WO2001055082A2 - Intermediates for biologically active compounds - Google Patents

Intermediates for biologically active compounds Download PDF

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Publication number
WO2001055082A2
WO2001055082A2 PCT/US2001/000652 US0100652W WO0155082A2 WO 2001055082 A2 WO2001055082 A2 WO 2001055082A2 US 0100652 W US0100652 W US 0100652W WO 0155082 A2 WO0155082 A2 WO 0155082A2
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WIPO (PCT)
Prior art keywords
cιo
alkyl
alkenyl
alkynyl
halo
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PCT/US2001/000652
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French (fr)
Inventor
Mark Joseph Mulvihill
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Rohm And Haas Company
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Publication date
Priority claimed from US09/493,865 external-priority patent/US6376548B1/en
Application filed by Rohm And Haas Company filed Critical Rohm And Haas Company
Priority to PCT/US2001/000652 priority Critical patent/WO2001055082A2/en
Priority to AU2001232752A priority patent/AU2001232752A1/en
Priority to US09/804,704 priority patent/US20010039343A1/en
Publication of WO2001055082A2 publication Critical patent/WO2001055082A2/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom
    • A01N47/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom containing —O—CO—O— groups; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/12—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, neither directly attached to a ring nor the nitrogen atom being a member of a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/24—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing the groups, or; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N57/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds
    • A01N57/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having alternatively specified atoms bound to the phosphorus atom and not covered by a single one of groups A01N57/10, A01N57/18, A01N57/26, A01N57/34
    • A01N57/04—Biocides, pest repellants or attractants, or plant growth regulators containing organic phosphorus compounds having alternatively specified atoms bound to the phosphorus atom and not covered by a single one of groups A01N57/10, A01N57/18, A01N57/26, A01N57/34 containing acyclic or cycloaliphatic radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen 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
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/02—Compounds containing any of the groups, e.g. carbazates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
    • C07F9/44—Amides thereof
    • C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4407—Amides of acyclic saturated acids which can have further substituents on alkyl

Definitions

  • This invention relates to intermediate compounds which are useful to make enhanced propertied pesticides which can be used as fungicides, herbicides, insecticides, rodenticides or biocides.
  • An enhanced propertied pesticide is one which overcomes one or more deficiencies of a traditional pesticide for the end user application.
  • the traditional pesticide may be slow acting and/or may have a limited spectrum of activity and/or may not possess a sufficiency of rain- fastness in the field to have a good residual activity.
  • many traditional pesticides In order to be effective against the targeted pest, many traditional pesticides must be applied in an undesirably high use rate from an environmental perspective. This can cause crop damage, especially with herbicides, because of lower than desired selectivity.
  • the targeted pest builds up a resistance to the applied pesticide and requires larger amounts of it in order to be controlled.
  • Many traditional tank mixes of traditional pesticides cannot be accomplished because of their mutual incompatibility. Additionally, separately applied pesticide combinations arrive at the target pest at different rates, thus muting some of their mutual effectiveness. Some traditional pesticides have adverse water solubilities for their intended application. Many traditional pesticides are of the contact variety and hence possess no systemicity to completely protect the desired crop from the unwanted pest.
  • the intermediates of the present invention allow one to make enhanced propertied pesticides in order to overcome various deficiencies of traditional pesticides. These intermediate compounds are substituted with a moiety comprising a substituent which enhances or changes the properties of the subsequently made pesticidal compound.
  • This substituent can be tailored on the intermediate compound in order to increase the rate of desired pesticidal action, to increase residual control against the pest, to decrease the overall use rate of the pesticide, increase the selectivity of the pesticide, change the water solubility of the pesticide, and increase the systemicity of the pesticide which is made from the intermediate compound.
  • the substituent on the intermediate compound may optionally comprise a pesticidal compound which may be the same as or different from the pesticidal compound on which substitution of the intermediate compound occurs. This allows a combination of pesticides to be applied simultaneously as a single compound to the target pest or its locus.
  • intermediate compounds are additionally useful to make enhanced propertied pharmaceutical compounds for both human and veterinary application.
  • the chemical modification of drugs into labile derivatives with enhanced physicochemical properties that enable better transport through biological barriers is a useful approach for improving- drug delivery.
  • This modification can be conveniently practiced on ionizable molecules containing moieties such as a carboxy group, an amino group or a hydroxy group that can be utilized for derivatization in order to modify their ionization at physiological pH and to render desirable partition and solubiHty properties.
  • the enhanced propertied drug is non-toxic and, when administered to a warm-blooded animal including a human being, is enzymatically and/or chemically cleaved in such a manner as to release the drug at its target or site of activity, quantitatively and at a desirable rate, while the remaining cleaved moiety remains non-toxic and is metabolized in such a manner that non-toxic metabolic products are produced. It is naturally also desirable that the enhanced propertied drug can be provided without excessive costs in connection with its production, in particular without an appreciable loss of the unmodified drug itself during its production and recovery, since the unmodified drug is usually the more expensive part of the enhanced propertied drug.
  • the substituent on the intermediate compound may optionally comprise a pharmaceutical compound which may be the same as or different from the pharmaceutical compound on which substitution of the intermediate compound occurs.
  • a pharmaceutical compound which may be the same as or different from the pharmaceutical compound on which substitution of the intermediate compound occurs.
  • the intermediate used to react with either the pesticide or the drug in providing the enhanced propertied pesticide or pharmaceutical drug, respectively, should advantageously be stable and still be reasonably reactive.
  • the enhanced propertied pesticides and pharmaceuticals which may be produced using the intermediates of this invention can be collectively termed enhanced propertied biologically active compounds.
  • Such enhanced propertied biologically active compounds may be described by, but not limited to, a compound of Formula I
  • G 10 , G 11 and G 20 are each independently an oxygen atom or a sulfur atom
  • G 21 is an oxygen atom, a sulfur atom or NR 3 ,
  • X 1 is an oxygen atom, a sulfur atom, a phosphorous atom or a nitrogen atom attached to Z 1 ,
  • X 2 is an oxygen atom,. a sulfur atom, a phosphorous atom, a nitrogen atom or a carbon atom attached to Z 2 , m, q and t are each independently 0 or 1,
  • Z 1 (X 1 ) is a biologically active moiety when m is 1 wherein Z 1 (X 1 ) m -H represents the biologically active compound,
  • Z 1 (X 1 ) when m is 0, is a hydrogen atom, halo, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, ace tylamino alkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkyl
  • Z 2 (X 2 ) q is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkyl
  • heteroaryl heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SOsNR 3 R 4 and NR 3 R 4 , heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO 2 NR 3 R 4 and NR 3 R 4 , alkylcarbonylalkyl, alkenylcarbonylalkyl, alkyny
  • G 30 is an oxygen atom or a sulfur atom
  • G 31 is an oxygen atom, a sulfur atom or NR 3 , t' and d are each independently 0 or 1, X 3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z 3 when t' is 0, a nitrogen atom attached to Z 3 when t' is 1 and G 31 is NR 3 , or a carbon atom attached to Z 3 when t' is 1 and G 31 is an oxygen atom or a sulfur atom,
  • Z 3 (X 3 )d(G 31 )t ' is a biologically active moiety when d is 1 wherein Z 3 (X 3 )d(G 31 )t ' -H represents the biologically active compound,
  • Z 3 (X 3 )d when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkylalkyl, carboxycycloalkeny
  • R 2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl,
  • one intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula
  • G 10 and G 11 are each independently an oxygen atom or a sulfur atom
  • G 30 is an oxygen atom or a sulfur atom
  • G 31 is an oxygen atom
  • t' and d are each independently 0 or 1
  • X 3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z 3 when t' is 0, a nitrogen atom attached to Z 3 when t' is 1 and G 31 is NR 3 , or a carbon atom attached to Z 3 when t' is 1 and G 31 is an oxygen atom or a sulfur atom,
  • Z 3 (X 3 )d(G 31 )f is a biologically active moiety when d is 1 wherein Z 3 (X 3 )d(G 31 )t'-H represents the biologically active compound,
  • Z 3 (X 3 )d when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxy alkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkylalkyl, carboxycycloalkeny
  • R 2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl,
  • R 3 , R 4 and R 5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkynyl,
  • Y 2 is chloro, bromo, iodo, OCCI3 . mesyl or tosyl,
  • R 12 is alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkynyl, carboxyalkyl
  • Y 1 is chloro, bromo, iodo or SR 12 .
  • Y 1 is chloro, bromo or iodo.
  • Y 1 is SR 12 .
  • R 12 is alkyl.
  • Y 2 is chloro, bromo or iodo.
  • R 2 is a hydrogen atom.
  • d is 0.
  • the intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula wherein
  • G 10 and G ⁇ are each independently an oxygen atom or a sulfur atom, RXs
  • G 30 is an oxygen atom or a sulfur atom
  • G 31 is an oxygen atom
  • t' and d are each independently 0 or 1
  • X 3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z 3 when t' is 0, a nitrogen atom attached to Z 3 when t' is 1
  • G 31 is NR 3 , or a carbon atom attached to Z 3 when t' is 1 and G 31 is an oxygen atom or a sulfur atom
  • Z 3 (X 3 )d(G 31 )f is a biologically active moiety when d is 1 wherein Z 3 (X 3 )d(G 31 )t'-H represents the biologically active compound,
  • Z 3 (X 3 )d when d is 0 and t' is 1, is a hydrogen atom, (C ⁇ -C2 0 )alkyl, (Ci- C ⁇ o)alkylcarbonyloxy(C ⁇ -C ⁇ o)alkyl, (Ci-C2o)alkylcarbonyl, hydroxy(Ci-C2o)alkyl, (Ci- C ⁇ o)alkylsulfonyl(C ⁇ -C ⁇ o)alkyl, acetylamino(C ⁇ -C ⁇ o) alkyl, halo(C ⁇ -C2o) alkyl, (C2- C ⁇ o)alkenyl, acetylamino(C2-C ⁇ o)alkenyl, halo(C2-C ⁇ o)alkenyl, (C2-C ⁇ o)alkynyl, halo(C2- C ⁇ o)alkynyl, cyclo(C3-C8)alkyl, cyclo(C3
  • SiR 3 R 4 R 5 aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, (C ⁇ -C ⁇ o)alkyl, (C ⁇ -C ⁇ o)alkylsulfonyl(C ⁇ - C ⁇ o)alkyl, (C2-C10) alkenyl, (C2-C 10) alkynyl, halo(C ⁇ -C ⁇ o)alkyl, halo(C2-C ⁇ o)alkenyl, halo(C 2 -C ⁇ o)alkynyl, (C ⁇ -C ⁇ o)alkoxy, halo(C ⁇ -C ⁇ o)alkoxy, SO 2 NR 3 R 4 and NR 3 R 4 , ar(C ⁇ - C ⁇ o)alkyl, ar(C2-C ⁇ o)alkenyl, ar(C2-C 10) alkynyl, arcyclo(C3-C8)alkyl, ar(
  • R 2 is a hydrogen atom, (C1-C20) alkyl, (C2-C 10) alkenyl, (C2-C1Q) alkynyl, (Ci- C ⁇ o)alkoxy(C ⁇ -C ⁇ o)alkyl, (C ⁇ -C ⁇ 0 )alkoxy(C2-C ⁇ o)alkenyl, (C ⁇ -C ⁇ 0 )alkoxy(C 2 -C ⁇ o)alkynyl, (C ⁇ -C ⁇ o)alkylthio(C ⁇ -C 10 )alkyl, (C ⁇ -C 10 )alkylthio(C2-C ⁇ o)alkenyl, (C ⁇ -C ⁇ o)alkylthio(C 2 - C ⁇ o)alkynyl, carboxy, a carboxylate salt, carboxy(C ⁇ -C 20 )alkyl ; carboxy(C 2 -C 2 o)alkenyl, carboxy(C2-C2o)alkynyl
  • R 3 , R 4 and R 5 are each independently a hydrogen atom, (C ⁇ -C 2 o)alkyl, cyclo(C3- C 8 )alkyl, cyclo(C3-C 8 )alkenyl, cyclo(C3-C 8 )alkyl(C ⁇ -C ⁇ o)alkyl, cyclo(C 3 -C 8 )alkyl(C 2 - C ⁇ o)alkenyl, cyclo(C3-C8)alkyl(C2-C ⁇ o)alkynyl, eyclo(C3-C8)alkenyl(C ⁇ -C ⁇ o)alkyl, cyclo(C3-C8)alkenyl(C2-C ⁇ o)alkenyl, cyclo(C3-C 8 )alkenyl(C2-C ⁇ o)alkynyl, carboxy(C ⁇ - C2o)alkyl, carboxy(C2-C ⁇ o)alkenyl, carboxy(C2-
  • cyclo(C 3 - Cs)alkyl cyclo(C3-C 8 )alkenyl, cyclo(C3-C 8 )alkyl(C ⁇ -C ⁇ o)alkyl, cyclo(C3-C 8 )alkyl(C 2 - C ⁇ o)alkenyl, cyclo(C3-C 8 )alkyl(C2-C ⁇ o)alkynyl, cyclo(C3-Cs)alkenyl(C ⁇ -C ⁇ o)alkyl, cyclo(C3-C8)alkenyl(C2-C ⁇ o)alkenyl, cyclo(C3-C 8 )alkenyl(C2-C ⁇ o)alkynyl, carboxy(C ⁇ - C2o)alkyl, carboxy(C2-C 10) alkenyl, carboxy(C2-C ⁇ o)alkynyl, heterocyclyl, heterocyclyl(C ⁇ -C ⁇ o)alkyl, hetero
  • Y 1 is chloro, bromo, iodo, OCCI3, OR 12 , SR 12 or N-hydroxysuccinimide
  • Y 2 is chloro, bromo, iodo, OCC , mesyl or tosyl,
  • R 12 is (C ⁇ -C 2 o)alkyl, cyclo(C 3 -C 8 )alkyl, cyclo(C3-C 8 )alkenyl, cyclo(C3-Cs)alkyl(C ⁇ - C ⁇ o)alkyl, cyclo(C3-C8)alkyl(C 2 -C ⁇ o)alkenyl, cyclo(C3-C8)alkyl(C 2 -C ⁇ o)alkynyl, cyclo(C3- C 8 )alkenyl(C ⁇ -C ⁇ o)alkyl, cyclo(C3-C 8 )alkenyl(C2-C ⁇ o)alkenyl, cyclo(C3-C8)alkenyl(C2- C ⁇ o)alkynyl, carboxy(C ⁇ -C2o)alkyl, carboxy (C2-C2o) alkenyl, carboxy (C2-C2o) alkenyl, carboxy (C2-C
  • Y 1 is chloro, bromo or iodo. In another more preferred first embodiment of this invention, Y 1 is SR 12 .
  • R 12 is (Ci- C ⁇ 0 )alkyl.
  • Y 2 is chloro, bromo or iodo.
  • R 2 is a hydrogen atom.
  • d is 0.
  • one intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula
  • G 10 , G 11 and G 20 are each independently an oxygen atom or a sulfur atom
  • G 21 is an oxygen atom
  • q and t are each independently 0 or.l
  • R 1 is
  • G 31 is an oxygen atom, a sulfur atom or NR 3 , t' and d are each independently 0 or 1,
  • X 3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z 3 when t' is 0, a nitrogen atom attached to Z 3 when t' is 1 and G 31 is NR 3 , or a carbon atom attached to Z 3 when t' is 1 and G 31 is an oxygen atom or a sulfur atom,
  • Z 3 (X 3 )d(G 31 )f is a biologically active moiety when d is 1 wherein Z 3 (X 3 )d(G 31 )t ' -H represents the biologically active compound, Z 3 (X 3 )d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycl
  • R 2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl,
  • R 3 , R 4 and R 5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkynyl,
  • X 2 is an oxygen atom, a sulfur atom, a phosphorous atom, a nitrogen atom or a carbon atom attached to Z 2 ,
  • Z 2 (X 2 ) q is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkyl
  • Z 2 (X 2 )q is halo, NR 3 R 4 , ⁇ (NR 3 R 4 R 5 ) + M " ⁇ , OR 3 , S(O)jR 3 or SO 2 NR 3 R 4 when both q and t are 0 wherein M " is halo, hydroxy, alkoxy or the anion of a carboxylic acid and j is 0, 1 or 2, Y 1 is chloro, bromo, iodo, OCCI3, OR 12 , SR 12 or N-hydroxysuccinimide,
  • R 12 is alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkynyl, carboxyalkyl
  • Y 1 is chloro, bromo, iodo or SR 12 . In another preferred second embodiment of this invention, Y 1 is chloro, bromo or iodo.
  • Y 1 is SR 12 .
  • R 12 is alkyl.
  • d is 0.
  • q is 0. In another preferred second embodiment of this invention, (d + q) is 1 or 2.
  • t is 1.
  • both q and t are 1 and X 2 is a carbon atom.
  • the intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula
  • G 10 , G 11 and G 20 are each independently an oxygen atom or a sulfur atom
  • G 21 is an oxygen atom, a sulfur atom or NR 3 , q and t are each independently 0 or 1, R ! is
  • G 30 is an oxygen atom or a sulfur atom
  • G 31 is an oxygen atom, a sulfur atom or NR 3 , t' and d are each independently 0 or 1, X 3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z 3 when t' is 0, a nitrogen atom attached to Z 3 when t' is 1 and G 31 is NR 3 , or a carbon atom attached to Z 3 when t' is 1 and G 31 is an oxygen atom or a sulfur atom, Z 3 (X 3 )d(G 31 )t' is a biologically active moiety when d is 1 wherein Z 3 (X 3 )d(G 31 )r-H represents the biologically active compound,
  • Z 3 (X 3 )d when d is 0 and t' is 1, is a hydrogen atom, (Ci-C2o)alkyl, (Ci- C ⁇ o)alkylcarbonyloxy(C ⁇ -C ⁇ o)alkyl, (C ⁇ -C2 0 )alkylcarbonyl, hydroxy(C ⁇ -C2o)alkyl, (Ci- C ⁇ o)alkylsulfonyl(C ⁇ -C ⁇ o)alkyl, acetylamino(C ⁇ -C ⁇ o)alkyl, halo(Ci-C2o)alkyl, (C 2 - C ⁇ o)alkenyl, acetylamino(C2-C ⁇ o)alkenyl, halo(C2-C ⁇ o)alkenyl, (C2-C ⁇ o)alkynyl, halo(C 2 - C ⁇ o)alkynyl, cyclo(C3-C8)alkyl, cycl
  • R 2 is a hydrogen atom, (C ⁇ -C2 0 )alkyl, (C 2 -C ⁇ c)alkenyl, (C 2 -C ⁇ o) alkynyl, (Ci-
  • halo(C 2 - C ⁇ o)alkenyl halo (C 2 -C ⁇ o) alkynyl, (C ⁇ -C ⁇ o)alkoxy, halo(C ⁇ -C ⁇ o)alkoxy, carboxy, (Ci- C 4 )alkoxycarbonyl, SO 2 NR 3 R 4 and NR 3 R 4 , ar(C ⁇ -C ⁇ o)alkyl, ar(C 2 -C ⁇ o) alkenyl, ar(C 2 - C ⁇ o)alkynyl, or ar(C ⁇ -C ⁇ o)alkyl J ar(C2-C ⁇ o)alkenyl, ar(C2-C ⁇ o)alkynyl substituted with one or more substituents independently selected from halo, (C ⁇ -C ⁇ o)alkyl, (C2- C ⁇ 0 )alkenyl, (C 2 -C ⁇ o)alkynyl, halo(C ⁇ -C ⁇ o)alkyl, halo(
  • Z 2 (X 2 ) q is halo, NR 3 R 4 , ⁇ (NR 3 R 4 R 5 ) + M ⁇ ⁇ , OR 3 , S(O) : R 3 or SO 2 NR 3 R 4 when both q and t are 0 wherein M ⁇ is halo, hydroxy, (C ⁇ -C 8 )alkoxy or the anion of a carboxylic acid and j is 0, 1 or 2,
  • Y 1 is chloro, bromo, iodo, OCCI3, OR 12 , SR 12 or N-hydroxysuccinimide
  • R 12 is (C ⁇ -C 20 )alkyl, cyclo(C 3 -Cs) alkyl, cyclo(C 3 -Cs) alkenyl, cyclo(C 3 -Cs)alkyl(C ⁇ -
  • Y 1 is chloro, bromo, iodo or SR 12 .
  • Y 1 is chloro, bromo or iodo.
  • Y 1 is SR 12 .
  • R 12 is (Ci- C ⁇ o)alkyl.
  • d is 0.
  • q is 0.
  • (d + q) is 1 or 2.
  • t is 1. In another more preferred second embodiment of this invention, both q and t are 1 and X 2 is a carbon atom.
  • one intermediate compound used for making enhanced propertied biologicaUy active compounds is a compound of the formula
  • G 10 and G 11 are each independently an oxygen atom or a sulfur atom, m is 0 or 1,
  • G 30 is an oxygen atom or a sulfur atom
  • G 31 is an oxygen atom
  • t' and d are each independently 0 or 1
  • X 3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z 3 when t' is 0, a nitrogen atom attached to Z 3 when t' is 1 and G 31 is NR 3 , or a carbon atom attached to Z 3 when t' is 1 and G 31 is an oxygen atom or a sulfur atom,
  • Z 3 (X 3 )d(G 31 )t' is a biologically active moiety when d is 1 wherein Z 3 (X 3 )d(G 31 )t'-H represents the biologicaUy active compound,
  • Z 3 (X 3 )d when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloaUcenylalkynyl, carboxycycloalkylal
  • R 2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl, cycloalkylalkenyl,
  • ZXX 1 is a biologicaUy active moiety when m is 1 wherein represents the biologicaUy active compound
  • Y 2 is chloro, bromo, iodo, OCCI3, mesyl or tosyl, or the biologicaUy active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
  • Y 2 is chloro, bromo or iodo.
  • R 2 is a hydrogen atom.
  • d is 0.
  • m is 0.
  • (d + m) is 1 or 2.
  • the intermediate compound used for making enhanced propertied biologicaUy active compounds is a compound of the formula
  • n G 10 and G 11 are each independently an oxygen atom or a sulfur atom.
  • m is 0 or 1
  • G 30 is an oxygen atom or a sulfur atom
  • G 31 is an oxygen atom
  • t' and d are each independently 0 or 1
  • X 3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z 3 when t' is 0, a nitrogen atom attached to Z 3 when t' is 1 and G 31 is NR 3 , or a carbon atom attached to Z 3 when t' is 1 and G 31 is an oxygen atom or a sulfur atom
  • Z 3 (X 3 )d(G 31 )f is a biologicaUy active moiety when d is 1 wherein Z 3 (X 3 )d(G 31 )t'-H represents the biologicaUy active compound
  • Z 3 (X 3 )d when d is 0 and t' is 1, is a hydrogen atom, (C ⁇ -C 2 o)alkyl, (Ci- C ⁇ o)alkylcarbonyloxy(C ⁇ -C ⁇ o)alkyl, (C ⁇ -C2o)alkylcarbonyl, hydroxy(Ci-C2o)alkyl, (Ci- C ⁇ o)alkylsulfonyl(C ⁇ -C ⁇ o)alkyl, acetylamino(C ⁇ -C ⁇ o)alkyl, halo(C ⁇ -C2o)alkyl, (C2- C ⁇ o)alkenyl, acetylamino(C2-C ⁇ o)alkenyl, halo(C2-C ⁇ o)alkenyl, (C2-C ⁇ o)alkynyl, halo(C2- C ⁇ o)alkynyl, cyclo(C3-C 8 ) alkyl, cyclo(C
  • R 2 is a hydrogen atom, (C ⁇ -C2 0 )alkyl, (C2-C ⁇ o)alkenyl, (C2-C ⁇ 0 )alkynyl, (Ci- C ⁇ o)alkoxy(C ⁇ -C ⁇ o)alkyl, (C ⁇ -C ⁇ o)alkoxy(C 2 -C ⁇ o)alkenyl, (C ⁇ -C ⁇ o)alkoxy(C2-C ⁇ o)alkynyl, (C 1 -C ⁇ o)alkylthio(C ⁇ -C ⁇ o)alkyl, (C ⁇ -C ⁇ o)alkylthio(C 2 -C ⁇ o)alkenyl, (C ⁇ -C ⁇ o)alkylthio(C 2 - C ⁇ o)alkynyl, carboxy, a carboxylate salt, carboxy(C ⁇ -C2o)alkyl, carboxy(C2-C2o)alkenyl, carboxy(C2-C2o)alkyny
  • R 3 , R 4 and R 5 are each independently a hydrogen atom, (Ci-C2o)alkyl, cyclo(C3- C 8 )alkyl, cyclo(C3-C 8 )alkenyl, cyclo(C3-C 8 )alkyl(C ⁇ -C ⁇ o)alkyl, cyclo(C3-C 8 )alkyl(C 2 - C ⁇ o)alkenyl, cyclo(C3-C8)alkyl(C 2 -C ⁇ 0 )alkynyl, cyclo(C3-C8)alkenyl(C ⁇ -C ⁇ o)alkyl, cyclo(C3-C 8 )alkenyl(C 2 -C ⁇ o)alkenyl, cyclo(C3-C8)alkenyl(C 2 -C ⁇ o)alkynyl, carboxy(C ⁇ - C2o)alkyl, carboxy(C2-C ⁇ o)alkenyl,
  • X 1 is an oxygen atom, a sulfur atom, a phosphorous atom or a nitrogen atom attached to Z 1 , Z 1 (X 1 )m is a biologicaUy active moiety when m is 1 wherein represents the biologicaUy active compound,
  • Z ⁇ when m is 0, is a hydrogen atom, halo, (C ⁇ -C 2 o)alkyl, (Ci- C ⁇ 0 )alkylcarbonyloxy(C ⁇ -C ⁇ o)alkyl, (C ⁇ -C 20 ) alkylcarbonyl, hydroxy(C ⁇ -C 2 o)alkyl, (Ci- C ⁇ o)alkylsulfonyl(C ⁇ -C ⁇ o)alkyl, acetylamino(C ⁇ -C ⁇ o)alkyl, halo(C ⁇ -C2 ⁇ )alkyl, (C2-
  • halo(C ⁇ -C ⁇ o)alkyl halo(C 2 -C ⁇ o)alkenyl, halo(C 2 - C ⁇ o)alkynyl, (C ⁇ -C ⁇ o)alkoxy, halo(C ⁇ -C ⁇ o)alkoxy, SO 2 NR 3 R 4 and NR 3 R 4 , wherein j is 0, l or 2, Y 2 is chloro, bromo, iodo, OCCI3, mesyl or tosyl, or the biologicaUy active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
  • Y 2 is chloro, bromo or iodo.
  • R 2 is a hydrogen atom.
  • d is 0.
  • m is 0.
  • (d + m) is 1 or 2.
  • alkyl includes both branched and straight chain alkyl groups.
  • Typical alkyl groups are methyl, ethyl, 71-propyl, isopropyl, 71-butyl, sec-butyl, isobutyl, tert-butyl, 71-pentyl, isopentyl, 7i-hexyl, ? ⁇ - heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl and the like.
  • halo refers to fluoro, chloro, bromo or iodo.
  • haloalkyl refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8-chlorononyl and the like.
  • cycloalkyl refers to a cycUc aUphatic ring structure, optionally substituted with alkyl, hydroxy and halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl, 2-hydroxycyclopentyl, cyclohexyl, 4-chlorocyclohexyl, cycloheptyl, cyclooctyl and the like.
  • alkylcarbonyloxyalkyl refers to an ester moiety, for example acetoxymethyl, 7i-butyryloxyethyl and the like.
  • alkynylcarbonyl refers to an alkynylketo functionahty, for example propynoyl and the like.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl and the like.
  • alkylsulfonylalkyl refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl and the like.
  • alkylsulfonyl refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, 7i-propylsulfonyl and the like.
  • acetylaminoalkyl refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the Uke.
  • acetylaminoalkenyl refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the Uke.
  • alkenyl refers to an ethylenicaUy unsaturated hydrocarbon group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl, aUyl, 1- butenyl, 2-butenyl, isopropenyl, 2-pentenyl and the like.
  • haloalkenyl refers to an alkenyl group substituted with one or more halo groups.
  • cycloalkenyl refers to a cyclic aUphatic ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1,4- cyclohexadienyl and the like.
  • alkynyl refers to an unsaturated hydrocarbon group, straight or branched, having 1 or 2 acetylenic bonds, for example ethynyl, propargyl and the Uke.
  • haloalkynyl refers to an alkynyl group substituted with one or more halo groups.
  • alkylcarbonyl refers to an alkylketo functionahty, for example acetyl, n-butyryl and the Uke.
  • alkylcarbonylalkyl refers to an alkylketoalkyl functionahty, for example acetonyl and the Uke.
  • alkenylcarbonyl refers to an alkenylketo functionahty, for example, propenoyl and the Uke.
  • alkenylcarbonylalkyl refers to an alkenylketoalkyl functionahty, for example, propenoylmethyl and the like.
  • alkynylcarbonyl refers to an alkynylketoalkyl functionahty, for example, propynoyl and the like.
  • alkynylcarbonylalkyl refers to an alkynylketoalkyl functionaUty, for example, propynoylmethyl and the like.
  • aryl refers to phenyl or naphthyl which may be optionaUy substituted.
  • Typical aryl substituents include, but are not Umited to, phenyl, 4- chlorophenyl, 4-fLuorophenyl, 4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2- methylphenyl, 3-methyphenyl, 4-methylphenyl, 4-ethylphenyl, 2-methyl-3- methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6- trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl, 2-carboxyphenyl, 2-methoxycarbonylphenyl, 4- nitrophenyl, 2,4-dini
  • arylcarbonylalkyl refers to an arylcarbonyl group as defined previously attached to an alkyl group, for example phenacyl and the Uke.
  • heteroaryl refers to a substituted or unsubstituted 5 or 6 membered unsaturated ring containing one, two or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including one heteroatom selected from oxygen, nitrogen and sulfur.
  • heteroaryls include, but is not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl and isoquinolyl.
  • the heterocyclic ring may be optionally substituted with up to two substituents.
  • heteroarylcarbonyl refers to a heteroaryl group as defined above attached to a keto group, for example 2-pyridylcarbonyl and the Uke.
  • heteroarylcarbonylalkyl refers to a heteroarylcarbonyl group as defined above attached to an group, for example 2-pyridylcarbonylmethyl and the like.
  • aralkyl is used to describe a group wherein the alkyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a terminal portion of the aralkyl moiety.
  • aralkyl groups include, but are not hmited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2- methoxyphenyl)ethyl, 2-(3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(3,5- dimethoxyphenyl)ethyl, 3-phenylpropyl
  • aralkylcarbonyl refers to an aralkyl group as defined above attached to a keto group, for example phenylacetyl and the Uke.
  • aralkylcarbonylalkyl refers to an aralkylcarbonyl group as defined above attached to an alkyl group, for example phenylacetylmethyl and the like.
  • aralkoxy refers to an aryl group as defined above attached to an alkoxy group, for example benzyloxy and the Uke.
  • aralkoxycarbonyl refers to an aralkoxy group as defined above attached to a keto group, for example benzyloxycarbonyl and the like.
  • aralkoxycarbonylalkyl refers to an aralkoxycarbonyl group as defined above attached to an alkyl group, for example benzyloxycarbonylmethyl and the like.
  • aromatickyl is used to describe a group wherein the aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like.
  • aralkenyl is used to describe a group wherein the alkenyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a terminal portion of the aralkenyl moiety, for example styryl (2- phenylvinyl), phenpropenyl and the like.
  • aralkynyl is used to describe a group wherein the alkynyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a terminal portion of the aralkynyl moiety, for example 3-phenyl-l-propynyl and the like.
  • aroxy is used to describe an aryl group attached to a terminal oxygen atom. Typical aroxy groups include phenoxy, 3,4-dichlorophenoxy and the like.
  • aromatic carbonylalkyl is used to describe an aroxy group as defined above attached to an alkylcarbonyl group, for example phenoxycarbonylmethyl and the Uke.
  • heteroaroxycarbonylalkyl is used to describe a heteroaroxy group as defined above attached to an alkylcarbonyl group, for example pyridyloxycarbonylmethyl and the Uke.
  • aromaticalkyl is used to describe a group wherein an alkyl group is substituted with an aroxy group, for example pentafluorophenoxymethyl and the like.
  • heteroaryl group is used to describe an heteroaryl group attached to a terminal oxygen atom.
  • Typical heteroaroxy groups include 4,6-dimethoxypyrimidin- 2-yloxy and the like.
  • heteroaralkyl is used to describe a group wherein the alkyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a terminal portion of the heteroaralkyl moiety, for example 3- furylmethyl, thenyl, furfuryl and the like.
  • heteroaralkenyl is used to describe a group wherein the alkenyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a terminal portion of the heteroaralkenyl moiety, for example 3-(4-pyridyl)-l-propenyl.
  • heteroaralkynyl is used to describe a group wherein the alkynyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a terminal portion of the heteroaralkynyl moiety, for example
  • heterocyclyl refers to a substituted or unsubstituted 5 or 6 membered saturated or partiaUy saturated ring containing one, two or three heteroatoms, preferably three nitrogen atoms, two nitrogen atoms and an oxygen or a sulfur atom, one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic ring system containing up to 10 atoms including one heteroatom selected from oxygen, nitrogen and sulfur wherein the ring containing the heteroatom is saturated.
  • heterocyclyls include, but are not limited to, tetrahydrofuryl, pyrroUdinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, triazolonyl, oxadiazolonyl, thiadiazolonyl, pyrazolonyl, imidazolonyl, pyridonyl, primidinoyl, pyrazinoyl, triazonyl and 5-methyl-6-chromanyl.
  • heterocyclylcarbonyl refers to a heterocyclyl group as defined before attached to a keto group, for example tetrahydrofurylcarbonyl and the Uke.
  • heterocyclylcarbonylalkyl refers to a heterocyclylcarbonyl group as defined before attached to an alkyl group, for example tetrahydrofurylcarbonylmethyl and the like.
  • heterocyclyloxy refers to a heterocyclyl group as defined above attached to an oxygen atom, for example piperidinoxy and the Uke.
  • heterocyclyloxycarbonyl refers to a heterocyclyloxy group as defined above attached to a keto group, for example piperidinoxycarbonyl and the like.
  • heterocyclyloxycarbonylalkyl refers to a heterocyclyloxycarbonyl group as defined above attached to an alkyl group, for example piperidinoxycarbonylmethyl and the Uke.
  • heterocyclylalkyl is used to describe a group wherein the alkyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinabove, forming a terminal portion of the heterocyclylalkyl moiety, for example
  • heterocyclylalkenyl is used to describe a group wherein the alkenyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a terminal portion of the heterocyclylalkenyl moiety, for example 2-morpholinyl-l-propenyl.
  • heterocyclylalkynyl is used to describe a group wherein the alkynyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a terminal portion of the heterocyclylalkynyl moiety, for example 2-pyrroUdinyl-l-butynyl.
  • carboxyalkyl includes both branched and straight chain alkyl groups as defined hereinbefore attached to a carboxy (-CO OH) group.
  • carboxyalkenyl includes both branched and straight chain alkenyl groups as defined hereinbefore attached to a carboxy group.
  • carboxyalkynyl includes both branched and straight chain alkynyl groups as defined hereinbefore attached to a carboxy group.
  • Carboxycycloalkyl refers to a carboxy group attached to a cyclic aliphatic ring structure as defined hereinbefore.
  • Carboxycycloalkenyl refers to a carboxy group attached to a cycUc aliphatic ring structure having 1 or 2 ethylenic bonds as defined hereinbefore.
  • cycloalkylalkyl refers to a cycloalkyl group as defined hereinbefore attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl and the like.
  • cycloalkylalkenyl refers to a cycloalkyl group as defined hereinbefore attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylaUyl and the like.
  • cycloalkylalkynyl refers to a cycloalkyl group as defined hereinbefore attached to an alkynyl group, for example cyclopropylpropargyl, 4- cyclopentyl-2-butynyl and the like.
  • cycloalkenylalkyl refers to a cycloalkenyl group as defined hereinbefore attached to an alkyl group, for example 2-(cyclopenten-l-yl)ethyl and the Uke.
  • cycloalkenylalkenyl refers to a cycloalkenyl group as defined hereinbefore attached to an alkenyl group, for example l-(cyclohexen-3-yl)aUyl and the like.
  • cycloalkenylalkynyl refers to a cycloalkenyl group as defined hereinbefore attached to an alkynyl group, for example l-(cyclohexen-3-yl)propargyl and the Uke.
  • Carboxycycloalkylalkyl refers to a carboxy group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined hereinbefore.
  • carboxycycloalkylalkenyl refers to a carboxy group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined hereinbefore.
  • carboxycycloalkylalkynyl refers to a carboxy group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined hereinbefore.
  • carboxycycloalkenylalkyl refers to a carboxy group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined hereinbefore.
  • carboxycycloalkenylalkenyl refers to a carboxy group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined hereinbefore.
  • carboxycycloalkenylalkynyl refers to a carboxy group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined hereinbefore.
  • alkoxy includes both branched and straight chain alkyl groups attached to a terminal oxygen atom. Typical alkoxy groups include methoxy, ethoxy, 7i-propoxy, isopropoxy, tert-butoxy and the Uke.
  • haloalkoxy refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy and the like.
  • alkoxyalkoxyalkyl refers to an alkyl group substituted with an alkoxy moiety which is in turn substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl and the like.
  • alkylthio includes both branched and straight chain alkyl groups attached to a terminal sulfur atom, for example methylthio.
  • haioalkylthio refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl.
  • alkoxyalkenyl refers to an alkenyl group substituted with an aUcoxy group, for example 3-methoxyaUyl.
  • alkoxy alkynyl refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl.
  • alkoxycarbonylalkyl refers to a straight chain or branched alkyl substituted with an alkoxycarbonyl, for example ethoxycarbonylmethyl, 2- (methoxycarbonyl)propyl and the Uke.
  • alkoxycarbonylalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkoxycarbonyl, for example 4- (ethoxycarbonyl)-2-butenyl and the Uke.
  • alkoxycarbonylalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkoxycarbonyl, for example 4- (ethoxycarbonyl)-2-butynyl and the Uke.
  • haloalkoxyalkyl refers to a straight chain or branched alkyl as defined hereinbefore substituted with a haloalkoxy, for example 2- chloroethoxymethyl, trifluoromethoxymethyl and the like.
  • haloalkoxyalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with a haloalkoxy, for example 4- (chloromethoxy)-2-butenyl and the like.
  • haloalkoxyalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(2- fluoroethoxy) - 2-butynyl and the hke .
  • alkylthioalkyl refers to a straight chain or branched alkyl as defined hereinbefore substituted with an alkylthio group, for example methylthiomethyl, 3-(isobutylthio)heptyl and the Uke.
  • alkylthioalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkylthio group, for example 4-(methylthio)- 2-butenyl and the like.
  • alkylthioalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkylthio group, for example 4-(ethylthio)-2- butynyl and the like.
  • haloalkylthioalkyl refers to a straight chain or branched alkyl as defined hereinbefore substituted with an haioalkylthio group, for example 2- chloroethylthiomethyl, trifluoromethylthiomethyl and the like.
  • haloalkylthioalkenyl refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an haioalkylthio group, for example 4- (chloromethylthio)-2-butenyl and the like.
  • haloalkylthioalkynyl refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an haioalkylthio group, for example 4-(2- fluoroethylthio)-2-butynyl and the like.
  • dialkoxyphosphorylalkyl refers to two straight chain or branched alkoxy groups as defined hereinbefore attached to a pentavalent phosphorous atom, containing an oxo substituent, which is in turn attached to an alkyl, for example diethoxyphosphorylmethyl.
  • bicycloalkyl refers to bicyclic alkyl groups, for example bicyclo[2.2. l]-hept-2-yl (norbornyl).
  • bicycloalkenyl refers to bicychc alkenyl groups, for example bicyclo[2.2. l]-2-heptenyl (nobornylenyl).
  • oligomer refers to a low-molecular weight polymer, whose number average molecular weight is typicaUy less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.
  • biologically active moiety refers to one or more chemical radicals which coUectively form the actual biologically active compound.
  • a compound of Formula I- A [compound of Formula I where R 1 equals a compound of Formula II is reacted with a compound of Formula III in a suitable solvent in the presence of a suitable base.
  • suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula II.
  • the compounds of Formula II are generaUy commerciaUy avaUable or can be prepared according to known procedures.
  • a compound of Formula IV is treated with a suitable halogenating agent in a suitable solvent, where the suitable halogenating agents include chlorine gas, thionyl chloride, and sulfuryl chloride, however, the preferred halogenating agent is sulfuryl chloride.
  • suitable solvents for use in the above process include, but are not limited to, hexanes, chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, and the Uke, however, the reactions are normally run neat. The above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • a compound of Formula V is reacted with a compound of Formula VI in a suitable solvent in the presence of a suitable base.
  • suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • acetonitrUe chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula VI.
  • the compounds of Formula VI are generally commerciaUy avaUable or can be prepared according to known procedures.
  • a compound of Formula VII is reacted with a compound of Formula VIII in a suitable solvent in the presence of a suitable base.
  • suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is diethyl ether.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is sodium hydride.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula VIII.
  • the compounds of Formula VIII are generaUy commercially avaUable or can be prepared according to known procedures. Conversion of Y 2 from Cl to Br or Cl to I in compound of Formula V can be prepared according to literature procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4 th ed.; WUey and Sons: New York, 1992; pp 430-431.
  • a compound of Formula IX is reacted with a compound of Formula X (or a suitable precursor of compound of Formula X) in a suitable solvent in the presence of a suitable base.
  • suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the Uke; aromatic solvents such as benzene and toluene; acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2), carbon tetrachloride (CC1 4 ) or chloroform (CHCI3).
  • Suitable catalysts for use in the above process include, but are not limited to, pyridine, thioureas and ureas such as tetra-71-butylurea, phosphoramides such as hexamethylphosphotriamide, substituted amides such as dimethylformamide, quaternary ammonium hahdes such as tetrabutyl or tributylbenzyl ammonium chloride, arylamines such as N,N-dimethylaminopyridine, N,N-dimethylaniline, tertiary phosphines such as trioctyl phosphine, and alkali metal or alkaline earth metal hahdes such as cesium or potassium chloride which are used in conjunction with a sequestering agent such as a crown ether (18-crown- 6).
  • a sequestering agent such as a crown ether (18-crown- 6).
  • Compound of Formula IX may in some cases exist in a polymeric form. If so, the monomeric form can be achieved via known procedures, one being through thermal depolymerization.
  • phosgene phosgene equivalents
  • phosgene phosgene equivalents
  • the above process may be carried out at temperatures between about - 78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 100 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • the catalyst is normaUy used in lower amounts than that of both compounds of Formula IX and X.
  • the compounds of Formula IX and X are generally commercially avaUable or can be prepared according to known procedures.
  • Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the Uke
  • chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the • preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula VI.
  • the compounds of Formula VI are generaUy commerciaUy avaUable or can be prepared according to known procedures.
  • a compound of Formula II is reacted with a compound of Formula VII in a suitable solvent in the presence of a suitable base.
  • suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula II.
  • the compounds of Formula II are generaUy commercially avaUable or can be prepared according to known procedures. Conversion of Y 2 from Cl to Br or Cl to I in compound of Formula XI can be prepared according to literature procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4 th ed.; WUey and Sons: New York, 1992; pp 430-431.
  • a compound of Formula XI is reacted with a compound of Formula VI-A in a suitable solvent.
  • suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 200 °C.
  • the reaction is carried out between 0 °C and about 100 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of compound of Formula XI is used per equivalent of starting material of compound of Formula VI-A.
  • the compounds of Formula VI-A are generally commerciaUy avaUable or can be prepared according to known procedures.
  • the compounds of Formula XI can be prepared by the same process as that of Scheme 7.
  • Suitable solvents include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the Uke; esters such as ethyl acetate; acetonitrUe; alcohols such as methanol or ethanol; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3).
  • Suitable catalysts in the presence of at least one equivalent of hydrogen include, paUadium, platinum, nickel, rhodium, iridium and ruthenium.
  • the catalysts are normaUy adsorbed or admixed on an inert support material which includes carbon, alumina, calcium sulfate, or barium sulfate, however, the preferred catalyst and support is paUadium on carbon.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • One skilled in the art would recognize that a hydrogenation reaction to remove a benzyl group as described above would only be utilized when aU other functional groups present within compound of Formula I-A are deemed compatible with the reaction conditions. See Greene, T. W.; Wuts, P. G. M.
  • Suitable solvents for use in the above process include, but are not limited to, hexanes, ethers such as tetrahydrofuran, glyme, and the like; chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, and the like, however, the reactions are normally run neat with a catalytic amount of dimethylformamide present.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula I-C. Suitable reaction conditions for the conversion of can be found in Larock, R. C. Comprehensive Organic Transformations, 2 nd ed.; WUey and Sons: New York, 1999; pp 1952-1954.
  • suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula I-B.
  • Suitable coupling reagents for use in the above process include, but are not Umited to, Upases, diazo compounds, anhydrides, acid chlorides, carbodiimides, and carbo ⁇ umidazoles.
  • Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • ethers such as tetrahydrofuran (THF), glyme, and the like
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • acetonitrUe chlorinated solvents
  • CH2CI2CI2 methylene chloride
  • CHCI3 chloroform
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable hahdes include, but are not Umited to, alkyl hahdes such as benzyl chloride, benzyl bromide, methyl iodide, and ethyl iodide.
  • the preferred hahde is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about - 78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula I-B.
  • Suitable reaction conditions for the conversion of to can be found in Larock, R. C. Comprehensive Organic Transformations, 2 nd ed.; WUey and Sons: New York, 1999; pp 1938-1940.
  • Suitable solvents include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the Uke; esters such as ethyl acetate; acetonitrUe; alcohols such as methanol or ethanol; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3).
  • THF tetrahydrofuran
  • glyme glyme
  • esters such as ethyl acetate
  • acetonitrUe alcohols
  • alcohols such as methanol or ethanol
  • chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3).
  • CH2CI2CI2 methylene chloride
  • CHCI3 chloroform
  • Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • one equivalent of base is used per equivalent of starting material of compound of Formula I-A.
  • Suitable reaction conditions would involve the foUowing:
  • Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula I-B.
  • Suitable coupling reagents for use in the above process include, but are not limited to, lipases, diazo compounds, anhydrides, acid chlorides, carbodiimides, and carbodiimidazoles.
  • Suitable reaction conditions would involve the foUowing:
  • Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • Suitable solvents for use in the above process include, but are not hmited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • THF tetrahydrofuran
  • DMSO dimethylsulfoxide
  • chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • CH2CI2CI2 or chloroform (CHCI3) chloroform
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula II.
  • the compounds of Formula II are generaUy commerciaUy avaUable or can be prepared according to known procedures.
  • a compound of Formula III-A a compound of
  • Formula VII-A is reacted with a compound of Formula VI in a suitable solvent in the presence of a suitable base.
  • suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula VI.
  • the compounds of Formula VI are generaUy commerciaUy available or can be prepared according to known procedures.
  • Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is diethyl ether.
  • ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the like
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • acetonitrUe chlorinated solvents
  • chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is diethyl ether.
  • Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is pyridine.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula VIII -A.
  • the compounds of Formula VIII -A are generaUy commerciaUy avaUable or can be prepared according to known procedures. Conversion of Y 2 from Cl to Br or Cl to I in compound of Formula V can be prepared according to Htera ure procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4 th ed.; Wiley and Sons: New York, 1992; pp 430-431.
  • the compounds of Formula VII can be prepared as shown in Method A, Scheme 5.
  • Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF.
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is sodium hydride.
  • the above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 1Q0 °C.
  • Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula XIII.
  • the compounds of Formula XIII can be prepared according to patented methods such as those found in U.S. 5,530,028 and 6,013,836.
  • Conversion of Y 2 from Cl to Br or Cl to I in compound of Formula XII can be prepared according to literature procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4 th ed.; WUey and Sons: New York, 1992; pp 430-431. Also, see synthesis Example 55 for conversion of Y 2 from Cl to I in compound of Formula XII.
  • Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF.
  • Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is dusopropylethylamine.
  • the above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula VI.
  • the compounds of Formula VI are generaUy commerciaUy avaUable or can be prepared according to known procedures.
  • Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF.
  • the above method may be carried out at temperatures between about -78 °C and about 200 °C. Preferably, the reaction is carried out between 0 °C and about 100 °C.
  • Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. Generally, one equivalent of compound of Formula XII is used per equivalent of starting material of compound of Formula VI-A.
  • the compounds of Formula VI-A are generally commerciaUy avaUable or can be prepared according to known procedures. AppUcation of Method D (Scheme 9) as described previously for the synthesis of compounds of Formula I-B, I-C, and I-A to the synthesis of compounds of Formula XV-A, XV-B, and XV, respectively, is described below in Scheme 17.
  • Suitable solvents include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the hke; esters such as ethyl acetate; acetonitrUe; alcohols such as methanol or ethanol; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is ethyl acetate.
  • Suitable catalysts in the presence of at least one equivalent of hydrogen include, but are not hmited to, paUadium, platinum, nickel, rhodium, iridium and ruthenium.
  • the catalysts are normaUy adsorbed or admixed on an inert support material which includes carbon, alumina, calcium sulfate, or barium sulfate, however, the preferred catalyst and support is paUadium on carbon.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • Formula XV-A is treated with a suitable halo-de-hydroxylation reagent in a suitable solvent
  • suitable halo-de-hydroxylation reagents include, but are not Umited to, thionyl chloride, oxalyl chloride, oxalyl bromide, triphenyl phosphine in carbon tetrachloride, phosphorus trichloride, and phosphorus pentachloride, however, the preferred halo-de-hydroxylation reagent is thionyl chloride.
  • Suitable solvents for use in the above process include, but are not hmited to, hexanes, ethers such as tetrahydrofuran, glyme, and the Uke; chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, and the like, however, the reactions are normaUy run neat with a catalytic amount of dimethylformamide present.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • Compounds of Formula XV-B can be also be synthesized directly from compounds of Formula XV.
  • a compound of Formula XV-B is reacted with Z 3 (X 3 )d(G 31 )t-H in a suitable solvent in the presence of a suitable base.
  • suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • one equivalent of base is used per equivalent of starting material of compound of Formula XV-B.
  • a compound of Formula XV can also be prepared via the reaction of a compound of Formula XV-A in a suitable solvent with Z 3 (X 3 )d(G 31 )t'-H and a suitable coupling reagent.
  • suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used.
  • the preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates.
  • Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. lf desired, mixtures of these bases may be used.
  • the preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula XV-A.
  • Suitable coupUng reagents for use in the above process include but are not hmited to, hpases, diazo compounds, anhydrides, acid chlorides, carbodumides, alkyl hahdes, and carbodiimidazoles.
  • Suitable solvents for use in the above process include, but are not hmited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2), carbon tetrachloride (CC1 ) or chloroform (CHCI3).
  • ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like
  • acetonitrUe chlorinated solvents such as methylene chloride (CH2CI2), carbon tetrachloride (CC1 ) or chloroform (CHCI3).
  • mixtures of these solvents may be used.
  • Suitable catalysts for use in the above process include, but are not limited to, pyridine, thioureas and ureas such as tetra-/ ⁇ -butylurea, phosphoramides such as hexamethylphosphotriamide, substituted amides such as dimethylformamide, quaternary ammonium hahdes such as tetrabutyl or tributylbenzyl ammonium chloride, arylamines such as N, N,- dimethylaminopyridine, N, N -dimethylanUine, tertiary phosphines such as trioctyl phosphine, and alkah metal or alkahne earth metal hahdes such as cesium or potassium chloride which are used in conjunction with a sequestering agent such as a crown ether (18-crown-6).
  • a sequestering agent such as a crown ether (18-crown-6).
  • Compound of Formula XVI may in some cases exist in a polymeric form. If so, the monomeric form can be achieved via known procedures, one being through thermal depolymerization.
  • phosgene phosgene equivalents
  • phosgene phosgene equivalents
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 100 °C.
  • the above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • the catalyst is normaUy used in lower amounts than that of both compounds of Formula XVI and XVII.
  • the compounds of Formula XVI and XVII are generaUy commerciaUy avaUable or can be prepared according to known procedures.
  • Suitable solvents for use in the above process include, but are not hmited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3).
  • Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is sodium hydride. The above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • Preparation of the compounds of the present invention by the above process is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3).
  • ethers such as tetrahydrofuran (THF), glyme, diethyl ether and the like
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3).
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is dusopropylethylamine.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • Preparation of the compounds of the present invention by the above process is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula VI.
  • the compounds of Formula VI are generaUy commerciaUy avaUable or can be prepared according to known procedures.
  • Suitable halogenating agents include chlorine gas, thionyl chloride, and sulfuryl chloride, however, the preferred halogenating agent is sulfuryl chloride.
  • Suitable solvents for use in the above process include, but are not hmited to, hexanes, chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like, however, the reactions are normaUy run neat.
  • the above process may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • Preparation of the compounds of the present invention by the above process is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • Suitable solvents include chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the Uke; hexanes; tetrahydrofuran, diethyl ether, and the like.
  • the reactions are normally run neat.
  • the reaction can be carried out at temperatures between about -78 °C and about 200 °C.
  • the reaction is carried out between 0 °C and about 150 °C.
  • Preparation of compound of Formula XXVI of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • the preferred amount is a slight excess of HMDS.
  • Compounds of the Formula XXV are generally commerciaUy avaUable or can be prepared according to known procedures. Compounds of Formula XXV and XXVI can be found in the foUowing reference: Franz, J. E.; Mao, M. K.; Sikorski, J. A.
  • Suitable solvents for use in the above method include ethers such as tetrahydrofuran (THF), glyme, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) and chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is methylene chloride.
  • the above method may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out between 0 °C and about 50 °C.
  • Preparation of the compound of Formula XXIV of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • Suitable solvents for use in the above method include ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) and chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF.
  • Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; 4-dimethylaminopyridine (DMAP) or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is DMAP.
  • the above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out at 22 °C.
  • Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula XXVIII.
  • Suitable solvents for use in the above method include ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) and chloroform (CHCI3).
  • Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; 4-dimethylaminopyridine (DMAP), potassium exert(trimethylsUyl)amide (KHMDS) or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is KHMDS.
  • metal hydrides such as sodium or potassium hydride
  • metal alkoxides such as sodium or potassium alkoxides
  • alkah metal hydroxides such as sodium or potassium hydroxide
  • tertiary amines such as triethylamine or diisopropylethylamine
  • an alkali metal carbonate such as sodium or potassium
  • the above method may be carried out at temperatures between about -78 °C and about 100 °C.
  • the reaction is carried out at -78 °C to 0 °C.
  • Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
  • Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
  • GeneraUy one equivalent of base is used per equivalent of starting material of compound of Formula XXX.
  • Example 2 above, except isopropyl glyoxylate was substituted for ethyl glyoxylate.
  • Example 8 Iodo-ethylsulfanylcarbonyloxy-acetic acid ethyl ester (Compound 2-2 of Table 2) To a stirred solution of chloro-ethylsulfanylcarbonyloxy-acetic acid ethyl ester (33.5 g, 148 mmol) in 160 mL of dry acetone was added Nal (28.8. g, 192 mmol). The mixture was stirred at room temperature for 4h. The acetone was removed and the remaining slurry was diluted with 100 mL of diethyl ether. The mixture was filtered through Cehte and concentrated under reduced pressure to yield a brown hquid.
  • Table B2 Compounds (B2-l)-(B2-25) are compounds of Formula V where R 12 , G 10 , Gn, G 30 , Y 2 , G 31 , R 2 , t ⁇ and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals methyl.
  • Table B3 Compounds (B3-l)-(B3-25) are compounds of Formula V where R i2 , G 10 , Gn, G 30 , Y 2 , G 3 , R 2 , t', and d are identical to those in Table Bl except for (X 3 )dZ 3 which equals propyl.
  • Table B4 Compounds (B4-l)-(B4-25) are compounds of Formula V where R 12 , G 10 , Gn, G 3o ; ⁇ 2> G 3i ; R 2> t ', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals isopropyl.
  • Table B5 Compounds (B5-l)-(B5-25) are compounds of Formula V where R i2 , G 10 , Gn, G 3o ; ⁇ 2 ; G 3i ; R 2 , t ' ; an d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals 7i-butyl.
  • Table B6 Compounds (B6-l)-(B6-25) are compounds of Formula V where R 12 , G i °, QU G 30 j ⁇ 2 ; G si ; R2 ; t > ; an d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals tert-butyl.
  • Table B7 Compounds (B7-l)-(B7-25) are compounds of Formula V where R i2 , G i °, G 11 , G 30 , Y 2 , G 81 , R 2 , t ⁇ and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals hexyl.
  • Table B8 Compounds (B8-l)-(B8-25) are compounds of Formula V where R 12 , G 10 , G 11 , G 30 , Y 2 , G 3i , R 2 , f, and d are identical to those in Table Bl except for (X 3 )dZ 3 which equals octyl.
  • Table B9 Compounds (B9-l)-(B9-25) are compounds of Formula V where R i2 , G 10 , G", G 30 , Y 2 , G 31 , R 2 , f , and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals pentyl.
  • Table Bll Compounds (Bll-l)-(B 11-25) are compounds of Formula V where R 22 , G 10 , Gn, G 30 , Y 2 , G 81 , R 2 , t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals cyclopentyl.
  • Table B12 Compounds (B 12- 1)-(B 12-25) are compounds of Formula V where R i2 , G 10 , Gn, 3 0) ⁇ 5 G 3i ⁇ R2 ; t ', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals cyclopropyl.
  • Table B13 Compounds (B13-l)-(Bl3-25) are compounds of Formula V where R 2 , G °, Gn, G 3 0) ⁇ 2; G 3i ; R2; t ' ; and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals benzyl.
  • Table B14 Compounds (B14-1)-(B 14-25) are compounds of Formula V where R i2 , G 10 , Gn, G 3o ; ⁇ 2; G 3i, R2, t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals phenyl.
  • G 10 , Gn, G 3 0j ⁇ 2> QS ⁇ R2j t ' ; an d d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals 4-methoxyphenyl.
  • Table B16 Compounds (B16-l)-(Bl6-25) are compounds of Formula V where R 12 , G °, G 11 , G 30 , Y 2 , G 31 , R 2 , t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals 2,3,4,5, 6-pentafluorophenyl.
  • Table B17 Compounds (B17-l)-(Bl7-25) are compounds of Formula V where R i2 , G 10 , Gn, G 30 , Y 2 , G 3i , R 2 , t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals aUyl.
  • Table B18 Compounds (B18-l)-(B18-25) are compounds of Formula V where R 12 , G 10 , Gn, G 30 , Y 2 , G 3i , R 2 , t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals methoxyethyl.
  • Table B19 Compounds (B 19- 1)-(B 19-25) are compounds of Formula V where R 12 , G i °, Gn, G 30 , Y 2 , G 3 ⁇ R 2 , t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals ethoxymethyl.
  • Table B20 Compounds (B20-l)-(B20-25) are compounds of Formula V where R 12 , G 10 , Gn, G 30 , Y 2 , G 81 , R 2 , t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals 2-(phenyl)ethyl.
  • Table B21 Compounds (B21-l)-(B21-25) are compounds of Formula V where R i2 , G i °, Gn, G 30 , Y 2 , G 81 , R 2 , t', and d are identical to those in Table Bl except for (X 3 ) d Z 3 which equals 3-(phenyl)propyl.
  • Tables B22-B42 Compounds [(B22-l)-(B22-25)] - [(B42-l)-(B42-25)] are compounds of Formula V where R i2 , G i °, G 11 , G 30 , Y 2 , R 2 , t', (X 3 ) d Z 3 , and d are identical to those in Tables B1-B21 except for G 31 which equals S.
  • Example 21 2,5-Dichloro-6-methoxybenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-9 of Table 3)
  • Example 23 Benzoic acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-11 of Table 3)
  • Acetyl methyl carbamic acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-16 of Table 3) The title compound was prepared according to the procedure described in
  • Example 23 above except for the substitution of acetyl methyl carbamic acid for benzoic acid.
  • ⁇ -NMR 300 MHz, CDC1 3 ) ⁇ (ppm): 1.30 (m, 9H), 2.10 (d, 3H), 2.90 (m, 2H), 3.10 (d, 3H), 4.20 (m, 2H), 5.10 (m, IH), 6.90 (s, IH).
  • Example 13 above except for the substitution of pivahc acid for 2-methylpropanoic acid and iodoethylsulfanylcarbonyloxy-acetic acid butyl ester for iodoethylsulfanylcarbonyloxy-acetic acid ethyl ester.
  • ⁇ -NMR 300 MHz, CD3OD
  • ppm 1.25 (s, 9H), 1.31-1.45 (m, 8H), 1.65 (m 2H), 2.95 (q, 2H), 4.25 (m, 2H), 6.92 (s, IH).
  • Table C2 Compounds (C2-l)-(C2-20) are compounds of Formula IV where R i2 , G 10 , Gn, R 2 ; G 20 , G 21 , G 30 , G 31 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals propyl.
  • Table C3 Compounds (C3-l)-(C3-20) are compounds of Formula IV where R 12 , G 10 , G 11 , R 2 , G 20 , G 21 , G 30 , G 81 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals methyl.
  • Table C4 Compounds (C4-l)-(C4-20) are compounds of Formula IV where R 2 , G °, Gn, R 2 , G 20 , G 2 ⁇ G 30 , G 81 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals heptyl.
  • Table C5 Compounds (C5-l)-(C5-20) are compounds of Formula IV where R i2 , G 10 , Gn, R 2 , G 20 , G 21 , G 30 , G 81 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals cyclopropyl.
  • Table C6 Compounds (C6-l)-(C6-20) are compounds of Formula IV where R i2 , G 10 , G 11 , R 2 , G 20 , G 21 , G 30 , G 31 , t ⁇ d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals cyclopentyl.
  • Table C7 Compounds (C7-l)-(C7-20) are compounds of Formula IV where R i2 , G 10 , G 11 , R 2 , G 20 , G i , G 30 , G 31 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals phenyl.
  • Table C8 Compounds (C8-l)-(C8-20) are compounds of Formula IV where R i2 , G 10 , Gn, R 2 , G 20 , G 21 , G 30 , G 31 , f , d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals benzyl.
  • Table C9 Compounds (C9-l)-(C9-20) are compounds of Formula IV where R i2 , G 10 , Gn, R 2 , G 20 , G 21 , G 30 , G 3i , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals 4-nitrophenyl.
  • Compounds (C10-l)-(C10-20) are compounds of Formula IV where R i2 , G 10 , Gn, R 2 , G 20 , G , G 30 , G 3i , f , d, t, q, and (X 2 ) q Z 2 are identical to those in Table Cl except for (X 3 )dZ 3 which equals 4-methoxyphenyl.
  • Tables C11-C20 Compounds [(Cll-l)-(Cll-20)] - [(C20-l)-(C20-20)] are compounds of Formula IV where (X 3 )dZ 3 , G 10 , G 11 , R 2 , G 20 , G 2i , G 30 , G 31 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Tables C1-C10 except for R 12 which equals methyl.
  • Tables C21-C30 Compounds [(C21-l)-(C21-20)] - [(C30-l)-(C30-20)] are compounds of Formula IV where (X 3 ) d Z 3 , G 10 , G 11 , R 2 , G 20 , G 2i , G 30 , G 3i , f, d, t, q, and (X 2 ) q Z 2 are identical to those in Tables C1-C10 except for R 12 which equals propyl.
  • Tables C31-40 Compounds [(C31-l)-(C31-20)] - [(C40-l)-(C40-20)] are compounds of Formula IV where (X 3 ) d Z 3 , GTM, G 11 , R 2 , G 20 , G 2i , G 30 , G 3 ⁇ , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Tables C1-C10 except for R i2 which equals t-butyl.
  • Tables C41-C50 Compounds [(C41-l)-(C41-20)] - [(C50-l)-(C50-20)] are compounds of Formula IV where (X 3 ) d Z 3 , G i °, G", R 2 , G 20 , G 21 , G 30 , G 3 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Tables C1-C10 except for R 12 which equals 71-butyl.
  • Tables C51-C60 Compounds [(C51-l)-(51-20)] - [(C60-l)-(C60-20)] are compounds of Formula IV where (X 3 ) d Z 3 , G i °, G u , R 2 , G 20 , G 2i , G 30 , G 3 ⁇ f , d, t, q, and (X 2 ) q Z 2 are identical to those in Tables C1-C10 except for R 12 which equals phenyl.
  • Tables C61-C70 Compounds [(C61-l)-(C61-20)] - [(C70-l)-(C70-20)] are compounds of Formula IV where (X 3 ) d Z 3 , G 10 , G 11 , R 2 , G 20 , G 2 , G 30 , G 3i , t ⁇ d, t, q, and (X 2 ) q Z 2 are identical to those in Tables C1-C10 except for R 12 which equals 2-pyridyl.
  • Example 32 except for the substitution propionic acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.4 equiv of sulfuryl chloride and starting the reaction at 5 °C.
  • ⁇ -NMR 300 MHz, CDCls
  • ppm 1.21 (t, 3H), 1.35 (t, 3H), 2.53 (q,2H), 4.32 (q, 2H), 6.84 (s, IH).
  • Example 35 Example 35:
  • Example 32 above except for the substitution benzoic acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.2 equiv of sulfuryl chloride and starting the reaction at 5 °C.
  • ⁇ -NMR 300 MHz, CDCls
  • ppm 1.36 (t, 3H), 4.32 (q, 2H), 7.09 (s, IH), 7.50 (t, 2H), 7.63 (t, IH), 8.10 (d, 2H).
  • Example 32 above except for the substitution 2,4-dichlorophenoxybutyric acid ethoxycarbonylethyl-sulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl ethylsulfanylcarbonyl-oxy-methyl ester, using 1.45 equiv of sulfuryl chloride and starting the reaction at 5 °C.
  • the title compound was prepared according to the procedure described in Example 32 above except for the substitution 2'-(2,4-dichlorophenoxy)propionic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.80 equiv of sulfuryl chloride and starting the reaction at 5 °C.
  • Example 32 above except for the substitution 2,5-dichloro-6-methoxybenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.45 equiv of sulfuryl chloride and starting the reaction at 5 °C.
  • ⁇ -NMR 300 MHz, CDCls) ⁇ (ppm): 1.34 (t, 3H), 3.95 (s, 3H), 4.36 (q, 2H), 7.08 (s, IH), 7.18 (d, IH), 7.42 (d, IH).
  • Example 32 above except for the substitution of 2,4,6-trimethylbenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.45 equiv of sulfuryl chloride and starting the reaction at 5 °C.
  • ⁇ -NMR 300 MHz, CDCls) ⁇ (ppm): 1.34 (t, 3H), 2.28 (s, 3H), 2.35 (s, 6H), 4.34 (q, 2H), 6.89 (s, IH), 7.06 (s, IH), 7.12 (s, IH).
  • Example 41 Example 41:
  • Example 32 above except for the substitution of pivahc acid butoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.9 equiv of sulfuryl chloride and starting the reaction at 5 °C.
  • ⁇ -NMR 300 MHz, CDCls
  • ppm 0.95 (t, 3H), 1.27 (s, 9H), 1.35-1.45 (m, 2H), 1.65-1.75 (m 2H), 4.31 (m, 2H), 6.85 (s, IH).
  • Example 32 above except for the substitution of isobutyric acid isobutoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.9 equiv of sulfuryl chloride and starting the reaction at 5 °C. .
  • ⁇ -NMR 300 MHz, CDCls) ⁇ (ppm): 1.22-1.30 (m, 6H), 1.30-1.40 (m, 6H), 2.70 (heptet, IH), 5.14 (heptet, IH), 6.77 (s, IH).
  • Table D2 Compounds (D2-l)-(D2-20) are compounds of Formula III where Y 1 , G 10 , G 11 , R 2 , G 20 , G 21 , G 30 , G 3i , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals propyl.
  • Table D3 Compounds (D3-l)-(D3-20) are compounds of Formula III where Y 1 , G 10 , G 11 , R 2 , G 20 , G 2i , G 30 , G 31 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals methyl.
  • Table D4 Compounds (D4-l)-(D4-20) are compounds of Formula III where Y 1 , G 10 , G 11 , R 2 , G 20 , G 2i , G 30 , G 3i , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals heptyl.
  • Table D5 Compounds (D5-l)-(D5-20) are compounds of Formula III where Y 1 , G 10 , Gn, R 2 , G 20 , G 2i , G 30 , G 31 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals cyclopropyl.
  • Table D6 Compounds (D6-l)-(D6-20) are compounds of Formula III where Y , G i °, Gn, R 2 , G 20 , G 21 , G 30 , G 81 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals cyclopentyl.
  • Table D7 Compounds (D7-l)-(D7-20) are compounds of Formula III where Y 1 , G 10 , Gn, R 2 , G 20 , G 21 , G 30 , G 3i , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals phenyl.
  • Table D8 Compounds (D8-l)-(D8-20) are compounds of Formula III where Y 1 , G 10 , G 11 , R 2 , G 20 , G 21 , G 30 , G 3i , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals benzyl.
  • Table D9 Compounds (D9-l)-(D9-20) are compounds of Formula III where Y x , G 10 , Gn, R 2 , G 20 , G 2 G 30 , G 3 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals 4-nitrophenyl.
  • Table D10 Compounds (D 10- 1)-(D 10-20) are compounds of Formula III where Y 1 , G 10 , Gn, R 2 , G 20 , G 2i , G 30 , G 31 , t', d, t, q, and (X 2 ) q Z 2 are identical to those in Table Dl except for (X 3 )dZ 3 which equals 4-methoxyphenyl.
  • Isobutyric acid (carboxymethyl-phosphonomethyl-carbamoyloxy)-ethoxycarbonyl- methyl ester isopropylamine salt (Compound 5-1 of Table 5)
  • a stirred solution of phosphonomethyl glycine (0.88 g, 5.2 mmol) in hexamethyldisUazane (2.35 mL, 11.2 mmol) was slowly heated to 90 °C (at this temperature gassing of ammonia occurred). The temperature was increased to 125 °C for 150 min at which time the reaction became homogeneous.
  • the solution was aUowed to cool to room temperature and dry methylene chloride (5 mL) was added.
  • the reaction was vacuum filtered and concentrated under reduced pressure.
  • the oU was dissolved with 20 mL of dry acetone and aUowed to stand for 1 h, vacuum filtered, and concentrated under vacuum.
  • the solid was triturated with 10 mL of warm hexanes and then placed under vacuum to afford isobutyric acid (carboxymethyl-phosphonomethyl- carbamoyloxy)-ethoxycarbonyl-methyl ester (0.67 g), which was dissolved in 20 mL of acetone to which isopropylamine (0.148 mL) was added. After 15 min of stirring the solvent was removed under vacuum.
  • Example 43 above except for the substitution of benzoic acid ethoxycarbonyl- chlorocarbonyloxymethyl ester for 2-methylpropionic acid ethoxycarbonyl- chlorocarbonyloxymethyl ester.
  • Example 46 2,4-Dichlorophenoxybutyric acid carboxymethyl-phosphonomethyl-carbamoyloxy)- ethoxycarbonyl- methyl ester isopropylamine salt (Compound 5-4 of Table 5)
  • Example 47 Pivahc acid (carboxymethyl-phosphonomethylcarbamoyloxy)isopropoxycarbonyl- methyl ester (Compound 5-5 of Table 5)
  • Example 48 Pivahc acid (carboxymethyl-phosphonomethyl-carbamoyloxy)isopropoxycarbonyl- methyl ester-isopropylamine salt (Compound 5-6 of Table 5)
  • Example 48 except for the substitution of benzoic acid (carboxymethyl- phosphonomethyl-carbamoyloxy)isopropoxycarbonyl-methyl ester for pivahc acid
  • Example 54 except for the substitution of ethyl 2-chloro-2- [(chlorocarbonyl)oxy] acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate.
  • LC/MS was conducted for confirmation of structure and purity (Table 7A).
  • Example 60 .
  • Example 54 above except for the substitution of ethyl 2-chloro-2- [(chlorocarbonyl)oxy] acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate and the substitution of N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazide for N-tert- butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazide.
  • LC/MS was conducted for confirmation of structure and purity (Table 7A).
  • Example 54 except for the substitution of isopropyl 2-chloro-2- [(chlorocarbonyl)oxy]-acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate and the substitution of N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazide for N-tert- butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazide.
  • LC/MS was conducted for confirmation of structure and purity (Table 7A).
  • Example 70 Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- benzyloxycarbonylmethyl ester (Compound 7-1 of Table 7)
  • Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- carboxymethyl ester (Compound 7-2 of Table 7)
  • Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyl- oxy]benzyloxycarbonylmethyl ester (150 mg, 0.3 mmol), 10 % palladium on carbon (10-20 mg) and ethyl acetate (5 mL) were combined and hydrogenated in a Parr shaker at room temperature under 55 psi hydrogen for 2 h.
  • Example 72 Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- chlorocarbonylmethyl ester (Compound 7-3 of Table 7)
  • Example 73 above except for the substitution of hydroxymethyl dibenzyl phosphonate for diethylamine. LC/MS was conducted for confirmation of structure and purity (Table 7A).
  • Example 73 above except for the substitution of methylamine for diethylamine. LC/MS was conducted for confirmation of structure and purity (Table 7A).
  • Example 76 Example 76:
  • Example 73 above except for the substitution of sarcosine benzyl ester for diethylamine. LC/MS was conducted for confirmation of structure and purity (Table 7A).
  • Example 71 above except for the substitution of propionic acid [N'-benzoyl-N-tert- butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]-(bis-benzyloxy-phosphorylmethoxy- carbonyl)-methyl ester for propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chloro- benzoyl)hydrazinocarbonyloxy]benzyloxycarbonylmethyl ester.
  • ⁇ - ⁇ MR 300 MHz,
  • Example 79 Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- (carboxymethylmethylcarbamoyl)methyl ester (Compound 7-10 of Table 7)
  • Example 106 above, except isopropanol was substituted for ethanol.
  • LC/MS was conducted for confirmation of structure and purity (Table 7A).
  • Example 108 Isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(l-propyloxycarbonylmethyl) ester (Compound
  • Example 106 above, except 1-propanol was substituted for ethanol.
  • LC/MS was conducted for confirmation of structure and purity (Table 7A).

Description

Intermediates for Biologically Active Compounds
This invention relates to intermediate compounds which are useful to make enhanced propertied pesticides which can be used as fungicides, herbicides, insecticides, rodenticides or biocides. An enhanced propertied pesticide is one which overcomes one or more deficiencies of a traditional pesticide for the end user application. For instance, the traditional pesticide may be slow acting and/or may have a limited spectrum of activity and/or may not possess a sufficiency of rain- fastness in the field to have a good residual activity. In order to be effective against the targeted pest, many traditional pesticides must be applied in an undesirably high use rate from an environmental perspective. This can cause crop damage, especially with herbicides, because of lower than desired selectivity. Frequently the targeted pest builds up a resistance to the applied pesticide and requires larger amounts of it in order to be controlled. Many traditional tank mixes of traditional pesticides cannot be accomplished because of their mutual incompatibility. Additionally, separately applied pesticide combinations arrive at the target pest at different rates, thus muting some of their mutual effectiveness. Some traditional pesticides have adverse water solubilities for their intended application. Many traditional pesticides are of the contact variety and hence possess no systemicity to completely protect the desired crop from the unwanted pest. The intermediates of the present invention allow one to make enhanced propertied pesticides in order to overcome various deficiencies of traditional pesticides. These intermediate compounds are substituted with a moiety comprising a substituent which enhances or changes the properties of the subsequently made pesticidal compound. This substituent can be tailored on the intermediate compound in order to increase the rate of desired pesticidal action, to increase residual control against the pest, to decrease the overall use rate of the pesticide, increase the selectivity of the pesticide, change the water solubility of the pesticide, and increase the systemicity of the pesticide which is made from the intermediate compound. Furthermore, the substituent on the intermediate compound may optionally comprise a pesticidal compound which may be the same as or different from the pesticidal compound on which substitution of the intermediate compound occurs. This allows a combination of pesticides to be applied simultaneously as a single compound to the target pest or its locus. The application of such a compound provides many advantages such as a greater spectrum of activity against various pests, an attenuation of the build up of pest resistance since the pest is being controlled with two different modes of action, and the ability to combine two pesticidal compounds which would otherwise be incompatible with one another in a tank mix.
These intermediate compounds are additionally useful to make enhanced propertied pharmaceutical compounds for both human and veterinary application. The chemical modification of drugs into labile derivatives with enhanced physicochemical properties that enable better transport through biological barriers is a useful approach for improving- drug delivery. This modification can be conveniently practiced on ionizable molecules containing moieties such as a carboxy group, an amino group or a hydroxy group that can be utilized for derivatization in order to modify their ionization at physiological pH and to render desirable partition and solubiHty properties. A necessary requirement of this approach is that the enhanced propertied drug is non-toxic and, when administered to a warm-blooded animal including a human being, is enzymatically and/or chemically cleaved in such a manner as to release the drug at its target or site of activity, quantitatively and at a desirable rate, while the remaining cleaved moiety remains non-toxic and is metabolized in such a manner that non-toxic metabolic products are produced. It is naturally also desirable that the enhanced propertied drug can be provided without excessive costs in connection with its production, in particular without an appreciable loss of the unmodified drug itself during its production and recovery, since the unmodified drug is usually the more expensive part of the enhanced propertied drug.
Furthermore, the substituent on the intermediate compound may optionally comprise a pharmaceutical compound which may be the same as or different from the pharmaceutical compound on which substitution of the intermediate compound occurs. This allows a combination of pharmaceutical compounds to be applied simultaneously as a single compound to the host. The application of such a compound provides many advantages such as a greater spectrum of activity against the disease being treated and an attenuation of the build up of disease resistance since the disease is being controlled with two different modes of action. This type of enhance propertied pharmaceutical compound will naturally comprise two different pharmaceutical moieties which are compatible with one another and which can be used without an antagonistic interactive effect upon the host. Such combinations should be apparent to one of ordinary skill in the art.
The intermediate used to react with either the pesticide or the drug in providing the enhanced propertied pesticide or pharmaceutical drug, respectively, should advantageously be stable and still be reasonably reactive. The enhanced propertied pesticides and pharmaceuticals which may be produced using the intermediates of this invention can be collectively termed enhanced propertied biologically active compounds. Such enhanced propertied biologically active compounds may be described by, but not limited to, a compound of Formula I
Figure imgf000004_0001
wherein G10, G11 and G20 are each independently an oxygen atom or a sulfur atom,
G21 is an oxygen atom, a sulfur atom or NR3,
X1 is an oxygen atom, a sulfur atom, a phosphorous atom or a nitrogen atom attached to Z1,
X2 is an oxygen atom,. a sulfur atom, a phosphorous atom, a nitrogen atom or a carbon atom attached to Z2, m, q and t are each independently 0 or 1,
Z1(X1) is a biologically active moiety when m is 1 wherein Z1(X1)m-H represents the biologically active compound,
Z2(X2)q(C(=G20)G21)t is a biologically active moiety when q is 1 wherein
Figure imgf000004_0002
represents the biologicaUy active compound,
Z1(X1) , when m is 0, is a hydrogen atom, halo, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, ace tylamino alkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, NR3R4, S02NR3R4, OR3, S(O)jR3, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2N 3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z2(X2)q is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, NR3R4, SO2NR3R4, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, dialkoxyphosphorylalkyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4. heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SOsNR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, alkylcarbonylalkyl, alkenylcarbonylalkyl, alkynylcarbonylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkyl, heterocyclyloxycarbonylalkyl, arylcarbonyl, arylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl, aroxycarbonylalkyl, aralkoxycarbonylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaroxycarbonylalkyl, or arylcarbonyl, arylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl, aroxycarbonylalkyl, aralkoxycarbonylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaroxycarbonylalkyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, and C(=N-G22)R2 when q is 0 and t is 1,
G22 is OR3, OCOR3, S(0)jR3, OS(O)jR3, NR3R4, OSO2NR3R4, OP(=0)OR3NR3R4, OP(=O)(OR3)2 or N=CR3R4, j is 0, 1 or 2, Z2(X2)q is halo, NR3R4, {(NR3R4R5)+ M'}, OR3, S(O)jR3 or SO2NR3R4 when both q and t are 0 wherein M" is halo, hydroxy. alkoxy or the anion of a carboxylic acid and j is 0, 1 or 2,
Ri is
Figure imgf000007_0001
wherein
G30 is an oxygen atom or a sulfur atom,
G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1, X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom,
Z3(X3)d(G31)t' is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, NR3R4, OR3, S(O)jR3, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4 aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(O)jR3 or SO2NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, or alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO2NR3 4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl or arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl or heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl or heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring, R3, R4 and R5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl, aralkyl, aralkenyl, aralkynyl, or aryl, aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
U.S. 4,760,057, U.S. 4,916,230, U.S. 5,401,868, U.S. 5,459,155, U.S. 5,583,148, U.S. 5,684,018, WO 98/16537, WO 98/43970 and WO 99/61017 describe certain pharmaceutical compounds which are substituted with moieties to alter the properties of pharmaceutical compounds; however, the moieties employed in the intermediates of the present invention are neither disclosed nor suggested.
U.S. 5,284,863, U.S. 4,912,090, U.S. 5,385,880, U.S. 5,391,537, JP 1275565 A2, WO 96/36613, WO 99/35141, WO 00/29378, WO 00/40582, DE 4343831 Al, JP 53-43571 B and JP 54-1771 B disclose certain pesticidal compounds which are substituted with moieties to alter the properties of pesticidal compounds; however, the moieties employed in the intermediates of the present invention are neither disclosed nor suggested.
In a first embodiment of this invention, one intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula
Figure imgf000010_0001
wherein G10 and G11 are each independently an oxygen atom or a sulfur atom,
R s
Figure imgf000010_0002
wherein
G30 is an oxygen atom or a sulfur atom, G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom,
Z3(X3)d(G31)f is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxy alkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, NR3R4, OR3, S(O)jR3, SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(O)jR3 or SO2NR R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, or alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO2NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl or arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl or heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SU2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl or heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring,
R3, R4 and R5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl, aralkyl, aralkenyl, aralkynyl, or aryl, aralkyl,, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring, Y1 is chloro, bromo, iodo, OCCI3, OR12, SR12 or N-hydroxysuccinimide,
Y2 is chloro, bromo, iodo, OCCI3. mesyl or tosyl,
R12 is alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, haloalkyl, haloalkenyl, haloalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkylsulfonyl and arylsulfonyl, aralkyl, aralkenyl, aralkynyl, or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
In a preferred first embodiment of this invention, Y1 is chloro, bromo, iodo or SR12.
In another preferred first embodiment of this invention, Y1 is chloro, bromo or iodo.
In another preferred first embodiment of this invention, Y1 is SR12.
In another preferred first embodiment of this invention, R12 is alkyl. In another preferred first embodiment of this invention, Y2 is chloro, bromo or iodo.
In another preferred first embodiment of this invention, R2 is a hydrogen atom.
In another preferred first embodiment of this invention, d is 0.
In a more preferred first embodiment of this invention, the intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula
Figure imgf000015_0001
wherein
G10 and Gπ are each independently an oxygen atom or a sulfur atom, RXs
Figure imgf000015_0002
wherein
G30 is an oxygen atom or a sulfur atom, G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1, X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom,
Z3(X3)d(G31)f is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, (Cι-C20)alkyl, (Ci- Cιo)alkylcarbonyloxy(Cι-Cιo)alkyl, (Ci-C2o)alkylcarbonyl, hydroxy(Ci-C2o)alkyl, (Ci- Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo) alkyl, halo(Cι-C2o) alkyl, (C2- Cιo)alkenyl, acetylamino(C2-Cιo)alkenyl, halo(C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(C2- Cιo)alkynyl, cyclo(C3-C8)alkyl, cyclo(C3-Cs)alkenyl, carboxycyclo(C3-C8)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(Cι-C_.o)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- C8)alkyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkyl(C2-Cιo)alkenyl. carboxycyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)alkyl(C2-Cιo)alkynyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(C 1- C 10) alkyl, heterocyclyl(C2- C 10) alkenyl, heterocyclyl(C2- C 10) alkynyl,
Figure imgf000015_0003
(Cι-Cι0)alkoxy(Cι-Cιo)alkoxy(Cι-Cι0)alkyl, (Cι- Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cι0)alkynyl, (Cι-Cιo)alkoxycarbonyl(Cι- Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2- Cιo)alkynyl, halo(Cι-Cι0)alkoxy(Cι-Cιo)alkyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkenyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkynyl) (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2- Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, NR3R4, OR3, S(O)jR3,
SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, (Cι-Cιo)alkyl, (Cι-Cιo)alkylsulfonyl(Cι- Cιo)alkyl, (C2-C10) alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-C 10) alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cι0)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι- Cιo)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cιo)alkyl, cycloalkyl, (C2-Cιo)alkenyl, (C2-Cι0) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι- Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Ci- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci-C 10) alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C_>-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cι0) alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci-C 10) alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2, Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(O)jR3 or SO2NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, (C1-C20) alkyl, (C2-C 10) alkenyl, (C2-C1Q) alkynyl, (Ci- Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-Cι0)alkoxy(C2-Cιo)alkenyl, (Cι-Cι0)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι-C10)alkyl, (Cι-C10)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2- Cιo)alkynyl, carboxy, a carboxylate salt, carboxy(Cι-C20)alkyl; carboxy(C2-C2o)alkenyl, carboxy(C2-C2o)alkynyl, (Cι-C2o)alkoxycarbonyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkynyl, (Ci- C20) alkylcarbonyl, (C2-C2o)alkenylcarbonyl, (C2-C20) alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cι0)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3- Cβ) alkyl(C2- C 10) alkynyl, cyclo(C3- Cβ) alkenyl(C2- C IQ) alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, or (Ci-C2o)alkyl, (C2-Cιo)alkenyl, (C2-Cι0)alkynyl, (C1-Cιo)alkoxy(Cι-Cιo)alkyl, (Ci- Cιo)alkoxy(C2-Cι0)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo) alkynyl, (Cι-Cιo)alkylthio(Cι- Cιo)alkyl, (Cι-Cι0)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, carboxy(Cι-C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, (Ci- C20) alkoxycarbonyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2- Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιθ)alkynyl, (Cι-C2o)alkylcarbonyl, (C2-
Cιo)alkenylcarbonyl, (C2-C 10) alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO2NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, (C1-C10) alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, carboxy, (Ci- C4)alkoxycarbonyl, SO2NR3R4 and NR3R4, ar(Cι-Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2- Cιo)alkynyl, or ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cι0)alkynyl substituted with one or more substituents independently selected from halo, (Ci-C 10) alkyl, (C2- Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2-Cιo)alkynylcarbonyl or arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2- Cio) alkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, (Ci- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4, heteroar(Cι- Cιo)alkyl, heteroar(C2-Cιo) alkenyl, heteroar(C2-Cιo)alkynyl or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cι0)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-C10) alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkylcarbonyl, heteroar(C2-Cι0)alkenylcarbonyl, heteroar(C2-C 10) alkynylcarbonyl or heteroar(Cι- C 10) alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cι0)alkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy,
SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring,
R3, R4 and R5 are each independently a hydrogen atom, (Cι-C2o)alkyl, cyclo(C3- C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, eyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl; (C2-Cι0)alkenyl, (C2-Cιo)alkynyl, or (Cι-Cιo)alkyl. cyclo(C3- Cs)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-Cs)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-C 10) alkenyl, carboxy(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-Cιo)alkenyl or (C2-Cιo)alkynyl substituted with one or more halo, aryl, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl or aryl, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cι0)alkyl, (C2-C 10) alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo (C2-Cι0) alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Ci-C 10) alkyl, (C2-C 10) alkenyl, (C2-C 10) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring,
Y1 is chloro, bromo, iodo, OCCI3, OR12, SR12 or N-hydroxysuccinimide, Y2 is chloro, bromo, iodo, OCC , mesyl or tosyl,
R12 is (Cι-C2o)alkyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-Cs)alkyl(Cι- Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxy(Cι-C2o)alkyl, carboxy (C2-C2o) alkenyl, carboxy (C2-C20) alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-C20) alkenyl, (C2-C2o) alkynyl, or (Ci- C2o)alkyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cι0)alkynyl, cyclo(C3- C8)alkenyl(C_.-Cι0) alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2- Cι0)alkynyl, carboxy(Cι-C2o)alkyl, carboxy(C2-C20)alkenyl, carboxy(C2-C2o)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-C2o)alkenyl or (C2-C2o)alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, halo(Cι-Cιo)alkyl, halo (C2-C1Q) alkenyl, halo(C2-Cιo)alkynyl, (Ci-C 10) alkylcarbonyl, (C2-Cιc)alkenylcarbonyl, (C2-
C 10) alkynylcarbonyl, arylcarbonyl, (Cι-Cιo)alkylsulfonyl and arylsulfonyl, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl, or ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cio)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιc)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof. In another more preferred first embodiment of this invention, Y1 is chloro, bromo, iodo or SR12.
In another more preferred first embodiment of this invention, Y1 is chloro, bromo or iodo. In another more preferred first embodiment of this invention, Y1 is SR12.
In another more preferred first embodiment of this invention, R12 is (Ci- Cι0)alkyl.
In another more preferred first embodiment of this invention, Y2 is chloro, bromo or iodo. In another more preferred first embodiment of this invention, R2 is a hydrogen atom.
In another more preferred first embodiment of this invention, d is 0.
In a second embodiment of this invention, one intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula
G10
Y1 C II G11 ? C — (G21- fC)t-(X2)qZ2
R2 wherein
G10, G11 and G20 are each independently an oxygen atom or a sulfur atom, G21 is an oxygen atom, a sulfur atom or NR3, q and t are each independently 0 or.l, R1 is
C-(G31)t,-(X3)dZ3 wherein G30 is an oxygen atom or a sulfur atom,
G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom,
Z3(X3)d(G31)f is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologically active compound, Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, NR3R4 OR3, S(O)jR3, SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2, Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(O)iR3 or SO2NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, or alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl,
SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4 arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl or arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl or heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl or heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring,
R3, R4 and R5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl, aralkyl, aralkenyl, aralkynyl, or aryl, aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring,
X2 is an oxygen atom, a sulfur atom, a phosphorous atom, a nitrogen atom or a carbon atom attached to Z2,
Z2(X2)q(C(=G20)G21)t is a biologically active moiety when q is 1 wherein
Figure imgf000023_0001
represents the biologically active compound,
Z2(X2)q is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, NR3R4, SO2NR3R4, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, dialkoxyphosphorylalkyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2N 3R and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, alkylcarbonylalkyl, alkenylcarbonylalkyl, alkynylcarbonylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkyl, heterocyclyloxycarbonylalkyl, arylcarbonyl, arylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl, aroxycarbonylalkyl, aralkoxycarbonylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaroxycarbonylalkyl, or arylcarbonyl, arylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl, aroxycarbonylalkyl, aralkoxycarbonylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaroxycarbonylalkyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, and C(=N-G22)R2 when q is 0 and t is 1,
G22 is OR3, OCOR3, S(O)jR3, OS(O)jR3, NR3R4, OSO2NR3R4, OP(=O)OR3NR3R4, OP(=O)(OR3)2 or N=CR3R4, j is 0, 1 or 2,
Z2(X2)q is halo, NR3R4, {(NR3R4R5)+ M"}, OR3, S(O)jR3 or SO2NR3R4 when both q and t are 0 wherein M" is halo, hydroxy, alkoxy or the anion of a carboxylic acid and j is 0, 1 or 2, Y1 is chloro, bromo, iodo, OCCI3, OR12, SR12 or N-hydroxysuccinimide,
R12 is alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, haloalkyl, haloalkenyl, haloalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkylsulfonyl and arylsulfonyl, aralkyl, aralkenyl, aralkynyl, or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
In a preferred second embodiment of this invention, Y1 is chloro, bromo, iodo or SR12. In another preferred second embodiment of this invention, Y1 is chloro, bromo or iodo.
In another preferred second embodiment of this invention, Y1 is SR12.
In another preferred second embodiment of this invention, R12 is alkyl. In another preferred second embodiment of this invention, R2 is a hydrogen atom except when a part of the C(=N-G22)R2 moiety, wherein said C(=N-G22)R2 moiety, R2 is as previously defined.
In another preferred second embodiment of this invention, d is 0.
In another preferred second embodiment of this invention, q is 0. In another preferred second embodiment of this invention, (d + q) is 1 or 2.
In another preferred second embodiment of this invention, t is 1.
In another preferred second embodiment of this invention, both q and t are 1 and X2 is a carbon atom.
In a more preferred second embodiment of this invention, the intermediate compound used for making enhanced propertied biologically active compounds is a compound of the formula
.10
,-.20
Y1 C G11 C I — (G21- tC)t-(X2)qZ2
R2 wherein G10, G11 and G20 are each independently an oxygen atom or a sulfur atom,
G21 is an oxygen atom, a sulfur atom or NR3, q and t are each independently 0 or 1, R! is
G30 C-(G31)t.-(X3)dZ3 wherein
G30 is an oxygen atom or a sulfur atom,
G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1, X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom, Z3(X3)d(G31)t' is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)r-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, (Ci-C2o)alkyl, (Ci- Cιo)alkylcarbonyloxy(Cι-Cιo)alkyl, (Cι-C20)alkylcarbonyl, hydroxy(Cι-C2o)alkyl, (Ci- Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Ci-C2o)alkyl, (C2- Cιo)alkenyl, acetylamino(C2-Cιo)alkenyl, halo(C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(C2- Cιo)alkynyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, carboxycyclo(C3-Cs)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-Cs)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- C8)alkyl(Cι-Cιo) alkyl, carboxycyclo(C3-C8)alkyl(C2-Cιo)alkenyl, carboxycyclo(C3-
C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-Cs)alkenyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)alkyl(C2-Cιo) alkynyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocy clyl(C i- C io) alkyl, heter ocyclyl(C2- C io) alkenyl, heterocyclyl(C2- C io) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-Clo)alkoxy(Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Ci- Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cι0)alkynyl, (Cι-Cιo)alkoxycarbonyl(Cι- Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2- C10)alkynyl, halo(Cι-Cιo)alkoxy(Cι-Cι0)alkyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkenyl, halo(Cι-Cιo)alkoxy(C2-Cι0)alkynyl5 (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2- Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkynyl, carboxy(Cι- C20)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, NR R4, OR3, S(O)jR3, SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, (Cι-Cιo)alkyl, (Cι-Cιo)alkylsulfonyl(Cι- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-Cs)alkyl, aroxy(Cι-Cι0)alkyl, or ar(Cι-Cιo) alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cι0)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι- Cι0)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (C1-C10) alkyl, cycloalkyl, (C2-Cio)alkenyl, (C2-Cιo) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι- Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Ci- Cιo)alkyl, (C2-C10) alkenyl, (C2-Cι0)alkynyl, halo(C1-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-
Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cι0)alkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(O)jR3 or SO2NR R4 when both d and t' are 0 and j is 0, 1 or 2, R2 is a hydrogen atom, (Cι-C20)alkyl, (C2-Cιc)alkenyl, (C2-Cιo) alkynyl, (Ci-
Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-CiQ)alkoxy(C2-Cι0)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-C10)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2- Cιo)alkynyl, carboxy, a carboxylate salt, carboxy(Cι-C20)alkyl, carboxy(C2-C2o)alkenyl, carboxy(C2-C2o)alkynyl, (Cι-C2o)alkoxycarbonyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cι0)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-C_.o)alkynyl, (Ci-
C20) alkylcarbonyl, (C2-C2o)alkenylcarbonyl, (C2-C2o)alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-Cs)alkyl(C2-Cιo)alkenyl, cyclo(C3-Cs)alkenyl(C2-Cιo)alkenyl, cyclo(C3- Cβ)alkyl(C2-C 10) alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-C 10) alkynyl, or (Cι-C20)alkyl, (C2-Cιo)alkenyl, (C2-C10)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Ci- Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι- Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cι0)alkenyl, (Cι-Cι0)alkylthio(C2-Cιo)alkynyl, carboxy(Cι-C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, (Ci- C20) alkoxycarbonyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2- Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkynyl, (Cι-C2o)alkylcarbonyl, (C2- CIQ) alkenylcarbonyl, (C2-Cιo)alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιc)alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2-Cιo) alkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO2NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cι0)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl. halo(C2- Cιo)alkenyl, halo (C2-Cιo) alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, carboxy, (Ci- C4)alkoxycarbonyl, SO2NR3R4 and NR3R4, ar(Cι-Cιo)alkyl, ar(C2-Cιo) alkenyl, ar(C2- Cιo)alkynyl, or ar(Cι-Cιo)alkylJ ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2- Cι0)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (C1-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, arylcarbonyl, ar(Cι-Cι0)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2-Cι0)alkynylcarbonyl or arylcarbonyl, ar(Cι-Cι0)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2- C 10) alkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-C10)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, (Ci- Cι0)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4, heteroar(Cι- Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cι0)alkynyl or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Ci-Cio) alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo (C2-C 10) alkynyl, (Ci-
Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO NR3R4 and NR3R4, heteroar(Cι-Cιo)alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cιo)alkynylcarbonyl or heteroar(Cι- Cιo)alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, (Cι-Cιo)alkyl, (C2-C1C.) alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring, R3, R4 and R5 are each independently a hydrogen atom, (Cι-C 0)alkyl, cyclo(C3- Cβ)alkyl, cyclo(C3-C8) alkenyl, cyclo(C3-C8)alkyl(Cι-Cι0)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-Cβ)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-Cs)alkenyl(C2-Cio)alkenyl, cyclo(C3-C8)alkenyl(C2-CiQ)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, heterocyclyl, heterocy clyl(C i- C io) alkyl, heterocyclyl(C2- C io) alkenyl, heterocyclyl(C2- C io) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-Cι0)alkenyl, (C2-CIQ) alkynyl, or (Cι-Cιo)alkyl, cyclo(C3- Cs)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C20)alkyl, carboxy(C2-Cι0)alkenyl, carboxy(C2-Cιo) alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-C1C1) alkenyl or (C2-C 10) alkynyl substituted with one or more halo, aryl, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl or aryl, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-C 10) alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo (C2-C 10) alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)allcenyl, heteroar(C2-Cιo)alkynyl or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C -Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cι0)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring, X2 is an oxygen atom, a sulfur atom, a phosphorous atom, a nitrogen atom or a carbon atom attached to Z2,
Figure imgf000030_0001
is a biologically active moiety when q is 1 wherein
Figure imgf000030_0002
represents the biologicaUy active compound, Z2(X2)q is a hydrogen atom, (Cι-C20)aUcyl, (Cι-Cι0)alkylcarbonyloxy(Cι-
Cιo)alkyl, (Cι-C2o)alkylcarbonyl, (Cι-C2o)alkenylcarbonyl, (Cι-C2o)alkynylcarbonyl, hydroxy(Cι-C2θ)alkyl, (Cι-Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cι0)alkyl, halo(Cι-C2θ)alkyl, (C2-C2o)alkenyl, halo(C2-C2o)alkenyl, acetylamino(C2-Cιo)alkenyl, (C2-C20) alkynyl, halo(C2-C2o)alkynyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, carboxycyclo(C3-Cδ)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)aIkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3- C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxycyclo(C3-C8)alkyl(Cι-Cιo)a!kyl, carboxy(C3-C8)cycloalkyl(C2-
Cιo)alkenyl, carboxycyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkenyl(C2- Cιo)alkenyl, carboxycyclo(C3-C8)alkyl(C2-CiQ)alkynyl, carboxycyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-C 10) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-C5)alkoxy(Cι- C5)alkoxy(C1-Cιo)alkyl, (Cι-Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Ci- Cι0)alkoxycarbonyl(C2-Cιo)alkynyl, halo(Cι-Cιo)alkoxy(Cι-Cιo)alkyl, halo(Cι- Cιo)alkoxy(C2-Cιo)alkenyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι- Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, halo(Cι- Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι-
Cιo)aIkylthio(C2-Cιc)alkynyl, SO2NR3R4, NR3R4, carboxy(Cι-C2o)alkyl, carboxy(C2- C2θ)alkenyl, carboxy(C2-C2o)alkynyl, di(Cι-Cιo)alkoxyphosphoryl(Cι-Cιo)alkyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, (Cι-Cιo)alkyl, (Cι-Cιo)alkylsulfonyl(Cι-Cιo)alkyl, (Ci- Cιo)alkylsulfonyl, thiocyanato, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cι0)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4, and NR3R4, ar(Cι-Cιo)a!kyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Cι-Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2- Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cιo)alkyl, cyclo(C3-C8)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-
Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4, heteroar(Cι-Cιo)aU yl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cι0)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιc)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, (Ci- Cιo)alkylcarbonyl(Cι-C10)alkyl, (C2-Cιo)alkenylcarbonyl(Cι-Cιo)alkyl, (C2- Cι0)alkynylcarbonyl(Cι-Cιo)alkyl, heterocyclylcarbonyl, heterocyclylcarbonyl(Cι- Cιo)alkyl, heterocyclyloxycarbonyl(Cι-Cιo)alkyl, arylcarbonyl, arylcarbonyl(Cι- Cιo)alkyl, ar(Cι-Cι0)alkylcarbonyl, ar(Cι-Cιo)alkylcarbonyl(Cι-Cι0)alkyl, aroxycarbonyl(Cι-Cιo)alkyl, ar(Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, heteroarylcarbonyl, heteroarylcarbonyl(Cι-Cιo)alkyl, heteroaroxycarbonyl(Cι- Cι0)alkyl, or arylcarbonyl, arylcarbonyl(Cι-Cιo)alkyl, ar(Cι-Cιo)alkylcarbonyl, ar(Cι- Cιo)alkylcarbonyl(Cι-Cιo)alkyl, aroxycarbonyl(Cι-Cι0)alkyl, ar(Cι- Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, heteroarylcarbonyl, heteroarylcarbonyl(Cι-Cι0)alkyl, heteroaroxycarbonyl(Cι-Cιo)alkyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-
Cιo)alkynyl, (Cι-Cι0)alkoxy, halo(Cι-Cιo)a!koxy, SO2NR3R4 and NR3R4, and C(=N- G22)R2 when q is 0 and t is 1,
G22 is OR3, OCOR3, S(O),R3, OS(O)jR3, NR3R4, OSO2NR3R4, OP(=0)OR3NR3R4, OP(=O)(OR )2 or N=CR3R4, j is 0, 1 or 2,
Z2(X2)q is halo, NR3R4, {(NR3R4R5)+ M~}, OR3, S(O):R3 or SO2NR3R4 when both q and t are 0 wherein M~ is halo, hydroxy, (Cι-C8)alkoxy or the anion of a carboxylic acid and j is 0, 1 or 2,
Y1 is chloro, bromo, iodo, OCCI3, OR12, SR12 or N-hydroxysuccinimide, R12 is (Cι-C20)alkyl, cyclo(C3-Cs) alkyl, cyclo(C3-Cs) alkenyl, cyclo(C3-Cs)alkyl(Cι-
Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-CiQ)alkenyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxy(Cι-C2o)alkyl, carboxy(C2-C2o)alkenyl, carboxy(C2-C2o)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2- Cιo)alkynyl, (Cι-Cι0)alkoxy(Cι-Cι0)alkyl, (C2-C20) alkenyl, (C2-C20) alkynyl, or (Ci- C2o)aUcyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)aUcyl(Cι-Cιo)aU5:yl, cyclo(C3-C8)alkyl(C2-Cιo)aIkenyl, cyclo(C3-C8)alkyl(C2-CiQ)aUcynyl, cyclo(C3- C8)alkenyl(Cι-Cιo)aIkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxy(Cι-C20)alkyl, carboxy (C2-C2C)) alkenyl, carboxy(C2-C2o)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2- Cιo)alkynyl, (Cι-Cι0)alkoxy(Cι-Cιo)alkyl, (C2-C20)alkenyl or (C2-C20)alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkylcarbonyl, (C2-C 10) alkenylcarbonyl, (C2- Cιo)alkynylcarbonyl, arylcarbonyl, (Cι-Cιo)alkylsulfonyl and arylsulfonyl, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl, or ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Ci-C 10) alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo (C2-C 10) alkynyl, (Cι-Cι0)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2- Cι0)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
In another more preferred second embodiment of this invention, Y1 is chloro, bromo, iodo or SR12.
In another more preferred second embodiment of this invention, Y1 is chloro, bromo or iodo.
In another more preferred second embodiment of this invention, Y1 is SR12.
In another more preferred second embodiment of this invention, R12 is (Ci- Cιo)alkyl. '
In another more preferred second embodiment of this invention, R2 is a hydrogen atom except when a part of the C(=N-G22)R2 moiety, wherein said C(=N- G22)R2 moiety, R2 is as previously defined.
In another more preferred second embodiment of this invention, d is 0. In another more preferred second embodiment of this invention, q is 0.
In another more preferred second embodiment of this invention, (d + q) is 1 or 2.
In another more preferred second embodiment of this invention, t is 1. In another more preferred second embodiment of this invention, both q and t are 1 and X2 is a carbon atom.
In a third embodiment of this invention, one intermediate compound used for making enhanced propertied biologicaUy active compounds is a compound of the formula
Figure imgf000034_0001
wherein
G10 and G11 are each independently an oxygen atom or a sulfur atom, m is 0 or 1,
R s
Figure imgf000034_0002
wherein
G30 is an oxygen atom or a sulfur atom, G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom,
Z3(X3)d(G31)t' is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologicaUy active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloaUcenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, NR3R4, OR3, S(O)jR3, SiR3R R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3; N(R3)-N=CR3R4, S(O)jR3 or SO2NR R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, or alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO2NR3R4 and NR3R4 aryl or aryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl or arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R and NR3R4, heteroaryl or heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl or heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring, R3, R4 and R5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl, aralkyl, aralkenyl, aralkynyl, or aryl, aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocycUc ring, X1 is an oxygen atom, a sulfur atom, a phosphorous atom or a nitrogen atom attached to Z1,
ZXX1)..! is a biologicaUy active moiety when m is 1 wherein
Figure imgf000037_0001
represents the biologicaUy active compound,
Z^X1).!!, when m is 0, is a hydrogen atom, halo, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, NR3R4, SO2NR3R4 OR3, S(O)jR3, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfons alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SU2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Y2 is chloro, bromo, iodo, OCCI3, mesyl or tosyl, or the biologicaUy active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
In a preferred third embodiment of this invention, Y2 is chloro, bromo or iodo.
In another preferred third embodiment of this invention, R2 is a hydrogen atom.
In another preferred third embodiment of this invention, d is 0. In another preferred third embodiment of this invention, m is 0.
In another preferred third embodiment of this invention, (d + m) is 1 or 2.
In a more preferred third embodiment of this invention, the intermediate compound used for making enhanced propertied biologicaUy active compounds is a compound of the formula
Figure imgf000038_0001
m G10 and G11 are each independently an oxygen atom or a sulfur atom. m is 0 or 1,
R s
Figure imgf000039_0001
wherein
G30 is an oxygen atom or a sulfur atom, G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom, Z3(X3)d(G31)f is a biologicaUy active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologicaUy active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, (Cι-C2o)alkyl, (Ci- Cιo)alkylcarbonyloxy(Cι-Cιo)alkyl, (Cι-C2o)alkylcarbonyl, hydroxy(Ci-C2o)alkyl, (Ci- Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Cι-C2o)alkyl, (C2- Cιo)alkenyl, acetylamino(C2-Cιo)alkenyl, halo(C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(C2- Cιo)alkynyl, cyclo(C3-C8) alkyl, cyclo(C3-Cs)alkenyl, carboxycyclo(C3-C8)alkyl, carboxycyclo(C3-C8) alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- C8)alkyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkyl(C2-Cιo)alkenyl, carboxycyclo(C3-
C8)alkenyl(Ci-C 10) alkyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)aUcyl(C2-C 10) alkynyl, carboxycyclo(C3-C8)alkenyl(C2-Cι0)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cι0) alkenyl, heterocyclyl(C2-C 10) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-Cιo)aEioxy(Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Ci- C 10) alkoxy(C2-Cι0) alkenyl, (Cι-Cι0)alkoxy(C2-Cι0)alkynyl, (Cι-Cιo)alkoxycarbonyl(Cι- C 10) alkyl, (C 1- C IQ) alkoxycarbonyl(C2- C IO) alkenyl, (C 1- C 10) alkoxycarbonyl(C2- Cιo)alkynyl, halo(Cι-Cι0)alkoxy(Cι-Cιo)alkyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkenyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2- Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-CiQ)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι-Cι0)alkylthio(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cι0)alkynyl, NR3R4, OR3, S(O)jR3, SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, (Cι-Cι0)alkyl, (Cι-Cιo)alkylsulfonyl(Cι- Cιo)alkyl, (C2-C10) alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)a!kenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-Cs)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι- Cι0)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cι0)alkyl, cycloalkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι- Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Ci- C:o)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)a!koxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Ci-C 10) alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cι0)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(O)jR3 or SO2NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, (Cι-C20)alkyl, (C2-Cιo)alkenyl, (C2-Cι0)alkynyl, (Ci- Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (C1-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2- Cιo)alkynyl, carboxy, a carboxylate salt, carboxy(Cι-C2o)alkyl, carboxy(C2-C2o)alkenyl, carboxy(C2-C2o)alkynyl, (Cι-C2θ)alkoxycarbonyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)aIkynyl, (Ci- C20) alkylcarbonyl, (C2-C2o)alkenylcarbonyl, (C2-C20) alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-Cs)alkyl(Cι-Cιo)aU_;yl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3- C8)alkyl(C2-C 10) alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, or (Cι-C2o)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Ci- Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)aIkynyl, (Cι-Cιo)alkylthio(Cι- Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)aIkylthio(C2-Cιo)alkynyl, carboxy(Cι-C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cι0)alkynyl, (Ci- C20) alkoxycarbonyl, (Ci- C 10) alkoxycarbonyl(C 1- C IQ) alkyl, (C 1- C 10) alkoxycarbonyl(C2- Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkynyl, (C1-C20) alkylcarbonyl, (C2- Cιo)aU enylcarbonyl, (C2-Cιo)alkynylcarbonyl, cyclo(C3-Cs) alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)aIkyl, cyclo(C3-C8)aUjenyl(Cι-Cιo)aU?:yl, cyclo(C3-Cs)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cι0)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)aUζynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO2NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-C 10) alkenyl, (C2-CIQ) alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-C_.o)alkynyl, (Cι-Cι0)alkoxy, halo(Cι-Cιo)alkoxy, carboxy, (Ci- C4)alkoxycarbonyl, SO2NR3R4 and NR3R4, ar(Cι-Cιo)alkyl, ar(C2-C 10) alkenyl, ar(C2- Cιo)alkynyl, or ar(Cι-Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO NR3R4 and NR3R4, arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2-Cιo)alkynylcarbonyl or arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-C 10) alkenylcarbonyl, ar(C2-
Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl. (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-C 10) alkenyl, halo(C2-Cι0)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, (Ci- Cι0)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cι0)alkoxy and NR3R4, heteroar(Cι- Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cι0)alkynylcarbonyl or heteroar(Cι- Cio) alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cι0)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (C1-C10) alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring,
R3, R4 and R5 are each independently a hydrogen atom, (Ci-C2o)alkyl, cyclo(C3- C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cι0)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cι0)alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2-Cιo) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, or (Cι-Cιo)alkyl, cyclo(C3- C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C20)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιc)alkynyl, heterocyclyl, heterocyclyl(C i- C io) alkyl, heterocyclyl(C2- C io) alkenyl, heter ocyclyl(C2- C io) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-Cιo)alkenyl or (C2-Cιo)alkynyl substituted with one or more halo, aryl, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo) alkynyl or aryl, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo) alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-C10) alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Ci-C 10) alkyl, (C2-Cιo) alkenyl, (C2-C1C.) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cι0)alkoxy and halo(Cι-Cιo)alkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocycUc ring,
X1 is an oxygen atom, a sulfur atom, a phosphorous atom or a nitrogen atom attached to Z1, Z1(X1)m is a biologicaUy active moiety when m is 1 wherein
Figure imgf000043_0001
represents the biologicaUy active compound,
Z^^ , when m is 0, is a hydrogen atom, halo, (Cι-C2o)alkyl, (Ci- Cι0)alkylcarbonyloxy(Cι-Cιo)alkyl, (Cι-C20) alkylcarbonyl, hydroxy(Cι-C2o)alkyl, (Ci- Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Cι-C2θ)alkyl, (C2-
C2o)alkenyl, halo(C2-C2o)alkenyl, acetylamino(C2-Cιo)alkenyl, (C2-C20) alkynyl, halo(C2- C2o)alkynyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, carboxycyclo(C3-C8)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-Cs)alkyl(C2- Cιo)alkenyl, cyclo(C3-Cs)alkenyl(Cι-Cιo)aU∑yl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- Cβ) alkyl(C 1- C io) alkyl, carboxy (C3- C8)cycloalkyl(C2- C 10) alkenyl, carboxycyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, carboxycyclo(C3- Cs)alkyl(C2-C 10) alkynyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-C 10) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-C5)alkoxy(Cι-C5)alkoxy(Cι-Cιo)alkyl, (Ci-
C 10) alkoxy (C2- C 10) alkenyl, (C 1- C 10) alkoxy (C2- C IQ) alkynyl, (C 1- C io) alkoxycarbonyl(C 1- Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cι0)alkenyl, (Cι-Cι0)alkoxycarbonyl(C2- Cιo)alkynyl, halo(Cι-Cιo)alkoxy(Cι-Cιo)alkyl, halo(Cι-Cιc)alkoxy(C2-Cιo)alkenyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2- Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)aUcenyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkynyl, SO2NR3R4, NR3R4, OR3, S(O)jR3, carboxy(Cι-C2o)alkyl, carboxy(C2-C2o)alkenyl, carboxy(C2- C2o)alkynyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, (Cι-Cιo)alkyl, (Cι-Cιo)alkylsulfonyl(Cι- Cιo)alkyl, (Cι-Cιo)alkylsulfonyl, thiocyanato, (C2-C 10) alkenyl, (C2-Cιo)alkynyl, halo(Cι- Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4, and NR3R4, ar(Cι-C10)alkyl, ar(C2-Cιo)alkenyl, ar(C2-C 10) alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Cι-Cι0)alkyl, ar(C2-Cιo)alkenyl, ar(C2- Cι0)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cι0)alkyl, cyclo(C3-C8)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci-C ID) alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cι0)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl. halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, wherein j is 0, l or 2, Y2 is chloro, bromo, iodo, OCCI3, mesyl or tosyl, or the biologicaUy active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
In another more preferred third embodiment of this invention, Y2 is chloro, bromo or iodo. In another more preferred third embodiment of this invention, R2 is a hydrogen atom.
In another more preferred third embodiment of this invention, d is 0.
In another more preferred third embodiment of this invention, m is 0.
In another more preferred third embodiment of this invention, (d + m) is 1 or 2.
In all embodiments of this invention, the term "alkyl" includes both branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, 71-propyl, isopropyl, 71-butyl, sec-butyl, isobutyl, tert-butyl, 71-pentyl, isopentyl, 7i-hexyl, ?ι- heptyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl and the like.
The term "halo" refers to fluoro, chloro, bromo or iodo.
The term "haloalkyl" refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8-chlorononyl and the like.
The term "cycloalkyl" refers to a cycUc aUphatic ring structure, optionally substituted with alkyl, hydroxy and halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl, 2-hydroxycyclopentyl, cyclohexyl, 4-chlorocyclohexyl, cycloheptyl, cyclooctyl and the like.
The term "alkylcarbonyloxyalkyl" refers to an ester moiety, for example acetoxymethyl, 7i-butyryloxyethyl and the like. The term "alkynylcarbonyl" refers to an alkynylketo functionahty, for example propynoyl and the like.
The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl and the like.
The term "alkylsulfonylalkyl" refers to an alkyl group substituted with an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl and the like.
The term "alkylsulfonyl" refers to a sulfonyl moiety substituted with an alkyl group, for example mesyl, 7i-propylsulfonyl and the like.
The term "acetylaminoalkyl" refers to an alkyl group substituted with an amide moiety, for example acetylaminomethyl and the Uke. The term "acetylaminoalkenyl" refers to an alkenyl group substituted with an amide moiety, for example 2-(acetylamino)vinyl and the Uke.
The term "alkenyl" refers to an ethylenicaUy unsaturated hydrocarbon group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl, aUyl, 1- butenyl, 2-butenyl, isopropenyl, 2-pentenyl and the like. The term "haloalkenyl" refers to an alkenyl group substituted with one or more halo groups.
The term "cycloalkenyl" refers to a cyclic aUphatic ring structure, optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1,4- cyclohexadienyl and the like.
The term "alkynyl" refers to an unsaturated hydrocarbon group, straight or branched, having 1 or 2 acetylenic bonds, for example ethynyl, propargyl and the Uke.
The term "haloalkynyl" refers to an alkynyl group substituted with one or more halo groups.
The term "alkylcarbonyl" refers to an alkylketo functionahty, for example acetyl, n-butyryl and the Uke. The term "alkylcarbonylalkyl" refers to an alkylketoalkyl functionahty, for example acetonyl and the Uke.
The term "alkenylcarbonyl" refers to an alkenylketo functionahty, for example, propenoyl and the Uke. The term "alkenylcarbonylalkyl" refers to an alkenylketoalkyl functionahty, for example, propenoylmethyl and the like.
The term "alkynylcarbonyl" refers to an alkynylketoalkyl functionahty, for example, propynoyl and the like.
The term "alkynylcarbonylalkyl" refers to an alkynylketoalkyl functionaUty, for example, propynoylmethyl and the like.
The term "aryl" refers to phenyl or naphthyl which may be optionaUy substituted. Typical aryl substituents include, but are not Umited to, phenyl, 4- chlorophenyl, 4-fLuorophenyl, 4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2- methylphenyl, 3-methyphenyl, 4-methylphenyl, 4-ethylphenyl, 2-methyl-3- methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6- trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl, 4-(trifluoromethyl)phenyl, 2-carboxyphenyl, 2-methoxycarbonylphenyl, 4- nitrophenyl, 2,4-dinitrophenyl, 2,3,4,5,6-pentafluorophenyl and 2-iodo-4- methylphenyl. The term "arylcarbonyl" refers to an aryl group as defined previously attached to a keto group, for example benzoyl and the Uke.
The term "arylcarbonylalkyl" refers to an arylcarbonyl group as defined previously attached to an alkyl group, for example phenacyl and the Uke.
The term "heteroaryl" refers to a substituted or unsubstituted 5 or 6 membered unsaturated ring containing one, two or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including one heteroatom selected from oxygen, nitrogen and sulfur. Examples of heteroaryls include, but is not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl and isoquinolyl. The heterocyclic ring may be optionally substituted with up to two substituents. The term "heteroarylcarbonyl" refers to a heteroaryl group as defined above attached to a keto group, for example 2-pyridylcarbonyl and the Uke.
The term "heteroarylcarbonylalkyl" refers to a heteroarylcarbonyl group as defined above attached to an group, for example 2-pyridylcarbonylmethyl and the like.
The term "aralkyl" is used to describe a group wherein the alkyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a terminal portion of the aralkyl moiety. Examples of aralkyl groups include, but are not hmited to, optionally substituted benzyl, phenethyl, phenpropyl and phenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2-(3-fluorophenyl)ethyl, 2-(4-methylphenyl)ethyl, 2-(4-(trifluoromethyl)phenyl)ethyl, 2-(2- methoxyphenyl)ethyl, 2-(3-nitrophenyl)ethyl, 2-(2,4-dichlorophenyl)ethyl, 2-(3,5- dimethoxyphenyl)ethyl, 3-phenylpropyl, 3-(3-chlorophenyl)propyl, 3-(2- methylphenyl)propyl, 3-(4-methoxyphenyl)propyl, 3-(4- (trifluoromethyl)phenyl)propyl, 3-(2,4-dichlorophenyl)propyl, 4-phenylbutyl, 4-(4- chlorophenyl)butyl, 4-(2-methylphenyl)butyl, 4-(2,4-dichlorophenyl)butyl, 4-(2- methoxphenyl)butyl and 10-phenyldecyl.
The term "aralkylcarbonyl" refers to an aralkyl group as defined above attached to a keto group, for example phenylacetyl and the Uke. The term "aralkylcarbonylalkyl" refers to an aralkylcarbonyl group as defined above attached to an alkyl group, for example phenylacetylmethyl and the like.
The term "aralkoxy" refers to an aryl group as defined above attached to an alkoxy group, for example benzyloxy and the Uke.
The term "aralkoxycarbonyl" refers to an aralkoxy group as defined above attached to a keto group, for example benzyloxycarbonyl and the like.
The term "aralkoxycarbonylalkyl" refers to an aralkoxycarbonyl group as defined above attached to an alkyl group, for example benzyloxycarbonylmethyl and the like.
The term "arcycloalkyl" is used to describe a group wherein the aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like. The term "aralkenyl" is used to describe a group wherein the alkenyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a terminal portion of the aralkenyl moiety, for example styryl (2- phenylvinyl), phenpropenyl and the like. The term "aralkynyl" is used to describe a group wherein the alkynyl chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a terminal portion of the aralkynyl moiety, for example 3-phenyl-l-propynyl and the like.
The term "aroxy" is used to describe an aryl group attached to a terminal oxygen atom. Typical aroxy groups include phenoxy, 3,4-dichlorophenoxy and the like.
The term "aroxycarbonylalkyl" is used to describe an aroxy group as defined above attached to an alkylcarbonyl group, for example phenoxycarbonylmethyl and the Uke. The term "heteroaroxycarbonylalkyl" is used to describe a heteroaroxy group as defined above attached to an alkylcarbonyl group, for example pyridyloxycarbonylmethyl and the Uke.
The term "aroxyalkyl" is used to describe a group wherein an alkyl group is substituted with an aroxy group, for example pentafluorophenoxymethyl and the like.
The term "heteroaroxy" is used to describe an heteroaryl group attached to a terminal oxygen atom. Typical heteroaroxy groups include 4,6-dimethoxypyrimidin- 2-yloxy and the like.
The term "heteroaralkyl" is used to describe a group wherein the alkyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a terminal portion of the heteroaralkyl moiety, for example 3- furylmethyl, thenyl, furfuryl and the like.
The term "heteroaralkenyl" is used to describe a group wherein the alkenyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a terminal portion of the heteroaralkenyl moiety, for example 3-(4-pyridyl)-l-propenyl.
The term "heteroaralkynyl" is used to describe a group wherein the alkynyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, forming a terminal portion of the heteroaralkynyl moiety, for example
4- (2-thienyl) - 1 -butynyl.
The term "heterocyclyl" refers to a substituted or unsubstituted 5 or 6 membered saturated or partiaUy saturated ring containing one, two or three heteroatoms, preferably three nitrogen atoms, two nitrogen atoms and an oxygen or a sulfur atom, one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic ring system containing up to 10 atoms including one heteroatom selected from oxygen, nitrogen and sulfur wherein the ring containing the heteroatom is saturated. Substituents can include halo, alkyl, haloalkyl, hydroxy, alkoxy, nitro or oxo (=O) on the heterocyclyl ring. Examples of heterocyclyls include, but are not limited to, tetrahydrofuryl, pyrroUdinyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, triazolonyl, oxadiazolonyl, thiadiazolonyl, pyrazolonyl, imidazolonyl, pyridonyl, primidinoyl, pyrazinoyl, triazonyl and 5-methyl-6-chromanyl. The term "heterocyclylcarbonyl" refers to a heterocyclyl group as defined before attached to a keto group, for example tetrahydrofurylcarbonyl and the Uke.
The term "heterocyclylcarbonylalkyl" refers to a heterocyclylcarbonyl group as defined before attached to an alkyl group, for example tetrahydrofurylcarbonylmethyl and the like. The term "heterocyclyloxy" refers to a heterocyclyl group as defined above attached to an oxygen atom, for example piperidinoxy and the Uke.
The term "heterocyclyloxycarbonyl" refers to a heterocyclyloxy group as defined above attached to a keto group, for example piperidinoxycarbonyl and the like. The term "heterocyclyloxycarbonylalkyl" refers to a heterocyclyloxycarbonyl group as defined above attached to an alkyl group, for example piperidinoxycarbonylmethyl and the Uke.
The term "heterocyclylalkyl" is used to describe a group wherein the alkyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinabove, forming a terminal portion of the heterocyclylalkyl moiety, for example
3-piperidinylmethyl and the like.
The term "heterocyclylalkenyl" is used to describe a group wherein the alkenyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a terminal portion of the heterocyclylalkenyl moiety, for example 2-morpholinyl-l-propenyl.
The term "heterocyclylalkynyl" is used to describe a group wherein the alkynyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a terminal portion of the heterocyclylalkynyl moiety, for example 2-pyrroUdinyl-l-butynyl.
The term "carboxyalkyl" includes both branched and straight chain alkyl groups as defined hereinbefore attached to a carboxy (-CO OH) group.
The term "carboxyalkenyl" includes both branched and straight chain alkenyl groups as defined hereinbefore attached to a carboxy group.
The term "carboxyalkynyl" includes both branched and straight chain alkynyl groups as defined hereinbefore attached to a carboxy group.
The term "carboxycycloalkyl" refers to a carboxy group attached to a cyclic aliphatic ring structure as defined hereinbefore. The term "carboxycycloalkenyl" refers to a carboxy group attached to a cycUc aliphatic ring structure having 1 or 2 ethylenic bonds as defined hereinbefore.
The term "cycloalkylalkyl" refers to a cycloalkyl group as defined hereinbefore attached to an alkyl group, for example cyclopropylmethyl, cyclohexylethyl and the like. The term "cycloalkylalkenyl" refers to a cycloalkyl group as defined hereinbefore attached to an alkenyl group, for example cyclohexylvinyl, cycloheptylaUyl and the like.
The term "cycloalkylalkynyl" refers to a cycloalkyl group as defined hereinbefore attached to an alkynyl group, for example cyclopropylpropargyl, 4- cyclopentyl-2-butynyl and the like.
The term "cycloalkenylalkyl" refers to a cycloalkenyl group as defined hereinbefore attached to an alkyl group, for example 2-(cyclopenten-l-yl)ethyl and the Uke.
The term "cycloalkenylalkenyl" refers to a cycloalkenyl group as defined hereinbefore attached to an alkenyl group, for example l-(cyclohexen-3-yl)aUyl and the like. The term "cycloalkenylalkynyl" refers to a cycloalkenyl group as defined hereinbefore attached to an alkynyl group, for example l-(cyclohexen-3-yl)propargyl and the Uke.
The term "carboxycycloalkylalkyl" refers to a carboxy group attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined hereinbefore.
The term "carboxycycloalkylalkenyl" refers to a carboxy group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined hereinbefore.
The term "carboxycycloalkylalkynyl" refers to a carboxy group attached to the cycloalkyl ring portion of a cycloalkylalkynyl group as defined hereinbefore. The term "carboxycycloalkenylalkyl" refers to a carboxy group attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined hereinbefore.
The term "carboxycycloalkenylalkenyl" refers to a carboxy group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined hereinbefore.
The term "carboxycycloalkenylalkynyl" refers to a carboxy group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as defined hereinbefore.
The term "alkoxy" includes both branched and straight chain alkyl groups attached to a terminal oxygen atom. Typical alkoxy groups include methoxy, ethoxy, 7i-propoxy, isopropoxy, tert-butoxy and the Uke.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy and the like.
The term "alkoxyalkoxyalkyl" refers to an alkyl group substituted with an alkoxy moiety which is in turn substituted with a second alkoxy moiety, for example methoxymethoxymethyl, isopropoxymethoxyethyl and the like. The term "alkylthio" includes both branched and straight chain alkyl groups attached to a terminal sulfur atom, for example methylthio.
The term "haioalkylthio" refers to an alkylthio group substituted with one or more halo groups, for example trifluoromethylthio.
The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, for example isopropoxymethyl.
The term "alkoxyalkenyl" refers to an alkenyl group substituted with an aUcoxy group, for example 3-methoxyaUyl. The term " alkoxy alkynyl" refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl.
The term "alkoxycarbonylalkyl" refers to a straight chain or branched alkyl substituted with an alkoxycarbonyl, for example ethoxycarbonylmethyl, 2- (methoxycarbonyl)propyl and the Uke.
The term "alkoxycarbonylalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkoxycarbonyl, for example 4- (ethoxycarbonyl)-2-butenyl and the Uke.
The term "alkoxycarbonylalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkoxycarbonyl, for example 4- (ethoxycarbonyl)-2-butynyl and the Uke.
The term "haloalkoxyalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with a haloalkoxy, for example 2- chloroethoxymethyl, trifluoromethoxymethyl and the like. The term "haloalkoxyalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with a haloalkoxy, for example 4- (chloromethoxy)-2-butenyl and the like.
The term "haloalkoxyalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(2- fluoroethoxy) - 2-butynyl and the hke .
The term "alkylthioalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with an alkylthio group, for example methylthiomethyl, 3-(isobutylthio)heptyl and the Uke.
The term "alkylthioalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an alkylthio group, for example 4-(methylthio)- 2-butenyl and the like.
The term "alkylthioalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an alkylthio group, for example 4-(ethylthio)-2- butynyl and the like. The term "haloalkylthioalkyl" refers to a straight chain or branched alkyl as defined hereinbefore substituted with an haioalkylthio group, for example 2- chloroethylthiomethyl, trifluoromethylthiomethyl and the like. The term "haloalkylthioalkenyl" refers to a straight chain or branched alkenyl as defined hereinbefore substituted with an haioalkylthio group, for example 4- (chloromethylthio)-2-butenyl and the like.
The term "haloalkylthioalkynyl" refers to a straight chain or branched alkynyl as defined hereinbefore substituted with an haioalkylthio group, for example 4-(2- fluoroethylthio)-2-butynyl and the like.
The term "dialkoxyphosphorylalkyl" refers to two straight chain or branched alkoxy groups as defined hereinbefore attached to a pentavalent phosphorous atom, containing an oxo substituent, which is in turn attached to an alkyl, for example diethoxyphosphorylmethyl.
The term "bicycloalkyl" refers to bicyclic alkyl groups, for example bicyclo[2.2. l]-hept-2-yl (norbornyl).
The term "bicycloalkenyl" refers to bicychc alkenyl groups, for example bicyclo[2.2. l]-2-heptenyl (nobornylenyl). The term "oligomer" refers to a low-molecular weight polymer, whose number average molecular weight is typicaUy less than about 5000 g/mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one and typically equal to or less than about 50.
The term "biologically active moiety" refers to one or more chemical radicals which coUectively form the actual biologically active compound.
The compounds of Formula I of this invention and the intermediates used in the synthesis of the compounds of this invention can be prepared according to the following methods. Method A can be used when preparing compounds of Formula I- A [compound of Formula I where R1 equals
Figure imgf000053_0001
as shown below in Scheme 1:
Method A:
Scheme 1
Figure imgf000053_0002
III l-A where Zi(Xi)m-H, Z (X2)q, Z3(X3)d, Zrøm, G10, G", G2o, G21, G30, G31, and R2 are as defined previously for compound of Formula I-A and t = 0 or 1, t' = 0 or 1, q = 0 or 1, d = 0 or 1, and Y1 = halogen such as chlorine.
In a typical preparation, according to Method A, of a compound of Formula I- A [compound of Formula I where R1 equals
Figure imgf000054_0001
a compound of Formula II is reacted with a compound of Formula III in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula II. The compounds of Formula II are generaUy commerciaUy avaUable or can be prepared according to known procedures.
The compounds of Formula III of Scheme 1 are prepared as shown in Scheme 2. Scheme 2
halogenating agent solvent
Figure imgf000055_0001
Figure imgf000055_0002
IV III where Z2(X2)q, Z3(X3)d, G10, G11, G20, G21, G30, G31, and R2 are as defined previously for compound of Formula I-A and t = 0 or 1, t' = 0 or 1, q = 0 or 1, d = 0 or 1, R12 is an alkyl, aralkyl, or aryl group, and Y1 = halogen such as chlorine.
In a typical preparation of a compound of Formula III, a compound of Formula IV is treated with a suitable halogenating agent in a suitable solvent, where the suitable halogenating agents include chlorine gas, thionyl chloride, and sulfuryl chloride, however, the preferred halogenating agent is sulfuryl chloride. Suitable solvents for use in the above process include, but are not limited to, hexanes, chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, and the Uke, however, the reactions are normally run neat. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
The compounds of Formula IV of Scheme 2 are prepared as shown in Scheme
Scheme 3
Figure imgf000055_0003
where Z2(X2)q[(C=G2°)-G21]t-H, Z2(X2)q, Z3(X3)d, G10, G11, G2°, G21, G30, G31, and R2 are as defined previously for compound of Formula I-A and t = 0 or 1, t' = 0 or 1, q = 0 or 1, d = 0 or 1, R12 is an alkyl, aralkyl, or aryl group, and Y2 = halogen such as chlorine.
In a typical preparation of a compound of Formula IV, a compound of Formula V is reacted with a compound of Formula VI in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula VI. The compounds of Formula VI are generally commerciaUy avaUable or can be prepared according to known procedures.
The compounds of Formula V of Scheme 3 are prepared as shown in Scheme 4: Scheme 4
Figure imgf000057_0001
VII v where Z3(X3)d, G10, G11, G30, G31, and R2 are as defined previously for compound of Formula I-A and f = 0 or 1, d = 0 or 1, R12 = alkyl, aralkyl, or aryl, and Y1 and Y2 = halogen such as chlorine, bromine, or iodine.
In a typical preparation of a compound of Formula V, a compound of Formula VII is reacted with a compound of Formula VIII in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is diethyl ether. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is sodium hydride. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula VIII. The compounds of Formula VIII are generaUy commercially avaUable or can be prepared according to known procedures. Conversion of Y2 from Cl to Br or Cl to I in compound of Formula V can be prepared according to literature procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4th ed.; WUey and Sons: New York, 1992; pp 430-431.
The compounds of Formula VII of Scheme 4 are prepared as shown in Scheme 5:
Scheme 5
Figure imgf000058_0001
IX X VII where Z3(X3)d, G10, G11, G30, G31, and R2 are as defined previously for compound of Formula I-A, t' = 0 or 1, d = 0 or 1, and Y1 and Y2 = halogen such as chlorine, bromine, or iodine.
In a typical preparation of a compound of Formula VII, a compound of Formula IX is reacted with a compound of Formula X (or a suitable precursor of compound of Formula X) in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the Uke; aromatic solvents such as benzene and toluene; acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2), carbon tetrachloride (CC14) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable catalysts for use in the above process include, but are not limited to, pyridine, thioureas and ureas such as tetra-71-butylurea, phosphoramides such as hexamethylphosphotriamide, substituted amides such as dimethylformamide, quaternary ammonium hahdes such as tetrabutyl or tributylbenzyl ammonium chloride, arylamines such as N,N-dimethylaminopyridine, N,N-dimethylaniline, tertiary phosphines such as trioctyl phosphine, and alkali metal or alkaline earth metal hahdes such as cesium or potassium chloride which are used in conjunction with a sequestering agent such as a crown ether (18-crown- 6). If desired, mixtures of these catalysts may be used, however, the preferred catalyst is pyridine. Compound of Formula IX may in some cases exist in a polymeric form. If so, the monomeric form can be achieved via known procedures, one being through thermal depolymerization. Compound of Formula X when G10 = O and Y1 and Y2 = Cl is phosgene, C(=O)Cl2. However, other forms of phosgene, phosgene equivalents, can be utilized such as trichloromethyl chloroformate (compound of Formula X in which G10 = O, Y1 = Cl, and Y2 = OCCl3) or di(trichloromethyl)carbonate (compound of Formula X in which G10 = O and Y1 and Y2 = OCCI3). The above process may be carried out at temperatures between about - 78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 100 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. The catalyst is normaUy used in lower amounts than that of both compounds of Formula IX and X. The compounds of Formula IX and X are generally commercially avaUable or can be prepared according to known procedures.
The compounds of Formula I-A [compound of Formula I where R1 equals
Figure imgf000059_0001
can be prepared according to Method B as shown in Scheme 6: Method B:
Scheme 6
Figure imgf000059_0002
I-A XI where Zrøm, Z2(X2)q, Z3(X3)d, G10, G11, G20, G21, G30, G31, and R2 are as defined previously for compound of Formula I-A and m = 0 or 1, t = 0 or 1, q = 0 or 1, t' = 0 or 1, d = 0 or 1, and Y2 = halogen such as chlorine, bromine, or iodine.
In a typical preparation, according to Method B, Scheme 6, of a compound of Formula I-A [compound of Formula I where R1 equals
Figure imgf000059_0003
a compound of Formula XI is reacted with a compound of Formula VI in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The • preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula VI. The compounds of Formula VI are generaUy commerciaUy avaUable or can be prepared according to known procedures.
The compounds of Formula XI of Scheme 6 are prepared as shown in Scheme 7: Scheme 7
Figure imgf000060_0001
VII XI where Z^ H, Z3(X3)d, Zrøm, G10, G11, G30, G31, and R2 are as defined previously for compound of Formula I-A and m = 0 or 1, t' = 0 or 1, d = 0 or 1, and Y1 and Y2 = halogen such as chlorine.
In a typical preparation of a compound of Formula XI, a compound of Formula II is reacted with a compound of Formula VII in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula II. The compounds of Formula II are generaUy commercially avaUable or can be prepared according to known procedures. Conversion of Y2 from Cl to Br or Cl to I in compound of Formula XI can be prepared according to literature procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4th ed.; WUey and Sons: New York, 1992; pp 430-431.
The compounds of Formula I-A [compound of Formula I where R1 equals
Figure imgf000061_0001
can be prepared according to Method C as shown in Scheme 8: Method C:
Scheme 8
Figure imgf000062_0001
XI l-A (t = 0) where Y2 = halogen such of as iodine, bromine, or chlorine,
Figure imgf000062_0002
Z3(X3)d, G10, G11, G30, G31, and R2 are as defined previously for compound of Formula I-A and m = 0 or 1, t = 0, q = 0 or 1, t' = 0 or 1, and d = 0 or 1 where Z2(X2)q = NR3R4, NR3R4R5, or {(NR3R4R5)M) and when q = 0, in compound of Formula VI -A, Z2 can be a tertiary amine where in compound of Formula I, Z2 is a quaternary amine salt, and when q = 1, in compound of Formula VI-A, X2Z2 can be a tertiary amine where in compound of Formula I, X2Z2 is a quaternary amine salt.
In a typical preparation of a compound of Formula I-A [compound of Formula I where R1 equals
Figure imgf000062_0003
according to Method C, a compound of Formula XI is reacted with a compound of Formula VI-A in a suitable solvent. Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 200 °C. Preferably, the reaction is carried out between 0 °C and about 100 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.' GeneraUy, one equivalent of compound of Formula XI is used per equivalent of starting material of compound of Formula VI-A. The compounds of Formula VI-A are generally commerciaUy avaUable or can be prepared according to known procedures. The compounds of Formula XI can be prepared by the same process as that of Scheme 7.
The compounds of Formula I-B, I-C, and I-A [compounds of Formula I where R1 equals
Figure imgf000063_0001
respectively] can be prepared according to Method D as shown below in Scheme 9: Method D:
Scheme 9
Figure imgf000063_0002
I-A l-B
(G31)t-H
(G3 )t.(X3)dZ31 (G31)t-H
Y1
Y1 (G31)t.(X3)dZ3
Figure imgf000063_0003
I-C I-A where Zrøm, Z2(X2)q, Z3(X )d) G10, G", G20, G21, G30, G31, and R2 are as defined above for compound of Formula I-A and m = 0 or 1, t = 0 or 1, t' = 0 or 1, q = 0 or 1, d = 0 or 1, and Y1 = halogen such as chlorine.
In a typical preparation of a compound of Formula I-B [compound of Formula I where R1 equals
Figure imgf000063_0004
a compound of Formula I-A [compound of Formula I where R1 equals C(=G30)-(G31)t'(X3)dZ3] is treated with a suitable solvent under suitable reaction conditions which can successfully transform (G31)t'(X3)dZ3 to (G31)t-H via methods known to one skilled in the art. For example, if d = 0, Z3 = benzyl (Bn), t' = 1, and G30 and G31 = oxygen, then typical reaction conditions for the transformation of C(=G30)-G31Z3 (CO2Bn) to C(=G30)-G31H (CO2H) would involve the foUowing: Suitable solvents include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the Uke; esters such as ethyl acetate; acetonitrUe; alcohols such as methanol or ethanol; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is ethyl acetate. Suitable catalysts in the presence of at least one equivalent of hydrogen include, paUadium, platinum, nickel, rhodium, iridium and ruthenium. The catalysts are normaUy adsorbed or admixed on an inert support material which includes carbon, alumina, calcium sulfate, or barium sulfate, however, the preferred catalyst and support is paUadium on carbon. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. One skilled in the art would recognize that a hydrogenation reaction to remove a benzyl group as described above would only be utilized when aU other functional groups present within compound of Formula I-A are deemed compatible with the reaction conditions. See Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 2nd ed.; Wiley and Sons: New York, 1991; pp 227-265 for additional suitable reaction conditions and appropriate C(=G30)-(G31)t'(X3)dZ3 chemical moieties for the transformation of (G31)t'(X3)dZ3 to (G31)t'-H.
In a typical preparation of a compound of Formula I-C [compound of Formula I where R1 equals C(=G30)-Y1], a compound of Formula I-B [compound of Formula I where R1 equals C(=G30)-(G31)t'-H] is treated with a suitable halo-de-hydroxylation reagent in a suitable solvent, where suitable halo-de-hydroxylation reagents include, but are not limited to, thionyl chloride, oxalyl chloride, oxalyl bromide, triphenyl phosphine in carbon tetrachloride, phosphorus trichloride, and phosphorus pentachloride, however, the preferred halo-de-hydroxylation reagent is thionyl chloride. Suitable solvents for use in the above process include, but are not limited to, hexanes, ethers such as tetrahydrofuran, glyme, and the like; chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, and the like, however, the reactions are normally run neat with a catalytic amount of dimethylformamide present. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. Compounds of Formula I-C [compound of Formula I where R1 equals C(=G30)-Y1] can also be synthesized directly from compounds of Formula I-A [compound of Formula I where R1 equals
Figure imgf000065_0001
In a typical preparation of a compound of Formula I-C, a compound of Formula I-A is treated with a suitable solvent in the presence of suitable reaction conditions which can successfuUy transform
Figure imgf000065_0002
via methods known to one skilled in the art. For example, if d = 0, t' = 1, and Z3 = trimethylsilyl and G30 and G31 = oxygen, then typical reaction conditions for the transformation of C(=G30)- G31Z3 (CO2SiMe3) to C(=G30)-Y1 [C(=O)-Cl] would involve treatment of the compound of Formula I-A in which C(=G30)-G31Z3 is CO2SiMe3 with oxalyl chloride in a suitable solvent such as THF at a temperature ranging from -78 °C and about 100 °C. See arock, R. C. Comprehensive Organic Transformations, 2nd ed, New York, 1999; p 1968 as weU as Greene,T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 2nd ed.; WUey and Sons: New York, 1991; pp 261-262 for additional suitable reaction conditions for the transformation of
Figure imgf000065_0003
One skiUed in the art would recognize that a halogenation reaction to convert a silyl ester to an acid chloride as described above would only be utilized when all other functional groups present within compounds of Formula I-A are deemed compatible with the reaction conditions. Compound of Formula I-C in which Y1 is chlorine can be interconverted to other halo derivatives via reaction conditions listed in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; WUey and Sons: New York, 1999; pp 1950-1951. In a typical preparation of a compound of Formula I-A [compound of Formula
I where R1 equals
Figure imgf000065_0004
from a compound of Formula I-C [compound of Formula I where R1 equals C(=G30)-Y1], a compound of Formula I-C is reacted with Z3(X3)d(G31)t'-H in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula I-C. Suitable reaction conditions for the conversion of
Figure imgf000066_0001
can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; WUey and Sons: New York, 1999; pp 1952-1954.
AdditionaUy, a compound of Formula I-A [compound of Formula I where R1 equals
Figure imgf000066_0002
can be prepared via the reaction of a compound of
Formula I-B [compound of Formula I where R1 equals C(=G30)-(G31)t'-H] in a suitable solvent with Z3(X3)d-H and a suitable coupling reagent. Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula I-B. Suitable coupling reagents for use in the above process include, but are not Umited to, Upases, diazo compounds, anhydrides, acid chlorides, carbodiimides, and carboάumidazoles. Suitable reaction conditions for the conversion of
Figure imgf000067_0001
can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; WUey and Sons: New York, 1999; pp 1932-1949. Alternatively, transformation of a compound of Formula I-B [compound of
Formula I where R1 equals C(=G30)-(G31)t'-H] to a compound of Formula I-A [compound of Formula I where R1 equals C(=G30)-(G31)t'(X3)dZ3] can also be accompUshed by reaction of a compound of Formula I-B in a suitable solvent with a suitable base in the presence of a suitable commerciaUy available halide, such as an alkyl halide. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable hahdes include, but are not Umited to, alkyl hahdes such as benzyl chloride, benzyl bromide, methyl iodide, and ethyl iodide. The preferred hahde is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about - 78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula I-B. Suitable reaction conditions for the conversion of
Figure imgf000068_0001
to
Figure imgf000068_0002
can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; WUey and Sons: New York, 1999; pp 1938-1940.
The compounds of Formula I-D of this invention and the intermediates used in the synthesis of the compounds of this invention can be prepared according to the following methods. Method E can be used when preparing compounds of Formula I- D as shown below in Scheme 10:
Method E:
Scheme 10
Figure imgf000068_0003
I-C where ZiQ )m, Z3(X3)d) G10, G11, G2°, G21. G30, G31, and R2 are as defined above for compound of Formula I-A, m = 0 or 1, Y1 = halogen such as chlorine, and q = 0 and Z2 = CR13R14G32, where G32 is an oxygen atom, a sulfur atom or NR3, and R13 and R14 are independently defined as for R2. In a typical preparation of a compound of Formula I-D, a compound of
Formula I-A [compound of Formula I where R1 equals
Figure imgf000069_0001
where the C(=G30)-(G31)t'(X3)dZ3 moiety is reacted intramolecularly with the (X2)qZ2 moiety (where q = 0 and Z2 = CR13R14G32) in a suitable solvent in the presence of a suitable base to afford cychc [-C(=G30)-G32-CR13R14C(=G20)G21C(R2)-]. Suitable solvents include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the Uke; esters such as ethyl acetate; acetonitrUe; alcohols such as methanol or ethanol; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. Generally, one equivalent of base is used per equivalent of starting material of compound of Formula I-A.
A compound of Formula I-D can also be prepared via. the reaction of a compound of Formula I-B [compound of Formula I where R1 equals C(=G30)-(G31)t'-H], where
Figure imgf000069_0002
is reacted intramolecularly with (X2)qZ2, where Z2 = CR13R14G32, in a suitable solvent in the presence of a suitable base along with a suitable coupling reagent. Suitable reaction conditions would involve the foUowing: Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula I-B. Suitable coupling reagents for use in the above process include, but are not limited to, lipases, diazo compounds, anhydrides, acid chlorides, carbodiimides, and carbodiimidazoles. Suitable reaction conditions for the conversion of H-(G31)t'-(G30=)C-C(R )-(G21[G20=]C)t(X2)qZ2, where Z2 = CR13R1 G32, to cychc [-C(=G30)-G32-CR13R14C(=G20)G21C(R2)-] can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999; pp 1932-1949.
In a typical preparation of a compound of Formula I-D, a compound of Formula I-C [compound of Formula I where R1 equals C(=G30)-Y1] where the C(=G30)Y1 moiety is reacted intramolecularly with the (X2)qZ2 moiety (where Z2 = CR13R14G32) in a suitable solvent in the presence of a suitable base. Suitable reaction conditions would involve the foUowing: Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula I-C. Suitable reaction conditions for the conversion of Y1-(G30=)C-C(R2)-
Figure imgf000071_0001
G32CR13R14C(=G20)G21C(R2)-] can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999; pp 1952-1954.
The compounds of Formula I of this invention and the intermediates used in the synthesis of the compounds of this invention can be prepared according to the foUowing methods. Method F can be used when preparing compounds of Formula I- A [compound of Formula I where R1 equals
Figure imgf000071_0002
as shown below in Scheme 11: Method F:
Scheme 11
Figure imgf000072_0001
lll-A l'A where Zrøm-H, Z2(X2)q, Z3(X3)d, Zi(Xi)m, G10, G11, G2°, G21, G30, G31, and R2 are as defined previously for compound of Formula I-A and t = 0 or 1, t' = 0 or 1, q = 0 or 1, d = 0 or 1, and Y3 = an appropriate leaving group taken from the following: substituted phenols such as p-nitrophenol or pentafluorophenol, or N- hydroxysuccinimide .
In a typical preparation, according to Method F, of a compound of Formula I- A [compound of Formula I where R1 equals
Figure imgf000072_0002
a compound of
Formula II is reacted with a compound of Formula III-A in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not hmited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula II. The compounds of Formula II are generaUy commerciaUy avaUable or can be prepared according to known procedures.
The compounds of Formula III -A of Scheme 11 are prepared as shown in Scheme 12:
Scheme 12
Figure imgf000073_0001
Vll-A "I-A where
Figure imgf000073_0002
Z2(X2)q, Z3(X3)d, G10, G11, G2°, G21, G30, G31, and R2 are as defined previously for compound of Formula I-A and t = 0 or 1, t' = 0 or 1, q = 0 or 1, d = 0 or 1, Y2 = halogen such as chlorine, and Y3 = an appropriate leaving group taken from the foUowing: substituted phenols such as p-nitrophenol or pentafluorophenol, or N-hydroxysuccinimide. In a typical preparation of a compound of Formula III-A, a compound of
Formula VII-A is reacted with a compound of Formula VI in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula VI. The compounds of Formula VI are generaUy commerciaUy available or can be prepared according to known procedures.
The compounds of Formula VII-A of Scheme 12 are prepared as shown in Scheme 13:
Scheme 13
Figure imgf000074_0001
VII VII-A where Z3(X3)d, G10, G11, G30, G31, and R2 are as defined previously for compound of Formula I-A and t' = 0 or 1, d = 0 or 1, Y1 and Y2 = halogen such as chlorine, bromine, or iodine, and Y3 = an appropriate leaving group taken from the foUowing: substituted phenols such as p-nitrophenol or pentafluorophenol, or N- hy droxy succinimide . In a typical preparation of a compound of Formula VII-A, a compound of
Formula VII is reacted with a compound of Formula VIII-A in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is diethyl ether. Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is pyridine. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula VIII -A. The compounds of Formula VIII -A are generaUy commerciaUy avaUable or can be prepared according to known procedures. Conversion of Y2 from Cl to Br or Cl to I in compound of Formula V can be prepared according to Htera ure procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4th ed.; Wiley and Sons: New York, 1992; pp 430-431. The compounds of Formula VII can be prepared as shown in Method A, Scheme 5.
AppHcation of Method B (Scheme 7) as described previously for the synthesis of compound of Formula XI to the synthesis of compound of Formula XII is described below in Scheme 14. Compound of Formula XIII (compound of Formula II in which m = 1 and Z1(X1) -H is a suitably substituted pesticidal hydrazine) is reacted with compound of Formula XIV (compound of Formula VII in which G10, G11, and G30 = O and Y1 = Cl) to afford compound of Formula XII (compound of Formula XI in which m = 1, Z1(X1) is a suitably substituted pesticidal hydrazine moiety, and G10, G11, and G30 = O): Method B:
Scheme 14
Figure imgf000076_0001
XIII XII where Z3(X3)d, G31 and R2 are as defined previously for compound of Formula I-A, Ra- Rh are as defined in Table 6 and 7, t' = 0 or 1, d = 0 or 1, and Y2 = halogen such as chlorine, bromine, or iodine.
Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is sodium hydride. The above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 1Q0 °C. Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula XIII. The compounds of Formula XIII can be prepared according to patented methods such as those found in U.S. 5,530,028 and 6,013,836. Conversion of Y2 from Cl to Br or Cl to I in compound of Formula XII can be prepared according to literature procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4th ed.; WUey and Sons: New York, 1992; pp 430-431. Also, see synthesis Example 55 for conversion of Y2 from Cl to I in compound of Formula XII.
Application of Method B (Scheme 6) as described previously for the synthesis of compound of Formula I-A to the synthesis of compound of Formula XV is described below in Scheme 15. Compound of Formula VI (in which t = 1) is reacted with compound of Formula XII (compound of Formula XI in which m = 1,
Figure imgf000077_0001
is a suitably substituted pesticidal hydrazine moiety, and G10, G11, and G30 = O) to afford compound of Formula XV (compound of Formula I-A in which t = 1, m = 1, q = 0 or 1, Z1^1).... is a suitably substituted pesticidal hydrazine moiety, and G10, G11, and G30 = O):
Scheme 15
Figure imgf000078_0001
XII XV (t = 1) where Z2(X2)q, Z3(X3)d, R2, G20, G21, G31 are as defined previously for compound of Formula I-A, Ra-Rh are as defined in Table 6 and 7, t' = 0 or 1, d = 0 or 1, and Y2 = halogen such as iodine, bromine, or chlorine.
Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF. Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is dusopropylethylamine. The above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula VI. The compounds of Formula VI are generaUy commerciaUy avaUable or can be prepared according to known procedures.
Application of Method C (Scheme 8) as described previously for the synthesis of compound of Formula I-A to the synthesis of compound of Formula XV is described below in Scheme 16. Compound of Formula VI-A in which Z2(X2)q = NR3R R5, q = 0 or 1, and t = 0 is reacted with compound of Formula XII (compound of Formula XI where m = 1, Z1^1^ is a suitably substituted pesticidal hydrazine moiety, G10, G11, and G30 = 0) to afford compound of Formula XV [compound of Formula I-A in which m = 1, t = 0, Z1(X1)m is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G", and G30 = O, Z2 = NR3R4 or {(NR3R R5)+M-} when q = 0, and Z2(X2)q = NR3R4 or {(NR3R R5) +M-} when q = 1, where M = Y2]:
Scheme 16
Figure imgf000079_0001
XII XV (t = 0) where Z3(X3)d, G31, and R2 are as defined previously for compound of Formula I-A, Ra- Rh are as defined in Table 6 and 7, t' = 0 or 1, d = 0 or 1, and Y2 = halogen such as iodine, bromine, or chlorine. Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF. The above method may be carried out at temperatures between about -78 °C and about 200 °C. Preferably, the reaction is carried out between 0 °C and about 100 °C. Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. Generally, one equivalent of compound of Formula XII is used per equivalent of starting material of compound of Formula VI-A. The compounds of Formula VI-A are generally commerciaUy avaUable or can be prepared according to known procedures. AppUcation of Method D (Scheme 9) as described previously for the synthesis of compounds of Formula I-B, I-C, and I-A to the synthesis of compounds of Formula XV-A, XV-B, and XV, respectively, is described below in Scheme 17. Compound of Formula XV is reacted under suitable conditions to afford compound of Formula XV- A (compound of Formula I-B in which m = 1, Z1(X1)m is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, Gu, and G30 = O). Compound of Formula XV-A (compound of Formula I-B in which m = 1,
Figure imgf000080_0001
is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G11, and G30 = O) is reacted under suitable conditions to afford compound of Formula XV-B (compound of Formula I-C in which m = 1,
Figure imgf000080_0002
is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G11, and G30 = O). Compound of Formula XV is reacted under suitable conditions to afford compound of Formula XV-B (compound of Formula I-C in which m = 1, Z^X^m is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G11, and G30 = O). Compound of Formula XV-A (compound of Formula I-B in which m = 1, is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G11, and G30 = O) is reacted under suitable conditions to afford compound of Formula XV (compound of Formula I-A in which m = 1, Z1(X1)m is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G11, and G30 = O). Compound of Formula XV-B (compound of Formula I-C in which m = 1, Z^X^m is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G11, and G30 = O) is reacted under suitable conditions to afford compound of Formula XV (compound of Formula I-A in which m = 1, Z1^1).* is a suitably substituted pesticidal hydrazine moiety, q = 0 or 1, G10, G11, and G30 = O):
Scheme 17
Figure imgf000081_0001
XV-B XV where Z2(X2)q, Z3(X3)d, G20, G21, G31, t, f , d, q , and R2 are as defined previously for compound of Formula I-A, Ra-Rh are as defined in Table 6 and 7, and Y1 = halogen such as chlorine, bromine, or fluorine.
In a typical preparation of a compound of Formula XV-A, a compound of Formula XV is treated with a suitable solvent in the presence of suitable reaction conditions which can successfuUy transform
Figure imgf000082_0001
to C(=0)-(G31)t'-H via methods known to one skUled in the art. For example, if d = 0, t' = 1, Z3 = benzyl (Bn), and G31 = O, then typical reaction conditions for the transformation of Cθ2Bn to CO2H would involve the foUowing reaction conditions: Suitable solvents include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the hke; esters such as ethyl acetate; acetonitrUe; alcohols such as methanol or ethanol; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is ethyl acetate. Suitable catalysts in the presence of at least one equivalent of hydrogen include, but are not hmited to, paUadium, platinum, nickel, rhodium, iridium and ruthenium. The catalysts are normaUy adsorbed or admixed on an inert support material which includes carbon, alumina, calcium sulfate, or barium sulfate, however, the preferred catalyst and support is paUadium on carbon. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. One skilled in the art would recognize that a hydrogenation reaction to remove a benzyl group as described above would only be utilized when aU other functional groups present within compound of Formula XV are deemed compatible with the reaction conditions. See Greene, T. W.; Wutz, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; WUey and Sons: New York, 1991; pp 224-276 for suitable reaction conditions and appropriate C(=0)- (G31)t'(X3)dZ3 chemical moieties for the transformation of
Figure imgf000082_0002
to C(=O)- (G31)t-H. In a typical preparation of a compound of Formula XV-B, a compound of
Formula XV-A is treated with a suitable halo-de-hydroxylation reagent in a suitable solvent, where suitable halo-de-hydroxylation reagents include, but are not Umited to, thionyl chloride, oxalyl chloride, oxalyl bromide, triphenyl phosphine in carbon tetrachloride, phosphorus trichloride, and phosphorus pentachloride, however, the preferred halo-de-hydroxylation reagent is thionyl chloride. Suitable solvents for use in the above process include, but are not hmited to, hexanes, ethers such as tetrahydrofuran, glyme, and the Uke; chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, and the like, however, the reactions are normaUy run neat with a catalytic amount of dimethylformamide present. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. Compounds of Formula XV-B can be also be synthesized directly from compounds of Formula XV. In a typical preparation of a compound of Formula XV-B, a compound of Formula XV is treated with a suitable solvent in the presence of suitable reaction conditions which can successfuUy transform C(=0)-(G31)t'(X3)dZ3 to C(=0)-Y1 via methods known to one skiUed in the art. For example, if d = 0, t' = 1, Z3 = trimethylsUyl, Y1 = Cl, and G31 = O, then typical reaction conditions for the transformation of C(=0)-G 1Z3 (C02SiMe3) to C(=G30)-Y! [C(=O)-Cl] would involve treatment of the compound of Formula XV with oxalyl chloride in a suitable solvent such as THF at a temperature ranging from -78 °C and about 100 °C. One skiUed in the art would recognize that a halogenation reaction to convert a sUyl ester to an acid chloride as described above would only be utihzed when aU other functional groups present within compound of Formula XV are deemed compatible with the reaction conditions. See Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; WUey and Sons: New York, 1999; p 1968 for additional suitable reaction conditions for the transformation of C(=0)-( G31)t-(X3)dZ3 to C(=0)-Y1. Compound of Formula XV-B in which Y1 is chlorine can be inter converted to other halo derivatives via reaction conditions Usted in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; WUey and Sons: New York, 1999; pp 1950-1951.
In a typical preparation of a compound of Formula XV from a compound of Formula XV-B, a compound of Formula XV-B is reacted with Z3(X3)d(G31)t-H in a suitable solvent in the presence of a suitable base. Suitable solvents for use in the above process include, but are not Umited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkaU metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. Generally, one equivalent of base is used per equivalent of starting material of compound of Formula XV-B. Suitable reaction conditions and appropriate C(=0)Yx chemical moieties for the transformation of C(=0)-Y1 to C(=0)- (G31)t'(X3)dZ3 can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999; pp 1952-1954.
A compound of Formula XV can also be prepared via the reaction of a compound of Formula XV-A in a suitable solvent with Z3(X3)d(G31)t'-H and a suitable coupling reagent. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. Suitable bases for use in the above process include, but are not Umited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. lf desired, mixtures of these bases may be used. The preferred base is dependent upon the substrates employed and is selected according to the properties of the substrates. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula XV-A. Suitable coupUng reagents for use in the above process include but are not hmited to, hpases, diazo compounds, anhydrides, acid chlorides, carbodumides, alkyl hahdes, and carbodiimidazoles. Suitable reaction conditions and appropriate C(=0)-(G31)t'-H chemical moieties for the transformation of C(=0)-(G31)t'-H to
Figure imgf000085_0001
can be found in Larock, R. C. Comprehensive Organic Transformations, 2nd ed.; Wiley and Sons: New York, 1999; pp 1932-1949 as weU as in Greene, T. W.; Wutz, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley and Sons: New York, 1991; pp 224-276.
AppUcation of Method A (Scheme 5) as described previously for the synthesis of compound of Formula VII to the synthesis of compound of Formula XVIII is described below in Scheme 18. Compound of Formula XVI (compound of Formula IX where G11 and G30 = O) is reacted with compound of Formula XVII (compound of Formula X where G10 = O) to afford compound of Formula XVIII (compound of Formula VII where G10, G11, and G30 = O): Scheme 18
Figure imgf000086_0001
XVI XVII XVIII where Z3(X3)d, d, t', G31, and R2 are as defined previously for compound of Formula I- A, Y1 and Y2 = halogen such as chlorine, bromine, or iodine. Suitable solvents for use in the above process include, but are not hmited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether, dioxane and the like; acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2), carbon tetrachloride (CC1 ) or chloroform (CHCI3). If desired, mixtures of these solvents may be used. The preferred solvent is dependent upon the substrates employed and is selected according to the properties of the substrates. For example, in the reaction of compound of Formula XVI, where t' = 1, G31 = O, d = 0, R2 = H, and Z3 = benzyl (Bn), with compound of Formula XVII, where Y1 and Y2 = Cl, to afford compound of Formula XVIII where f = 1, G31 = 0, d = 0, R2 = H, Z3 = benzyl (Bn), and Y1 and Y2 = Cl, then the preferred solvent is carbon tetrachloride. However, in the reaction of compound of Formula XVI, where t' = 1, G31 = O, d = 0, R2 = H, and Z3 = ethyl (Et), with compound of Formula XVII, where Y1 and Y2 = Cl, to afford compound of Formula XVIII, where f = 1, G31 = O, d = 0, R2 = H, Z3 = ethyl (Et), and Y1 and Y2 = Cl, then the preferred solvent is tetrahydrofuran. Suitable catalysts for use in the above process include, but are not limited to, pyridine, thioureas and ureas such as tetra-/ι-butylurea, phosphoramides such as hexamethylphosphotriamide, substituted amides such as dimethylformamide, quaternary ammonium hahdes such as tetrabutyl or tributylbenzyl ammonium chloride, arylamines such as N, N,- dimethylaminopyridine, N, N -dimethylanUine, tertiary phosphines such as trioctyl phosphine, and alkah metal or alkahne earth metal hahdes such as cesium or potassium chloride which are used in conjunction with a sequestering agent such as a crown ether (18-crown-6). If desired, mixtures of these catalysts may be used, however, the preferred catalyst is pyridine. Compound of Formula XVI may in some cases exist in a polymeric form. If so, the monomeric form can be achieved via known procedures, one being through thermal depolymerization. Compound of Formula XVTI in which Y1 and Y2 = Cl is phosgene, C(=O)Cl2. However, other forms of phosgene, phosgene equivalents, can be utilized such as trichloromethyl chloroformate (compound of Formula XVII in which Y1 = Cl, and Y2 = OCCI3) or di(trichloromethyl)carbonate (compound of Formula XVII in which Y1 and Y2 = OCCI3). The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 100 °C. The above process to produce compounds of the present invention is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. The catalyst is normaUy used in lower amounts than that of both compounds of Formula XVI and XVII. The compounds of Formula XVI and XVII are generaUy commerciaUy avaUable or can be prepared according to known procedures.
AppUcation of Method A (Scheme 4) as described previously for the synthesis of compound of Formula V to the synthesis of compound of Formula XX is described below in Scheme 19. Compound of Formula XIX (compound of Formula VIII where R12 = Et and R12S-H is taken together to equal Et-S-L) is reacted with compound of Formula XVIII (compound of Formula VII where G10, G11, and G30 = O) to afford compound of Formula XX (compound of Formula V where G10, G11, and G30 = O, and R12 = Et):
Scheme 19
Figure imgf000087_0001
XVIII XX where Z3(X3)d, d, t', G31 and R2 are as defined previously for compound of Formula I- A, L = metal cation such as Na or K, and Y1 and Y2 = halogen such as chlorine, bromine, or iodine. Suitable solvents for use in the above process include, but are not hmited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is diethyl ether. Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkah metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is sodium hydride. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. Preparation of the compounds of the present invention by the above process is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula XIX except when L = Na or K, then no base is required. The compounds of Formula XIX are generaUy commerciaUy avaUable or can be prepared according to known procedures. For example, R12S-L = EtS-Na, is commercially available. Conversion of Y2 from Cl to Br or Cl to I in compound of Formula XX can be prepared according to literature procedures. A general description of the synthesis of halogen exchange (Finkelstein reaction) is described in March, J. Advanced Organic Chemistry, 4th ed.; WUey and Sons: New York, 1992; pp 430-431. Also, see synthesis Example 8 for conversion of Y2 from Cl to I in compound of Formula XX.
Application of Method A (Scheme 3) as described previously for the synthesis of compound of Formula IV to the synthesis of compound of Formula XXII is described below in Scheme 20. Compound of Formula XX (compound of Formula V where R12 = Et and G10, G11, and G30 = O) is reacted with compound of Formula VI (where t = 1 and q = 0 or 1) to afford compound of Formula XXII (compound of Formula IV in which t = 1, G10, G11, and G30 = O, R12 = Et, and q = 0 or 1): Scheme 20
Figure imgf000089_0001
xx xπ where Z2(X2)q, Z3(X3)d, d, f , G20, G21, G31, and R2 are as defined previously for compound of Formula I-A, and Y2 = halogen such as chlorine, bromine, or iodine. Suitable solvents for use in the above process include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, diethyl ether and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or dusopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is dusopropylethylamine. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. Preparation of the compounds of the present invention by the above process is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula VI. The compounds of Formula VI are generaUy commerciaUy avaUable or can be prepared according to known procedures.
Application of Method A (Scheme 2) as described previously for the synthesis of compound of Formula III to the synthesis of compound of Formula XXIII is described below in Scheme 21. Compound of Formula XXII (compound of Formula IV where R12 = Et, G10, G11, and G30 = O, and q = 0 or 1) is reacted with a suitable halogenating agent to afford compound of Formula XXIII (compound of Formula III where G10, G11, and G30 = O, Y1 = Cl, and q = 0 or 1):
Scheme 21
Figure imgf000090_0001
XXII XXIII where Z2(X2)q, Z3(X3)d, d, f , G20, G21, G31, and R2 are as defined previously for compound of Formula I-A and t = 1.
Suitable halogenating agents include chlorine gas, thionyl chloride, and sulfuryl chloride, however, the preferred halogenating agent is sulfuryl chloride. Suitable solvents for use in the above process include, but are not hmited to, hexanes, chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like, however, the reactions are normaUy run neat. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. Preparation of the compounds of the present invention by the above process is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
Application of Method A (Scheme 1) as described previously for the synthesis of compound of Formula I-A to the synthesis of compound of Formula XXIV is described below in Scheme 22. Compound of Formula XXV in which R6 = H, and R7 and R8 = OH (compound of Formula II where m = 1 and Z1(X1)m-H is a suitably substituted phosphonomethylglycine) is reacted with hexamethyldisilazane (HMDS) to afford compound of Formula XXVI where R6 = SiMeβ, and R7 and R8 = OSiMeβ. Compound of Formula XXVI (where R6 = SiMe3, and R7 and R8 = OSiMes) is then reacted with compound of Formula XXIII (compound of Formula III where Y1 = Cl, G10, G11, and G30 = O, t = 1, and q = 0 or 1) to afford compound of Formula XXIV in which R6 = H, and R7 and R8 = OH (compound of Formula I-A where m = 1, t = 1, q ; 0 or 1, Z^X1)..! = phosphonomethylglycine moiety, and G10, G11, and G30 = 0):
Scheme 22
Figure imgf000091_0001
XXIV XXV XXVI where Z2(X2)q, Z3(X3)d, d, f , G20, G21, G3*, and R2 are as defined previously for compound of Formula I-A.
In the reaction of a compound of Formula XXV with HMDS to afford a compound of Formula XXVI, the foUowing conditions can be used: Suitable solvents include chlorinated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the Uke; hexanes; tetrahydrofuran, diethyl ether, and the like. However, the reactions are normally run neat. The reaction can be carried out at temperatures between about -78 °C and about 200 °C. Preferably, the reaction is carried out between 0 °C and about 150 °C. Preparation of compound of Formula XXVI of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired.
Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. The preferred amount is a slight excess of HMDS. Compounds of the Formula XXV are generally commerciaUy avaUable or can be prepared according to known procedures. Compounds of Formula XXV and XXVI can be found in the foUowing reference: Franz, J. E.; Mao, M. K.; Sikorski, J. A.
Glyphosate A Unique Global Herbicide , ACS Monograph 189: Washington DC, 1997. In the reaction of a compound of Formula XXVI with a compound of Formula XXIII to afford a compound of Formula XXIV, the foUowing conditions can be used: Suitable solvents for use in the above method include ethers such as tetrahydrofuran (THF), glyme, and the Uke; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) and chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is methylene chloride. The above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out between 0 °C and about 50 °C. Preparation of the compound of Formula XXIV of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired.
Application of Method A (Scheme 1) as described previously for the synthesis of compound of Formula I-A to the synthesis of compound of Formula XXVII is described below in Scheme 23. Compound of Formula XXVIII (compound of Formula II where m = 1 and
Figure imgf000092_0001
equals fluoxetine hydrochloride) is reacted with compound of Formula XXIII (compound of Formula III where Y1 = Cl, G10, Gu, and G30 = O, t = 1, and q = 0 or 1) to afford compound of Formula XXVII (compound of Formula I-A where m = 1, t = 1, q = 0 or 1, Z^1)* = fluoxetine, and G10, G11, and G30 = 0):
Scheme 23
Figure imgf000092_0002
XXVIII xxvii where Z2(X2)q, Z3(X3)d, d, f , G20, G21, G31, and R2 are as defined previously for compound of Formula I-A.
In the reaction of a compound of Formula XXVIII with a compound of Formula XXIII to afford a compound of Formula XXVII, the foUowing conditions can be used: Suitable solvents for use in the above method include ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) and chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF. Suitable bases for use in the above process include, but are not hmited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkali metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkaU metal carbonate such as sodium or potassium carbonate; 4-dimethylaminopyridine (DMAP) or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is DMAP. The above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out at 22 °C. Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. SubstantiaUy equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula XXVIII.
Application of Method A (Scheme 1) as described previously for the synthesis of compound of Formula I-A to the synthesis of compound of Formula XXIX is described below in Scheme 24. Compound of Formula XXX (compound of Formula II where m = 1 and Z^X^m-H equals fluconazole) is reacted with compound of Formula XXIII (compound of Formula III where Y1 = Cl, G10, G11, and G30 = O, t = 1, and q = 0 or 1) to afford compound of Formula XXIX (compound of Formula I-A where m = 1, t = 1, q = 0 or 1, Z!(X = fluconazole, and G10, G11, and G30 = O):
Scheme 24
Figure imgf000093_0001
where Z2(X )q, Z3(X3)d, d, t', G20, G21, G31, and R2 are as defined previously for compound of Formula I-A. In the reaction of a compound of Formula XXX with a compound of Formula XXIII to afford a compound of Formula XXIX, the foUowing conditions can be used: Suitable solvents for use in the above method include ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethylsulfoxide (DMSO); acetonitrUe; chlorinated solvents such as methylene chloride (CH2CI2) and chloroform (CHCI3). If desired, mixtures of these solvents may be used, however, the preferred solvent is THF. Suitable bases for use in the above process include, but are not limited to, metal hydrides such as sodium or potassium hydride; metal alkoxides such as sodium or potassium alkoxides; alkah metal hydroxides such as sodium or potassium hydroxide; tertiary amines such as triethylamine or diisopropylethylamine; an alkali metal carbonate such as sodium or potassium carbonate; 4-dimethylaminopyridine (DMAP), potassium fois(trimethylsUyl)amide (KHMDS) or pyridine. If desired, mixtures of these bases may be used, however, the preferred base is KHMDS. The above method may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction is carried out at -78 °C to 0 °C. Preparation of the compounds of the present invention by the above method is preferably carried out at about atmospheric pressure although higher or lower pressures can be used if desired. Substantially equimolar amounts of reactants are preferably used although higher or lower amounts can be used if desired. GeneraUy, one equivalent of base is used per equivalent of starting material of compound of Formula XXX.
FoUowing the general methods described hereinbefore, the foUowing compounds of Formula VII (where R2 = H) as listed in Table 1 were prepared.
Figure imgf000094_0001
VII Table 1: Listing of Compounds of Formula VII
Cmpd # Y1 Q10 G11 G30 Y2 Q31 t' d (X3)dZ3
1-1 Cl 0 0 0 Cl 0 1 0 benzyl
1-2 Cl 0 0 0 Cl 0 1 0 ethyl
1-3 Cl 0 0 0 Cl 0 1 0 methyl
1-4 Cl 0 0 0 Cl 0 1 0 isopropyl
1-5 Cl 0 0 0 Cl 0 1 0 tert-butyl
1-6 Cl 0 0 0 Cl 0 1 0 ?ι-butyl
The foUowing Examples are provided for guidance to the practitioner in order to practice the invention.
Example 1:
Benzyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate (Compound 1-1 of Table 1)
To a 3-neck round-bottom flask, equipped with nitrogen inlet, a thermometer and a sohd addition funnel, was added benzyl glyoxylate (50.9 g, 300 mmol), pyridine (2.5 mL, 31.0 mmol) and 1500 mL of carbon tetrachloride. The solution was cooled with dry ice/acetone to -20 °C and triphosgene (230 g, 770 mmol) was added over 5 minutes, maintaining the temperature between -10 °C and -20 °C. The reaction was graduaUy warmed to room temperature over 2 h, then warmed to 50 °C and was stirred at that temperature for 1 h. The reaction was then cooled and placed in the freezer overnight. The precipitates were filtered by gravity, washing with carbon tetrachloride. The solvent was removed in vacuo, with low heat, to yield 58 g of the desired benzyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate as a clear colorless oU. Η- NMR (300 MHz, CDCls) δ (ppm): 5.24 (s, 2H), 6.45 (s, 1H), 7.32 (s, 5H).
Example 2:
Ethyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate (Compound 1-2 of Table 1)
Pyridine (0.145 mL, 1.79 mmol) was added to a solution of polymeric ethyl glyoxylate (18.51 g, 181 mmol) and triphosgene (48.5 g, 163 mmol) in dry THF at room temperature in a flask fitted with a reflux condenser and connected to a N2 bubbler. After 10 min the flask was placed in a pre-heated 65 °C oil bath. After 21 h, the reaction was aUowed to cool to room temperature, and then the mixture was concentrated under vacuum. Ether was added to the residue, the mixture was filtered through Cehte, and the filtrate was concentrated, affording 34.6 g (87% yield) of a yeUow oil. Η-NMR (300 MHz, CDCls) δ (ppm): 1.36 (t, 3H) 4.36 (q, 2H), 6.48 (s, 1H).
Example 3: Methyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate (Compound 1-3 of Table 1)
The title compound was prepared according to the procedure described in Example 2 above, except methyl glyoxylate was substituted for ethyl glyoxylate. Η- NMR (300 MHz, CDCls) δ (ppm): 3.92 (s, 3H), 6.52 (s, 1H).
Example 4:
Isopropyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate (Compound 1-4 of Table 1)
The title compound was prepared according to the procedure described in
Example 2 above, except isopropyl glyoxylate was substituted for ethyl glyoxylate.
Η-NMR (300 MHz, CDCI3) δ (ppm): 1.33 (s, 3H), 1.35 (s, 3H), 5.2 (q, 1H), 6.44 (s, 1H).
Example 5: tert-Butyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate (Compound 1-5 of Table 1)
The title compound was prepared according to the procedure described in Example 2 above, except tert-butyl glyoxylate was substituted for ethyl glyoxylate. Η-NMR (300 MHz, CDCls) δ (ppm): 1.53 (s, 9H), 6.35 (s, 1H).
Example 6:
/ι-Butyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate (Compound 1-6 of Table 1) The title compound was prepared according to the procedure described in
Example 2 above, except 71-butyl glyoxylate was substituted for ethyl glyoxylate. Η- NMR (300 MHz, CDCls) δ (ppm): 0.94 (t, 3H), 1.40 (q, 2H), 1.68 (m, 2H), 4.28 (m, 2H), 6.49 (s, 1H).
FoUowing the general methods described hereinbefore, the foUowing compounds of Formula VII (where R2 = H) as hsted in Table Al can be prepared.
Figure imgf000097_0001
VII
Table Al: Listing of Compounds of Formula VII
Cmpd # Y1 Gιo G11 G30 Y2 G3i t' d (X3)dZ3
AM Cl 0 0 0 Cl 0 1 0 cyclopropyl
Al-2 Cl 0 0 0 Cl 0 1 0 cyclopentyl
Al-3 Cl 0 0 0 Cl 0 1 0 cyclohexyl
Al-4 Cl 0 0 0 Cl 0 1 0 n.-propyl
Al-5 Cl 0 0 0 Cl 0 1 0 7i-pentyl
Al-6 Cl 0 0 0 Cl 0 1 0 ?ι-hexyl
Al-7 Cl 0 0 0 Cl 0 1 0 7i-octyl
Al-8 Cl 0 0 0 Cl 0 1 0 4-methoxybenzyl
Al-9 Cl 0 0 0 Cl 0 1 0 2,2,2-trifluoroethyl
Al-10 Cl 0 0 0 Cl 0 1 0 allyl
AMI Cl 0 0 0 Cl 0 1 0 phenyl
Al-12 Cl 0 0 0 Cl 0 1 0 4-chlorop henyl
Al-13 Cl 0 0 0 Cl 0 1 0 4-nitrophenyl
Al-14 Cl 0 0 0 Cl 0 1 0 4-fluorophenyl
Al-15 Cl 0 0 0 Cl 0 1 0 4-methoxyp henyl
Al-16 Cl 0 0 0 Cl 0 1 0 2-methoxyphenyl
Al-17 Cl 0 0 0 Cl 0 1 0 2-fluorophenyl
Al-18 Cl 0 0 0 Cl 0 1 0 2-chlorophenyl
Al-19 Cl 0 0 0 Cl 0 1 0 2,3,4,5,6- pentafluorop henyl
Al-20 Cl 0 0 0 Cl S 1 0 ethyl
Al-21 Cl 0 0 0 Cl S 1 0 phenyl
Al-22 Cl 0 0 0 Cl 0 1 0 methoxyethyl
Al-23 Cl 0 0 0 Cl 0 1 0 ethoxymethyl
Al-24 Cl 0 0 0 Cl 0 1 0 2-phenylethyl
Al-25 Cl 0 0 0 Cl 0 1 0 3-phenylpropyl
Al-26 Cl 0 0 0 Cl N(Me) 1 0 phenyl
Al-27 Cl 0 0 0 Cl N(Et) 1 0 phenyl
Al-28 Cl 0 0 0 Cl N(Me) 1 0 benzyl
Following the general methods described hereinbefore, the foUowing compounds of Formula V (where R2 = H) as hsted in Table 2 were prepared.
Figure imgf000098_0001
Table 2: Listing of Compounds of Formula V
Cmpd # R12 G10 G11 G30 Y2 G31 t' d (X3)dZ3
2-1 Et 0 0 0 Cl 0 1 0 ethyl
2-2 Et 0 0 0 I 0 1 0 ethyl
2-3 Et 0 0 0 Cl 0 1 0 ?ι-butyl
2-4 Et 0 0 0 I 0 1 0 7i-butyl
2-5 Et 0 0 0 Cl 0 1 0 isopropyl
2-6 Et 0 0 0 I 0 1 0 isopropyl
The following Examples are provided for guidance to the practitioner in order to practice the invention.
Example 7:
Chloro-ethylsulfanylcarbonyloxy-acetic acid ethyl ester (Compound 2-1 of Table 2)
A 1000 mL round bottom flask was charged with sodium ethylthiolate (13.3 g, 158 mmol) and 500 mL of dry diethyl ether. The mixture was cooled to -70 °C in an acetone dry ice bath. Ethyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate(32.8 g, 155 mmol) was added as a solution in 20 mL of diethyl ether over 1.5 h at such a rate that the reaction temperature did not exceed -65 °C. The reaction was aUowed to warm to room temperature and stir for 16 h. The reaction was vacuum filtered, the filtrate dried (MgS0 ), gravity filtered, and concentrated under reduced pressure to yield 33.5 g of a clear liquid. Η-NMR (300 MHz, CDCls) δ (ppm): 1.33 (m, 6H), 2.94 (q, 2H), 4.31 (q, 2H), 6.65 (s, 1H).
Example 8: Iodo-ethylsulfanylcarbonyloxy-acetic acid ethyl ester (Compound 2-2 of Table 2) To a stirred solution of chloro-ethylsulfanylcarbonyloxy-acetic acid ethyl ester (33.5 g, 148 mmol) in 160 mL of dry acetone was added Nal (28.8. g, 192 mmol). The mixture was stirred at room temperature for 4h. The acetone was removed and the remaining slurry was diluted with 100 mL of diethyl ether. The mixture was filtered through Cehte and concentrated under reduced pressure to yield a brown hquid. The hquid was redissolved in 50 mL of diethyl ether and gravity filtered to afford 37.1 g of a brown hquid. Η-NMR (300 MHz, CDCls) δ (ppm): 1.33 (m, 6H), 2.95 (q, 2H), 4.30 (q, 2H), 7.21 (s, 1H).
Example 9:
Chloro-ethylsulfanylcarbonyloxy-acetic acid butyl ester (Compound 2-3 of Table 2) The title compound was prepared according to the procedure described in
Example 7 above except for the substitution of rc-butyl 2-chloro-2-
[(chlorocarbonyl)oxy] acetate for ethyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate. 1H- NMR (300 MHz, CDCls) δ (ppm): 0.95 (t, 3H), 1.33-1.43 (m, 5H), 1.67-1.72 (m, 2H),
2.93 (q, 2H), 4.25-4.30 (m, 2H), 6.65 (s, 1H).
Example 10:
Iodo-ethylsulfanylcarbonyloxy-acetic acid butyl ester (Compound 2-4 of Table 2) The title compound was prepared according to the procedure described in
Example 8 above except for the substitution of chloro-ethylsulfanylcarbonyloxy-acetic acid butyl ester for chloro-ethylsulfanylcarbonyloxy-acetic acid ethyl ester. Η-NMR
(300 MHz, CDC13) δ (ppm): 0.95 (t, 3H), 1.32-1.43 (m, 5H), 1.65-1.70 (m, 2H), 2.92-
2.95 (m, 2H), 4.22-4.26 (m, 2H), 7.21 (s, 1H).
Example 11:
Chloro-ethylsulfanylcarbonyloxy-acetic acid isopropyl ester (Compound 2-5 of Table
2)
The title compound was prepared according to the procedure described in Example 7 above except for the substitution of isopropyl 2-chloro-2-
[(chlorocarbonyl)oxy] acetate for ethyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate. XH-
NMR (300 MHz, CDCls) δ (ppm): 1.30 (t, 9H), 2.90 (q, 2H), 5.10 (s, 1H), 6.60 (s, 1H). Example 12:
Iodo-ethylsulfanylcarbonyloxy-acetic acid isopropyl ester (Compound 2-6 of Table 2)
The title compound was prepared according to the procedure described in Example 8 above except for the substitution of chloro-ethylsulfanylcarbonyloxy-acetic acid isopropyl ester for chloro-ethylsulfanylcarbonyloxy-acetic acid ethyl ester. Η- NMR (300 MHz, CDCls) δ (ppm): 1.30 (t, 9H), 2.90 (q, 2H), 5.10 (s, 1H), 7.15 (s, 1H).
FoUowing the general methods described hereinbefore, the foUowing compounds of Formula V (where R2 = H) as hsted in Tables B1-B42 can be prepared.
Figure imgf000100_0001
rable Bl: Li isting of Compou nds of Formula V
Cmpd # R12 Gιo Qii G30 Y2 G31 t' d (X3)dZ3
Bl-1 propyl O 0 0 Cl O 1 0 ethyl
Bl-2 propyl O 0 0 Br 0 1 0 ethyl
Bl-3 propyl 0 0 0 I 0 1 0 ethyl
Bl-4 2-propyl 0 0 0 Cl 0 1 0 ethyl
Bl-5 2-propyl 0 0 0 Br 0 1 0 ethyl
Bl-6 2-propyl 0 0 0 I 0 1 0 ethyl
Bl-7 t-butyl 0 0 0 Cl 0 1 0 ethyl
Bl-8 t-butyl 0 0 0 Br 0 1 0 ethyl
Bl-9 t-butyl 0 0 0 I 0 1 0 ethyl
Bl-10 phenyl 0 0 0 Cl 0 1 0 ethyl
Bl-11 phenyl 0 0 0 Br 0 1 0 ethyl
Bl-12 phenyl 0 0 0 I 0 1 0 ethyl
Bl-13 2-pyridyl 0 0 0 Cl 0 1 0 ethyl
Bl-14 2-pyridyl 0 0 0 Br 0 1 0 ethyl
Bl-15 2-pyridyl 0 0 0 I 0 1 0 ethyl
Bl-16 benzyl 0 0 0 Cl 0 1 0 ethyl
Bl-17 benzyl 0 0 0 Br 0 1 0 ethyl
Bl-18 benzyl 0 0 0 I 0 1 0 ethyl
Bl-19 phenylethyl 0 0 0 Cl 0 1 0 ethyl
Bl-20 phenylethyl 0 0 0 Br 0 1 0 ethyl
Bl-21 phenylethyl 0 0 0 I 0 1 0 ethyl Bl-22 phenylpropyl 0 0 0 Cl 0 1 0 ethyl
Bl-23 phenylpropyl 0 0 0 I 0 1 0 ethyl
Bl-24 2-(phenyl)ethenyl 0 0 0 Cl 0 1 0 ethyl
Bl-25 2-(phenyl)ethenyl 0 0 0 I 0 1 0 ethyl
Table B2: Compounds (B2-l)-(B2-25) are compounds of Formula V where R12, G10, Gn, G30, Y2, G31, R2, t\ and d are identical to those in Table Bl except for (X3)dZ3 which equals methyl.
Table B3: Compounds (B3-l)-(B3-25) are compounds of Formula V where Ri2, G10, Gn, G30, Y2, G3 , R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals propyl.
Table B4: Compounds (B4-l)-(B4-25) are compounds of Formula V where R12, G10, Gn, G3o; γ2> G3i; R2> t', and d are identical to those in Table Bl except for (X3)dZ3 which equals isopropyl.
Table B5: Compounds (B5-l)-(B5-25) are compounds of Formula V where Ri2, G10, Gn, G3o; γ2; G3i; R2, t'; and are identical to those in Table Bl except for (X3)dZ3 which equals 7i-butyl.
Table B6: Compounds (B6-l)-(B6-25) are compounds of Formula V where R12, Gi°, QU G30j γ2; Gsi; R2; t > ; and are identical to those in Table Bl except for (X3)dZ3 which equals tert-butyl.
Table B7: Compounds (B7-l)-(B7-25) are compounds of Formula V where Ri2, Gi°, G11, G30, Y2, G81, R2, t\ and d are identical to those in Table Bl except for (X3)dZ3 which equals hexyl.
Table B8: Compounds (B8-l)-(B8-25) are compounds of Formula V where R12, G10, G11, G30, Y2, G3i, R2, f, and d are identical to those in Table Bl except for (X3)dZ3 which equals octyl. Table B9: Compounds (B9-l)-(B9-25) are compounds of Formula V where Ri2, G10, G", G30, Y2, G31, R2, f , and d are identical to those in Table Bl except for (X3)dZ3 which equals pentyl.
Table BIO: Compounds (B 10- 1)-(B 10-25) are compounds of Formula V where 2, Gi°, Gn, G30; γ2j G3i 5 R2; t'; and d are identical to those in Table Bl except for (X3)dZ3 which equals cyclohexyl.
Table Bll: Compounds (Bll-l)-(B 11-25) are compounds of Formula V where R22, G10, Gn, G30, Y2, G81, R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals cyclopentyl.
Table B12: Compounds (B 12- 1)-(B 12-25) are compounds of Formula V where Ri2, G10, Gn, 30) γ 5 G3i} R2; t', and d are identical to those in Table Bl except for (X3)dZ3 which equals cyclopropyl.
Table B13: Compounds (B13-l)-(Bl3-25) are compounds of Formula V where R 2, G °, Gn, G30) γ2; G3i; R2; t'; and d are identical to those in Table Bl except for (X3)dZ3 which equals benzyl.
Table B14: Compounds (B14-1)-(B 14-25) are compounds of Formula V where Ri2, G10, Gn, G3o; γ2; G3i, R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals phenyl.
Table B15: Compounds (B15-l)-(Bl5-25) are compounds of Formula V where i2,
G10, Gn, G30j γ2> QS^ R2j t'; and d are identical to those in Table Bl except for (X3)dZ3 which equals 4-methoxyphenyl.
Table B16: Compounds (B16-l)-(Bl6-25) are compounds of Formula V where R12, G °, G11, G30, Y2, G31, R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals 2,3,4,5, 6-pentafluorophenyl. Table B17: Compounds (B17-l)-(Bl7-25) are compounds of Formula V where Ri2, G10, Gn, G30, Y2, G3i, R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals aUyl.
Table B18: Compounds (B18-l)-(B18-25) are compounds of Formula V where R12, G10, Gn, G30, Y2, G3i, R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals methoxyethyl.
Table B19: Compounds (B 19- 1)-(B 19-25) are compounds of Formula V where R12, Gi°, Gn, G30, Y2, G3\ R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals ethoxymethyl.
Table B20: Compounds (B20-l)-(B20-25) are compounds of Formula V where R12, G10, Gn, G30, Y2, G81, R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals 2-(phenyl)ethyl.
Table B21: Compounds (B21-l)-(B21-25) are compounds of Formula V where Ri2, Gi°, Gn, G30, Y2, G81, R2, t', and d are identical to those in Table Bl except for (X3)dZ3 which equals 3-(phenyl)propyl.
Tables B22-B42: Compounds [(B22-l)-(B22-25)] - [(B42-l)-(B42-25)] are compounds of Formula V where Ri2, Gi°, G11, G30, Y2, R2, t', (X3)dZ3, and d are identical to those in Tables B1-B21 except for G31 which equals S.
Following the general methods described hereinbefore, the following compounds of Formula IV (where G10, G11, G20, G2 , G30, and G3 = O, and R2 = H) as hsted in Table 3 were prepared.
Figure imgf000103_0001
IV Table 3: Listing of Compounds of Formula IV
Cmpd # R 2 t' d (X3)dZ3 t q (X )qZ2
3-1 Et 1 0 ethyl 1 0 2-propyl
3-2 Et 1 0 ethyl 1 0 t-butyl
3-3 Et 1 0 ethyl 1 0 ethyl
3-4 Et 1 0 ethyl 1 0 2-ethoxyphenyl
3-5 Et 1 0 ethyl 1 0 phenyl
3-6 Et 1 0 ethyl 1 1 2 , -dichlorop henoxy methyl
3-7 Et 1 0 ethyl 1 1 3-(2,4-dichlorophenoxy)propyl
3-8 Et 1 0 ethyl 1 1 l-(2,4-dichlorophenoxy)ethyl
3-9 Et 1 0 • ethyl 1 1 2,5-dichloro-6-methoxyphenyl
3-10 Et 1 0 ethyl 1 0 2,4,6 -trimethylp henyl
3-11 Et 1 0 2-propyl 1 0 phenyl
3-12 Et 1 0 2-propyl 1 0 t-butyl
3-13 Et 1 0 2-propyl 1 0 1-methyl- 1-cyclopropyl
3-14 Et 1 0 2-propyl 1 0 2-propyl
3-15 Et 1 0 2-propyl 1 0 ethyl
3-16 Et 1 0 2-propyl 1 0 N-acetyl-N- methyl- aminomethyl
3-17 Et 1 0 7i-butyl 1 0 (diethoxyphosphoryl)methyl
3-18 Et 1 0 /i-butyl 1 0 t-butyl
3-19 Et 1 0 2-propyl 1 1 3,7-dichloro-8-quinoline
The foUowing Examples are provided for guidance to the practitioner in order to practice the invention.
Example 13:
2-Methylpropanoic acid ethoxycarbonyl-ethylsulfanylcarbonylbxy-methyl ester
(Compound 3-1 of Table 3)
To a stirred ice cold solution of iodo-ethylsulfanylcarbonyloxy-acetic acid ethyl ester (5.4 g, 17.0 mmol) in 20 mL of dry THF was added 2-methylpropanoic acid (1.94 g, 22.1 mmol) foUowed by dusopropylethylamine (DIEA) (2.85 g, 22.1 mmol). The reaction was allowed to stir at room temperature for 16 h. The reaction was diluted with 100 L of diethyl ether, gravity filtered, and concentrated under reduced pressure. The liquid was suction filtered through a pad of flash grade silica gel and eluted with 20% methylene chloride/hexanes. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.24 (m, 6H), 1.33 (m, 6H), 2.66 (m, 1H), 2.90 (q, 2H), 4.28 (q, 2H), 5.92 (s, 1H).
Example 14:
Pivalic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-2 of
Table 3) The title compound was prepared according to the procedure described in Example 13 above except for the substitution of pivalic acid for 2-methylpropanoic acid. Ή-NMR (300 MHz, CDCls) δ (ppm): 1.25 (s, 9H), 1.33 (m, 6H), 2.88 (q, 2H), 4.28 (q, 2H), 6.82 (s, IH).
Example 15:
Propionic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-3 of Table 3)
The title compound was prepared according to the procedure described in Example 13 above except for the substitution of propionic acid for 2-methylpropanoic acid. Ή-NMR (300 MHz, CDCls) δ (ppm): 1.16 (t, 3H), 1.30 (m, 6H), 2.47 (q, 2H), 2.93 (q, 2H), 4.29 (q, 2H), 6.94 (s, IH).
Example 16: 2-Ethoxybenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester
(Compound 3-4 of Table 3)
The title compound was prepared according to the procedure described in
Example 13 above except for the substitution of 2-ethoxybenzoic acid for 2- methylpropanoic acid. Η-NMR (300 MHz, CDCls) δ (ppm): 1.23 (m, 6H), 1.44 (t, 3H), 2.92 (q, 2H), 4.12 (q, 2H), 4.31 (q, 2H), 6.96 (m, 2H), 7.15 (s, IH), 7.43 (t, IH), 7.92 (d,
IH).
Example 17
Benzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-5 of Table 3)
The title compound was prepared according to the procedure described in
Example 13 above except for the substitution of benzoic acid for 2-methylpropanoic acid. Ή-NMR (300 MHz, CDCls) δ (ppm): 1.32 (m, 6H), 2.93 (q, 2H), 4.35 (q, 2H),
7.19 (s, IH), 7.35 (t, 2H), 7.48 (t, IH), 8.10 (d, 2H).
Example 18
2, 4-Dichlorophenoxyacetic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy- methyl ester (Compound 3-6 of Table 3) The title compound was prepared according to the procedure described in Example 13 above except for the substitution of 2,4-dichlorophenoxyacetic acid for 2- methylpropanoic acid. Η-NMR (300 MHz, CDCls) δ (ppm): 1.32 (m, 6H), 2.92 (q, 2H), 4.29 (q, 2H), 4.82 (s, 2H), 6.83 (d, IH), 6.95 (s, IH), 7.24 (dd, IH), 7.38 (s, IH).
Example 19:
4-(2,4-Dichlorophenoxy)butyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-7 of Table 3)
The title compound was prepared according to the procedure described in Example 13 above except for the substitution of 4-(2,4-diclorophenoxy)butyric acid for 2-methylpropanoic acid. Η-NMR (300 MHz, CDCls) δ (ppm): 1.32 (m, 6 H), 2.18 (m, 2H), 2.76 (t, 2H), 2.97 (q, 2H), 4.02 (q, 2H), 4.31 (q, 2H), 6.83 (d, IH), 6.86 (s, IH), 7.15 (d, IH), 7.35 (d, IH).
Example 20:
2'-(2,4-Dichlorophenoxy)propionic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy- methyl ester (Compound 3-8 of Table 3)
The title compound was prepared according to the procedure described in
Example 13 above except for the substitution of 2'-(2,4-diclorophenoxy)propionic acid for 2-methylpropanoic acid. Η-NMR (300 MHz, CDC13) δ (ppm): 1.32 (m, 6H), 1.74
(m, 3H), 2.91 (q, 2H), 4.26 (q, 2H), 4.88 (m, IH), 6.88 (m, IH), 6.95 (s, IH), 7.18 (d,
IH), 7.38 (s, IH).
Example 21: 2,5-Dichloro-6-methoxybenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-9 of Table 3)
The title compound was prepared according to the procedure described in
Example 13 above except for the substitution of 2,5-dichloro-6-methoxybenzoic acid for 2-methylpropanoic acid. Η-NMR (300 MHz, CDCls) δ (ppm): 1.34 (m, 6H), 2.93 (q, 2H), 3.94 (s, 3H), 4.34 (q, 2H), 7.16 (d, IH), 7.18 (s, IH), 7.39 (d, IH). Example 22:
2,4,6-Trimethylbenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester
(Compound 3-10 of Table 3)
The title compound was prepared according to the procedure described in Example 13 above except for the substitution of 2,4,6-trimethylbenzoic acid for 2- methylpropanoic acid. Η-NMR (300 MHz, CDCls) δ (ppm): 1.33 (m, 6H), 2.27 (s, 3H), 2.34 (s, 6H), 2.90 (q, 2H), 4.31 (q, 2H), 6.86 (s, 2H), 7.16 (s, IH).
Example 23: Benzoic acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-11 of Table 3)
To a stirred ice cold solution of iodo-ethylsulfanylcarbonyloxy-acetic acid isopropyl ester (3.1 g, 9.3 mmol) in 40 mL of dry THF was added benzoic acid (1.5 g, 12.0 mmol) foUowed by DIEA (2.1 mL, 12.0 mmol). The reaction was allowed to stir at room temperature for 16h. The solvent was removed under reduced pressure.
The residue was dissolved in ether and washed 3 times with a saturated solution of sodium bicarbonate and once with brine. The ether layer was dried over MgS04 and concentrated to yield 2.0 g (66%) of the desired product, which was used without further purification. Η-NMR (300 MHz, CDC13) δ (ppm): 1.30 (m, 9H), 2.90 (q, 2H), 5.15 (m, IH), 7.13 (s, IH), 7.55 (m, 3H), 8.10 (m, 2H).
Example 24:
Pivahc acid isopropoxycarbonyl-ethyl sulfanylcarbonyloxy-methyl ester (Compound 3-12 of Table 3) The title compound was prepared according to the procedure described in
Example 23 above except for the substitution of pivahc acid for benzoic acid. Η- NMR (300 MHz, CDCls) δ (ppm): 1.30 (m, 18H), 2.90 (q, 2H), 5.10 (m, IH), 6.85 (s, IH).
Example 25:
1-Methyl-l-cyclopropanecarboxylic acid isopropoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester (Compound 3-13 of Table 3) The title compound was prepared according to the procedure described in Example 23 above except for the substitution of 1-methyl-l-cyclopropanecarboxylic acid for benzoic acid. Η-NMR (300 MHz, CDCls) δ (ppm): 0.75 (d, 2H), 1.35 (m, 14H), 2.90 (m, 2H), 5.10 (m, IH), 6.85 (s, IH).
Example 26:
Isobutyric acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester
(Compound 3-14 of Table 3)
The title compound was prepared according to the procedure described in Example 23 above except for the substitution of isobutyric acid for benzoic acid. Η- NMR (300 MHz, CDCls) δ (ppm): 1.25 (m, 15H), 2.65 (m, IH), 2.90 (m, 2H), 5.10 (m, IH), 6.90 (s, IH).
Example 27: Propionic acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound
3-15 of Table 3)
The title compound was prepared according to the procedure described in
Example 23 above except for the substitution of propionic acid for benzoic acid. 1H-
NMR (300 MHz, CDCls) δ (ppm): 1.15 (t, 3H), 1.30 (m, 9H), 2.45 (q, 2H), 2.90 (q, 2H), 5.10 (m, IH), 6.90 (s, IH).
Example 28:
Acetyl methyl carbamic acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-16 of Table 3) The title compound was prepared according to the procedure described in
Example 23 above except for the substitution of acetyl methyl carbamic acid for benzoic acid. Η-NMR (300 MHz, CDC13) δ (ppm): 1.30 (m, 9H), 2.10 (d, 3H), 2.90 (m, 2H), 3.10 (d, 3H), 4.20 (m, 2H), 5.10 (m, IH), 6.90 (s, IH).
Example 29
Diethylphosphonoacetic acid butoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3- 17 of Table 3) The title compound was prepared according to the procedure described in Example 13 above except for the substitution of diethylphosphonoacetic acid for 2- methylpropanoic acid and iodoethylsulfanylcarbonyloxy-acetic acid butyl ester for iodoethylsulfanylcarbonyloxy-acetic acid ethyl ester. Η-NMR (300 MHz, CD3OD) δ (ppm): 1.35 (t, 6H), 2.89 (q, 2H), 3.03 (d, 2H), 4.18 (q, 4H), 5.84 (s, 2H).
Example 30
Pivahc acid butoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester (Compound 3-18 of Table 3) The title compound was prepared according to the procedure described in
Example 13 above except for the substitution of pivahc acid for 2-methylpropanoic acid and iodoethylsulfanylcarbonyloxy-acetic acid butyl ester for iodoethylsulfanylcarbonyloxy-acetic acid ethyl ester. Η-NMR (300 MHz, CD3OD) δ (ppm): 1.25 (s, 9H), 1.31-1.45 (m, 8H), 1.65 (m 2H), 2.95 (q, 2H), 4.25 (m, 2H), 6.92 (s, IH).
Example 31:
3, 7-Dichloro-8-quinolinecarboxylic acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy- methyl ester (Compound 3-19 of Table 3) The title compound was prepared according to the procedure described in
Example 23 above except for the substitution of 3,7-dichloro-8-quinolinecarboxyhc acid for benzoic acid. Η-NMR (300 MHz, CDCls) d (ppm): 1.35 (m, 9H), 2.95 (q, 2H), 5.15 (m, IH), 7.25 (s, IH), 7.57 (d, IH), 7.76 (d, IH), 8.14 (s, IH) 8.83 (s, IH).
Following the general methods described hereinbefore, the following compounds of Formula IV (where G10, Gu, G20, G21, G30, and G3i = 0, and R2 = H) as hsted in Table C1-C70 can be prepared.
Figure imgf000109_0001
IV Table Cl: Listing of Compounds of Formula IV
Cmpd # R 2 t' d (X3)dZ3 t q (X2)qZ2
CM Et 1 0 t-butyl 1 0 2-propyl
Cl-2 Et 1 0 t-butyl 1 0 t-butyl
Cl-3 Et 1 0 t-butyl 1 0 ethyl
Cl-4 Et 1 0 t-butyl 1 0 2-ethoxyphenyl
Cl-5 Et 1 0 t-butyl 1 0 phenyl
Cl-6 Et 1 0 t-butyl 1 1 2,4-dichlorophenoxymethyl
Cl-7 Et 1 0 t-butyl 1 1 3-(2,4-dichlorophenoxy)propyl
Cl-8 Et 1 0 t-butyl 1 1 l-(2,4-dichlorophenoxy)ethyl
Cl-9 Et 1 0 t-butyl 1 1 2,5-dichloro-6-methoxyphenyl
Cl-10 Et 1 0 t-butyl 1 0 2,4,6-trimethylphenyl
Cl-11 Et 1 0 t-butyl 1 0 heptyl
Cl-12 Et 1 0 t-butyl 1 0 hexyl
Cl-13 Et 1 0 t-butyl 1 0 octyl
Cl-14 Et 1 0 t-butyl 1 0 methoxymethyl
Cl-15 Et 1 0 t-butyl 1 0 ethoxymethyl
Cl-16 Et 1 0 t-butyl 1 0 cyclohexyl
Cl-17 Et 1 0 t-butyl 1 0 cyclopentyl
Cl-18 Et 1 0 t-butyl 1 0 cyclop ropyl
Cl-19 Et 1 0 t-butyl 1 0 methyl
Cl-20 Et 1 0 t-butyl 1 0 propyl
Table C2: Compounds (C2-l)-(C2-20) are compounds of Formula IV where Ri2, G10, Gn, R2 ; G20, G21, G30, G31, t', d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals propyl.
Table C3: Compounds (C3-l)-(C3-20) are compounds of Formula IV where R12, G10, G11, R2, G20, G21, G30, G81, t', d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals methyl.
Table C4: Compounds (C4-l)-(C4-20) are compounds of Formula IV where R 2, G °, Gn, R2, G20, G2\ G30, G81, t', d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals heptyl.
Table C5 Compounds (C5-l)-(C5-20) are compounds of Formula IV where Ri2, G10, Gn, R2, G20, G21, G30, G81, t', d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals cyclopropyl. Table C6: Compounds (C6-l)-(C6-20) are compounds of Formula IV where Ri2, G10, G11, R2, G20, G21, G30, G31, t\ d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals cyclopentyl.
Table C7: Compounds (C7-l)-(C7-20) are compounds of Formula IV where Ri2, G10, G11, R2, G20, G i, G30, G31, t', d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals phenyl.
Table C8: Compounds (C8-l)-(C8-20) are compounds of Formula IV where Ri2, G10, Gn, R2, G20, G21, G30, G31, f , d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals benzyl.
Table C9: Compounds (C9-l)-(C9-20) are compounds of Formula IV where Ri2, G10, Gn, R2, G20, G21, G30, G3i, t', d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals 4-nitrophenyl.
Table CIO: Compounds (C10-l)-(C10-20) are compounds of Formula IV where Ri2, G10, Gn, R2, G20, G , G30, G3i, f , d, t, q, and (X2)qZ2 are identical to those in Table Cl except for (X3)dZ3 which equals 4-methoxyphenyl.
Tables C11-C20: Compounds [(Cll-l)-(Cll-20)] - [(C20-l)-(C20-20)] are compounds of Formula IV where (X3)dZ3, G10, G11, R2, G20, G2i, G30, G31, t', d, t, q, and (X2)qZ2 are identical to those in Tables C1-C10 except for R12 which equals methyl.
Tables C21-C30: Compounds [(C21-l)-(C21-20)] - [(C30-l)-(C30-20)] are compounds of Formula IV where (X3)dZ3, G10, G11, R2, G20, G2i, G30, G3i, f, d, t, q, and (X2)qZ2 are identical to those in Tables C1-C10 except for R12 which equals propyl.
Tables C31-40: Compounds [(C31-l)-(C31-20)] - [(C40-l)-(C40-20)] are compounds of Formula IV where (X3)dZ3, G™, G11, R2, G20, G2i, G30, G3ι, t', d, t, q, and (X2)qZ2 are identical to those in Tables C1-C10 except for Ri2 which equals t-butyl. Tables C41-C50: Compounds [(C41-l)-(C41-20)] - [(C50-l)-(C50-20)] are compounds of Formula IV where (X3)dZ3, Gi°, G", R2, G20, G21, G30, G3 , t', d, t, q, and (X2)qZ2 are identical to those in Tables C1-C10 except for R12 which equals 71-butyl.
Tables C51-C60: Compounds [(C51-l)-(51-20)] - [(C60-l)-(C60-20)] are compounds of Formula IV where (X3)dZ3, Gi°, Gu, R2, G20, G2i, G30, G3\ f , d, t, q, and (X2)qZ2 are identical to those in Tables C1-C10 except for R12 which equals phenyl.
Tables C61-C70: Compounds [(C61-l)-(C61-20)] - [(C70-l)-(C70-20)] are compounds of Formula IV where (X3)dZ3, G10, G11, R2, G20, G2 , G30, G3i, t\ d, t, q, and (X2)qZ2 are identical to those in Tables C1-C10 except for R12 which equals 2-pyridyl.
FoUowing the general methods described hereinbefore, the foUowing compounds of Formula III (where G10, G", G20, G2i, G30, and G31 = O and R2 = H) as hsted in Table 4 were prepared.
Figure imgf000112_0001
III Table 4: Listing of Compounds of Formula III
*
Cmpd # Yi f d (X3)dZ3 t q (X2)qZ2
4-1 Cl 1 0 ethyl 1 0 2-propyl
4-2 Cl 1 0 ethyl 1 0 t-butyl
4-3 Cl 1 0 ethyl 1 0 ethyl
4-4 Cl 1 0 ethyl 1 0 2-ethoxyphenyl
4-5 Cl 1 0 ethyl 1 0 phenyl
4-6 Cl 1 0 ethyl 1 1 3-(2,4-dichlorophenoxy)propyl
4-7 Cl 1 0 ethyl 1 1 l-(2,4-dichlorophenoxy)ethyl
4-8 Cl 1 0 ethyl 1 1 2,5-dichloro-6-methoxyphenyl
4-9 Cl 1 0 ethyl 1 0 2,4,6-trimethylphenyl
4-10 Cl 1 0 7i-butyl 1 0 diethylphosphonomethyl
4-11 Cl 1 0 71-butyl 1 0 t-butyl
4-12 Cl 1 0 2-propyl 1 0 2-propyl
The foUowing Examples are provided for guidance to the practitioner in order to practice the invention. Example 32:
2-Methylpropionic acid ethoxycarbonyl-chlorocarbonyloxy-methyl ester (Compound 4- 1 of Table 4) A 100 mL round bottom flask was charged with 2-methylpropionic acid ethoxycarbonyl-ethyl sulfanylcarbonyloxy-methyl ester (4.4 g, 15.8 mmol) and cooled to 5 °C. Sulfuryl chloride (2.70 g, 20.0 mmol) was added over 1 min. After 30 min of stirring, the coohng bath was removed and the reaction was aUowed to stir for 3 h at room temperature and then placed under vacuum. The material was used without purification. Η-NMR (300 MHz, CDCls) δ (ppm): 1.26 (m, 9H), 2.58 (m, IH), 4.32 (q, 2H), 6.83 (s, IH).
Example 33:
Pivalic acid ethoxycarbonyl-chlorocarbonyloxy methyl ester (Compound 4-2 of Table 4)
The title compound was prepared according to the procedure described in Example 32 above except for the substitution of pivahc acid ethoxycarbonyl- ethylsulfanylcarbonyloxy methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester. Η-NMR (300 MHz, CDCls) δ (ppm): 1.25 (s, 9H), 1.33 (t, 3H), 4.32 (q, 2H), 6.78 (s, IH).
Example 34:
Propionic acid ethoxycarbonyl-chlorocarbonyloxy-methyl ester (Compound 4-3 of
Table 4) The title compound was prepared according to the procedure described in
Example 32 above except for the substitution propionic acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.4 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 1.21 (t, 3H), 1.35 (t, 3H), 2.53 (q,2H), 4.32 (q, 2H), 6.84 (s, IH). Example 35:
2-Ethoxybenzoic acid ethoxycarbonyl-chlorocarbonyloxy-methyl ester (Compound 4-4 of Table 4)
The title compound was prepared according to the procedure described in Example 32 above except for the substitution 2-ethoxybenzoic acid ethoxycarbonylethylsulfanyl-carbonyloxy methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.4 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 1.36 (t, 3H), 1.45 (t, 3H), 4.13 (q, 2H), 4.36 (q, 2H), 6.95 (m, 2H), 7.02 (s, IH), 7.47 (t, IH), 7.91(d, IH).
Example 36:
Benzoic acid ethoxycarbonyl-chlorocarbonyloxy-methyl ester (Compound 4-5 of Table
4) The title compound was prepared according to the procedure described in
Example 32 above except for the substitution benzoic acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.2 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 1.36 (t, 3H), 4.32 (q, 2H), 7.09 (s, IH), 7.50 (t, 2H), 7.63 (t, IH), 8.10 (d, 2H).
Example 37:
2,4-Dichlorophenoxybutyric acid ethoxycarbonyl-chlorocarbonyloxy-methyl ester
(Compound 4-6 of Table 4) . The title compound was prepared according to the procedure described in
Example 32 above except for the substitution 2,4-dichlorophenoxybutyric acid ethoxycarbonylethyl-sulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl ethylsulfanylcarbonyl-oxy-methyl ester, using 1.45 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 1.34 (t, 3H), 2.21 (m, 2H), 2.56 (t, 2H), 4.07 (t, 2H), 4.31 (q, 2H), 6.83 (d, IH), 6.86 (s, IH), 7.17 (d, IH), 7.35 (d, IH). Example 38:
2'- (2, 4-Dichlorophenoxy)propionic acid ethoxycarbonyl-chlorocarbonyloxy-methyl ester (Compound 4-7 of Table 4)
The title compound was prepared according to the procedure described in Example 32 above except for the substitution 2'-(2,4-dichlorophenoxy)propionic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.80 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 1.37 (t, 3H), 1.92 ( m, 3H), 4.33 (q, 2H), 4.83 (m, IH), 6.84 (m, 2H), 7.16 (dd, IH), 7.38 (d, IH).
Example 39:
2,5-Dichloro-6-methoxybenzoic acid ethoxycarbonyl-chlorocarbonyloxy- methyl ester
(Compound 4-8 of Table 4) The title compound was prepared according to the procedure described in
Example 32 above except for the substitution 2,5-dichloro-6-methoxybenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.45 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 1.34 (t, 3H), 3.95 (s, 3H), 4.36 (q, 2H), 7.08 (s, IH), 7.18 (d, IH), 7.42 (d, IH).
Example 40:
2,4,6-Trimethylbenzoic acid ethoxycarbonyl-chlorocarbonyloxy- methyl ester
(Compound 4-9 of Table 4) The title compound was prepared according to the procedure described in
Example 32 above except for the substitution of 2,4,6-trimethylbenzoic acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.45 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 1.34 (t, 3H), 2.28 (s, 3H), 2.35 (s, 6H), 4.34 (q, 2H), 6.89 (s, IH), 7.06 (s, IH), 7.12 (s, IH). Example 41:
Diethylphosphonoacetic acid butoxycarbonyl-chlorocarbonyloxy-methyl ester
(Compound 4-10 of Table 4)
The title compound was prepared according to the procedure described in Example 32 above except for the substitution diethylphosphonoacetic acid butoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester, using 1.9 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 0.96 (t, 3H), 1.37 (t, 6H), 1.72 (m, 2H), 2.01 (m, 2H), 3.15 (d, 2H), 4.27 (m, 6H), 6.85 (s, IH).
Example 42-A:
Pivalic acid butoxycarbonyl-chlorocarbonyloxy-methyl ester (Compound 4-11 of Table
4) The title compound was prepared according to the procedure described in
Example 32 above except for the substitution of pivahc acid butoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.9 equiv of sulfuryl chloride and starting the reaction at 5 °C. Η-NMR (300 MHz, CDCls) δ (ppm): 0.95 (t, 3H), 1.27 (s, 9H), 1.35-1.45 (m, 2H), 1.65-1.75 (m 2H), 4.31 (m, 2H), 6.85 (s, IH).
Example 42-B:
2-Methylpropanoic acid (chlorocarbonyloxy)-[(l-methylethoxy)carbonyl]methyl ester
Compound 4-12 of Table 4) The title compound was prepared according to the procedure described in
Example 32 above except for the substitution of isobutyric acid isobutoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for isobutyric acid ethoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester, using 1.9 equiv of sulfuryl chloride and starting the reaction at 5 °C. . Η-NMR (300 MHz, CDCls) δ (ppm): 1.22-1.30 (m, 6H), 1.30-1.40 (m, 6H), 2.70 (heptet, IH), 5.14 (heptet, IH), 6.77 (s, IH). FoUowing the general methods described hereinbefore, the foUowing compounds of Formula III (where G">, G11, G20, G2 , G30, and G3i = O and R2 = H) as hsted in Tables D1-D10 can be prepared.
Figure imgf000117_0001
III
Table Dl: Listing of Compounds < af Formula III
Cmpd # Y t' d (X3)dZ3 t q (X2)qZ2
DM Cl 1 0 t-butyl 1 0 2-propyl
Dl-2 Cl 1 0 t-butyl 1 0 t-butyl
Dl-3 Cl 1 0 t-butyl 1 0 ethyl
Dl-4 Cl 1 0 t-butyl 1 0 2-ethoxyphenyl
Dl-5 Cl 1 0 t-butyl 1 0 phenyl
Dl-6 Cl 1 0 t-butyl 1 1 3-(2,4-dichlorophenoxy)propyl
Dl-7 Cl 1 0 t-butyl 1 0 benzyl
Dl-8 Cl 1 0 t-butyl 1 1 2,5-dichloro-6-methoxyphenyl
Dl-9 Cl 1 0 t-butyl 1 0 2,4,6-trimethylphenyl
Dl-10 Cl 1 0 t-butyl 1 0 diethylphosphonomethyl
Dl-11 Cl 1 0 t-butyl 1 0 cyclopropyl
Dl-12 Cl 1 0 t-butyl 1 0 pentyl
Dl-13 Cl 1 0 t-butyl 1 0 cyclohexyl
Dl-14 Cl 1 0 t-butyl 1 0 octyl
Dl-15 Cl 1 0 t-butyl 1 0 methoxymethyl
Dl-16 Cl 1 0 t-butyl 1 0 4-methoxyphenyl
DM7 Cl 1 0 t-butyl 1 0 phenoxymethyl
Dl-18 Cl 1 0 t-butyl 1 0 cyclopentyl
Dl-19 Cl 1 0 t-butyl 1 0 2,4,6-trimethylphenyl
Dl-20 Cl 1 0 t-butyl 1 0 methyl
Table D2: Compounds (D2-l)-(D2-20) are compounds of Formula III where Y1, G10, G11, R2, G20, G21, G30, G3i, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals propyl.
Table D3: Compounds (D3-l)-(D3-20) are compounds of Formula III where Y1, G10, G11, R2, G20, G2i, G30, G31, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals methyl. Table D4: Compounds (D4-l)-(D4-20) are compounds of Formula III where Y1, G10, G11, R2, G20, G2i, G30, G3i, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals heptyl.
Table D5 Compounds (D5-l)-(D5-20) are compounds of Formula III where Y1, G10, Gn, R2, G20, G2i, G30, G31, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals cyclopropyl.
Table D6: Compounds (D6-l)-(D6-20) are compounds of Formula III where Y , Gi°, Gn, R2, G20, G21, G30, G81, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals cyclopentyl.
Table D7: Compounds (D7-l)-(D7-20) are compounds of Formula III where Y1, G10, Gn, R2, G20, G21, G30, G3i, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals phenyl.
Table D8: Compounds (D8-l)-(D8-20) are compounds of Formula III where Y1, G10, G11, R2, G20, G21, G30, G3i, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals benzyl.
Table D9: Compounds (D9-l)-(D9-20) are compounds of Formula III where Yx, G10, Gn, R2, G20, G2 G30, G3 , t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals 4-nitrophenyl.
Table D10: Compounds (D 10- 1)-(D 10-20) are compounds of Formula III where Y1, G10, Gn, R2, G20, G2i, G30, G31, t', d, t, q, and (X2)qZ2 are identical to those in Table Dl except for (X3)dZ3 which equals 4-methoxyphenyl.
FoUowing Method A described hereinbefore, the following compounds of Formula XXIV (where R6 = H, W = OH, R2 = H, and G20, G , and G3i = O) as Usted in Table 5 were prepared.
Figure imgf000119_0001
XXIV
Table 5: Listing of Compounds of Formula XXIV
Cmpd # R8 t' d (X3)dZ3 t q (X2)qZ2
5-1 0-NH3Φr 1 0 ethyl 1 0 2-propyl
5-2 O-NHuΦr 1 0 ethyl 1 0 t-butyl
5-3 O-NHsΦr 1 0 ethyl 1 0 phenyl
5-4 O-NHsΦr 1 0 ethyl 1 1 3-(2,4-dichlorophenoxy)propyl
5-5 OH 1 0 2-propyl 1 0 t-butyl
5-6 O-NHs'Pr 1 0 2-propyl 1 0 t-butyl
5-7 OH 1 0 2-propyl 1 0 phenyl
5-8 O-NHsΦr 1 0 2-propyl 1 0 phenyl
5-9 O-NHsΦr 1 0 ?7,-butyl 1 0 (diethoxyphosphoryl)methyl
5-10 OH 1 0 7i-butyl 1 0 t-butyl
5-11 O-NHsΦr 1 0 7i-butyl 1 0 t-butyl
The foUowing Examples are provided for guidance to the practitioner in order to practice the invention.
Example 43:
Isobutyric acid (carboxymethyl-phosphonomethyl-carbamoyloxy)-ethoxycarbonyl- methyl ester isopropylamine salt (Compound 5-1 of Table 5) A stirred solution of phosphonomethyl glycine (0.88 g, 5.2 mmol) in hexamethyldisUazane (2.35 mL, 11.2 mmol) was slowly heated to 90 °C (at this temperature gassing of ammonia occurred). The temperature was increased to 125 °C for 150 min at which time the reaction became homogeneous. The solution was aUowed to cool to room temperature and dry methylene chloride (5 mL) was added. The material was syringed into a flask and placed under N2. Methylene chloride (5 mL) was added and the solution cooled in a dry ice/acetone bath. A solution of 2-methylpropionic acid ethoxycarbonyl-chlorocarbonyloxy-methyl ester (1.2 g, 4.8 mmol) in 1 mL of methylene chloride was added dropwise over 2 min through a 1 mL syringe. After 10 min the coohng bath was removed and the reaction was aUowed to warm to room temperature and stir for 12 h. The reaction solution was concentrated under reduced pressure and dissolved in 25 mL of 10% water:acetone and aUowed to stand for 1 h. The reaction was vacuum filtered and concentrated under reduced pressure. The oU was dissolved with 20 mL of dry acetone and aUowed to stand for 1 h, vacuum filtered, and concentrated under vacuum. The solid was triturated with 10 mL of warm hexanes and then placed under vacuum to afford isobutyric acid (carboxymethyl-phosphonomethyl- carbamoyloxy)-ethoxycarbonyl-methyl ester (0.67 g), which was dissolved in 20 mL of acetone to which isopropylamine (0.148 mL) was added. After 15 min of stirring the solvent was removed under vacuum. The sohd was washed with diethyl ether and subsequently dried under vacuum to afford 0.62 g of the title product as a tannish sohd. Η-NMR (300 MHz, D20) δ (ppm): 1.16 (m, 6H), 1.27 (m, 9H), 2.76 (m, IH), 3.55 (m, 3H), 4.15 (m, 2H), 4.38 (q, 2H), 6.78 (d, IH).
Example 44:
Pivahc acid (carboxymethyl-phosphonomethyl-carbamoyloxy)-ethoxycarbonyl-methyl ester isopropylamine salt (Compound 5-2 of Table 5)
The title compound was prepared according to the procedure described in Example 43 above except for the substitution of pivalic acid ethoxycarbonyl- chlorocarbonyloxy-methyl ester for 2-methylpropanoic acid chlorocarbonyloxymethyl ester. Η-NMR (300 MHz, D20) δ (ppm): 1.26 (m, 18H), 3.68 (m, 3H), 4.12 (m, 2H), 4.36 (m, 2H), 6.74 (d, IH).
Example 45:
Benzoic acid carboxymethyl-phosphonomethyl-carbamoyloxy)ethoxycarbonyl- methyl ester isopropylamine salt (Compound 5-3 of Table 5) The title compound was prepared according to the procedure described in
Example 43 above except for the substitution of benzoic acid ethoxycarbonyl- chlorocarbonyloxymethyl ester for 2-methylpropionic acid ethoxycarbonyl- chlorocarbonyloxymethyl ester. Η-NMR (300 MHz, D2O) δ (ppm): 1.29 (d, 9H), 3.59 (m, 3H), 4.10 (d, 2H), 4.35 (m, 2H), 6.90 (d, IH), 7.01 (d IH), 7.53 (t, 2H), 7.74 (t, IH), 8.10 (m, IH).
Example 46: 2,4-Dichlorophenoxybutyric acid carboxymethyl-phosphonomethyl-carbamoyloxy)- ethoxycarbonyl- methyl ester isopropylamine salt (Compound 5-4 of Table 5)
The title compound was prepared according to the procedure described in Example 43 above except for the substitution of 2,4-dichlorophenoxybutyric acid ethoxycarbonyl-chlorocarbonyloxymethyl ester for 2-methylpropionic acid ethoxycarbonyl-chlorocarbonyloxymethyl ester. Η-NMR (300 MHz, CD3OD) δ (ppm): 1.19 (m, 9H), 2.03 (m, 2H), 2.54 (t, 2H), 3.42 (m, 3H), 3.55 (m, 2H), 3.99 (t, 2H), 4.18 (m, 2H), 6.67 (d, IH), 6.97 (d, IH), 7.10 (dd, IH), 7.27 (d, IH).
Example 47: Pivahc acid (carboxymethyl-phosphonomethylcarbamoyloxy)isopropoxycarbonyl- methyl ester (Compound 5-5 of Table 5)
A 25 mL round bottom flask was charged with pivahc acid isopropoxycarbonyl-ethylsulfanylcarbonyloxy-methyl ester and 4 mL of methylene chloride, then cooled to 10 °C. Sulfuryl chloride (0.22 mL, 2.7 mmol) was added, under N2 atmosphere. After stirring cold for 2 h, the coohng bath was removed, and the reaction was aUowed to stir for 1 h at room temperature and then placed under vacuum for 15 min. The material was used without purification. In a separate flask, with mechanical stirring, a mixture of phosphonomethyl glycine (20.15 g, 119 mmol) in hexamethyldisUazane (55mL, 238 mmol) was slowly heated to 125 °C and stirred for 1 h. The mixture became homogeneous. The solution was allowed to cool to room temperature. The sUylated phosphonomethylglycine solution (1.3 mL, 2.26 mmol) was added by syringe in two portions, under N2, to an ice/water cooled solution of the chloroformate generated above, in 4 mL of methylene chloride. The reaction was allowed to warm to room temperature and stir for 16 h. The reaction solution was concentrated under reduced pressure and dissolved in 15 mL of a 9:1 mixture of acetone/water and, allowed to stand for 4 h. The reaction was dried with MgS04, vacuum filtered, and concentrated under reduced pressure. The sohd was triturated twice with hexanes and then placed under vacuum to afford the desired product (0.9 g, 99%). Ή-NMR (300 MHz, d4-MeOH) δ (ppm): 1.15 (m, 15H), 3.65 (m, 2H), 4.10 (m, 2H), 5.00 (m, IH) 6.60 (m, IH).
Example 48: Pivahc acid (carboxymethyl-phosphonomethyl-carbamoyloxy)isopropoxycarbonyl- methyl ester-isopropylamine salt (Compound 5-6 of Table 5)
To a stirred ice cold solution of pivahc acid (carboxymethyl-phosphonomethyl- carbamoyloxy)isopropoxycarbonyl-methyl ester (0.5 g, 1.21 mmol) in 5 mL of acetone was added isopropylamine (0.10 mL, 1.21 mmol). After 15 min of stirring, the solvent was removed under vacuum. The sohd was washed with diethyl ether and subsequently dried under vacuum to afford 505 mg of the desired product as tan sohds. Η-NMR (300 MHz, D20) δ (ppm): 1.20 (m, 21H), 3.55 (m, 2H), 3.70 (m, IH), 4.25 (m, 2H), 5.10 (m, IH), 6.65 (m, IH).
Example 49:
Benzoic acid (carboxymethyl-phosphonomethyl-carbamoyloxy)isopropoxycarbonyl- methyl ester (Compound 5-7 of Table 5)
The title compound was prepared according to the procedure described in
Example 47 above except for the substitution of benzoic acid isopropoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester for pivalic acid isopropoxycarbonyl- ethylsulfanylcarbonyloxy-methyl ester. Η-NMR (300 MHz, d4-MeOH) δ (ppm): 1.20
(m, 6H), 3.60 (m, 2H), 4.10 (d, 2H), 5.05 (m, IH), 6.90 (d, IH), 7.40 (t, 2H), 7.60 (m,
IH), 8.00 (m, 2H).
Example 50:
Benzoic acid (carboxymethyl-phosphonomethyl-carbamoyloxy)-isoproyloxycarbonyl- methyl ester-isopropylamine salt (Compound 5-8 of Table 5)
The title compound was prepared according to the procedure described in
Example 48 above except for the substitution of benzoic acid (carboxymethyl- phosphonomethyl-carbamoyloxy)isopropoxycarbonyl-methyl ester for pivahc acid
(carboxymethyl-phosphonomethyl-carbamoyloxy)isopropoxycarbonyl- methyl ester.
Η-NMR (300 MHz, D2O) δ (ppm): 1.30 (d, 12H), 3.55 (m, 3H), 4.15 (m, 2H), 5.15 (m,
IH), 6.95 (m, IH), 7.60 (t, 2H), 7.70 (t, IH), 8.10 (m, 2H). Example 51:
Diethylphosphonoacetic acid (carboxymethyl-phosphonomethyl-carbamoyloxy)- butoxycarbonyl-methyl ester isopropylamine salt (Compound 5-9 of Table 5) The title compound was prepared according to the procedure described in
Example 43 above except for the substitution diethylphosphonoacetic acid butoxycarbonyl-chlorocarbonyloxymethyl ester for 2-methylpropionic acid ethoxycarbonyl-chlorocarbonyloxy- methyl ester. -NMR (300 MHz, D2O) δ (ppm): 0.85 (m, 3H), 1.32 (m, 12H), 3.22 (d, 2H), 3.45 (m, 3H), 3.68 (m, 2H), 4.21 (m, 6H), 6.74 (d, IH).
Example 52:
Pivalic acid (carboxymethyl-phosphonomethyl-carbamoyloxy)-butoxycarbonyl-methyl ester (Compound 5-10 of Table 5) The title compound was prepared according to the procedure described in
Example 47 above except for the substitution of pivahc acid butoxycarbonyl- chlorocarbonyloxymethyl ester for pivahc acid isopropoxycarbonyl-chlorocarbonyloxy- methyl ester. -NMR (300 MHz, D2O) δ (ppm): 0.84 (t, 3H), 1.11 (s, 9H), 1.25-1.35 (m, 2H), 1.50-1.60 (m 2H), 3.50-3.75 (m, 2H), 4.15 (m, 4H), 6.65 (d, IH).
Example 53:
Pivalic acid (carboxymethyl-phosphonomethyl-carbamoyloxy) -butoxycarbonyl- methyl ester isopropylamine salt (Compound 5-11 of Table 5)
The title compound was prepared according to the procedure described in Example 48 above except for the substitution pivalic acid (carboxymethyl- phosphonomethyl-carbamoyloxy)butoxycarbonyl-methyl ester for pivahc acid (carboxymethyl-phosphonomethyl-carbamoyloxy)isopropoxycarbonyl-methyl ester. Η-NMR (300 MHz, D2O) δ (ppm): 0.98 (t, 3H), 1.25 (s, 9H), 1.33 (d, 6H), 1.40-1.50 (m, 2H), 1.70 (m 2H), 3.40-3.75 (m, 3H), 4.25 (m, 4H), 6.82 (d, IH).
FoUowing Method B described hereinbefore, the foUowing compounds of Formula XII (where R2 = H) as hsted in Table 6 v/ere prepared.
Figure imgf000124_0001
XII Table 6: Listing of Compounds of Formula XII
Cmpd # Ra Rb Rc Rd Re Rf e Rh Y2 G3 t' d (X3)dZ3
6-1 Me OMe H Me H Me C(CH3)s H Cl 0 1 0 benzyl
6-2 Me OMe H Me H Me C(CHs)3 H I 0 1 0 benzyl
6-3 Me OMe H Me H Me C(CH3)3 H Cl 0 1 0 ethyl
6-4 Me OMe H Me H Me C(CH3)3 H I 0 1 0 ethyl
6-5 Me OMe H Me H Me C(CH3)s H Cl 0 1 0 methyl
6-6 Me OMe H Me H Me C(CH3)3 H I 0 1 0 methyl
6-7 Me OMe H Me H Me C(CH3)3 H Cl 0 1 0 t-butyl
6-8 Me OMe H Me H Me C(CH3)s H I 0 1 0 t-butyl
6-9 Me OMe H Me H Me C(CH3)3 H Cl 0 1 0 72,-butyl
6-10 Me OMe H Me H Me C(CHs)3 H I 0 1 0 7i-butyl
6-11 H H H H H H C(CHs)3 Cl Cl 0 1 0 ethyl
6-12 H H H H H H C(CHs)3 Cl I 0 1 0 ethyl
6-13 H H H H H H C(CH3)3 Cl Cl 0 1 0 isopropyl
6-14 H H H H H H C(CH3)3 Cl I 0 1 0 isopropyl
6-15 H H H H H H C(CHs)s Cl Cl 0 1 0 benzyl
6-16 H H H H H H , C(CH3)3 Cl I 0 1 0 benzyl
The foUowing Examples are provided for guidance to the practitioner in order to practice the invention. Example 54:
[N-tert-Butyl-N'-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxyjchloroacetic acid benzyl ester (Compound 6-1 of Table 6)
To a suspension of sodium hydride (4.2 g, 106 mmol, 60% by wt in oU) in 1.4 L of tetrahydrofuran (THF) was added N-tert-butyl-N-(3,5-dimethylbenzo}rl)-N-(3- methoxy-2-methylbenzoyl)hydrazide portionwise (30.0 g, 81 mmol) over 5 min. The mixture was then heated to reflux for 3 h, aUowed to cool to room temperature and stirred for an additional 2 h. Benzyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate (27.8 g, 106 mmol) was dUuted with 100 mL of THF and then added to the yeUow homogeneous mixture in one portion. The mixture was stirred at room temperature for 2 h. THF was then removed under vacuum and the resulting waxy solid was purified via sUiea gel chromatography (2:1 hexanes:EtOAc) to afford the desired product as a white sohd (24.7 g) in 50% yield, LC MS was conducted for confirmation of structure and purity (Table 7A).
Example 55:
[iV-tert-butyl-Λp-(3!5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxyjiodoacetic acid benzyl ester (Compound 6-2 of Table 6)
To a solution of [iV-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazine-carbonyloxy]chloroacetic acid benzyl ester (24.7 g, 41.0 mmol) in 200 L of acetone was added sodium iodide (18.6 g, 124.0 mmol) and heated to 35 °C for 2 h. The acetone was removed and the slurry was treated with ether. The ether solution was filtered through cehte. The ether was removed under reduced pressure to afford the desired product as brown oily solids (27 g). LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 56:
[N-fert-butyl-iV-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxyjchloroacetic acid ethyl ester (Compound 6-3 of Table 6) The title compound was prepared according to the procedure described in
Example 54 above except for the substitution of ethyl 2-chloro-2- [(chlorocarbonyl)oxy] acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate. LC/MS was conducted for confirmation of structure and purity (Table 7A). Example 57:
[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy]iodoacetic acid ethyl ester (Compound 6-4 of Table 6) The title compound was prepared according to the procedure described in Example 55 above except for the" substitution of [N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinecarbonyloxy]chloroacetic acid ethyl ester for [N- tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy]chloroacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 58:
[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy]chloroacetic acid methyl ester (Compound 6-5 of Table 6) The title compound was prepared according to the procedure described in
Example 54 above except for the substitution of methyl 2-chloro-2- [(chlorocarbonyl)oxy] acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 59:
[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy]iodoacetic acid methyl ester (Compound 6-6 of Table 6)
The title compound was prepared according to the procedure described in Example 55 above except for the substitution of [N-tert-butyl-N-(3,5- dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinecarbonyloxy]-chloro-acetic acid methyl ester for [N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazine-carbonyloxy]chloroacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 60: .
[N-tert-butyl-N'-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy]chloroacetic acid tert-butyl ester (Compound 6-7 of Table 6) The title compound was prepared according to the procedure described in Example 54 above except for the substitution of tert-butyl 2-chloro-2- [(chlorocarbonyl)oxy] -acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxyJ acetate. LC/MS was conducted for confirmation of structure and purity (Table 7 A).
Example 61:
[N-tert-butyl-N'-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy]iodoacetic acid tert-butyl ester (Compound 6-8 of Table 6)
The title compound was prepared according to the procedure described in Example 55 above except for the substitution of [N-tert-butyl-N-(3,5- dimethylbenzoyl) -N- (3 -methoxy-2-methylbenzoyl)hydrazinecarbonyloxy] chloroacetic acid tert-butyl ester for [N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazine-carbonyloxy]chloroacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 62:
[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy] chloroacetic acid 7i-butyl ester (Compound 6-9 of Table 6)
The title compound was prepared according to the procedure described in Example 54 above except for the substitution of τι-butyl 2-chloro-2-
[(chlorocarbonyl)oxy] acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate. Η- ΝMR (300 MHz, CDC13) δ (ppm): 0.94 (t, 3H), 1.30-1.60 (m, 4H), 1.67 (s, 9H), 1.90 (bs, 3H), 2.25 (s, 6H), 3.78 (s, 3H), 4.20-4.40 (m, 2H), 6.30 (s, IH), 6.80-7.20 (m, 6H).
Example 63:
[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxyjiodoacetic acid 71-butyl ester (Compound 6-10 of Table 6)
The title compound was prepared according to the procedure described in Example 55 above except for the substitution of [N-tert-butyl-iV-(3,5- dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinecarbonyloxy]chloroacetic acid 7i-butyl ester for [N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazine-carbonyloxy]chloroacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A). Example 64:
[N-Benzoyl-ΛP-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]chloroacetic acid ethyl ester (Compound 6-11 of Table 6) The title compound was prepared according to the procedure described in
Example 54 above except for the substitution of ethyl 2-chloro-2- [(chlorocarbonyl)oxy] acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy] acetate and the substitution of N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazide for N-tert- butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazide. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 65:
[N-Benzoyl-Λ -tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]iodoacetic acid ethyl ester (Compound 6-12 of Table 6) The title compound was prepared according to the procedure described in
Example 55 above except for the substitution of [N-benzoyl-N-tert-butyl-N-(4- chlorobenzoyl)-hydrazinocarbonyloxy]-chloro-acetic acid ethyl ester for [N-tert-butyl- N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy] chloroacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 66:
[N-Benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]chloroacetic acid isopropyl ester (Compound 6-13 of Table 6) The title compound was prepared according to the procedure described in
Example 54 above except for the substitution of isopropyl 2-chloro-2- [(chlorocarbonyl)oxy]-acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate and the substitution of N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazide for N-tert- butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazide. LC/MS was conducted for confirmation of structure and purity (Table 7A). Example 67:
[N-Benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]iodoacetic acid isopropyl ester (Compound 6-14 of Table 6)
The title compound was prepared according to the procedure described in Example 55 above except for the substitution of [N-benzoyl-N-tert-butyl-N-(4- chlorobenzoyl)-hydrazinocarbonyloxy]chloroacetic acid isopropyl ester for [N-tert- butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy] chloroacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 68:
[N-Benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]chloroacetic acid benzyl ester (Compound 6-15 of Table 6)
The title compound was prepared according to the procedure described in Example 54 above except for the substitution of benzyl 2-chloro-2-
[(chlorocarbonyl)oxy] acetate for benzyl 2-chloro-2-[(chlorocarbonyl)oxy]acetate and the substitution of N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazide for N-tert- butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazide. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 69:
[N-Benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]iodoacetic acid benzyl ester (Compound 6-16 of Table 6)
The title compound was prepared according to the procedure described in Example 55 above except for the substitution of [N-benzoyl-N-tert-butyl-N-(4- chlorobenzoyl)-hydrazinocarbonyloxy]chloroacetic acid benzyl ester for [N-tert-butyl- N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazine- carbonyloxy] chloroacetic acid benzyl ester. -ΝMR (300 MHz, CDCI3) δ (ppm) (mixture of rotational isomers): 1.63 and 1.64 (two s, 9H), 5.10 - 5.30 (m, 2H), 6.50 - 6.65 (m, 2H), 6.90 (d, IH) 7.00 - 7.50 (m, 12H). Following Method B described hereinbefore, the following compounds of Formula XV {where R2 = H, G20 and G2X = O, t = 1, and Rg = C(CHs)3} as listed in Table 7 were prepared.
Figure imgf000130_0001
XV
Table 7; Listing of Compounds of Formula XV
Cmpd# Ra Rb Rc Rd Re Rf Rh (X3)dZ3 G3i d q (X2)qZ2
7-1 H H H H H H Cl Bn 0 1 0 0 ethyl
7-2 H H H H H H Cl H 0 1 0 0 ethyl
7-3 H H H H H H Cl Cl 0 0 0 ethyl
7-4 H H H H H H Cl Et N(Et) 1 0 0 ethyl
7-5 H H H H H H Cl CH2P(=0)-(OBn)2 0 1 0 0 ethyl
7-6 H H H H H H Cl Me N(H) 1 0 0 ethyl
Figure imgf000131_0001
o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o
φ φ OO O OO O O O O O O O O O O O O O O O O O O O O O O
Figure imgf000131_0002
φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ
W iH H MM MM M hH
Figure imgf000131_0003
φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ
O O O O O O O O O O O O O O O O O O O O O O O l_l ___l ___ ____; <U <D <D Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ Φ !D φ ω
t- oo o- i-H N C ^ ifl ffl t- B O- O H i W rf iO tD h oO ffl O H N n r-H τ-H r→ rH τ-H ι-H τ-l r→ c CI (N NI Cl W Cl Cl θq O r O t- c~ o t __- _ t- t~ l t l _ o _ _ t— ir~ c — c— C— t— ι_— tr— -34 Me OMe H Me H Me H Me 0 1 0 0 3-thiophenemethyl -35 Me OMe H Me H Me H Me 0 1 0 0 benzyl -36 Me OMe H Me H Me H Me 0 1 0 0 2,5-dioxoimidazolidin-4-ylmethyl -37 Me OMe H Me H Me H Et 0 1 0 0 2-propyl -38 Me OMe H Me H Me H ipr 0 1 0 0 2-propyl -39 Me OMe H Me H Me H Pr 0 1 0 0 2-propyl -40 H H H H H H Cl Bn 0 1 0 0 2-propyl -41 H H H H H H Cl Bn 0 1 0 0 N-acetyl-N-methylaminomethyl -42 H H H H H H Cl Bn 0 1 0 0 C(CHs)3 -43 Me OMe H Me H Me H Bn 0 1 0 0 2-propyl -44 Me OMe H Me H Me H H 0 1 0 0 2-propyl -45 Me OMe H Me H Me H H 0 1 0 0 lH-pyrazol-4-yl -46 Me OMe H Me H Me H H 0 1 0 0 2-methoxyethoxymethyl -47 Me OMe H Me H Me H H 0 1 0 0 3-pyridyl -48 Me OMe H Me H Me H H 0 1 0 0 4-methanesulfanylphenyl -49 Me OMe H Me H Me H H 0 1 0 0 nonyl -50 Me OMe H Me H Me H H 0 1 0 0 C(CΗ3)3 -51 Me OMe H Me H Me H H 0 1 0 0 methyl -52 H H H H H H Cl H 0 1 0 0 2-propyl -53 H H H H H H Cl H 0 1 0 0 l-(tert-butoxycarbonyl)piperidin-4-yl -54 H H H H H H Cl H 0 1 0 0 N-acetyl-N-methylaminomethyl -55 H H H H H H Cl H 0 1 0 0 C(CH3)3
Figure imgf000132_0001
-59 H H H H H H Cl (CH2)2-S02Me 0 1 0 0 C(CH3)3
Figure imgf000133_0001
o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o
Figure imgf000133_0002
o o o o o o o o o o o o o a a a a a a a 8 a a a a a a a a a Φ Φ Φ Φ
K a a a a a a a a a a a a a a a a
W W a a a a a a a a a a a Φ Φ Φ
W a a B a a a a a a a a a a a a a Φ Φ
W a a B a a a a a a a a a o o o o a a a a a a a a a a a a a φ Φ Φ s o co io CD t- 00 C3 O i-H C C0 t< l0 CD
CD CD CD CD CD CD CD CD t _ 0 _ t~ t _
D~ c- _ t trt- t~ t- » __- t t~ t I t~ t- The following Examples are provided for guidance to the practitioner in order to practice the invention.
Example 70: Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- benzyloxycarbonylmethyl ester (Compound 7-1 of Table 7)
To a solution of [N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazino- carbonyloxyjiodoacetic acid benzyl ester (8.3 g, 12.8 mmol) in THF (50 mL) was added propionic acid (1.25 mL, 16.7 mmol) and diisopropylethylamine (DIEA) (2.9 mL, 16.7 mmol). The mixture was stirred for 16 h upon which time the THF was removed under vacuum. Ethyl acetate (100 mL) was added and then washed with water (2X). The ethyl acetate layer was dried over magnesium sulfate, filtered, and concentrated to an oil. Silica gel chromatography (4:1 hexanes:EtOAc) afforded 6.0 g of the title compound in 75% yield. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 71:
Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- carboxymethyl ester (Compound 7-2 of Table 7) Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyl- oxy]benzyloxycarbonylmethyl ester (150 mg, 0.3 mmol), 10 % palladium on carbon (10-20 mg) and ethyl acetate (5 mL) were combined and hydrogenated in a Parr shaker at room temperature under 55 psi hydrogen for 2 h. The catalyst was removed by filtration through Cehte, and evaporation of the solvent from the filtrate afforded the pure product as a colorless oil in 94% yield. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.13 - 1.29 (m, 3H), 1.62 - 1.64 (d, 9H), 2.20 - 2.55 (m, 2H), 6.40 - 7.45 (m, 10H), 8.45 (bs, IH).
Example 72: Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- chlorocarbonylmethyl ester (Compound 7-3 of Table 7)
Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyl- oxy]-carboxymethyl ester (1.8 g, 3.6 mmol) was dissolved in thionyl chloride (5 mL, 25 mmol) in a round bottom flask. The resulting mixture was heated at 50 °C for 1 h. The excess thionyl chloride was removed under reduced pressure to afford the desired acid chloride (1.4 g). This material was stored in the freezer. Η-NMR (300 MHz, CDCls) δ (ppm): 1.05-1.30 (m, 3H), 1.61-1.64 (d, 9H), 2.25-2.60 (m, 2H), 6.40- 7.50 (m, 10H).
Example 73:
Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- diethylcarbamoylmethyl ester (Compound 7-4 of Table 7) Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyl- oxy]-chlorocarbonylmethyl ester (0.10 g, 0.2 mmol) was dissolved in THF (10 mL).
Diethylamine (0.04 mL, 0.4 mmol) was added, followed by addition of DIEA (0.07 mL, 0.4 mmol). The resulting mixture was stirred at room temperature for 1 h.
Reaction was monitored by TLC. The solvent was removed under reduced pressure, and the crude product was purified by sihca gel chromatography (80:20 hexane/ethyl acetate) affording 60 mg of the desired product. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 74: Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]-
(bis-benzyloxyphosphorylmethoxycarbonyl)methyl ester (Compound 7-5 of Table 7) The title compound was prepared according to the procedure described in
Example 73 above except for the substitution of hydroxymethyl dibenzyl phosphonate for diethylamine. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 75:
Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy] - methylcarbamoylmethyl ester (Compound 7-6 of Table 7) The title compound was prepared according to the procedure described in
Example 73 above except for the substitution of methylamine for diethylamine. LC/MS was conducted for confirmation of structure and purity (Table 7A). Example 76:
Propionic acid [N,-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- (benzyloxycarbonylmethylcarbamoyl)methyl ester (Compound 7-7 of Table 7) The title compound was prepared according to the procedure described in
Example 73 above except for the substitution of sarcosine benzyl ester for diethylamine. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 77:
Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]-(2- methanesulfanylethoxycarbonyl)methyl ester (Compound 7-8 of Table 7)
The title compound was prepared according to the procedure described in
Example 73 above except for the substitution of 2-methanesulfanylethanol for diethylamine. LC/MS was conducted for confirmation of structure and purity (Table
7A).
Example 78:
Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- phosphonomethoxycarbonylmethyl ester (Compound 7-9 of Table 7)
The title compound was prepared according to the procedure described in
Example 71 above except for the substitution of propionic acid [N'-benzoyl-N-tert- butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]-(bis-benzyloxy-phosphorylmethoxy- carbonyl)-methyl ester for propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chloro- benzoyl)hydrazinocarbonyloxy]benzyloxycarbonylmethyl ester. Η-ΝMR (300 MHz,
CDCls) δ (ppm): 1.10-1.20 (m, 3H), 1.64 (s, 9H), 2.20-2.60 (m, 2H), 4.20-4.60 (bs, 2H),
6.50-7.50 (m, 10H), 7.60-8.00 (bs, 2H).
Example 79: Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]- (carboxymethylmethylcarbamoyl)methyl ester (Compound 7-10 of Table 7)
The title compound was prepared according to the procedure described in Example 71 above except for the substitution of propionic acid [N'-benzoyl-N'-tert- butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy](benzyloxycarbonylmethyl- carbamoyl)methyl ester for propionic acid [N'-benzoyl-N'-tert-butyl-N-(4- chlorobenzoyl)hydrazinocarbonyloxy]benzyloxycarbonylmethyl ester. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.10-1.20 (m, 3H), 1.62-1.68 (d, 9H), 2.20-2.60 (m, 2H), 2.98 (s, 3H), 4.10-4.50 (m, 2H), 6.50-7.50 (m, 10H).
Examples 80-83:
Z2 acid l-[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy] (7i-butoxycarbonyl)methyl ester (Compounds (7-11) through (7-14) of Table 7)
Compounds (7-ll)-(7-14) were prepared according to the procedure described in Example 70 above except for the substitution of Z2C02H (see Table 7 for definition of Z2) for propionic acid and the substitution of [N-tert-butyl-N-(3,5-dimethyl- benzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinecarbonyloxy]-iodo-acetic acid n- butyl ester for [N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]- iodoacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Examples 84-89: Z2 acid l-[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy] (benzyloxycarbonylmethyl ester (Compounds (7-15) through (7-20) of Table 7)
Compounds (7-15)-(7-20) were prepared according to the procedure described in Example 70 above except for the substitution of Z2C02H (see Table 7 for definition of Z2) for propionic acid and the substitution of [N-te7-t-butyl-N-(3,5-dimethyl- benzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinecarbonyloxy]-iodo-acetic acid benzyl ester for [N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]- iodoacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A). Examples 90-99:
Z2 acid l-[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy] (tert-butoxycarbonyl)methyl ester (Compounds (7-21) through (7-30) of Table 7) Compounds (7-21)-(7-30) were prepared according to the procedure described in Example 70 above except for the substitution of Z2C02H (see Table 7 for definition of Z2) for propionic acid and the substitution of [N-tert-butyl-N-(3,5-dimethyl- benzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinecarbonyloxy] -iodo-acetic acid tert- butyl ester for [N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]- iodoacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Examples 100-105:
Z2 acid l-[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy](tert-butoxycarbonyl)methyl ester (Compounds (7-31) through (7-36) of Table 7)
Compounds (7-31)-(7-36) were prepared according to the procedure described in Example 70 above except for the substitution of Z2Cθ2H (see Table 7 for definition of Z2) for propionic acid and the substitution of [N-tert-butyl-N'-(3,5-dimethyl- benzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinecarbonyloxy] -iodo-acetic acid methyl ester for [N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]- iodoacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 106:
Isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methyl- benzoyl)hydrazinocarbonyloxy(ethoxycarbonylmethyl) ester (Compound 7-37 of Table 7)
Isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester (10.0 mg, 0.0180 mmol) in thionyl chloride (0.5 mL) was heated at 45 °C for 1 h. Then, the excess thionyl chloride was removed in vacuo, ethanol was added, and the reaction was again heated at 45 °C for 1 h. The volatiles were removed in vacuo and the product was purified by sihca gel chromatography. The title compound was obtained as a colorless oil in 73% yield. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 107:
Isobutyric acid N-tert-butyl-N'-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(2-propyloxycarbonylmethyl) ester (Compound 7-38 of Table 7) The title compound was prepared according to the procedure described in
Example 106 above, except isopropanol was substituted for ethanol. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 108: Isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(l-propyloxycarbonylmethyl) ester (Compound
7-39 of Table 7)
The title compound was prepared according to the procedure described in
Example 106 above, except 1-propanol was substituted for ethanol. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Examples 109-111:
Z2 acid [N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy] - (benzyloxycarbonylmethyl ester (Compounds (7-40) through (7-42) of Table 7) Compounds (7-40)-(7-42) were prepared according to the procedure described in Example 70 above except for the substitution of Z2Cθ2H (see Table 7 for definition of Z2) for propionic acid. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 112:
Isobutyric acid l-[N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy] (benzyloxycarbonylmethyl ester (Compound 7- 43 of Table 7) Compound 7-43 was prepared according to the procedure described in Example 70 above except for the substitution of isobutyric acid for propionic acid and the substitution of [N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinecarbonyloxy] -iodo-acetic acid benzyl ester for [N-benzoyl-N- tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]iodoacetic acid benzyl ester. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 113:
Isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methyl- benzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-44 of Table 7) Isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester (148 mg, 0.229 mmol), 10 % palladium on carbon (10-20 mg) and methanol (5 mL) were combined and hydrogenated in a Parr shaker at room temperature under 55 psi hydrogen for 2 h. The catalyst was removed by filtration through Cehte, and evaporation of the solvent from the filtrate afforded the pure product as a colorless oil in 94 % yield. 1H- ΝMR (300 MHz, CDCls) δ (ppm) (mixture of rotational isomers): 1.14 and 1.21 (m, 6H), 1.55 - 1.70 (m, 9H), 1.90 (bs, 3H), 2.09 and 2.25 (two s, 6H), 2.45 and 2.55 (two heptets, IH), 3.76 (m, 3H), 5.0 (bs, IH), 6.49 - 7.25 (m, 7H).
Example 114:
4-Pyrazolecarboxylic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-45 of Table
7) The title compound was prepared according to the procedure described in
Example 113 above, except 4-pyrazolecarboxylic acid N-tert-butyl-N-(3,5- dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy- (benzyloxycarbonylmethyl) ester was substituted for isobutyric acid N-tert-butyl-N- (3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy- (benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.50 - 1.80 (m, 9H), 1.90 (bs, 3H), 2.15 - 2.30 (m, 6H), 3.62 - 3.75 (m, 3H), 6.50 - 7.10 (m, 7H), 7.96 (s, IH), 7.90 (s, IH), 10.30 (bs, 2 H). Example 115:
2-(2-Methoxyethoxy)acetic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy- 2-methylbenzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-46 of Table 7)
The title compound was prepared according to the procedure described in Example 113 above, except 2-(2-methoxyethoxy)acetic acid N-terϊ-butyl-N-(3,5- dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy- (benzyloxycarbonylmethyl) ester was substituted for isobutyric acid N-iert-butyl-N- (3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy-
(benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDC13) δ (ppm): 1.50 - 1.70 (m, 9H), 1.90 (bs, 3H), 2.17 - 2.30 (m, 6H), 3.37 - 3.44 (m, 3H), 3.50 - 3.75 (m, 2H), 3.75 - 3.82 (m, 3H), 4.10 - 4.29 (m, 2 H), 6.67 - 7.05 (m, 7H), 8.10 (bs, IH).
Example 116:
Νicotinic acid N-tert-butyl-N-(3, 5-dimethylbenzoyl)-N-(3-methoxy-2-methyl- benzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-47 of Table 7) The title compound was prepared according to the procedure described in Example 113 above, except nicotinic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester was substituted for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCI3) δ (ppm): 1.59 - 1.72 (m, 9H), 1.90 (bs, 3H), 2.19 - 2.30 (m, 6H), 3.59 - 3.72 (m, 3H), 6.25 - 7.08 (m, 7H), 7.57 - 7.67 (m, IH), 8.36 - 8.61 (m, IH), 8.83 - 8.92 (m, IH), 9.21 - 9.31 (m, IH), 11.70 (bs, 1 H).
Example 117:
4-(Methylsulfanyl)benzoic acid N-tert-butyl-N-(3, 5-dimethylbenzoyl)-N-(3-methoxy- 2-methylbenzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-48 of Table 7)
The title compound was prepared according to the procedure described in Example 113 above, except 4-(methylsulfanyl)benzoic acid N-tert-butyl-N-(3,5- dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy- (benzyloxycarbonylmethyl) ester was substituted for isobutyric acid N-tert-butyl-N- (3,5-dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy- (benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.55 - 1.71 (m, 9H), 1.90 (bs, 3H), 2.16 - 2.33 (m, 6H), 3.09 (s, 3H), 3.62 - 3.74 (m, 3H), 6.45 - 7.08 (m, 7H), 8.03 - 8.29 (m, 4H), 9.40 (bs, 1 H).
Example 118:
Decanoic acid V-tert-butyl-N'-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methyl- benzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-49 of Table 7) The title compound was prepared according to the procedure described in
Example 113 above, except decanoic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester was substituted for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCls) δ (ppm) (mixture of rotational isomers): 0.86 - 0.90 (m, 3H), 1.26 (bs,
14H), 1.58 - 1.71 (m, 9H), 1.90 (bs, 3H), 2.15 - 2.45 (m, 2H), 2.24 and 2.28 (two s, 6H), 3.70 - 3.85 (m, 3H), 6.63 - 7.10 (m, 7H), 8.80 (bs, IH).
Example 119: Trimethylacetic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methyl- benzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-50 of Table 7) The title compound was prepared according to the procedure described in Example 113 above, except trimethylacetic acid N-tert-butyl-N'-(3,5- dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(benzyloxy— carbonylmethyl) ester was substituted for isobutyric acid N-tert-butyl-N-(3,5- dimethylbenzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy (benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.12 - 1.29 (m, 9H), 1.55 - 1.70 (m, 9H), 1.90 (bs, 3H), 2.20 - 2.27 (m, 6H), 3.70 - 3.85 (m, 3H), 6.61 - 7.10 (m, 7H), 8.05 (bs, IH).
Example 120:
Acetic acid N-tert-butyl-N-(3, 5-dimethylbenzoyl)-N-(3-methoxy-2-methyl- benzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-51 of Table 7) The title compound was prepared according to the procedure described in Example 113 above, except acetic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester was substituted for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCls) δ (ppm) (mixture of rotational isomers): 1.62 and 1.65 (two s, 9H), 1.90 (bs, 3H), 1.99 and 2.05 (two s, 3H), 2.28 and 2.30 (two s, 6H), 3.75 (s, SR), 6.63 and 6.72 (two s, 1 H), 6.74 - 7.10 (m, 6H), 8.88 (bs, IH).
Example 121:
2-Methylpropionic acid N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-52 of Table 7)
The title compound was prepared according to the procedure described in Example 113 above, except for the substitution of 2-methylpropionic acid N-benzoyl- N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(benzyloxycarbonyl)methyl ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCI3) δ (ppm) (mixture of rotational isomers): 1.17 (m, 6H), 1.63 and 1.64 (two s, 9H), 2.60 (m, IH), 6.40 - 6.80 (m, 3H), 7.00 - 7.40 (m, 7H), 8.40 (bs, IH).
Example 122: tert-Butoxycarbonxylpiperidine-4-carboxylic acid N-benzoyl-N-tert-butyl-N-(4- chlorobenzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-53 of Table
7). The title compound was prepared according to the procedure described in
Example 113 above, except for the substitution of tert-butoxycarbonylpiperidine-4- carboxylic acid N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy- (benzyloxycarbonyl)methyl ester for isobutyric acid N-tert-butyl-N-(3,5-dimethyl- benzoyl)-N-(3-methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonyl- methyl) ester. Η-ΝMR (300 MHz, CDCI3) δ (ppm) (mixture of rotational isomers):
1.46 and 1.47 (two s, 9H), 1.62 and 1.64 (two s. 9H), 1.90 (bs, 2H), 2.40 - 2.60 (m, IH), 2.90 (m, 2H), 3.95 and 4.20 (bs, 4H), 6.40 - 6.80 (m, 3H), 7.10 - 7.40 (m, 7H). Example 123:
N-Acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-54 of Table 7) The title compound was prepared according to the procedure described in
Example 113 above, except for the substitution of N-acetyl-N-methylaminoacetic acid N-benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(benzyloxy- carbonyl)-methyl ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester, ■ and ethyl acetate was substituted for methanol. Η-ΝMR (300 MHz, CDCls) δ (ppm) (mixture of rotational isomers): 1.62 and 1.64 (two s, 9H), 2.18 and 2.21 (two s, 3H), 3.09 and 3.11 (two s, 3H), 3.96 - 4.39 (m, 2H), 6.54 - 6.69 (m, 2H), 6.66 and 6.73 (two s, IH), 7.01 - 7.37 (m, 8H).
Example 124:
2, 2 -Dimethylpropionic acid N - tert-butyl-N-benzoyl-N- (4-chlorobenzoyl) - hydrazinocarbonyloxy(carboxymethyl) ester (Compound 7-55 of Table 7)
The title compound was prepared according to the procedure described in Example 113 above, except for the substitution of 2,2-dimethylpropionic acid N- benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy(benzyloxycarbonyl)- methyl ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy- 2-methylbenzoyl)hydrazinocarbonyloxy(benzyloxycarbonylmethyl) ester. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.24 (s, 9H), 1.64 (s, 9H), 6.20-7.50 (m, 10H).
Example 125:
Isopropylammonium, {2-[N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy] -2-propionyloxyacetoxy}methanephosphonate (Compound 7-56 of Table 7)
Propionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)-hydrazino- carbonyloxy]phosphonomethoxycarbonylmethyl ester (60 mg, 0.10 mmol) was dissolved in acetone. Isopropylamine (9 μl, 0.10 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. Acetone was then removed, and the resulting precipitate was washed several times with ether, then dried under vacuum, affording the title compound as a white foam. Η-NMR (300 MHz, CDCI3) δ (ppm) (mixture of rotational isomers): 1.00 - 1.30 (m, 9H), 1.59 and 1.60 (two s, 9H), 2.15 - 2.45 (m, 2H), 3.20 (m, IH), 4.10 - 4.35 (m, 2H), 6.40 - 6.80 (m, 3H), 7.10 - 7.40 (m, 7H).
Example 126:
2,2-Dimethylpropionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino- carbonyloxy]-(bis-benzyloxyphosphorylmethoxycarbonyl)methyl ester (Compound 7- 57 of Table 7) The title compound was prepared according to the procedure described in
Example 106 above, except for the substitution of 2,2-dimethylpropionic acid N-tert- butyl-N-benzoyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of hydroxymethyl dibenzyl phosphonate for ethanol. Η-ΝMR (300 MHz, CDCls) δ
(ppm) (mixture of rotational isomers): 1.21 and 1.26 (two s, 9H), 1.62 (s, 9H), 4.30 - 4.55 (m, 2H), 5.00 - 5.20 (m, 4H), 6.50 - 6.80 (m, 3H), 7.00 - 7.40 (m, 15H).
Example 127: 2,2-Dimethylpropionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino- carbonyloxy] - [(benzyloxycarbonylmethyl)(methyl)carbamoyl)methyl ester (Compound 7-58 of Table 7)
The title compound was prepared according to the procedure described in Example 106 above, except for the substitution of 2,2-dimethylpropionic acid N-tert- butyl-N-benzoyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of methylaminoacetic acid benzyl ester for ethanol. Η-ΝMR (300 MHz, CDCI3) δ (ppm): 1.24 (s, 9H), 1.59 (s, 9H), 2.90 (s, 3H), 3.95 (m, 2H), 5.15 (m, 2H), 6.50-6.80 (m, 3H), 7.00-7.40 (m, 12H). Example 128:
2,2-Dimethylpropionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino- carbonyloxy]-(2-methanesulfanylethoxycarbonyl)methyl ester (Compound 7-59 of Table 7) The title compound was prepared according to the procedure described in
Example 106 above, except for the substitution of 2,2-dimethylpropionic acid N-tert- butyl-N-benzoyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of 2- methanesulfanyl-ethanol for ethanol. Η-ΝMR (300 MHz, CDCls) δ (ppm): 1.20 (s,
9H), 1.63 (s, 9H), 2.92 (s, 3H), 3.35 (m, 2H), 4.70 (m, 2H), 6.50-6.80 (m, 3H), 7.00-7.40 (m, 7H).
Example 129: 2,2-Dimethylpropionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino- carbonyloxy]-[(carboxymethyl)(phosphonomethyl)carbamoyl]methyl ester (Compound
7-60 of Table 7)
The title compound was prepared according to the procedure described in
Example 106 above, except for the substitution of 2,2-dimethylpropionic acid N-tert- butyl-N-benzoyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of phosphonomethyl-aminoacetic acid for ethanol. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 130:
2,2-Dimethylpropionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino- carbonyloxy]-[bis-(2-hydroxymethyl)carbamoyl]methyl ester (Compound 7-61 of Table
7) The title compound was prepared according to the procedure described in
Example 106 above, except for the substitution of 2,2-dimethylpropionic acid N-tert- butyl-N-benzoyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of 2- (2-hydroxyethyl-amino)ethanol for ethanol. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 131:
N-Acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy-(N,N-dimethylcarbamoylmethyl) ester (Compound 7-62 of Table 7) l-[(3-Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride salt (15 mg, 0.078 mmol) was added to N-acetyl-N-methylaminoacetic acid N-tert-butyl-N- benzoyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(carboxymethyl) ester (44 mg, 0. 078 mmol) in CH2CI2 under Ν2 , followed within 15 seconds by the simultaneous addition of DIEA (136 μL, 0. 078 mmol) and dimethylamine (39 μL of a 2.0 M solution in toluene, 0.078 mmol). After 1 h, sihca gel was added, the volatile materials were removed on a rotary evaporator, and the product was purified by silica gel chromatography. The title compound was obtained as a viscous, colorless oil in 9% yield. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 132:
N-Acetyl-N-methylaminoacetic acid N-teri-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy(methoxycarbonyl)methyl ester (Compound 7-63 of Table 7)
To a solution of N-acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl- N-(4-chlorobenzoyl)-hydrazinocarbonyloxy(carboxymethyl) ester (38 mg, 0.068 mmol) in CH2CI2 (1 mL) under Ν2 at room temperature were added, in quick succession and all within a minute, first methanol (30 μL of a 10 v/v % solution in CH2CI2, 0.074 mmol), then 1,3-dicyclohexylcarbodiimide (75 μL of a 1.0 M solution in CH2CI2, 0.075 mmol) and finally 4-pyrrolidinopyridine (37 μL of a 0.18 M solution in CH2CI2, 0.0067 mmol). A white precipitate formed almost immediately. After 17 h, the precipitate was removed by filtration through Cehte, and the crude product was adsorbed onto sihca gel and purified by silica gel chromatography to afford the title compound as a colorless oil in 13% yield. LC/MS was conducted for confirmation of structure and purity (Table 7A). Example 133:
2,2-Dimethylpropionic acid [N'-benzoyl-NJ-tert-butyl-N-(4-chlorobenzoyl)hydrazino- carbonyloxy]-[(carboxymethyl)methylcarbamoyl]methyl ester (Compound 7-64 of Table 7)
The title compound was prepared according to the procedure described in Example 71 above, except for the substitution of 2,2-dimethylpropionic acid N- benzoyl-N-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy-[(benzyloxycarbonyl- methyl)-methylcarbamoyl]methyl ester for propionic acid [N'-benzoyl-N-tert-butyl-N- (4-ehlorobenzoyl)hydrazinocarbonyloxy]benzyloxycarbonylmethyl ester. Η-ΝMR
(300 MHz, CDCls) δ (ppm): 1.17 (s, 9H), 1.63 (s, 9H), 3.00 (s, 3H), 4.20 (m, 2H), 6.50- 6.90 (m, 3H), 7.00-7.40 (m, 7H).
Example 134: 2,2-Dimethylpropionic acid [N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino- carbonyloxyjphosphonomethoxycarbonylmethyl ester (Compound 7-65 of Table 7) The title compound was prepared according to the procedure described in
Example 71 above, except for the substitution of 2,2-dimethylpropionic acid [N'- benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino-carbonyloxy]-(bis- benzyloxyphosphoryl-methoxycarbonyl)methyl ester for propionic acid [N'-benzoyl-N'- tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy]benzyloxycarbonylmethyl ester.
LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 135: Isopropylammonium, {2-[N,-benzoyl-N'-fert-butyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy]-2-(2,2-dimethylpropionyloxy)acetoxy}methanephosphonate
(Compound 7-66 of Table 7)
The title compound was prepared according to the procedure described in
Example 125 above except for the substitution of 2,2-dimethylpropionic acid [N'- benzoyl-NJ-tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxy]phosphonomethoxy- carbonyl-methyl ester for propionic acid [N'-benzoyl-N-tert-butyl-N-(4- chlorobenzoyl)hydrazinocarbonyloxy]phosphonomethoxycarbonylmethyl ester. XH- NMR (300 MHz, CDCls) δ (ppm): 1.17-1.26 (m, 15H), 1.61 (s, 9H), 3.20 (m, IH), 4.10- 4.35 (m, 2H), 6.40-6.80 (m, 3H), 7.10-7.40 (m, 7H).
Example 136: N-Acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy-(2-propyloxycarbonyl)methyl ester (Compound 7-67- of Table 7)
The title compound was prepared according to the procedure described in Example 132 above, except isopropanol was substituted for methanol and the initial addition of reagents was done at 0 °C. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 137:
N-Acetyl-N-methylaminoacetic acid Ν'-tert-butyl-Ν'-benzoyl-Ν-(4-chlorobenzoyl)- hydrazinocarbonyloxy-(2-methoxyethoxycarbonyl)methyl ester (Compound 7-68 of Table 7)
The title compound was prepared according to the procedure described in Example 132 above, except 2-methoxyethanol was substituted for methanol and the initial addition of reagents was done at 0 °C. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 138:
N-Acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy-(2-methylsulfanylethoxycarbonyl)methyl ester (Compound 7-
69 of Table 7) The title compound was prepared according to the procedure described in
Example 132 above, except 2-(methylsulfanyl)ethanol was substituted for methanol and the initial addition of reagents was done at 0 °C. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 139:
N-Acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy-(N-methylcarbamoyl)methyl ester (Compound 7-70 of Table 7) The title compound was prepared according to the procedure described in Example 132 above, except methylamine was substituted for methanol and the initial addition of reagents was done at 0 °C. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 140:
N-Acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy-(N,N-6is-(2-hydroxyethyl)carbamoyl)methyl ester (Compound 7-71 of Table 7) The title compound was prepared according to the procedure described in
Example 132 above, except diethanolamine was substituted for methanol and the initial addition of reagents was done at 0 °C. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 141:
N-Acetyl-N-methylaminoacetic acid N-tert-butyl-N-benzoyl-N-(4-chlorobenzoyl)- hydrazinocarbonyloxy(dibenzyloxyphosphinoylmethoxycarbonyl)methyl ester
(Compound 7-72 of Table 7)
The title compound was prepared according to the procedure described in Example 132 above, except dibenzyl hydroxymethylphosphonate was substituted for methanol and the initial addition of reagents was done at 0 °C. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 142: Trimethylacetic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)-hydrazinocarbonyloxy-(N,N-dimethylcarbamoylmethyl) ester
(Compound 7-73 of Table 7)
Trimethylacetic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)hydrazinocarbonyloxy(carboxymethyl) ester (500 mg, 0.87 mmol) was dissolved in 5 mL of dichloromethane. l-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (170 mg, 0.88 mmol) was added, followed by 0.14 mL (0.88 mmol) of dimethylamine. The reaction was followed by TLC, the organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum. The sample was purified by sihca gel column chromatography over sihca with hexanes:ethyl acetate to afford 310 mg of the title compound. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 143:
Trimethylacetic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)-hydrazinocarbonyloxy-(N,N-diethylcarbamoylmethyl) ester (Compound 7-74 of Table 7) The title compound was prepared according to the procedure described in
Example 106 above, except for the substitution of trimethylacetic acid N-tert-butyl- N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methyl-benzoyl)hydrazinocarbonyloxy- (carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of diethylamine for ethanol. LC/MS was conducted for confirmation of structure and purity (Table 7A).
Example 144:
Trimethylacetic acid N-tert-butyl-N-(3, 5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)-hydrazinocarbonyloxy-[N,N-diisopropylcarbamoylmethyl] ester
(Compound 7-75 of Table 7)
The title compound was prepared according to the procedure described in
Example 106 above, except for the substitution of trimethylacetic acid N-tert-butyl-
N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methyl-benzoyl)hydrazinocarbonyloxy- (carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of diisopropylamine for ethanol. LC/MS was conducted for confirmation of structure and purity (Table 7A). Example 145:
Trimethylacetic acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2- methylbenzoyl)-hydrazinocarbonyloxy(ethylthiocarbonyl)methyl ester (Compound 7- 76 of Table 7) The title compound was prepared according to the procedure described in
Example 106 above, except for the substitution of trimethylacetic acid N-teri-butyl- N-(3,5-dimethylbenzoyl)-N-(3-methoxy-2-methyl-benzoyl)hydrazinocarbonyloxy- (carboxymethyl) ester for isobutyric acid N-tert-butyl-N-(3,5-dimethylbenzoyl)-N-(3- methoxy-2-methylbenzoyl)hydrazinocarbonyloxy(carboxy)methyl ester and the substitution of ethanethiol for ethanol. LC/MS was conducted for confirmation of structure and purity (Table 7A).
For liquid chromatography (LC) / ultraviolet (UV) mass spectrometry (MS) analysis, the samples were dissolved in acetonitrile:water (1:1). Concentrations were 100 μg/mL to 1000 μg/mL. Analysis was performed using LC/UV MS system HPLC 1100-VG Platform. UV and MS were connected in sequence and carried out in one injection where UV afforded purity (%) and MS confirmed molecular weight. UV was carried out using diode array detector (DAD) scanning 200-300 nm. MS was carried out in positive mode scanning 100-1000 daltons. A short C18 HPLC column (3mm ID, 5 cm length) was used with a flow rate of 1 mL/min where the flow was split after UV detection from 1 to 25 in which 1 part went to the MS. Typically, the HPLC gradient began at 25% water: 75% acetonitrile and went to 100% acetonitrile in 5 min in which the mobile phases contained 0.1% formic acid. Injection volume varied between 1 and 25 μL. Similar results should be reproduced with slight variations of HPLC parameters including mobile phase percentages which are allowed to optimize any HPLC system. Variations of UV/MS parameters including ion mode (positive or negative), UV wavelengths, and solvent buffers (no buffer, formic acid, acetic acid, or ammonia acetate) are allowed to optimize the MS system. Any other variations of C- 8 and C-18 columns and instrumentation brand could be used if 0.5 μg/mL (or lower) standard can be analyzed. The data is presented in Table 7A. Table 7A: LC/UV MS data for those compounds in Tables 7 where NMR is not described in the correspondin Exam les.
Figure imgf000153_0001
Figure imgf000154_0002
Following Method A described hereinbefore, the following compound of Formula XXVII as listed in Table 8 was prepared.
Figure imgf000154_0001
XXVII
Table 8: Listing of Compound of Formula XXVII
Cmpd # G20 Q21 Q31 R2 t' d (X3)dZ3 t q (X2)qZ2
8-1 O 0 O H 1 0 2-propyl 1 0 2-propyl
The following Example is provided for guidance to the practitioner in order to practice the invention.
Example 146:
2-Methylpropionic acid (N-methyl-3-phenyl-3-[(4- trifluoromethyl)phenoxy]propylcarbamoyloxy)-(2-propyloxycarbonyl)methyl ester (Compound 8-1 of Table 8)
2-Methylpropanoic acid (chlorocarbonyloxy)-[(l-methylethoxy)carbonyl]methyl ester (Compound 4-12, 28 μL, 0.12 mmol) was added via syringe to a solution of fluoxetine hydrochloride (Sigma Chemical Co., 42.5 mg, 0.123 mmol) and 4- (dimethylamino)pyridine (30.0 mg, 0.246 mmol) in tetrahydrofuran (1.9 mL) at room temperature under N2. The reaction was allowed to stir for 16 h. Then saturated aqueous ammonium chloride was added, the product was extracted into ethyl acetate, the extract was dried over Na2SO4, and the volatiles were removed in vacuo. The crude product was purified by flash chromatography on sihca gel using a hexanes-ethyl acetate gradient. The title compound was isolated cleanly as a pale yellow oil in 74 % yield and consisted of a mixture of diastereomers. Η-NMR (300 MHz, CDCls) δ (ppm): 1.14-1.28 (m, 12H), 2.10-2.32 (m, 2H), 3.53-3.75 (m, IH), 2.93- 2.95 (m, 3H), 3.51 (t, 2H), 5.05-5.17 (m, IH), 5.17-5.27 (m, IH), 6.70-6.75 (four singlets, IH), 6.89 (d, 2H), 7.22-7.36 (m, 5H), 7.42 (d, 2H).
Following Method A described hereinbefore, the following compound of Formula XXIX as hsted in Table 9 was prepared.
Figure imgf000155_0001
XXIX
Table 9: Listing of Compound of Formula XXIX
Cmpd # G20 G2i G3 R2 t' d (X3)dZ3 t q (X2)qZ2
9-1 O O O H 1 0 2-propyl 1 0 2-propyl
The following Example is provided for guidance to the practitioner in order to practice the invention.
Example 147:
2-Methylpropionic acid [(2,4-difluoro-l-phenyl)-6is-(lH-l,2,4-triazol-l- ylmethyl)]methyloxycarbonyloxy-(2-propyloxycarbonyl)methyl ester (Compound 9-1 of Table 9)
Potassium bis(trimethylsilyl)amide (0.327 mL of a 0.5 M solution in toluene, 0.16 mmol) was added via syringe to a solution of fluconazole (Pfizer, 50.5 mg, 0.165 mmol) in tetrahydrofuran (1.5 mL) at -78 °C under N2. The reaction was allowed to stir at -78 °C for 10 min, then at 0 °C for 35 min, at which time 2-methylpropanoic acid (chlorocarbonyloxy)-[(l-methylethoxy)carbonyl]methyl ester (Compound 4-12, 76 μL, 0.16 mmol) was added via syringe. The reaction was allowed to warm slowly to room temperature over 22 h. Then saturated aqueous ammonium chloride was added, the product was extracted into ethyl acetate, the extract was dried over Na2S04, and the volatiles were removed in vacuo. The crude product was purified by flash chromatography on sihca gel using an ethyl acetate-methanol gradient. The title compound was isolated as a pale yellow oil in 40 % yield; unreacted fluconazole was also recovered (28 %). Η-NMR (300 MHz, CDCls) δ (ppm): 1.22-1.25 (m, 6H), 1.28-1.31 (m, 6H), 2.70 (heptet, IH), 5.06-5.24 (m, 5H), 6.73 (s, IH), 6.73-6.81 (m, IH), 6.82-6.96 (m, 2H), 7.85 (s, IH), 7.86 (s, IH), 8.08 (s, IH), 8.12 (s, IH).

Claims

I CLAIM:
1. A compound of the formula
Figure imgf000157_0001
wherein
G10 and Gn are each independently an oxygen atom or a sulfur atom, R! is
Figure imgf000157_0002
wherein G30 is an oxygen atom or a sulfur atom,
G3i is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G3i is an oxygen atom or a sulfur atom,
Z3(X3)d(G3i)t' is a biologically active moiety when d is 1 wherein Z3(X3)d(G3r)t'-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, NR3R4, OR3, S(O)jR3, SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4 wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(0)jR3 or S02NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, or alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, S02NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl or arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaryl or heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SU2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl or heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, or Ri and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring, R3, R4 and R5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl, aralkyl, aralkenyl, aralkynyl, or aryl, aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring, Yi is chloro, bromo, iodo, OCCI3, ORi2, SRi2 or N-hydroxysuccinimide,
Y2 is chloro, bromo, iodo, OCCI3, mesyl or tosyl,
R12 is alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, haloalkyl, haloalkenyl, haloalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkylsulfonyl and arylsulfonyl, aralkyl, aralkenyl, aralkynyl, or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
2. The compound of claim 1 wherein Y1 is chloro, bromo, iodo or SR12.
3. The compound of claim 1 wherein Y1 is chloro, bromo or iodo.
4. The compound of claim 1 wherein Y1 is SR12.
5. The compound of claim 1 wherein R12 is alkyl.
6. The compound of claim 1 wherein Y2 is chloro, bromo or iodo.
7. The compound of claim 1 wherein R2 is a hydrogen atom.
8. The compound of claim 1 wherein d is 0.
9. A compound of the formula
Figure imgf000161_0001
wherein
G10 and G11 are each independently an oxygen atom or a sulfur atom,
R is
G30
C-(G31)t,-(X3)dZ3 wherein
G30 is an oxygen atom or a sulfur atom,
G31 is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G31 is an oxygen atom or a sulfur atom,
Z3(X3)d(G31)f is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologically active compound, Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, (Cι-C2o)alkyl, (Ci- Cιo)alkylcarbonyloxy(Cι-Cιo) alkyl, (Cι-C2o)alkylcarbonyl, hydroxy(Cι-C2o)alkyl, (Ci- Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Cι-C2o)alkyl, (C2- Cιo)alkenyl, acetylamino(C2-Cιo)alkenyl, halo(C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(C2- Cio) alkynyl, cyclo(C3-Cs) alkyl, cyclo(C3-C8)alkenyl, carbόxycyclo(C3-C8)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cι0)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cι0)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- C8)alkyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, carboxycyclo(C3- Cβ) alkyl(C2- C io) alkynyl, carboxy cyclo(C3- Cs) alkenyl(C2- C io) alkynyl, heterocyclyl, heterocyclyl(C 1- C 10) alkyl, heterocyclyl(C2- C 10) alkenyl, heterocyclyl(C2- C 10) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Ci- C io) alkoxy (C2- C 10) alkenyl, (C 1- C 10) alkoxy (C2- C io) alkynyl, (C 1- C IQ) alkoxycarbonyl(C 1- Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-
Cιo)alkynyl, halo(Cι-Cιo)alkoxy(Cι-Cιo)alkyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkenyl, halo(C1-Cιo)alkoxy(C2-Cι0)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2- Cιo)alkenyl, (Cι-CiQ)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, NR3R4, OR3, S(0)jR3,
SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, (Cι-Cιo)alkyl, (Cι-Cιo)alkylsulfonyl(Cι- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo) alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Cι-Cι0)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι- Cι0)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cιo)alkyl, cycloalkyl, (C2-C1Q) alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (C1-C10) alkoxy, halo(Cι- Cι0)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Ci- Cι0)alkyl, (C2-Cιo)alkenyl, (C2-Cι0)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cι0)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)aIkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(C1-Cιo)alkoxy, S02NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R )-N=CR3R4, S(0)jR3 or S02NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, (Ci-C2o)alkyl, (C2-Cιo)alkenyl, (C2-C10) alkynyl, (Ci- Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cιo)alkenyl; (Cι-Cιo)alkylthio(C2- Cι0)alkynyl, carboxy, a carboxylate salt, carboxy(Ci-C20)alkyl, carboxy(C2-C2o)alkenyl, carboxy (C2- C20) alkynyl, (C _.- C20) alkoxycarbonyl, (C 1- C 10) alkoxycarbonyl(C 1- C 10) alkyl, (Cι-Cιθ)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cι0)alkynyl, (Ci- C20) alkylcarbonyl, (C2-C2o) alkenylcarbonyl, (C2-C20) alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3- Cs) alkyl(C2- C 10) alkynyl, cyclo(C3- Cβ) alkenyl(C2- C 10) alkynyl, heterocyclyl, heterocyclyl(Cι-Cι0)alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2-Cιo)alkynyl, or (Cι-C2o)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl] (Ci- Cιo)alkoxy(C2-Cιo)alkenyl, (Ci-Ci0)alkoxy(C2-Ci0)alkynyl, (Cι-Cιo)alkylthio(Cι- Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl) carboxy(Cι-C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-C 10) alkynyl, (Ci- C2o)alkoxycarbonyl, (Cι-Cι0)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2- Cιo)alkenyl, (Cι-Cι0)alkoxycarbonyl(C2-Cιo)alkynyl, (Cι-C2o)alkylcarbonyl, (C2-
Cιo)alkenylcarbonyl, (C2-C 10) alkynylcarbonyl, cyclo(C3-Cs)alkyl, cyclo(C3-C8)alkenyl, cyclo(Cs-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-Cs)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3- Cβ) alkenyl(C2- C IQ) alkynyl, heterocyclyl, heterocyclyl(C ι - C IQ) alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cι0)alkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, Sθ2NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, (Cι-Cι0)alkyl, (C2-C 10) alkenyl, (C2-C1Q) alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo) alkoxy, carboxy, (Ci- C4)alkoxycarbonyl, SO2NR3R4 and NR3R4, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2- Cιo)alkynyl, or ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cι0) alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-
Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2-Cιo)alkynylcarbonyl or arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2- Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, (Ci- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4, heteroar(Cι-
Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, heteroar(Cι-Cιo)alkylcarbonyl, heteroar(C2-Cι0)alkenylcarbonyl, heteroar(C2-Cιo)alkynylcarbonyl or heteroar(Cι- C 10) alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cι0) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy,
S02NR3R4 and NR3R4, or Ri and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring,
R3, R4 and R5 are each independently a hydrogen atom, (Cι-C2o)alkyl, cyclo(C3- Cs)alkyl. cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-Cs)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl; cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cι0)alkenyl, carboxy(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2-C 10) alkynyl, (Cι-Cιo)alkoxy(Cι-C10)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, or (Cι-Cιc)alkyl, cyclo(C3- C8)alkyl, cyclo(Cs-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkylJ cyclo(Cs-C8)alkyl(C2- Cι0)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cι0)alkynyl, heterocyclyl, heter ocyclyl(C ι - C io) alkyl, he terocyclyl(C2- C io) alkenyl, heterocyclyl(C2- C io) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-Cιo)alkenyl or (C2-Cιo)alkynyl substituted with one or more halo, aryl, ar(Cι-Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo)alkynyl or aryl, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Ci-Cio) alkyl, (C2-Cιo)alkenyl, (C2-
Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιc)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocychc ring,
Y1 is chloro, bromo, iodo, OCCI3, OR12, SRi2 or N-hydroxysuccinimide, Y2 is chloro, bromo, iodo, OCCI3, mesyl or tosyl,
R12 is (Cι-C20)alkyl, cyclo(Cs-C8)alkyl, cyclo(Cs-C8) alkenyl, cyclo(Cs-C8)alkyl(C1- Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cι0)alkenyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxy(Cι-C2o)alkyl, car boxy (C2-C20) alkenyl, carboxy(C2-C2o) alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-C2o)alkenyl, (C2-C2o)alkynyl, or (Ci- C20)alkyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8) alkyl(C2-C 10) alkenyl, cyclo(C3- Cβ) alkyl(C2- C IQ) alkynyl, cyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxy(Cι-C20) alkyl, carboxy (C2-C20) alkenyl, carboxy(C2-C2o)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2- Cι0)alkynyl, (Cι-Cιθ)alkoxy(Cι-Cιo)alkyl, (C2-C2o)alkenyl or (C2-C2 )) alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, halo(Cι-Cιo)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cι0)alkynyl, (Cι-Cι0)alkylcarbonyl, (C2-C10) alkenylcarbonyl, (C2- Cιo)alkynylcarbonyl, arylcarbonyl, (Cι-Cιo)alkylsulfonyl and arylsulfonyl, ar(Cι- Cιo)alkyl, ar(C2-C 10) alkenyl, ar(C2-Cιo)alkynyl, or ar(Cι-Cι0)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo) alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-C10) alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cι0)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroaryl, heteroar(Cι-Cι0)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cι0)alkoxy and halo(Cι-Cι0)alkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
10. The compound of claim 9 wherein Y1 is chloro, bromo, iodo or SR12.
11. The compound of claim 9 wherein Y1 is chloro, bromo or iodo.
12. The compound of claim 9 wherein Y1 is SRi2.
13. The compound of claim 9 wherein Ri2 is (Cι-Cι0)alkyl.
14. The compound of claim 9 wherein Y2 is chloro, bromo or iodo.
15. The compound of claim 9 wherein R2 is a hydrogen atom.
16. The compound of claim 9 wherein d is 0.
17. A compound of the formula »10
R' G ~2200
I I
Y 11 — c " — G11 — c- -(G21-C)t-(X2)qZ2
wherein
G10, G11 and G20 are each independently an oxygen atom or a sulfur atom, G21 is an oxygen atom, a sulfur atom or NR3, q and t are each independently 0 or 1,
R is
Figure imgf000167_0001
wherein
G30 is an oxygen atom or a sulfur atom, G3i is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t1 is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G3i is an oxygen atom or a sulfur atom,
Z3(X3)d(G3X)t' is a biologically active moiety when d is 1 wherein Z3(X3)d(G3X)t'-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, NR3R4, OR3, S(0)jR3, SiR3R R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3 4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4 S(0)JR3 or S02NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, or alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, "heterocyclylalkenyl, heterocyclylalkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, S02NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, SO2NR3 4 and NR3R4, aralkyl, aralkenyl, aralkynyl or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl or arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaryl or heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl or heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, or R1 and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring, R3, R4 and R5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl, aralkyl, aralkenyl, aralkynyl, or aryl, aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring, X2 is an oxygen atom, a sulfur atom, a phosphorous atom, a nitrogen atom or a carbon atom attached to Z2,
Z2(X2)q(C(=G20)G2i)t is a biologically active moiety when q is 1 wherein
Figure imgf000170_0001
represents the biologically active compound, Z (X2)q is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, NR3R4, SO2NR3R4, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, dialkoxyphosphorylalkyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkj , alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3 4 and NR3R4, alkylcarbonylalkyl, alkenylcarbonylalkyl, alkynylcarbonylalkyl, heterocyclylcarbonyl, heterocyclylcarbonylalkyl, heterocyclyloxycarbonylalkyl, arylcarbonyl, arylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl, aroxycarbonylalkyl, aralkoxycarbonylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaroxycarbonylalkyl, or arylcarbonyl, arylcarbonylalkyl, aralkylcarbonyl, aralkylcarbonylalkyl, aroxycarbonylalkyl, aralkoxycarbonylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, heteroaroxycarbonylalkyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, and C(=N-G22)R2 when q is 0 and t is 1, G22 is OR3, OCOR3, S(0)jR3, OS(0)jR3, NR3R4, OS02NR3R4, OP(=0)OR3NR3R4,
OP(=O)(OR3)2 or N=CR3R4, j is 0, 1 or 2,
Z2(X2)q is halo, NR3R4, {(NR3R4R5)+ M"}, OR3, S(0)jR3 or S02NR3R4 when both q and t are 0 wherein M" is halo, hydroxy, alkoxy or the anion of a carboxylic acid and j is 0, 1 or 2,
Yi is chloro, bromo, iodo, OCCI3, OR 2, SR12 or N-hydroxysuccinimide, R12 is alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, haloalkyl, haloalkenyl, haloalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, alkylsulfonyl and arylsulfonyl, aralkyl, aralkenyl, aralkynyl, or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
18. The compound of claim 17 wherein Y1 is chloro, bromo, iodo or SRi2.
19. The compound of claim 17 wherein Y1 is chloro, bromo or iodo.
20. The compound of claim 17 wherein Y1 is SR 2.
21. The compound of claim 17 wherein Ri2 is alkyl.
22. The compound of claim 17 wherein R2 is a hydrogen atom except when a part of the C(=N-G2 )R2 moiety, wherein said C(=N-G22)R2 moiety, R2 is as previously defined.
23. The compound of claim 17 wherein d is 0.
24. The compound of claim 17 wherein q is 0.
25. The compound of claim 17 wherein (d + q) is 1 or 2.
26. The compound of claim 17 wherein t is 1.
27. A compound of the formula
G10
Y C II G11 ? C — (G21- tC)t°— (X2)qZ2
R2 wherein
G10, Gn an(\ G20 are each independently an oxygen atom or a sulfur atom, G21 is an oxygen atom, a sulfur atom or NR3, q and t are each independently 0 or 1, R! is
Figure imgf000173_0001
wherein
G30 is an oxygen atom or a sulfur atom,
G3X is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G3X is NR3, or a carbon atom attached to Z3 when t' is 1 and G3i is an oxygen atom or a sulfur atom,
Z3(X3)d(G3i)f is a biologically active moiety when d is 1 wherein Z3(X3)d(G3i)t'-H represents the biologically active compound, Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, (Cι-C2o)alkyl, (Ci-
Cι0)alkylcarbonyloxy(Cι-Cιo)alkyl, (Ci-C2o)alkylcarbonyl, hydroxy(Cι-C2o)alkyl, (Ci- Cι0)alkylsulfonyl(Cι-Cι0)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Cι-C2o)alkyl, (C2- Cιo)alkenyl, acetylamino(C2-C 10) alkenyl, halo(C2-Cι0)alkenyl, (C2-Cι0)alkynyl, halo(C2- Cιo)alkynyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, carboxycyclo(C3-C8)alkyl, carboxycyclo(C3-C8) alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-Cs)alkyl(C2- Cι0)alkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-Ca)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- C8)alkyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkyl(C2-Cι0)alkenyl, carboxycyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)alkyl(C2-Cιo) alkynyl, carboxycyclo(C3-Cs)alkenyl(C2-CiQ)alkynyl, heterocyclyl, heter ocy clyl(Cι- C 10) alkyl, heterocyclyl(C2- C 10) alkenyl, heterocyclyl(C2- C io) alkynyl, (Cι-Cιo)alkoxy(Cι-Cι0)alkyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Ci- Cι0)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cι0)alkynyl, (Cι-Cιo)alkoxycarbonyl(Cι- Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2- Cιo)alkynyl, halo(Cι-Cι0)alkoxy(Cι-Cιo)alkyl, halo(Cι-Cιo)alkoxy(C2-Cι0)alkenyl, halo(Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2- Cιo)alkenyl, (Cι-Cι0)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-Cι0)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι-Cι0)alkylthio(C2-Cι0)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo) alkynyl, NR3R4, OR3, S(0)jR3,
SiR3R R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, (Cι-Cι0)alkyl, (Cι-Cιo)alkylsulfonyl(Cι- Cι0)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo (Ci-Cio) alkoxy, S02NR3R4 and NR3R4, ar(Cι- Cιo)alkyl, ar(C2-Cιo) alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Ci-Cιo) alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo) alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι- Cιo)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cιo)alkyl, cycloalkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo) alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cι0)alkoxy, halo(Cι- Cι0)alkoxy, Sθ2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Ci- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroar(Cι-Cι0)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cι0)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cι0)alkoxy, S02NR3R4 and NR3R4, wherein j is 0, 1 or 2, Z3(X3)d is halo, NR3R4 OR3, N(R3)-N=CR3R4 S(0)jR3 or SO2NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, (Cι-C2o)alkyl, (C2-Cιo)alkenyl, (C2-Cιo) alkynyl, (Ci- Ci0)alkoxy(Ci-Ci0)alkyl, (Cι-Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cι0)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2- Cιo)alkynyl, carboxy, a carboxylate salt, carboxy(Cι-C2o)alkyl, carboxy(C2-C2o)alkenyl, carboxy(C2-C2o)alkynyl, (Cι-C2o)alkoxycarbonyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkynyl, (Ci- C20) alkylcarbonyl, (C2-C2o)alkenylcarbonyl, (C2-C20) alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cι0)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cι0)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3- Cβ) alkyl(C2- C 10) alkynyl, cyclo(C3- Cs) alkenyl(C2- C 10) alkynyl, heterocyclyl, heterocycryl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, or (Cι-C20)alkyl, (C2-CIQ) alkenyl, (C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιθ)alkyl, (Ci- Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι- Cιo)alkyl, (Cι-Cιo)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, carboxy(Cι-C2o)alkyl, carboxy(C2-Cι0) alkenyl, carboxy(C2-Cιo)alkynyl, (Ci- C20) alkoxycarbonyl, (C 1- C 10) alkoxycarbonyl(C 1- C IQ) alkyl, (C 1- C 10) alkoxycarbonyl(C2- Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkynyl, (Cι-C2o)alkylcarbonyl, (C2-
Cιo)alkenylcarbonyl, (C2-C 10) alkynylcarbonyl, cyclo(C3-Cs)alkyl, cyclo(C3-Cs) alkenyl, cyclo(Cs-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(Cι-CiQ)alkyl, cyclo(Cs-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(C_.-Cιo)alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, S02NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, (Ci-C 10) alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cι0)alkynyl, (Cι-C10)alkoxy, halo(Cι-Cι0)alkoxy, carboxy, (Ci- C4)alkoxycarbonyl, SO2NR3R4 and NR3R4, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2- Cιo)alkynyl, or ar(Cι-Cι0)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cι0)alkyl, (C2- Cι0)alkenyl, (C2-Cι0) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cι0)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2-Cιo)alkynylcarbonyl or arylcarbonyl, ar(Cι-Cι0)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2- Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Ci-C 10) alkyl, (C2-C 10) alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, Sθ2N 3 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, (Ci- Cιo)alkyl, (C2-Cι0)alkenyl, (C2-C10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cι0)alkoxy, halo(Cι-Cι0)alkoxy and NR3R4, heteroar(Cι-
Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cι0)alkynyl or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cι0)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cι0)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci- Cι0)alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, heteroar(Cι-Cιo)alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cι0)alkynylcarbonyl or heteroar(Cι- Cι0)alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, (Cι-Cιo)alkyl, (C2-Cι0)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy,
Sθ2NR3R4 and NR3R4, or Ri and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring,
R3, R4 and R5 are each independently a hydrogen atom, (Cι-C20)alkyl, cyclo(C3- C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(Cs-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cι0)alkenyl, cyclo(Cs-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cι0)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C20)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-C 10) alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, (Cι-Cι0)alkoxy(Cι-Cι0)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, or (Cι-Cι0)alkyl, cyclo(C3- C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(Cs-C8)alkyl(Cι-CiQ)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-Cs)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cι0)alkyl, (C2-C 10) alkenyl or (C2-Cιo)alkynyl substituted with one or more halo, aryl, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo) alkynyl or aryl, ar(Cι- Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cι0) alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-C 10) alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Ci-Cio) alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cι0)alkynyl, (CI-CIQ) alkoxy and halo(Cι-Cι0)alkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocychc ring,
X2 is an oxygen atom, a sulfur atom, a phosphorous atom, a nitrogen atom or a carbon atom attached to Z2,
Figure imgf000177_0001
is a biologically active moiety when q is 1 wherein
Figure imgf000177_0002
represents the biologicaUy active compound,
Z2(X2)q is a hydrogen atom, (Cι-C2o)alkyl, (Cι-Cιo)alkylcarbonyloxy(Cι- Cιo)alkyl, (C1-C20) alkylcarbonyl, (Cι-C2α)alkenylcarbonyl, (Ci-C2o)alkynylcarbonyl, hydroxy(Cι-C2o)alkyl, (Cι-Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Cι-C2o)alkyl, (C2-C2o)alkenyl, halo(C2-C20)alkenyl, acetylamino(C2-Cιo)alkenyl, (C2-C20) alkynyl, halo(C2-C o)alkynyl, cyclo(C3-Cs) alkyl, cyclo(C3-C8)alkenyl, carboxycyclo(C3-C8)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cι0)alkyl, cyclo(C3-C3)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-
C8)alkenyl(C2-Cι0)alkenyl, cyclo(C3-C8)alkyl(C2-Cι0)alkynyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxycyclo(C3-C8)alkyl(Cι-Cι0)alkyl, carboxy(C3-C8)cycloalkyl(C2- Cι0)alkenyl, carboxycyclo(C3-C8)alkenyl(Cι-Cι0)alkyl, carboxycyclo(C3-C8)alkenyl(C2- Cιo)alkenyl, carboxycyclo(C3-C8)alkyl(C2-Cιo)alkynyl, carboxycyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cι0) alkyl, heterocyclyl(C2-Cι0)alkenyl, heterocyclyl(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-C5)alkoxy(Cι- C5)alkoxy(Cι-Cιo)alkyl, (Cι-Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cι0)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Ci- Cιo)alkoxycarbonyl(C2-Cι0)alkynyl, halo(Cι-Cιθ)alkoxy(Cι-Cιo)alkyl, halo(Cι- Cιo)alkoxy(C2-Cιo)alkenyl, halo(Cι-Cιo)alkoxy(C2-C10)alkynyl, (Cι-Cιo)alkylthio(Cι- Cιo)alkyl, (Cι-Cι0)alkylthio(C2-C10)alkenyl, (Cι-Cι0)alkylthio(C2-Cιo)alkynyl, halo(Cι- Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι- Cι0)alkylthio(C2-Cιo)alkynyl, S02NR3R4, NR3R4, carboxy(Cι-C2o)alkyl, carboxy(C2- C2o)alkenyl, carboxy (C2-C20) alkynyl, di(Cι-Cιo)alkoxyphosphoryl(Cι-Cιo)alkyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, (Cι-Cιo)alkyl, (Cι-Cιo)alkylsulfonyl(Cι-Cιo)alkyl, (Ci- C 10) alkylsulfonyl, thiocyanato, (C2-C1Q) alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, • S02NR3R4, and NR3R4 ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2- Cιo)alkynyl, arcyclo(C3-Cs) alkyl, aroxy(Cι-Cιo)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cι0)alkyl, cyclo(C3-C8)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-
Cιo)alkenyl, halo(C2-Cι0)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-Cι0)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-C10)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4 heteroar(Cι-C10)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cι0)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cι0)alkyl, (C2-Cιo)alkenyl, (C2-C10)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo) alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, (Ci- C 10) alkylcarbonyl(C 1- C IQ) alkyl, (C2- C 10) alkenylcarbonyl(C 1- C 10) alkyl, (C2- Cιo)alkynylcarbonyl(Cι-Cιo)alkyl, heterocyclylcarbonyl, heterocyclylcarbonyl(Cι- Cιo)alkyl, heterocyclyloxycarbonyl(Cι-Cι0)alkyl, arylcarbonyl, arylcarbonyl(Cι- Cι0)alkyl, ar(C_.-Cι0)alkylcarbonyl, ar(Cι-Cιo)alkylcarbonyl(Cι-Cιo)alkyl, aroxycarbonyl(Cι-Cιo)alkyl, ar(Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, heteroarylcarbonyl, heteroarylcarbonyl(Cι-Cιo)alkyl, heteroaroxycarbonyl(Cι- Cιo)alkyl, or arylcarbonyl, arylcarbonyl(Cι-Cι0)alkyl, ar(Cι-Cιo)alkylcarbonyl, ar(Cι- Cιo)alkylcarbonyl(Cι-Cι0)alkyl, aroxycarbonyl(Cι-Cι0)alkyl, ar(Cι- Cι0)alkoxycarbonyl(Cι-Cιo)alkyl, heteroarylcarbonyl, heteroarylcarbonyl(Cι-Cιo)alkyl, heteroaroxycarbonyl(Cι-Cιo)alkyl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, (Cι-Cι0)alkyl, (C2- Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, and C(=N- G22)R2 when q is 0 and t is 1,
G22 is OR3, OCOR3, S(0),R3, OS^ 3, NR3R4, OS02NR3R4, OP(=0)OR3NR3R4, OP(=0)(OR3)2 or N=CR3R4, j is 0, 1 or 2,
Z2(X2)q is halo, NR3R4, {(NR3R RS)+ M"}, OR3, S(0)3R3 or S02NR3R4 when both q and t are 0 wherein M~ is halo, hydroxy, (Cι-Cs)alkoxy or the anion of a carboxylic acid and j is 0, 1 or 2,
Y1 is chloro, bromo, iodo, OCCI3, OR12, SRi2 or N-hydroxysuccinimide, R12 is (Cι-C20)alkyl, cyclo(Cs-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-
Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cι0)alkynyl, cyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-Cs)alkenyl(C2- Cιc)alkynyl, carboxy(Cι-C20)alkyl, carboxy(C2-C20)alkenyl, carboxy(C2-C2o)alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-C 10) alkenyl, heterocyclyl(C2- Cι0)alkynyl, (Cι-Cιo)alkoxy(Cι-Cι0)alkyl, (C2-C2o) alkenyl, (C2-C20) alkynyl, or (Ci- C2o)alkyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cι0)alkyl, cyclo(C3-C8)alkyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3- C8)alkenyl(Cι-Cι0)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2- Cιo)alkynyl, carboxy(Cι-C2o) alkyl, carboxy(C2-C2o) alkenyl, carboxy (C2-C20) alkynyl, heterocyclyl, he terocyclyl(Cι-Cιo) alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-
Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C -C2o)alkenyl or (C2-C2o)alkynyl substituted with one or more halo, aryl or aryl substituted with one or more substituents independently selected from halo, nitro, cyano, halo(Cι-Cιo)alkyl, halo(C2-CiQ)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkylcarbonyl, (C2-Cιo)alkenylcarbonyl, (C2- Cιo)alkynylcarbonyl, arylcarbonyl, (Ci-C 10) alkylsulfonyl and arylsulfonyl, ar(Cι-
Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-C 10) alkynyl, or ar(Cι-Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C1Q) alkynyl, halo(Cι-Cι0)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cι0)alkynyl, (CI-CIQ) alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cι0)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cι0)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2- Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cι0)alkenyl, halo(C2- Cι0)alkynyl, (Cι-Cι0)alkoxy and halo(Cι-Cιo)alkoxy, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
28. The compound of claim 27 wherein Y1 is chloro, bromo, iodo or SR12.
29. The compound of claim 27 wherein Y1 is chloro, bromo or iodo.
30. The compound of claim 27 wherein γι is SRi2.
31. The compound of claim 27 wherein Ri2 is (Cι-Cιo)alkyl.
32. The compound of claim 27 wherein R2 is a hydrogen atom except when a part of the C(=N-G22)R2 moiety, wherein said C(=N-G22)R2 moiety, R2 is as previously defined.
33. The compound of claim 27 wherein d is 0.
34. The compound of claim 27 wherein q is 0.
35. The compound of claim 27 wherein (d + q) is 1 or 2.
36. The compound of claim 27 wherein t is 1.
37. A compound of the formula
Figure imgf000180_0001
wherein
G10 and Gu are each independently an oxygen atom or a sulfur atom, m is 0 or 1, Ri is
C-(G31)t,-(X3)dZ3 wherein
G30 is an oxygen atom or a sulfur atom, G3i is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t' is 1 and G31 is NR3, or a carbon atom attached to Z3 when t' is 1 and G3i is an oxygen atom or a sulfur atom,
Z3(X3)d(G31)f is a biologically active moiety when d is 1 wherein Z3(X3)d(G3r)t'-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, NR3R4, OR3, S(O)jR3, SiR3R R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X )d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(0)jR3 or SO2NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxy, a carboxylate salt, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, or alkyl, alkenyl, alkynyl, alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, SO2NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, Sθ2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl or aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl or arylcarbonyl, aralkylcarbonyl, aralkenylcarbonyl, aralkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, heteroaryl or heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl or heteroaralkylcarbonyl, heteroaralkenylcarbonyl, heteroaralkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, S02NR3R4 and NR3R4, or Rx and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring,
R3, R4 and R5 are each independently a hydrogen atom, alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl, alkynyl, or alkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkenylalkynyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkenyl or alkynyl substituted with one or more halo, aryl, aralkyl, aralkenyl, aralkynyl, or aryl, aralkyl, aralkenyl, aralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaryl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy and haloalkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring, χι is an oxygen atom, a sulfur atom, a phosphorous atom or a nitrogen atom attached to Z1, Z1^1^ is a biologically active moiety when m is 1 wherein Zi(Xi)m-H represents the biologically active compound,
Zi(Xi)m, when m is 0, is a hydrogen atom, halo, alkyl, alkylcarbonyloxyalkyl, alkylcarbonyl, hydroxyalkyl, alkylsulfonylalkyl, acetylaminoalkyl, haloalkyl, alkenyl, acetylaminoalkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkenyl, carboxycycloalkyl, carboxycycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenylalkyl, cycloalkenylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, carboxycycloalkylalkyl, carboxycycloalkylalkenyl, carboxycycloalkenylalkyl, carboxycycloalkenylalkenyl, carboxycycloalkylalkynyl, carboxycycloalkenylalkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, alkoxyalkyl, alkoxyalkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxycarbonylalkyl, alkoxycarbonylalkenyl, alkoxycarbonylalkynyl, haloalkoxyalkyl, haloalkoxyalkenyl, haloalkoxyalkynyl, alkylthioalkyl, alkylthioalkenyl, alkylthioalkynyl, haloalkylthioalkyl, haloalkylthioalkenyl, haloalkylthioalkynyl, NR R4, S02NR R4, OR3, S(O)jR3, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, alkyl, alkylsulfonylalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl, or aralkyl, aralkenyl, aralkynyl, arcycloalkyl, aroxyalkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, SO2NR3R4 and NR3R4, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, or heteroaralkyl, heteroaralkenyl, heteroaralkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, haloalkoxy, Sθ2NR3R4 and NR3R4, wherein j is 0, 1 or 2, Y2 is chloro, bromo, iodo, OCCI3. mesyl or tosyl, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
38. The compound of claim 37 wherein Y2 is chloro, bromo or iodo.
39. The compound of claim 37 wherein R2 is a hydrogen atom.
40. The compound of claim 37 wherein d is 0.
41. The compound of claim 37 wherein m is 0.
42. The compound of claim 37 wherein (d + m) is 1 or 2.
43. A compound of the formula
Figure imgf000185_0001
wherein
G10 and G11 are each independently an oxygen atom or a sulfur atom, m is 0 or 1, R1 is
Figure imgf000185_0002
wherein
G30 is an oxygen atom or a sulfur atom, .
G3J is an oxygen atom, a sulfur atom or NR3, t' and d are each independently 0 or 1,
X3 is an oxygen atom, a sulfur atom, a nitrogen atom, a phosphorous atom or a carbon atom attached to Z3 when t' is 0, a nitrogen atom attached to Z3 when t1 is 1 and G3X is NR3, or a carbon atom attached to Z3 when t' is 1 and G3i is an oxygen atom or a sulfur atom, Z3(X3)d(G31)f is a biologically active moiety when d is 1 wherein Z3(X3)d(G31)t'-H represents the biologically active compound,
Z3(X3)d, when d is 0 and t' is 1, is a hydrogen atom, (Cι-C2o)alkyl, (Ci- Cι0)alkylcarbonyloxy(Cι-Cιo)alkyl, (Cι-C2o)alkylcarbonyl, hydroxy(Ci-C2o)alkyl, (Ci- Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Cι-C2o)alkyl, (C2-
Cι0)alkenyl, acetylamino(C2-Cιo)alkenyl, halo(C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(C2- Cιo)alkynyl, cyclo(C3-Cβ) alkyl, cyclo(C3-Cs)alkenyl, carboxycyclo(C3-Cs)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cι0)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- C8)alkyl(Cι-Cιo)alkyl, carboxycyclo(C3-Cs)alkyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkenyl(C2-Cι0)alkenyl, carboxycyclo(C3- Cs)alkyl(C2-Cιo)alkynyl, carboxycyclo(C3-Cs)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(C 1- C 10) alkyl, heterocyclyl(C2- C 10) alkenyl, heterocyclyl(C2- C 10) alkynyl, (Cι-C_.o)alkoxy(Cι-Cιo)alkyl, (Cι-Cιo)alkoxy(Cι-Cι0)alkoxy(Cι-Cιo)alkyl, (Ci-
Cι0)alkoxy(C2-Cι0)alkenyl, (Cι-Cι0)alkoxy(C2-Cιo)alkynyl, (Cι-Cι0)alkoxycarbonyl(Cι- Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2- Cιo)alkynyl, halo(Cι-Cιθ)alkoxy(Cι-Cιo)alkyl, halo(Cι-Cι0)alkoxy(C2-CiQ)alkenyl, halo(C1-Cιo)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2- Cιo)alkenyl, (Cι-Cιθ)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cι0)alkylthio(C2-Cιo)alkenyl, halo(Cι-Cι0)alkylthio(C2-Cι0)alkynyl, carboxy(Cι- C20)alkyl, carboxy(C2-Cι0) alkenyl, carboxy(C2-C 10) alkynyl, NR3R4, OR3, S(0)jR3, SiR3R4R5, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, thiocyanato, (Cι-Cιo)alkyl, (Cι-C10)alkylsulfonyl(Cι- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-C10)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, ar(Cι- Cι0)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl, or ar(Cι-Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι- Cι0)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cιo)alkyl, cycloalkyl, (C2-Cι0)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cιo)alkynyl, (Ci-C 10) alkoxy, halo(Cι- Cι0)alkoxy, SO2NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Ci- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C10) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cι0)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-CiQ)alkyl, (C2-Cιo)alkenyl, (C2-Cι0)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo (C2-Cι0) alkynyl, (Ci-C 10) alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, wherein j is 0, 1 or 2,
Z3(X3)d is halo, NR3R4, OR3, N(R3)-N=CR3R4, S(0)jR3 or S02NR3R4 when both d and t' are 0 and j is 0, 1 or 2,
R2 is a hydrogen atom, (Ci-C2o)alkyl, (C2-C 10) alkenyl, (C2-C 10) alkynyl, (Ci- Cιo)alkoxy(Cι-Cιo)alkyl, (Cι-Cιo)alkoxy(C2-Cι0)alkenyl, (Ci-C 10) alkoxy(C -C 10) alkynyl, (C.ι-CiQ)alkylthio(Cι-Cιo)alkyl, (Cι-Cιo)alkylthio(C2-C10)alkenyl, (Cι-C10)alkylthio(C2- Cιo)alkynyl, carboxy, a carboxylate salt, carboxy(Ci-C2o)alkyl, carboxy(C2-C20)alkenyl, carboxy(C2-C2Q)alkynyl, (C1-C20) alkoxycarbonyl, (Cι-Cιo)alkoxycarbonyl(Cι-Cιo)alkyl, (Cι-Cι0)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Ci0)alkynyl, (Ci- C2o) alkylcarbonyl, (C2-C2o)alkenylcarbonyl, (C2-C20) alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-Cβ) alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2-Cι0)alkenyl, cyclo(C3-C8)alkenyl(C2-Cι0)alkenyl, cyclo(C3- C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cι0)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, or (Cι-C20)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, (Cι-Cι0)alkoxy(Cι-Cιo)alkyl, (Ci- Cι0)alkoxy(C2-Cκ>)alkenyl, (Cι-Cι0)alkoxy(C2-Cι0)alkynyl, (Cι-C10)alkylthio(Cι- Cιo)alkyl, (Cι-Cι0)alkylthio(C2-Cιo)alkenyl, (Cι-Cιo)alkylthio(C2-Cιo)alkynyl, carboxy(Cι-C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-C 10) alkynyl, (Ci-
C2o) alkoxycarbonyl, (C 1- C 10) alkoxycarbonyl(C 1- C 10) alkyl, (C 1- C ι0) alkoxycarbonyl(C2- Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιθ)alkynyl, (Cι-C20)alkylcarbonyl, (C2- Cι0)alkenylcarbonyl, (C2-C 10) alkynylcarbonyl, cyclo(C3-C8)alkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(C1-Cιo)alkyl, cyclo(C3-C8)alkenyl(C1-Cι0)alkyl) cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cι0)alkenyl, cyclo(C3-C8)alkyl(C2-Cι0)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(Cι-Cι0)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-C 10) lkynyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, Sθ2NR3R4 and NR3R4, aryl or aryl substituted with one or more substituents independently selected from halo, (CI-CIQ) alkyl, (C2-C10) alkenyl, (C2-Cι0)alkynyl, halo(Cι-Cιo)alkyl, halo(C2- Cιo)alkenyl, halo(C2-Cιo)alkynyl, (CI-CIQ) alkoxy, halo(Cι-Cιo)alkoxy, carboxy, (Ci- C4)alkoxycarbonyl, S02NR3R4 and NR3R4, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2- Cιo)alkynyl, or ar(Cι-Cιo)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cι0) alkynyl substituted with one or more substituents independently selected from halo, (Ci-C 10) alkyl, (C2- Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (CI-CIQ) alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2-Cι0)alkynylcarbonyl or arylcarbonyl, ar(Cι-Cιo)alkylcarbonyl, ar(C2-Cιo)alkenylcarbonyl, ar(C2-
Cιo)alkynylcarbonyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cι0)alkyl, (C2-Cι0)alkenyl, (C2- Cι0)alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cι0)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, S02NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, (Ci- Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-C10)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cι0)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4, heteroar(Cι- Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroar(Cι-Cι0)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cι0)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cι0)alkyl, (C2-C1Q) alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cι0)alkynyl, (Ci- Cιo)alkoxy, halo(Cι-Cιo)alkoxy, SO2NR3R4 and NR3R4, heteroar(Cι-Cιo)alkylcarbonyl, heteroar(C2-Cιo)alkenylcarbonyl, heteroar(C2-Cιo)alkynylcarbonyl or heteroar(Cι- C IQ) alkylcarbonyl, heter oar (C2- C 10) alkenylcarbonyl, heteroar (C2- C IQ) alkynylcarbonyl substituted with one or more substituents independently selected from halo, cyano, hydroxy, nitro, (Cι-Cιo)alkyl, (C2-Cι0) alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(C_.-Cιo)alkoxy, Sθ2NR3R4 and NR3R4, or Ri and R2 taken together with the carbon atom to which they are attached form a 5-7 membered saturated or unsaturated ring, R3, R4 and R5 are each independently a hydrogen atom, (Cι-C2o)alkyl, cyclo(C3-
C8)alkyl, cyclo(C3-C8)a]kenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cι0)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo) alkynyl, heterocyclyl, heterocyclyl(Cι- C 10) alkyl, heterocyclyl(C2- C IQ) alkenyl, heterocyclyl(C2- C io) alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, or (Cι-Cιo)alkyl, cyclo(C3- C8)a*lkyl, cyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(C1-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-Cs)alkyl(C2-Cιo)alkynyl, cyclo(C3-Cs)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxy(Cι- C2o)alkyl, carboxy(C2-Cιo)alkenyl, carboxy(C2-Cιo) alkynyl, heterocyclyl, heterocyclyl(Cι-Cιo)alkyl, heterocyclyl(C2-Cιo)alkenyl, heterocyclyl(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy(Cι-Cιo)alkyl, (C2-Cιo)alkenyl or (C2-Cιo)alkynyl substituted with one or more halo, aryl, ar(Cι-Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl or aryl, ar(Cι- Cιo)alkyl, ar(C2-Cιo)alkenyl, ar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2- Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl or heteroaryl, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, (Cι-Cιo)alkyl, (C2-C10) alkenyl, (C2-C 10) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2-Cιo)alkynyl, (Cι-Cιo)alkoxy and halo(Cι-Cιo)alkoxy, or R3 and R4 taken together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocyclic ring,
X1 is an oxygen atom, a sulfur atom, a phosphorous atom or a nitrogen atom attached to Z1,
Zi(Xi)m is a biologically active moiety when m is 1 wherein
Figure imgf000189_0001
represents the biologically active compound, Zi(Xi) , when m is 0, is a hydrogen atom, halo, (Cι-C2o)alkyl, (Ci-
Cιo)alkylcarbonyloxy(Cι-Cιo)alkyl, (Cι-C2o) alkylcarbonyl, hydroxy(Cι-C2o)alkyl, (Ci- Cιo)alkylsulfonyl(Cι-Cιo)alkyl, acetylamino(Cι-Cιo)alkyl, halo(Cι-C2o)alkyl, (C2- C2o)alkenyl, halo(C2-C2o)alkenyl, acetylamino(C2-Cιo)alkenyl, (C2-C20) alkynyl, halo(C2- C2o)alkynyl, cyclo(C3-Cs)alkyl, cyclo(C3-Cs)alkenyl, carboxycyclo(C3-Cs)alkyl, carboxycyclo(C3-C8)alkenyl, cyclo(C3-C8)alkyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkyl(C2- Cιo)alkenyl, cyclo(C3-C8)alkenyl(Cι-Cιo)alkyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, cyclo(C3-C8)alkyl(C2-Cιo)alkynyl, cyclo(C3-C8)alkenyl(C2-Cιo)alkynyl, carboxycyclo(C3- C8)alkyl(Cι-Cιo)alkyl, carboxy(C3-C8)cycloalkyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)alkenyl(Cι-Cιo)alkyl, carboxycyclo(C3-C8)alkenyl(C2-Cιo)alkenyl, carboxycyclo(C3- C8)alkyl(C2-Cιo)alkynyl, carboxycyclo(C3-C8)alkenyI(C2-Cιo)alkynyl, heterocyclyl, heterocyclyl(C i- C io) alkyl, heterocyclyl(C2- C io) alkenyl, he terocyclyl(C2- C ιo)alky nyl, (Cι-Cιo)alkoxy(Cι-Cι0)alkyl, (Cι-C5)alkoxy(Cι-C5)alkoxy(Cι-Cιo)alkyl, (Ci- Cιo)alkoxy(C2-Cιo)alkenyl, (Cι-Cι0)alkoxy(C2-Cιo)alkynyl, (Cι-Cιo)alkoxycarbonyl(Cι- Cιo)alkyl, (Cι-Cιo)alkoxycarbonyl(C2-Cιo)alkenyl, (Cι-Cιo)alkoxycarbonyl(C2- Cιo)alkynyl, halo(Ci-Cιo)alkoxy(Cι-Cιo)alkyl, halo(Cι-Cι0)alkoxy(C2-Cι0)alkenyl, halo(Cι-Cιo)alkoxy(C2-CiQ)alkynyl, (Cι-Cιo)alkylthio(Cι-Cιθ)alkyl, (Cι-Cι0)alkylthio(C2- Cιo)alkenyl, (Cι-CiQ)alkylthio(C2-Cιo)alkynyl, halo(Cι-Cιo)alkylthio(Cι-Cιo)alkyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkenyl, halo(Cι-Cιo)alkylthio(C2-Cιo)alkynyl, SO2NR3R4, NR3R4, OR3, S(O)jR3, carboxy(Cι-C2Q)alkyl. carboxy(C2-C20)alkenyl, carboxy(C2- C2o)alkynyl, aryl, aryl substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, (Cι-Cιo)alkyl, (Cι-Cι0)alkylsulfonyl(Cι- Cιo)alkyl, (Cι-Cιo)alkylsulfonyl, thiocyanato, (C2-Cιo)alkenyl, (C2-Cι0)alkynyl, halo(Cι- Cι0)alkyl, halo(C2-Cι0)alkenyl, halo(C2-Cι0)alkynyl, (CI-CIQ) alkoxy, halo(Cι-Cι0)alkoxy, S02NR3R4, and NR3R4, ar(Cι-Cι0)alkyl, ar(C2-Cι0)alkenyl, ar(C2-Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cι0)alkyl, or ar(Cι-Cι0)alkyl, ar(C2-Cιo)alkenyl, ar(C2- Cιo)alkynyl, arcyclo(C3-C8)alkyl, aroxy(Cι-Cιo)alkyl substituted with one or more substituents independently selected from halo, nitro, hydroxy, cyano, (Cι-Cιo)alkyl, cyclo(C3-C8)alkyl, (C2-Cιo)alkenyl, (C2-Cιo)alkynyl, halo(Cι-Cιo)alkyl, halo(C2-
Cιo)alkenyl, halo(C2-Cι0)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cι0)alkoxy, S02NR3R4 and NR3R4, heteroaryl, heteroaryl substituted with one or more substituents independently selected from halo, hydroxy, nitro, cyano, (CI-CIQ) alkyl, (C2- Cι0)alkenyl, (C2-C 10) alkynyl, halo(Cι-Cι0)alkyl, halo(C2-Cι0)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cι0)alkoxy, halo(Cι-Cιo)alkoxy and NR3R4, heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl, or heteroar(Cι-Cιo)alkyl, heteroar(C2-Cιo)alkenyl, heteroar(C2-Cιo)alkynyl substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, (Cι-Cιo)alkyl, (C2-Cιo)alkenyl, (C2-C1C.) alkynyl, halo(Cι-Cιo)alkyl, halo(C2-Cιo)alkenyl, halo(C2- Cιo)alkynyl, (Cι-Cιo)alkoxy, halo(Cι-Cι0)alkoxy, S02NR3R4 and NR3R4, wherein j is 0, l or 2,
Y2 is chloro, bromo, iodo, OCCI3, mesyl or tosyl, or the biologically active acceptable salts, isomers, tautomers, enantiomers and mixtures thereof.
44. The compound of claim 43 wherein Y2 is chloro, bromo or iodo.
45. The compound of claim 43 wherein R2 is a hydrogen atom.
46. The compound of claim 43 wherein d is 0.
47. The compound of claim 43 wherein m is 0.
48. The compound of claim 43 wherein (d + m) is 1 or 2.
49. The compound of claim 17 or 27 wherein both q and t are 1 and X2 is a carbon atom.
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CN107827815B (en) * 2017-11-10 2021-08-03 西南大学 Fluoroquinolone amino derivatives and application thereof in preventing and treating citrus diseases
CN111808032A (en) * 2020-07-31 2020-10-23 深圳市橄榄生物医药科技有限公司 Pyrazine compound with multiple effects and preparation method thereof

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