.77 I 8.40 J 7.9 Hz, 1 8.13 J~ 6.8 Hz, I 7.83 J= 7.9 Hz, I H), 7.61 J 2.60 Hz, 1 7.20 (in, 221 -CHO -OBn -GCl 3 220 6 D-2 7.21 (mn, 1 7.18 8.3 Hz, I 5.18 2 3.72 3 3.35 J 5.8 Hz, 2 1. 96 (in, 1 H), 1.01 J= 6.8 Hz, 6 H1); MS 447.4 222 -CO 2 H -OBn -CH 3 221 E MS 461.3 223 -CO 2 MEM -OBn -CH 3 222 F MS 573.33 (M+fNa)-' 224 -CO 2 MEM -O)H -CR 3 223 G MS 461.36 225 -CO 2 MEM -OSO 2 CF, -CU 3 224 B-2 MS 615.58 (M+Na) 4 226 -CO 2 MEM -C~H=CH 2
-CH
3 225 D-3 or D-12 MS (ESD: 381.35 [(M-MEM)-1] 227 -C0 2 11 -CH=CH 2
-CR
3 226 I-1 MS (E5S): 381.35 264 Cpd.
No.
Starting Method Analytical Data NHl 228 0 NH CH=CH 2
-CR
3 227 J MS (S:500.35
NN
229 0I N2-CH=CH 2 -N1 228 1-2 MS 486.32
N&
H
245 -CHO -OH -CH 3 221 AD MS 357.40 246 -CHO -OSOCF 3 -CH-I 245 B-2 Characterized in the next step 247 -CHO -CH=C1 2 -elI 3 246 D-3 MS 367.42 NHnf 248 N /-CH=CH 2 -H 247 AE-3 MS 472.39 H 2
NB
249 0N2 -OBn -CU 3 222 j MS 580.4
AN
H
26~5 Cpd.
No.
Starting rMethod From I Used Analytical Data
NH
250 0 -OBn -H 249 1-2 MS(S':56.
-AIN MS (ESD): 564.3
HN
251 0 NIL -OH -H 250 G MS 476.3 N&MS 474.2
NN
H MS 473.44 252 N /-CH=CH 2 H 24 E3 MS 471.43 N NEI 2
CHO
0 Br- 0 Cpd. -R Starting Method Analytical Data No. From Used 1 HNMR (CDC1 3 8 10.17 J 0.75 Hz, I H), 231b -CO 2
CH
3 230 AG-3 7.62 J =8.3 Hz, 1 6.94 (dd, f 8.3, 0.75 Hz, 1 6.51 1 3.90 3 H) 2G7 Cpd. -R R" Starting 1Method Analytical Data No. jFrom j Used II HRNMIR (CDCI 3 8 9.64 1 8.44 J 2 Hz, 1 8.02 (dd, J =8 and 2 Hz, 1 7.60 J3 8.3 Hz, 1 7.40 J 8 Hz, 1 H), 232a -H -CHO -eli 3 231a ±6a D-6 or D-7 6.96 J 8 Hz, 1 6.32 J 6 and 5 Hz, 1 6.01 2 3.72 3 Hi), 3.33 J Hz, 2 1.93 (mn, 11-H), 1.00 (d,J =6.8 6 MS (ES 4 384.3 and 406.3 (M+Na) 4 'ITNMVR (DMSO-d 6 6 9.87 I 9.49 I 8.64 J3 2 Hz, 1 8.3 I 7.97 J 8 Hz, I 7.43 (dd, J 8 and 2.6 Hz, I 232b -CO 2 H -CHO -CH 3 231b +6a D-6 orD-7 7.35 (in, 2 6.94 (in, 11-H), 6.05 0.4 5.98 0.6 3.55 1.8 3.52 1.2 3.02 J =6.5 Hz, 21H), 1.78 (mn, 1 H), J 6 .6 Hz, 6 MS 426.2 1 HNMR (DMNSO-d 6 8 12.29 (bs, I 8.69 (t, J 5.5 Hz, I 8.38 J3 2 Hz, 1 8.03 (dd, J 8 and 2 Hz, 1 7.58 J3 8.5 Hz, 1 233a -H -CO 2 H -CH 3 232a E 7.36 J3 8 Hz, I 7.00 J3 8.5 Hz, I 6.02 2 3.64 3 3.12 J Hz, 2 1.87 1 H),O0.91 J= 6.8 Hz, 6 MS 398.2 Cpd. -R r ~Starting fMethod Analytical Data No.1 -R [RR From Used HM(DSd HNM (DSO- 6 8 8.64 J =5.5 Hz, 1 8.38 J =4 Hz, 1 8.00 (dd, J and 4 Hz, 1 7.59 (dd, J 8.5 and 4 Hz, 1 233b -CO 2 H -CO 2 H -C11 3 232b E 7.30 (dd, J1 8 and 2.5 Hz, 1 6.52 (s, 6.48 0.5 3.60 1.5 3.58 (s, 3.08 J 6.5 Hz, 2 1.84 (in, 11-H), J =6.8 Hz, 6 H)
NH
234a -H 0 H -CH, 233a J MS 517.4
-N&
H
1 1{NMR (DMSO-d 6 8 12.41 (bs, 1 11.09 1 10.96 1 9.22 (bs. 21H), 8.96 NH (bs, 2 8.70 (in, 1 8.38 (dd, J 2 and 13 Hz, 1 8.04 J =8 Hz, I 7.82 (mn, 4 234b -CO0 2 H H, .CH 3 233b J 7.65 (dd,J =S8and 5Hz, IH), 7.39 (dd, J AN 8 and 2:5Hz, IH), 7.11 (dd, J =8.5 andl1.7 H Hz, 1 6.05 1 3.67 1.5 3.50 (s, fl), 3. 10 J1 6.5 Hz, 2 1.88 (in, I H), 0.90 J 6.8 Hz, 6 H) 1 HNMR (IJMSO-d 6 fDCI one drop): 8 8.34 (d, H J 2Hz, 1 7.97 (dd, J1=8 and 2 Hz, I H), 7.75 (in, 4 7.33 (dd, J 3.8 and 8.1 Hz, 2 235a -H 0 NH, -H 234a 1-2 HM, 7.04 J1 8.1 Hz, I 6.01 J 6 Hz, 1 1 2 3.07 J 6.5 Hz, 2 1.83 (in, 111), A N& 0.86 J =6.8 Hz, 6 MS 501.3; 14 503.3 Cpd.
No.
Starting From Method Used Analytical Data
-CH(OH)-CH
2 OH -Boc -CH3 161d 'Hi NMR (DMSO-d6): 8 10.47 iH), 9.07 (s, 211), 8.72 J =5.7 Hz, iH), 8.29 J 2 Hz, 114), 8.08 (dd, 8.0,2 Hz, IH), 7.95 11H), 7.92 1 7.67 (in, 2 7.62 J 6.5 Hz, 1 H), 7.46 J 8 Hz, 1H), 7.31 J 8 Hz, i11), 5.50 J 4.5 Hz, IN), 4.91 J 5.7 Hz, 1H), 4.74 (in, 1 4.25 1 3.63 3H1), 3.15 J =6.4 Hz, 2H), 1.91 (in, 1H), 1.50 9 0.95 J 6.7 Hz, 611) -CHO -Boc -CH 3 'H NMR (DMSO-d6): 8 10.69 i14), 10. 17 1 9. 10 (bs, 2 8.72 J 5.7 Hz, 11H), 8.30 (d, J 1.5 Hz, iH), 8.22 J 1.5 Hz, iH), 8.22 (dd, J 1.5 and 8 Hz, 1 8.07 (dd, J 1.5 and 8 Hz, 1 7.89 in1), 7.86 1 7.65 1 7.62 1 7.57 J 8 Hz, 1H), 7.44 J1 8 Hz, iH), 3.57 3H1), 3.11 J 6.4 Hz, 2H), 1.85 (in, 11n), 1.44 9 0.89 J 6.7 Hz, 6H) 242 -CH-(O.H)-CH=CH 2 -Boc -CH 3 241 AG MS 629.39 243 -CH(OH)-CH=CH 2 -H -CH 3 242 S MS 529.38 244 -CH(OH)-CH=CH 2 -H -H 243 1-2 MS 515.35 270 Cpd. -R Starting Method }Analytical Data No. [F rom I Used
NH
254 H 253 AE-3 MS 318.2, 320.2
N
2 Nil 255 H 254 R MS 418 WO 02/34711 WO 0234711PCT/USO1/32582 The following non-limiting examples are presented to fairther illustrate the present invention.
{4-[Amino(imino)methyljphenyl} amino)carbonyl]-4- [(isobutylamino)carbonyly4'.thien2yl 1,1 '-biphenyl-2-carboxylic acid t 4 -[Amino(imino)methyl]phenyl} amnino)carbonyll-4- [(isobutylanino)carbonyl]p4'-thien-3y 1,1 '-biphenyl-2-carboxylic acid {4-[Nmino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonylj- 1, 1 "-terphenyl-2-carboxylic acid 4 -IlAmino(imino)methyl]phenyl} amnino)earbonyl]-4'-(3-fiiryl)-4- [(isobutylamino)carbonyl] -1,1 '-biphenyl-2-earboxylic acid {4-FAmino(imino)niethyl]phenyl} amino)carbonyl]-4- [(isobutylainino)carbonyl1-4'-pyridin-4y..1,1 -bipheny1-2-carhioxylic acid 4 -[Amino(imino)methyl]pheny} amnino)carbonyl]-4- [(isobutylamino)arbony 4(Hpol2yl}1,1 '-biphenyl-2-carboxylic acid 4 -[Amino(iinino)methyl]phenylI amino)carbonlyl]-4'-[2-(hydroxymnethyl)thien- 3 -yfl-4-[(isobutylamino)carbonyll 1,1 '-biphenyl-2-carboxylic acid {4-llAmino(imino)methyl]phenyl} amino)carbonyl]-4'-[3-(hydroxymethyl)thien- 2 -yl]- 4 -[(isobutylamino)carbonyl]- 1,1 '-biphenyl-2-carboxylic acid 4 -IlAmino(iminc)methyllphenyl) amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-vinyl 1,1 '-biphenyl-2-carboxylic acid 272 WO 02/34711 WO 0234711PCT/USO1/32582 4'-Allyl-2'-[(f 4-f amino(imino)methyljphenyl} arnino)carbonyl]-4- [(isobutylamino)carbanyl]- 1, I'-biphenyl-2-carboxylate 4 -[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylarnino)carbonyl]-4'-(1 ,3 -thiazol-2-yl)-1, 1'-biphenyl-2-carboxylic acid 2'-[({4-[Amino(ixnino)methyljphenyl} amino)carbonyl]-4'-[3-(hydroxymethyl)-2.
furyll-4-[(isobutylamino)carbonyl]- 1,1'-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)rnethyl]phenyl} arnino)carbonyll-4- [(isobutylamino)carbonylj-4'-prop-1-ynyl-1 ,1 '-bipheny.-2--carboxylic acid {4-[Ainino(imino)methyl]phenyl} amino)carbony1]-4'-(3-hydroxy-3-methylbut- 1 -ynyl)-4-[(isobutylan-ino)carbony1j 1,1 '-biphenyl-2-carboxylic acid {4-[Amino(imino)methyljphenyl} amino)carbonyl-4-E(3methylbutanoyl)amino] -4'-vinyl-1 ,1 '-biphenyl-2-carboxylic acid 4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(4-hydroxybut-1 -ynyl)-4- [(isobutylamino)carbonyll- 1,1 t -biphenyl-2-carboxylic acid {4-[Amino(imino)inethyl]phenyl} amino)carbonyll-4- [(isobutylamino)carbonyl]-4'-[(1 E)-3 -methylbuta- 1,3-dienyl]- 1,1 '-biphenyl-2carboxylic acid {4-IlAmino(imino)methyljphenyl} amino)carbony1]-4'-(3-hydroxyprop-1I-ynyl)- 4-[(isobutylamino)carbonyl] -1,1 '-biphenyl-2-carboxylic acid 273 WO 02/34711 WO 0234711PCT/USO1/32582 4 -[Amino(imino)methyllphenyl} amino)carbonyl]-4'-(2-fry1)-4- [(propylamino)carbonylj- 1,1 Thiphenyl-2-carboxylic acid 4 -[Amino(imino)methyljphenyl} amino)carbonyl]-4-[(secbutylamino)carbonyl]-4'-(2-fiiryl) 1,1 '-biphenyl-2.-carboxylic acid 4 -[Amino(imino)methyl]phenyl}amino)carbonyljy4I(2.tjryl)y4-{[(2,2,2.
trifluoroethyl)amnino]carbonyl} -1,1 '-biphenyl-2-carboxylic acid 24-( {4-[Amino(imino)methyllphcnyl) amnino)carbony1]-4'-(24fryl)-4- hydroxybutyl)amino]carbonyl} -1,1 '-biphenyl-2-carboxylic acid {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(ethylamino)carbonyly-4'- (2-faryl)- 1,1 '-bipheny]-2-carboxylic acid 2 '-[(f{4-[Amino(imino)methyljphenyl) amino)carbonyl]-4- I(isobutylamino)carbonyl]-5'..-ethoxy4-vinyl 1,1 '-biphenyl-2-carboxylic acid 4 -[Amino(imino)rnethyl]phenyl} arnino)carbonyl]-4- [(isobutylamnino)carbony1]-4-(thien-2ymethy)I 1 -biphenyl-2-carboxylic acid {4-fAmino(imino)methyl]phenyl} amino)carbonyl]pyridin-4-yl} [(isobutylamino)carbonyllbenzoic acid {4-[Aniino(imino)methyl]phenyl} amino)carbonyl]-4- [(cyclopentylamino)carbonyl-4'vinyl4 ,1 '-biphenyl-2-carboxylic acid WO 02/34711 PCT/USOI/32582 WO 02/34711 PCT/USO1/32582 {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-5'-ethoxy-4- [(isobutylamnino)caxbonyl]-4'-vinyl- 1,1 '-biphenyl-2-carboxylic acid Methyl [(acetyloxy)lnethoxylcarbonyl} amino)(imino~inethyllphenyl) arnino)carbonylj-4-[(isobutylamino)carbonylj-4'-vinyl 1,1 '-biphenyl-2-carboxylate Methyl [(benzyloxy)carbonyl] amino) (imino)methyl]phenyl} amino) carbonyl]-4-[(isobutylamino)carbonyly-4'-vinyl-1,1 -biphenyl-2-carboxylate {4-[Amiino(imino)methyl]phenyl} -NS-isobutyl-6-oxo-61--benzo[c]cliromenie- 1 ,8-dicarboxamnide [Amino (imino)methyl]phenyl} amino)methyl]-4-[(isobutylarnino)carbonyl]- 4'-vinyl- 1,1 -biphenyl-2-carboxylic acid {[4-(4,5-Dibydro-l1H-imidazol-2-yl)phenyljaminolcarbonyl)-4 [(isobutylamino)carbonyl]-1 ,1 '-biphenyl-2-carboxylic acid {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-5'-thien-2-yl- 1,1'-biphenyl-2-carboxylic acid {4-[Amino(imino)methyllphenyl ainino)carbonyl]-5'-(2-amino-2-oxoethoxy)-4- [(isobutylaminco)carbonyll-1 ,1 '-biphenylb2-carboxylic acid {4-[Amino(imino)methyllpbenylI amino)carbonyl]-4'-ethoxy-4- [(isob-utylamino)carbonyl] -1,1 '-biphenyl-2-carboxylic acid WO 02/34711 PTUO/28 PCT/USOI/32582 2- {4-fAmino(imino)methyljphenylI amino)carbonylj- 1 ,3-benzodioxol-4-yl) [(isobutylamino)carbonyl]benzoic acid {4-[Amnino(imino)methyl]phenyl} amino)ethyl]-4-[(isobutylamino)carbonyl]- 1,1 '-biphenyl-2-carboxylic acid 4 -[Amnino(imino)methyljphenyll amino)carbonyl]-4-(benzyloxy)phenyl]y& [(isobutylamino)carbonyl]pyridine-2-carboxylio acid 3 2 4 -Carbamnimidoyl-phenylcarbamoyl)-4viny-phe11yI6-isubauiycarbamoy- 'pyridine-2-carboxylic acid 2 '-[(5-Carbamimidoy1-pyidin-2-yamino)methyly4-isobutylcarbamoy14t-vinyl biphenyl-2-carboxylic acid f 4 -(N-T-ydroxycarbamimidoyl)-phenylamino]-methylI -4-isobutylcarbamoyl-4'vinyl-biphenyl-2-carboxylic acid f 4 -CN-Hydroxycarbamimidoyl)-phenylamino]-methylI -4-isobutylcarbamoyl-4'vinyl-biphenyl-2-carboxylic acid methyl ester 3- 2 4 -Carbamimidoyl-phenylamino)-methylp4-vinyl-phenyl) -6isobutylcarbamoyl-pyridine-2-carboxylic acid WO 02/34711 PCT/US01/32582 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
OD
40 5 was utilized. The IC5o of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
TF/FVIIa assay reactions were performed in a 200 4L mixture containing 4 nM FVIIa, 10 nM lipidated tissue factor, in an assay buffer containing 100 mM Tris, pH 7.2, 150 mM NaC1, 5 mM calcium chloride, 0.1 bovine serum albumin (BSA), and 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 500 OM substrate Spectrozyme-FVIIa. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 40 5 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. IC5o 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 gL mixture containing human thrombin at (1 U/mL) in an assay buffer containing 100 mM HEPES, 10 mM calcium 277 WO 02/34711 PCT/US01/32582 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 OD 4 0 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 KC4A data reduction software (Bio-Tek Instrunents) to interpolate percent inhibition from observed Vmax values.
Trypsin assay reactions were performed in a 200 ttL mixture containing human pancreatic trypsin at 1 p.g/mL in an assay buffer containing 200 mM triethanolamine (TEA), 10 mM calcium chloride, 10 DMSO, pH 7.8. 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 OD 405 nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
WO 02/34711 WO 0234711PCT/USOI/32582 Biological Data
IC
50 Values of Some Selected Compounds on Different Serine Protease Enzymes
,NHR'
R (With Respect to R' TF/FVIIa Trypsin Thrombin Phenyl. Ring /C N(4) 1
OH
3 sCH 3 S
OH
3 I(4) O H 4 N 3
OH
3 01-3 OH C3++
CH
3 CH
CH
3 3 O H 3 (3)3 s O- H 3 0 WO 02/34711 WO 0234711PCT/US01/32582 /o 2- CH CH 3 Cit-
IC
50 values: meal's >1 I M; means >1 00 nM; means 100 nM 280 WO 02/34711 PCT/US01/32582 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.
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.
WO 02/34711 PCT/US01/32582 These compounds may be used as anti-inflammatory agents.
According to a further 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, stents 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.
WO 02/34711 PCT/US01/32582 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 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 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 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 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 from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and WO 02/34711 PCT/US01/32582 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 bisulfite, sodium 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.
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.
284 WO 02/34711 PCT/US01/32582 Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and 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 mg of microcystalline cellulose, 11 mg of starch, and 9.98 mg 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.
WO 02/34711 PCT/US01/32582 In another embodiment of the invention, a compound of the invention can be used in an assay to identify the presence of factor Vila and other serine protease or to isolate factor VIIla 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.
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 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 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 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 (3)

1. Compound baving the structure shown below: R BI I) E 1 W- E2 B I I phalrnatwentically X (R2 o P acceptable salts thereof; 0 Vi- L--V and prodrugs thereof; C~ VVI-- L--V as hereinbefore described. X A) Each EB1 and L individually is a 5 to 7 memnbered saturated or unsaturated carbon ring, 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, and S(0 2 which may be saturated or unsaturated; R is -CH=Cl-R 2 -C-C-R 2 -C(R)=CH2, -C(R1)C(Rb), -CH=NR, -C(R 2 )=N-R 3
4-7 menbered saturated or unsaturated carbon ring system with or without substitution, 4-7 mcmbered 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 R R 2 or R 3 with the proviso that these R, R 1 R 2 or R 3 do not include -(C24 alkenyl)-C0 2 -C-g alkyl, -(C24 alkenyl)-C0 2 -Cr..s alkyl-phenyl, and -(C24 alkenyl)-COz7 C.s allkyl-O-CI.A alkyl; R' is IH, -NOz, -CN, -halo, -N 3 -C 1-8 alkyl, -(CH 2 ).COZR 2 -2-9 alkenyl-CO 2 R, -O(CH 2 ),CO 7 R 2 -C(0)NRR 3 alkyl substituted 287 COMS ID No: SBMI-05802021 Received by IP Australia: Time 16:14 Date 2007-01-03 WO 02/34711 WO 0234711PCT/USOI/32582 -(CH 2 ).,O(CH 2 aryl, -NR, -(CH 2 OW 2 -(CH 2 SR 2 -N(R 2 )C(O)R 3 -S(0 2 )NR 2 R 3 -N(R 2 )S(0 2 )R 3 -(C1IR 2 NRR, (CH 2 N(R 3 )C(O)R 3 N(R 2 )CR 2 R 3 substituted or unsubstituted (CH 2 )11-cycloalkyL, substituted or unsubstituted (CH 2 phenyl, or substituted or unsubstituted (CH 2 )1-heterocycle which may be saturated or unsaturated; m is 1 except that when El is a cyclic ring of more than 5 atoms, then m is I or higher, depending upon the size of the ring; R is H, -halo, -alkyl, -haloalkyl, -(CH 2 -phenyl, -(CH2)i.. 3 -biphenyl, -(CH 2 14 -Ph- -(CH 2 ),,O(CH 2 ),CH 3 -CF 3 -C 2 -5 acyl, -(CHR 3 ),,NI1R 4 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- (CHR )n heterocycle, or substituted or unsubstittuted-(CHR 3 )n cycloalkyl which may be saturated or unsaturated; When n is more than 1, the substitutions R' and R 3 may be same or different; R 3 is H, -OH, -CN, substituted alkyl, -C 2 -8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R 1 )R 2 or 5-6 membered saturated substituted or unsubstituted hetero ring; -NR 2 R 3 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; WO 02/34711 WO 0234711PCT/US01/32582 W is a direct bond, -CHR 2 -CH=CR 2 -CR 2 -CR 2 CR 2 -O--CHR 2 CF -CH 2 -CH(R')-N(R 2 -S-CHR 2 -CHER 2 -S(0 2 )-N(R 2 -C(O)N(R 2 -C(R'R 2 -NWR)-S(0 2 -R 2 C(O)NR-, -RNC(O)NR.-, -CONR 2 CO-, -C("NR 2 )NR 2 -NR 2 C(=NR)NR 2 -NR 2 -N=XCHR 2 or -C(O)NIRSO 2 E 2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, C 1 8 alkyl, C2-8 alkenyl, C 28 alkynyl, alkylaryl, arailcyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino; each X individually is a direct bond, substituted or unsubstituted. C1_4 methylene chain, 0, S, NW S(0 2 or N(0) containing one or two CI- 4 substituted or unsubstituted methylene chains; X at different places may be same or different; B is IH, -halo, -CN, -Nfl 2 -(CH 2 ,-C(=NR)NIR 5 -(CH 2 )n-NHWR, (CH 2 4 )NR 5 -(CH 2 ).-OR 4 8 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; B and B may be same or different; 2 2 There may be more than one similar or different W groups present on E when E 2 is a cyclic group Of More than 5 atoms; p is 1 except that when EB 2 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 R'; 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; WO 02/34711 WO 0234711PCT/USOI/32582 Each V and V1 individually is selected from R' and N-alkyl substituted carboxamidyl CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N N- disubstituted carboxamidyl of the formula -CONR 1 R 2 where RI and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different; mono- or disubstituted sulfonamides of the formula S0 2 NHTR or -SO 2 NRIR 2 and methylene- or polymethylene chain-extended variants thereof; Each W 4 and R5~ individually is H, -(CH 2 )nOH, -C(O)0R 6 -C(O)SR 6 -(CH 2 )n C(O)NR 7 R 8 -O-C(O)-O-R 7 an amnino acid or a dipeptide; Bach R 6 is H, R -C(R 7 )(Rg)-(CH 2 )n-O-C(O)-R 9 -(CH- 2 )-C(R 7 9 -(CH 2 C(R 7 )(R 8 9 or -C(R 7 2 )n-O-C(O)-O-R 9 and Each R 7 R' and R' 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 CH 2 CO 2 alkyl. WO 02/34711 WO 0234711PCT/USOI/32582 2. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OH, -OS0 2 CF 3 and and R' is selected from the group consisting of CH 3 H "YN 0 yN GBC 3 0 CH 3 H CH 3 0 H 0 H Y N~ CH 3 0 H [3CF, 0 CH 3 H N CH 3 0 H H 0 0 H -CO 2 MEM, 0CH 0 CR 3 H3 CH 3 H N ,-NOH H Boo CH 3 3 CH 3 and -CH 2 NH 2 and pharmaceutically acceptable salts thereof, and prodrugs thereof.
291. WO 02/34711 WO 0234711PCT/USOI/32582 3. The compound of claim 1 represented by the structure H wherein R is selected from the group consisting of -OBn, -OH, -OSO 2 CF 3 0 C CH:C3 CHO 0 CHO 0 -0O0 /and -OCH 3 and R' is selected from the group consisting of -CHO, -CO 2 H, and -CO 2 MEM; and pharmaceutically acceptable salts thereof; and procinigs thereof. 292 WO 02/34711 PCT/US01/32582 4. The compound of claim 1 represented by the structure R COBn R' wherein R is -OSO 2 CF 3 and R' is selected from the group consisting of CH 3 H -CHO, -CO2H, N3'.CH; and pharmaceutically acceptable salts thereof; 0 and prodrugs thereof. WO 02/34711 WO 0234711PCT/US01/32582 The compound of claim 1 by the structure BnO 2 wherein R is selected from the group consisting -OBn, -OH, -OSO 2 CF 3 SD S HGC 0 0 -3C S aN N) N H 3\ N Ch 3 I' S Gil 3 CH, CH OH Gi 2 CH 3 Gl 2 O CH 3 CH-I OH /=TMS GCl I OH' CH-O Gil 3 CH 3 CHOI 294 WO 02/34711 WO 0234711PCT/USO1/32582 OHC N CH 2 OH ~CH (S BnU 2 c OH 5 OH ,and HOH C _C and R' is selected from the group consisting of -CHJO, -CO 2 H, and -CO 2 MEM; and pharmaceutically acceptable salts thereof; and prodrugs thereof WO 02/34711 WO 0234711PCT/USOI/32582 6. The compound of claim 1 represented by the structure H *wherein R is selected from the group consisting of S S0 3 S 0 0 HGC S NN N H3C /O S N 01 Ui1 3 N CH 2 Gil: C 3 GCHI 3 OH CH 2 H 3 G H C CH G 3 Gil 2 Gil 3 5 OH GHl 2 Oil CH 3 GH 3 WO 02/34711 WO 0234711PCT/USO1/32582 CH 2 O ZL-,OH' OH BnCO 2 HOH C-- Boc OH OH and and pharmaceutically acceptable salts thereof, and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 7. The compound of claim I represented by the structure wherein R is selected from the group consisting of S H 3 C- 0 0 I H3C aN1N 0 NN CI-'3 CIT 2 S CH" 3 Gil 3 C 0 3 H CH 2 x- OH CH 2 /OH ~CH CH 3 CH 3 OH, CH-' 2 298 WO 02/34711 WO 0234711PCT/USOI/32582 OH OHS 2C- HOHC OH OHGiCH, N H NH 2 0 OH C 3 CH 3 rG/ H2 CH 2 01 0 NH, HOH 2 C 0 0 -OCR, CH, and S NH, and R' is selected from the group consisting of CH 3 "_CH 3 CH 3 CH3 1 WO 02/34711 WO 0234711PCT/USO1/32582 2 "x CH3 ;H CH 3 CH 3 'OH -0 1 CH 3 CH 3 3 N 2H CH 3 cH 3 C 'OH OH ,and CH 3 CH 3 and pharmaceutically acceptable salts thereof, arnd prodnigs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 8. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of S 2 0 -0-01 -OBn, -OGH 3 and prodrugs thereof. ;and pharmaceutically acceptable salts thereof; and WO 02/34711 WO 0234711PCT/USO1/32582 9. The compound of claim I represented by the structure wherein R is selected from the group consisting of /TIPS O0C3 _O N ,and /-NH 200 and R' is -H or K On; and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO 2 CF 3 ,-CH=CH 2 and -H; 0 S R' is selected from the group consisting of -CHO, -CO 2 H, and -CO 2 MEM; and R' is selected from the group consisting of 200 CH 3 H CH, J0C Cii, -CO 2 MEM, N 7 N N CH3 CH GB 3 GB 3 H N "YH 0 H N~ CF 0 H N CH 3 .0 CH 3 CH 3 and CO 2H 0 and pharmaceutically acceptable salts thereof;, and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 11. The compound of claim 1 represented by the structure NH 0 NHX R N H HICO 2 C t wherein R is selected from the group consisting of -OBn, 0OH, 0OS0 2 CF 3 ,CH=CH 2 0 R' is -H or -IBoc; and R" is -CO 2 MEM or -CO 2 H; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 304 WO 02/34711 WO 0234711PCT/USOI/32582 12. The compound of claim 1 represented by the structure wherein R is -CH 3 and R' is selected from the group consisting of Gil 3 CCH CH4 3 CHl 3 CH 3 CH, 3 CH 3 0 Gil 3 CH 3 Gil 3 GilC 3 OH CH1 E 3 Gil CH 3 OH OH 0 WO 02/34711 PCT/USO1/32582 OH OH1 -0 'and OH 0 or NHR' -No or NHR'- 1I and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 13. The compound of claim 1 represented by the structure wherein R is R' is selected from the group consisting of CHCH 2CH 3 CE 3 CH 3 CH 3 C 3 CH 3 CHE OH -"CH 3 CH 3 3 CF 3 ,3, CH 3 0 CH 3 CH 3 3 fN ~~CH OH ~C 3 OH 0, 307 WO 02/34711 PCT/USO1/32582 -01 OH 0 T1RM=~ -No NHR-N GE C 3 and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 PCT/US01/32582 14. The compound of claim 1 represented by the structure wherein R is and -CH=CH 2 and R' is selected from the group consisting of 0 CH 3 CH, ,and CH eo' and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 The compound of claim 1 represented by the structure wherein R is -GEL 3 and R' is selected from the group consisting of CH 3 CF, 2' CH 3 CH 3 Gl 3 O CEX 3n -0 ~CH 3 ~CH 3 CH 3 ,CH 3 CE C CH 3 NH 2 ,"CH, 3 CH 3 and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 16. The compound of claim 1 represented by the structure 53 1 wherein at least one R is selected from the group consisting of -OCH 3 -OH, -OSO 2 CF 3 -CH=CH 2 -OCH 2 CO 2 C 2 H 5 -OCII 2 COMT1 2 0-0 0 0H 3H'' CH 3 OAc 'N o,--OAc -O13n, -OH, -OSO 2 CF 3 OCH- 3 -OBn, -OBn, and -CH=CH 2 R'is selected from the group consisting of NH -CHO, -C0 2 -CO 2 MEM, Ho 400 WO 02/34711 WO 0234711PCT/USO1/32582 CH 3 K OH NH N-OH ,N& H ,and WO 02/34711 PCT/USO1/32582 H and R" is selected from the group consisting of -CH 3 and -Bn; and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 17. The compound of claim 1 represented by the structure wherein at least one R is selected from the group consisting of _CH=CH 2 -OSO 2 CF 3 -OCH 2 CO 2 C 2 H 5 -OCH 2 CONI{ 2 I 0 ,-C4,11 H -C 3 ,8 H 0 CH 3 3 -O-CH 2 -CH,-OAc, -OH, CH 3 -OCH 2 CO 2 H, -O-CH 2 -CH 2 -OH, -CH(OH)CH 2 OH, -CH 2 OH, -CO 2 H, O -OBn, -OH, -OCH 3 -OBn, -OH, -0C 2 H 5 -OBn, -OGH 3 and -GH(OH)CH 3 and R' is selected from the group consisting of -CH 3 -CH 2 C 6 H 5 -Bn, and pharmaceutically acceptable salts thereof; and prodrugs thereof 314 WO 02/34711 WO 0234711PCT/USO1/32582 18. The compound of claim 1 represented by the structure wherein at least one R is selected from the group consisting of -CH=CH 2 -CH(OM'CH 2 OH, -CH=O, -CH 2 OH, -CO 2 H, -OCH 3 -CH=CH 2 and pharmaceutically acceptable salts thereof; and prodrugs thereof. 315 WO 02/34711 PCT/US01/32582 19. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of halo and -B(OH) 2 RI is selected from the group consisting of -OCH 3 -OBn; R2 is selected from the group consisting of 0 -OCH3, -OC 2 H 5 -OCH(CH 3 2 and C(CH3) R3 is selected from the group consisting of-H, -OH, -OBn; and R4 is -OBn or and pharmaceutically acceptable salts thereof; and prodrugs thereof. 20. The compound of claim 19 wherein said halo is -Br. WO 02/34711 PCT/US01/32582 21. The compound of claim 1 represented by the structure 0 0 and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/US01/32582 22. The compound of claim 1 represented by the structure 00 -CH- 3 -C 2 H 5 -CH(CH 3 2 C(CH 3 )A R' is selected from the group consisting of-O13n, -OH, -OSO 2 CF 3 and -CH=CH 2 R" is selected from the group consisting Of -CO 2 H, -CO 2 MEM, or -CHO; and is selected from the group consisting of CHR 3 -CH 3 CH 3 2 5 H C U 3 C H CR' 3 CH 3 CHXN 'C 3 ~H _"CR 3 and H;and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 23. The compound of claim 1 represented by the structure NH NHZ N& H RONHW R'0 2 C 0 wherein R is selected ftrm the group consisting of 0 -CH 3 -C 2 H 5 -CH(CH 3 2 C(H and -H1; R' is -H or alkyl; and R" is selected from the group consisting of C H 3C 3 CH 3 C CH 3 CH,, CH,, -<-CH 2 CF CH 3 CH 3 CH 3 CA CH 3 and C and pharmaceutically acceptable salts thereof, and prodrugs thereof. 24. The compound of claim 23 wherein said alkyl is CH 3 WO 02/34711 WO 0234711PCT/USOI/32582 The compound of claim 1 represented by the structure HH NN H N-O -CF 3 CF 3 H- CF 3 /N-6 F H -N 0- F H N-b 3-N N NC H N N_ S a OMe' N H WO 02/34711 WO 0234711PCT/USO1/32582 N \/X H OH N-b N N N N N H OH 1 \H N- O H H H HH N H N OH NNN NN I OH H 3 H N N N -C H H N &OH N OH CH3 H N~N H N N H N N -OH, N NH 2 IN-: NH 2 N Cl N /N- WO 02/34711 WO 0234711PCT/USOI/32582 z~ 4 H H CHCN, CHNH 2 and/ R' is -CH=CH 2 and R" is -H or alkyl; arnd pharmaceutically acceptable salts thereof; and prodnigs thereof. 26. The compound of claim 25 wherein said alkyl is -CH 3 WO 02/34711 PCT/US01/32582 27. The compound of claim 1 represented by the structure wherein R is selected from the group consisting of -CH=CH 2 and R' is -H or alkyl; and R" is selected o s from the group consisting of BCH 3 Boc CH 3 and CH3 CH, thereof. CH 28. The compound of c and pharmaceutically acceptable salts thereof; and prodrugs laim 27 wherein said alkyl is -CH 3 323 WO 02/34711 PCT/US01/32582 29. The compound of claim 1 represented by the structure 2 N I R'OzC TO2O 0 wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of-CHO, -CO 2 H, and H O NH 2 H and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof. The compound of claim 29 wherein said alkyl is -CH 3 WO 02/34711 WO 0234711PCT/US01/32582 31. The compound of claim 1 represented by the structure pNI1 0 0 N OR -I H N& H N 0 wherein R is selected from the group consisting of -CH 3 -C 2 H 5 -CH 2 C 6 H 5 -C(CH 3 3 -CH 2 -CC1 3 OMe, OF~ 0 10 CH 3 0 CH )CH, ,and J CH 3 CH3 CH 3 and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 32. The compound of claim 31 wherein alkyl is CH 3 WO 02/34711 PCT/US01/32582 33. The compound of claim 1 represented by the structure R K R'O,CH 2 C wherein R is selected from the group consisting of NH 0 NH 2 -CHO, -CO 2 H, and and R' is -H or alkyl; and N H pharmaceutically acceptable salts thereof; and prodrugs thereof. 34. The compound of claim 33 wherein said alkyl is -CH 3 WO 02/34711 PCT/US01/32582 The compound of claim 1 represented by the structure 4 'NHR 2 .NHR" R'"O,C T O wherein at least one R is selected from the group consisting of -CH=CH2, -OCH3, -OBn, -OH, and R' is NH NH I NH 2 or fNH R" is selected from the group consisting of R" is selected from the group consisting of CH 3 CH CF 3 and CH 3 and is and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USO1/32582 36. The compound of claim I represented by the structure BnO, 0 wherein R is -CH 2 OII or) and W~ is -Boc, or and pharmaceutically acceptable salts thereof; and prodrugs thereof. WO 02/34711 WO 0234711PCT/USOI/32582 37. The compound of claim 1 represented by the structure R R' NI R' wherein R is -OCH 3 -OH, -OSO 2 CF 3 -C(=NII)NH 2 and -H; R' is Y Akl or -NH 2 0~A~y NH and R" is halo, -CH=CH 2 -CO 2 CH 3 and NH 2 and pharmaceutically acceptable salts thereof; and prodrugs thereof. 38. The compound of claim 37 wherein said halo is -Br. WO 02/34711 PCT/US01/32582 39. The compound of claim 1 represented by the structure R' R R"O2C wherein R is selected from the group consisting of -CHO, -COzH, -COzMEM, NH N H R' is selected from the group consisting of-OBn, -OH, -OSO 2 CF 3 and -CH=CH 2 and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 40. The compound of claim 39 wherein said alkyl is -CH 3 WO 02/34711 PCT/USOI/32582 41. The compound of claim 1 represented by the structure o B 0- R wherein R is -CO 2 CH 3 and pharmaceutically acceptable salts thereof; and prodrugs thereof WO 02/34711 PCT/US01/32582 42. The compound of claim 1 represented by the structure wherein R is -H or -CO 2 H; R' is selected from the group consisting of-CHO, -C0 2 H, and NB o NH 2 N H and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 43. The compound of claim 42 wherein said alkyl is -CH 3 332 WO 02/34711 PCT/US01/32582 44. The compound of claim 1 represented by the structure NH 0 MNHR N H H R"0,CN- R"O C 0 wherein R is selected from the group consisting of -CH(OH)-CH 2 0H, -CHO, and -CH(OH)-CH=CH 2 R' is -Boc or and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof. The compound of claim 44 wherein said alkyl is -CH 3 I WO 02/34711 PCT/US01/32582 46. The compound of claim 1 represented by the structure Br wherein R is -N 1 /~NH H Hor B NH 2 NHBoc 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. 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. 334 WO 02/34711 PCT/US01/32582 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. 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 ofheparin, 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. WO 02/34711 PCT/US01/32582 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 0 wherein R is alkyl and R' is selected from the group consisting of >~CH 3 ~CH CHCH CH 3 CH, CH 3 GilC 3 CH3 CH, CH 3 OH SCH.' CH 3 WO 02/34711 WO 0234711PCT/USOI/32582 -~CF 3 N C, CH 3 CR 3 CH 3 0 OH OH and OH 0 or NHWE -No or NHR' C- 3 and pharmaceutically acceptable salts thereof; and prodrugs thereof I 64. A compound having the structure of claim 1 and being substantially as herein described and exemplified. A method for inhibiting serine protease in a patient, said method being substantially as herein described and exemplified. 66. A method for inhibiting the coagulation cascade and preventing or limiting coagulation, said method being substantially as herein described and exemplified. 67. A method for inhibiting the formation of emboli or thromboli in blood vessels, said method being substantially as herein described and exemplified. 68. A method for treating at least one condition selected from the group consisting of thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thromboarteritis, said method being substantially as herein described and exemplified. 69. A method for inhibiting thrombus formation following angioplasty, said method being substantially as herein described and exemplified. A method for preventing arteria occlusion following thrombolytic therapy said method being substantially as herein described and exemplified. 71. A method for treating metastatic diseases, said method being substantially as herein described and exemplified. 72. A method for treating a patient in need of an anti-inflammatory agent, said method being substantially as herein described and exemplified. 73. A method for inhibiting in vitro clotting of blood, said method being substantially as herein described and exemplified. 74. An extraarpereal device having a coating therein which comprises a compound according to any one of claims 1-47 and 64. A method for detecting fUture presence of a serine protease, said method being substantially as herein described and exemplified. Dated this 31st day of March 2003 BIOCRYST PHARMACEUTICALS, NC By HODGKINSON OLD McTNNES Patent Attorneys for the Applicant 338 2555F
AU2002213393A 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors Expired AU2002213393B2 (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
AU2002213393A1 AU2002213393A1 (en) 2002-07-11
AU2002213393B2 true AU2002213393B2 (en) 2007-02-15

Family

ID=26934639

Family Applications (2)

Application Number Title Priority Date Filing Date
AU1339302A Pending AU1339302A (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors
AU2002213393A Expired AU2002213393B2 (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
AU1339302A Pending AU1339302A (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors

Country Status (8)

Country Link
AU (2) AU1339302A (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 (42)

* 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
EP1332129A2 (en) * 2000-11-07 2003-08-06 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
HUP0400651A2 (en) * 2000-11-07 2004-06-28 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors and pharmaceutical compositions containing them
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
WO2002100347A2 (en) * 2001-06-11 2002-12-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6818787B2 (en) 2001-06-11 2004-11-16 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
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
US7122559B2 (en) 2003-02-11 2006-10-17 Bristol-Myers Squibb Company Phenylglycine derivatives useful as serine protease inhibitors
EP1594845A4 (en) 2003-02-11 2008-05-21 Bristol Myers Squibb Co 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
EP1745800A4 (en) * 2004-04-26 2009-11-18 Ono Pharmaceutical Co Novel blt2-mediated disease, and blt2 binding agent and compound
FR2871157A1 (en) * 2004-06-04 2005-12-09 Aventis Pharma Sa BIARYL AROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF
NZ554737A (en) 2004-11-04 2011-04-29 Xenoport Inc Gabapentin prodrug sustained release oral dosage forms
PE20061117A1 (en) 2005-01-10 2006-10-13 Bristol Myers Squibb Co DERIVATIVES OF PHENYLGLYCINAMIDE AS INHIBITORS OF FACTOR VIIa
US7754717B2 (en) 2005-08-15 2010-07-13 Amgen Inc. Bis-aryl amide compounds and methods of use
WO2007087442A2 (en) 2006-01-25 2007-08-02 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
KR20090116782A (en) 2007-02-06 2009-11-11 베링거 인겔하임 인터내셔날 게엠베하 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
AR065948A1 (en) 2007-04-06 2009-07-15 Neurocrine Biosciences Inc GONADOTROPINE LIBERATING HORMONE RECEIVER ANTAGONISTS AND PROCEDURES RELATED TO THEMSELVES
WO2008124614A1 (en) 2007-04-06 2008-10-16 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
KR20100111291A (en) 2008-02-07 2010-10-14 베링거 인겔하임 인터내셔날 게엠베하 Spirocyclic heterocycles, medicaments containing said compounds, use thereof and method for their production
WO2009138781A1 (en) 2008-05-13 2009-11-19 Astrazeneca Ab Fumarate salt of 4- (3-chloro-2-fluoroanilino) -7-methoxy-6- { [1- (n-methylcarbamoylmethyl) piperidin- 4-yl] oxy}quinazoline
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
EP3532057B1 (en) * 2016-10-31 2022-12-21 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
TW201920081A (en) 2017-07-11 2019-06-01 美商維泰克斯製藥公司 Carboxamides as modulators of sodium channels
TWI794742B (en) 2020-02-18 2023-03-01 美商基利科學股份有限公司 Antiviral compounds
CN117120444A (en) 2021-04-16 2023-11-24 吉利德科学公司 Method for preparing carbanucleoside using amide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999041231A1 (en) * 1998-02-17 1999-08-19 Ono Pharmaceutical Co., Ltd. Amidino derivatives and drugs containing the same as the active ingredient

Family Cites Families (3)

* 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
EP0987274A1 (en) 1998-09-15 2000-03-22 Hoechst Marion Roussel Deutschland GmbH Factor VIIa Inhibitors
BR0008755A (en) 1999-01-13 2007-05-29 Genentech Inc serine protease inhibitor compounds, composition, method of inhibiting tf / factor viia, factor xa, thrombin or calicrein activity, method of treating a tf / factor viia, factor xa, thrombin or calicrein mediated dysfunction and method of prevention of thrombosis or treatment of abnormal thrombosis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999041231A1 (en) * 1998-02-17 1999-08-19 Ono Pharmaceutical Co., Ltd. Amidino derivatives and drugs containing the same as the active ingredient

Also Published As

Publication number Publication date
NZ526003A (en) 2005-09-30
CA2426430C (en) 2014-10-07
AU1339302A (en) 2002-05-06
IL155202A0 (en) 2003-11-23
HK1062676A1 (en) 2004-11-19
DK1383731T3 (en) 2009-12-07
CA2426430A1 (en) 2002-05-02
MXPA03009130A (en) 2004-02-26
WO2002034711A1 (en) 2002-05-02

Similar Documents

Publication Publication Date Title
AU2002213393B2 (en) Biaryl compounds as serine protease inhibitors
EP1383731B1 (en) Biaryl compounds as serine protease inhibitors
AU2002213393A1 (en) Biaryl compounds as serine protease inhibitors
JP4199309B2 (en) Novel acetamide derivatives and protease inhibition
JP4157601B2 (en) Substituted oxazolidine calpain and / or cathepsin B inhibitor
KR100933652B1 (en) Activator of Peroxysome Proliferative Responsive Receptor δ
EP1406609B1 (en) Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
US20170152206A1 (en) IRE-1alpha INHIBITORS
US20090048219A1 (en) Organic nitric oxide donor salts of nonsteroidal antiinflammatory compounds, compositions and methods of use
JP2013121919A (en) Plasma kallikrein inhibitor
JP3545416B2 (en) Huperzine A derivatives, their production and their use
CN104610230A (en) Compounds for the treatment of cancer
AU2002249812A1 (en) Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
TWI403320B (en) Compounds and methods for inhibiting the interaction of bcl proteins with binding partners
EA010017B1 (en) Substituted arylthiourea derivatives useful as inhibitors of viral replication
CZ20021528A3 (en) Polycyclic derivatives of dihydrothiazole, process of their preparation and their use as medicaments
AU2007243403A1 (en) Anti-viral agents that activate RNase L
WO2007016136A2 (en) Organic nitric oxide enhancing salts of cyclooxygenase-2 selective inhibitors, compositons and methods of use
CN108752412B (en) Boswellic acid derivatives and their use
CN114014866A (en) 5, 7-dihydrofuro [3,4-d ] pyrimidine compound and preparation method and application thereof
EP0738705B1 (en) Gamma-diketone compound having platelet aggregation inhibiting effect
WO2004024186A2 (en) Treatment of cyclooxygenase-3 mediated diseases and disorders
JP7324930B2 (en) Carbamate-substituted styryl sulfone compound, method for producing the same, and use thereof
KR101096427B1 (en) Novel 4-aryl-4-oxobutanoic acid amide derivates or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical compositions containing the same as an active gredient
JP2837318B2 (en) Angiotensin II antagonistic pyridine derivative

Legal Events

Date Code Title Description
FGA Letters patent sealed or granted (standard patent)
MK14 Patent ceased section 143(a) (annual fees not paid) or expired