EP1007515A1 - Arylpyridazinone als hemmer der biosynthese der prostaglandin-endoperoxid-h-synthase - Google Patents

Arylpyridazinone als hemmer der biosynthese der prostaglandin-endoperoxid-h-synthase

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Publication number
EP1007515A1
EP1007515A1 EP98938451A EP98938451A EP1007515A1 EP 1007515 A1 EP1007515 A1 EP 1007515A1 EP 98938451 A EP98938451 A EP 98938451A EP 98938451 A EP98938451 A EP 98938451A EP 1007515 A1 EP1007515 A1 EP 1007515A1
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Prior art keywords
group
alkyl
heterocyclic
aryl
phenyl
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English (en)
French (fr)
Inventor
Lawrence A. Black
Anwer Basha
Teodozyj Kolasa
Michael E. Kort
Huaqing Liu
Catherine M. Mccarty
Meena V. Patel
Jeffrey J. Rohde
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Abbott Laboratories
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/18—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention encompasses novel pyridazinone compounds useful in the treatment of cyclooxygenase-2 mediated diseases. More particularly, this invention concerns a method of inhibiting prostaglandin biosynthesis, particularly the induced prostaglandin endoperoxide H synthase (PGHS-2, cyclooxygenase-2, COX-2) protein.
  • PGHS-2 induced prostaglandin endoperoxide H synthase
  • the prostaglandins are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range.
  • the discovery of two forms of prostaglandin endoperoxide H synthase, isoenzymes PGHS-1 and PGHS-2, that catalyze the oxidation of arachidonic acid leading to prostaglandin biosynthesis has resulted in renewed research to delineate the role of these two isozymes in physiology and pathophysiology. These isozymes have been shown to have different gene regulation and represent distinctly different prostaglandin biosynthesis pathways.
  • the PGHS-1 pathway is expressed constitutively in most cell types.
  • the PGHS-2 pathway involves an induction mechanism which has been linked to inflammation, mitogenesis and ovulation phenomena.
  • Prostaglandin inhibitors provide therapy for pain, fever, and inflammation, and are useful therapies, for example in the treatment of rheumatoid arthritis and osteoarthritis.
  • the non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen and fenamates inhibit both isozymes.
  • Inhibition of the constitutive enzyme PGHS-1 results in gastrointestinal side effects including ulcers and bleeding and incidence of renal problems with chronic therapy.
  • Inhibitors of the induced isozyme PGHS-2 may provide anti-inflammatory activity without the side effects of PGHS-1 inhibitors.
  • the problem of side-effects associated with NSAID administration has never completely been solved in the past. Enteric coated tablets and co-administration with misoprostol, a prostaglandin derivative, have been tried in an attempt to minimize stomach toxicity. It would be advantageous to provide compounds which are selective inhibitors of the induced isozyme PGHS-2.
  • the present invention discloses novel compounds which are selective inhibitors of PGHS-2.
  • the present invention discloses pyridazinone compounds which are selective inhibitors of cyclooxygenase-2 (COX-2).
  • the compounds of the present invention have the formula I:
  • X is selected from the group consisting of O, S, NR 4 , N-OR a , and N-NRbR 0 , wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl, and arylalkyl; and R a , Rb, and R c are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, hetero
  • R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl;
  • Rd and R e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;
  • X' is halogen; n is from 0 to about 10, and m is 0 to about 5; at least one of R , R 2 and R 3 is
  • X 1 is selected from the group consisting of -SO2-, -SO(NR 10 )-, -SO-, Se ⁇ 2-, PO(OR 1 )-, and -PO(NR12R13).
  • X 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl;
  • R 10 , R 1 1 , R 12 , and R 13 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 1 2 and R 1 3 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, halolkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalk
  • R 1 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl),
  • R 1 6 , R 7 , and R 1 9 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
  • R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; heir pharmaceutically acceptable salts, esters, or prodrugs thereof.
  • COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1 ) which is an important "housekeeping" enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys.
  • the compounds of the present invention have the formula I :
  • X is selected from the group consisting of O, S, NR 4 , N-OR a , and N-NR' D RC I wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl, and arylalkyl; and R a , Rb, and R c are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, halolkoxyhydroxyalkyl, hetero
  • R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, halo
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;
  • R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl;
  • Rd and R e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;
  • X' is halogen; n is from 0 to about 10, and m is 0 to about 5; at least one of R 1 , R 2 and R 3 is
  • X 1 is selected from the group consisting of -SO2-, -SO(NR 1 0 )-, -SO-, Se ⁇ 2-, PO(ORl 1 )-, and -P0(NR1 2 R13).
  • X 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl; R 1 0 , R 1 1 , R 1 2 , and R 1 3 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 1 2 and R 1 3 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms.
  • R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, halolkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalk
  • R14 j s selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl),
  • R 16 , R 17 , and R 1 9 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
  • R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula II:
  • X 1 is selected from the group consisting of -SO2-, -SO-, -Se ⁇ 2-
  • R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH2, dialkylamino, alkoxy, thiol, alkylthiol, protecting groups, and protecting groups attached to X 1 by an alkylene;
  • R 1 0 is selected from the group consisting of hydrogen, alkyl, and cycloalkyl;
  • X 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, hetero
  • R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic alkyl; wherein R6 is alkylene or alkenylene, or halo-substituted alkylene halo-substituted alkenylene;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;
  • R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl;
  • Rd and R e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;
  • X' is halogen; n is from 0 to about 10, and m is 0 to about 5;
  • R 1 , and R 3 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyaikylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, halolkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloaikenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino
  • R 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl), R "1 6 , R 1 7 , and R 1 9 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
  • R 2"1 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III:
  • compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -SO2-, -SO-, - Se ⁇ 2-, and -SO(NR 0 )-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen;
  • X is selected from the group consisting of O, S, NR 4 , N-OR a , and N-NRbR C , wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl, and arylalkyl; and R a , R b , and R c .are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl
  • R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl;
  • X' is halogen; n is from 0 to about 10, m is from 0 to about 5;
  • R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkoxyalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, aryloxy, heterocyclic, heterocyclic alkyl, cyano, nitro, and -Y-R 1 4 , wherein Y is selected from the group consisting of, -O-, -S-, -C(R 1 6) (R 1 )-, -C(O)NR 21 R 22 -, -C(O)
  • R1 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl), R 1 6 , R 1 7 , and R 1 9 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
  • R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -SO2-, -SO-, -Se ⁇ 2-, and -SO(NR 1 0 )-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino; X 2 is selected from the group consisting of hydrogen and halogen;
  • X is selected from the group consisting of O, S, NR 4 , N-OR a , and N-NR ⁇ R C , wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and R a , R&, and R c .are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, -(CH2)nC(O)R 5 > and - wherein R 5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl;
  • R 20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl; n is from 0 to about 10;
  • R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic(alkyl), cyano, nitro, and -Y-R 1 4 , wherein Y is selected from the group consisting of, -O-, -S-, -C(R 1 6 )
  • R14 is S ⁇
  • R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -SO2-, -SO-, -Se ⁇ 2-, and -SO(NR 1 0 )-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
  • X 2 is selected from the group consisting of hydrogen and halogen
  • X is selected from the group consisting of O, S, NR 4 , N-OR a , and N-NR D RC ; wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and R a , R ) and R c .are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, carboxyalkyl, cyanoalkyl, haloalkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkenyl, arylalkynyl, heterocyclic, heterocyclic alkyl, arylalkyl, and -(CH2)nC(O)R 5 >; wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, haloalkyl, heterocyclic, and heterocyclic alkyl; and n is from 0 to about 10;
  • R 1 and R 3 are independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylthioalkyl, aryloxyalkyl, arylthioalkyl, amido, amidoalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, amino, aminocarbonyl, aminocarbonylalkyl, alkylamino, alkylaminoalkyl, dialkylamino, arylamino, arylalkylamino, diarylamino, aryl, heterocyclic, heterocyclic(alkyl), cyano, nitro, and -Y-R 1 4 , wherein Y is selected from the group consisting of, -O-, -S-, -C(R 16 ) (
  • R14 ⁇ s selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl); R 1 5 , R 1 6 , R 1 7 , and R 1 9 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl or cyano;
  • R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -SO2-, -SO-, - Se ⁇ 2-, and -SO(NR 10 )-, and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
  • X 2 is selected from the group consisting of hydrogen and halogen
  • X is selected from the group consisting of O, S, NR 4 , N-ORa, and N-NRbRC, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and R a , R , and R c .are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and - (CH 2 )n-R 2 0 where is R 20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen; n is from 0 to about 10;
  • R 1 is selected from the group consisting of alkoxy, alkenyloxy, hydroxyalkoxy, aryloxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, and -Y-R "1 4 , wherein Y is selected from the group consisting of, -0-, -S-, -C(R 1 6 ) (R 1 7 )-, -C(O)-, - C(0)0-, -NH-, -NC(O)-, and -NR 1 9-.
  • R1 4 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl,
  • R 3 is hydrogen;
  • R 1 5 , R 1 6 , R 1 7 , and R 1 9 are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and
  • R 21 and R 22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -SO2-, -SO-, and -SO(NR 1 0 )-, and R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
  • X 2 is selected from the group consisting of hydrogen and halogen
  • X is selected from the group consisting of O, S, NR 4 , N-OR a , and N-NRbRC, wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and R a , Rb, and R c .are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from alkyl, haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and - (CH2)n-R 20 where is R 20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen; n is from 0 to about 10;
  • R 1 is selected from the group consisting of alkoxy, alkenyloxy, hydroxyalkoxy, aryloxy, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl; and R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is -SO2- and and R 9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, alkylamino, or dialkylamino;
  • X 2 is selected from the group consisting of hydrogen and halogen;
  • X is selected from the group consisting of O, S, NR 4 , N-ORa, and N-NRbR C , wherein R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylcycloalkenyl, aryl, heterocyclic, and arylalkyl; and R a , Rb ; and R c .are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;
  • R is selected from haloalkyl, aryl, heterocyclic, heterocyclic alkyl, and - (CH2)n-R 20 where is R 20 is substituted and unsubstituted aryl wherein the substituted aryl compounds are substituted with halogen; n is from 0 to about 10; R 1 is selected from the group consisting of unsubstituted aryl, and substituted aryl with one, two, or three substituents selected from the group consisting of fluorine and chlorine including, but not limited to, p-chlorophenyl, p- fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, and the like; and
  • R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is -SO2-,and R 9 is selected from the group consisting of alkyl and amino; X 2 is selected from the group consisting of hydrogen and halogen;
  • X is O
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl;
  • R 1 is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, halalkoxy, arylalkyl, alkyl, and aryloxy;
  • R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is -SO2-, and R 9 is selected from the group consisting of alkyl and amino X 2 is selected from hydrogen and fluorine;
  • R is selected from haloalkyl, aryl, and alkyl; n is from 0 to about 10;
  • R 1 is selected from the group consisting of isobutyloxy, isopentyloxy, 1 -(3- methyl-3-butenyl)oxy, 2-hydroxy-2-methyl-propyloxy, 3-hydroxy-3-methyl-butyloxy, neopentyloxy, isopentyl, aryloxy including 4-fluorophenoxy, unsubstituted aryl, and substitued aryl with one, two, or three substituents selected from the group consisting of fluorine and chlorine including, , 4-fluorophenyl, 4-chlorophenyl, 4- chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and the like; and R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is selected from the group consisting of -SO2-, and -S0(NR10)-, and R9 is alkyl,
  • X 2 is selected from the group consisting of hydrogen and fluorine
  • X is O
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl;
  • R "1 is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, alkyl, and aryloxy;
  • R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is -SO2-, R 9 is amino;
  • X 2 is selected from the group consisting of hydrogen and fluorine
  • X is O
  • R is selected from the group consisting of alkyl, alkenyl, alkynyl, haloalkyl, aryl, and arylalkyl;
  • R 1 is selected from the group consisting of alkoxy, aryl, alkenyloxy, hydroxyalkoxy, alkyl, and aryloxy;
  • R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is -SO2-, and R 9 is methyl;
  • X 2 is selected from the group consisting of hydrogen
  • X is O;
  • R is selected from the group consisting t-butyl, 3-chlorophenyl, 3,4- difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, and CF 3 CH 2 -, ;
  • R 1 is selected from the group consisting of aryloxy including 4- fluorophenoxy, isobutyloxy, isopentyloxy, 1 -(3-methyl-3-butenyl)oxy, 2-hydroxy-2- methyl-propyloxy, 3-hydroxy-3-methyl-butyloxy, neopentyloxy, isopentyl, 4- fluorophenyl, 4-chiorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl; and
  • R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof.
  • compounds of the present invention have the formula III, wherein X 1 is -SO2-, and R 9 is amino;
  • X 2 is selected from the group consisting of hydrogen
  • X is O
  • R is selected from the group consisting t-butyl, 3-chlorophenyl, 3,4- difluorophenyl, 4-fluorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl and CF 3 CH 2 -, ;
  • R 1 is selected from the group consisting of aryloxy including 4- fluorophenoxy, isobutyloxy, isopentyloxy, 1 -(3-methyl-3-butenyl)oxy, 2-hydroxy-2- methyl-propyloxy, 3-hydroxy-3-methyl-butyloxy, neopentyloxy, isopentyl, 4- fluorophenyl, 4-chlorophenyl, 4-chloro-3-fluoro-phenyl, 3-chloro-4-fluoro-phenyl; and R 3 is hydrogen; or a pharmaceutically acceptable salt, ester, or prodrug thereof
  • protecting groups includes “carboxy protecting group” and “N- protecyting groups” .
  • Carboxy protecting group refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” pp. 152-186 (1981 ), which is hereby incorporated herein by reference.
  • a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo , for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V.
  • carboxy protecting groups are Ci to Cs alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cylcopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cylcopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoalkyl (e.g., dimethylaminoalkyl (e.g
  • alkoxycarbonylaminoalkyl such as t-butyloxycarbonylaminomethyl and the like
  • alkylaminocarbonylaminoalkyl such as methylaminocarbonylaminomethyl and the like
  • alkanoylaminoalkyl such as acetylaminomethyl and the like
  • heterocycliccarbonyloxyalkyl such as 4- methylpiperazinylcarbonyloxymethyl and the like
  • dialkylaminocarbonylalkyl such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like
  • (5- (loweralkyl)-2-oxo-1 ,3-dioxolen-4-yl)alkyl such as (5-t-butyl-2-oxo-1 ,3-dioxolen-4- yl)methyl and the like
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures.
  • N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1981 )), which is hereby incorporated by reference.
  • N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyl
  • 2,4-dimethoxybenzyloxycarbonyl 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1 -methylethoxycarbonyl, ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,- trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (t-Boc) and benzyloxycarbonyl (Cbz).
  • aikanoyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a carbonyl (-C(O)-) group.
  • Examples of aikanoyl include acetyl, propionyl and the like.
  • alkanoylamino refers to an aikanoyl group as previously defined appended to an amino group. Examples alkanoylamino include acetamido, propionylamido and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. Alkenyl groups include, for example, vinyl (ethenyl), allyl (propenyl), butenyl, 1 -methyl-2-buten-1 -yl and the like.
  • alkenylene denotes a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • alkenyloxy refers to an alkenyl group, as previously defined, connected to the parent molecular moiety through an oxygen (-0-) linkage. Examples of alkenyloxy include isopropenoxy, butenyloxy and the like.
  • alkoxy refers to R41 O- wherein R41 is a loweralkyl group, as defined herein.
  • alkoxy include, but are not limited to, ethoxy, isobutyloxy, isopentyloxy, tert-butoxy, and the like.
  • alkoxyalkylamino refers to an alkoxy as defined herein appended to the parent molecular moiety through an alkylamino as defined herein.
  • alkoxyalkylamino examples include, but are not limited to, ethoxymethylamino, isobutyloxyethylamino and the like
  • alkoxyalkoxy refers to R ⁇ oO-R ⁇ l O- wherein R ⁇ o is loweralkyl as defined above and R ⁇ l is alkylene.
  • Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
  • alkoxycarbonyl refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group.
  • alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyi and the like.
  • alkoxycarbonylalkenyl refers to an alkoxycarbonyl group as previously defined appended to the parent molecular moiety through an alkenylene.
  • alkoxycarbonylalkenyl include methoxycarbonylethenylene, ethoxycarbonylpropenylene, and the like.
  • alkoxyalkoxyalkyl refers to an alkoxyalkoxy group as previously defined appended to an alkyl radical.
  • Representative examples of alkoxyalkoxyalkyl groups include methoxyethoxyethyl, methoxymethoxymethyl, and the like.
  • alkoxyalkoxyalkenyl refers to an alkoxyalkoxy group as previously defined appended to an alkenyl radical.
  • Representative examples of alkoxyalkoxyalkenyl groups include methoxyethoxyethenyl, methoxymethoxymethenyl, and the like.
  • alkoxyalkyl refers to an alkoxy group as previously defined appended to an alkyl radical as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.
  • (alkoxycarbonyl)thioalkoxy refers to an alkoxycarbonyl group as previously defined appended to a thioalkoxy radical.
  • Examples of (alkoxycarbonyl)thioalkoxy include methoxycarbonylthiomethoxy, ethoxycarbonylthiomethoxy and the like.
  • alkyl and “loweralkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 15 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1 -methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n- hexyl and the like.
  • alkylamino refers to R51 NH- wherein R51 is a loweralkyl group, for example, ethylamino, butylamino, and the like.
  • alkylaminoalkyl refers to a loweralkyl radical to which is appended an alkylamino group.
  • alkylaminocarbonyl refers to an alkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • alkylaminocarbonyl include methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl and the like.
  • alkylaminocarbonylalkenyl refers to an alkenyl radical to which is appended an alkylaminocarbonyl group.
  • alkylcarbonylalkyl refers to R4rj-C(O)- R41 - wherein R40 is an alkyl group and R41 is an alkylene group.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 15 carbon atoms by the removal of two hydrogen atoms, for example -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -
  • alkylsulfonyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonyl (-S(O)2-) group.
  • alkylsulfonyl include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.
  • alkylsulfonylalkyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylalkyl (-S(O)2-R-) group.
  • alkylsulfonylalkyl include methylsulfonylmethyl, ethylsulfonylmethyl, isopropylsulfonylethyl and the like.
  • alkylsulfonylamino refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylamino (-S(O)2-NH-) group.
  • alkylsulfonylamino include methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino and the like.
  • alkylsulfonylarylalkyl refers to an alkyl group as previously defined appended to the parent molecular moiety through a sulfonylalkyl (-S(O)2-R45R33-) group wherein R45 is aryl and R33 is alkylene.
  • alkylsulfonylarylalkyl include methylsulfonylphenylmethyl ethylsulfonylphenylmethyl, isopropylsulfonylphenylethyl and the like.
  • alkylthio refers to R53S- wherein R53 is alkyl.
  • alkylthioalkyl refers to alkylthio as defined herein appended to the parent molecular moiety through an alkylene group.
  • alkylthioalkoxy refers to alkylthio as defined herein appended to the parent molecular moiety through an alkoxyl group as defined herein.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include -C ⁇ C-H, H-C ⁇ C- CH 2 -, H-C ⁇ C-CH(CH 3 )- and the like.
  • amidoalkyl refers to R34-C(O)-NHR35- wherein R34 is alkyl and R35 is alkylene.
  • amino refers -NH2.
  • aminoalkoxy refers to an amino group appended to the parent molecular moiety through an alkoxyl group as defined herein.
  • aminocarbonyl refers to H2N-C(O)-.
  • aminocarbonylalkyl refers to an aminocarbonyl as described above appended to the parent molecular moiety through an alkylene.
  • aminocarbonylalkenyl refers to an alkenyl radical to which is appended an aminocarbonyl (NH 2 C(O)-) group.
  • aminocarbonylalkoxy refers to H2N-C(O)- appended to an alkoxy group as previously defined. Examples of aminocarbonylalkoxy include aminocarbonylmethoxy, aminocarbonylethoxy and the like.
  • aroyloxyalkyl refers to R32-C(0)-0-R33- wherein
  • R32 is an aryl group and R33 is an alkylene group.
  • aroyloxyalkyl include benzoyloxymethyl, benzoyloxyethyl and the like.
  • aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
  • aryl may have up to five halo substituents.
  • substituted aryl include 3- chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methylsulfonylphenyl, pentaflurophenyl, and the like.
  • arylalkenyl refers to an alkenyl radical to which is appended an aryl group, for example, phenylethenyl and the like.
  • arylalkynyl refers to an alkynyl radical to which is appended an aryl group, for example, phenylethynyl and the like
  • arylalkoxy refers to R42O- wherein R42 is an arylalkyl group, for example, benzyloxy, and the like.
  • arylalkoxyalkyl refers to a loweralkyl radical to which is appended an arylalkoxy group, for example, benzyloxymethyl and the like.
  • arylalkyl refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
  • arylalkylamino refers to an arylalkyl group as previously defined, appended to the parent molecular moiety through an amino group.
  • arylalkylthio refers to an arylalkyl group as previously defined, appended to the parent molecular moiety through an thiol group.
  • arylamino refers to R45NH2- wherein R45 is an aryl.
  • arylcarbonylalkyl refers to R45C(O)R33- wherein R45 is an aryl group and R33 is an alkylene group.
  • arylhaloalkyl refers to an aryl group as previously defined, appended to the parent molecular moiety through a haloalkyl as defined herein.
  • arylhaloalkyl include, phenyl-2-fluoropropyl, and the like.
  • arylhydroxyalkyl refers to an aryl group as previously defined, appended to the parent molecular moiety through a hydroxyalkyl as defined herein.
  • arylhydroxyalkyl include, phenyl-2- hydroxypropyl, and the like.
  • aryloxy refers to R45O- wherein R45 is an aryl group, for example, phenoxy, and the like.
  • aryloxyalkyl refers to an aryloxy group as previously defined appended to an alkyl radical. Examples of aryloxyalkyl include phenoxymethyl, 2- phenoxyethyl and the like.
  • aryloxyhaloalkyl refers to an aryloxy group as previously defined, appended to the parent molecular moiety through a haloalkyl as defined herein. Examples of aryloxyhaloalkyl include, phenyloxy-2-fluoropropyl, and the like.
  • aryloxyhydroxyalkyl refers to an aryloxy group as previously defined, appended to the parent molecular moiety through a hydroxyalkyl as defined herein.
  • aryloxyhydroxyalkyl include, phenyoxy-2-hydroxypropyi, and the like.
  • carboxaldehyde refers to a formaldehyde radical, -C(O)H.
  • carboxamide refers to -C(O)NH2-
  • carboxy refers to a carboxylic acid radical, -C(O)OH.
  • carboxyalkyl refers to a carboxy group as previously defined appended to an alkyl radical as previously defined.
  • Examples of carboxyalkyl include 2-carboxyethyl, 3-carboxy-1 -propyl and the like.
  • carboxyalkenyl refers to a carboxy group as previously defined appended to an alkenyl radical as previously defined.
  • Examples of carboxyalkenyl include 2-carboxyethenyl, 3-carboxy-1 -ethenyl and the like.
  • carboxyalkoxy refers to a carboxy group as previously defined appended to an alkoxy radical as previously defined. Examples of carboxyalkoxy include carboxymethoxy, carboxyethoxy and the like.
  • cyano refers a cyano (-CN) group.
  • cyanoalky refers to an alkyl radical as previously defined to which is appended a cyano (-CN) group.
  • cyanoalkyl examples include 3-cyanopropyl, 4-cyanobutyl, and the like.
  • cyanoalkoxy refers to a cyano (-CN) group appended to the parent molecular moiety through an alkoxy radical. Examples of cyanoalkoxy include 3-cyanopropoxy, 4-cyanobutoxy and the like.
  • cycloalkanoyloxyalkyl refers to a loweralkyl radical to which is appended a cycloalkanoyloxy group (i.e., Rgg-C(O)-O- wherein Rg ⁇ is a cycloalkyl group).
  • cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyciopentyl, cyclohexyl, and the like.
  • cycloalkenyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings containing at least one double bond in the ring structure.
  • cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
  • cycloalkylalkoxy refers to a cycloalkyl group appended to an alkoxyl group as defined herein, including but not limited to cyclohexylmethyoxy.
  • cycloalkylamino refers to a cycloalkyl group appended to the parent molecular moiety through an amino group as defined herein, including but not limited to cyclohexylamino and the like.
  • cycloalkylalkylamino refers to a cycloalkyl group appended to the parent molecular moiety through an alkylamino group as defined herein, including but not limited to cyclohexylmethylamino and the like.
  • cycloalkyloxy refers to a cycloalkyl group appended to the parent molecular moiety through an oxygen atom, including but not limited to cyclohexyloxy and the like.
  • cycloalkenylalkyl refers to a cycloalkenyl group appended to a loweralkyl radical, including but not limited to cyclohexenylmethyl.
  • cycloalkenylalkoxy refers to a cycloalkenyl group appended to a alkoxyl group as defined herein, including but not limited to cyclohexenylmethyoxy and the like.
  • dialkylamino refers to R56R57N- wherein R56 and R57 are independently selected from loweralkyl, for example diethylamino, methyl propylamino, and the like.
  • dialkylaminoaryloxy refers a dialkylamino as defined herein appended to the parent molecular moiety through an aryloxy as defined herein.
  • diarylamino refers to (R45)(R46)N- wherein R45 and R46 are independently aryl, for example diphenylamino and the like.
  • dialkylaminoalkyl refers to a loweralkyl radical to which is appended a dialkylamino group.
  • dialkylaminocarbonyl refers to a dialkylamino group, as previously defined, appended to the parent molecular moiety through a carbonyl (-C(O)-) linkage.
  • dialkylaminocarbonyl include dimethylaminocarbonyl, diethylaminocarbonyl and the like.
  • dialkyiaminocarbonylalkenyl refers to an alkenyl radical to which is appended a dialkylaminocarbonyl group.
  • dialkylaminocarbonylalkyl refers to
  • halo or halogen as used herein refers to I, Br, Cl or F.
  • haloalkyl refers to an alkyl radical, as defined above, which has at least one halogen substituent, for example, chloromethyl, fluoroethyl, trifluoromethyl or pentafluoroethyl, 2,3-difluoropentyl, and the like.
  • haloalkenyl refers to an alkenyl radical which has at least one halogen substituent, for example, chloromethenyl, fluoroethenyl, trifiuoromethenyl or pentafluoroethenyl, 2,3-difluoropentenyl, and the like.
  • haloalkenyloxy refers to an haloalkenyl group as defined herein appended to the parent molecular moiety through an oxygen atom.
  • haloalkynyl refers to an alkynyl radical which has at least one halogen substituent, for example, chloromethynyl, fluoroethynyl, thfluoromethyny! or pentafiuoroethynyl, 2,3-difluoropentynyl, and the like.
  • haloalkoxy refers to an alkoxy radical as defined above, bearing at least one halogen substituent, for example, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, 2,2,3,3,3-pentafluoropropoxy and the like.
  • haloalkoxyalkyl refers to a loweralkyl radical to which is appended a haloalkoxy group.
  • haloalkoxyhydroxyalkyl refers to a haloalkoxy group as defined herein appended to the parent molecular moiety through a hydroxyalkyl, as defined herein.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • heterocycles include, but are not limited to, thiophene, pyrrole, and furan.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cycloalkane ring or another heterocyclic ring (for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like).
  • Heterocyclics include: aziridinyl, azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl
  • Heterocyclics also include compounds of the formula where X * is
  • Y * is -C(O)- or [-C(R")2-]v
  • R" is hydrogen or C ⁇ -C-4-alkyl and v is 1 , 2 or 3 such as 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like.
  • Heterocyclics also include bicyclic rings such as quinuclidinyl and the like.
  • nitrogen containing heterocycles can be N-protected.
  • heterocyclic alkoxy refers to a heterocyclic group as defined above appended to an alkoxy radical as defined above.
  • heterocyclic(alkoxy) include 4-pyhdylmethoxy, 2-pyridylmethoxy and the like.
  • heterocyclic amino refers to a heterocyclic group as defined above appended to an amino as defined above.
  • heterocyclic amino include 4-pyridylamino, 2-pyridylamino and the like
  • heterocyclic oxy refers to a heterocyclic group as defined above appended to the parent molecular moiety through an oxygen. Examples of heterocyclic oxy include 4-pyridyloxy, 2-pyridyloxy and the like.
  • heterocyclic alkyl refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above.
  • heterocyclic alkylamino refers to a heterocyclic group as defined above appended to a alkylamino as defined above
  • heterocyclic carbonyloxyalkyl refers to R46-C(O)-O-R47- wherein R46 is a heterocyclic group and R47 is an alkylene group.
  • heterocyclic thio refers to a heterocyclic group as defined above appended to the parent molecular moiety through an thiol.
  • heterocyclic thio include 4-pyridylthio, 2-py dylthio and the like
  • hydroxy refers to -OH.
  • hydroxyalkenyl refers to an alkenyl radical to which is appended a hydroxy group. Examples of hydroxyalkenyl include 3- hydroxypropenyl, 3, 4-dihydroxybutenyl and the like
  • hydroxyalkoxy refers to an alkoxy radical as previously defined to which is appended a hydroxy (-OH) group.
  • hydroxyalkoxy include 3-hydroxypropoxy, 4-hydroxybutoxy and the like.
  • hydroxyalkyl refers to a loweralkyl radical to which is appended a hydroxy group.
  • examples of hydroxyalkyl include 1 -hydroxypropyl, 4-hydroxybutyl, 1 ,3-dihydroxyisopentyl, and the like.
  • hydroxyalkylamino refers to a hydroxyalkyl group appenmded to the parent molecular moiety through an amino.
  • examples of hydroxyalkylamino include 1 -hydroxypropylamino, 4-hydroxybutylamino, 1 ,3- dihydroxyisopentylamino, and the like.
  • hydroxyalkylthio refers to a hydroxyalkyl group appenmded to the parent molecular moiety through an thiol.
  • hydroxyalkylamino examples include 1 -hydroxypropylthio, 4-hydroxybutylthio, 1 ,3- dihydroxyisopentylthio, and the like
  • mercapto or "thiol” as used herein refers to -SH.
  • nitro refers to -NO2-
  • oxoalkoxy refers to a carbonyl group attached to the parent molecular moiety through an alkoxy group.
  • mercaptoalkoxy or 'thioalkoxy as used herein refers to R70S- wherein R70 is alkoxy.
  • thioalkoxy include, but are not limited to, methylthio, ethylthio and the like.
  • tetrazolyl refers to a radical of the formula
  • tetrazolylalkoxy refers to a tetrazolyl radical as defined above appended to an alkoxy group as defined above.
  • examples of tetrazolylalkoxy include tetrazolylmethoxy, tetrazolylethoxy and the like.
  • thioalkoxyalkoxy refers to R ⁇ S-R ⁇ lO- wherein R ⁇ O is loweralkyl as defined above and R ⁇ l is alkylene.
  • alkoxyalkoxy groups include CH 3 SCH 2 O-, EtSCH 2 O-, t-BuSCH 2 O- and the like.
  • thioalkoxyalkoxyalkyl refers to a thioalkoxyalkoxy group appended to an alkyl radical.
  • alkoxyalkoxyalkyl groups include CH 3 SCH 2 CH 2 OCH 2 CH 2 -, CH 3 SCH 2 OCH 2 -, and the like.
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
  • These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesuifonate, oxalate, pamoate, pectinate, persulfate,
  • the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
  • long chain halides
  • Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I), or separately by reacting a carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
  • Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • Examples of particular esters includes formates, acetates, propionates, butyates, acrylates and ethylsuccinates.
  • prodrug refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • prodrug refers to compounds that are rapidly transformed in vivo to provide the parent compound having the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems. Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design. American Pharmaceutical Association and Pergamon Press, 1967, both of which are incorporated herein by reference.
  • metabolically cleavable group denotes a moiety which is readily cleaved in vivo from the compound bearing it, wherein said compound, after cleavage remains or becomes pharmacologically active.
  • Metabolically cleavable groups form a class of groups reactive with the carboxyl group of the compounds of this invention are well known to practitioners of the art.
  • aikanoyl such as acetyl, propionyl, butyryl, and the like
  • unsubstituted and substituted aroyl such as benzoyl and substituted benzoyl
  • alkoxycarbonyl such as ethoxycarbonyl
  • trialkylsilyl such as trimethyl- and triethysilyl
  • monoesters formed with dicarboxylic acids such as succinyl, and the like.
  • Asymmetric centers may exist in the compounds of the present invention.
  • the present invention contemplates the various stereoisomers and mixtures thereof.
  • Individual stereoisomers of compounds of the present invention are made by synthesis from starting materials containing the chiral centers or by preparation of mixtures of enantiomeric products followed by separation as, for example, by conversion to a mixture of diastereomers followed by separation by recrystallization or chromatographic techniques, or by direct separation of the optical enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods detailed below and resolved by techniques well known in the organic chemical arts.
  • Compounds useful in practicing the present invention include, but are not limited to:
  • More preffered compounds of the present invention include, but are not limited to:
  • the compounds of the invention may be prepared by a variety of synthetic routes. Representative procedures are outlined in Schemes1 -3, below.
  • the 5-hydroxypyridazinone product was treated with triflic anhydride followed by substitution on the pyridazinone ring using 4- methylthiobenzeneboronic acid. This furnished the methyl thioether compound which was reacted with peracetic acid in acetic acid and methylene chloride to provide the methyl sulfone.
  • the benzyl group is removed using aluminum bromide or another suitable Lewis acid.
  • the R group can be added via substitution using an appropriate alkylating agent and base.
  • the product is then coupled with a second boronic acid such as 4-fluorobenzeneboronic acid (shown) and a palladium catalyst to provide the thioether.
  • a second boronic acid such as 4-fluorobenzeneboronic acid (shown) and a palladium catalyst to provide the thioether.
  • MCPBA meta-chloroperoxybenzoic acid
  • the benzyl group is removed using aluminum bromide or another suitable Lewis acid.
  • the R group can be added via substitution using an appropriate alkylating agent and base.
  • the dithioacetal ketene was directly cyclized to the unsubstituted pyridazinone using hydrazine and a salt.
  • the pyridazinone was oxidized with peroxyacetic acid to provide the sulfonyl pyridazone.
  • the thioacetal ketene was treated with perchloric acid to provide an ester-aldehyde as a mixture of diastereomers.
  • the oxidation products were treated with hydrazine and then oxidized with peroxyacetic acid to obtain the sulfonyl dihydropyridazinone.
  • the dihydropyridazinone can be dehydrogenated to form the pyridazinone by treatment with reagents such as bromine in acetic acid.
  • the R group may be added via substitution using an appropriate alkylating agent and base.
  • a general route to the compounds of the invention having Formula III, where the aryl group at the 5-position on the pyridazinone ring is substituted with a sulfonyl group ring is described in Scheme 5, below.
  • a mucohalo acid such as, for example, mucobromic or mucochloric acid
  • an hydrazine having the desired R group is reacted with an hydrazine having the desired R group to provide the dihalopyridazinone compound, 5A.
  • Treatment of the dihalo-compound with an alcohol in the presence of a base, such as, for example, sodium or potassium hydride, will provide an alkoxide, 5B. (If the alkoxy group is to be removed at a .
  • Reaction of the alkoxy-halide with a methylthiophenyl boronic will provide the alkoxy-pyridazinone 5C.
  • the alkoxy group can be converted to a hydrocarbyl group by treatment with a Ghgnard reagent to provide the thioether 5D.
  • the thioether can be oxidized with an oxidizing agent, such as, for example, peracetic acid, meta-chloroperoxybenzoic acid and the like, to form the sulfinyl compound 5G, or the methylsulfone compound 5E. Rearrangement and hydrolysis of the sulfinyl compound, 5G, provides the thiophenol.
  • the thiophenol is then oxidized, activated and aminated to convert it to the amino-sulfonyl compound 5H.
  • the methylsulfonyl compound, 5E can be converted to the amino- sulfonyl compound by 5H by treatment of the methylsulfonyl compound with a diazodicarboxylate, such as, for example, DBAD, DIAD, DEAD and the like, and a disilazane anion, such as, for example, lithium HMDS and the like, followed by treatment with sodium acetate and hydroxylamine-O-sulphonic acid in water provides the aminosulfonyl compound, 5H.
  • a diazodicarboxylate such as, for example, DBAD, DIAD, DEAD and the like
  • a disilazane anion such as, for example, lithium HMDS and the like
  • the alkoxy-pyridazinone 5C can be oxidized, as shown in Scheme 5A.
  • the first step is employing an oxidizing agent, such as, for example, peracetic acid, meta-chloroperoxybenzoic acid and the like, to form the sulfinyl compound 5G ⁇ or the methylsulfone compound 5E'.
  • an oxidizing agent such as, for example, peracetic acid, meta-chloroperoxybenzoic acid and the like
  • Rearrangement and hydrolysis of the sulfinyl compound provides the thiophenol.
  • the thiophenol is then oxidized, activated and aminated to convert it to the amino-sulfonyl compound 5H'.
  • the methylsulfonyl compound can be converted to the aminosulfonyl compound by 5H' by treatment of the methylsulfonyl compound 5E' with a diazodicarboxylate, such as, for example, DBAD, DIAD, DEAD and the like, and a disilazane anion, such as, for example, lithium HMDS and the like, followed by treatment with sodium acetate and hydroxylamine-O-sulphonic acid in water provides the aminosulfonyl compound, 5H'.
  • a diazodicarboxylate such as, for example, DBAD, DIAD, DEAD and the like
  • a disilazane anion such as, for example, lithium HMDS and the like
  • the bromo compound can be reacted with a thio compound in the presence of a base, such as, for example, silver carbonate, to provide the 4-alkyl-thioether, 6C.
  • a base such as, for example, silver carbonate
  • the bromo compound can be reacted with an amine and a weak base, such as, for example, sodium or potassium carbonate to provide the 4-alkyl amino-alkyl compound 6D.
  • the dichloromethane solution was dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure.
  • the residue was purified by column chromatography (silica gel, 7:3 hexanes/ethyl acetate) to provide the desired sulfone product. Further elution with 100% ethyl acetate removed the sulfoxide from the column.
  • the sulfoxide product was re-subjected to the MCPBA oxidant (0.04 g, 1 hour, 0 °C) and worked-up as described above.
  • the residue obtained was combined with the sulfone from the first column and the mixture was purified by column chromatography (silica gel, 7:3 hexanes/ethyl acetate).
  • the 2-phenyl-4-chloro-5-methoxy-3(2H)-pyridazinone compound was prepared according to the method of S. Cho et al. described in J. Het. Chem., 1996, 33, 1579-1582, , starting with the N-phenyl-dichloropyridazinone.
  • the 2-phenyl-4-(4-fluorophenyl)-5-hydroxy-3(2H)-pyridazinone product was sulfonylated according to the method of Example ⁇ to furnish 2-phenyl-4-(4- fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)-pyridazinone (yield: 1.35 g; 96%) MS (DCI-NH3) m/z 415 (M+H)+, 432 (M+NH4)+. 12E.
  • 2-Phenyl-4- 4-fluorophenvn-5-[4-fmethylsulfonvnphenyl1-3f2HVpyridazinone
  • the 2-phenyl-4-(4-fluorophenyl)-5-trifluoromethanesulfonyloxy-3(2H)- pyridazinone was coupled with 4-(methylthio)phenylboronic acid as in Example 9 to provide 2-phenyl-4-(4-Fluorophenyl)-5-[4-(methylthio)phenyl]-3(2H)- pyridazinone (yield: 915 mg, 92%) which was immediately oxidized with peracetic acid as in Example 9 to provide the title compound after column chromatography (silica gel, 1 :1 hexanes-ethyl acetate) and crystallization from diethyl ether-hexanes (yield: 2 ⁇ mg, 69%). M.p. 219-220 °C
  • a catalytic amount (0.5 mL) of concentrated sulfuric acid was added to a solution of 4-fluorophenyiacetic acid (30.8 g, 0.20 mol) in 500 mL of methanol. The solution was stirred at reflux for 4 hours. The volatile materials were removed under reduced pressure to furnish a colorless oil which was dissolved in ether/ethyl acetate and washed with 2 N aqueous Na2CO3, brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an oil which was dried overnight under high vacuum (yield: 33.6 g; 95%).
  • the aldehyde-ester, hydrate, and hydroxy lactone prepared in Example 16 (0.10 g, 3 mmol), were dissolved in 100 mL of ethanol. This solution was treated with hydrazine monohydrate (0.15 mL, 30 mmol) and the resulting solution was stirred at reflux in a Soxhelet apparatus containing molcular sieves. After 1 ⁇ hours, the reaction mixture was cooled and the volatile materials removed under reduced pressure. The residue was partitioned between ethyl acetate and aqueous HCl. The aqueous layer was washed twice with ethyl acetate. The combined organic extracts were washed twice with brine, dried over MgS04, and filtered.
  • the dihydropyridazinone product prepared according to the method of Example 18 (47 mg, 0.136 mmol) was dissolved in acetic acid (25 mL). Bromine (0.025 mL, 0.16 mmol) was added to the solution and the reaction mixture was stirred at 95 °C for 20 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgS04 and filtered. The filtrate was concentrated under reduced pressure to provide a solid which was eluted through a short pad of silica gel with ethyl acetate.
  • Example 40 2-(2.3.3.4.4.4-Hexafluoro-n-buten-1 -vh-4-(4-fluoroph ⁇ nyl)-5-[4-(m ⁇ thylsulfonyl)- phenyl]-3(2H)-pyridazinone
  • Example 48 2-fPropargv ⁇ -4-(4-fluorophenylV5-[4-(methylsulfonvnphenyl]-3(2H pyridazinone
  • Example 53 2-Benzyl-4-(4-chloropheny ⁇ -5-[4-(methylsulfony ⁇ phenyl]-3(2H)-pyridazinone
  • the title compound was prepared according to the method described in Examples 6-10 except substituting 4-chlorobenzeneboronic acid for 4-fluoro- benzeneboronic acid in Example 6.
  • Example 63 The product of Example 63 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (3 mL) and treated with 1 ,1 ,1 -trifluoro-2-iodoethane (27.5 mL, 280 mmol) in presence of anhydrous sodium carbonate (130 mg, 1.2 mmol) at 50-60 °C for 2 hours. The reaction mixture was partitioned between water and ethyl acetate to provide the desired compound as an amorphous solid (60 mg, 48%).
  • the title compound was prepared by coupling 4-(n-propyl)phenylboronic acid with 2-benzyl-4-bromo-5-methoxy-3(2H)-pyhdazinone (J. Het. Chem., 1996, 33, 1579-1582) according to the method of Example 6. This product was converted to the 5-hydroxy- derivative according to the method of Example 7. This product was converted to the 5-trifluoromethylsufonyloxy-derivative according to the method of Example 8.
  • the title compound was prepared by first coupling 3-fluoro-4- chlorophenylboronic acid with 2-benzyl-4-chloro-5-methoxy-3(2H)-pyridazinone according to the method of Example 6.
  • the product was converted to the 5-hydroxy compound according to the method of Example 7.
  • This 5-hydroxy compound was converted to the 5-trifluoromethylsufonyloxy-derivative according to the method of Example 8.
  • Coupling of 4-(methylthio)phenylboronic acid to the triflate according to the method of Example 9 provided the 5-[4-(methylthio)phenyl]-intermediate which was oxidized according to the method of Example 10 to provide the final product (yield: 170 mg, 84%).
  • the product was coupled with 4-chlorophenylboronic acid following the method of Example 6.
  • the product was N-debenzylated according to the method of Example 11 and N-alkylated with 2-iodo-1 ,1 ,1 -trifluoroethane according to the method of Example 20 to provide the sulfice compound.
  • Example 83 The methyl sulfide intermediate prepared in Example 83 was oxidized with one equivalent of mera-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 396 mg, 60%). M.p. 158-160 °C. 1 H NMR (300 MHz, CDCI3) ⁇
  • Example 76 The methyl sulfide intermediate of Example 76 was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example
  • An alternative method for preparing 2-fluorothioanisole begins with a solution of 1 ,2-difluorobenzene (0.79 mL, 8 mmol) in anhydrous DMF (50 mL) was treated with sodium thiomethoxide (0.59 g, 8 mmol). The reaction mixture was stirred at room temperature for 6 hours, and partitioned between hexanes and water. The organic layer was washed with brine, dried over MgS04, and filtered.
  • This product was N-debenzylated according to the method of Example 11 and N-arylated with 4-fluoroiodobenzene according to the method of Example 62.
  • the resulting sulfide was oxidized with one equivalent of meta-chloroperoxybenzoic acid to provide the methylsulfoxide which was converted to the sulfonamide final product according to the method of Example 68 (yield: 500 mg, 75%).
  • Example 67 The methyl sulfide intermediate prepared in Example 67 was oxidized with one equivalent of met ⁇ -chloroperoxybenzoic acid, according to the method of
  • Example 68 to provide the methyl sulfoxide.
  • the methyl sulfoxide was converted to the sulfonamide product according to the method of Example 68 (yield: 1.5 g, 63%).
  • This product was N-debenzylated according to the method of Example 11 and N-alkylated with 2- iodo-1 ,1 ,1 -trifluoroethane according to the method of Example 20.
  • the resulting sulfide was oxidized to the corresponding sulfoxide with one equivalent of meta- chloroperoxybenzoic acid, according to the method of Example 5 to provide the title compound (yield: 130 mg, 70%). M.p. 154-155 °C.
  • Example 65 The product described in Example 65 was N-debenzylated according to the method of Example 1 1.
  • the intermediate was N-alkylated according to the method of Example 20, substituting 2-iodo-1 ,1 ,1 -trifluoroethane in place of 4-fluorobenzyl bromide to provide the title compound (yield: 165 mg, 55%). M.p. 197-198 °C.
  • 2,3,3-Thfluoro-2-propen-1 -ol was prepared as reported in J. Org. Chem., 1989, 54, 5640-5642.
  • the mesylate was obtained by reacting 2,3,3- trifluoro-2-propen-1 -ol with mesyl chloride in diethyl ether. Standard workup provided the product, which was used without purification.
  • Example 108 2-(4-Fluorophenv ⁇ -4-( , 4-fluorophenoxy 5-[4-(methylsulfonvhphenyl]-3(2HV pvridazinone 108A. 4-( , 4-FluorophenoxyV5-[4-(methylsulfonv ⁇ phenyl -3f2H)-pyridazinone
  • Example 108A The title compound was prepared according to Example 93, substituting 1 - bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4- fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 185 mg, 39%). M.p. 178-180 °C. 1 H NMR (300 MHz, CDCI3) ⁇ 3.11 (s, 3H), 6.89-
  • Example 108A The title compound was prepared according to Example 93, substituting 1 ,3- dibromobenzene in place of 4-bromothioanisole and 4-(4-fluorophenoxy)-5-[4- (methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4- fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 260 mg, 50.5%). M.p. 208-210 °C. 1 H NMR (300 MHz, CDCI3) ⁇ 3.09 (s, 3H), 6.89-7.04 (m,
  • Example 108A The title compound was prepared according to Example 93, substituting 1 - bromo-3,4-difluorobenzene in place of 4-bromothioanisole and 4-(4- fluorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 108A) in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 175 mg, 37%).
  • Example 115 2-(4-Hydroxybenzy ⁇ -4-(4-fluoropheny ⁇ -5-[4-(methylsulfony ⁇ phenyl]-3(2H)- pvridazinone
  • the bromo-styrene compound, prepared above, in 10 mL of THF was added dropwise to a heated mixture of magnesium turnings (120 mg, 5 mmol) and a few drops of 1 ,2-dibromoethane in THF (20 mL) at a rate to maintain a gentle reflux.
  • the mixture was refluxed for the next 30 minutes and cooled to room temperature.
  • the Grignard reagent solution was cooled to -78 °C and added, dropwise, to a solution of 2-(3,4-difluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)- pyridazinone (540 mg, 1.5 mmol) in THF (20 mL).
  • the reaction mixture was allowed to warm to room temperature for 12 hours. Afterwards, a saturated solution of NH4CI was added and the mixture was extracted with ethyl acetate to provide 320 mg of crude sulfide.
  • the intermediate sulfide product was dissolved in CH2CI2 (10 mL) and treated at 0 °C with 33% solution of CH3CO3H in CH3CO2H (0.7 mL) for 1 hour.
  • the sulfonyl compound, prepared above, was dissolved in acetone (50 mL) and treated with 2 N HCl (10 mL). The resulting mixture was refluxed for 16 hours and concentrated in vacuo. The residue was extracted with ethyl acetate to provide 900 mg of 2-(3,4-difluorophenyl)-4-(2-formylethyl)-5-[4-(methylsulfonyl)phenyl]- 3(2H)-pyridazinone (crude aldehyde, contaminated with some unreacted starting dioxane derivative).

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CA2299300A1 (en) 1999-03-04
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