USRE44048E1 - 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-YL]benzenesulfonamide for the treatment of inflammation or an inflammation-associated disorder - Google Patents

4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-YL]benzenesulfonamide for the treatment of inflammation or an inflammation-associated disorder Download PDF

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USRE44048E1
USRE44048E1 US12/205,319 US20531996A USRE44048E US RE44048 E1 USRE44048 E1 US RE44048E1 US 20531996 A US20531996 A US 20531996A US RE44048 E USRE44048 E US RE44048E
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pyrazol
benzenesulfonamide
trifluoromethyl
phenyl
chloro
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John J. Talley
Stephen R. Bertenshaw
Julie M. Miyashiro
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GD Searle LLC
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    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D409/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
  • NSAIDs common non-steroidal anti-inflammatory drugs
  • An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
  • styryl pyrazole esters for antidiabetes drugs is described [H. Mokhtar et al, Pharmazie, 33, 649-651 (1978)].
  • styryl pyrazole carboxylic acids for antidiabetes drugs is described [R. Soliman et al, Pharmazie, 33, 184-5 (1978)].
  • a series of 443 4,4,3-substituted methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamides has been prepared as intermediates for anti-diabetes agents, and more specifically, 4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide [H. Feid-Allah, Pharmazie, 36, 754 (1981)].
  • 1-(4-[aminosulfonyl]phenyl)-5-phenylpyrazole-3-carboxylic acid has been prepared from the above described 443 4,4,3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide compound [R. Soliman et al, J.Par-m. Pharm. Sci., 70, 602 (1981)].
  • a class of compounds useful in treating inflammation-related disorders is defined by Formula I:
  • R 1 is selected from aryl and heteroaryl, wherein R 1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, alkyl, alkoxy, hydroxyl, haloalkyl and
  • R 2 is selected from hydrido, halo, alkyl, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, cyanoalkyl, alkoxycarbonylcyanoalkenyl, aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclicaminocarbonyl, carboxyalkylaminocarbonyl, aralkoxycarbonylalkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, haloaralkyl, carboxyhaloalkyl, alkoxycarbony
  • R 3 is selected from hydrido, alkyl, halo, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, aminocarbonyl, alkoxy, N-alkylamino, N,N-dialkylamino, aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N,N-dialkylaminos
  • R 4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkenyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxylakyl, haloalkoxy, sulfamyl, N-alkylaminosulfonyl, amino, N-alkylamino, N,N-dialkylamino, heterocyclic, cycloalkylalkyl, nitro,
  • A is selected from phenyl and five or six membered heteroaryl
  • R 5 is alkyl
  • R 6 is one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, alkyl, alkenyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylaminosulfonyl, amino, N-alkylamino, N,N-dialkylamino, heterocyclic, cycloalkylalkyl, nitro and acylamino; and
  • R 7 is selected from hydrido, alkyl, aryl and aralkyl
  • R 2 and R 3 are not identical radicals selected from hydrido, carboxyl and ethoxycarbonyl; further provided that R 2 is not carboxyl or methyl when R 3 is hydrido and when R 4 is phenyl; further provided that R 4 is not triazolyl when R 2 is methyl; further provided that R 4 is not aralkenyl when R 2 is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R 4 is not phenyl when R 2 is methyl and R 3 is carboxyl; further provided that R 4 is not unsubstituted thienyl when R 2 is trifluoromethyl; and further provided that R 4 is aryl substituted with sulfamyl or R 6 is sulfamyl, when R 1 is phenyl not substituted with sulfamyl; or a pharmaceutically-acceptable salt thereof.
  • Compounds of Formula I the present invention would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever.
  • compounds of Formula I the present invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • Such compounds of Formula I the present invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns and dermatitis.
  • Compounds of Formula I the present invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention of colorectal cancer.
  • Compounds of Formula I the present invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, myocardial ischemia, and the like.
  • the compounds are useful as antiinflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects.
  • the present invention preferably includes compounds which selectively inhibit cyclooxygenase II over cyclooxygenase I.
  • the compounds have a cyclooxygenase II IC 50 of less than about 0.2 ⁇ M, and also have a selectivity ratio of cyclooxygenase II inhibition over cyclooxygenase I inhibition of at least 50, and more preferably of at least 100.
  • the compounds have a cyclooxygenase I IC 50 of greater than about 1 ⁇ M, and more preferably of greater than 10 ⁇ M.
  • Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
  • a preferred class of compounds consists of those compounds of Formula I wherein R 1 is selected from aryl selected from phenyl, naphthyl and biphenyl, and five- or six-membered heteroaryl, wherein R 1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy, hydroxyl, lower haloalkyl and
  • R 2 is selected from hydrido, halo, lower alkyl, lower haloalkyl, cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, amidino, cyanoamidino, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, aminocarbonyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl, lower heterocyclicaminocarbonyl, lower carboxyalkylaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl, lower haloaralkyl, lower carboxyhalo
  • R 3 is selected from hydrido, lower alkyl, halo, lower haloalkyl, cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, amidino, cyanoamidino, aminocarbonyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, lower N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower alkylcarbonyl, lower alkylcarbonylalkyl, lower hydroxyalkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower N-alkylaminosulfonyl, N-arylaminosulfonyl,
  • R 4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower N-alkylaminosulfonyl, amino, lower N-alkylamino, lower N
  • A is selected from phenyl and five or six membered heteroaryl
  • R 5 is lower alkyl
  • R 6 is one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower alkyl, lower alkenyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower haloalkyl, hydrido, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower N-alkylaminosulfonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five- or six membered heterocyclic, lower cycloalkylalkyl, nitro and acylamino; and
  • R 7 is selected from hydrido, lower alkyl, aryl and lower aralkyl
  • a more preferred class of compounds consists of those compounds of Formula I where R 1 is phenyl, wherein R 1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy, hydroxyl, lower haloalkyl and
  • R 2 is selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl
  • R 3 is selected from hydrido, lower alkyl, halo, cyano, lower hydroxyalkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lower N,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl and lower cycloalkyl;
  • R 4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower alkylaminosulfonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five or six membered heterocyclic, lower cycloalkylalkyl, nitro,
  • A is selected from phenyl and five or six membered heteroaryl
  • R 5 is lower alkyl
  • R 6 is one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, amino, lower N-alkylamino, lower N,N-dialkylamino, lower cycloalkylalkyl and nitro; and
  • R 7 is selected from hydrido, lower alkyl, aryl and lower aralkyl
  • An even more preferred class of compounds consists of those compounds of Formula I wherein R 1 is phenyl, wherein R 1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy and
  • R 2 is selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl
  • R 3 is selected from hydrido, lower alkyl, halo, cyano, lower hydroxyalkyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower alkylthio, lower alkylsulfonyl and lower cycloalkyl;
  • R 4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five or six membered heterocyclic, lower cycloalkylalkyl, nitro,
  • A is selected from phenyl and five membered heteroaryl
  • R 5 is lower alkyl
  • R 6 is one or more radicals selected from halo, lower alkyl, lower alkylsulfonyl, lower haloalkyl, lower alkoxy, sulfamyl, amino and nitro;
  • R 7 is selected from hydrido, lower alkyl, aryl and lower aralkyl
  • R 2 is selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl
  • R 3 is selected from hydrido, lower alkyl, halo, cyano, lower hydroxyalkyl, lower alkoxy, lower alkylthio, lower N-alkylamino, lower N,N-dialkylamino, lower alkylsulfonyl and lower cycloalkyl;
  • R 4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower alkylaminocarbonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five or six membered heterocyclic, lower cycloalkylalkyl, nitro,
  • R 5 is lower alkyl
  • R 7 is selected from hydrido, lower alkyl, aryl and lower aralkyl
  • a class of compounds of particular interest consists of those compounds of Formula I wherein R 1 is phenyl, substituted at a substitutable position with one or more radicals selected from fluoro, chloro, methyl, sulfamyl and
  • R 2 is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoromethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano, carboxyl methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexan
  • R 3 is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl, fluoro, chloro, bromo, cyano, methoxy, methylthio, methylsulfonyl, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyclopropyl, cyclopentyl, hydroxypropyl, hydroxymethyl, and hydroxyethyl; and
  • R 4 is selected from phenylethenyl, phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, 1-cyclopentenyl, 4-cyclopentenyl, benzofuryl, 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydronaphthyl, benzothienyl, indenyl, indanyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R
  • R 7 is selected from hydrido, methyl, ethyl, phenyl and benzyl;
  • R 1 is phenyl substituted at a substitutable position with sulfamyl
  • R 2 is selected from lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl and lower hydroxyalkyl; wherein R 3 and R 4 together form
  • m is 2; wherein A is selected from phenyl and five membered heteroaryl; and where R 6 is one or more radicals selected from halo, lower alkyl, lower alkylsulfonyl, lower haloalkyl, lower alkoxy, amino and nitro; or a pharmaceutically-acceptable salt thereof.
  • a class of compounds of particular interest consists of those compounds of Formula I wherein R 2 is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl, aminocarbonyl, N-methyla
  • R 1 is selected from phenyl, naphthyl, biphenyl, and five- or six-membered heteroaryl, wherein R 1 is substituted at a substitutable position with one or more radicals selected from halo, lower alkyl, lower alkoxy, hydroxyl and lower haloalkyl; wherein R 2 is selected from lower haloalkyl; wherein R 3 is hydrido; and wherein R 4 is aryl substituted at a substitutable position with sulfamyl; or a pharmaceutically-acceptable salt thereof.
  • a class of compounds of particular interest consists of those compounds of Formula I wherein R 1 is selected from phenyl, naphthyl, benzofuryl, benzothienyl, indolyl, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R 1 is substituted at a substitutable position with one or more radicals selected from fluoro, chloro, bromo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichloropropyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, methyl, ethyl, propyl
  • R 2 is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl;
  • R 3 is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo;
  • R 4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfanyl, heterocyclic and amino;
  • R 2 and R 3 are not both hydrido; further provided that R 2 is not carboxyl or methyl when R 3 is hydrido and when R 4 is phenyl; further provided that R 4 is not triazolyl when R 2 is methyl; further provided that R 4 is not aralkenyl when R 2 is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R 4 is not phenyl when R 2 is methyl and R 3 is carboxyl; and further provided that R 4 is not unsubstituted thienyl when R 2 is trifluoromethyl;
  • a class of compounds of particular interest consists of those compounds of Formula II wherein R 2 is selected from hydrido, lower alkyl, lower haloalkyl, lower alkoxycarbonyl, cyano, lower cyanoalkyl, carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower cycloalkylaminocarbonyl, arylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl, lower aminocarbonylalkyl, lower carboxyalkyl, lower alkoxycarbonylcyanoalkenyl and lower hydroxyalkyl;
  • R 3 is selected from hydrido, lower alkyl, cyano, lower hydroxyalkyl, lower cycloalkyl, lower alkylsulfonyl and halo;
  • R 4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R 4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfonyl, cyano, nitro, lower haloalkyl, lower alkyl, hydroxyl, lower alkenyl, lower hydroxyalkyl, carboxyl, lower cycloalkyl, lower alkylamino, lower dialkylamino, lower alkoxycarbonyl, aminocarbonyl, lower alkoxy, lower haloalkoxy, sulfamyl, five or six membered heterocyclic and amino; or a pharmaceutically-acceptable salt thereof.
  • a family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:
  • One compound of the present invention is 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
  • Another compound of the present invention is 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
  • Another compound of the present invention is 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
  • Another compound of the present invention is 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
  • Another compound of the present invention is 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
  • Another compound of the present invention is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
  • hydro denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (—CH 2 —) radical.
  • alkyl is used, either alone or within other terms such as “haloalkyl” and “alkylsulfonyl”, it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms.
  • alkyl radicals having one to about six carbon atoms.
  • examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.
  • alkenyl embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkyl radicals are “lower alkenyl” radicals having two to about six carbon atoms.
  • radicals examples include ethyl, n-propenyl, butenyl, and the like.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are amonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals.
  • a monohaloalkyl radical, or one example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are “lower hydroxylalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
  • alkoxy and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
  • alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.
  • alkoxyalkyl also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxyalkyl radicals are “lower alkoxyalkyl” radicals having one to six carbon atoms and one or two alkoxy radicals.
  • radicals examples include methoxymethyl, methoxyethyl, ethoxyethyl, methoxybutyl and methoxypropyl.
  • the “alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” or “haloalkoxyalkyl” radicals.
  • halo atoms such as fluoro, chloro or bromo
  • examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.
  • heterocyclic embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g.
  • heteroaryl embraces unsaturated hetereocyclic radicals.
  • heteroaryl radicals examples include unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotraizolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridinzinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and
  • benzoxazolyl, benzoxadiazolyl, etc.] unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, triazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like.
  • the term also embraces radicals where heterocyclic radicals are fused with aryl radicals.
  • fused bicyclic radicals examples include benzofuran, benzothiophene, and the like.
  • Said “heterocyclic group” may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino.
  • Preferred heterocyclic radicals include five to ten membered fused or unfused radicals.
  • heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl.
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO 2 —.
  • Alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl.
  • arylsulfonyl embraces aryl radicals as defined above, attached to a sulfonyl radical. Examples of such radicals include phenylsulfonyl.
  • sulfamyl denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (—SO 2 NH 2 ).
  • N-alkylaminosulfonyl and “N,N-dialkylaminosulfonyl” denote sulfamyl radicals substituted, respectively, with one alkyl radical, or two alkyl radicals. More preferred alkylaminosulfonyl radicals are “lower alkylaminosulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl.
  • N-arylaminosulfonyl and “N-alkyl-N-arylaminosulfonyl” denote sulfamyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. More preferred N-alkyl-N-arylaminosulfonyl radicals are “lower N-alkyl-N-arylsulfonyl” radicals having alkyl radicals of one to six carbon atoms.
  • N-alkyl-N-aryl aminosulfonyl radicals examples include N-methyl-phenylaminosulfonyl and N-ethyl-phenylaminosulfonyl
  • carboxy or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO 2 H.
  • alkanoyl or “carboxyalkyl” embrace radicals having a carboxy radical as defined above, attached to an alkyl radical.
  • alkanoyl radicals may be substituted or unsubstituted, such as formyl, acetyl, propionyl (propanoyl), butanoyl (butyryl), isobutanoyl (isobutyryl), valeryl (pentanoyl), isovaleryl, pivaloyl, hexanoyl or the like.
  • carbonyl whether used alone or with other terms, such as “alkylcarbonyl”, denotes —(C ⁇ O)—.
  • alkylcarbonyl embraces radicals having a carbonyl radical substituted with an alkyl radical.
  • alkylcarbonyl radicals are “lower alkylcarbonyl” radicals having one to six carbon atoms. Examples of such radicals include methylcarbonyl and ethylcarbonyl.
  • alkylcarbonylalkyl denotes an alkyl radical substituted with an “alkylcarbonyl” radical.
  • alkoxycarbonyl means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical.
  • “lower alkoxycarbonyl” embraces alkoxy radicals having one to six carbon atoms.
  • lower alkoxycarbonyl ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl.
  • alkoxycarbonylalkyl embraces radicals having “alkoxycarbonyl”, as defined above substituted to an alkyl radical. More preferred alkoxycarbonylalkyl radicals are “lower alkoxycarbonylalkyl” having lower alkoxycarbonyl radicals as defined above attached to one to six carbon atoms.
  • Examples of such lower alkoxycarbonylalkyl radicals include methoxycarbonylmethyl, tert-butoxycarbonylethyl, and methoxycarbonylethyl.
  • N-alkylaminocarbonyl and “N,N-dialkylaminocarbonyl” denote aminocarbonyl radicals which have been substitute with one alkyl radical and with two alkyl radicals, respectively. More preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to an aminocarbonyl radical.
  • N-arylaminocarbonyl and “N-alkyl-N-arylaminocarbonyl” denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical.
  • aminocarbonylalkyl embraces alkyl radicals substituted with aminocarbonyl radicals.
  • N-cycloalkylaminocarbonyl denoted aminocarbonyl radicals which have been substituted with at least one cycloalkyl radical. More preferred are “lower cycloalkylaminocarbonyl” having lower cycloalkyl radicals of three to seven carbon atoms, attached to an aminocarbonyl radical.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals.
  • alkylaminoalkyl embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical.
  • aminodino denotes an —C( ⁇ NH)—NH 2 radical.
  • heterocyclicalkyl embraces heterocyclic-substituted alkyl radicals. More preferred heterocyclicalkyl radicals are “lower heterocyclicalkyl” radicals having one to six carbon atoms and a heterocyclic radical. Examples include such radicals as pyrrolidinylmethyl, pyridylmethyl and thienylmethyl.
  • aralkyl embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms.
  • radicals examples include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.
  • benzyl and phenylmethyl are interchangeable.
  • cycloalkyl embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to seven carbon atoms.
  • radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkenyl embraces unsaturated cyclic radicals having three to ten carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
  • An example of “alkylthio” is methylthio, (CH 3 —S—).
  • alkylsulfinyl embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S( ⁇ O)— atom.
  • aminoalkyl embraces alkyl radicals substituted with amino radicals. More preferred aminoalkyl radicals are “lower aminoalkyl” having one to six carbon atoms. Examples include aminomethyl, aminoethyl and aminobutyl.
  • alkylaminoalkyl embraces aminoalkyl radicals having the nitrogen atom substituted with at least one alkyl radical.
  • More preferred alkylaminoalkyl radicals are “lower alkylaminoalkyl” having one to six carbon atoms attached to a lower aminoalkyl radical as described above.
  • the terms “N-alkylamino” and “N,N-dialkylamino” denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively.
  • More preferred alkylamino radicals are “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom.
  • Suitable “alkylamino” may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.
  • arylamino denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino.
  • the “arylamino” radicals may be further substituted on the aryl ring portion of the radical.
  • aralkylamino denotes amino groups which have been substituted with one or two aralkyl radicals, such as N-benzylamino.
  • the “aralkylamino” radicals may be further substituted on the aryl ring portion of the radical.
  • the terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denote amino groups which have been substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
  • the terms “N-arylaminoalkyl” and “N-aralkylaminoalkyl” denote amino groups which have been substituted with one aryl radical or one aralkyl radical, respectively, and having the amino group attached to an alkyl radical.
  • More preferred arylaminoalkyl radicals are “lower arylaminoalkyl” having the arylamino radical attached to one to six carbon atoms.
  • Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl.
  • N-alkyl-N-arylaminoalkyl and “N-aralkyl-N-alkylaminoalkyl” denote N-alkyl-N-arylamino and N-alkyl-N-aralkylamino groups, respectively, and having the amino group attached to alkyl radicals.
  • acyl denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
  • acylamino embraces an amino radical substituted with an acyl group.
  • An examples of an “acylamino” radical is acetylamino or acetamido (CH 3 C( ⁇ O)—NH—) where the amine may be further substituted with alkyl, aryl or aralyl.
  • arylthio embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom.
  • arylthio is phenylthio.
  • aralkylthio embraces aralkyl radicals as described above, attached to a divalent sulfur atom.
  • An example of “aralkylthio” is benzylthio.
  • aryloxy embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy.
  • aralkoxy embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are “lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above.
  • haloaralkyl embraces aryl radicals as defined above attached to haloalkyl radicals.
  • carboxyhaloalkyl embraces carboxyalkyl radicals as defined above having halo radicals attached to the alkyl portion.
  • alkoxycarbonylhaloalkyl embraces alkoxycarbonyl radicals as defined above substituted on a haloalkyl radical.
  • aminocarbonylhaloalkyl embraces aminocarbonyl radicals as defined above substituted on a haloalkyl radical.
  • alkylaminocarbonylhaloalkyl embraces alkylaminocarbonyl radicals as defined above substituted on a haloalkyl radical.
  • alkoxycarbonylcyanoalkenyl embraces alkoxycarbonyl radicals as defined above, and a cyano radical, both substituted on an alkenyl radical.
  • carboxyalkylaminocarbonyl embraces aminocarbonyl radicals substituted with carboxyalkyl radicals, as defined above.
  • aralkoxycarbonylalkylaminocarbonyl embraces aminocarbonyl radicals substituted with aryl-substituted alkoxycarbonyl radicals, as defined above.
  • cycloalkylalkyl embraces cycloalkyl radicals having three to ten carbon atoms attached to an alkyl radical, as defined above.
  • More preferred cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to lower alkyl radicals as defined above. Examples include radicals such as cyclopropylmethyl, cyclobutylmethyl, and cyclohexylethyl.
  • aralkenyl embraces aryl radicals attached to alkenyl radicals having two to ten carbon atoms, such as phenylbutenyl, and phenylethenyl or styryl.
  • the present invention comprises a pharmaceutical composition for the treatment of inflammation and inflammation-associated disorders, such as arthritis, comprising a therapeutically-effective amount of a compound of Formula I the present invention in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
  • the present invention also comprises a therapeutic method of treating inflammation or inflammation-associated disorders in a subject, the method comprising administering to a subject having such inflammation or disorder a therapeutically-effective amount of a compound of Formula I the present invention.
  • pharmaceutically-acceptable salts are also included in the family of compounds of Formula I the present invention.
  • pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I the present invention may be prepared from an inorganic acid or from an organic Acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, ⁇ -hydroxybutyric, sali
  • Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I the present invention by reacting, for example, the appropriate acid or base with the compound of Formula I the present invention.
  • Synthetic Scheme I shows the preparation of tetrasubstituted pyrazoles from starting material 1.
  • the phenyl-methyl ketone (1) is treated with a base and an alkylating reagent (R 3 X, where X represents a leaving group such as tosyl) to give the substituted ketone (2).
  • the substituted ketone (2) is treated with base, such as sodium methoxide, and an acylating reagent such as an ester (R 2 CO 2 CH 3 ), or ester equivalent (R 2 CO-imidazole, to give the intermediate diketone (3) in a procedure similar to that developed by Reid and Calvin, J. Amer. Chem.
  • step 3 the diketone (3) is reacted with a substituted hydrazine in acetic acid or an alcoholic solvent to give a mixture of pyrazoles (4) and (5). Separation of the desired pyrazole (4) can be achieved by chromatography or recrystallization.
  • Synthetic Scheme II shows the preparation of compounds embraced by Formula I, where R 3 is a hydrogen atom.
  • ketone (1) is treated with a base, preferably NaOMe or NaH, and an ester, or ester equivalent, to form the intermediate diketone (6) which is used without further purification.
  • diketone (6) in an anhydrous protic solvent such as absolute ethanol or acetic acid, is treated with the hydrochloride salt or the free base of a substituted hydrazine at reflux for 10 to 24 hours to afford a mixture of pyrazoles (7) and (8). Recrystallization from diethyl ether/hexane or chromatography affords (7), usually as a light yellow or tan solid.
  • Synthetic Scheme III shows the procedure for preparation of 4,5-dihydrobenz[g]indazole compounds embraced by Formula I.
  • step 1 ethyl trifluoroacetate is reacted with base, such as 25% sodium methoxide in a protic solvent, such as methanol, and a 1-tetralone derivative (9) to give the intermediate diketone (10).
  • step 2 the diketone (10) in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the free base or hydrochloride salt of a substituted hydrazine at reflux for 24 hours to afford a mixture of pyrazoles (11) and (12). Recrystallization gives the 4,5-dihydro benz[g]indazolyl-benzenesulfonamide (11).
  • Synthetic Scheme IV shows the preparation of pyrazole compounds (13), where R 3 is chlorine, from the available pyrazole compounds (7), where R 3 is hydrogen. Chlorination results from passing a stream of chlorine gas at room temperature through a solution containing (7).
  • Synthetic Scheme V shows the preparation of substituted ketones 18 which are not commercially available as used in Scheme I.
  • the ketones can be prepared by standard Friedel-Craft acylation of the starting substituted benzenes 14 with acid chlorides or anhydrides 15.
  • the ketones can be prepared from phenylcarbonitriles 16 by standard organometallic techniques where M represents metals such as lithium, magnesium, and the like.
  • An alternative organometallic route is shown from the aldehydes 17 where M represents metals such as lithium, magnesium, and the like. Oxidation with a suitable oxidizing agent, such as CrO 3 , follows to produce the ketones.
  • Synthetic Scheme VI shows an alternative regioselective method of constructing the pyrazole 21.
  • Commercially available enones 19 can be epoxidized to give epoxyketones 20, which are treated with 4-sulfonamidophenylhydrazine hydrochloride to provide the pyrazole 21.
  • Synthetic Scheme VII shows the preparation of pyrazoles 23 (where R 4 is 3-amino-4-substituted phenyl) from starting material 22.
  • Appropriate 5-(4-substituted aryl)pyrazoles can be nitrated next to the R-group under standard nitration conditions and the nitro group reduced to the amino group, preferably with hydrazine and Pd/C.
  • the amino compounds can be further manipulated by alkylation of the amino group.
  • Synthetic Scheme VIII shows the preparation of pyrazoles 26 from esters 24. Reduction of the ester 24 to the alcohol, preferably with lithium aluminum hydride (LAH) followed by oxidation, preferably with MnO 2 , gives the aldehyde 25. Various nucleophiles (such as hydroxamates and 1,3-dicarbonyl compounds) can be condensed with the aldehyde to give the desired oximines or olefins 26.
  • LAH lithium aluminum hydride
  • MnO 2 oxidation
  • nucleophiles such as hydroxamates and 1,3-dicarbonyl compounds
  • Ethyl trifluoroacetate (23.52 g, 166 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in methyl tert-butyl ether (75 mL). To the stirred solution was added 25% sodium methoxide (40 mL, 177 mmol) via an addition funnel over a 2 minute period. Next 4′-chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyl tert-butyl ether (20 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (15.75 hours), 3N HCl (70 mL) was added.
  • Step 2 Preparation of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
  • Example 2 was prepared in a similar manner using the appropriate acetophenone.
  • Methyl iodide 0.5 mL, 8.1 mmol
  • potassium carbonate 1.1 g, 8.1 mmol
  • the reaction was stirred at 50° C., for 4 hours and poured into hexane and water. The organic layer was separated, dried over magnesium sulfate and concentrated to afford 1.1 g of desired material.
  • Step 1 To a solution of the product in Example 6, Step 1 (3 g, 17.0 mmol) in 50 mL of ethanol was added a catalytic amount of 4% Pd/C. The reaction mixture was stirred in a Parr shaker at room temperature at 5 psi hydrogen for 0.5 hours. The reaction was filtered and concentrated to afford 4 g of pure 3-propyl-4-methoxy acetophenone.
  • Step 1 To a solution of the product in Example 6, Step 1 (3 g, 17.0 mmol) and catalytic Pd(OAc) 2 in 20 mL Et 2 O was added ethereal diazomethane until starting material was consumed. The reaction was filtered, concentrated and chromatographed on a 4000 micron chromatotron plate (20% EA/80% hexane as eluant) to afford 2.5 g of desired ketone.
  • Example 2 The product from Example 2 (1.13 g, 3.0 mmol) and N-bromosuccinimide (NBS, 0.64 g, 3.6 mmol) were dissolved in 40 mL of benzene and irradiated with a UV lamp for 3 hours. The reaction was cooled to room temperature and poured into 50 mL of H 2 O. The organic phase was separated, washed with brine and dried over MgSO 4 . The crude pyrazole was obtained as an amber oil. The oil was purified via radical band chromatography eluting with 30% ethyl acetate/70% hexane to afford the 4-bromomethyl compound as a yellow oil which crystallized upon standing.
  • the bromo methyl compound from Step 1 was dissolved in 30 mL of acetone/4 mL of H 2 O and refluxed for 120 hours. The reaction was concentrated and the residue dissolve in 50 mL of ethyl acetate and dried over MgSO 4 . The crude product was obtained as an amber oil. The oil was purified via radial band chromatography eluting with 30% ethyl acetate/70% hexane to afford the title compound as a yellow solid: Anal. calc'd for C 17 H 14 N 3 O 3 SF 3 : C, 51.38; H, 3.55; N, 10.57. Found: C, 51.28; H, 3.59; N, 10.31.
  • Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a 500 mL three-necked round bottom flash, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4′-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (18 hours), 1N HCl (250 mL) and ether (250 mL) were added.
  • Ethyl difluoroacetate (4.06 g, 32.7 mmol) was placed in a 250 mL Erlenmeyer flask, and dissolved in methyl tert-butyl ether (50 mL). To the stirred solution was added 25% sodium methoxide (7.07 g, 32.7 mmol) followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (5.0 g, 29.7 mmol). After stirring for 16 hours, 1N HCl (50 mL) was added.
  • Step 3 Preparation of 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • Dimethyl oxalate (23.6 g, 200 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4′-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 3 minutes. After stirring overnight (18 hours), 1N HCl (400 mL) and ethyl acetate (750 mL) were added.
  • This liquid was distilled (30° C., 1 mm) yielding 12.5 g of a clear liquid which was a mixture of 3,5-difluoro-4-methoxyacetophenone and 3,5-difluoro-4-acetoxyacetophenone in an 85:15 ratio. The yield based upon this ratio was 41%.
  • This ketone was used as is.
  • Step 1 Preparation of 4,4,5,5,6,6,6-heptafluoro-1-[4-(chloro)phenyl]hexane-1,3-dione
  • Ethyl heptafluorobutyrate (5.23 g, 21.6 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (20 mL). To the stirred solution was added 25% sodium methoxide (4.85 g, 22.4 mmol) followed by 4-chloroacetophenone (3.04 g, 19.7 mmol). The reaction was stirred at room temperature overnight (15.9 hours) and treated with 3N HCl (17 mL).
  • the 4-sulfonamidophenylhydrazine hydrochloride (290 mg, 1.30 mmol) was added to a stirred solution of the diketone from Step 1 (400 mg, 1.14 mmol) in ethanol (5 mL). The reaction was heated to reflux and stirred overnight (23.8 hours).
  • Step 1 Preparation of 4-chloro-4,4-difluoro-1-[4-(chloro)phenyl]-butane-1,3-dione
  • Methyl 2-chloro-2,2-difluoroacetate (4.20 g, 29 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (10 mL). To the stirred solution was added 25% sodium methoxide (6.37 g, 29 mmol) followed by 4′-chloroacetophenone (4.10 g, 26.5 mmol).
  • the ester was prepared from the butanoate in Step 1 using the procedure described in Example 2, Step 2.
  • Step 2 Preparation of 5-acetyl-4-methyl-1,3-benzodioxole (A) and 6-acetyl-4-methyl-1,3-benzodioxole (B)
  • Steps 3 and 4 4-[5-(4-methyl-1,3-benzodioxol-5yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
  • Example 142 4-[5-(1-Cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol (15 mL), 10% palladium on charcoal was added, and the suspension was stirred at room temperature under hydrogen (36 psi) for 18.25 hours.
  • a 60% dispersion of sodium hydride in mineral oil (4.0 g, 100 mmol) was twice washed with hexane (100 mL each) and dried under a stream of nitrogen.
  • Ether 300 mL was added followed by dropwise addition of ethanol (0.25 mL) and ⁇ -butyrolactone (4.0 mL, 52 mmol).
  • the mixture was cooled to 10° C. and acetophenone (5.8 mL, 50 mmol) in ether (40 mL) was added dropwise over 1 hour.
  • the mixture was warmed to 25° C. and stirred overnight.
  • the mixture was cooled to 0° C.
  • Step 3 To a solution of the alcohol prepared in Example 131, Step 3 (1.1 g, 3.3 mmol) in ethyl acetate (20 mL) was added MnO 2 (5 g, 60 mmol) and the mixture stirred at room temperature overnight. The mixture was filtered through Celite and the solution was concentrated to provide the crude aldehyde.
  • Example 1 A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (Example 1) (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water.
  • the diketone from Step 1 was dissolved in absolute ethanol (25 mL) and 4-sulfonamidophenylhydrazine hydrochloride (2.0 g, 9.0 mmol) was added. The mixture was heated at reflux for 19 hours. Volatiles were removed in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with water and brine, dried and concentrated.
  • Example 235 4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]benzenesulfonamide was isolated from the purification of Example 235 (0.153 g, 28%): High Resolution Mass Spectrum (M+) calc'd: 457.0208. Found: 457.0157. Elemental analysis calc'd for C 19 H 16 N 5 O 2 BrS: 49.79; H, 3.52: N, 15.28; Br, 17.43; S, 6.99. Found: C, 49.85; H, 3.56; N, 15.10; Br, 17.52; S, 6.87.
  • Step 2 Preparation of N,N-bis(4-methoxybenzyl)-4-[1-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzenesulfonamide
  • the carrageenan foot edema test was performed with materials, reagents and procedures essentially as described by Winter, et al., (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)).
  • Male Sprague-Dawley rats were selected in each group so that the average body weight was as close as possible. Rats were fasted with free access to water for over sixteen hours prior to the test. The rats were dosed orally (1 mL) with compounds suspended in vehicle containing 0.5% methylcellulose and 0.025% surfactant, or with vehicle alone.
  • the analgesia test using rat carrageenan was performed with materials, reagents and procedures essentially as described by Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated as previously described for the Carrageenan Foot Pad Edema test. Three hours after the injection of the carrageenan, the rats were placed in a special plexiglass container with a transparent floor having a high intensity lamp as a radiant heat source, positionable under the floor. After an initial twenty minute period, thermal stimulation was begun on either the injected foot or on the contralateral uninjected foot. A photoelectric cell turned off the lamp and timer when light was interrupted by paw withdrawal. The time until the rat withdraws its foot was then measured. The withdrawal latency in seconds was determined for the control and drug-treated groups, and percent inhibition of the hyperalgesic foot withdrawal determined. Results are shown in Table XI.
  • the compounds of this invention exhibited inhibition in vitro of COX II.
  • the COX II inhibition activity of the compounds of this invention illustrated in the Examples was determined by the following methods.
  • a 2.0 kb fragment containing the coding region of either human or murine COX-I or human or murine COX-II was cloned into a BamHI site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-I and COX-II in a manner similar to the method of D. R. O'Reilly et al (Baculovirus Expression Vectors: A Laboratory Manual (1992)).
  • Recombinant baculoviruses were isolated by transfecting 4 ⁇ g of baculovirus transfer vector DNA into SF9 insect cells (2 ⁇ 10 e8) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate method.
  • Recombinant viruses were purified by three rounds of plaque purification and high titer (10E7-10E8 pfu/ml) stocks of virus were prepared.
  • high titer 10E7-10E8 pfu/ml
  • SF9 insect cells were infected in 10 liter fermentors (0.5 ⁇ 10 6 /ml) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1.
  • the cells were centrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS).
  • the homogenate was centrifuged at 10,000 ⁇ G for 30 minutes, and the resultant supernatant was stored at ⁇ 80° C. before being assayed for COX activity.
  • COX activity was assayed as PGE 2 formed/ ⁇ g protein/time using an ELISA to detect the prostaglandin released, CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme were incubated in a potassium phosphate buffer (50 mM, pH 8.0) containing epinephrine, phenol, and heme with the addition of arachidonic acid (10 ⁇ M). Compounds were pre-incubated with the enzyme for 10-20 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic add and the enzyme was stopped after ten minutes at 37° C./room temperature by transferring 40 ⁇ l of reaction mix into 160 ⁇ l ELISA buffer and 25 ⁇ M indomethacin. The PGE 2 formed was measured by standard ELISA technology (Cayman Chemical). Results are shown in Table XII.
  • compositions comprising one or more compounds of Formula I the present invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients.
  • carrier non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants
  • the compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
  • the amount of therapeutically active compound that is administered and the dosage regiment for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 100 mg.
  • a daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably from about 1 to 20 mg/kg body weight, may be appropriate.
  • the daily dose can be administered in one to four doses per day.
  • the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers of diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Abstract

A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula II:
Figure USRE044048-20130305-C00001
or a pharmaceutically-acceptable salt thereof. A method of treating inflammation or an inflammation-associated disorder in a subject by administering a therapeutically-effective dose of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof, to the subject.

Description

RELATED CASE
This is an application under 35 USC §371 of International Application PCT/US 94/12720, with an international filing date of Nov. 14, 1994, which is a continuation-in-part of U.S. patent application Ser. No. 08/223,629, filed Apr. 6, 1994, now issued as U.S. Pat. No. 5,521,207, which is a continuation-in-part of U.S. patent application Ser. No. 08/160,594, filed Nov. 30, 1993, now issued as U.S. Pat. No. 5,466,823. This application is a reissue of U.S. Pat. No. 5,760,068, which issued from U.S. application Ser. No. 08/648,113 filed on Sep. 6, 1996, which is a 35 USC §371 National Stage Application of PCT/US 94/12720 filed Nov. 14, 1994, and a divisional of U.S. application Ser. No. 08/160,594 filed Nov. 30, 1993 (now issued as U.S. Pat. No. 5,466,823).
FIELD OF THE INVENTION
This invention is in the field of anti-inflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
BACKGROUND OF THE INVENTION
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of anti-inflammatory drug discovery. However, common non-steroidal anti-inflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named “cyclooxygenase II (COX II)” or “prostaglandin G/H synthase II”) provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
Pyrazoles have been described for use in the treatment of inflammation. U.S. Pat. No. 5,134,142 to Matsuo et at described 1,5-diaryl pyrazoles, and specifically, 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-trifluoromethyl pyrazole, as having anti-inflammatory activity.
U.S. Pat. No. 3,940,418 to R. Hamilton described tricyclic 4,5-dihydrobenz[g]indazoles as antiinflammatory agents. In addition, R. Hamilton [J. Heterocyclic Chem., 13, 545 (1976)] describes tricyclic 4,5-dihydrobenz[g]indazoles as antiinflammatory agents. U.S. Pat. No. 5,134,155 describes fused tricyclic pyrazoles having a saturated ring bridging the pyrazole and a phenyl radical as HMG-CoA reductase inhibitors. European publication EP 477,049, published Mar. 25, 1992, described [4,5-dihydro-1-phenyl-1H-benz[g]indazol-3-yl]amides as having antipsychotic activity. European publication EP 347,773, published Dec. 27, 1989, describes [4,5-dihydro-1-phenyl-1H-benz[g]indazol-3yl]propanamides as immunostimulants. M. Hashem et al [J. Med. Chem., 19, 229 (1976)] describes fused tricyclic pyrazoles, having a saturated ring bridging the pyrazole and a phenyl radical, as antibiotics.
Certain substituted pyrazolyl-benzenesulfonamides have been described in the literature as synthetic intermediates. Specifically, 4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1yl]benzenesulfonamide has been prepared from a pyrazoline compound as an intermediate for compounds having hypoglycemic activity [R. Soliman et al, J. Pharm. Sci., 76, 626 (1987)]. 4-[5-[2-(4-Bromophenyl)-2H-1,2,3-triazol-4-yl]-3-methyl-1H-pyrazol-1-yl]benzenesulfonamide has been prepared from a pyrazoline compound and described as potentially having hypoglycemic activity [H. Mokhtar, Pak. J. Sci. Ind. Res., 31, 762 (1988)]. Similarly, 4-[4-bromo-5-[2-(4-chlorophenyl)-2H-1,2,3-triazol-4yl]-3-methyl-1H-pyrazol-1-yl]benzenesulfonamide has been prepared [H. Mokhtar et al, Pak. J. Sci. Ind. Res., 34, 9 (1991)].
The phytotoxicity of pyrazole derivatives is described [M. Cocco et al. Il. Farmaco-Ed. Sci., 40, 272 (1985)], specifically for 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3,4-dicarboxylic acid.
The use of styryl pyrazole esters for antidiabetes drugs is described [H. Mokhtar et al, Pharmazie, 33, 649-651 (1978)]. The use of styryl pyrazole carboxylic acids for antidiabetes drugs is described [R. Soliman et al, Pharmazie, 33, 184-5 (1978)]. The use of 4-[3,4,5-trisubstituted-pyrazol-1-yl]benzenesulfonamides as intermediates for sulfonylurea anti-diabetes agents is described, and specifically, 1-[4-(aminosulfonyl)phenyl]-3-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid [R. Soliman et al, J. Pharm. Sci., 72, 1004 (1983)]. A series of 443 4,4,3-substituted methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamides has been prepared as intermediates for anti-diabetes agents, and more specifically, 4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide [H. Feid-Allah, Pharmazie, 36, 754 (1981)]. In addition, 1-(4-[aminosulfonyl]phenyl)-5-phenylpyrazole-3-carboxylic acid has been prepared from the above described 443 4,4,3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide compound [R. Soliman et al, J.Par-m. Pharm. Sci., 70, 602 (1981)].
DESCRIPTION OF THE INVENTION
A class of compounds useful in treating inflammation-related disorders is defined by Formula I:
Figure USRE044048-20130305-C00002
wherein R1 is selected from aryl and heteroaryl, wherein R1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, alkyl, alkoxy, hydroxyl, haloalkyl and
Figure USRE044048-20130305-C00003
wherein R2 is selected from hydrido, halo, alkyl, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, cyanoalkyl, alkoxycarbonylcyanoalkenyl, aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, cycloalkylaminocarbonyl, heterocyclicaminocarbonyl, carboxyalkylaminocarbonyl, aralkoxycarbonylalkylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, haloaralkyl, carboxyhaloalkyl, alkoxycarbonylhaloalkyl, aminocarbonylhaloalkyl, alkylaminocarbonylhaloalkyl, N-alkylamino, N,N-dialkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, heterocyclic,
Figure USRE044048-20130305-C00004
wherein R3 is selected from hydrido, alkyl, halo, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, amidino, cyanoamidino, aminocarbonyl, alkoxy, N-alkylamino, N,N-dialkylamino, aminocarbonylalkyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylcarbonyl, alkylcarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl, cycloalkyl, heterocyclic, heterocyclicalkyl and aralkyl;
wherein R4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkyl, alkenyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxylakyl, haloalkoxy, sulfamyl, N-alkylaminosulfonyl, amino, N-alkylamino, N,N-dialkylamino, heterocyclic, cycloalkylalkyl, nitro, acylamino,
Figure USRE044048-20130305-C00005
or wherein R3 and R4 together form
Figure USRE044048-20130305-C00006
wherein m is 1 to 3, inclusive;
wherein A is selected from phenyl and five or six membered heteroaryl;
wherein R5 is alkyl;
wherein R6 is one or more radicals selected from halo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N-arylaminocarbonyl, alkyl, alkenyl, N,N-dialkylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, haloalkyl, hydrido, hydroxyl, alkoxy, hydroxyalkyl, haloalkoxy, sulfamyl, N-alkylaminosulfonyl, amino, N-alkylamino, N,N-dialkylamino, heterocyclic, cycloalkylalkyl, nitro and acylamino; and
wherein R7 is selected from hydrido, alkyl, aryl and aralkyl;
provided R2 and R3 are not identical radicals selected from hydrido, carboxyl and ethoxycarbonyl; further provided that R2 is not carboxyl or methyl when R3 is hydrido and when R4 is phenyl; further provided that R4 is not triazolyl when R2 is methyl; further provided that R4 is not aralkenyl when R2 is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R4 is not phenyl when R2 is methyl and R3 is carboxyl; further provided that R4 is not unsubstituted thienyl when R2 is trifluoromethyl; and further provided that R4 is aryl substituted with sulfamyl or R6 is sulfamyl, when R1 is phenyl not substituted with sulfamyl; or a pharmaceutically-acceptable salt thereof.
The phrase “further provided”, as used in the above description, is intended to mean that the denoted proviso is not to be considered conjunctive with any of the other provisos.
Compounds of Formula I the present invention would be useful for, but not limited to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of Formula I the present invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of Formula I the present invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns and dermatitis. Compounds of Formula I the present invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention of colorectal cancer. Compounds of Formula I the present invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, myocardial ischemia, and the like. The compounds are useful as antiinflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects.
The present invention preferably includes compounds which selectively inhibit cyclooxygenase II over cyclooxygenase I. Preferably, the compounds have a cyclooxygenase II IC50 of less than about 0.2 μM, and also have a selectivity ratio of cyclooxygenase II inhibition over cyclooxygenase I inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase I IC50 of greater than about 1 μM, and more preferably of greater than 10 μM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
A preferred class of compounds consists of those compounds of Formula I wherein R1 is selected from aryl selected from phenyl, naphthyl and biphenyl, and five- or six-membered heteroaryl, wherein R1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy, hydroxyl, lower haloalkyl and
Figure USRE044048-20130305-C00007
wherein R2 is selected from hydrido, halo, lower alkyl, lower haloalkyl, cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, amidino, cyanoamidino, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, aminocarbonyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl, lower heterocyclicaminocarbonyl, lower carboxyalkylaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower alkylcarbonyl, lower alkylcarbonylalkyl, lower alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, arylthio, lower aralkylthio, lower hydroxylakyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lower N,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl, heterocyclic,
Figure USRE044048-20130305-C00008
wherein R3 is selected from hydrido, lower alkyl, halo, lower haloalkyl, cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, amidino, cyanoamidino, aminocarbonyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, lower N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower alkylcarbonyl, lower alkylcarbonylalkyl, lower hydroxyalkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lower N,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl, lower cycloalkyl, heterocyclic, lower heterocyclicalkyl and lower aralkyl;
wherein R4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower N-alkylaminosulfonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five- or six-membered heterocyclic, lower cycloalkylalkyl, nitro, acylamino,
Figure USRE044048-20130305-C00009

or wherein R3 and R4 together form
Figure USRE044048-20130305-C00010
wherein m is 1 to 3, inclusive;
wherein A is selected from phenyl and five or six membered heteroaryl;
wherein R5 is lower alkyl;
wherein R6 is one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower alkyl, lower alkenyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower haloalkyl, hydrido, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower N-alkylaminosulfonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five- or six membered heterocyclic, lower cycloalkylalkyl, nitro and acylamino; and
wherein R7 is selected from hydrido, lower alkyl, aryl and lower aralkyl;
or a pharmaceutically-acceptable salt thereof.
A more preferred class of compounds consists of those compounds of Formula I where R1 is phenyl, wherein R1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy, hydroxyl, lower haloalkyl and
Figure USRE044048-20130305-C00011
wherein R2 is selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, aryloxy, lower aralkoxy, lower alkoxy, lower alkylthio, arylthio, lower aralkylthio, aminocarbonyl, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl,
Figure USRE044048-20130305-C00012
wherein R3 is selected from hydrido, lower alkyl, halo, cyano, lower hydroxyalkyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, lower N,N-dialkylaminosulfonyl, lower N-alkyl-N-arylaminosulfonyl and lower cycloalkyl;
wherein R4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower alkylaminosulfonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five or six membered heterocyclic, lower cycloalkylalkyl, nitro,
Figure USRE044048-20130305-C00013
or wherein R3 and R4 together form
Figure USRE044048-20130305-C00014
wherein m is 2;
wherein A is selected from phenyl and five or six membered heteroaryl;
wherein R5 is lower alkyl;
wherein R6 is one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, amino, lower N-alkylamino, lower N,N-dialkylamino, lower cycloalkylalkyl and nitro; and
wherein R7 is selected from hydrido, lower alkyl, aryl and lower aralkyl;
or a pharmaceutically-acceptable salt thereof.
An even more preferred class of compounds consists of those compounds of Formula I wherein R1 is phenyl, wherein R1 is substituted at a substitutable position with one or more radicals selected from sulfamyl, halo, lower alkyl, lower alkoxy and
Figure USRE044048-20130305-C00015
wherein R2 is selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower alkoxy, aryloxy, lower aralkoxy, lower alkylthio, arylthio, lower aralkylthio, aminocarbonyl, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower heterocyclicaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl,
Figure USRE044048-20130305-C00016
wherein R3 is selected from hydrido, lower alkyl, halo, cyano, lower hydroxyalkyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower alkylthio, lower alkylsulfonyl and lower cycloalkyl;
wherein R4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five or six membered heterocyclic, lower cycloalkylalkyl, nitro,
Figure USRE044048-20130305-C00017

or wherein R3 and R4 together form
Figure USRE044048-20130305-C00018
wherein m is 2;
wherein A is selected from phenyl and five membered heteroaryl;
wherein R5 is lower alkyl;
wherein R6 is one or more radicals selected from halo, lower alkyl, lower alkylsulfonyl, lower haloalkyl, lower alkoxy, sulfamyl, amino and nitro; and
wherein R7 is selected from hydrido, lower alkyl, aryl and lower aralkyl;
or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a subclass of compounds which consists of compounds wherein R1 is phenyl substituted at a substitutable position with one or more radicals selected from halo, lower alkyl, sulfamyl and
Figure USRE044048-20130305-C00019
wherein R2 is selected from hydrido, lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, lower alkoxycarbonylcyanoalkenyl, lower haloaralkyl, lower carboxyhaloalkyl, lower alkoxycarbonylhaloalkyl, lower aminocarbonylhaloalkyl, lower alkylaminocarbonylhaloalkyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamino, lower N-alkyl-N-aralkylamino, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-alkylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-arylaminoalkyl, lower N-aralkylaminoalkyl, lower N-alkyl-N-aralkylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower alkoxy aryloxy, lower aralkoxy, lower alkylthio, arylthio, lower aralkylthio, aminocarbonyl, lower aminocarbonylalkyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl, lower hydroxyalkyl,
Figure USRE044048-20130305-C00020
wherein R3 is selected from hydrido, lower alkyl, halo, cyano, lower hydroxyalkyl, lower alkoxy, lower alkylthio, lower N-alkylamino, lower N,N-dialkylamino, lower alkylsulfonyl and lower cycloalkyl;
wherein R4 is selected from lower aralkenyl, aryl, lower cycloalkyl, lower cycloalkenyl and five to ten membered heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower haloalkoxy, sulfamyl, lower alkylaminocarbonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five or six membered heterocyclic, lower cycloalkylalkyl, nitro,
Figure USRE044048-20130305-C00021
wherein R5 is lower alkyl; and
wherein R7 is selected from hydrido, lower alkyl, aryl and lower aralkyl;
or a pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula I wherein R1 is phenyl, substituted at a substitutable position with one or more radicals selected from fluoro, chloro, methyl, sulfamyl and
Figure USRE044048-20130305-C00022
wherein R2 is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoromethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano, carboxyl methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl, cyanomethyl, ethoxycarbonylcyanoethenyl, 1,1-difluoro-1-phenylmethyl, 1,1-difluoro-1-phenylethyl, difluoroacetyl, methoxycarbonyldifluoromethyl, difluoroacetamidyl, N,N-dimethyldifluoroacetamidyl, N-phenyldifluoroacetamidyl, N-ethylamino, N-methylamino, N,N-dimethylamino, N,N-diethylamino, N-phenylamino, N-benzylamino, N-phenylethylamino, N-methyl-N-benzylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, N-phenylaminomethyl, N-benzylaminomethyl, N-methyl-N-benzylaminomethyl, N-methyl-N-phenylaminomethyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, phenylthio, benzylthio, N-methylurea, N-methylthiourea, N-methylacetamidyl, urea, ureamethyl, thiourea, thioureamethyl, acetamidyl, N-phenylthioureamethyl, N-benzylthioureamethyl, N-methylthioureamethyl, N-phenylureamethyl, N-benzylureamethyl, N-methylureamethyl, N-phenylacetamidylmethyl, N-benzylacetamidylmethyl, N-methylacetamidylmethyl, aminocarbonyl, aminocarbonylmethyl, N-methylaminocarbonyl, N-ethylaminocarbonyl, N-isopropylaminocarbonyl, N-propylaminocarbonyl, N-butylaminocarbonyl, N-isobutylaminocarbonyl, N-tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-phenylaminocarbonyl, N,N-dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-(3-fluorophenyl)aminocarbonyl, N-(4-methylphenyl)aminocarbonyl, N-(3-chlorophenyl)aminocarbonyl, N-methyl-N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminocarbonyl, N-methyl-N-phenylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, carboxymethylaminocarbonyl, benzyloxycarbonylmethylaminocarbonyl, hydroxypropyl, hydroxymethyl, and hydroxypropyl;
wherein R3 is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl, fluoro, chloro, bromo, cyano, methoxy, methylthio, methylsulfonyl, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyclopropyl, cyclopentyl, hydroxypropyl, hydroxymethyl, and hydroxyethyl; and
wherein R4 is selected from phenylethenyl, phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, 1-cyclopentenyl, 4-cyclopentenyl, benzofuryl, 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydronaphthyl, benzothienyl, indenyl, indanyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from fluoro, chloro, bromo, methylthio, methylsulfinyl, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, hexyl, ethylenyl, propenyl, methylsulfonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, aminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, bromodifluoromethyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, sulfamyl, methylaminosulfonyl, hydroxypropyl, hydroxyisopropyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, amino, N-methylamino, N-ethylamino, N-ethyl-N-methylamino, N,N-dimethylamino, N,N-diethylamino, formylamino, methylcarbonylamino, trifluroracetamino, piperadinyl, piperazinyl, morpholino, cyclohexylmethyl, cyclopropylmethyl, cyclopentylethyl, nitro,
Figure USRE044048-20130305-C00023

and
wherein R7 is selected from hydrido, methyl, ethyl, phenyl and benzyl;
or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a second sub class of compounds of high interest wherein R1 is phenyl substituted at a substitutable position with sulfamyl; wherein R2 is selected from lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyalkyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylaminocarbonyl, lower N,N-dialkylaminocarbonyl, lower N-alkyl-N-arylaminocarbonyl, lower cycloalkylaminocarbonyl and lower hydroxyalkyl; wherein R3 and R4 together form
Figure USRE044048-20130305-C00024

wherein m is 2; wherein A is selected from phenyl and five membered heteroaryl; and where R6 is one or more radicals selected from halo, lower alkyl, lower alkylsulfonyl, lower haloalkyl, lower alkoxy, amino and nitro; or a pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula I wherein R2 is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl, aminocarbonyl, N-methylaminocarbonyl, N-ethylaminocarbonyl, N-isopropylaminocarbonyl, N-propylaminocarbonyl, N-butylaminocarbonyl, N-isobutylaminocarbonyl, N-tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-phenylaminocarbonyl, N,N-dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-(3-fluorophenyl)aminocarbonyl, N-(4-methylphenyl)aminocarbonyl, N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminocarbonyl, N-methyl-N-phenylaminocarbonyl, cyclohexylaminocarbonyl, hydroxypropyl, hydroxymethyl and hydroxyethyl; wherein A is selected from phenyl, furyl and thienyl; and wherein R6 is one or more radicals selected from fluoro, chloro, bromo, methylsulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, amino, and nitro; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a third subclass of compounds of high interest wherein R1 is selected from phenyl, naphthyl, biphenyl, and five- or six-membered heteroaryl, wherein R1 is substituted at a substitutable position with one or more radicals selected from halo, lower alkyl, lower alkoxy, hydroxyl and lower haloalkyl; wherein R2 is selected from lower haloalkyl; wherein R3 is hydrido; and wherein R4 is aryl substituted at a substitutable position with sulfamyl; or a pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula I wherein R1 is selected from phenyl, naphthyl, benzofuryl, benzothienyl, indolyl, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R1 is substituted at a substitutable position with one or more radicals selected from fluoro, chloro, bromo, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichloropropyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, methyl, ethyl, propyl, hydroxyl, methoxy, ethoxy, propoxy and n-butoxy; wherein R2 is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, difluoroethyl, dichlorofluoromethyl, difluoropropyl, dichloroethyl and dichloropropyl; wherein R3 is hydrido; and wherein R4 is phenyl substituted at a substitutable position with sulfamyl; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a subclass of compounds of high interest represented by Formula II:
Figure USRE044048-20130305-C00025
wherein R2 is selected from hydrido, alkyl, haloalkyl, alkoxycarbonyl, cyano, cyanoalkyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, carboxyalkylaminocarbonyl, carboxyalkyl, aralkoxycarbonylalkylaminocarbonyl, aminocarbonylalkyl, alkoxycarbonylcyanoalkenyl and hydroxyalkyl;
wherein R3 is selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halo; and
wherein R4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfonyl, cyano, nitro, haloalkyl, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, haloalkoxy, sulfanyl, heterocyclic and amino;
provided R2 and R3 are not both hydrido; further provided that R2 is not carboxyl or methyl when R3 is hydrido and when R4 is phenyl; further provided that R4 is not triazolyl when R2 is methyl; further provided that R4 is not aralkenyl when R2 is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R4 is not phenyl when R2 is methyl and R3 is carboxyl; and further provided that R4 is not unsubstituted thienyl when R2 is trifluoromethyl;
or a pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula II wherein R2 is selected from hydrido, lower alkyl, lower haloalkyl, lower alkoxycarbonyl, cyano, lower cyanoalkyl, carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower cycloalkylaminocarbonyl, arylaminocarbonyl, lower carboxyalkylaminocarbonyl, lower aralkoxycarbonylalkylaminocarbonyl, lower aminocarbonylalkyl, lower carboxyalkyl, lower alkoxycarbonylcyanoalkenyl and lower hydroxyalkyl;
wherein R3 is selected from hydrido, lower alkyl, cyano, lower hydroxyalkyl, lower cycloalkyl, lower alkylsulfonyl and halo; and
wherein R4 is selected from aralkenyl, aryl, cycloalkyl, cycloalkenyl and heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfonyl, cyano, nitro, lower haloalkyl, lower alkyl, hydroxyl, lower alkenyl, lower hydroxyalkyl, carboxyl, lower cycloalkyl, lower alkylamino, lower dialkylamino, lower alkoxycarbonyl, aminocarbonyl, lower alkoxy, lower haloalkoxy, sulfamyl, five or six membered heterocyclic and amino; or a pharmaceutically-acceptable salt thereof.
A family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:
  • 4-[5-(4-(N-ethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-fluoro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-methyl-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N,N-dimethylamino)-3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3chloro-4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N,N-dimethylamino)-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N-ethyl-N-methylamino)-3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N-ethyl-N-methylamino)-3-methylphenyl)-3-3(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N,N-diethylamino)-3-fluorophenyl)-3-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(3-chloro-4-(N,N-diethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N,N-diethylamino)-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-fluorophenyl]-N-methylacetamide;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-chlorophenyl]-N-methylacetamide;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methylphenyl]-N-methylacetamide;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-fluorophenyl]-N-methylurea;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-chlorophenyl]-N-methylurea;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methylphenyl]-N-methylurea;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-fluorophenyl]-N-methylthiourea;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-chlorophenyl]-N-methylthiourea;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methylphenyl]-N-methylthiourea;
  • 4-[5-(3-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chloro-3-(N-methylamino)phenyl)-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methyl-3-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl]-N-methylacetamide;
  • N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-fluorophenyl]-N-methylacetamide;
  • N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-methylphenyl]-N-methylurea;
  • N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-fluorophenyl]-N-methylthiourea;
  • 4-[5-(2-(N-ethyl-N-methylamino)-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-methylphenyl]-N-methylurea;
  • N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-4-fluorophenyl]-N-methylthiourea;
  • 4-[5-(1H-indol-5-yl)-3-trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(7-fluoro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-(1-ethyl-1H-indol-5-yl)-3-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(7-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(7-chloro-1-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3-dihydro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(7-fluoro-1-methyl-2,3-dihydro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-aminomethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N-methylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N,N-dimethylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-phenyl-3-(N-phenylamino)methyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N-benzylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N-benzyl-N-methylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N-methyl-N-phenylamino)methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]acetamide;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-methylacetamide;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-phenylacetamide;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-benzylacetamide;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]urea;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-methylurea;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-phenylurea;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-benzylurea;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]thiourea;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-methylthiourea;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-phenylthiourea;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]methyl]-N-benzylthiourea;
  • 4-[4-methoxy-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-methylthio-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-(N-methylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-(N,N-dimethylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-methoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-ethoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-phenoxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-benzyloxy-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-methylthio-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-benzylthio-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N-methylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N,N-dimethylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(N-benzyl-N-methylamino)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]acetamide;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylacetamide;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylacetamide;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]urea;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylurea;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylurea;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]thiourea;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-methylthiourea;
  • N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-N-benzylthiourea;
  • 4-[5-phenyl-3-(1,1-difluoro-1-phenylmethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-phenyl-3-(1,1-difluoro-2-phenylethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetic acid;
  • methyl 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetate;
  • 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetamide;
  • N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetamide;
  • N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-difluoroacetamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-5-acetic acid;
  • 1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-difluoroacetic acid;
  • 1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-difluoroacetic acid;
  • 1-[4-(aminosulfonyl)phenyl]-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-3-acetic acid;
  • 1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-acetic acid;
  • (R)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]propanoic acid;
  • (S)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]propanoic acid;
  • (R)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-yl]propanoic acid;
  • (S)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-yl]propanoic acid;
  • (R)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-yl]propanoic acid;
  • (S)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl]propanoic acid;
  • 2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-methylpropanoic acid;
  • 2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazol-3-yl]-2-methylpropanoic acid;
  • 2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazol-3-yl]-2-methylpropanoic acid;
  • 2-fluoro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 3-fluoro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 2-methyl-4-[5-phenyl-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 3-methyl-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • ethyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • ethyl 1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate;
  • isopropyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-aminophenyl)-1H-pyrazole-3-carboxylate;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid;
  • tert-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • propyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • isobutyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • pentyl-1-[4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-3-carboxylate;
  • methyl-1-[4-aminosulfonyl)phenyl]-5-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazole-3-carboxylate;
  • N-[4-methylphenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
  • N-[3-chlorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
  • N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
  • N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • phenylmethyl N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carbonyl]glycinate;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
  • N-(4-methoxyphenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
  • N-(4-methylphenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-methyl-N-ethyl-1-[4-aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-methyl-N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-isopropyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-propyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-isobutyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-tert-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-pentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-cyclohexyl-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
  • N-cyclopentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • 4-[5-(4-chlorophenyl)-3-(piperidinocarboxamide)-1H-pyrazol-1-yl]benzenesulfonamide;
  • N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-(2-pyridyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • N-methyl-N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-methylthiophenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carboxamide;
  • N-methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide;
  • N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carbonyl]glycine;
  • 1-[4-(aminosulfonyl)phenyl]-5-(3-bromo-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(3,5-dichloro-4-methoxyl)-1H-pyrazole-3-carboxamide;
  • 4-[5-(4-bromophenyl)3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-cyano-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-cyano-5-(4-methylthiophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methoxyphenyl)3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-dichloro-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-bromo-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-nitrophenyl)-3-(cyano)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-bromo-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-bromo-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-bromo-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(3,5-difluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-fluoro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-4-methylsulfonyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-ethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-ethyl-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-ethyl-5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-ethyl-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-ethyl-5-(3-fluoro-4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-methyl-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-bromo-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-bromo-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-chloro-5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-bromo-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • ethyl [1-(4-aminosulfonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;
  • methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;
  • ethyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;
  • methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate;
  • methyl [1-(4-aminosulfonylphenyl)-4-bromo-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate;
  • methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylate;
  • methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylate;
  • methyl [1-(4-aminosulfonylphenyl)-5-(3-bromo-4-methoxyphenyl)-4-chloro-1H-pyrazol-3-yl]carboxylate;
  • [1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]carboxamide;
  • [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxamide;
  • [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide;
  • [1-(4-aminosulfonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxamide;
  • [1-(4-aminosulfonylphenyl)-4-bromo-5-phenyl-1H-pyrazol-3yl]carboxamide;
  • [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylic acid;
  • [1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]carboxylic acid;
  • [1-(4-aminosulfonylphenyl)-4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylic acid;
  • 4-[4-chloro-3-isopropyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-3-hydroxymethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]propanoic acid;
  • 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-dimethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-bromo-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-hydroxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methoxyphenyl)-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methoxy-3-(1-propenyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methoxy-3-propylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-difluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-fluoro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzoic acid;
  • 4-[5-(3-methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-amino-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • methyl-4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5yl]benzoate;
  • 4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzamide;
  • 4-[5-(3,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-methylsulfinylphenyl)-3-(trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-fluoro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluoro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chloro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dihydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl]phenyl]acetamide;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl]phenyl]formamide;
  • N-[4-[1-[4-(aminosulfonyl)phenyl]-3-trifluoromethyl-1H-pyrazol-5-yl]phenyl]trifluoroacetamide;
  • 4-[5-(4-[N-methylaminosulfonyl]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-n-butoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-[aminosulfonyl]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,5-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,4-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4,5-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,5,6-trifluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,4,5-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,4,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,5,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(pentafluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,4-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,5,6-trichlorophenyl)3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,4,5-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,4,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,5,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3,4,5,6-pentachlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-tert-butylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-isobutylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-trifluoromethylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylthiophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(1-morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-phenyl-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dimethylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[1-[4-(aminosulfonyl)phenyl]-3-(difluoromethyl)-1H-pyrazol-5yl]benzoic acid;
  • methyl 4-[1-[4-(aminosulfonyl)phenyl]-3-(difluoromethyl)-1H-pyrazol-5-yl]benzoate;
  • 4-[1-(4-aminosulfonylphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzamide;
  • 4-[5-(2-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-cyanophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chloro-3-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dimethoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-difluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-bromo-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylsulfonylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1,4-benzodioxan-6-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(difluoromethyl)-5-(4-methylcyclohexyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(methyl-1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-methyl-1-cyclopentenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(benzofuran-2-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1,3-benzodioxol-5-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-(morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,5-dimethyl-3-furyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-methyl-2-furyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1-chloro-1-methyl-4-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dibromo-4-methylcyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-methoxycyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,4-dimethyl-3-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,5-dichloro-3-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-()benzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-bromo-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-chloro-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-indanyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-methyl-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2,3-dihydrobenzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-benzothienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,4-dihydro-2H-1-benzothiopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-phenylethenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methyl-1,3-benzodioxol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-pyrazinyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(biphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1,2,3,4-tetrahydronaphth-6-yl])-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-thioazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-oxazolyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(cyclohexyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(cyclopentyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(cycloheptyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(1-cyclopentenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(2-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(6-methyl-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-pyridyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylcyclohex-4-ene-1-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-chloro-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(5-bromo-2-furyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(chlorodifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methoxyphenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(chlorodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(phenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(bromodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(dichlorofluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamide;
  • 4-[5-(4-fluorophenyl)-3-(trichloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(1,1-difluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(1,1-difluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(1,1-dichloroethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(1,1-dichloropropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-nitro-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(amidino)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(methylsulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-methyl-aminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluorophenyl)-3-(imidazolyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluorophenyl)-3-(2-pyridyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-cyanoamidino)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(tetrazolyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(phenylsulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-phenylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N,N-dimethylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-methyl-N-phenylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-ethylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-isopropylaminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-methyl-N-ethylaminosulfonyl)-1H-pyrazol-1yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-methyl-N-(3-chlorophenyl)aminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(N-methyl-N-(2-pyridyl)aminosulfonyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-methyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-isobutyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(3-hydroxypropyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylphenyl)-3-(2-hydroxyisopropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-propanoic acid;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-propanoic acid;
  • 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-propanamide;
  • methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazol-3-propanoate;
  • 4-[3-(3-hydroxymethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(3-hydroxymethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-chloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazol-1yl]benzenesulfonamide;
  • ethyl 3-[1-(4-aminosulfonylphenyl)-5-(phenyl)-1H-pyrazol-3-yl]-2-cyano-2-propenoate;
  • 4-[5-(4-chlorophenyl)-3-(chloro)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(bromo)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(fluoro)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1yl]benzenesulfonamide;
  • 4-[3-(difluoromethyl)-4,5-dihydro-7-methyl-1H-benz[g]indazol-1yl]benzenesulfonamide;
  • 4-[4,5-dihydro-7-methoxy-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;
  • 4-[4,5-dihydro-3-(trifluoromethyl)-1H-benz[g]indazol-1yl]benzenesulfonamide;
  • 4-[4,5-dihydro-7-methyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;
  • 4-[4,5-dihydro-6,8-dimethyl-3-(trifluoromethyl)-1 H-benz[g]indazol-1yl]benzenesulfonamide;
  • 4-[4,5-dihydro-6,8-dimethoxy-3(trifluoromethyl)-1H-benz[g]indazol-1yl]benzenesulfonamide;
  • methyl[1-(4-aminosulfonylphenyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-3yl]carboxylate;
  • 4-[4,5-dihydro-3-trifluoromethyl-1H-thieno[3,2g]indazol-1-yl]benzenesulfonamide;
  • 4-[1-phenyl-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;
  • 4-[1-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;
  • 4-[1-(4-fluorophenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;
  • 4-[1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;
  • 4-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;
  • 4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide;
  • 4-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide; and
  • 4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide.
  • A family of specific compounds of particular interest within Formula II consists of compounds and pharmaceutically-acceptable salts thereof as follows:
  • 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(difluoromethyl)-5-(4--methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
  • 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide; and
  • 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1yl]benzenesulfonamide.
One compound of the present invention is 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
Another compound of the present invention is 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
Another compound of the present invention is 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
Another compound of the present invention is 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
Another compound of the present invention is 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
Another compound of the present invention is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, and pharmaceutically acceptable salts thereof.
The term “hydrido” denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (—CH2—) radical. Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl” and “alkylsulfonyl”, it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term “alkenyl” embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Examples of such radicals include ethyl, n-propenyl, butenyl, and the like. The term “halo” means halogens such as fluorine, chlorine, bromine or iodine atoms. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are amonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, or one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. “Lower haloalkyl” embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term “hydroxyalkyl” embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are “lower hydroxylalkyl” radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term “alkoxyalkyl” also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxyalkyl radicals are “lower alkoxyalkyl” radicals having one to six carbon atoms and one or two alkoxy radicals. Examples of such radicals include methoxymethyl, methoxyethyl, ethoxyethyl, methoxybutyl and methoxypropyl. The “alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” or “haloalkoxyalkyl” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The term “heterocyclic” embraces saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g. pyrrolindinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The term “heteroaryl” embraces unsaturated hetereocyclic radicals. Examples of unsaturated heterocyclic radicals, also termed “heteroaryl” radicals include unsaturated 5 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotraizolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridinzinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, triazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclic group” may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include benzofuryl, 2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO2—.
“Alkylsulfonyl” embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are “lower alkylsulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The term “arylsulfonyl” embraces aryl radicals as defined above, attached to a sulfonyl radical. Examples of such radicals include phenylsulfonyl. The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” whether alone or used with terms such as “N-alkylaminosulfonyl”, “N-arylaminosulfonyl”, “N,N-dialkylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl”, denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (—SO2NH2). The terms “N-alkylaminosulfonyl” and “N,N-dialkylaminosulfonyl” denote sulfamyl radicals substituted, respectively, with one alkyl radical, or two alkyl radicals. More preferred alkylaminosulfonyl radicals are “lower alkylaminosulfonyl” radicals having one to six carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl. The terms “N-arylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl” denote sulfamyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. More preferred N-alkyl-N-arylaminosulfonyl radicals are “lower N-alkyl-N-arylsulfonyl” radicals having alkyl radicals of one to six carbon atoms. Examples of such lower N-alkyl-N-aryl aminosulfonyl radicals include N-methyl-phenylaminosulfonyl and N-ethyl-phenylaminosulfonyl The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO2H. The terms “alkanoyl” or “carboxyalkyl” embrace radicals having a carboxy radical as defined above, attached to an alkyl radical. The alkanoyl radicals may be substituted or unsubstituted, such as formyl, acetyl, propionyl (propanoyl), butanoyl (butyryl), isobutanoyl (isobutyryl), valeryl (pentanoyl), isovaleryl, pivaloyl, hexanoyl or the like. The term “carbonyl”, whether used alone or with other terms, such as “alkylcarbonyl”, denotes —(C═O)—. The term “alkylcarbonyl” embraces radicals having a carbonyl radical substituted with an alkyl radical. More preferred alkylcarbonyl radicals are “lower alkylcarbonyl” radicals having one to six carbon atoms. Examples of such radicals include methylcarbonyl and ethylcarbonyl. The term “alkylcarbonylalkyl”, denotes an alkyl radical substituted with an “alkylcarbonyl” radical. The term “alkoxycarbonyl” means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. Preferably, “lower alkoxycarbonyl” embraces alkoxy radicals having one to six carbon atoms. Examples of such “lower alkoxycarbonyl” ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term “alkoxycarbonylalkyl” embraces radicals having “alkoxycarbonyl”, as defined above substituted to an alkyl radical. More preferred alkoxycarbonylalkyl radicals are “lower alkoxycarbonylalkyl” having lower alkoxycarbonyl radicals as defined above attached to one to six carbon atoms. Examples of such lower alkoxycarbonylalkyl radicals include methoxycarbonylmethyl, tert-butoxycarbonylethyl, and methoxycarbonylethyl. The term “aminocarbonyl” when used by itself or with other terms such as “aminocarbonylalkyl”, “N-alkylaminocarbonyl”, “N-arylaminocarbonyl”, “N,N-dialkylaminocarbonyl”, “N-alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl” and “N-alkyl-N-hydroxyaminocarbonylalkyl”, denotes an amide group of the formula —C(═O)NH2. The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denote aminocarbonyl radicals which have been substitute with one alkyl radical and with two alkyl radicals, respectively. More preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to an aminocarbonyl radical. The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. The term “aminocarbonylalkyl” embraces alkyl radicals substituted with aminocarbonyl radicals. The term “N-cycloalkylaminocarbonyl” denoted aminocarbonyl radicals which have been substituted with at least one cycloalkyl radical. More preferred are “lower cycloalkylaminocarbonyl” having lower cycloalkyl radicals of three to seven carbon atoms, attached to an aminocarbonyl radical. The term “aminoalkyl” embraces alkyl radicals substituted with amino radicals. The term “alkylaminoalkyl” embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical. The term “amidino” denotes an —C(═NH)—NH2 radical. The term “cyanoamidino” denotes an —C(═N—CN)—NH2 radical. The term “heterocyclicalkyl” embraces heterocyclic-substituted alkyl radicals. More preferred heterocyclicalkyl radicals are “lower heterocyclicalkyl” radicals having one to six carbon atoms and a heterocyclic radical. Examples include such radicals as pyrrolidinylmethyl, pyridylmethyl and thienylmethyl. The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term “cycloalkyl” embraces radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term “cycloalkenyl” embraces unsaturated cyclic radicals having three to ten carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of “alkylthio” is methylthio, (CH3—S—). The term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S(═O)— atom. The term “aminoalkyl” embraces alkyl radicals substituted with amino radicals. More preferred aminoalkyl radicals are “lower aminoalkyl” having one to six carbon atoms. Examples include aminomethyl, aminoethyl and aminobutyl. The term “alkylaminoalkyl” embraces aminoalkyl radicals having the nitrogen atom substituted with at least one alkyl radical. More preferred alkylaminoalkyl radicals are “lower alkylaminoalkyl” having one to six carbon atoms attached to a lower aminoalkyl radical as described above. The terms “N-alkylamino” and “N,N-dialkylamino” denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Suitable “alkylamino” may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term “arylamino” denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The “arylamino” radicals may be further substituted on the aryl ring portion of the radical. The term “aralkylamino” denotes amino groups which have been substituted with one or two aralkyl radicals, such as N-benzylamino. The “aralkylamino” radicals may be further substituted on the aryl ring portion of the radical. The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denote amino groups which have been substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group. The terms “N-arylaminoalkyl” and “N-aralkylaminoalkyl” denote amino groups which have been substituted with one aryl radical or one aralkyl radical, respectively, and having the amino group attached to an alkyl radical. More preferred arylaminoalkyl radicals are “lower arylaminoalkyl” having the arylamino radical attached to one to six carbon atoms. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The terms “N-alkyl-N-arylaminoalkyl” and “N-aralkyl-N-alkylaminoalkyl” denote N-alkyl-N-arylamino and N-alkyl-N-aralkylamino groups, respectively, and having the amino group attached to alkyl radicals. The term “acyl”, whether used alone, or within a term such as “acylamino”, denotes a radical provided by the residue after removal of hydroxyl from an organic acid. The term “acylamino” embraces an amino radical substituted with an acyl group. An examples of an “acylamino” radical is acetylamino or acetamido (CH3C(═O)—NH—) where the amine may be further substituted with alkyl, aryl or aralyl. The term “arylthio” embraces aryl radicals of six to ten carbon atoms, attached to a divalent sulfur atom. An example of “arylthio” is phenylthio. The term “aralkylthio” embraces aralkyl radicals as described above, attached to a divalent sulfur atom. An example of “aralkylthio” is benzylthio. The term “aryloxy” embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The term “aralkoxy” embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are “lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above. The term “haloaralkyl” embraces aryl radicals as defined above attached to haloalkyl radicals. The term “carboxyhaloalkyl” embraces carboxyalkyl radicals as defined above having halo radicals attached to the alkyl portion. The term “alkoxycarbonylhaloalkyl” embraces alkoxycarbonyl radicals as defined above substituted on a haloalkyl radical. The term “aminocarbonylhaloalkyl” embraces aminocarbonyl radicals as defined above substituted on a haloalkyl radical. The term “alkylaminocarbonylhaloalkyl” embraces alkylaminocarbonyl radicals as defined above substituted on a haloalkyl radical. The term “alkoxycarbonylcyanoalkenyl” embraces alkoxycarbonyl radicals as defined above, and a cyano radical, both substituted on an alkenyl radical. The term “carboxyalkylaminocarbonyl” embraces aminocarbonyl radicals substituted with carboxyalkyl radicals, as defined above. The term “aralkoxycarbonylalkylaminocarbonyl” embraces aminocarbonyl radicals substituted with aryl-substituted alkoxycarbonyl radicals, as defined above. The term “cycloalkylalkyl” embraces cycloalkyl radicals having three to ten carbon atoms attached to an alkyl radical, as defined above. More preferred cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to lower alkyl radicals as defined above. Examples include radicals such as cyclopropylmethyl, cyclobutylmethyl, and cyclohexylethyl. The term “aralkenyl” embraces aryl radicals attached to alkenyl radicals having two to ten carbon atoms, such as phenylbutenyl, and phenylethenyl or styryl.
The present invention comprises a pharmaceutical composition for the treatment of inflammation and inflammation-associated disorders, such as arthritis, comprising a therapeutically-effective amount of a compound of Formula I the present invention in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a therapeutic method of treating inflammation or inflammation-associated disorders in a subject, the method comprising administering to a subject having such inflammation or disorder a therapeutically-effective amount of a compound of Formula I the present invention.
Also included in the family of compounds of Formula I the present invention are the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I the present invention may be prepared from an inorganic acid or from an organic Acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, salicyclic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I the present invention by reacting, for example, the appropriate acid or base with the compound of Formula I the present invention.
GENERAL SYNTHETIC PROCEDURES
The compounds of the invention can be synthesized according to the following procedures of Schemes I-VIII, wherein the R1-R7 substituents are as defined for Formula I, above, except where further noted.
Figure USRE044048-20130305-C00026
Synthetic Scheme I shows the preparation of tetrasubstituted pyrazoles from starting material 1. In step 1 of synthetic Scheme I, the phenyl-methyl ketone (1) is treated with a base and an alkylating reagent (R3X, where X represents a leaving group such as tosyl) to give the substituted ketone (2). In step 2, the substituted ketone (2) is treated with base, such as sodium methoxide, and an acylating reagent such as an ester (R2CO2CH3), or ester equivalent (R2CO-imidazole, to give the intermediate diketone (3) in a procedure similar to that developed by Reid and Calvin, J. Amer. Chem. Soc., 72, 2948-2952 (1950). In step 3, the diketone (3) is reacted with a substituted hydrazine in acetic acid or an alcoholic solvent to give a mixture of pyrazoles (4) and (5). Separation of the desired pyrazole (4) can be achieved by chromatography or recrystallization.
Figure USRE044048-20130305-C00027
Synthetic Scheme II shows the preparation of compounds embraced by Formula I, where R3 is a hydrogen atom. In step 1, ketone (1) is treated with a base, preferably NaOMe or NaH, and an ester, or ester equivalent, to form the intermediate diketone (6) which is used without further purification. In step 2, diketone (6) in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the hydrochloride salt or the free base of a substituted hydrazine at reflux for 10 to 24 hours to afford a mixture of pyrazoles (7) and (8). Recrystallization from diethyl ether/hexane or chromatography affords (7), usually as a light yellow or tan solid.
Figure USRE044048-20130305-C00028
Synthetic Scheme III shows the procedure for preparation of 4,5-dihydrobenz[g]indazole compounds embraced by Formula I. In step 1, ethyl trifluoroacetate is reacted with base, such as 25% sodium methoxide in a protic solvent, such as methanol, and a 1-tetralone derivative (9) to give the intermediate diketone (10). In step 2, the diketone (10) in an anhydrous protic solvent, such as absolute ethanol or acetic acid, is treated with the free base or hydrochloride salt of a substituted hydrazine at reflux for 24 hours to afford a mixture of pyrazoles (11) and (12). Recrystallization gives the 4,5-dihydro benz[g]indazolyl-benzenesulfonamide (11).
Figure USRE044048-20130305-C00029
Synthetic Scheme IV shows the preparation of pyrazole compounds (13), where R3 is chlorine, from the available pyrazole compounds (7), where R3 is hydrogen. Chlorination results from passing a stream of chlorine gas at room temperature through a solution containing (7).
Figure USRE044048-20130305-C00030
Synthetic Scheme V shows the preparation of substituted ketones 18 which are not commercially available as used in Scheme I. The ketones can be prepared by standard Friedel-Craft acylation of the starting substituted benzenes 14 with acid chlorides or anhydrides 15. Alternatively, the ketones can be prepared from phenylcarbonitriles 16 by standard organometallic techniques where M represents metals such as lithium, magnesium, and the like. An alternative organometallic route is shown from the aldehydes 17 where M represents metals such as lithium, magnesium, and the like. Oxidation with a suitable oxidizing agent, such as CrO3, follows to produce the ketones.
Figure USRE044048-20130305-C00031
Synthetic Scheme VI shows an alternative regioselective method of constructing the pyrazole 21. Commercially available enones 19 can be epoxidized to give epoxyketones 20, which are treated with 4-sulfonamidophenylhydrazine hydrochloride to provide the pyrazole 21.
Figure USRE044048-20130305-C00032
Synthetic Scheme VII shows the preparation of pyrazoles 23 (where R4 is 3-amino-4-substituted phenyl) from starting material 22. Appropriate 5-(4-substituted aryl)pyrazoles can be nitrated next to the R-group under standard nitration conditions and the nitro group reduced to the amino group, preferably with hydrazine and Pd/C. The amino compounds can be further manipulated by alkylation of the amino group.
Figure USRE044048-20130305-C00033
Synthetic Scheme VIII shows the preparation of pyrazoles 26 from esters 24. Reduction of the ester 24 to the alcohol, preferably with lithium aluminum hydride (LAH) followed by oxidation, preferably with MnO2, gives the aldehyde 25. Various nucleophiles (such as hydroxamates and 1,3-dicarbonyl compounds) can be condensed with the aldehyde to give the desired oximines or olefins 26.
The following examples containing provide detailed description of the methods of preparation of compounds of Formulas I-II the present invention. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention the present invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centrigrade unless otherwise indicated. HRMS is an abbreviation for High resolution mass spectrometry. In the following tables, “ND” represents “not determined”.
EXAMPLE 1
Figure USRE044048-20130305-C00034
Step 1: Preparation of 4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione
Ethyl trifluoroacetate (23.52 g, 166 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in methyl tert-butyl ether (75 mL). To the stirred solution was added 25% sodium methoxide (40 mL, 177 mmol) via an addition funnel over a 2 minute period. Next 4′-chloroacetophenone (23.21 g, 150 mmol) was dissolved in methyl tert-butyl ether (20 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (15.75 hours), 3N HCl (70 mL) was added. The organic layer was collected, washed with brine (75 mL), dried over MgSO4, filtered, and concentrated in vacuo to give a 35.09 g of yellow-orange solid. The solid was recrystallized from iso-octane to give 31.96 g (85%) of the dione: mp66°-67° C.
Step 2: Preparation of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
4-Sulphonamidophenylhydrazine hydrochloride (982 mg, 4.4 mmol 1.1 equivalent) was added to a stirred solution of 4,4,4-trifluoro-1-[4-(chloro)phenyl]-butane-1,3-dione from Step 1 (1.00 g, 4.0 mmol) in ethanol (50 mL). The reaction was heated to reflux and stirred for 20 hours. (HPLC area percent showed a 96:3 ratio of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide to its regioisomer (4-[3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide). After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water and with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a light brown solid which was recrystallized from ethyl acetate and iso-octane to give the pyrazole (1.28 g, 80%, mp 143°-145° C.). HPLC showed that the purified material was a 99.5:0.5 mixture of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide to its regioisomer. 1H NMR (CDCl3/CD3OD 10/1) d 5.2 (s, 2H), 6.8 (s, 1H), 7.16 (d, j=8.5 Hz, 2H), 7.35 (d, j=8.5 Hz, 2H), 7.44 (d, j=8.66, 2H), 7.91 (d, j=8.66, 2H); 13C NMR (CDCl3/CD3OD 10/1) d 106.42 (d, j=0.03 Hz), 121.0 (q, j=276 Hz), 125.5, 126.9, 127.3, 129.2, 130.1, 135.7, 141.5, 143.0, 143.9 (q, j=37 Hz), 144.0; 19F NMR (CDCl3OD 10/1) d -62.9; EI GC-MS M+=401.
Example 2 was prepared in a similar manner using the appropriate acetophenone.
EXAMPLE 2
Figure USRE044048-20130305-C00035
Step 1: Preparation of 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione
4′-Methylacetophenone (5.26 g, 39.2 mmol) was dissolved in 25 mL of methanol under argon and 12 mL (52.5 mmol) sodium methoxide in methanol (25%) was added. The mixture was stirred for 5 minutes and 5.5 mL (46.2 mmol) ethyl trifluoroacetate was added. After refluxing for 24 hours, the mixture was cooled to room temperature and concentrated. 100 mL 10% HCl was added and the mixture extracted with 4×75 mL ethyl acetate. The extracts were dried over MgSO4, filtered and concentrated to afford 8.47 g (94%) of a brown oil which was carried on without further purification.
Step 2: Preparation of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
To the dione from Step 1 (4.14 g, 18.0 mmol) in 75 mL absolute ethanol was added 4.26 g (19.0 mmol) 4-sulphonamidophenylhydrazine hydrochloride. The reaction was refluxed under argon for 24 hours. After cooling to room temperature and filtering, the reaction mixture was concentrated to afford 6.13 g of an orange solid. The solid was recrystallized from methylene chloride/hexane to give 3.11 g (8.2 mmol, 46%) of the product as a pale yellowYellow solid: mp 157°-159° C.; Anal. calc'd for C17H14N3O2SF3: C, 53.54; H, 3.70; N, 11.02. Found: C, 53.17; H, 3.81; N, 10.90.
EXAMPLE 3
Figure USRE044048-20130305-C00036
Step 1: Preparation of 3,5-dichloro-4-methoxyacetophenone
To a cooled solution (0° C.) of 7.44 g (55.8 mmol) AlCl3 in 25 mL of CH2Cl2 under argon was added 2.5 mL of acetic anhydride dropwise. After stirring for 0.5 hours, 4.18 g (23.6 mmol) of 2,6-dichloroanisole was added dropwise. The reaction was stirred at 0° C. for 1 hour, warmed to room temperature and stirred for 12 hours. The reaction was poured into 6 mL conc. hydrochloric acid/80 mL ice water. The aqueous phase was extracted with ethyl acetate (3×75 mL). The combined organic washes were dried over MgSO4, filtered, and stripped to afford the crude product as a yellow oil. NMR analysis showed that acylation only occured para to the methoxy. The crude oil was used without any further purification.
Steps 2 and 3: Preparation of 4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared in the same manner as Example 2, Steps 1 and 2 and was purified on a prep plate eluting with 10:1 hexane/ethyl acetate to afford a yellow solid: Anal. cal'd for C17H12N3O3SF3Cl2.H2O: C, 42.16; H, 2.91; N, 8.68. Found: C, 42.03; H, 2.54; N, 8.45.
EXAMPLE 4
Figure USRE044048-20130305-C00037
Step 1: Preparation of 3-ethyl-4-methoxyacetophenone
AlCl3 (4.9 g, 36.8 mmol) was added to a solution of 2-ethylanisole (2.5 g, 18.4 mmol) in methylene chloride (50 mL). Acetyl chloride (1.3 mL, 18.4 mmol) was added dropwise to the reaction mixture, which was then stirred at reflux for 0.5 hours. After cooling to room temperature, the reaction was poured over crushed ice and followed up with a methylene chloride/water extraction. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was chromatographed on a 4000 micron chromatotron plate with 10% ethyl acetate/90% hexane as eluant to afford 2.3 g of desired material.
Steps 2 and 3: Preparation of 4-[5-(3-ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared using the procedure describe din Example 2, Steps 1 and 2: Anal. calcd for C19H18N3O3SF3: C, 53.64; H, 4.26; N, 9.88. Found: C, 53.69; H, 4.36; N, 9.88.
EXAMPLE 5
Figure USRE044048-20130305-C00038
Step 1: Preparation of 2-methylthioanisole
Methyl iodide (0.5 mL, 8.1 mmol) and potassium carbonate (1.1 g, 8.1 mmol) were added to a solution of o-thiocresol (1.0 g, 8.1 mmol) in 10 mL of DMF. The reaction was stirred at 50° C., for 4 hours and poured into hexane and water. The organic layer was separated, dried over magnesium sulfate and concentrated to afford 1.1 g of desired material.
Steps 2, 3 and 4: Preparation of 4-[5-(3-methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared using the procedures found in Example 4, Steps 1, 2 and 3: Anal. calcd. for C18H16N3O2S2F3: C, 50.58; H, 3.77; N, 9.83. Found: C, 50.84; H, 3.62; N, 9.62.
EXAMPLE 6
Figure USRE044048-20130305-C00039
Step 1: Preparation of 3-allyl-4-methoxyacetophenone
Potassium hydroxide (3.2 g, 56.8 mmol) was added to a solution of 3-allyl-4-hydroxyacetophenone (10 g, 56.8) in 125 mL THF. Dimethyl sulfate (excess) was added and the reaction was stirred at 50° C. for 16 hours. The reaction was cooled, concentrated and poured into EtOAc and water. The organic layer was separated and washed with dilute sodium hydroxide to get rid of unreacted starting material. The ethyl acetate layer was dried and concentrated to afford 9.2 g of 3-allyl-4-methoxy acetophenone.
Steps 2 and 3: Preparation of 4-[5-(3-propenyl)-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared using the procedures described in Example 2, Steps 1 and 2: Anal. calc'd for C20H18N3F3O3S: C, 54.92; H, 4.15; N, 9.61. Found: C, 54.70; H, 4.12; N, 9.43.
EXAMPLE 7
Figure USRE044048-20130305-C00040
Step 1: Preparation of 3-n-propyl-4-methoxyacetophenone
To a solution of the product in Example 6, Step 1 (3 g, 17.0 mmol) in 50 mL of ethanol was added a catalytic amount of 4% Pd/C. The reaction mixture was stirred in a Parr shaker at room temperature at 5 psi hydrogen for 0.5 hours. The reaction was filtered and concentrated to afford 4 g of pure 3-propyl-4-methoxy acetophenone.
Steps 2 and 3: Preparation of 4-[5-(3-n-propyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared using the procedures described in Example 2, Steps 1 and 2: Anal. calcd. for C20H20N3F3O3S: C, 54.66; H, 4.59; N, 9.56. Found: C, 54.84; H, 4.65; N, 9.52.
EXAMPLE 8
Figure USRE044048-20130305-C00041
Step 1: Preparation of 3-cyclopropylmethyl-4-methoxyacetophenone
To a solution of the product in Example 6, Step 1 (3 g, 17.0 mmol) and catalytic Pd(OAc)2 in 20 mL Et2O was added ethereal diazomethane until starting material was consumed. The reaction was filtered, concentrated and chromatographed on a 4000 micron chromatotron plate (20% EA/80% hexane as eluant) to afford 2.5 g of desired ketone.
Steps 2 and 3: Preparation of 4-[5-(3-cyclopropylmethy-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared using the procedures described in Example 2, Steps 1 and 2: Anal. calc'd. for C21H20N3F3SO3: C, 55.87; H, 4.47; N, 9.31. Found: C, 55.85; H, 4.27; N, 9.30.
EXAMPLE 9
Figure USRE044048-20130305-C00042
To a solution of the product of Example 2 (500 mg, 1.31 mmol) in 5 mL of sulfuric acid was added nitric acid (0.6 mL, 1.31 mmol) and the reaction was stirred at room temperature for 0.5 hours. The mixture was poured over ice, the solid precipitate was filtered and chromatographed on a 4000 micron plate (20% EtOAc/80% hexane as eluant) to afford 410 mg of desired material: Anal. calc'd for C17H13N4O4SF3: C, 47.89; H, 3.07; N, 13.14. Found: C, 47.86; H, 2.81; N, 13.15.
EXAMPLE 10
Figure USRE044048-20130305-C00043
A catalytic amount of 10% Pd/C was added to a solution of hydrazine hydrate (0.022 mL, 0.7 mmol) in 10 mL of ethanol. The reaction mixture was refluxed for 15 minutes before the addition of the compound from Example 9 (100 mg, 0.23 mmol), and the resulting reaction mixture was refluxed for another 2 hours. The reaction was cooled, filtered through Celite and concentrated to afford 100 mg of title compound: Anal. calc'd for C17H15N4O2SF3.0.5 CO2: C, 50.24; H, 3.61; N, 13.39. Found: C, 50.49; H, 3.44; N, 13.37.
EXAMPLE 11
Figure USRE044048-20130305-C00044
Step 1: Preparation of 4-[5-(4-bromomethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The product from Example 2 (1.13 g, 3.0 mmol) and N-bromosuccinimide (NBS, 0.64 g, 3.6 mmol) were dissolved in 40 mL of benzene and irradiated with a UV lamp for 3 hours. The reaction was cooled to room temperature and poured into 50 mL of H2O. The organic phase was separated, washed with brine and dried over MgSO4. The crude pyrazole was obtained as an amber oil. The oil was purified via radical band chromatography eluting with 30% ethyl acetate/70% hexane to afford the 4-bromomethyl compound as a yellow oil which crystallized upon standing.
Step 2: Preparation of 4-[5-(4-hydroxymethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The bromo methyl compound from Step 1 was dissolved in 30 mL of acetone/4 mL of H2O and refluxed for 120 hours. The reaction was concentrated and the residue dissolve in 50 mL of ethyl acetate and dried over MgSO4. The crude product was obtained as an amber oil. The oil was purified via radial band chromatography eluting with 30% ethyl acetate/70% hexane to afford the title compound as a yellow solid: Anal. calc'd for C17H14N3O3SF3: C, 51.38; H, 3.55; N, 10.57. Found: C, 51.28; H, 3.59; N, 10.31.
EXAMPLE 12
Figure USRE044048-20130305-C00045
To the product from Example 11 in 2 mL of acetone was added 1.33M Jones reagent until an orange color persisted. The reaction was poured into 20 mL of ethyl acetate and 20 mL of H2O and the organic layer separated, washed with saturated sodium bisulfite and dried over MgSO4. The crude product was filtered through silica gel/Celite to afford the title compound as a yellow solid: HRMS m/z 411.0507 (calc'd for C17H12N3O4SF3, 411.0500).
The following compounds in Table I were prepared according to procedures similar to that exemplified in Examples 1-12, with the substitution of in a similar manner using the appropriate acetophenone.
TABLE I
Figure USRE044048-20130305-C00046
Ex. A M.P.(° C.) Analytical
13 4-Br 137-139 Calc. C, 43.07; H, 2.48; N, 9.42;
Br, 17.91
Obs. C, 43.01; H, 2.32; N, 9.39;
Br, 17.62
14 3-Cl 154-155 Calc. C, 47.83; H, 2.76; N, 10.46;
Cl, 8.82
Obs. C, 47.61; H, 2.85; N, 10.31;
Cl, 8.43
15 2-Cl 159-160 Calc. C, 47.83; H, 2.76; H, 10.46
Obs. C, 47.47; H, 2.65; N, 10.31
16 4-CF3 144-145 Calc. C, 46.90; H, 2.55; N, 9.65
Found: C, 46.98; H, 2.57; N, 9.61
17 4-F 168-169 Calc. C, 49.87; H, 2.88; N, 10.90
Found: C, 49.83; H, 2.89; N, 10.86
18 H 164-165 Calc. C, 52.31; H, 3.29; N, 11.43
Found: C, 52.14; H, 3.07; N, 11.34
19 4-OCH3 153-154 Calc. C, 51.38; H, 3.55; N, 10.57
Found: C, 51.00; H, 3.48; N, 10.24
20 4-OCF3 101-103 Calc. C, 45.24; H, 2.46; N, 9.31
Found: C, 45.22; H, 2.37; N, 9.29
21 2-CH3 126-128 Calc. C, 53.54; H, 3.70; N, 11.02
Found: C, 53.52; H, 3.55; N, 11.06
22 2,4-di-F 127-130 M + H 404
23 2,6-di-F 178-180 M + H 404
24 4-CN 196-197.5
25 3,4-di-Cl 145-147 Calc. C, 44.05; H, 2.31; N, 9.63;
Cl, 16.25
Found: C, 44.00; H, 2.20; N, 9.63;
Cl, 16.46
26 2,4-di-Cl 153-155 Calc. C, 43.87; H, 2.35; N, 9.59
Found: C, 43.78; H, 2.13; N, 9.56
27 4-NO2 169-172 Calc. C, 46.61; H, 2.69; N, 13.59;
S, 7.78
(dec) Obs.: C, 46.52; H, 2.67; N, 13.51;
S, 7.84
28 2-F 165-166 Calc. C, 49.87; H, 2.88; N, 10.90
Found: C, 49.49; H, 2.62; N, 10.79
29 4-NH2 124-127 HRMS: 382.0671
(dec)
30 4-F, 2-CH3 170-171 Calc. C, 51.13; H, 3.28; N, 10.52
Found: C, 50.83, H, 2.98; N, 10.55
31 3-CH3 135-137 Calc. C, 53.54; H, 3.70; N, 11.02
Found: C, 53.15; H, 3.58; N, 10.96
32 4-OCH2CH3 141-142 Calc. C, 51.43; H, 4.08; N, 9.99
Found: C, 51.49; H, 3.80; N, 10.08
33 4-OCH3, 143-144 Calc. C, 53.64; H, 4.26; N, 9.87
3,5-di-CH3 Found: C, 53.49; H, 4.39; N, 9.64
34 3-F 143-144 Calc. C, 49.87; H, 2.88; N, 10.90
Found: C, 49.80; H, 2.80; N, 10.84
35 4-OCH, 3-F 155-156 Calc. C, 49.16; H, 3.15; N, 10.11
Found: C, 48.77; H, 2.93; N, 9.96
36 4-SCH3 165-166 Calc. C, 49.39; H, 3.41; N, 10.16
Found: C, 49.48; H, 3.46; N, 10.26
37 4-Cl, 3-CH3 ND Calc. C, 49.10; H, 3.15; N, 10.11
Found: C, 49.00; H, 3.00; N, 10.10
38 4-CH2CH3 ND Calc. C, 54.68; H, 4.08; N, 10.63
Found: C, 54.54; H, 3.73; N, 10.67
39 2,4-di-CH3 ND Calc. C, 54.68; H, 4.08; N, 10.63
Found: C, 54.31; H, 4.32; N, 10.39
40 2-OCH3 167-168 Calc. C, 51.38; H, 3.55; N, 10.57
Found: C, 51.29; H, 3.34; N, 10.52
41 4-OCH3, 146-147
3-CH3
42 4-SCH3, 3-Br 141-144 HRMS: 490.9595
43 4-CH3, 3-Cl 186-190 Calc. C, 49.10; H, 3.15; N, 10.11
Found: C, 49.21; H, 3.17; N, 10.10
44 3,4-di-OCH3 192-193 Calc. C, 50.58; H, 3.77; N, 9.83
Found: C, 50.58; H, 3.83; N, 9.72
45 4-OCH3, 3-Cl 166-168 Calc. C, 47.29; H, 3.03; N, 9.73
Found: C, 47.21; H, 2.91; N, 9.55
46 4-OCH3, ND Calc. C, 48.49; H, 3.39; N, 9.42
3-Cl, 5-CH3 Found: C, 48.27; H, 3.42; N, 9.22
47 2-OCH3, 4-F 163-164 Calc. C, 49.16; H, 3.15; N, 10.12
Found: C, 49.32; H, 3.27; N, 10.18
48 2,4-di-OCH3 ND Calc. C, 50.58; H, 3.77; N, 9.83
Found: C, 50.40; H, 3.78; N, 9.83
49 4-F, 3-Cl ND Calc. C, 45.78; H, 2.40; N, 10.01
Found: C, 45.75; H, 2.34; N, 10.15
50 4-OCH3, ND Calc. C, 47.12; H, 2.79; N, 9.70
3,5-di-F Found: C, 46.72; H, 2.75; N, 9.54
51 4-SCH3, 3-F ND Calc. C, 47.33; H, 3.04; N, 9.74
Found: C, 47.25; H, 3.39; N, 9.45
52 4-SCH3, 3-Cl ND Calc. C, 45.59; H, 2.93; N, 9.38
Found: C, 45.56; H, 2.76; N, 9.52
53 4-N(CH3)2 ND HRMS: 410.1016
54 4-N(CH2CH3)2 ND HRMS: 438.1353
EXAMPLE 55
Figure USRE044048-20130305-C00047
To a solution of the product of Example 41 (240 mg, 0.58 mmol) in DMF (3 mL) was added NaSMe (205 mg, 2.9 mmol) and the mixture heated to reflux for 2 hours. The mixture was cooled, poured into 0.1N HCl and extracted with EtOAc (3×). The combined extracts were dried over MgSO4 and concentrated. Flash chromatography using 1:1 hexane/ethyl acetate provided 31 mg of the title compound: Anal. calc'd for C17H14N3O3SF3.0.25 H2O: C, 50.80; H, 3.64; N, 10.45. Found: C, 50.71; H, 3.47; N, 10.39.
EXAMPLE 56
Figure USRE044048-20130305-C00048
To a solution of the product from Example 53 (431 mg, 1.0 mmol) in 10 ml methanol was added 36 mg (0.17 mmol) ruthenium, (III) chloride hydrate, followed by 1.5 mL 30% hydrogen peroxide (14.7 mmol) over 2 hours. The reaction was quenched with 25 mL of 1M KOH in methanol and concentrated to give 1.24 g of a brown solid. The solid was purified on a prep plate eluting with 2/97/1 methanol/methylene chloride/ammonium chloride to give 52 mg (0.14 mmol, 12%) of the product as a yellow solid.
EXAMPLE 57
Figure USRE044048-20130305-C00049
19 mg (0.051 mmol) of the product from Example 56 was treated with 0.03 mL acetic anhydride (0.32 mmol) and 0.03 mL triethylamine (0.22 mmol) in 3 mL methylene chloride at room temperature for 12 hours. The reaction matured was concentrated and the residue dissolved in 10 mL ethyl acetate. After washing with brine (2×10 mL), the solution was dried over MgSO4, filtered and concentrated to afford the title compound (18.4 mg, 74%) as a yellow solid: HRMS m/e 438.0976 (calc'd for C19H17N4O3SF3, 438.0974).
EXAMPLE 58
Figure USRE044048-20130305-C00050
Step 1: Preparation of 4,4-difluoro-1-[4-(chloro)phenyl]-butane-1,3-dione
Ethyl difluoroacetate (24.82 g, 200 mmol) was placed in a 500 mL three-necked round bottom flash, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4′-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 5 minutes. After stirring overnight (18 hours), 1N HCl (250 mL) and ether (250 mL) were added. The organic layer was collected, washed with brine (250 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 46.3 g of a yellow solid. The solid was recrystallized from methylene chloride and iso-octane to give 31.96 g (69%) of the dione: mp 65°-66.5° C.
Step 2: Preparation of 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
4-Sulphonamidophenylhydrazine hydrochloride (1.45 g, 6.5 mmol 1.3 equivalent) and 4,4-difluoro-1-[4-(chloro)phenyl]butane-1,3-dione from Step 1 (1.16 g, 5 mmol) were dissolved in ethanol (10 mL). The reaction was heated to reflux and stirred for 20 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (100 mL) and washed with water (100 mL) and with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 1.97 g of a light brown solid which was recrystallized from ethanol and water to give 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (1.6 g, 93% yield,): mp 185°-186° C.
EXAMPLE 59
Figure USRE044048-20130305-C00051
Step 1: Preparation of 3′-fluoro-4′-methoxyacetophenone
Aluminum chloride, (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5°-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition at 5°-10° C. of 2-fluoroanisole (62.6 g, 0.5 mol). The mixture was stirred at 0°-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92°-94° C.; 1H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Step 2: Preparation of 4,4-difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione
Ethyl difluoroacetate (4.06 g, 32.7 mmol) was placed in a 250 mL Erlenmeyer flask, and dissolved in methyl tert-butyl ether (50 mL). To the stirred solution was added 25% sodium methoxide (7.07 g, 32.7 mmol) followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (5.0 g, 29.7 mmol). After stirring for 16 hours, 1N HCl (50 mL) was added. The organic layer was collected, washed with water (2×50 mL), dried over anhydrous MgSO4, filtered, and added to hexanes to precipitate a tan solid (7.0 g, 96%): mp 70°-72° C.; 1H NMR (DMSO-d6) 8.0 (m, 3H), 7.3 (t, 1H), 6.9 (s, 1H), 6.5 (t, 1H), 3.9 (s, 3H).
Step 3: Preparation of 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
4,4-Difluoro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step 2 (7.0 g, 28.4 mmol) was dissolved in ethanol (150 mL). To the stirred mixture was added 4-sulphonamidophenylhydrazine hydrochloride (7.4 g, 33 mmol) and stirred at reflux overnight (16 hours). The mixture was cooled and water was added until crystals slowly appeared. The product was isolated by filtration and air dried to provide the desired product as a light tan solid (9.8 g, 87%): mp 159°-161° C.; 1H NMR (DMSO-d6) 7.85 (d, 2H), 7.5 (m, 6H), 7.3-6.9 (m, 5H), 3.8 (s 3H). Anal. Calc'd for C17H14N3SO3F3: C, 51.38; H, 3.55; N, 10.57. Found: C, 51.46; H, 3.52; N, 10.63.
EXAMPLE 60
Figure USRE044048-20130305-C00052
Step 1: Preparation of 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-dione
To a stirred solution of 4-methoxyacetophenone (11.43 g, 76.11 mmol) and ethyl difluoroacetate (8.4 mL, 10.4 g, 83.72 mmol) in diethyl ether (300 mL) in a 500 mL round bottomed flask was added sodium methoxide in methanol (18.2 mL of a 25% solution, 79.91 mmol). The solution became a dark lavender color within thirty minutes, and then a gray suspension within 1.5 hours. The reaction was stirred for 60 hours. Diethyl ether (300 mL) was added and the mixture was acidified (pH 2) with 1N HCl. The mixture was transferred to a separatory funnel, mixed and separated. The ethereal phase was washed with water, dried over magnesium sulfate, and filtered. Hexane was added causing precipitation of an orange solid 5.25 g of 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-dione. An additional 3.43 g of product was obtained by recrystallization of the concentrated mother liquor from hexane: 1H NMR (CDCl3) 400 mHz 15.58 (br s, 1H), 7.94 (d, J=8.87 Hz, 2H), 6.98 (d, J=8.87 Hz, 2H), 6.49 (s, 1H), 6.00 (t, J=54.55 Hz, 1H), 3.89 (s, 3H).
Step 2: Preparation of 4-[5-(4-methoxyphenyl)-3-difluoromethyl-1-H-pyrazol-1-yl]benzenesulfonamide
A mixture of 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-dione from Step 1 (2.006 g, 8.79 (mmol) and 4-sulfonamidophenylhydrazine hydrochloride salt (2.065 g, 9.23 mmol) dissolved in ethanol (25 mL) was heated to reflux for 16 hours. The reaction was cooled to room temperature, was concentrated and recrystallized from methanol yielding 4-[5-(4-methoxyphenyl)-3-difluoromethyl-1-H-pyrazol-1-yl]benzenesulfonamide as fluffy tan crystals (1.49 g, 45%): mp 133°-135° C.; 1H NMR (CDCl3) 300 mHz 7.90 (d, J=8.863 Hz, 2H), 7.45 (d, J=8.863 Hz, 2H), 7.14 (d, J=8.863 Hz, 2H), 6.88 (d, J=8.863 Hz, 2H), 6.77 (t, J=56.47 Hz, 1H), 6.68 (s, 1H), 4.96 (br s, 2H), 3.83 (s, 3 H); 19NMR (CDCl3) 300 mHz −112.70 (d, J=57.9 Hz). High resolution mass spectrum Calc'd for C17H15F2N3O3S: 379.0802. Found: 379.0839. Elemental analysis calc'd for C17H15F2N3O3S: C, 53.82; H, 3.99; N, 11.08. Found: C, 53.75; H, 3.99; N, 11.04.
The following compounds in Table II were obtained according to procedures similar to that exemplified in Examples 58-60, with the substitution of in a similar manner using the appropriate acetophenone.
TABLE II
Figure USRE044048-20130305-C00053
Ex. A M.P.(° C.) Anal.
61 4-CF3 202-205 M + H 418
62 4-SCH3 157-158
63 4-(1-morpholino) 167-171 M + 434
64 4-CH3 158-159 Calc. C, 56.19; H, 4.16; N, 11.56
Obs. C, 56.25; H, 4.17; N, 11.61
65 3,4-di—CH3 168-171 Calc. C, 57.28; H, 4.54; N, 11.13
Obs. C, 57.34; H, 4.59; N, 11.16
66 4-CO2CH3 157-158 Calc. C, 53.56; H, 3.09; N, 15.61
Obs. C, 53.45; H, 3.11; N, 15.62
67 4-CONH2 235-236 HRMS: 393.0833
68 4-CO2H 258-260 HRMS: 394.0662
(dec)
69 2-F, 4-OCH3 138-140 Calc. C, 51.38; H, 3.55; N, 10.57
Obs. C, 51.14; H, 3.48; N, 10.40
70 4-CN 222-224 Calc. C, 54.54; H, 3.23; N, 14.97
Obs.: C, 54.58; H, 3.21; N, 15.06
71 3-Cl, 4-CH3 156-158 Calc. C, 51.32; H, 3.55; N, 10.56
Obs: C, 51.46; H, 3.53; N, 10.53
72 3-Cl, 4-OCH3 160 Calc. C, 49.34; H, 3.41; N, 10.15;
Cl, 8.57; S, 7.75
Obs.: C, 49.41; H, 3.37; N, 10.17;
Cl, 8.62; S, 7.67
73 4-Cl, 3-CH3 163-165 Calc. C, 51.32; H, 3.55; N, 10.56
Obs.: C, 51.42; H, 3.57; N, 10.53
74 3,4-di-OCH3 181-185 Calc. C, 52.81; H, 4.19; N, 10.26
Obs.: C, 52.86; H, 4.19; N, 10.20
75 3,5-di-Cl, 170-173 Calc. C, 45.55; H, 2.92; N, 9.37
4-OCH3 Obs.: C, 45.83; H, 3.05; N, 9.31
76 3,5-di-F, 149-150 Calc. C, 49.16; H, 3.15; N, 10.12
4-OCH3 Obs.: C, 49.24; H, 3.16; N, 10.13
77 2-OCH3 129-132 Calc. C, 53.82; H, 3.99; N, 11.08
Obs.: C, 53.82; H, 3.97; N, 11.15
78 3-Br, 4-OCH3 164 HRMS: 456.9883
79 4-SO2CH3 209-210
80 4-C6H5 167-170 M + 425
81 H 171-172 HRMS: 349.0737
EXAMPLE 82
Figure USRE044048-20130305-C00054
Step 1. Preparation of 1-(1,3-benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione
Ethyl difluoroacetate (1.72 g, 11 mmol) was dissolved in ether (25 mL). To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol) followed by 3′,4′-(methylenedioxy)acetoxyphenone (1.64 g, 10 mmol). After stirring 16 hours, 1N HCl (25 mL) was added. The organic layer was collected and washed with water (2×25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude dione was used in the next step without further purification or characterization.
Step 2. Preparation of 5-(1,3-benzodioxol-5-yl)-4-[3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
1-(1,3-Benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione from Step 1 (2.4 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (3.3 g, 84%): mp 214°-218° C. 1H NMR (D6-DMSO): 7.86 (d, J=8.7Hz, 2H), 7.51 (d, J=8.7Hz, 2H), 7.49 (brs, 2H), 7.3-6.7 (m, 5H), 6.06(s, 2H). Anal. Calc'd for C17H13N3SO4F2: C, 51.91; H, 3.33; N, 10.68. Found: C, 51.90; H, 3.25; N, 10.65.
EXAMPLE 83
Figure USRE044048-20130305-C00055
Step 1: Preparation of Methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate
Dimethyl oxalate (23.6 g, 200 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4′-chloroacetophenone (25.94 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 3 minutes. After stirring overnight (18 hours), 1N HCl (400 mL) and ethyl acetate (750 mL) were added. The organic layer was collected, washed with brine (350 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 45.7 g of a yellow solid. The solid was recrystallized from ethyl acetate and iso-octane to give 23 g (48%) of the dione: mp 108.5°-110.5° C.
Step 2: Preparation of 4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic Acid
4-Sulphonamidophenylhydrazine hydrochloride (1.45 g, 6.5 mmol, 1.3 equivalent) and methyl-4-[4-(chloro)phenyl]-2,4-dioxobutanoate (1.2 g, 5 mmol) were dissolved in ethanol (50 mL). The reaction was heated to reflux and stirred for 20 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give 1.7 g of a light brown solid which was recrystallized from methanol and water to yield 1.6 g (85%) of a white solid. This material was dissolved in methanol (150 mL) and 3N NaOH (75 mL) and stirred at reflux for 3 hours. The methanol was removed in vacuo and the aqueous solution acidified with concentrated HCl. The product was extracted into ethyl acetate (200 mL), which was washed with brine (100 mL), dried over MgSO4 filtered and concentrated to give 4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid, 1.4 g (74%): mp 135° C. (dec).
EXAMPLE 84
Figure USRE044048-20130305-C00056
Step 1. Preparation of 3,5-difluoro-4-methoxyacetophenone
To a stirred suspension of AlCl3 (24.05 g, 180.40 mmol) in chloroform (300 mL, dried by passage through alumina) at 4° C. (ice bath) under nitrogen was added acetyl chloride (11.0 mL, 152.65 mmol) over 20 minutes. This chilled suspension was stirred at 0° C. for 30 minutes and 2,6-difluoro anisole was added dropwise over 30 minutes. The resulting suspension was warmed to room temperature and stirred overnight. The reaction was quenched by slowly pouring it into a rapidly stirred ice/water mixture. The water layer was extracted with methylene chloride (2×50 mL) and the organic phases were combined and concentrated in vacuo yielding a clear mobile oil. In a 50 mL round bottomed flask was added the above clear oil, DMF (25 mL), K2CO3 (15 g). Methyl iodide (6 mL) was added and the suspension stirred at 45° C. under nitrogen overnight. Water (1 mL) was added and the mixture was heated for an additional 14 hours. The crude reaction mixture was cooled to room temperature, diluted with water (250 mL) and extracted with diethyl ether (3×100 mL). The ether phase was washed with sodium bicarbonate saturated solution, potassium bisulfate (0.1N solution), dried over MgSO4, filtered and concentrated in vacuo yielding a clear mobile liquid. This liquid was distilled (30° C., 1 mm) yielding 12.5 g of a clear liquid which was a mixture of 3,5-difluoro-4-methoxyacetophenone and 3,5-difluoro-4-acetoxyacetophenone in an 85:15 ratio. The yield based upon this ratio was 41%. This ketone was used as is.
Step 2. Preparation of Methyl 1-(4-aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate
To a stirred solution of 3,5-fluoro-4-methoxyacetophenone from Step 1 (6.46 g, 34.70 mmol) and dimethyl oxalate (6.15 g, 52.05 mmol) in methanol (80 mL), was added sodium methoxide solution (13.4 mL of 25% solution, 58.99 mmol) in one portion and the reaction stirred overnight. The crude reaction was diluted with methylene chloride, washed with potassium bisulfate (0.1N solution), brine, dried over MgSO4, filtered, and concentrated in vacuo yielding methyl 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate as an off white crystalline solid which was used as is. A mixture of 4-(3,5-difluoro-4-methoxyphenyl)-2,4-dioxo-butanoate and 4-sulfonamidophenylhydrazine hydrochloride salt (7.76 g, 34.70 mmol) dissolved in methanol was warmed to reflux for 9 hours. Upon allowing the clear reaction to cool to room temperature, a crystalline precipitate formed which was collected by vacuum filtration yielding 5.45 g, (37% based upon the 3,5-difluoro-4-methoxyacetophenone) of methyl 1-(4-aminosulfonylphenyl)-5-(3,5-difluoro-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate as an off-white solid: mp 185°-190° C.; 1H NMR (CDCl3/300 mHz) 7.95 (d, J=8.86, 2H), 7.49 (d, J=8.86, 2H), 7.02 (s, 1H), 6.77 (m, 2H), 4.99 (s, 2H, 4.04 (s, 3H), 3.98 (s, 3H); 19F NMR (CDCl3/300 mHz) −126.66. Anal. Calc'd for C17H13F2N3O3S: C, 51.06; H, 3.57; N, 9.92. Found: C, 51.06; H, 3.54, N, 9.99.
EXAMPLE 85
Figure USRE044048-20130305-C00057
Step 1. Preparation of Methyl 4-[4-(chloro)phenyl]-2,4-dioxobutanoate
Dimethyl oxalate (15.27 g, 0.129 mol) and 4′-chloroacetophenone (20.0 g, 0.129 mol) were charged to a 500 mL round-bottom flask, with provisions made for magnetic stirring, and diluted with methanol (300 mL). Sodium methoxide (25% in methanol, 70 mL) was added in one portion. The reaction was stirred at room temperature for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then concentrated hydrochloric acid (70 mL) was added, and the white suspension was stirred vigorously at room temperature for sixty minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was washed with cold water (100 mL). Upon drying, methyl 4-[4-(chloro)phenyl]-2,4-dioxobutanoate was obtained (16.94 g, 54.4%) as the enol: 1H NMR (CDCl3/300 MHz) 7.94 (d, J=8.66 Hz, 2H), 7.48 (d, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H), 3.48 (s, 1H).
Step 2. Preparation of Methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3yl]carboxylate
A 100 mL round-bottomed flask equipped with magnetic stirrer and nitrogen inlet was charged with methyl 4-[4-(chloro)phenyl]-2,4-dioxobutanoate from Step 1 (5.0 g, 20.78 mmol), 4-sulfonamidylphenylhydrazine hydrochloride (5.11 g, 22.86 mmol) and methanol (50 mL). The reaction vessel was heated to reflux and held for 16 hours. A precipitate formed overnight. The suspension was cooled to 0° C., held for 0.5 hour, filtered and washed with cold water to provide, after air-drying, 7.91 g (91%) of crude product. Recrystallized 3.50 g from boiling ethanol to yield 3.14 g (97%) of pure methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate: mp 227° C.; 1H NMR (CDCl3/300 MHz) 7.91 (d, J=8.86 Hz, 2H), 7.44 (d, J=8.86 Hz, 2H), 7.33 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 7.03 (s, 1H), 3.96 (s, 3H). Mass Spectrum, MH+=392. Anal. Calc'd for C17H14N3O4ClS: C, 52.11; H, 3.60; N, 10.72; Cl, 9.05; S, 8.18. Found: C, 52.07; H, 3.57; N, 10.76; Cl, 9.11; S, 8.27.
EXAMPLE 86
Figure USRE044048-20130305-C00058
Methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in absolute ethanol (10 mL) and a catalytic amount of 21% NaOEt/EtOH was added. The reaction was stirred without temperature control for 72 hours, then water (10 mL) was added. The product crystallized, the suspension was cooled to 0° C. and held for 30 minutes. The product was filtered, washed with water (5 mL) and dried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal. Calc'd for C18H16N3O4ClS: C, 53.27; H, 3.97; N, 10.35; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.69; S, 7.97.
The following compounds in Table III were prepared according to procedures similar to that exemplified in Examples 83-86, with the substitution of the appropriate reagents.
TABLE III
Figure USRE044048-20130305-C00059
Ex. A B M.P. (° C.) Analytical.
87 4-NO2 —CH3 216-220 MH+ = 403
88 4-F —CH3 ND Calc. C, 54.40; H, 3.76; N, 11.19; S, 8.54
Obs. C, 54.49; H, 3.70; N, 11.25; S, 8.50
89 4-NH2 —CH3 267-269(dec) MH+ = 373
90 4-Br —CH3 221-224 MH+ = 438
91 4-OCH3 —CH3 169-171 HRMS: 387.0930
92 4-CH3 —CH3 213-215 HRMS: 371.0965
93 4-CH3 —CH2CH3 219-220 Calc. C, 59.21; H, 4.97; N, 10.90
Obs. C, 58.73; H, 4.96; N, 10.78
94 4-Cl —CH2CH2CH3 ND Calc. C, 54.35; H, 4.32; N, 10.01; Cl, 8.44; S, 7.64
Obs. C, 54.11; H, 4.28; N, 10.14; Cl, 8.54; S, 7.64
95 3,5-di-Cl, 4-OCH3 —CH3 225-229

EXAMPLE 96
Figure USRE044048-20130305-C00060
4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid (Example 83) (1.08 g, 2.86 mmol), HOBt (0.66 g, 4.3 mmol) and EDC (0.66 g, 3.4 mmol) were dissolved in dimethylformamide (DMF) (20 mL) and stirred at ambient temperature for 5 minutes. To this solution was added NH4OH (30%, 2.9 mL) and the reaction stirred for an additional 18 hours. This solution was then poured into ethyl acetate (200 mL) and 1N HCl (200 mL), shaken and separated. The organic layer was washed with saturated NaHCO3 (150 mL) and brine (150 mL), dried over MgSO4, filtered and concentrated to yield 0.9 g of a white solid which was recrystallized from ethyl acetate and iso-octane to yield 4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide (0.85 g, 79%): mp 108°-110° C.
Figure USRE044048-20130305-C00061
A 250 mL three-neck round-bottom flask, equipped with a thermometer, gas sparging tube, reflux condenser and provisions for magnetic stirring, was charged with methyl [1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate (Example 88) (3.0 g, 7.99 mmol), methanol (100 mL), and a catalytic amount of sodium cyanide. Anhydrous ammonia gas was sparged through the reaction vessel for 16 hours without temperature control. The suspension turned a deep red during this time. The reaction was sparged with anhydrous nitrogen at room temperature for 20 minutes, cooled to 0° C. and held for 30 minutes. The solid was filtered and washed with cold water (50 mL) to yield, upon drying, 1.87 g (65%) of [1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide as a white solid: mp 214°-216° C.; 1H NMR (CDCl3/CD3OD/300 MHz) 7.64 (d, J=8.66 Hz, 2H), 7.14 (d, J=8.66 Hz, 2H), 6.95 (m, 2H), 6.82-6.67 (m,6H), 6.39(s, 1H); 19F NMR (CDCl3/CD3OD/282.2 MHz) −112.00(m). Mass spectrum, MH+=361. Anal. Calc'd for C16H13N4O3FS: C, 53.33; H, 3.64; N, 15.55; S, 8.90. Found: C, 53.41; H, 3.69; N, 15.52; S, 8.96.
EXAMPLE 98
Figure USRE044048-20130305-C00062
Step 1. Preparation of Methyl 4-[4-fluorophenyl]-2,4-dioxobutanoate
Dimethyl oxalate (18.80 g, 0.159 mol) and 4′-fluoroacetophenone (20.0 g, 0.145 mol) were charged to a 1000 mL round-bottom flask and diluted with methanol (400 mL). The reaction flask was placed in a sonication bath (Bransonic 1200), and sodium methoxide (25% in methanol, 70 mL) was added over 25 minutes. The reaction was sonicated at 45° C. for 16 hours. The reaction became an insoluble mass during this time. The solid was mechanically broken up, then poured into a hydrochloric acid solution (1N, 500 mL). A magnetic stirrer was added, and the white suspension was stirred vigorously at room temperature for 60 minutes. The suspension was cooled to 0° C. and held for 30 minutes. The solid was filtered, and the filter cake was then washed with cold water (100 mL). Upon drying, methyl 4-[4-fluorophenyl]-2,4-diketobutanoate was obtained (22.91 g, 70.6%) as the enol: 1H NMR (CDCl3/300 MHz) 8.03 (ddd, J=8.86 Hz, J=8.66 Hz, J=5.03 Hz, 2H), 7.19 (dd, J=8.86 Hz, J=8.66 Hz, 2H), 7.04 (s, 1H), 3.95 (s, 3H). 19F NMR (CDCl3/282.2 MHz) −103.9(m).
Step 2. Preparation of Methyl 4-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate
A 500 mL one-neck round-bottom flask equipped for magnetic stirring was charged with methyl 4-[4-fluorophenyl]-2,4-diketobutanoate from Step 1 (1.00 mg, 44.61 mmol), 4-sulfonamidylphenylhyrazine hydrochloride (10.98 g, 49.07 mmol) and methanol (200 mL). The suspension was heated and held at reflux for three hours, then cooled to room temperature. The suspension was cooled to 0° C., held for 30 minutes, filtered, washed with water (100 mL), and dried to yield 14.4 g (86%) of methyl 4-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate as a white solid: 1H NMR (CDCl3/300 MHz) 7.85 (d, J=8.66 Hz, 2H), 7.36 (d, J=8.66 Hz, 2H), 7.18 (ddd, J=8.66 Hz, J=8.46 Hz, J=4.85 Hz, 2H), 7.00 (dd, J=8.66 Hz, J=8.46 Hz, 2H), 6.28 (s, 1H), 3.90 (s, 3H). 19F NMR (CDCl3/282.2 MHz: −111.4(m). Mass spectrum. MH+=376. Anal. Calc'd for C17N14N3O4FS: C, 54.40; H, 3.76; N, 11.19; S, 8.54. Found: C, 54.49; H, 3.70; N, 11.25; S, 8.50.
Step 3. Preparation of [1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylic Acid
A 500 mL one-neck round-bottom flask, equipped with provisions for magnetic stirring, was charged with methyl 4-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate from Step 2 (10.0 g, 26.64 mmol) and tetrahydrofuran (200 mL). Aqueous sodium hydroxide (2.5N, 27 mL) and water (25 mL) were added, and the suspension was heated to reflux and held for 16 hours. The solids all dissolved during this time. The reaction was cooled to room temperature, and hydrochloric acid solution (1N, 110 mL) was added. The aqueous suspension was extracted with methylene chloride (2×200 mL). The combined organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an oil. Trituration with 300 mL of methylene chloride yielded, upon filtration and drying, 9.0 g, (94%) of [1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylic acid as a white solid: mp 138°-142° C. (dec); 1H NMR (CD3OD/300 MHz) 7.93 (d, J=8.66 Hz, 2H), 7.51 (d, J=8.66 Hz, 2H), 7.31 (ddd, J=8.86 Hz, J=8.66 Hz, J=4.83 Hz, 2H), 7.11 (dd, J=8.86 Hz, J=8.66 Hz, 2H), 7.06 (s, 1H). 19F NMR (CD3OD/282.2 MHz): −114.01(m).
Step 4. Preparation of N-(3-chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide
A 100 mL one-neck round-bottom flask, equipped with provisions for magnetic stirring, was charged with [1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylic acid from Step 3 (0.500 g, 1.38 mmol), 1-hydroxybenzotriazole hydrate (0.206 g, 1.522 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.318 g, 1.66 mmol) and N,N-dimethylformamide (30 mL). The solution was stirred at room temperature for forty minutes, then 3-chloroaniline (0.154 mL, 1.453 mmol) was added. The reaction was held at room temperature for sixteen hours, then poured into an aqueous solution of citric acid (5%, 100 mL). The aqueous solution was extracted with ethyl acetate (2×60 mL), and the combined organic solutions were washed with aqueous citric acid (60 mL), saturated sodium bicarbonate solution (2×60 mL) and 50% saturated sodium chloride solution (2×60 mL). The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to an oil. Trituration with 20 mL of dichloromethane yielded, upon filtration and drying, 0.439 g (67%) of N-(3-chlorophenyl)-[1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide as a white solid: mp 207°-212° C.; 1H NMR (CDCl3/CD3OD/300 MHz) 8.90 (s, 1H), 7.86 (d, J=8.66 Hz, 2H), 7.79 (t, J=2.01 Hz, 1H), 7.46 (dd, J=7.05 Hz, J=2.01 Hz, 1H), 7.33 (d, J=8.86 Hz, 2H), 7.21-7.11 (m, 3H), 7.02-6.94 (m, 4H). 19F NMR (CDCl3/CD3OD/282.2 MHz): −111.38(m). Mass spectrum, MH+=470. Anal. Calc'd for C22H16N4O3ClFS: C, 56.11; H, 3.42; N, 11.90; Cl, 6.81; S, 7.53. Found: C, 55.95; H, 3.50; N, 11.85; Cl, 6.82; S, 7.50.
The following compounds in Table IV were prepared according to procedures similar to that exemplified in Examples 96-98, with substitution of the appropriate starting material.
TABLE IV
Figure USRE044048-20130305-C00063
Ex. A B MP. ° C. Analytical
99 4-Br H 143-145 MH+ = 421
100 4-F phenyl- 233-236 MH+ = 436
101 4-NO2 H 278-281 MH+ = 387
102 4-F 4-CH3O-phenyl- 209-211 MH+ = 466
103 4-F 4-CH3-phenyl- 222-225 MH+ = 451
104 4-F cyclohexyl- 224-227 MH+ = 442
105 4-F 3-F-phenyl- 227 MH+ = 454
106 4-Cl 3-F-phenyl- 174-176(dec) MH+ = 471
107 H H ND MH+ = 343
108 4-OCH3, 3-Cl H ND MH+ = 408
109 4-SCH3 H 115(dec) HRMS: 389.0743
110 4-OCH3 H 115-140 Calc. C, 54.83; H, 4.33; N, 15.04
Obs. C, 54.76; H, 4.34; N, 14.98
111 4-CH3 H 139-140 HRMS•H2O: 356.0939
112 4-OCH3 —CH3 209 MH+ = 387
113 4-Cl glycine benzyl ester 136 MH+ = 525
114 4-Cl glycine 124-130 MH+ = 435
115 4-OCH3, 3-Br H ND M + Li = 457/459
116 4-OCH3, 3,5-di-Cl H 185(dec) HRMS: 440.0113

EXAMPLE 117
Figure USRE044048-20130305-C00064
A dry 100 ml three-neck flask, equipped with a reflux condenser, thermometer, pressure-equalizing addition funnel and provisions for magnetic stirring was charged with anhydrous DMF (20 mL) and cooled to 0° C. Oxalyl chloride (0.530 mL, 6.105 mmol) was added over twenty seconds, causing a 5° C. exotherm. The white precipitate formed dissolved as the reaction cooled to 0° C. The reaction was held at 0° C. for ten minutes, then a solution of [1-(4-aminosulfonylphenyl)-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxamide (Example 97) in anhydrous DMF was added to the vigorously stirring solution over approximately two minutes. After fifteen minutes, pyridine (1.0 mL, 12.21 mmol) was added to quench the reaction. The mixture was poured into dilute hydrochloric acid (1N, 100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic solution was washed with 1N HCl (2×100 mL) and with 50% saturated NaCl (3×100 mL). The organic solution was dried over magnesium sulfate, filtered and concentrated in vacuo to a crude oil. The oil was applied to a column of silica gel and eluted with ethyl acetate and hexane (40% ethyl acetate) to obtain, upon concentration of the appropriate fractions, 0.66 g (69%) of 4-[3-cyano-5-(4-fluorophenyl-1H-pyrazol-1-yl]benzenesulfonamide as a white solid: mp 184°-185° C.; 1H NMR (CDCl3/300 MHz) 7.94 (d, J=8.86 Hz, 2H), 7.44 (d, J=8.86 Hz, 2H), 7.23-7.07 (m, 4H), 6.87 (s, 1H), 4.88 (brs, 2H); 19F NMR (CDCl3/282.2 MHz) −109.90(m). Mass spectrum, MH+=343. Anal. Calc'd for C16H11N4O2FS: C, 56.14; H, 3.24; N, 16.37; S, 9.36. Found: C, 56.19; H, 3.16; N, 16.39; S, 9.41.
The following compounds in Table V were prepared according to procedures similar to that exemplified in Example 117, with the substitution of the appropriate starting material.
TABLE V
Figure USRE044048-20130305-C00065
Ex. A M.P. (° C.) Anal.
118 4-Br 156-157 HRMS: 401.9833
119 4-Cl 142-143
120 4-OCH3 ND HRMS: 354.0774
121 4-CH3 90-95 HRMS: 338.0849
122 4-SCH3 192-193
123 4-OCH3, 3-Cl 179 MH+ = 389
124 4-OCH3, 3,5-di-Cl 121-125 HRMS: 422.0051
125 4-OCH3, 3-Br 213 MH+ = 433
126 4-NO2 230-232 MH+ = 370
127 H ND MH+ = 325

EXAMPLE 108
Figure USRE044048-20130305-C00066
Step 1: Preparation of 4,4,5,5,6,6,6-heptafluoro-1-[4-(chloro)phenyl]hexane-1,3-dione
Ethyl heptafluorobutyrate (5.23 g, 21.6 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (20 mL). To the stirred solution was added 25% sodium methoxide (4.85 g, 22.4 mmol) followed by 4-chloroacetophenone (3.04 g, 19.7 mmol). The reaction was stirred at room temperature overnight (15.9 hours) and treated with 3N HCl (17 mL). The organic layer was collected, washed with brine, dried over MgSO4, concentrated in vacuo, and recrystallized from iso-octane to give the diketone as a white solid (4.27 g, 62%): mp 27°-30° C.; 1H NMR (CDCl3) 300 MHz 15.20 (br s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 6.58 (S, 1H); 19F NMR (CDCl3) 300 MHz: −80.94 (t), −121.01 (t), −127.17 (s); M+H 351.
Step 2: Preparation of 4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide
The 4-sulfonamidophenylhydrazine hydrochloride (290 mg, 1.30 mmol) was added to a stirred solution of the diketone from Step 1 (400 mg, 1.14 mmol) in ethanol (5 mL). The reaction was heated to reflux and stirred overnight (23.8 hours). The ethanol was removed in vacuo, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give a white solid which was passed through a column of silica gel with ethyl acetate/hexane (40%) and recrystallized from ethyl acetate/isooctane to give the pyrazole as a white solid (0.24 g, 42%): mp 168°-71° C.; 1H NMR (CDCl3) 300 MHz 7.90 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 6.79 (s, 1H), 5.20 (br s, 2H); 19F NMR (CDCl3) 300 MHz: −80.48 (t), −111.54 (t), −127.07 (s).
EXAMPLE 129
Figure USRE044048-20130305-C00067
Step 1: Preparation of 4-chloro-4,4-difluoro-1-[4-(chloro)phenyl]-butane-1,3-dione
Methyl 2-chloro-2,2-difluoroacetate (4.20 g, 29 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (10 mL). To the stirred solution was added 25% sodium methoxide (6.37 g, 29 mmol) followed by 4′-chloroacetophenone (4.10 g, 26.5 mmol). The reaction was stirred at room temperature overnight (20.4 hours), then poured into a separatory funnel and washed with 3N HCl (15 mL), brine (20 mL), dried over MgSO4, and concentrated in vacuo and recrystallized from iso-octane to give the diketone as a yellow solid (3.78 g, 53%): mp 53°-55° C.; 1H NMR (CDCl3) 300 MHz 14.80 (br s, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 6.49 (S, 1H); 19F NMR (CDCl3) 300 MHz: −66.03 (s); M+ 267.
Step 2: Preparation of 4-[5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
4-Sulfonamidophenylhydrazine hydrochloride (1.39 g, 6.2 mmol) was added to a stirred solution of the diketone from Step 1 (1.43 g, 5.7 mmol) in ethanol (10 mL). The reaction was heated to reflux and stirred overnight (15.75 hours). The ethanol was removed in vacuo, and the residue was dissolved in ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give a white solid which was recrystallized from ethyl acetate/isooctane to give the pyrazole as a white solid (0.32 g, 41%): mp 130°-33° C.; 1H NMR (CDCl3) 300 MHz 7.90 (d, J≦8.9 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 6.76 (s, 1 H), 5.13 (br s, 2H); 19F NMR (CDCl3) 300 MHz: −48.44 (s); M+ 417/419.
EXAMPLE 130
Figure USRE044048-20130305-C00068
Step 1. Preparation of 3′-fluoro-4′-methoxyacetophenone
Aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution was added acetyl chloride (51.0 g, 0.65 mol) dropwise, maintaining the temperature between 5°-10° C. The mixture was allowed to stir for 10 minutes at 5° C. before the dropwise addition at 5°-10° C. of 2-fluoroanisole (63.06 g, 0.5 mol. The mixture was stirred at 0°-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with methylene chloride (2×250 mL). The combined organic layers were washed with water (2×150 mL), dried over magnesium sulfate, and concentrated to 300 mL. Hexanes crystallized from the mixture: mp 92°-94° C.; 1H NMR (d6-DMSO) 7.8 (m, 2H), 7.3 (t, J=8.7Hz, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Step 2. Preparation of 4,4-dichloro-1-(3-fluoro-4-methoxyphenyl)-butene-1,3-dione
Methyl dichloroacetate (1.57 g, 11 mmol) was dissolved ether (25 mL). To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol) followed by 3′-fluoro-4′-methoxyacetophenone from Step 1 (1.68 g, 10 mmol). After stirring 16 hours 1N HCl (25 mL) was added. The organic layer was collected and washed with water (2×25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude dione was used in the next step without further purification or characterization.
Step 3. Preparation of 4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide
4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from Step 2 (2.8 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (2.7 g, 63%): mp 190°-193° C.: 1H NMR (DMSO-d6) 7.84 (d, J=8.4Hz, 2H), 7.53 (s, 1H), 7.48 (d, J=8.4Hz, 2H), 7.47 (brs, 2H), 7.3-7.0 (m, 3H), 6.95 (s, 1H), 3.85 (s, 3H). Anal. Calc'd for C17H14N3SO3FCl2: C, 47.45; H, 3.28; N, 9.76. Found: C, 47.68; H, 3.42; N, 10.04.
EXAMPLE 131
Figure USRE044048-20130305-C00069
Step 1: Preparation Methyl 4-phenyl-2,4-dioxobutanoate
To a solution of dimethyl oxalate (11.81 g, 100 mmol) in ether (200 mL) is added 24 mL of 25% sodium methoxide in methanol, followed by a solution of acetophenone (12.02 g, 100 mmol) in ether (20 mL) and the mixture stirred overnight at room temperature. The mixture was partitioned between 1N HCl and EtOAc and the organic layer was washed with brine, dried over MgSO4 and concentrated to give 18.4 g of crude butanoate.
Step 2. Preparation of Methyl 1-[(4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole 3-carboxylate
The ester was prepared from the butanoate in Step 1 using the procedure described in Example 2, Step 2.
Step 3. Preparation of 4-[3-hydroxymethyl-5-phenyl-1H-pyrazol-1-yl]benzene Sulfonamide
To a solution of ester in Step 2 (4.0 g, 10.4 mmol) in 50 mL THF was added LiAlH4 (0.592 g, 15.6 mmol) in portions and the mixture refluxed overnight. The reaction was cooled and quenched with 1N NaHSO4 and extracted with ether (3×). The combined extracts were dried over MgSO4 and concentrated to give 3.5 g crude alcohol. Flash chromatography using 1:1 hexane/EtOAc provided the title compound.
Step 4: Preparation 4-[3-fluoromethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide
To a mixture of the alcohol from Step 3 (212 mg, 0.64 mmol) in dichloromethane (4 mL) was added diethylaminosulfur trifluoride (0.13 mL, 1.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and partitioned between water and dichloromethane. The organic solution was washed with brine and concentrated. The residue was chromatographed on silica (72 mg, 34%): mp 162°-163° C.; Anal. calc'd for C16H14N3O2SF: C, 58.00; H, 4.26; N, 12.68. Found: C, 57.95; H, 4.03; N, 12.58.
The following compounds in Table VI were prepared according to procedures similar to that exemplified in Examples 128-131, with the substitution of the appropriate substituted acetyl and acetate starting materials.
TABLE VI
Figure USRE044048-20130305-C00070
Ex. A R2 M.P. (° C.) Anal.
132 4-Cl —CF2CF3 145.5-150
133 4-Cl —CH2Cl 198-201 Calc. C, 50.27; H, 3.43;
N, 10.99
Found C, 50.34; H, 3.43; N, 10.96
134 3- F, —CF2Cl 120-124 Calc. C, 47.29; H, 3.04;
4-OCH3 N, 9.74
Found C, 47.28; H, 3.37; N, 9.88
135 3- F, —CBrF2 120-122 Calc. C, 42.87; H, 2.75;
4-OCH3 N, 8.82
Found C, 42.99; H, 3.81; N, 9.92
136 3- Cl, —CH2Cl ND Calc. C, 49.53; H, 2.84;
4-OCH3 N, 8.66
Found C, 50.03; H, 3.81; N, 9.92

EXAMPLE 137
Figure USRE044048-20130305-C00071
Step 1: Preparation of 4,4-difluoro-1-(2-pyrazinyl)-butane-1,3-dione
Ethyl difluoroacetate (2.23 g, 18 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (10 mL). To the stirred solution was added 25% sodium methoxide (4.68 g, 22 mmol) followed by acetylpyrazine (2.00 g, 16 mmol). After two hours stirring at room temperature, a precipitate formed and THF (10 mL) was added to the reaction. The reaction was stirred an additional 25.9 hours, then treated with 3N HCl (10 mL). The organic layer was collected, washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo and recrystallized from methylene chloride/iso-octane to give the diketone as a brown solid (2.23 g, 68%); mp 103°-110° C.; 1H NMR (CDCl3) 300 MHz 14.00 (br s, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.68 (dd, J=1.4 Hz 2.4 Hz, 1H), 7.20 (s, 1H), 6.03 (t, J=54.0 Hz, 1H); 19F NMR (CDCl3) 300 MHz: −127.16 (d); M+ 200.
Step 2: Preparation of 4-[5-(2-pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
4-Sulfonamidophenylhydrazine hydrochloride (0.37 g, 1.65 mmol) was added to a stirred suspension of the diketone from Step 1 (0.30 g, 1.50 mmol) in ethanol (10 mL). The reaction was heated to reflux and stirred for 5.3 hours. The ethanol was removed in vacuo, and the residue was dissolved in ethyl acetate, washed with water (20 mL), brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a brown solid (0.36 g) which was recrystallized from ethyl acetate/ethanol/isooctane to give the pyrazole as a brown solid (0.20 g, 38%): mp 191°-94° C.; 1H NMR (acetone d6) 300 MHz 8.94(d, J=1.4 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.52 (dd, J=1.4 Hz, 2.4 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.30 (s, 1H), 7.02 (t, J=54.6 Hz, 1H), 6.73 (br s, 2 H); 19F NMR (acetone d6) 300 MHz: −113.67 (d): M+351.
EXAMPLE 138
Figure USRE044048-20130305-C00072
Step 1: Preparation of 4-methyl-1,3-benzodioxole
11.6 g Adogen 464 and 7 mL of dibromomethane were refluxed in 50 mL of H2O for 0.5 hours under argon. 3-Methylcatechol (8.89 g, 71.6 mmol) was added over 2 hours and the mixture refluxed for an additional 1 hour. Distillation of the product from the reaction mixture afforded the title compound as a yellow oil: HRMS m/e 136.0524 (calc'd for C8H8O2, 136.0524).
Step 2: Preparation of 5-acetyl-4-methyl-1,3-benzodioxole (A) and 6-acetyl-4-methyl-1,3-benzodioxole (B)
13.8 g of polyphosphoric acid and 5 mL of acetic anhydride were heated to 45° C. under a drying tube of CaSO4 until liquified. The product from Step 1 was added and the reaction was stirred at 45° C. for 4.5 hours. The reaction was cooled to room temperature and quenched with 150 mL of ice water. The aqueous phase was washed with ethyl acetate (4×50 mL). The combined organic extracts were dried over MgSO4 and filtered to give the crude product as a red oil. The oil was chromatographed on silica gel eluting with 10% ethyl acetate/90% hexane to afford two products: A: Anal. calcd for C10H10O3: C, 67.07; H, 5.66. Found: C, 67.41; H, 5.75, and B: MS, M+ 178.
Steps 3 and 4: 4-[5-(4-methyl-1,3-benzodioxol-5yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared from product A using the procedures described in Example 2, Steps 1 and 2: White solid: Anal. calcd for C18H14N3O4SF3: C, 50.82; H, 3.22; N, 9.88. Found: C, 50.71; H, 3.34; N, 9.55.
The following compounds in Table VII were prepared according to procedures similar to that exemplified in Examples 137-138, with the substitution of in a similar manner using the appropriate starting material.
TABLE VII
Figure USRE044048-20130305-C00073
Ex. A B M.P.(° C.) Anal.
139 5-bromo-2-thienyl CF2H 168-169 M + Li 440/442
140 2-thienyl CF2H 190-191 M + Li 367
141 5-chloro-2-thienyl CF2H 168-170 M + 389/391
142 1-cyclohexenyl CF2H 160-161 M + 353.
143 1,4-benzodioxan CF2H 115-119 Calc. C, 53.06; H, 3.71; N, 10.32
Obs. C, 52.40; H, 3.98; N, 9.96
144 4-methylcyclohex-3-ene-1-yl CF2H 164-168 HRMS: 367.1194
145 2-methylcyclopenten-1-yl CF2H 165-166 HRMS: 353.1033
146 2,5-dimethyl-3-thienyl CF2H 125-127 Calc. C, 50.12; H, 3.94; N, 10.96
Obs. C, 50.21; H, 3.92; N, 11.00
147 2,5-dimethyl-3-furyl CF2H 139-142 Calc. C, 52.31; H, 4.12; N, 11.44
Obs. C, 52.07; H, 4.16; N, 11.37
148 5-methyl-2-furyl CF2H 177-179 Calc C, 50.99; H, 3.71; N, 11.89
Obs. C, 51.08; H, 3.68; N, 11.95
149 4-bromo-4-methylcyclohex-1-yl CF2H 175- HRMS: 448.0520
178(dec)
150 4-methylcyclohex-1-yl CF2H 190-192 HRMS: 369.1341
151 4-chloro-4-methylcyclohex-1-yl CF2H 197-199 HRMS: 403.095
152 3,4-dibromo-4- CF2H 172-173
methylcyclohex-1-yl
153 2-methoxycyclohex-1-yl CF2H 177-179 HRMS: 386.1357
154 2-benzofuryl CF2H 215-217 Calc C, 55.52; H, 3.37; N, 10.79
Obs. C, 55.52; H, 3.32; N, 10.85
155 2,5-dichloro-3-thien-yl CF2H 154-156 Calc. C, 39.63; H, 2.14; N, 9.90
Obs. C, 39.63; H, 2.13; N, 9.89
156 2-benzofuryl CF3 227-228 Calc. C, 53.07; H, 2.97; N, 10.31
Obs. C, 53.02; H, 2.96; N, 10.39
157 5-chloro-2-thienyl CF3 161-165 HRMS: 406.9784]
158 5-bromo-2-thienyl CF3 ND Calc: C, 37.18; H, 2.01; N, 9.29;
Br, 17.67
Found: C, 37.25; H, 1.93; N, 9.45;
Br, 17.40
159 5-indanyl CF3 118-120 Calc: C, 56.01; H, 3.96; N, 10.31
Found: C, 56.02; H, 4.06; N, 10.22
160 5-methylthien-2-yl CF3 188-190 Calc. C, 46.51; H, 3.12; N, 10.85
Found: C, 46.17; H, 3.10; N, 10.75
161 2,3-dihydrobenzofuryl CF3 152-153 Calc. C, 52.81; H, 3.45; N, 10.26
Found: C, 52.67; H, 3.78; N, 10.13
162 1-cyclohexenyl CF3 135-138 HRMS: 371.0918
163 6-tetrahydronaphthyl CF3 143-145 Calc. C, 57.00; H, 4.31; N, 9.97
Found: C, 56.72; H, 4.27; N, 9.90
164 3-benzothienyl CF3 164-165 Calc. C, 51.06; H, 2.86; N, 9.92
Obs. C, 50.96; H, 2.73; N, 9.78
165 3,4-dihydrobenzopyranyl CF3 ND HRMS: 423.0855
166 styryl CF3 166-167 Calc. C, 54.96; H, 3.59; N, 10.68
Obs. C, 54.77; H, 3.59; N, 10.47
167 4-methyl-1,3-benzodioxol-6-yl CF3 ND Calc. C, 50.82; H, 3.22; N, 9.88
Obs. C, 50.64; H, 3.35; N, 9.72
168 3-pyridyl CF3 202-204 Calc. C, 48.91; H, 3.01; N, 15.21
Obs. C, 48.97; H, 3.16; N, 14.96
169 3,4-dihydrobenzothiopyranyl CF3 ND Calc. C, 51.95; H, 3.67; N, 9.56
Obs. C, 51.98; H, 3.78; N, 9.48
EXAMPLE 170
Figure USRE044048-20130305-C00074
4-[5-(1-Cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol (15 mL), 10% palladium on charcoal was added, and the suspension was stirred at room temperature under hydrogen (36 psi) for 18.25 hours. The reaction was filtered through celite, and the ethanol removed in vacuo to give a white solid, which was recrystallized from methylene chloride/isooctane (0.31 g, 99%); mp 199°-203° C.; 1H NMR (acetone-d6) 300 MHz 8.05 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 6.69 (t, J=55.0 Hz 1H), 6.47 (s, 1H), 5.02 (br s, 2H), 2.67 (m, 1H), 1.71-1.88(m, 5H), 1.24-1.43 (m, 5H); 19F NMR (acetone-d6) 300 MHz: −112.86 (d).
EXAMPLE 171
Figure USRE044048-20130305-C00075
4-[4-(Aminosulfonyl)phenyl-5-(4-chlorophenyl)-1H-pyrazol-3-carboxylic acid (Example 83) (3.8 g, 10 mmol) and tetrahydrofuran (100 mL) were stirred at room temperature during the dropwise addition of 1.0M borane-tetrahydrofuran complex (30 mL, 30 mmol). The mixture was heated to reflux for 16 hours. The solution was cooled and methanol was added dropwise until gas evolution ceased. Ethyl acetate (100 mL) was added and the mixture was washed successively with 1N hydrochloric acid, brine, sat. aq. sodium bicarbonate solution, and water, dried over magnesium sulfate, filtered and concentrated. The resultant product was recrystallized from ethanol:water to yield 2.6 g (71%) of a white solid: mp 192°-194° C.; 1H NMR (d6-DMSO/300 MHz) 7.81 (d, J=8.7Hz, 2H, 7.46 (d, J=8.4Hz, 2H), 7.42 (brs, 2H), 7.40 (d, J=8.7Hz, 2H), 7.26 (d, J=8.4Hz, 2H), 6.63 (s, 1H), 5.35 (t, J=8.0Hz, 1H), 4.50 (d, J=8.0Hz, 2H). Anal. Calc'd for C16H14N6SO2Cl: C, 52.82; H, 3.88; N, 11.55. Found: C, 52.91; H, 3.88; N, 11.50.
EXAMPLE 172
Figure USRE044048-20130305-C00076
A 60% dispersion of sodium hydride in mineral oil (4.0 g, 100 mmol) was twice washed with hexane (100 mL each) and dried under a stream of nitrogen. Ether (300 mL) was added followed by dropwise addition of ethanol (0.25 mL) and γ-butyrolactone (4.0 mL, 52 mmol). The mixture was cooled to 10° C. and acetophenone (5.8 mL, 50 mmol) in ether (40 mL) was added dropwise over 1 hour. The mixture was warmed to 25° C. and stirred overnight. The mixture was cooled to 0° C. and quenched with ethanol (5 mL) followed by 10% aqueous ammonium sulfate (100 mL). The organic solution was separated, dried over Na2SO4 and concentrated. The residue was chromatographed on silica gel with 1:1 hexane/ethyl acetate to give the desired diketone (3.4 g) as an oil. Pyridine (0.34 mL, 4.2 mmol) and the diketone (700 mg, 3.4 mmol) in methanol (3 mL) were added to a slurry of 4-sulfonamidophenylhydrazine-HCl (750 mg, 3.4 mmol) in methanol (8 mL). The mixture was stirred at 25° C. overnight and concentrated in vacuo. The residue was dissolved in methylene chloride and the solution washed with 1N HCl. The organic solution was separated, dried and concentrated. The residue was chromatographed on silica gel using ethyl acetate to give the desired pyrazole (435 mg) as a solid: Anal. calc'd for C18H19N3O3S: C, 60.49; H, 5.36; N, 11.75. Found: C, 60.22; H, 5.63; N, 11.54.
EXAMPLE 173
Figure USRE044048-20130305-C00077
Following the procedure of Example 172, but substituting 4-fluoroacetophenone for acetophenone afforded 4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide. Anal. calc'd for C18H18N3O3SF.0.25 H2O: C, 56.90; H, 4.91; N, 11.05. Found: C, 56.80; H, 4.67; N, 11.02.
EXAMPLE 174
Figure USRE044048-20130305-C00078
Jones reagent (0.64 mL of a 2.67M solution) was added dropwise to a solution of 4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide from Example 173 (295 mg, 0.78 mmol) in acetone (8 mL). The mixture was stirred at 25° C. for 2 hours. The solution was filtered and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water (3×). The organic solution was dried over MgSO4 and concentrated. The residual oil was crystallized from ether/hexane to give the desired acid (149 mg): mp 180°-182° C.; Anal. calc'd for C18H16N3O4SF: C, 55.52; H, 4.14; N, 10.79. Found: C, 55.47; H, 4.22; N, 10.50.
EXAMPLE 175
Figure USRE044048-20130305-C00079
Step 1: Preparation of 2,3-epoxy-5-methyl-1-phenyl-3-hexanone
To a solution of 5-methyl-1-phenyl-1-hexan-3-one (2.0 g, 10.6 mmol) in 15 mL EtOH and 5 mL acetone was added a mixture of 30% hydrogen peroxide (2 mL) and 4N NaOH (1.5 mL) dropwise and the mixture stirred at 25° C. for 1-3 hours. Water (50 mL) was added and the precipitate filtered and dried at 40° C. in vacuo to provide 1.9 g of the epoxide as a white solid: Anal. calc'd for C13H16O2.0.1 H2O: C, 75.77; H, 7.92; Found: C, 75.47; H, 7.56.
Step 2: Preparation of 4-(3-isobutyl-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide
The epoxide prepared above in Step 1 (1.26 g, 6.11 mmol) and 4-sulfonamidophenylhydrazine hydrochloride (1.38 g, 6.17 mmol) were stirred in 20 mL EtOH with AcOH (0.5 mL) and the mixture refluxed for 3 hours, cooled and quenched with 50 mL H2O. The aqueous layer was extracted with ethyl acetate (3×50 mL), the combined extracts were dried over MgSO4 and concentrated. Flash chromatography using 70:30 hexane/ethyl acetate provided the title compound (0.41 g, 19%) as a white solid: Calc'd for C19H21N3O2S: C, 64.20; H, 5.96; N, 11.82. Found: C, 64.31; H, 6.29; N, 11.73.
EXAMPLE 176
Figure USRE044048-20130305-C00080
Step 1: Preparation of 4-[3-formyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide
To a solution of the alcohol prepared in Example 131, Step 3 (1.1 g, 3.3 mmol) in ethyl acetate (20 mL) was added MnO2 (5 g, 60 mmol) and the mixture stirred at room temperature overnight. The mixture was filtered through Celite and the solution was concentrated to provide the crude aldehyde.
Step 2: Preparation of Ethyl 3-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazol-3-yl]-2-cyano-2-propenoate
To a solution of the aldehyde from Step 1 (1.2 g, 3.6 mmol) in benzene (18 mL) was added ethyl cyanoacetate (0.38 mL, 3.6 mmol), ammonium acetate (50 mg, 0.7 mmol) and glacial acetic acid (0.17 mL, 2.8 mmol). The solution was heated at reflux for 18 hours, cooled, and partitioned between water and ethyl acetate. The organic solution was washed with a saturated aqueous sodium bicarbonate solution, water and brine. The organic solution was dried and concentrated. The residue was chromatographed on silica (40% hexane in ethyl acetate) to give the desired product (1.0 g, 66%): Anal. calc'd for C21H18N4O4S: C, 59.82; H, 4.30; N, 13.22. Found: C, 59.70; H, 4.29; N, 13.26.
EXAMPLE 177
Figure USRE044048-20130305-C00081
To a suspension of 220 mg (0.58 mmol) 4-[5-(4-chlorophenyl)-3-formyl-1H-pyrazol-1-yl]benzenesulfonamide (prepared as described in Example 176, Step 1) in dichloromethane (3 mL) was added pyridine (0.12 mL, 1.3 mmol) and O-benzylhyroxylamine hydrochloride (110 mg, 0.68 mmol) and the reaction stirred at room temperature for 18 hours. The mixture was partitioned between pH 7 buffer and dichloromethane and the organic layer was washed with water, dried and concentrated. Flash chromatography on silica gel (2:1 hexane/EtOAc) provided the title compound (151 mg, 56%): mp 158°-159° C.; Anal. calc'd for C23H19N4O3SCl.0.25 H2O: C, 58.59; H, 4.17; N, 11.88. Found: C, 58.43; H, 4.03; N, 11.85.
The following compounds in Table VIII were prepared according to procedures similar to that exemplified in Examples 171-177, with the substitution of the appropriate starting material.
TABLE VIII
Figure USRE044048-20130305-C00082
Ex A R2 M.P. (° C.) Anal.
178 H —CH2OH 183-184 HRMS: 329.0845
179 4-OCH3 —CH2OH 140-142 Calc. C, 56.81; H, 4.77; N, 11.69
Found: C, 56.92; H, 4.76; N, 11.64
180 3,5-di-Cl, 4-OCH3 —CH2OH 191-193 HRMS 427.0199
181 3-Cl, 4-OCH3 —CH2OH ND Calc. C, 51.84; H, 4.09; N, 10.67
Cl, 9.00; S,8.14
Found: C, 51.77; H, 4.02; N, 10.73;
Cl, 9.11; S, 8.03
182 4-CH3 —C(CH3)2OH 178-179
183 4-Cl —(CH3)2CO2H 156-159
184 4-Cl —CH2CONH2 198-200
185 H —CH3 ND Calc. C, 60.46; H, 5.07; N, 13.21
Found: C, 60.48; H, 4.95; N, 13.19
186 4-Cl —CH2CN 212-214 Calc. C, 54.77; H, 3.51 N, 15.03
Found: C, 54.94; H, 3.61; N, 14.88

EXAMPLE 187
Figure USRE044048-20130305-C00083
Step 1: Preparation of 2-trifluoroacetyl-1-tetralone
A 250 mL one necked round bottom flask equipped with a reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with ethyl trifluoroacetate (28.4 g, 0.2 mol) and 75 mL of ether. To this solution was added 48 mL of 25% sodium methoxide in methanol (0.21 mol). A solution of 1-tetralone (29.2 g, 0.2 mol) in 50 mL of ether was added over about 5 minutes. The reaction mixture was stirred at room temperature for 14 hours and was diluted with 100 mL of 3N HCl. The phases were separated and the organic layer was washed with 3N HCl, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was taken up in 70 mL of boiling ethanol/water and cooled to room temperature, whereupon crystals of 2-trifluoroacetyl-1-tetralone formed which were isolated by filtration and air dried to give pure compound (32 g, 81%): mp 48°-49° C.; 1H NMR CDCl3 δ 2.8 (m, 2H), 2.9 (m, 2H), 7.2 (d, j=3.0 Hz, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.98 (m, 1H), 19F NMR CDCl3 δ −72.0. EI GC-MS M+=242.
Step 2: Preparation of 4-[4,5-dihydro-3-(trifluoromethyl)-1H)-benz[g]indazol-1-yl]benzenesulfonamide
A 100 mL one necked round bottomed flask equipped with reflux condenser, nitrogen inlet and provisions for magnetic stirring was charged with 2-trifluoroacetyl-1-tetralone from Step 1 (1.21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 mL of absolute ethanol. The solution was warmed to reflux for 15 hours and concentrated in vacuo. The residue was dissolved in ethyl acetate, and then washed with water, and with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and isooctane to give 1.40 g, 71% of pure product: mp 257°-258° C.; 1H NMR (CDCl3/CD3OD, 4:1) δ 2.7 (m, 2H), 2.9 (m, 2H), 6.6 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.16 (m, 1H), 7.53 (m, 2H), 7.92 (m, 2H); 19F NMR (CDCl3) δ −62.5. ( FAB-MS M+H=394.
EXAMPLE 188
Figure USRE044048-20130305-C00084
Step 1. Preparation of 6-methyl-2-(trifluoroacetyl)tetralone
Ethyl trifluoroacetate (5.33 g, 37.5 mmol) was dissolved in ether (50 mL) and treated with a sodium methoxide solution (25% in methanol, 9.92 g, 45.9 mmol) followed by 6-methyltetralone (5.94 g, 37.1 mmol). The reaction was stirred at room temperature for 6.1 hours then treated with 1N HCl (20 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (8.09 g) that was used in the next step without further purification.
Step 2. Preparation of 4-[4,5-dihydro-7-methyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide
4-Sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0 mmol) was added to a stirred solution of the diketone from Step 1 (1.86 g, 7.3 mmol) in ethanol (10 mL). The reaction was heated to reflux and stirred for 14.8 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, washed with water and with brine, dried over MgSO4 and reconcentrated in vacuo to give the pyrazole as a brown solid (1.90 g, 64%): mp 215°-218° C. 1H NMR (acetone-d6) 300 MHz 8.10 (d, 2H), 7.80 (d, 2H), 7.24 (s, 1H), 6.92 (d, 1H), 6.79 (br s, 2H), 6.88 (d,1H), 3.02 (m, 2H), 2.85 (m, 2H), 2.30 (s, 3H). 19F NMR (acetone-d6) 282 MHz −62.46 (s). High resolution mass spectrum Calc'd. for C19H17F3O2S: 408.0994. Found: 408.0989.
The following compounds in Table IX were prepared according to procedures similar to that exemplified in Examples 187-188, with the substitution of the appropriate ester.
TABLE IX
Figure USRE044048-20130305-C00085
Ex. R2 R6 M.P. (° C.) Anal.
189 —CHF2 6-OCH3 275-277 HRMS: 405.0961
190 —CHF2 7-CH3 240-241 HRMS: 390.1122
191 —CF3 6,8-CH3 284-288 HRMS: 422.1089
192 —CF3 7-OCH3 277-278 HRMS: 423.0838
193 —CF3 7,8-OCH3 269-275 HRMS: 453.1011
194 —CHF2 7-OCH3 256-257
195 —CO2CH3 7-OCH3 274-276 HRMS: 414.1117

EXAMPLE 196
Figure USRE044048-20130305-C00086
Step 1. Preparation of 4-keto-4,5,6,7-tetrahydrothianaphthene
4-(2-Thienyl)butyric acid (28.42 g, 167 mmol) was placed in a round bottom flask with acetic anhydride (30 mL) and phosphoric acid (0.6 mL), and heated to reflux for 3.2 hours. The reaction mixture was poured into 100 mL of water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oil (22.60 g) which was vacuum distilled (1 mm Hg, 107°-115° C.) to give a white solid (13.08 g, 51%): mp 34°-40° C.); 1H NMR (CDCl3) 300 MHz 7.29 (d, J=5.2 Hz, 1H), 6.99 (d, J=5.2 Hz, 1H, 2.95 (t, J=6.0 Hz, 2H), 2.47(m, 2H), 2.13(m, 2H). M+H=153.
Step 2. Preparation of 4-keto-4,5,6,7-tetrahydro-5-(trifluoroacetyl)thianaphthene
Ethyl trifluoroacetate (11.81 g, 83.1 mmol) was dissolved in ether (50 mL) and treated with a sodium methoxide solution (25% in methanol, 18.35 g, 84.9 mmol) followed by 4-keto-4,5,6,7-tetrahydrothianaphthene from Step 1 (12.57 g, 82.6 mmol) dissolved in ether (25 mL). The reaction was stirred for 69.4 hours at room temperature, then treated with 3N HCl (40 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown solid which was recrystallized from ether/hexane to give the diketone (10.77 g, 52%) as brown needles; mp 54°-64° C.; 1H NMR (CDCl3) 300 MHz 15.80 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.17 (d, J=5.2 Hz, 1H), 3.04 (m, 2H), 2.91 (m, 2H), 19F NMR (CDCl3) 282 MHz −70.37 (s). M+H=249.
Step 3. Preparation of 4-[4,5-dihydro-3-(trifluoromethyl)-1H thieno[3,2-g]indazol-1-yl]benzenesulfonamide
4-Sulfonamidophenylhydrazine hydrochloride (2.36 g, 10.6 mmol) was added to a stirred solution of the diketone from Step 2 (2.24 g, 9.0 mmol) in ethanol (20 mL). The reaction was heated to reflux and stirred 14.7 hours. The reaction mixture was filtered and washed with ethanol and with water to give the desired pyrazole as a white solid (2.69 g, 75%): mp 288°-290° C.; 1H NMR (acetone-d6) 300 MHz 8.12 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.27 (d, J=5.2 Hz, 1H), 6.81 (br s, 2H), 6.59 (s, J=5.4 Hz, 1H), 3.18 (m, 2H), 3.01 (m, 2H); 19F NMR (acetone-d6) 282 MHz −62.46 (s). High resolution mass spectrum Calc'd. for C16H12F3N3O2S2: 399.0323. Found: 399.0280.
EXAMPLE 197
Figure USRE044048-20130305-C00087
Step 1. Preparation of 3-[4-(chloro)phenyl]-propane-1,3-dione
Ethyl formate (8.15 g, 0.11 mol) and 4′-chloroacetophenone (15.4 g, 0.1 mol) were stirred in ether (150 mL) at room temperature. Sodium methoxide (25%) (23.77 g, 0.11 mol) was added dropwise. The mixture was stirred at room temperature for 16 hours and was then treated with 150 mL of 1N hydrochloric acid. The phases were separated and the ethereal solution washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 18.3 g of a yellow oil. The resulting crude mixture was used directly in the next step without purification.
Step 2. Preparation of 4-[5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide
3-[4-(Chloro)phenyl]-propane-1,3-dione from Step 1 (18.3 g, 0.1 mol) and 4-sulfonamidophenylhydrazine hydrochloride (22.4 g, 0.1 mol) were dissolved in 150 mL of absolute ethanol and heated to reflux for 16 hours. The solution was cooled to room temperature, diluted with 100 mL of water and let stand, whereupon crystals of pyrazole formed that were isolated by filtration to provide 8.4 g (25%) of a white solid: mp 185°-187° C.; 1H NMR (CDCl3/300 MHz) 7.89 (d, J=8.7Hz, 2H), 7.76 (d, J=1.8Hz, 1H), 7.43 (d,J=8.7Hz, 2H), 7.34 (d, J=8.7Hz, 2H), 7.17 (d, J=8.7Hz, 2H), 6.53 (d, J=1.8Hz, 1H), 4.93 (brs 2H). Anal. Calc'd for C15H12N3SO2Cl: C, 53.97; H, 3.62; N, 12.59. Found: C, 54.08; H, 3.57; N, 12.64.
Step 3. Preparation of 4-[5-(4-chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide
4-[5-(4-Chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide from Step 2 (3.0 g, 9 mmol) was dissolved in 50 mL of acetic acid, and 9 mL of 1M chlorine in acetic acid was added dropwise. The mixture was stirred for 16 hours when sat. aq. sodium bicarbonate solution was slowly added until the mixture was neutral to pH paper. The mixture was extracted with ethyl acetate (3×50 mL), combined and washed with sat. aq. sodium bicarbonate and with brine, dried over magnesium sulfate, filtered, and concentrated. The resultant product was recrystallized from isopropanol to yield 2.6 g (78%) of a white solid: mp 168°-171° C. (dec); 1H NMR (DMSO-D6/300 MHz) 8.08 (s, 1H), 7.83 (d, J=8.7Hz, 2H), 7.55 (d, J=8.7Hz, 2H), 7.46 (brs, 2H), 7.44 (d, J=8.7Hz, 2H), 7.35 (d, J=8.7Hz, 2H). Anal. Calc'd for C15H11N3SO2Cl2: C, 48.93; H, 3.01; N, 11.41. Found: C, 49.01; H, 2.97; N, 11.41.
EXAMPLE 198
Figure USRE044048-20130305-C00088
Step 1: Preparation of 2-fluoroacetophenone
To a solution of 2-hydroxyacetophenone (2.5 g, 18.4 mmol) in 100 mL CH2Cl2 at −78° C., was added triflic anhydride (10 g, 35.4 mmol) followed by 2,6-lutidine (4.1 mL, 35.4 mmol) and the mixture stirred at −78° C. for 50 minutes. The mixture was poured into CH2Cl2 and water and the CH2Cl2 layer separated, washed with brine, dried over Na2SO4 and concentrated to a peach solid. To a solution of the crude triflate in 100 mL THF was added 35 mL of 1N tetrabutylammonium fluoride in THF. The mixture was refluxed for 15 minutes, cooled and poured into ether and water. The ether layer was separated, washed with brine, dried over Na2SO4 and concentrated. Flash chromatography on silica gel using 20:1 hexane/EtOAc furnished the α-fluoroketone (0.852 g, 33.5%).
Step 2: Preparation of 4-(4-fluoro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide
A solution of 2-fluoroacetophenone (200 mg, 1.45 mmol) in 2 mL dimethylformamide-dimethylacetal was refluxed for 18 hours. The mixture was cooled and concentrated to give the crude enaminoketone. Without further purification, the enaminoketone was treated with 4-sulfonamidophenyl hydrazine hydrochloride (0.34 g, 1.52 mmol) in 10 mL EtOH at reflux for 17 hours. The mixture was cooled, filtered and the filtrate concentrated to a yellow gum. Flash chromatography using a gradient of 5:1 to 2:1 hexane/EtOAc provided 0.11 g of a yellow solid: Recrystallization from ether/hexane gave the product as a pale yellow solid. mp 194°-194.5° C.; Anal. calc'd for C15H12N3O2SF.0.2 H2O: C, 56.14; H, 3.89; N, 13.09. Found: C, 55.99; H, 3.65; N, 12.92.
EXAMPLE 199
Figure USRE044048-20130305-C00089
A 100 mL three-necked round-bottomed flask equipped with reflux condenser, gas dispersion tube and provisions for magnetic stirring was charged with 4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (Example 1) (500 mg, 1.2 mmol) and 50 mL of glacial acetic acid. The solution was stirred at room temperature and treated with a stream of chlorine gas for a period of 15 minutes. The solution was then stirred at room temperature for 1.25 hours and then diluted with 100 mL of water. The solution was then extracted three times with ether and the combined ethereal phase washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a white solid that was recrystallized from ether/petroleum ether to provide 390 mg (75%) of 4-[5-(4-chlorophenyl)-4-chloro-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide: mp 180°-182° C.; 1H NMR (CDCl3/300 MHz) 7.97 (d, J=6.6Hz, 2H, 7.49 (d, 2H), 7.45 (d, J=6.3Hz, 2H), 7.25 (d, J=6.6Hz, 2H), 5.78 (brs, 2H).
EXAMPLE 200
Figure USRE044048-20130305-C00090
Step 1: Preparation of 4,4,4-trifluoro-1-phenylbutane-1,3-dione
To a solution of 2-fluoroacetophenone from Step 1 of Example 198 (0.48 g, 3.4 mmol) in 25 mL THF at −78° C., was added 1N lithium bis(trimethylsilyl)amide (4 mL) and the mixture stirred at −78° C. for 45 minutes. 1-(Trifluoroacetyl)imidazole (0.65 mL, 5.7 mmol) was added and the mixture stirred at −78° C. for 30 minutes and at 0° C. for 30 minutes. The mixture was quenched with 0.5N HCl, poured into ether and water, and the ether layer separated, washed with brine, dried over Na2SO4 and concentrated. Flash chromatography on silica gel using a gradient of 10:1 to 4:1 hexane/EtOAc furnished the 1,3-diketone (0.34 g, 43%).
Step 2: Preparation of 4-[4-fluoro-5-phenyl-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide
The diketone from Step 1 (0.34 g, 1.45 mmol) was treated with 4-sulfonamidophenyl hydrazine hydrochloride (0.35 g, 1.56 mmol) in 15 mL EtOH at reflux for 15 hours. The mixture was cooled, filtered and the filtrate concentrated to a yellow gum. Flash chromatography using 3:1 hexane/EtOAc provided 0.28 g of a yellow solid. Recrystallization from CH2Cl2/hexane gave the product as a pale yellow solid: Anal. calc'd for C16H11N3O2SF4: C, 49.87; H, 2.88; N, 10.90. Found: C, 49.79; H, 2.88; N, 10.81.
EXAMPLE 201
Figure USRE044048-20130305-C00091
Step 1: Preparation of 2-methyl-1-phenyl-4,4,4-trifluorobutane-1,3-dione
To a solution of propiophenone (965 mg, 7.2 mmol) in THF (20 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (7.9 mL of a 1M solution in THF). The solution was kept at −78° C. for 0.5 hour and then warmed to −20° C. over 1 hour. The solution was cooled to −78° C. and 1-(trifluoroacetyl)imidazole (1.5 g, 9.1 mmol) in THF (4 mL) was added via cannula. The solution was warmed to room temperature and stirred overnight. The mixture was partitioned between 1N HCl and ether. The organic solution was dried (Na2SO4) and concentrated to give the crude diketone (1.9 g).
Step 2: Preparation of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The diketone from Step 1 was dissolved in absolute ethanol (25 mL) and 4-sulfonamidophenylhydrazine hydrochloride (2.0 g, 9.0 mmol) was added. The mixture was heated at reflux for 19 hours. Volatiles were removed in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with water and brine, dried and concentrated. The residue was chromatographed on silica (2:1 hexane/ethyl acetate) to give the title pyrazol (1.52 g, 49%): mp 145°-146° C.; Calc'd for C17H14N3O2SF3: C, 53.54; H, 3.70; N, 11.01. Found: C, 53.41; H, 3.66; N, 10.92.
EXAMPLE 202
Figure USRE044048-20130305-C00092
Step 1: Preparation of 4-methoxy-3-methylbutyrophenone
To a suspension of aluminum chloride (10.3 g, 77.2 mmol) in dichloromethane (40 mL) at 0° C. was added dropwise a solution of 2-methylanisole (5.0 mL, 35.3 mmol) and butyric anhydride (5.8 mL, 35.3 mmol). The reaction solution was kept at 0° C. for 2 hours and then warmed to room temperature and stirred overnight. The reaction solution was poured into conc. HCl (9 mL) and ice water (80 mL). The reaction was extracted with dichloromethane and the organic layer was washed with 2N NaOH and brine, dried and concentrated. The residue was chromatographed on silica (9:1 hexane:ethyl acetate) to give the desired product (5.2 g, 77%).
Steps 2 and 3: Preparation of 4-[4-ethyl-5-(3-methyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared from the butyrophenone in Step 1 using the procedure described in Example 201, Steps 1 and 2: mp 135°-136° C.; Calc'd for C20H20N3O3SF3: C, 54.66; H, 4.59; N, 9.56. Found: C, 54.11; H, 4.38; N, 9.43.
EXAMPLE 203
Figure USRE044048-20130305-C00093
Step 1: Preparation of 2-cyclopropylacetophenone
To a suspension of sodium cyanide (1.8 g, 37.0 mmol) in dimethyl sulfoxide (20 mL) at 60° C. was added dropwise (bromomethyl)cyclopropane (5.0 g, 37.0 mmol). The addition was done at such a rate to keep the temperature of the reaction at 60° C. After the addition was completed, the reaction mixture was heated at 80° C. for 15 minutes. The mixture was cooled and partitioned between ether and water. The organic solution was washed with 1N HCl and water, dried and concentrated. The residue was dissolved in ether (5 mL) and added to a solution of phenyl magnesium bromide (25 mL of a 3M solution in ether) in ether (20 mL) and benzene (25 mL). The reaction mixture was stirred at room temperature for 20 hours, then poured into a 1N HCl solution and stirred for 1.5 hours. The organic solution was separated and the aqueous solution extracted with dichloromethane. The organic solution was dried and concentrated. The residue was chromatographed on silica (9:1 hexane:ethyl acetate) to give the desired product (2.0 g, 34%).
Steps 2 and 3: Preparation of 4-[4-cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
The title compound was prepared from the acetophenone in Step 1 using the procedure described in Example 201), Steps 1 and 2: mp 173°-174° C.; Calc'd for C19H16N3O2SF3: C, 56.01; H, 3.96; N, 10.31. Found: C, 55.85; H, 3.78; N, 10.19.
EXAMPLE 204
Figure USRE044048-20130305-C00094
Step 1: Preparation of 4-[4-bromomethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
To a solution of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide prepared in Example 201 (500 mg, 1.3 mmol) in carbon tetrachloride (9 mL) and benzene (4 mL) was added N-bromosuccinimide (285 mg, 1.6 mmol). The mixture was irradiated with a sunlamp for 3.5 hours. The reaction mixture was partitioned between dichloromethane and water and the organic solution was dried and concentrated to give the desired product, 412 mg (69%).
Step 2: Preparation of 4-[4-formyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
To a solution of the compound prepared in Step 1 (362 mg, 0.79 mmol) in dimethyl sulfoxide (7 mL) was added collidine (0.14 mL, 1.0 mmol). The solution was heated at 120° C. for 3 hours and then kept at overnight at room temperature. The reaction solution was partitioned between ethyl acetate and water and the organic solution was washed with water, dried and concentrated. The residue was chromatographed (1:1 hexane:ethyl acetate) to give the desired product (205 mg, 66%).
Step 3: Preparation of 4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
To a solution of the aldehyde prepared in Step 2 (165 mg, 0.41 mmol) in methanol (3.5 mL) at 0° C. was added sodium borohydride (16 mg, 0.41 mmol). The reaction solution was kept at 0° C. for 2.5 hours. The reaction was quenched with the addition of an aqueous 1M KHSO4 solution (3 mL). The mixture was extracted with dichloromethane and the organic solution dried and concentrated. The residue was chromatographed on silica (1:1 hexane:ethyl acetate) to give the desired product (36 mg, 46%): m.p. 179°-180° C.; 1H NMR d 7.91 (m, 2H), 7.53-7.40 (m, 5H), 6.75 (s, 2H), 4.53 (d, 2h, J=5.0 Hz), 4.30 (t, 1H, J=5.0 Hz).
EXAMPLE 205
Figure USRE044048-20130305-C00095
To a solution of the pyrazole prepared in Example 175 (0.15 g, 0.42 mmol) in CH2Cl2 (10 mL) was added an excess of sulfuryl chloride slowly at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with water and the aqueous layer extracted three time with methylene chloride. The combined organic layers were dried over MgSO4 and concentrated to give an oil which was purified by flash chromatography on silica gel using 70:30 hexane/ethyl acetate as eluent to give the desired compound: HRMS m/z 389.0970 (calc'd for C19H20ClN3SO2, 389.0965).
The following compounds in Table X were prepared according to procedures similar to that exemplified in Examples 197-205, with the substitution of the appropriate starting material.
TABLE X
Figure USRE044048-20130305-C00096
Ex. R3 R2 A MP (° C.) Analytical
206 Cl H 4-F 175-178 Calc C, 51.22; H, 3.15; N, 11.94
Obs. C, 51.43; H, 3.10; N, 11.82
207 Br H 4-Cl 209-210 Calc. C, 43.66; H, 2.69; N, 10.18
Obs. C, 43.74; H, 2.70; N, 10.23
208 Cl H H 172-174 Calc. C, 53.98; H, 3.62; N, 12.59 Cl, 10.62; S, 9.60
Obs. C, 54.17; H, 3.64, N, 12.45 Cl, 10.46; S, 9.42
209 Cl H 3-di-Cl, 4-OCH3 211-212 Calc. C, 44.41; H, 2.80; N, 9.71
Obs. C, 44.72; H, 3.04, N, 9.72
210 Br H 4-CH3 ND HRMS: 391.0003
211 Cl H 4-CH3 160-163 Calc. C, 55.25; H, 4.06; N, 12.08
Obs. C, 55.06; H, 4.03. N, 12.02
212 Cl H 3-Cl, 4-OCH3 ND Calc. C, 48.25; H, 3.29; N, 10.55 Cl, 17.80; S, 8.05
Obs. C, 48.10; H, 3.31. N, 10.52 Cl, 17.70; S, 7.98
213 Cl H 4-OCH3 155-156 Calc. C, 52.82; H, 3.88; N, 11.55
Obs. C, 52.18;H, 3.93, N, 11.41
214 Br H 4-OCH3 130-132
215 CN H 4-OCH3 216-219 HRMS: 355.0860
216 Cl H 3,5-di-F, 4-OCH3 196-199 Calc. C, 48.07; H, 3.03; N, 10.51
Obs. C, 48.45; H, 355, N, 10.10
217 SO2CH3 H Cl 182-185 Calc. C, 46.66; H, 3.43; N, 10.20
Obs. C, 46.57; H, 3.49, N, 10.39
218 C2H5 CF3 H 177-178 Calc. C, 54.68; H, 4.08; N, 10.62
Obs. C, 54.61; H, 4.10; N, 1054
219 CH3 CF3 4-OCH3 158-159 Calc. C, 52.55; H, 3.92; N, 10.21
Obs. C, 52.27; H, 4.00; N, 10.16
220 CH3 CF3 4-Cl 154-155 Calc. C, 49.10; H, 3.15; N, 10.10
Obs. C, 49.05; H, 3.02; N, 9.96
221 CH3 CF3 44 103-104 Calc. C, 51.13; H, 3.28; N, 10.52
Obs. C, 51.09; H, 3.26; N, 1034
222 C2H5 CF3 4-Cl ND Calc. C, 50.30; H, 3.52; N, 9.77
Obs. C, 50.40; H, 3.51; N, 9.72
223 CH3 CF3 4-CH3 144-145 Calc. C, 54.68; H, 4.08; N, 10.62
Obs. C, 5438; H, 3.87; N, 1031
224 C2H5 CF3 4-CH3 142-143 Calc. C, 55.74; H, 4.43; N, 10.26
Obs. C, 55.60; H, 4.37; N, 10.17
225 C2H5 CF3 4-OCH3 160-161 Calc. C, 53.64; H, 4.26; N, 9.87
Obs. C, 53.55; 4.23; N, 9.65
226 C2H5 CF3 3-F, 4-OCH3 156-157 Calc. C, 51.46; H, 3-86; N, 9.47
Obs. C, 51.27; H, 3.75; N, 9.33
227 Br CHF2 4-Cl 224-226 Calc. C, 41.53; H, 2.40; N, 9.08
Obs. C, 41.50; H, 238; N, 9.00
228 Cl CHF2 3,5-di-Cl, 4-OCH3 92-102(dec) Calc C, 42.30; H, 2.51; N, 8.70
Obs. C, 42.50; H, 2.67, N, 8.56
229 Cl CHF2 H 174-176 Calc. C, 50.07; H, 3.15; N, 10.95
Obs. C, 50.07; H, 3.18, N, 10.98
230 Br CHF2 H 184-186 Calc. C, 44.87; H, 2.82; N, 9.81
Obs. C, 44.98; H, 2.81, N, 9.64
231 Cl CHF2 4-OCH3 171-172 HRMS: 413.0351
232 Cl CN H 174-l77(sub) Calc. C, 53.56; H, 3.09; N, 15.61;
Cl, 9.98; S, 8.94
Obs. C, 53.81; H, 3.18; N, 15.43;
Cl, 9.78; S, 8.91
233 Cl CN 4-Cl ND Calc. C, 48.87; H, 2.56; N, 14.25;
Cl, 18.03; S, 8.15
Obs. C, 48.99; H, 2.55; N, 14.30;
Cl, 17.96; S, 8.08
234 Cl CN 4-F ND Calc. C, 51.00; H, 2.68; N, 14.87;
Cl, 9.41; S, 8.51
Obs. C, 51.19; H, 2.73; N, 14.98;
Cl, 9.22; S, 8.56
235 Br CN 4-F ND Calc. C, 45.62; H, 239; N, 13.30;
Br, 18.97; S, 7.61
Obs. C, 45.51; H, 2.36; N, 13.21;
Br, 19.09; S, 7.51
236 Br CN H ND Calc. C, 47.66; H, 2.75; N, 13.89;
Br, 19.81; S, 7.95
Obs. C, 47.62; H, 2.77; N, 13.77;
Br, 19.74; S, 8.04
237 Br CO2C2H5 4-Cl ND HRMS: 482.9707
238 Cl CO2CH3 H ND HRMS: 342.0495
239 Cl CO2CH3 4-Cl ND HRMS: 426.0128
240 Cl CO2C2H5 4-Cl ND HRMS: 440.0207
241 Cl CO2CH3 4-F ND HRMS: 410.0391
242 Br CO2CH3 4-F ND HRMS: 453.9880
243 Cl CO2CH3 4-OCH3, 3-Cl ND Calc. C, 47.38; H, 331; N, 9.21;
Cl, 15.54; S, 7.03
Obs. C, 47.10; H, 3.26; N, 9.01;
Cl, 15.74; S, 6.92
244 Cl CO2CH3 4-OCH3, 3,5-di-Cl 198-199 Calc. C, 44.06; H, 2.88; N, 8.56
Obs. C, 43.59; H, 2.77; N, 8.44
245 Cl CO2CH3 4-OCH3, 3-Br ND Calc. C, 43.18, H, 3.02; N, 839; S, 6.40
Obs. C, 43.25; H, 257; N, 8.40; S, 6.59
246 Cl CONH2 H ND HRMS: 377.0539
247 Cl CONH2 4-Cl ND HRMS: 411.0115
248 Cl CONH2 4-F ND HRMS: 395.0397
249 Br CONH2 4-F ND Calc. C, 43.75, H, 2.75; N, 12.75;
Br, 18.19; S, 7.30
Obs. C, 43.65; H, 2.78; N, 12.66;
Br, 18.13; S, 7.21
250 Br CONH2 H ND HRMS: 419.9920
251 Cl CO2H H ND HRMS: 377.0249
252 Cl CO2H 4-Cl ND Calc. C, 46.62, H, 2,69; N, 10.19; Cl, 17.20; S, 7.78
Obs. C, 46.59, H, 2.68; N, 10.21; Cl, 17.25; S, 7.73
253 Cl CO2H 4-OCH3, 3,5-di-Cl 220(dec) Calc. C, 42.83: H, 2.54; N, 8.81
Obs. C, 43.65; H, 2.52; N, 8.78
254 Cl CH3 H ND Calc. C, 55.25; H, 4.06; N, 12.08
Obs. C, 55.24; H, 4.26; N, 12.17
255 Cl CH2OH H 195-197 HRMS: 363.0431
256 Cl CH2OH 4-Cl 203-204 Calc. C, 48.25; H, 3.29; N, 10.55
Obs. C, 48.36; H, 3.27; N, 10.50
257 Cl (CH2)2CO2H 4-Cl 212-214 Calc. C, 49.10; H, 3.43; N, 9.54
Obs. C, 49.23; H, 3.45; N, 9.49
258 OCH3 CF3 H 137-138 Calc. C, 51.38; H, 3.55; N, 10.57
Obs. C, 51.40; H, 3.47; N, 10.47

EXAMPLE 259
Figure USRE044048-20130305-C00097
Increasing the polarity of the eluant used in the purification in Example 234 to 60% ethyl acetate, upon concentration of the appropriate fractions, yielded 4-[4-chloro-3-cyano-5-[4-(fluoro)phenyl])-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]benzenesulfonamide (0.485 g, 15%): High Resolution Mass Spectrum (MLi+) calc'd: 438.0779. Found: 438.0714. Elemental analysis calc'd for C19H15N5O2FClS: C, 52.84; H, 3.50: N, 16.22; Cl, 8.21; S, 7.42. Found: C, 52.76; H, 3.52; N, 16.12; Cl, 8.11; S, 7.35.
EXAMPLE 260
Figure USRE044048-20130305-C00098
Similarly, 4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]benzenesulfonamide was isolated from the purification of Example 235 (0.153 g, 28%): High Resolution Mass Spectrum (M+) calc'd: 457.0208. Found: 457.0157. Elemental analysis calc'd for C19H16N5O2BrS: 49.79; H, 3.52: N, 15.28; Br, 17.43; S, 6.99. Found: C, 49.85; H, 3.56; N, 15.10; Br, 17.52; S, 6.87.
EXAMPLE 261
Figure USRE044048-20130305-C00099
Step 1: Preparation of N,N-bis(4-methoxybenzyl)-4-(aminosulfonyl)acetophenone
To a solution of 4-(aminosulfonyl)acetophenone (2.0 g, 9.0 mmol) in dimethylsulfoxide (25 mL) was added sodium hydride (450 mg, 19.0 mmol). The reaction mixture was stirred for 45 minutes and then 4-methoxybenzyl bromide (3.5 g, 19.0 mmol) in dimethylsulfoxide (5 mL) was added via cannula. The mixture was stirred at room temperature for 24 hours and partitioned between ethyl acetate and pH 7 buffer. The aqueous solution was extracted with ethyl acetate. The organic solution was dried (MgSO4) and concentrated. The residue was chromatographed on silica (2:1 hexane:ethyl acetate) to give the desired product (815 mg, 21%).
Step 2: Preparation of N,N-bis(4-methoxybenzyl)-4-[1-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzenesulfonamide
To a 25% sodium methoxide solution in methanol (0.2 mL) was added ethyl trifluoroacetate (75 mg, 0.53 mmol) and the protected acetophenone from Step 1 (235 mg, 0.53 mmol). THF (0.5 mL) was added and the reaction mixture was heated at reflux for 2 hours and then stirred at room temperature overnight. The mixture was partitioned between ether and 1N HCl solution. The organic solution was dried and concentrated to give the crude diketone (279 mg), which was diluted with absolute ethanol (2.5 mL). To this slurry was added pyridine (49 mg, 0.62 mmol) and 4-fluorophenylhydrazine hydrochloride (80 mg, 0.50 mmol). The mixture was stirred at room temperature for 24 hours and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with 1N HCl. The organic solution was dried and concentrated. The residue was chromatographed on silica (3:1 hexane:ethyl acetate) to give the protected pyrazole (159 mg, 51%).
Step 3: Preparation of 4-[1-(4-fluorophenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzenesulfonamide
To a solution of the protected pyrazole (50 mg, 0.08 mmol) in acetonitrile (1 mL) and water (0.3 mL) was added ceric ammonium nitrate (360 mg, 0.65 mmol). The reaction solution was kept at room temperature for 16 hours. The solution was poured into water (15 mL) and extracted with ethyl acetate (2×25 mL). The combined extracts were dried (MgSO4) and concentrated. The residue was chromatographed on silica (2:1 hexane:ethyl acetate) to give the desired product (13 mg, 42%): 1H NMR (CD3OD) 7.88 (d,2H), 7.46 (d, 2H), 7.39 (dd, 2H), 7.21 (t, 2H), 7.06 (s, 1H).
EXAMPLE 262
Figure USRE044048-20130305-C00100
The title compound was prepared using the procedure described in Example 261: HRMS m/z 397.0702 (calc'd for C17H14N3O3SF3. 397.0708).
BIOLOGICAL EVALUATION
    • Rat Carrageenan Foot Pad Edema Test
The carrageenan foot edema test was performed with materials, reagents and procedures essentially as described by Winter, et al., (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Male Sprague-Dawley rats were selected in each group so that the average body weight was as close as possible. Rats were fasted with free access to water for over sixteen hours prior to the test. The rats were dosed orally (1 mL) with compounds suspended in vehicle containing 0.5% methylcellulose and 0.025% surfactant, or with vehicle alone. One hour later a subplantar injection of 0.1 mL of 1% solution of carrageenan/sterile 0.9% saline was administered and the volume of the injected foot was measured with a displacement plethysmometer connected to a pressure transducer with a digital indicator. Three hours after the injection of the carrageenan, the volume of the foot was again measured. The average foot swelling in a group of drug-treated animals was compared with that of a group of placebo-treated animals and the percentage inhibition of edema was determined (Otterness and Bliven, Laboratory Models for Testing NSAIDS, in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)). The % inhibition shows the % decrease from control paw volume determined in this procedure and the data for selected compounds in this invention are summarized Results are shown in Table I.
Rat Carrageenan-induced Analgesia Test
The analgesia test using rat carrageenan was performed with materials, reagents and procedures essentially as described by Hargreaves, et al., (Pain, 32, 77 (1988)). Male Sprague-Dawley rats were treated as previously described for the Carrageenan Foot Pad Edema test. Three hours after the injection of the carrageenan, the rats were placed in a special plexiglass container with a transparent floor having a high intensity lamp as a radiant heat source, positionable under the floor. After an initial twenty minute period, thermal stimulation was begun on either the injected foot or on the contralateral uninjected foot. A photoelectric cell turned off the lamp and timer when light was interrupted by paw withdrawal. The time until the rat withdraws its foot was then measured. The withdrawal latency in seconds was determined for the control and drug-treated groups, and percent inhibition of the hyperalgesic foot withdrawal determined. Results are shown in Table XI.
TABLE XI
RAT PAW EDEMA ANALGESIA
Examples % Inhibition % Inhibition
Example @ 10 mg/kg body weight @ 30 mg/kg body Weight
1 44 94
 2 35 38
 58 36 65
 59 25 41
 60 49 39
 82  22*
 86  42*
 98  2*
117 32
129  47*
170  18*
171 14 37
188  32* 27
197  45*
199 35
*Assay Performed At 30 Mg/Kg Body Weight

Evaluation of COX I and COX II activity in vitro
The compounds of this invention exhibited inhibition in vitro of COX II. The COX II inhibition activity of the compounds of this invention illustrated in the Examples was determined by the following methods.
a. Preparation of recombinant COX baculoviruses
A 2.0 kb fragment containing the coding region of either human or murine COX-I or human or murine COX-II was cloned into a BamHI site of the baculovirus transfer vector pVL1393 (Invitrogen) to generate the baculovirus transfer vectors for COX-I and COX-II in a manner similar to the method of D. R. O'Reilly et al (Baculovirus Expression Vectors: A Laboratory Manual (1992)). Recombinant baculoviruses were isolated by transfecting 4 μg of baculovirus transfer vector DNA into SF9 insect cells (2×10 e8) along with 200 ng of linearized baculovirus plasmid DNA by the calcium phosphate method. See M. D. Summers and G. E. Smith, A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses were purified by three rounds of plaque purification and high titer (10E7-10E8 pfu/ml) stocks of virus were prepared. For large scale production, SF9 insect cells were infected in 10 liter fermentors (0.5×106/ml) with the recombinant baculovirus stock such that the multiplicity of infection was 0.1. After 72 hours the cells were centrifuged and the cell pellet homogenized in Tris/Sucrose (50 mM: 25%, pH 8.0) containing 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). The homogenate was centrifuged at 10,000×G for 30 minutes, and the resultant supernatant was stored at −80° C. before being assayed for COX activity.
b. Assay for COX I and COX II activity
COX activity was assayed as PGE2 formed/μg protein/time using an ELISA to detect the prostaglandin released, CHAPS-solubilized insect cell membranes containing the appropriate COX enzyme were incubated in a potassium phosphate buffer (50 mM, pH 8.0) containing epinephrine, phenol, and heme with the addition of arachidonic acid (10 μM). Compounds were pre-incubated with the enzyme for 10-20 minutes prior to the addition of arachidonic acid. Any reaction between the arachidonic add and the enzyme was stopped after ten minutes at 37° C./room temperature by transferring 40 μl of reaction mix into 160 μl ELISA buffer and 25 μM indomethacin. The PGE2 formed was measured by standard ELISA technology (Cayman Chemical). Results are shown in Table XII.
TABLE XII
Human COX II Human COX I
Example ID50 μM ID50 μM
1 <.1 18
2 <.1 15.0
3 <.1 >100
4 .6 37.5
5 <.1 6.3
6 .2 78.7
7 14 >100
8 37.7 >100
9 .1 55.2
10 2.7 >100
12 20 >100
55 22 77.9
56 <.1 11.7
57 47.9 >100
58 <.1 5.7
59 <.1 26.8
60 <.1 .8
82 <.1 1.1
84 <.1 65.5
85 73.6 >100
86 .5 >100
96 6.5 >100
97 96 >100
98 <.1 1.7
117 .3 >100
128 1.1 >100
129 <.1 13.5
130 3.6 12.5
131 .2 >100
138 .6 <.1
170 .1 >100
171 .8 >100
172 4.2 >100
173 4.7 >100
174 3.5 100
175 66.9 >100
176 .3 >100
187 1.1 13.6
188 .2 19.8
196 .6 4.1
197 <.1 3.4
198 4.2 56.5
199 <.1 <.1
200 <.1 .5
201 <.1 2.2
202 <.1 91
203 27 >100
204 6.7 >100
205 <.1 2.1
259 1.1 >100
260 1.1 >100
261 <.1 <.1
262 <.1 <.1

Also embraced within this invention is a class of pharmaceutical compositions comprising one or more compounds of Formula I the present invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.
The amount of therapeutically active compound that is administered and the dosage regiment for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredient in the range of about 0.1 to 2000 mg, preferably in the range of about 0.5 to 500 mg and most preferably between about 1 and 100 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably from about 1 to 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.
For therapeutic purposes, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers of diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

Claims (25)

1. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula I
Figure USRE044048-20130305-C00101
wherein R1 is phenyl substituted at a substitutable position with one or more radicals selected from halo, C1-C10-alkyl, and sulfamyl
wherein R2 is selected from hydrido, C1-C6-haloalkyl, cyano, carboxy, C1-C6-alkoxycarbonyl, C1-C6-carboxyalkyl, C1-C6-alkoxy, C1-C6-alkylthio, aminocarbonyl, aminocarbonyl-C1-C6-alkyl, C1-C6-N-alkylaminocarbonyl, N-arylaminocarbonyl, C1-C6-N,N-dialkylaminocarbonyl, C1-C6-N-alkyl-N-aryl-aminocarbonyl, and C1-C6-hydroxyalkyl;
wherein R3 is selected from hydrido, C1-C10-alkyl, halo, cyano, C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C6-alkylthio, and C1-C6-alkylsulfonyl;
wherein R4 is selected from aryl-C2-C6-alkenyl, aryl, C3-C7-cycloalkyl, C3-C7-cycloalkenyl and five to ten membered heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, C1-C6-alkylthio, C1-C6-alkylsulfinyl, C1-C10-alkyl, C1-C6-alkylsulfonyl, cyano, carboxyl, C1-C6-alkoxycarbonyl, aminocarbonyl, C1-C6-haloalkyl, hydroxyl, C1-C6-alkoxy, C1-C6-hydroxyalkyl, C1-C6-haloalkoxy, sulfamyl, C1-C6-N-alkylaminocrbonyl, amino, C1-C6-N-alkylamino, C1-C6-N,N-dialkylamino, five or six membered heterocyclic, nitro, and
Figure USRE044048-20130305-C00102
 and
wherein R7 is hydrido;
wherein aryl wherever occurring means phenyl, naphthyl, tetrahydronaphthyl, indene, biphenyl,
provided R2 and R3 are not identical radicals selected from hydrido, carboxyl and ethoxycarbonyl; further provided that R2 is not carboxyl or methyl when R3 is hydrido and when R4 is phenyl; further provided that R4 is not triazolyl when R2 is methyl; further provided that R4 is not aralkenyl when R2 is carboxyl, aminocarbonyl or ethoxycarbonyl; further provided that R4 is not phenyl when R2 is methyl and R3 is carboxyl; further provided that R4 is not 4-chlorophenyl when R2 is methyl and R3 is bromo; further provided that R4 is not unsubstituted thienyl when R2 is trifluoromethyl; and further provided that R4 is aryl substituted with sulfamyl when R1 is phenyl not substituted with sulfamyl; and further provided the compound is not 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1yl]benzenesulfonamide; or a pharmaceutically-acceptable salt thereof.
2. The method of claim 1 wherein R1 is phenyl, substituted at a substitutable position with one or more radicals selected from fluoro, chloro, methyl, and sulfamyl;
wherein R2 is selected from hydrido, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl, methoxy, ethoxy, methylthio, aminocarbonyl, aminocarbonylmethyl, N-methylaminocarbonyl, N-ethylaminocarbonyl, N-isopropylaminocarbonyl, N-propylaminocarbonyl, N-butylaminocarbonyl, N-isobutylaminocarbonyl, N-tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-phenylaminocarbonyl, N,N-dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-(3-fluorophenyl)aminocarbonyl, N-(4-methylphenyl)aminocarbonyl, N-(3-chlorophenyl)aminocarbonyl, N-methyl-N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminocarbonyl, N-methyl-N-phenylaminocarbonyl, hydroxymethyl, and hydroxypropyl;
wherein R3 is selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl, fluoro, chloro, bromo, cyano, methoxy, methylthio, methylsulfonyl, hydroxypropyl, hydroxymethyl, and hydroxyethyl; and
wherein R4 is selected from phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, 1-cyclopentenyl, 4-cyclopentenyl, benzofuryl, 2,3-dihydrobenzofuryl, 1,2,3,4-tetrahydronaphthyl, benzothienyl, indenyl, indanyl, indolyl, dihydroindolyl, chromanyl, benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from fluoro, chloro, bromo, methylthio, methylsulfinyl, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, hexyl, methylsulfonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, aminocarbonyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, bromodifluoromethyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, sulfamyl, methylaminosulfonyl, hydroxypropyl, hydroxyisopropyl, hydroxymethyl, hydroxyethyl, trifluoromethoxy, amino, N-methylamino, N-ethylamino, N-ethyl-N-methylamino, N,N-dimethylamino, N,N-diethylamino, formylamino, methylcarbonylamino, trifluoroacetamino, piperadinyl, piperazinyl, morpholino, nitro, and
Figure USRE044048-20130305-C00103
wherein R7 is hydrido;
or a pharmaceutically-acceptable salt thereof.
3. The method of claim 2 selected from compounds, and their pharmaceutically acceptable salts, of the group consisting of
ethyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
ethyl 1-[4-(aminosulfonyl)phenyl]-5-(4-methylphenyl)-1H-pyrazole-3-carboxylate;
isopropyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;
N-[4-methylphenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
N-[3-chlorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-fluorophenyl)-1H-pyrazole-3-carboxamide;
N-[3-fluorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;
phenylmethyl N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carbonyl]glycinate;
4-[5-(4-bromophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-cyano-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-cyano-5-(4-methylthiophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-chloro-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-bromo-4-methoxyphenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-bromo-5-(4-chlorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-bromo-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-bromo-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-cyano-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-ethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-ethyl-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-ethyl-5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-ethyl-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-ethyl-5-(3-fluoro-4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-methyl-5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-bromo-5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-bromo-3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-3-difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-3-cyano-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-bromo-3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-bromo-3-cyano-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
ethyl [1-(4-aminosulfonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;
methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-phenyl-1H-pyrazol-3-yl]carboxylate;
methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3yl]carboxylate;
ethyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazol-3-yl]carboxylate;
methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate;
methyl [1-(4-aminosulfonylphenyl)-4-bromo-5-(4-fluorophenyl)-1H-pyrazol-3-yl]carboxylate;
methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylate;
methyl [1-(4-aminosulfonylphenyl)-4-chloro-5-(3,5dichloro-4-methoxyphenyl)-1H-pyrazol-3-yl]carboxylate;
methyl [1-(4-aminosulfonylphenyl)-5-(3-bromo-4-methoxyphenyl)-4-chloro-1H-pyrazol-3-yl]carboxylate;
4-[4-chloro-3-hydroxymethyl-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,5-dimethylphenyl-4-methoxy)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chloro-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2,4-dimethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methoxy-3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-bromo-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,4-dimethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methoxy-5-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methoxy-3-(3-propenyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-amino-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methylthiophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-phenyl-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chloro-3-methylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,4-dimethoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,5-difluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-bromo-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methylsulfonylphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methoxyphenyl)-3-(chloromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-(chloro-difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(phenyl)-3-(fluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(1-cyclohexenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(1-cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(6-benzodioxanyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methylcyclohexyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-benzofuranyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(1,3-benzodioxol-5-yl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-benzofuryl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-bromo-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-chloro-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-indanyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(5-methyl-2-thienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2,3-dihydrobenzofuran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,
4-[5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(1,2,3,4-tetrahydronaphth-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(2-benzothienyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3,4-dihydro-2H-1-benzothiopyran-7-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methyl-1,3-benzodioxol-6-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; and
4-[5-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
4. The method of claim 3 where the compound is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
5. The method of claim 3 where the compound is 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
6. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula I
Figure USRE044048-20130305-C00104
wherein R1 is phenyl substituted at a substitutable position with sulfamyl;
wherein R2 is selected from C1-C5-haloalkyl, cyano, carboxyl, C1-C6-alkoxycarbonyl, C1-C5-carboxyalkyl, aminocarbonyl, C1-C6-N-alkylaminocarbonyl, N-arylaminocarbonyl, C1-C6-N,N-dialkylaminocarbonyl, C1-C6-N-alkyl-N-arylaminocarbonyl, and C1-C6-hydroxyalkyl;
wherein R3 and R4 together form
Figure USRE044048-20130305-C00105
wherein m is 2;
wherein A is phenyl; and
wherein R6 is one or more radicals selected from halo, C1-C10-alkyl, C1-C6-alkylsulfonyl, C1-C5-haloalkyl, C1-C6-alkoxy, amino and nitro;
wherein aryl wherever occurring means phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl;
or a pharmaceutically-acceptable salt thereof.
7. The method of claim 6 wherein R2 is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, cyano, carbonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl, aminocarbonyl, N-methylaminocarbonyl, N-ethylaminocarbonyl, N-isopropylaminocarbonyl, N-propylaminocarbonyl, N-butylaminocarbonyl, N-isobutylaminocarbonyl, N-tert-butylaminocarbonyl, N-pentylaminocarbonyl, N-phenylaminocarbonyl, N,N-dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, N-(3-fluorophenyl)aminocarbonyl, N-(4-methylphenyl)aminocarbonyl, N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminocarbonyl, N-methyl-N-phenylaminocarbonyl, hydroxypropyl, hydroxymethyl and hydroxyethyl; wherein A is phenyl; and wherein, R6 is one or more radicals selected from fluoro, chloro, bromo, methylsulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, amino, and nitro;
or a pharmaceutically-acceptable salt thereof.
8. The method of claim 7 selected from compounds, and their pharmaceutically acceptable salts, of the group consisting of
4-[3-(difluoromethyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-4,5-dihydro-7-methyl-1H-benz[g]indazol-1-yl]benzenesulfonamide;
4-[4,5-dihydro-7-methoxy-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;
4-[4,5-dihydro-3-(trifluoromethyl)-1H-benz[g]indazol-1yl]benzenesulfonamide;
4-[4,5-dihydro-7-methyl-3-(trifluoromethyl)-1H-benz[g]indazol-1-yl]benzenesulfonamide;
methyl[1-(4-aminosulfonylphenyl)-4,5-dihydro-7-methoxy-1H-benz[g]indazol-3-yl]carboxylate; and
4-[4,5-dihydro-3-trifluoromethyl-1H-thieno[3,2,g]indazol-1-yl]benzenesulfonamide.
9. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula I
Figure USRE044048-20130305-C00106
wherein R1 is phenyl, wherein R1 is substituted at a substitutable position with one or more radicals selected from halo, C1-C10-alkyl, C1-C6-alkoxy, hydroxyl and C1-C6-haloalkyl; wherein R2 is selected from C1-C6-haloalkyl; wherein R3 is hydrido; and wherein R4 is aryl substituted at a substitutable position with sulfamyl; or a pharmaceutically-acceptable salt thereof;
wherein aryl wherever occurring means phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl;
or a pharmaceutically-acceptable salt thereof.
10. The method of claim 9 selected from compounds, and their pharmaceutically acceptable salts, of the group consisting of
4-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide; and
4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide.
11. A method of treating inflammation or an inflammation-associated disorder in a subject, said method comprising administering to the subject having or susceptible to such inflammation or inflammation-associated disorder, a therapeutically-effective amount of a compound of Formula II
Figure USRE044048-20130305-C00107
wherein R2 is selected from hydrido, C1-C6-haloalkyl, C1-C6-alkoxycarbonyl, cyano, aminocarbonyl, arylaminocarbonyl, C1-C6-carboxyalkyl, and C1-C6-hydroxyalkyl;
wherein R3 is selected from hydrido, and halo; and
wherein R4 is selected from aryl, C3-C10-cycloalkyl, C3-C10-cycloalkenyl and heterocyclic; wherein R4 is optionally substituted at a substitutable position with one or more radicals selected from halo, C1-C6-alkylthio, C1-C6-alkylsulfonyl, cyano, nitro, C1-C6-haloalkyl, C1-C10-alkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, sulfamyl, five or six membered heterocyclic and amino; wherein aryl wherever occurring means phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl;
provided R2 and R3 are not both hydrido; and further provided that R4 is not unsubstituted thienyl when R2 is trifluoromethyl; and further provided the compound is not 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
or a pharmaceutically-acceptable salt thereof.
12. The method of claim 11 wherein the compounds are selected from compounds, and their pharmaceutically acceptable salts, of the group consisting of
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide; and
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.
13. The method of claim 1 for use in treatment of inflammation.
14. The method of claim 1 for use in treatment of an inflammation-associated disorder.
15. The method of claim 14 wherein the inflammation-associated disorder is arthritis.
16. The method of claim 14 wherein the inflammation-associated disorder is pain.
17. The method of claim 14 wherein the inflammation-associated disorder is fever.
18. The method of claim 1 for use in the prevention of colorectal cancer.
19. A method of treating arthritis in a subject, said method comprising administering to the subject having or susceptible to arthritis, a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
20. A method of treating pain in a subject, said method comprising administering to the subject having or susceptible to pain, a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
21. A method of treating osteoarthritis in a subject, said method comprising administering to the subject having or susceptible to osteoarthritis, a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
22. A method of treating rheumatoid arthritis in a subject, said method comprising administering to the subject having or susceptible to rheumatoid arthritis, a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
23. A method of treating juvenile arthritis in a subject, said method comprising administering to the subject having or susceptible to juvenile arthritis, a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
24. A method of treating spondyloarthropathy in a subject, said method comprising administering to the subject having or susceptible to spondyloarthropathies, a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
25. A method of treating menstrual cramps in a subject, said method comprising administering to the subject having or susceptible to menstrual cramps, a therapeutically-effective amount of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically-acceptable salt thereof.
US12/205,319 1993-11-30 1994-11-14 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-YL]benzenesulfonamide for the treatment of inflammation or an inflammation-associated disorder Expired - Lifetime USRE44048E1 (en)

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1 Oct. 18, 2006 Complaint DI 1.
10 Oct. 30, 2006 Order Granting Motion for Pro Hac Vice Admission of Stephen M. Craig for Plaintiffs DI 12.
100 May 5, 2008 Defendants' Memorandum in Opposition to Plaintiffs' Motion to Compel Amended Interrogatory Responses and to Deem Admitted Plaintiffs' Request for Admission DI 111.
101 May 5, 2008 Index of Exhibits to Defendants' Memorandum in Opposition to Plaintiffs' Motion to Compel Amended Interrogatory Responses and to Deem Admitted Plaintiffs' Request for Admission with Exhibits A-F.
102 May 19, 2008 Plaintiffs' Reply to Response to Motion to Compel Amended Interrogatory Responses and to Deem Admitted Plaintiffs' Request for Admission DI 112.
103 May 27, 2008 Defendants' Motion for Extension of Time to Comply with the Court's Mar. 26, 2008 Order Granting Plaintiffs' Motion to Compel Immediate Production of Documents for Defendant DI 113.
104 May 27, 2008 Defendants' Memorandum in Support of Motion for Extension of Time to Comply with the Court's Mar. 26, 2008 Order Granting Plaintiffs' Motion to Compel Immediate Production of Documents for Defendant DI 114.
105 May 27, 2008 Defendants' Motion for Relief from Order Compelling Discovery with Exhibit A DI 115.
106 May 27, 2008 Defendants' Memorandum in Support of Motion for Relief Discovery from Order Compelling Discovery with Exhibits A-J DI DI 116.
107 May 27, 2008 Defendants' Certification Concerning Discovery Efforts with Exhibits A-KK DI 117.
108 Jun. 5, 2008 Defendants' Motion to Compel Plaintiffs to Supplement Responses to Defendants' Interrogatory No. 8 and for Protective Order DI 118.
109 Jun. 5, 2008 Defendants' Memorandum in Support of Motion to Compel Plaintiffs to Supplement Responses to Defendants' Interrogatory No. 8 and for Protective Order with Exhibits A-J DI 119.
11 Nov. 13, 2006 Joint Motion and Stipulation for Order Extending Defendants' Time to Respond to the Complaint DI 17.
110 Jun. 5, 2008 Defendants' Motion to Compel the Depositions of Weilin Xie, Jeffrey Chipman, and Gary Evett 120.
111 Jun. 5, 2008 Defendants' Memorandum in Support of Motion to Compel the Depositions of Weilin Xie, Jeffrey Chipman, and Gary Evett with Exhibits A-H DI 121.
112 Jun. 5, 2008 Plaintiff' Notice of Removing Counsel from Service List filed by James S. Jardine. Attorney James S Jardine will no longer receive notice from the court in this including final judgment. DI 122.
113 Jun. 13, 2008 Docket Entry regarding Amended Notice of Hearing regarding Defendants' Motion tor extension of Time to Comply with the Court's Mar. 26, 2008 Order, Motion to Compel Amended Interrogatory Responses and to Deem Admitted BYU's Request for Admission, Defendants' Motion for Relief from Order Compelling Discovery, Defendants' Motion to Compel Plaintiffs to Supplement Responses to Defendants' Interrogatory No. 8 and for Protective Order, and Defendants' Motion to Compel the Depositions of Weilin Xie, Jeffrey Chipman and Gary Evett DI.
114 Jun. 16, 2008 Docket Text Order regarding due date for memoranda regarding compliance or noncompliance with the Court's Mar. 26, 2008 Order DI 124.
115 Jun. 17, 2008 Plaintiffs' Memorandum in Opposition to Motion for Extension of Time to Comply with the Court's Mar. 26, 2008 Order Granting BYU's Motion to Compel Immediate Production of Documents with Exhibits A-R DI 125.
116 Jun. 17, 2008 Plaintiffs' Memorandum in Opposition to Motion for Relief From Order Compelling Discovery DI 126.
117 Jun. 24, 2008 Plaintiffs' Memorandum in Opposition to Defendants' Motion to Compel Plaintiffs to Supplement Responses to Defendants' Interrogatory No. 8 and for Protective Order DI 127.
118 Jun. 24, 2008 Plaintiffs' Notice of Conventional Filing of Opposition to Defendants' Motion to Compel the Depositions of Weilin Xie, Jeffrey Chipman, and Gary Evett DI 128.
119 Jun. 30, 2008 Defendants' Reply to Response to Motion for Extension of Time to Comply with the Court's Mar. 26, 2008 Order Granting Plaintiffs' Motion to Compel Immediate Production of Documents DI 130.
12 Nov. 14, 2006 Order granting Joint Motion and Stipulation for Order Extending Defendants' Time to Respond to the Complaint DI 18.
120 Jun. 30, 2008 Defendants' Reply to Response to Motion for Relief from Order Compelling Discovery with Exhibits A-J DI 131.
121 Jul. 7, 2008 Defendants' Reply to Response to Motion to Compel the Depositions of Weilin Xie, Jeffrey Chipman, and Gary Evett with Exhibits I-J DI 132.
122 Jul. 7, 2008 Defendants' Reply to Response to Motion to Compel Plaintiffs to Supplement Responses to Defendants' Interrogatory No. 8 and for Protective Order DI 133.
123 Jul. 18, 2008 Notice of Conventional Filing of Defendants' Supplemental Certification Concerning Discovery Efforts and Defendants' Exhibits Supporting Supplemental Certification Concerning Discovery Efforts DI 134.
124 Jul. 18, 2008 Defendants' Supplemental Certification Concerning Discovery Efforts DI 137 (notice of filing).
125 Jul. 18, 2008 Exhibits Supporting Defendants' Supplemental Certification Concerning Discovery Efforts with Non-Confidential Exhibits in the Range 1-84 DI 138.
126 Jul. 18, 2008 Redacted Version of Plaintiffs' Memorandum for Jul. 29, 2008 Hearing with Redacted Exhibits 1-57 D 136.
127 Jul. 18, 2008 Notice of Conventional Filing of Plaintiffs' Memorandum for Jul. 29, 2008 Hearing and Exhibits DI 135.
128 Jul. 18, 2008 Conventionally Filed Non-Confidential Exhibits to Plaintiffs' Memorandum for Jul. 29, 2008 Hearing in the Range 1-57.
129 Jul. 28, 2008 Notice of Conventional Filing of Defendants' Response to Plaintiffs' Memorandum for Jul. 29, 2008 Hearing DI 142.
13 Nov. 14, 2006 Docket Entry Updating Answer Deadlines.
130 Aug. 5, 2008 Docket Entry regarding Minute Order as to hearing held on Jul. 29, 2008 and granting in part denying in part Motion to Compel Amended Interrogatory Responses and to Deem Admitted BYU's Request for Admission DI 143.
131 Aug. 7, 2008 Transcript of Proceedings held on Jul. 29, 2008—Transcript of Motions Hearing before Judge Brooke C. Wells DI 144.
132 Aug. 12, 2008 Plaintiffs' Proposed Discovery Order Regarding Jul. 29, 2008 Hearing.
133 Aug. 12, 2008 [Proposed] Finding of Facts and Conclusions of Law Regarding Pfizer's Document Production and BYU's Request for Sanctions.
134 Aug. 12, 2008 Notice of Conventional Filing of Defendants' Second Supplemental Certification Concerning Discovery Efforts DI 146.
136 Aug. 15, 2008 Notice of Conventional Filing of Plaintiffs' Response to Defendants' Second Supplemental Certification Concerning Discovery Efforts and Exhibits Thereto DI 148.
137 Aug. 19, 2008 Defendants' Notice of Conventional Filing of Defendants' Reply to Response to Second Supplemental Certification Concerning Discovery Efforts DI 150.
138 Aug. 21, 2008 Order Denying Defendants' Motion to Compel Depositions and Denying in Part and Granting in Part Defendants' Motion for Relief from Order Compelling Discovery. Follows oral order of Aug. 5, 2008 DI 152.
139 Aug. 21, 2008 Order Granting in Part and Denying in Part Defendants' Motion to Compel Plaintiffs to Supplement Responses to Defendants' Interrogatory No. 8 and for Protective Order. Follows oral order of Aug. 5, 2008 DI153.
14 Nov. 16, 2006 Motion and Consent of Local Counsel for Pro Hac Vice Admission of Lisa A. Schneider for Defendants DI 19.
140 Aug. 21, 2008 Order Granting in Part and Denying in Part Plaintiffs' Motion to Compel Amended Interrogatory Responses and to Deem Admitted BYU's Request for Admission. Follows oral order of Aug. 5, 2008 DI 154.
141 Sep. 8, 2008 Lodged Letter by W. Alper to Judge Wells DI 155.
142 Oct. 9, 2008 Plaintiffs' Stipulated Motion to Amend/Correct Scheduling Order DI 156.
143 Oct. 15, 2008 Defendants' Third Supplemental Certification Concerning Discovery Efforts DI 157.
144 Oct. 22, 2008 Plaintiffs' Preliminary Response to Defendants' Third Supplemental Certification Concerning Discovery Efforts DI 158.
145 Oct. 23, 2008 Amended Scheduling Order regarding Amended Pleadings, Joinder of Parties, Fact Discovery, Expert Discovery, Motions, Final Pretrial Conference, and Jury Trial DI 159.
146 Nov. 12, 2008 Plaintiffs' Supplemental Preliminary Response to Defendants' Third Supplemental Certification Concerning Discovery Efforts DI 160.
147 Nov. 13, 2008 Defendants' Motion to Compel Production of Documents DI 161.
148 Nov. 13, 2008 Defendants' Memorandum in Support of Motion to Compel Production of Documents DI 162.
149 Nov. 13, 2008 Notice of Conventional Filing of Defendants' Exhibits 3 and 16-17 to Defendants' Motion to Compel Production of Documents DI 163.
15 Nov. 16, 2006 Motion and Consent of Local Counsel for Pro Hac Vice Admission of Charles W. Douglas for Defendants DI 20.
150 Nov. 13, 2008 Exhibits 1-2, 4-15 and 18 to Defendants' Motion to Compel Production of Documents DI 164.
151 Dec. 4, 2008 Plaintiffs' Second Supplemental Preliminary Response to Defendants' Third Supplemental Certification Concerning Discovery Efforts D 166.
152 Dec. 10, 2008 Plaintiffs' Response to Defendants' Motion to Compel Production of Documents with Non-Confidential Exhibits A-B (Redacted Version) DI 167.
153 Dec. 10, 2008 Notice of Conventional Filing of Exhibit Supporting Plaintiffs' Response to'Defendants' Motion to Compel Production of Documents DI 168.
154 Dec. 15, 2008 Plaintiffs' Third Supplemental Preliminary Response to Defendants' Third Supplemental Certification Concerning Discovery Efforts DI 170.
155 Dec. 22, 2008 Defendants' Reply Brief in Support of Motion to Compel Production of Documents Exhibits 1-4 DI 171.
156 Jan. 7, 2008 Defendants' Motion for Leave From and Modification to the Protective Order DI 172.
157 Jan. 7, 2008 Defendants' Memorandum in Support of Motion for Leave From and Modification to the Protective Order DI 173.
158 Jan. 7, 2008 Notice of Conventional Filing Exhibits A-S and Appendices 1-6 to Defendants' Memorandum in Support of Motion for Leave From and Modification to the Protective Order DI 174.
159 Jan. 8, 2009 Notice of Conventional Filing Exhibits A-S and Appendices 1-6 to Defendants' Memorandum in Support of Motion for Leave From and Modification to the Protective Order DI 175.
16 Nov. 16, 2006 Motion and Consent of Local Counsel for Pro Hac Vice Admission of Todd L. Krause for Defendants DI 21.
16 Sep. 5, 2007 Plaintiffs' Second Request for Production of Documents.
160 Jan. 8, 2008 Docket Entry regarding Notice of Status Conference Hearing regarding Defendants' Motion for Extension of Time to Comply with the Court's Mar. 26, 2008 Order Granting BYU's Motion to Compel Immediate Production of Documents DI 176.
161 Jan. 8, 2008 Docket Entry regarding Notice of Hearing on Defendants' Motion to Compel Production of Documents DI 177.
17 Nov. 16, 2006 Motion and Consent of Local Counsel for Pro Hac Vice Admission of Neil H. Wyland for Defendants DI 22.
18 Nov. 16, 2006 Motion and Consent of Local Counsel for Pro Hac Vice Admission of Richard F. O'Malley, Jr. for Defendants DI 23.
19 Nov. 20, 2006 Notice of Appearance of Counsel by George M. Haley for Defendants DI 24.
1991 Thesis of Jeffrey Chipman, Cloning and Sequencing of a Novel Mouse Prostaglandin G/H Synthase Gene BYU-06-1355-1391.
1992 Winter Prostaglandin Conference, Jan. 8-11, 1992, Keystone, CO USA—List of Participants BYU-11-1834-1841.
2 Oct. 18, 2006 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of L. Richard Williams for Plaintiffs DI 2.
20 Nov. 28, 2006 Order Granting Motion for Pro Hac Vice Admission of Charles W. Douglas for Defendants DI 25.
21 Nov. 28, 2006 Order Granting Motion for Pro Hac Vice Admission of Todd L. Krause for Defendants DI 26.
22 Nov. 28, 2006 Order Granting Motion for Pro Hac Vice Admission of Richard F. O'Malley, Jr. For Defendants DI 27.
23 Nov. 28, 2006 Order Granting Motion for Pro Hac Vice Admission of Lisa A. Schneider for Defendants DI 28.
24 Nov. 28, 2006 Order Granting Motion for Pro Hac Vice Admission of Neil H. Wyland for Defendants DI 29.
25 Dec. 13, 2006 Defendants Pfizer Inc., G.D. Searle LLC and Pharmacia Corporation's Answers to Complaint DI 30.
26 Dec. 26, 2006 Notice of Alternative Dispute Resolution Program DI 31.
27 Jan. 26, 2007 Notice of Service of Plaintiffs' Initial Rule 26(a)(1) Disclosure Statement to Defendants DI 32.
28 Jan. 26, 2007 Certificate of Service of Defendants' Initial Disclosures to Plaintiffs DI 33.
29 Feb. 5, 2007 Attorneys' Planning Meeting Report DI 34.
3 Oct. 18, 2006 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Leo R. Beus for Plaintiffs DI 3.
30 Feb. 9, 2007 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Keith C. Ricker for Plaintiffs DI 35.
31 Feb. 13, 2007 Notice of Service of Plaintiffs' Response to Defendants' First Request for Production of Documents and First Set of Interrogatories DI 36.
32 Feb. 20, 2007 Order Granting Motion for Pro Hac Vice Admission of Keith C. Ricker for Plaintiffs DI 37.
33 Mar. 8, 2007 Notice of Appearance by Victoria Romney for Plaintiffs DI 38.
34 May 3, 2007 Notice of Service of Plaintiffs' Notice of Subpoenas for Production of Documents and Things DI 39.
35 May 4, 2007 Notice of Service of Plaintiffs' First Set of Interrogatories to Defendant Pfizer, Inc. DI 40.
36 May 11, 2007 Docket entry regarding Notice of Initial Pretrial Conference regarding Attorneys Planning Meeting Report and Proposed Scheduling Order DI 41.
37 Jun. 5, 2007 Stipulated Motion for Protective Order by Defendant Pfizer; Proposed Protective Order with Exhibit A-Declaration and Agreement to Bound DI 42.
37 Jun. 5, 2007 Stipulated Motion for Protective Order by Defendant Pfizer; Proposed Protective Order with Exhibit A—Declaration and Agreement to Bound DI 42.
38 Jun. 7, 2007 Protective Order (executed) DI 43.
39 Jun. 29, 2007 Docket Entry regarding Notice Reminder of Attorneys Planning Meeting Report and Initial Pretrial Conference DI 44.
4 Oct. 18, 2006 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Adam C. Anderson for Plaintiffs DI 4.
40 Jul. 3, 2007 Docket Entry regarding Notice of Hearing—The Court Vacates Initial Pretrial Conference DI 45.
41 Jul. 9, 2007 Lodged Letter to Judge Kimball from Stephen Craig regarding Attorneys Planning Meeting Report and Proposed Scheduling Order DI 46.
42 Jul. 25, 2007 Notice of Service of Plaintiffs' Request for Admission to Defendant Pfizer, Inc. DI 47.
43 Jul. 30, 2007 Scheduling Order DI 48.
44 Oct. 11, 2007 Notice of Service of Plaintiffs' Subpoena for Production of Documents and Things served upon Teva Pharmaceuticals USA, Inc. DI 49.
45 Oct. 12, 2007 Notice of Service of Plaintiffs' Subpoena for Production of Documents and Things served upon University of Connecticut and the University of California, Los Angeles DI 50.
46 Oct. 29, 2007 Notice of Service of Plaintiffs' Subpoena for Production of Documents and Things served upon Dr. Harvey Herschman and Dr. Timothy Hla DI 51.
47 Oct. 31, 2007 Notice of Service of Plaintiffs' Subpoena for Production of Documents and Things served upon American Red Cross DI 52.
48 Nov. 8, 2007 Stipulation to Amend Protective Order DI 53.
49 Nov. 8, 2007 Notice of Service of Plaintiffs' Subpoena for Production of Documents and Things served upon the Monsanto Company DI 54.
5 Oct. 18, 2006 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Timothy J. Paris for Plaintiffs DI 5.
50 Nov. 9, 2007 Order Regarding Stipulation to Amend Protective Order—granting Stipulation to amend paragraph 4(b) (3) of the Protective Order and to substitute S. Craig for E. Davis DI 55.
51 Nov. 12, 2007 Certificate of Service of Defendants' Notice of Taking Video Deposition of Michael Orme DI 56.
52 Nov. 27, 2007 Notice of Service of Defendants' Notice of Subpoena for Production of Documents and Things served upon Merck & Co., Inc./Merck Sharp & Dohme Limited DI 57.
53 Jan. 10, 2008 Plaintiffs' Motion to Compel Immediate Production of Documents DI 58.
54 Jan. 10, 2008 Plaintiffs' Memorandum in Support of Motion to Compel Immediate Production of Documents 59.
55 Jan. 11, 2008 Notice of Service of Plaintiffs' Second Set of Interrogatories to Defendant DI 60.
56 Jan. 14, 2008 Docket Entry regarding Order Referring Case to Magistrate Judge Paul M. Warner DI 61.
57 Jan. 15, 2008 Order of Recusal for Judge Paul W. Warner—Case reassigned to Judge Brooke C. Wells DI 63.
58 Jan. 18, 2008 Plaintiffs' Supplemental Memorandum in Support of Motion to Compel Immediate Production of Documents with Exhibits A & B DI 64.
59 Jan. 22, 2008 Plaintiffs' Motion to Compel Re-Designation of Documents DI 65.
6 Oct. 18, 2006 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Scot C. Stirling for Plaintiffs DI 6.
60 Jan. 22, 2008 Plaintiffs' Memorandum in Support Motion to Compel Re-Designation of Documents DI 66.
61 Jan. 22, 2008 Notice of Conventional Filing of Exhibits Supporting Plaintiffs' Motion to Compel Re-Designation of Documents DI 67.
62 Jan. 25, 2008 Defendants' Memorandum in Opposition to Motion to Compel Immediate Production of Documents DI 69.
63 Jan. 25, 2008 Notice of Conventional Filing of Exhibits Supporting Defendants' Memorandum in Opposition to Motion to Compel Immediate Production of Documents DI 70.
64 Jan. 29, 2008 Certificate of Service of Plaintiffs' Fourth Request for Production of Documents DI 72.
65 Feb. 6, 2008 Defendants' Memorandum in Opposition to Motion to Compel Re-Designation of Documents with Exhibits A-E DI 73.
66 Feb. 8, 2008 Plaintiffs' Reply Memorandum/Reply to Response to Motion to Compel Immediate Production of Documents DI 74.
67 Feb. 8, 2008 Notice of Conventional Filing of Exhibits to Plaintiffs' Reply Memorandum/Reply to Response to Motion to Compel Immediate Production of Documents DI 75.
68 Feb. 11, 2008 Docket Entry regarding Notice of Hearing on Motion to Compel Immediate Production of Documents and Motion to Compel Re-Designation of Documents DI 76.
69 Feb. 11, 2008 Notice of Service of Defendants' Second Request for Production of Documents and Things to Plaintiffs DI 77.
7 Oct. 24, 2006 Notice of Appearance of Counsel by Lee Andelin for Plaintiffs DI 8.
70 Feb. 12, 2008 Notice of Service of Plaintiffs' Notice of Subpoenas for Production of Documents and Things to Chandler Chicco Agency, David L. DeWitt and Michigan State University DI 78.
71 Feb. 13, 2008 Notice of Service of Plaintiffs' 30(b)(6) Notice of Deposition to Defendants DI 80.
72 Feb. 15, 2008 Certificate of Service of Defendants' Response to Plaintiffs' Second Set of Interrogatories DI 81.
73 Feb. 19, 2008 Docket Entry regarding Amended Notice of Hearing on Motion to Compel Immediate Production of Documents and Motion to Compel Re-Designation of Documents DI 82.
74 Feb. 19, 2008 Plaintiffs' Reply to Response to Motion to Compel Re-Designation of Documents DI 83.
75 Feb. 22, 2008 Certificate of Service of Defendants' Responses and Objections to Plaintiffs' 30(b)(6) Notice of Deposition DI 84.
76 Feb. 22, 2008 Defendants' Motion to Strike Reply Memorandum/Reply to Response to Motion to Compel Immediate Production of Documents DI 85.
77 Feb. 22, 2008 Defendants' Memorandum in Support of Motion to Strike Reply Memorandum/Reply to Response to Motion to Compel Immediate Production of Documents with Exhibits A-H DI 86.
78 Feb. 22, 2008 Certificate of Service of Defendants' Notice of Subpoenas for Production of Documents and Things to Fish & Richardson P.C. And Harvard University DI 87.
79 Feb. 25, 2008 Notice of Service of Plaintiffs' Notice of Subpoenas for Production of Documents and Things J. Masferrer, K. Seibert, A. Raz & P. Isakson DI 88.
8 Oct. 24, 2006 Orders Granting Motion for Pro Hac Vice Admissions of Scot Stirling, L. Richard Williams, Leo Beus, Adam Anderson and Timothy Paris on behalf of Plaintiffs DI 10.
80 Feb. 27, 2008 Notice of Service of Plaintiffs' Third Set of Interrogatories to Defendants DI 89.
81 Mar. 4, 2008 Certificate of Service of Defendants' Response to Plaintiffs'Fourth Request for Production of Documents DI 90.
82 Mar. 7, 2008 Docket Entry regarding Amended Notice of Hearing on Motion to Compel Immediate Production of Documents, Defendants' Motion to Strike Reply Memorandum/Reply to Response to Motion to Compel Immediate Production of Documents, and Motion to Compel Re-Designation of Documents DI 91.
83 Mar. 12, 2008 Notice of Appearance by Samuel C. Straight for Plaintiffs DI 93.
84 Mar. 12, 2008 Notice of Appearance by Arthur B. Berger for Plaintiffs DI 94.
85 Mar. 12, 2008 Notice of Appearance by M Bettilyon for Plaintiffs DI 95.
86 Mar. 12, 2008 Notice of Appearance by James S. Jardine for Plaintiffs DI 96.
87 Mar. 12, 2008 Notice of Appearance by Rick B. Hoggard for Plaintiffs DI 97.
88 Mar. 13, 2008 Plaintiffs' Memorandum in Response to Defendants' Motion to Strike Reply Memorandum/Reply to Response to Motion to Compel Immediate Production of Documents with Exhibits A-I DI 98.
89 Mar. 13, 2008 Notice of Conventional Filing of Plaintiffs' Memorandum in Response to Defendants' Motion to Strike and Exhibit F Supporting Plaintiffs' Memorandum in Response to Defendants' Motion to Strike DI 99.
9 Oct. 25, 2006 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Stephen M. Craig for Plaintiffs DI 9.
90 Mar. 19, 2008 Docket Entry regarding Minute Order granting Motion to Compel and adopting proposed order in part; denying Motion to Strike, granting request for modification of protective order, and finding as moot Motion to Compel DI 101.
91 Mar. 19, 2008 Hearing Transcripts Regarding Motion to Compel and Court's Ruling.
92 Mar. 24, 2008 Defendants' Objections to Plaintiffs' Proposed Orders with Exhibits A-D 102.
93 Mar. 25, 2008 Plaintiffs' Response to Defendants' Objections to Plaintiffs' Proposed Orders with Exhibits A-C DI 103.
94 Mar. 25, 2008 Order Denying Defendants' Motion to Strike Plaintiffs' Reply Memorandum Supporting Its Motion to Compel and Following oral order of Mar. 19, 2008 DI 104.
95 Mar. 26, 2008 Order Deeming Moot Plaintiffs' Motion for Re-Designation with Modifications DI 105.
96 Mar. 26, 2008 Order Granting Plaintiffs' Motion to Compel Immediate Production of Documents DI 106.
97 Apr. 18, 2008 Plaintiffs' Motion to Compel Amended Interrogatory Responses and to Deem Admitted Plaintiffs' Request for Admission DI 107.
98 Apr. 18, 2008 Plaintiffs' Memorandum in Support of Motion to Compel Amended Interrogatory Responses and to Deem Admitted Plaintiffs' Request for Admission DI 108.
99 Apr. 18, 2008 Notice of Conventional Filing of Exhibits Regarding Plaintiffs' Memorandum in Support of Motion to Compel Amended Interrogatory Responses and to Deem Admitted Plaintiffs' Request for Admission DI 109.
Abstract: Weilin Xie, et al., Cloning and Characterizations of a pp60v-arc-inducible prostaglandin Synthase, 75th Annual Meeting Atlanta, Georgia, Apr. 21-25, 1991, The FASEB Journal, Abstracts Part I ChipmanBYU-08-1021-1022.
Additional Exhibits in Support of Apr. 8, 2011 Memorandum Submitting BYU's Privilege Documents for In Camera Review Ex. 01: Excerpt from Plaintiffs' Opposition, Feb 22, 2011 and Letter to Dr. Hooper Ex. 02: Jun. 24, 1999 Email to Dr. Simmons from Tammy Gustin Ex. 03: Jun. 4, 2007 Memo to Dr. Simmons from Dr. Woolley Ex 06: Nov. 5, 1992 Email from Lynn Astle Ex. 08: Dec. 14, 1992 letter to Dr. Simmons from Ms. Hardman.
Amended Apr. 8, 2011 Subpoena to The Monsanto Company.
Amended Protective Order dated Mar. 16, 2010.
Amended Scheduling Order dated May 3, 2010.
Apr. 12, 2011 Notice of Conventional Filing of Response to Plaintiffs' Memorandum Submitting BYU's Privileged Documents for in Camera Review.
Apr. 13, 2009 Memorandum in Opposition re 218 Plaintiff's Motion to Amend/Correct 159 Scheduling Order, filed by Defendant Pfizer (DI 223).
Apr. 14, 2008 Letter from Beus Gilbert to L. Schneider enclosing BYU's updated privilege log as of Apr. 10, 2008.
Apr. 15, 2011 Notice of Conventional Filing of BYU's Response to Defendants' Statement in Support of Their In Camera Submission of Privileged Communications Between Pfizer and New Monsanto (Unredacted Version).
Apr. 17, 2009 Reply to Response to Motion re 212 Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics filed by Defendant Pfizer. (Exhibit 1) (DI 224).
Apr. 18, 2011 Declaration of Michael S. Wigotsky Regarding Plaintiffs' Access to Biological Materials Stored at Lancaster Laboratories, Feb. 8-9, 2011.
Apr. 18, 2011 Declaration of Stephen M. Craig.
Apr. 20, 2009 Notice of Hearing on Motion re: 194 Motion for Suspension of Reissue Proceedings, 214 Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 : (Notice generated by Kim Jones) Motion Hearing set for Jun. 5, 2009 09:30 AM in Room 220 before Judge Dale A. Kimball. Two hours have been set aside for the hearing. (kmj) (Entered: Apr. 20, 2009) (DI 225).
Apr. 22, 2008 Defendants' First Set of Requests for Admission to Plaintiff Brigham Young University.
Apr. 22, 2008 Defendants' First Set of Requests for Admission to Plaintiff Dr. Daniel L. Simmons.
Apr. 22, 2008 Exhibits to Defendants' First Set of Requests for Admission to Plaintiffs with Non-Confidential Exhibits 1-29.
Apr. 23, 2009 Stipulated Motion for Extension of Time to File Response/Reply as to 214 Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 filed by Plaintiff Brigham Young University. (Attachments: Text of Proposed Order) Motions referred to Brooke C. Wells. (DI 226).
Apr. 26, 2011 Ex Parte Motion for Leave to File Supplemental Response to Memorandum Submitting BYU's Documents for In Camera Review.
Apr. 27, 2009 Order granting 226 Motion for Extension of Time to File Response/Reply re 214 Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991. Responses due by May 22, 2009. Signed by Judge Dale A. Kimball on Apr. 27, 2009. (DI 227).
Apr. 27, 2009 Reply to Response to Motion re 218 Plaintiff's Motion to Amend/Correct 159 Scheduling Order, filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibit 1) (DI 228).
Apr. 27, 2009 Reset Deadline as to 194 Motion for Suspension of Reissue Proceedings, 172 Motion to Amend/Correct for Leave From and Modification to the Protective Order, and 214 Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991. Motion Hearing reset for Jun. 23, 2009 03:00 PM in Room 220 before Judge Dale A. Kimball. Docket Text Only.
Apr. 29, 1991 Seibert Fax to Simmons. BYU-08-0823-0824.
Apr. 3, 2009 Reply to Response to Motion re 179 Motion for Sanctions (Discovery) (Supplemental) filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibits 1-3) (DI 219).
Apr. 3, 2009 Response to Motion re 212 Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics (Redacted) filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibits 1-12) Redacted Version (DI 220).
Apr. 4, 2011 Joint Statement of the Parties Re: Apr. 7, 2011 Status Conference Ex. 01: Missing Documents or Tangible Things as of Apr. 4, 2011.
Apr. 5, 1991 Research Proposal to the Monsanto Company by Simmons BYU-11-2376-2378.
Apr. 6, 2011 Reply Memorandum in Support of Defendants' Request for Attorneys' Fees and Costs.
Apr. 7, 2009 and Apr. 8, 2009 Hearing Transcripts re: Motion for Discovery Sanctions.
Apr. 7, 2009 Minute Entry for proceedings held before Magistrate Judge Brooke C. Wells: Motion Hearing held on Apr. 7, 2009 re 179 Motion for Sanctions (Discovery) filed by Daniel L. Simmons, Brigham Young University. Counsel for both parties present. Court hears arguments. Matter is continued to Apr. 8, 2009 at 9:30 a.m. Court is adjourned. (DI 221).
Apr. 8, 2009 Minute Entry for proceedings held before Magistrate Judge Brooke C. Wells: Motion Hearing held on Apr. 8, 2009 re 179 Motion for Sanctions (Discovery) filed by Daniel L. Simmons, Brigham Young University. Discussion heard. Court takes motion under advisement. Court ordered that by May 11, 2009, the parties shall file the following in electronic format: Plaintiff shall file affidavits regarding attorney's fees ; Defendant shall complete all remaining discovery ; Defendant shall file affidavits by those attorney's that have participated in the discovery process ; Both parties shall file proposed findings of fact. Court Reporter: Kelly Hicken.(Time Start: 9:30, Time End: 11:15, Room 220.) (DI 222).
Apr. 8, 2011 Declaration of Daniel L. Simmons.
Apr. 8, 2011 Memorandum Submitting BYU's Privilege Documents for in Camera Review Ex. 01: Mar. 2, 2011 Hearing Transcript Ex. 02: Merrill Bateman Deposition, Oct. 22, 2010 Ex. 03: Daniel Simmons Deposition, Apr. 21, 2009 Ex. 04: Gary Hooper Deposition, Jan. 20, 2011.
Apr. 8, 2011 Notice of Conventional Filing of Declaration of Michael Orme.
Apr. 9, 1991 Needleman Letter to Simmons BYU-20-1566.
Article: Daniel Simmons, et al., "Multiple Cyclooxygenases: Cloning of a Mitogen-Inducible Form," Proceedings of the 11th International Washington Spring Symposium at The George Washington University, held May 13-17, 1991, Washington, D.C. BYU-18-1680-1688, 1758-1769.
Article: G. Evett, et al., Prostaglandin G/H Synthase Isoenzyme 2 Expression in Fibroblasts: Regulation by Dexamethasone, Mitogens, and Oncogenes, Archives of Biochemistry and Biophysics, Oct. 1991 BYU-11-1956-1964.
Article: G. Rosen, T. Birkenmeier, A. Raz, M. Holtzman, "Identification of a Cyclooxygenase-related Gene and Its Potential Role in Prostaglandin Formation," Biochemical and Biophysical research Communications, Nov. 15, 1989, vol. 164, No. 3, 1358-1365 BYU-12-0563-0570.
Article: J. Fu, et al., "The Induction and Suppression of Prostaglandin H2 Synthase (Cyclooxygenase) in Human Monocytes," Journal of Biological Chemistry, vol. 265, No. 26, Oct. 8, pp. 16737-16740, 1990 BYU-UR 000016311-16314; S00356252-S00356255.
Article: Weilin Xie, et al., "Expression of mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing," Proceedings of the National Academy of Sciences of the USA, Apr. 1, 1991, vol. 88, No. 7 BYU-18-4303-4304, 4306, 4391-4395.
Aug. 10, 2010 Order Granting Stipulated Motion for Extension of Time.
Aug. 11, 2009 letter from Scott A. Williams to Joseph M. Reisman.
Aug. 12, 2008 Defendants' Supplemental Response to Plaintiffs' First Request for Admission.
Aug. 12, 2011 Reply Memorandum in Support of Motion to Strike Portion of Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment Re: Paragraph 3.3 of the Research Agreement.
Aug. 12, 2011 Reply Memorandum in Support of Motion to Strike Portions of Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment Re: Paragraph 3.3 and 3.4 of the Research Agreement.
Aug. 15, 2011 Defendants' Supplemental Memorandum Re: Issue of Latent Ambiguity As Applied to Defendants' Motion for Partial Summary Judgment.
Aug. 15, 2011 Notice of Conventional Filing of Exhibits 1 through 3 to Plaintiffs' Supplemental Brief Regarding Application of the Latent Ambiguity Doctrine.
Aug. 15, 2011 Plaintiffs' Supplemental Brief Regarding Application of the Latent Ambiguity Doctrine, including the following exhibit: Exhibit 4: Oct. 29, 1991 Letter to Dr. Raz from Dr. Needleman.
Aug. 16, 2010 Defendants' Opposition to Plaintiffs' Motion to Compel Production and for Sanctions.
Aug. 16, 2010 Stipulated Motion for Extension of Time to File Opposition to Plaintiffs' Motion for Dispositive Sanctions. Exhibit A—[Proposed] Order Granting Stipulated Motion for Extension of Time to File Opposition to Plaintiffs' Motion for Dispositive Sanctions.
Aug. 17, 2010 Notice of Taking Video Deposition of Mark Currie.
Aug. 17, 2010 Order granting Stipulated Motion for Extension of Time to File Opposition to Plaintiffs' Motion for Dispositive Sanctions.
Aug. 18, 2009 Hearing Transcript.
Aug. 18, 2010 Order granting Motion for Leave to File Overlength Memorandum.
Aug. 23, 2010 Amended Notice of Taking Video Deposition of Dr. Daniela Salvemini.
Aug. 23, 2010 Defendants' Response to Plaintiffs Ninth Request for Production of Documents.
Aug. 25, 2010 Stipulated Motion for Extension of Time to File Opposition to Plaintiffs' Motion for Dispositive Sanctions Exhibit A: [Proposed] Order Granting Stipulated Motion for Extension of Time to File Opposition to Plaintiffs' Motion for Dispositive Sanctions.
Aug. 26, 2010 Order granting Stipulated Motion fo Extension of Time to File Opposition to Plaintiffs' Motion or Dispositive Sanctions.
Aug. 26, 2011 Motion for Partial Summary Judgment Regarding Count III (Breach of Fiduciary Duty) of Plaintiff's First Amended Complaint.
Aug. 26, 2011 Notice of Conventional Filing of Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Count III (Breach of Fiduciary Duty) of Plaintiff's First Amended Complaint and Exhibits.
Aug. 27, 2007 Defendant Pfizer Inc.'s Response to Plaintiffs' Request for Admission.
Aug. 27, 2010 Memorandum Decision and Order Denying Without Prejudice Plaintiffs' Motion for Sanctions.
Aug. 30, 2007 Merck & Co, Inc.'s and Merck Sharp & Dohme Limited's Responses and Objections to Brigham Young University's and Dr. Daniel L. Simmons' Rule 45 Subpoena Duces Tecum dated May 11, 2007.
Aug. 31, 2010 Defendants' Answers to First Amended Complaint.
Aug. 31, 2010 Memorandum in Support of Motion to Dismiss Counts IX (18 U.S.C. § 1962(c)) and X (18 U.S.C. § 1962 (D)) of Plaintiffs' First Amended Complaint.
Aug. 31, 2010 Motion to Dismiss Counts IX (18 U.S.C. § 1962(c)) and X (18 U.S.C. § 1962 (D)) of Plaintiffs' First Amended Complaint.
Aug. 4, 2011 Errata to Plaintiffs' Response in Opposition to Defendants' Motion for Partial Summary Judgment on Plaintiffs' Claims for Breach of Paragraph 3.3 of the Research Agreement.
Aug. 4, 2011 Memorandum in Support of Motion to Correct/Add Citations in Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment on Plaintiffs' Claims for Breach of Paragraphs and 3.4 of the Research Agreement.
Aug. 4, 2011 Motion to Correct/Add Citations in Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment on Plaintiffs' Claims for Breach of Paragraphs 3.3 and 3.4 of the Research Agreement.
Aug. 4, 2011 Notice of Errata relating to paragraph numbering in Plaintiffs' Response in Opposition to Defendants' Motion for Partial Summary Judgment on Plaintiffs' Claims for Breach of Paragraphs of the research Agreement.
Aug. 4, 2011 Order Requesting Additional Briefing.
Aug. 6, 2010 Stipulated Motion for Extension of Time for Defendants to respond to Plaintiffs' Motion to compel and for Sanctions Attachments: # 1 [Proposed] Order Granting Stipulated Motion for Extension of Time.
Aug. 7, 1990 Honors Thesis Submission Form of Jeffrey Chipman BYU-20-0164.
Aug. 8, 2006 Surrebuttal Expert Report of Ronald H. Smith (with correction to opening report).
Bandaru et al. Cancer Research, 56. pp. 4566-4569 (1996).
Bandaru Reddy, et al.; 1996; Evaluation of Cyclooxygenase-2 Inhibitor for Potential Chemopreventive Properties in Colon Carcinogenesis; 56; 4566-4569.
Bartlett et al., "Subst. 3-phenyl-7H-thiazolo(3,2-b)1,2,4)triazin-7-ones as Antiinflam. Agents w/ Immun. Properties." Drugs Under Experim. & Clinic Res. 1989, 521-26; vol. XV.
Bertenshaw et al., "3,4-Diarylthiophenes are Selective COX-2 Inhibitors." Bioorganic & Medicinal Chemistry Lett., 1995, pp. 2919-2922, vol. 5, No. 23.
Bosch et al, "Efficacy & Tolera. of Intramuscular & Oral Meloxicam in Patients w/ Acute Lumbago: A Comp. w/ Intramuscular . . ." Curr. Med. Res. Opin. 1997; p. 29-38; vol. 14; 1.
BYU Amended Subpoena to Monsanto Co. dated Jul. 16, 2008.
BYU Subpoena to Monsanto Co. dated Nov. 16, 2007.
BYU's Apr. 15, 2011 Reply Re Privileged Documents Submitted for in Camera Review.
BYU's Apr. 15, 2011 Response to Defendants' Statement in Support of Their in Camera Submission of Privileged Communications Between Pfizer and New Monsanto (Redacted Version) Ex. 01: Oct. 8, 2008 Letter to L. Williams from N. Wyland Ex. 02: Jul. 29, 2008 Letter to L. Williams from L. Schneider Ex. 03: Apr. 8, 2009 Hearing Transcript Ex. 04: Oct. 4, 2010 Letter to A. Anderson from K. Owen.
BYU's Jun. 1, 2011 Responses and Objections to Defendants' 30(b)(6) Notice of Deposition.
BYU's May 20, 2011 Responses and Objections to Defendants' 30(b)(6) Notice of Deposition.
Cocco, M., et al.;1985;Phytotoxic Activity in Pyrazole Derivatives; II Farmaco-Ed. Sci; 40; 272-284.
D. Utah electronic case filing registration form for D. Webb dated Feb. 9, 2010.
Dec. 1, 2010 Amended Notice of Taking Video Deposition of Thomas G. Warren.
Dec. 1, 2010 Notice of Taking Video Deposition of Diana McWilliams.
Dec. 1, 2010 Subpoena to Washington University at St. Louis.
Dec. 13, 2011 Stipulated Motion for Extension of Time: Proposed Order.
Dec. 14, 2010 Notice of Taking Video Deposition of Donald Robertson.
Dec. 14, 2010 Notice of Taking Video Deposition of Morris Robins.
Dec. 14, 2011 Stipulated Order.
Dec. 15, 2009 Notice of conventional filing of Joint Status Memorandum.
Dec. 17, 2007 Merck & Co, Inc.'s Responses and Objections to Pfizer, Inc.'s Rule 45 Subpoena Duces Tecum Served Nov. 28, 2007.
Dec. 17, 2010 Notice of Conventional Filing of Plaintiffs' Response in Opposition to Motion for Partial Summary Judgment on Counts I-III and V-X of the First Amended Complaint on Statute of Limitations Grounds and All Exhibits Thereto.
Dec. 19, 2011 Defendants' Expedited Motion to Strike Plaintiffs' Amended Memorandum in Support of Renewed Motion for Further Discovery Sanctions.
Dec. 19, 2011 Memorandum in Support of Defendants' Expedited Motion to Strike Plaintiffs' Amended Memorandum in Support of Renewed Motion for Further Discovery Sanctions and the following Exhibits: Exhibit A: Motion Hearing Transcript, Apr. 8, 2009 Exhibit B: Motion Hearing Transcript, Apr. 7, 2009.
Dec. 2009 Joint Status Memo, Exhibit P13.
Dec. 2009 Joint Status Memo, Exhibits D16-D18.
Dec. 2009 Joint Status Memo, Exhibits D4-D10.
Dec. 2009 Joint Status Memo, Exhibits P18-P20.
Dec. 2009 Joint Status Memo, Exhibits P4-P8.
Dec. 22, 2011 Brigham Young University and Daniel L. Simmons' Response to Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claim for Breach of Paragraph 1.6 of the Research Agreement (Pfizer Motion No. 11).
Dec. 22, 2011 BYU Memorandum in Opposition to Defendants' Motion for Partial Summary Judgment Regarding Paragraph 3.3 of the Research Agreement (BYU's Opposition to Defendants' Motion No. 10).
Dec. 22, 2011 BYU's Memorandum in Opposition to Pfizer's Motion for Partial Summary Judgment That Plaintiffs' Hypothetical Patent Claims 12-26 May Not be Relied Upon in Support of Any Claim For Relief (BYU's Opposition to Defendants' Motion No. 4).
Dec. 22, 2011 Defendants' Response to Plaintiffs' Motion for Partial Summary Judgment Concerning Defendants' Twenty-Eighth and Twenty-Ninth Defenses and the following exhibit: Exhibit 1: Excerpts from L. Astle Dep., Feb. 17, 2009.
Dec. 22, 2011 Errata to BYU Memorandum in Opposition to Defendants' Motion for Partial Summary Judgment Regarding Paragraph 3.3 of the Research Agreement (BYU's Opposition to Defendants' Motion No. 3) Corrected BYU Memorandum in Opposition to Defendants' Motion for Partial Summary Judgment Regarding Paragraph 3.3 of the Research Agreement (BYU's Opposition to Defendants' Motion No. 3).
Dec. 22, 2011 Index to Memorandum in Opposition to BYU's Motion for Partial Summary Judgment Regarding Defendants' (Alleged) Breach of Paragraph 4.1 of the Research Agreement and the following Exhibits: Exhibit 4: Declaration of Timothy Hla in Support of Defendants' Opposition to BYU's Motion to Partial Summary Judgment Regarding Defendants' (Alleged) Breach Paragraph 4.1 of the Research Agreement Exhibit 8: Dean A. Kujubu et al., TIS10, a Phorboi Ester Tumor Promoter-inducible mRNA from Swiss 3T3 cells, Encodes a Novel Prostaglandin Synthase/Cycooxygenase Homologue, 266(20) J. Biol. Chem., 12866-72 (Jul. 1991) Exhibit 9: May 20, 2012 Letter to P. Needleman from D. Simmons Exhibit 11: Sambrook, Extraction, Purification and Analysis of Messenger RNA from Eukaryotic Cells, (1989) Exhibit 12: Dewitt et al., The Aspirin and Heme Binding Sites of Ovine and Murine Prostaglandin Endoperoxide Syntheses, The Journal of Biological Chemistry, 265(9): 5192-5198 (1990)(DeWitt 1990) Exhibit 16: Mar.
Dec. 22, 2011 Memorandum in Opposition to Piaintiffs' Motion for Partial Summary Judgment to Dismiss Defendants Thirty-Second Defense With Prejudice.
Dec. 22, 2011 Notice of Conventional Filing of Consolidated Exhibits to Plaintiffs' Oppositions to Pfizer's Motions for Summary Judgment 1-13.
Dec. 22, 2011 Notice of Conventional Filing of Memorandum in Opposition to BYU's Motion for Partial Summary Judgment Regarding Defendants' (Alleged) Breach of Paragraph 4.1 of the Research Agreement and Exhibits 1, 2, 3, 5, 6, 7, 10, 13, 14, 15, 16, 17, 18, 19, 21, 22, 38, 39 and 40.
Dec. 22, 2011 Notice of Conventional Filing of Memorandum in Opposition to Plaintiffs' Motion for Partial Summary Judgment Re: mitigation of Damages and Failure to Patent as Described in Special Defenses Nos. 24 and 25 in the Amended Answer.
Dec. 22, 2011 Order Regarding Briefing on Defendants' Motion to Strike.
Dec. 22, 2011 Plaintiffs' Memorandum in Opposition to Defendants' Motion for Partial Summary Judgment Re: Ownership of the COX-2, Materials (BYU's Opposition to Defendants' Motion No. 10).
Dec. 22, 2011 Plaintiffs' Memorandum in Opposition to Defendants' Motion for Partial Summary Judgment That Plaintiffs' Alleged "Two-Cell Assay" Trade Secret Has Been Licensed to Defendants (Plaintiffs' Opposition to Defendants' Motion No. 8).
Dec. 22, 2011 Plaintiffs' Memorandum in Opposition to Defendants' Motion for Summary Judgment on Plaintiffs' Claim for Correction of Inventorship (BYU Opposition to Pfizer Motion No. 5)
Dec. 22, 2011 Plaintiffs' Memorandum in Opposition to Defendants' Motion to Dismiss for Lack of Stand (BYU's Oposition to Defendants Motion No. 9).
Dec. 22, 2011 Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment on Exclusions From "Project" (BYU Opposition to Pfizer Motion No. 2).
Dec. 22, 2011 Plaintiffs' Response in Opposition to Defendants Motion for Partial Summary Judgment dismissing Plaintiffs' Claim for Breach of Paragraph 3.1 of the Research Agreement (BYU Opposition to Pfizer Motion No. 12).
Dec. 22, 2011 Plaintiffs' Response to Defendants' Motion for Partial Summary Judgment Re Breach of Paragraphs 1.3, 3.4, 3.5 and 3.7 of the Research Agreement (Response to Pfizer MSJ No. 1).
Dec. 22, 2011 Plaintiffs' Response to Motion for Partial Summary Judgment Re Count II—Implied Covenant of Good Faith and Fair Dealing, Count III—Fiduciary Duty, Count V—Unjust Enrichment, Count VI—Fraud and Count VII—Negligent Misrepresentation of Plaintiffs' First Amended Complaint (BYU Opposition to Defendants' Motion No. 13).
Dec. 22, 2011 Response in Opposition to Defendants' Motion for Partial Summary Judgment on Plaintiffs' Claim That Defendants Have Misappropriated "Project" and "Compilation" Trade Secrets (Response to Defendants' Motion No. 6).
Dec. 22, 2011 Response in Opposition to Defendants' Motion for Partial Summary Judgment Regarding Plaintiffs' COX-1 Trade Secret Claims (Response to Defendants' Motion No. 7).
Dec. 23, 2010 Order Regarding Scheduling Deadlines.
Dec. 23, 2011 Notice of Conventional Filing—Amendment to Exhibit 2 to Memorandum in Opposition to BYU's Motion for Partial Summary Judgment Regarding Defendants' (Alleged) Breach of Paragraph 4.1 of the Research Agreement.
Dec. 27, 2010 Plaintiffs' Eleventh Request for Production of Documents.
Dec. 27, 2011 Plaintiffs'Response to Defendants' Motion for Partial Summary Judgment Re Breach of Paragraph 1.3, 3.4, 3.5 and 3.7 of the Research Agreement (Response to Pfizer MSJ No. 1).
Dec. 3, 2007 Defendants' Response to Plaintiffs' Third Request for Production of Documents.
Dec. 9, 2010 Supplemental Rule 26 Disclosures.
Dec. 9, 2011 Amended Memorandum in Support of Plaintiffs' Renewed Motion for Further Sanctions.
Dec. 9, 2011 Notice of Manual Filing of Exhibits to Amended Memorandum in Support of Plaintiffs' Renewed Motion for Further Sanctions.
Decision and Order (from University of Rochester v. G.D. Searle et al.) dated Mar. 28, 2002 (UOR 13-01072-UOR 13-01129).
Defendant Pfizer's Memorandum in support of Motion for Leave from Protective Order DI 173.
Defendant Pfizer's Responses and Objections to Plaintiffs' 30(b)(6) Notice of Deposition to Pfizer dated Feb. 22, 2008.
Defendants' (Pfizer Inc., G.D. Searle, LLC and Pharmacia Corporation) Feb. 22, 2010 Response to Plaintiffs' Eighth Request for Production of Documents.
Defendants' Apr. 22, 2011Reply to BYU's Responses to Defendants' Statement in Support of Their In Camera Submission of Privileged Communications Between Pfizer and New Monsanto.
Defendants' Apr. 7, 2011 Statement in Support of Their in Camera Submission of Privileged Communications Between Pfizer and New Monsanto Inspection.
Defendant's Aug. 6, 2010 Memorandum in Opposition to Plaintiffs' Motion for Leave to File Overlength Memorandum.
Defendants' Dec. 14, 2009 Fourth Reques or Production of Documents.
Defendants' Dec. 16, 2009 Fifth Request for Production of Documents.
Defendants' Dec. 6, 2010 Response to Plaintiffs' Tenth Request for Production of Documents.
Defendants' Dec. 7, 2010 Objections to Amended Notice of Video Deposition of Diana McWilliams.
Defendants' Dec. 7, 2010 Objections to Amended Notice of Video Deposition of Thomas G. Warren.
Defendants' Feb. 14, 2011 Motion to compel Testimony Persuant to Notice of 30(b)(6) Deposition, with the following exhibit: Ex. 1: Statement in Compliance with DUCivR 37-1(a).
Defendants' Feb. 14, 2011 Responses to Plaintiffs' Fourth Set of Interrogatories.
Defendants' Feb. 14, 2011 Responses to Plaintiffs' Second Set of Requests for Admission.
Defendants' Feb. 14, 2011 Responses to Plaintiffs' Twelfth Request for Production of Documents.
Defendants' Feb. 18, 2011 Motion to Compel Testimony Pursuant to Notice of 30(b)(6) Deposition, with the following exhibit: Ex. 1: Statement in Compliance with DUCivR 37-1(a).
Defendants' Feb. 25, 2010 Sixth Request or Production of Documents.
Defendants' Feb. 5, 2011 Responses and Objections to Plaintiff's 30(b)(6) Notice of Deposition to Pfizer.
Defendants' First Request for Admission to Plaintiffs dated Aug. 28, 2007.
Defendants' Jan. 12, 2011 Identification of Experts.
Defendants' Jan. 14, 2011 Motion to Strike Portions of Plaintiffs' Response in Opposition to Motion for Partial Summary Judgment.
Defendants' Jan. 19, 2011 Motion to Compel Production of Documents and Award of Attorney Fees.
Defendants' Jan. 19, 2011 Second Set of Interrogatories (Nos. 15-27).
Defendants' Jan. 19, 2011 Second Set of Requests for Admission.
Defendants' Jan. 19, 2011 Seventh Set of Requests for Production (Nos. 1-10).
Defendants' Jan. 26, 2011 Opposition to Plaintiffs' Motion for Admission Pro Hac Vice of G. Robert Blakey.
Defendants' Jan. 31, 2011 Response to Plaintiffs' Eleventh Request for Production of Documents.
Defendants' Jan. 5, 2011 Responses and Objections to Plaintiff's 30(b)(6) Notice of Deposition.
Defendants' Jan. 6, 2011 Notice of Service of Subpoena for Production of Documents and Things to Bristol—Myers Squib with the following exhibit: Ex. A: Subpoena for Production of Documents and Things to Bristol—Myers Squib.
Defendants' Jan. 7, 2011 Amended Responses and Objections to Plaintiff's 30(b)(6) Notice of Deposition.
Defendants' Mar. 1, 2010 Response and Objections to Plaintiffs' Amended Rule 30(b)(6) Deposition Notice to Defendants.
Defendants' Mar. 16, 2011 Memorandum in Opposition to Plaintiffs' Motion to Compel and Motion to Disqualify and the following exhibits: Ex. 1: Mar. 2, 2011 BYU V. Pfizer Hearing Transcript Ex. 2: Defendants' Identification of Experts Ex. 3: Declaration of Brent O. Hatch in Support of Defendants' Memorandum in Opposition to Plaintiffs' Motion to Compel and Motion to Disqualify Ex. 4: Mar. 4, 2011 Letter to B. Hatch from M. Bettilyon Ex. 5: Plaintiffs': (1) Disclosure of Expert Testimony Subject Areas and (2) Supplemental Disclosure of Percipient Witness Testimony Subject Areas Ex. 6: Declaration of Richard T. Mulloy in Support of Defendants' Memorandum in Opposition to Plaintiffs' Motion to Compel and Motion to Disqualify Ex. 7: Declaration of Richard F. O'Malley in Support of Defendants' Memorandum in Opposition to Plaintiffs' Motion to Compel and Motion to Disqualify Ex. 8: Declaration of Eugene C. Rzucidlo Ex. 9: Declaration of Max D. Wheeler Ex. 10: Filed Under Seal.
Defendants' May 24, 2011 Responses and Objections to Plaintiffs' Amended 30(b)(6) Notice of Deposition to Pfizer.
Defendants' May 28, 2010 Objections to Notice of Deposition of Karen Seibert.
Defendants' May 28, 2010 opposition to Plaintiffs' motion to extend trial date.
Defendants' Memorandum in Support of Motion for Protective Order Regarding Marketing Practices Litigation dated Mar. 5, 2010.
Defendants' Memorandum in Support of Motion for Protective Order Regarding Post-2001 Documents dated Mar. 8, 2010.
Defendants' Motion for Hearing re To Amend The Discovery Plan (dated Jan. 21, 2010).
Defendants' motion for leave to file an overlength opposition to Plaintiffs' motion for dispositive sanctions with proposed order dated Apr. 30, 2010.
Defendants' Motion for Protective Order Regarding Marketing Practices Litigation dated Mar. 5, 2010.
Defendants' Motion for Protective Order Regarding Post-2001 Documents dated Mar. 8, 2010.
Defendants' Notice of Taking Video Deposition of Brigham Young University Pursuant to Fed. R. Civ. P. 30 (b)(6) (Jul. 14, 2010).
Defendants' Notice of Taking Video Deposition of Denis Callewaert and Subpoena (Jul 28, 2010).
Defendants' Notice of Taking Video Deposition of Steven A. Fleming (Jun. 15, 2010).
Defendants' Opposition to Plaintiffs' (Alternative) Rule 56(f) Motion Opposing Defendants' Motion for Partial Summary Judgment Regarding Integration of the Research Agreement Dated Aug. 1, 1991 (including exhibits 1-6).
Defendants Pfizer Inc., G.D. Searle LLLC, and Pharmacia Corp.'s Response to Plaintiffs' First Request for Production of Documents dated Feb. 14, 2007.
Defendants' Reply Memorandum in Support of Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991.
Defendants' reply memorandum in support of motion or a hearing to amend the discovery plan dated Mar. 25, 2010.
Defendants' Response to Plaintiffs' Fifth Requests for Production of Documents dated Jun. 4, 2008.
Defendants' Response to Plaintiffs' First Request for Production of Documents dated Feb. 14, 2007.
Defendants' Response to Plaintiffs' Second Set of Interrogatories dated Feb. 13, 2008.
Deposition transcript dated Apr. 20, 2009 and errata for Daniel Simmons.
Deposition transcript dated Apr. 21, 2009 and errata for Daniel Simmons.
Dikshit et al., Synthesis and Biological Activity of 2,3- and 3,4-diarylfurans and 2,3,4-triaryl-2,5-dihydrofurans. Indian J. Chem., Sect. B, 1990, pp. 954-960, vol. 29B, No. 3.
Email from A. Anderson to M. Zucker dated Jan. 15, 2009.
Email from E. Coates to A. Anderson dated Jan. 16, 2009.
Email from I. Schneider to A. Anderson, L.R. Williams, and L. Beus dated Mar. 1, 2007.
Email from J. Spanbauer to M. Bettilyon dated May 19, 2009.
Email from J. Spanbauer to M. Bettilyon dated May 20, 2009.
Email from L. Schneider to L.R. Williams dated 3/30/07 attaching red-lined [Proposed] Protective Order.
Email from M. Bettilyon to J. Spanbauer dated May 19, 2009.
Email from M. Bettilyon to J. Spanbauer dated May 20, 2009.
Email J. Spanbauer to M. Bettilyon dated May 20, 2009.
Engelhardt, G., Pharmacology of Meloxicam, and New Non-Steroidal Anti-Inflammatory Drug with Improved Safety Profile Through Preferential Inhibition of Cox-2; 1996; 35; 4-12.
Ex. 31 Expert Report of Dr. G. Steven Geis Excerpt Ex. 32: Weilin Xie, Ph.D. Dep. 1, 126-129; 138-141, Mar. 27, 2009 Ex. 33: Philip Needleman, From a Twinkle in the Eye to a Blockbuster Drug, Nov.-Dec. 2001 Ex. 34: Apr. 29, 1991 Letter to K. Seibert and J. Masferrer from D. Simmons Ex. 35: Apr. 29, 1991 Fax to D. Simmons from K Seibert Ex. 36: Mar. 20, 1992 Letter to P. Needleman from D. Simmons enclosing Progress Report Ex. 37: May 20, 1992 Letter to P. Needleman from D. Simmons Ex. 38: B. Zweifel Western Blot analysis Ex. 39: May 23, 1992 Letter to P. Needleman from D. Simmons Ex. 40: Jun. 10, 1991 Fax to D. Simmons from K. Seibert Ex. 41: Jun. 14, 1991 Letter to L. Swaney from L. Astle Ex. 42: Jun. 20, 1991 Fax to D. Simmons/L. Astle from L. Swaney Ex. 43: Jul. 9, 1991 Letter to L. Swaney from C. Hardman Ex. 44: Chart Ex. 45: Oct. 29, 1991 Letter to A. Raz from P. Needleman Ex. 46: Laboratory Notebook No. 4,956,601, Issued Dec. 4, 1991 Ex. 47 Scott Hauser Dep. 1-4; 173-176, Oct. 27,
Excerpt of deposition of S. Hauser dated Jun. 10, 2009.
Excerpt of deposition transcript of D. Simmons.
Excerpt of Deposition Transcript of P. Needleman, IREF v. Pfizer, dated Apr. 24, 2007.
Excerpt of transcript from Apr. 7, 2009 motion hearing.
Excerpt of transcript from Apr. 8, 2009 motion hearing.
Excerpt of transcript from Mar. 19, 2008 Motion to Compel Hearing.
Excerpt of Transcript Mar. 9, 2008 Motion to Compel Hearing.
Excerpt of Transcript of Jul. 29, 2008 Motion Hearing.
Excerpt of Trial Transcript, IREF v. Prizer, dated Dec. 18, 2008.
Excerpted page from Judy Lewis Jun. 2, 2009 deposition transcript.
Executed, Aug. 1, 1991 Research Agreement between BYU and Monsanto BYU-11-0111-0127.
Exhibit 10 (dated May 23, 2008-Mar. 24, 2010) and Exhibit 11 (dated May 3, 2010) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 10—N. Kopinski Aff. Privilege Log.
Exhibit 11—L. Friedlieb Aff. Privilege Log.
Exhibit 13 (dated Jan. 29, 2010) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 15 (dated Apr. 7, 2009) and Exhibit 16 (dated Dec. 2, 2009) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 1—G. Haley Aff. Privilege Log.
Exhibit 2 (dated Jul. 22, 2009), Exhibit 3 (dated Feb. 11, 2010) and Exhibit 4 (dated Feb. 25, 2010) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 2 to Defendants' Memorandum in Support of Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 Excerpt of Deposition Transcript of L. Astle.
Exhibit 23 (dated Mar. 19, 2010) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 25 (dated Jun. 2, 2009) and Exhibit 26 (dated May 23, 2008) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 29 (dated Mar. 4, 2010) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 2—D. Parkinson Aff. Privilege Log.
Exhibit 34 (dated Nov. 16, 2007), Exhibit 35 (dated Jul. 16, 2008) and Exhibit 36 (dated Feb. 14, 2008)to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 39 (dated Nov. 19, 2009) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 41 (dated Sep. 2, 2008) and Exhibit 42(dated Feb. 10, 2009) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 48(dated Feb. 15, 2010) and Exhibit 49 (dated Apr. 22, 2008) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 51(dated Feb. 3, 2010) and Exhibit 52(dated Jul. 17, 2007) to Defendants' memorandum in opposition to Plaintiff's Motion for Dispositive Sanctions.
Exhibit 59: U.S. Patent No. 6,407,140 (filed Jan. 21, 2000) Exhibit 60: U.S. Patent No. 6,413,960 (filed May 30, 2000) Exhibit 61: U.S. Patent No. 6,426,360 (filed May 15, 2000) Exhibit 62: U.S. Patent No. 6,432,999 (filed Jun. 11, 2001) Exhibit 63: U.S. Patent No. 6,436,967 (filed Sep. 14, 2000) Exhibit 64: U.S. Patent No. 6,492,411 (filed Apr. 17, 2002) Exhibit 65: U.S. Patent No. 6,492,413 (filed Mar. 20, 2000) Exhibit 66: U.S. Patent No. 6,512,121 (filed Jun. 11, 2001) Exhibit 67: U.S. Patent No. 6,515,014 (filed Jun. 11, 2001) Exhibit 68: U.S. Patent No. 6,586,603 (filed Oct. 21, 2002) Exhibit 69: U.S. Patent No. 6,599,934 (filed Nov. 13, 2000) Exhibit 70: U.S. Patent No. 6,613,789 (filed Dec. 5, 2001) Exhibit 71: U.S. Patent No. 6,677,364 (filed Dec. 4, 2001) Exhibit 72: U.S. Patent No. 6,677,488 (filed Jan. 30, 2001) Exhibit 73: U.S. Patent No. 6,696,477 (filed Nov. 29, 2001) Exhibit 74: U.S. Patent No. 6,716,991 (filed Mar. 4, 2003) Exhibit 75: U.S. Patent No. 6,753.344 (filed
Exhibit 5—R. O'Malley Aff. Privilege Log.
Exhibit 61(dated Feb. 7, 2008, Feb. 11, 2008 and Feb. 19, 2008) and Exhibit 62 (dated Jan. 22, 2010) to Defendant's memorandum in opposition to Plaintiff's Motion for Depositive Sanctions.
Exhibit 61—Monsanto 1996 Annual Report.
Exhibit 6—L. Schneider Aff. Privilege Log.
Exhibit 6—Letter from L. Schneider to K. Ricker.
Exhibit 76—Plaintiffs' Supplemental Response to Defendants' Interrogatory No. 4, served Jun. 27, 2008.
Exhibit 78—Research Agreement between Brigham Young University and Monsanto Company, effective as of Aug. 1, 1991 (BYU-11-0111-0127).
Exhibit 7—N. Wyland Aff. Privilege Log.
Exhibit 9—J. Spanbauer Aff. Privilege Log.
Exhibits 1 and 2 to Plaintiff's motion for Extension of Time Amend Complaint dated Apr. 12, 2010.
Exhibits 1, 2, 3, 8, 9, 10 and 11 to Reply to Response to Motion re motion for Protective Order Regarding Marketing Practices Litigation dated Apr. 26, 2010.
Exhibits 1-12 to Redacted Plaintiffs' Memorandum in Opposition to Defendants' Motion for a Hearing to Amend the Discovery Plan dated Mar. 8, 2010.
Exhibits 120A and 317-318.
Exhibits 1-4 to Defendants' Memorandum in Support of Motion for Protective Order Regarding Post-2001 Documents dated Mar. 8, 2010.
Exhibits 1-4 to May 10, 2010 Reply in support of Plaintiffs' motion to set Date to Amend Complaint.
Exhibits 1-5 to Defendants' May 28, 2010 opposition to Plaintiffs' motion to extend trial date.
Exhibits 1-7 to Plaintiffs' May 18, 2010 motion to extend trial date.
Exhibits 1-7 to Plaintiffs' May 24, 2010 reply in support of motion for expedited briefing schedule and hearing concerning plaintiffs' motion to extend trial date and plaintiffs' emergency motion to adjust date of expert disclosures.
Exhibits 2 and 3 to Defendants' reply memorandum in support of motion for a hearing to amend the discovery plan dated Mar. 25, 2010.
Exhibits 223-224 to James Gierse Dec. 2, 2009 30(b)(6) deposition transcript.
Exhibits 240-242 (Exhibit 240: May 8, 2009 Coates Letter to A. Anderson; Exhibit 241: Code of Federal Regulations Title 21; Exhibit 242: May 11, 2009 Privilege Log of Pfizer Custodians Outlook Calendar Entries).
Exhibits 257-259 (Exhibit 257: Dec. 2, 1993 Letter to Editor at Science from Seibert enclosing manuscript; Exhibit 258: Dec. 19, 1995 US Patent 5,476,944; Exhibit 259: May 21, 2008 Letter to Ricker from Spanbauer).
Exhibits A, B and C to Motion for Admission Pro Hac Vice of Brad D. Brian dated May 3, 2010.
Exhibits A, B and C to Motion for Admission Pro Hac Vice of Dan K. Webb dated Feb. 10, 2010.
Exhibits A, B and C to Motion for Admission Pro Hac Vice of John Caleb Dougherty dated Feb. 10, 2010.
Exhibits A, B and C to Motion for Admission Pro Hac Vice of Kahty Owen dated Mar. 12, 2010.
Exhibits A, B and C to Motion for Admission Pro Hac Vice of Kristin S. Escalante dated May 3, 2010.
Exhibits A, B and C to Motion for Admission Pro Hac Vice of Raymond C. Perkins dated Mar. 12, 2010.
Exhibits A, B and C to Motion for Admission Pro Hac Vice of Richard T. Mulloy dated Mar. 12, 2010.
Exhibits A, B and C to Motion for Admission Pro Hac Vice of Stuart N. Senator dated May 3, 2010.
Exhibits A, B, C and D to Motion and Consent of Sponsoring Local Counsel for Admission Pro Hac Vice of Mark C. Dangerfield dated Feb. 18, 2010.
Exhibits Supporting Plaintifs' BYU Motion to Compel Immediate Production of Documents [Motion to Compel Immediate Production fo Documents Already Submitted to PTO on Jun. 19, 2009 (Jun. 19, 2009 IDS NPL Cite Nos. 121-122).].
Exhibits to Plaintiffs' Memorandum in Support of Motion to Compel Amended Interrogatory Responses and to Deem Admitted BYU's Request for Admission.
Faid-Allah et al., "Pyrazole Derivatives with Possible Hypoglycemic Activity." Indian Journal of Chemistry, 1988, pp. 245-249, vol. 27B, No. 3.
Feb. 1, 2007 Post-Trial Brief of Teva Pharmaceuticals USA, Inc.
Feb. 1, 2011 Notice of Conventional Filing of Exhibits 1, 2, 3, 5, 6A-C, 7, 8, 9, 10A-B, 17, 18, 19, 21, 22, 25, 28, 33 to Plaintiffs' Response in Opposition to Defendants' Motion to Strike Portions of Plaintiffs' Response to Motion for Partial Summary Judgment.
Feb. 1, 2012 Memorandum Support of Motion to Strike.
Feb. 1, 2012 Motion to Strike.
Feb. 11, 2008 Defendants' Second Request for Production of Documents to Plaintiffs.
Feb. 12, 2007 Plaintiffs' Response to Defendants' First Request for Production of Documents.
Feb. 12, 2007 Plaintiffs' Response to Defendants' First Set of Interrogatories.
Feb. 12, 2008 Plaintiffs' Notice of Subpoena for Production of Documents and Things to Chandler Chicco Agency, David L. DeWitt and Michigan State University.
Feb. 12, 2009 Plaintiffs' Sixth Request for Production of Documents.
Feb. 13, 2008 Defendant Pfizer Inc.'s Response to Plaintiffs' Second Set of Interrogatories.
Feb. 13, 2008 Plaintiffs' 30(b)(6) Notice of Deposition to Pfizer.
Feb. 13, 2009 Motion Ex Parte Motion to File Overlength Memorandum in Opposition to Plaintiff's Motion for Discovery Sanctions filed by Defendant Pfizer. (Attachments: # 1 Text of Proposed Order [Proposed] Order Regarding Pfizer's Ex Parte Motion to File Overlength Memorandum in Opposition to Plaintiffs' Motion for Discovery Sanctions) Motions referred to Brooke C. Wells. (DI 198).
Feb. 14, 2007 Defendants' Response to Plaintiffs' First Request for Production of Documents.
Feb. 14, 2011 Memorandum in Support of Defendants' Motion to Compel Testimony Pursuant to Notice of 30(b)(6) Deposition, with the following exhibits: Ex. 1: Amended Notice of Taking Video Deposition of Brigham Young University Pursuant to Fed. R. Civ. P. 30(b)(6), Nov. 5, 2010 Ex. 2: Nov. 18, 2010 Letter to R. Mulloy from A. Anderson Ex. 3: Dec. 10, 2010 Letter to A. Anderson from R. Mulloy Ex. 4: Dec. 20, 2010 Letter to A. Anderson from R. Mulloy Ex. 5: Foreclosure Mgmt. Co. v. Asset Mgmt. Holdings, LLC, No. 07-2388-DJW, 2008 WL 3895474 (D.Kan. Aug. 21, 2008). Ex. 6: Fed. Deposit Ins. Corp. v. Hays, No. CIVASA92CA653EP, 1998 WL 1782547 (W.D. Tex. Jan. 9, 1998). Ex. 7: E.E.O.C. v. Lowe's HIW, Inc., Nos. C08-0331-JCC, C08-5053, 2009 WL 811495 (W.D. Wash. Mar. 27, 2009).
Feb. 14, 2011 Motion to Compel Immediate Production of Documents and 30(b)(6) Deposition.
Feb. 14, 2011 Notice of Conventional Filing of Memorandum in Support of Motion to Compel Immediate Production of Documents and 30(b)(6) Deposition.
Feb. 14, 2012 Pfizer's Memorandum in Opposition to BYU's Motion for Permission to Provide Designated Documents to Teva Pharmaceuticals That Pfizer Has Labeled as Confidential Under the Protective Order and the following Exhibits: Exhibit 1: Pfizer Inc. 10-K Annual Report, filed on Feb. 29, 2008 Exhibit 2: Pfizer Inc. 10-K Annual Report, filed on Feb. 28, 2011 Exhibit 3: News Release, Teva Announces Launch of Generic Protonix Tablets, 20 mg and 40 mg Company Increases 2007 EPS Guidance to Between $2.34 and $2.36 Compant to Hold Conference Call at 8:45 a.m. Eastern Time Exhibit 4: Stipulated Protective Order, Pfizer Inc. v. Teva Phamaceuticals USA Inc., Aug. 31, 2004.
Feb. 16, 2007 Post-Trial Reply Brief of Teva Pharmaceuticals USA, Inc.
Feb. 16, 2009 Notice of Conventional Filing Under Seal of Pfizer's Memorandum in Opposition to Plaintiffs' Motion for Discovery Sanctions and Exhibits 1-105 filed by Defendant Pfizer (DI 199).
Feb. 17, 2009 Order granting 198 Ex Parte Motion to File Overlength Memorandum in Opposition to Plaintiff's Motion for Discovery Sanctions. Signed by Magistrate Judge Brooke C. Wells on Feb. 17, 2009. (DI 202).
Feb. 17, 2012 Memorandum in Opposition to BYU's Motion to Strike.
Feb. 17, 2012 Reply in Support of Motion for Permission to Provide Designated Documents to Teva Pharmaceuticals That Pfizer Has Labeled as Confidential Under the Protective Order and the following Exhibits: Exhibit 1: News Release, Pfizer Reports Fourth-Quarter and Full-Year 2011 Results; Updates 2012 Financial Guidance, Jan. 21, 2012; News Release, Teva Reports Fourth Quarter and Full-Year 2011 Results, Feb. 15, 2012 Exhibit 6: Expert Reports Filed in Connection with Summary Judgment Motions List.
Feb. 18, 2011 Ex Parte Motion for Leave to File Overlength Memorandum in Support of Plaintiffs' Motion to Compel Production of Invention Disclosure Statements, Draft Patent Applications, Communications with New Monsanto, and Other Documents with accompanying Proposed Order Granting Ex Parte Motion for Leave to File Overlength Memorandum in Support of Plaintiffs' Motion to Compel Production of Invention Disclosure Statements, Draft Patent Applications, Communications with New Monsanto, and Other Documents.
Feb. 18, 2011 Memorandum in Support of Defendants' Motion to Compel Testimony Pursuant to Notice of 30(b)(6) Deposition, with the following exhibits: Ex. 1: Notice of Taking Video Deposition of Brigham Young University Pursuant to Fed. R. Civ. P. 30(b)(6), Feb. 18, 2011 Ex. 2: http://en.wikipedia.org/wiki/Daniel—L.—Simmons ("the Daniel L. Simmons Wiki Page") Ex. 3: http://en.Wikipedia.org/wiki/PTGS2("the COX-2 Wiki Page")Ex. 4: http://en.Wikipedia.org/wiki/COX-2—inhibitor("the COX-2 Inhibitor Wiki Page") Ex. 5: http://en.Wikipedia.org/wiki/COX-3 ("the COX-3 Wiki Page") Ex. 6: Daniel L. Simmons, Creation of Daniel L. Simmons Wiki Page Ex. 7: Daniel L. Simmons, Revisions to the Daniel L. Simmons Wiki Page Ex. 8: PTGS2, Revisions to the COX-2 Wiki Page Ex. 9: Mar. 2010 Revisions to the COX-2 Wiki Page Ex. 10: COX-2 inhibitor, Revisions to the COX-2 Inhibitor Wiki Page Ex. 11: Feb. 16, 2011 Letter from A. Anderson to R. Mulloy Ex. 12: Feb. 17, 2011 Letter from R. Mulloy to A. Anderson.
Feb. 18, 2011 Motion to Compel Immediate Production of Documents and 30(b)(6) Deposition.
Feb. 18, 2011 Notice of Conventional Filing of Memorandum in Support of Motion to Compel Production of Invention Disclosure Statements, Draft Patent Applications, Communications with New Monsanto, and Other Documents.
Feb. 18, 2011 Supplemental Rule 26 Disclosures.
Feb. 2, 2012 Memorandum Decision and Order Denying Motion to Expedite.
Feb. 2, 2012 Memorandum Decision and Order Granting Motion to Expedite.
Feb. 2, 2012 Order Granting Stipulation to Extend Time to File Reply Memorandum.
Feb. 2, 2012 Stipulation to Extend Time to File Reply Memorandum; Proposed Order Granting Stipulation to Extend Time to File Reply Memorandum.
Feb. 20, 2012 Exhibits to Memorandum in Opposition to BYU's Motion to Strike, as follows: Exhibit 1: Memorandum Decision and Order Denying Plaintiff's Motion to Strike and Granting Defendants' Motion for Summary Judgment, Gray v. Gen. Elec. Co., Jun. 3, 2011 Exhibit 2: Reply Memorandum in Support of Defendant's Motion for Summary Judgment, Gray v. Gen. Elec. Co., Jan. 31, 2011 Exhibit 3: Appendices A and B, Gray v. Gen. Elec. Co..
Feb. 2009 Plaintiffs' Proposed, Continued 30(b)(6) Notice of Deposition to Pfizer.
Feb. 22, 2002 Monsanto Press Release. BYU-PFE 001414-1415.
Feb. 22, 2008 Defendant Pfizer's Response and Objections to Plaintiffs' 30(b)(6) Notice of Deposition to Pfizer.
Feb. 22, 2008 Defendants' Notice of Subpoenas for Production of Documents and Things to Fish & Richardson P.C. and Harvard University.
Feb. 22, 2011 Notice of Conventional Filing of Unredacted Version of Plaintiffs' Response to Pfizer's Motion to Compel Production of Documents and Award of Attorney Fees.
Feb. 22, 2011 Response to Pfizer's Motion to Compel Production of Documents and Award of Attorney Fees (Redacted Version), with the following exhibits: Ex. 1: Feb. 26, 2010 Letter to R. Leighton, Pfizer's former counsel, from K. Ricker Ex. 2: Jan. 7, 2011 Letter to B. Hatch from A. Anderson Ex. 3: William Bradshaw Deposition, Oct. 29, 2010 Ex. 4: Mar. 21, 1996 Letter to X. Lu and B. Bradshaw from D. Simmons, Dep. Ex. 608 Ex. 5: Daniel Simmons, Ph.D. Deposition, Apr. 20, 2009 Ex. 6: Merrill Bateman Deposition, Oct. 22, 2010 Ex. 7 Daniel Simmons, Ph.D. Deposition, Apr. 21, 2009, Ex. 8: Oct. 19, 1989 Letter to E. Woolley from D. Simmons, Dep. Ex. 18 Ex. 9: Dec. 11, 1998 Letter to M. Bateman from D. Simmons, Dep. Ex. 19 Ex. 10: Amended and Restated Bylaws of Brigham Young University, Dec. 20, 2002, § 3.03 (Filed Under Seal) Ex. 11: Feb. 28, 2007 Letter to R. O'Malley from L. Beus Ex. 12: Nov. 28, 2007 Letter to L. Schneider from L. R. Williams Ex. 13: Jan. 10, 2008 Letter to L. Schneider f
Feb. 23, 1011 Revised Order Denying Ex Parte Motion for Leave to File Overlength Memorandum in Support of Plaintiffs' Motion to Compel Production of Invention Disclosure Statements, Draft Patent Applications, Communications with New Monsanto, and Other Documents.
Feb. 23, 2011 Order Denying Ex Parte Motion for Leave to File Overlength Memorandum in Support of Plaintiffs' Motion to Compel Production of Invention Disclosure Statements, Draft Patent Applications, Communications with New Monsanto, and Other Documents.
Feb. 23, 2011 Request for Status and Scheduling Conference.
Feb. 24, 2009 Memorandum in Opposition re 194 Motion for Suspension of Reissue Proceedings filed by Defendant Pfizer (DI 204).
Feb. 24, 2009 Notice of Conventional Filing Under Seal of Reply Memorandum and Exhibits in Support of BYU and Dr. Simmons's Motion for Discovery Sanctions filed by Plaintiffs Brigham Young University, Daniel L. Simmons re 179 (DI 205).
Feb. 24, 2009 Reply to Response to Motion re 172 Motion to Amend/Correct for Leave From and Modification to the Protective Order filed by Defendant Pfizer (DI 203).
Feb. 24, 2011 Motion for Leave to File Overlength Memorandum Responding to Pfizer's Motion to Compel Production of Documents and Award Attorney's Fees with [Proposed] Order Granting Motion for Leave to File Overlength Memorandum Responding to Pfizer's Motion to Compel Production of Documents and Award Attorney's Fees.
Feb. 24, 2012 Memorandum in Support of Pfizer's Motion to Correct Memorandum in Opposition to BYU's Motion for Partial Summary Judgment Regarding Defendants' (Alleged) Breach of Paragraph 4.1 of the Research Agreement and the following Exhibit: Exhibit C: Index to the Memorandum in Opposition to BYU's Motion to Partial Summary Judgment Regarding Defendant's (Alleged) Breach of Paragraph 4.1 of the Reasearch Agreement.
Feb. 24, 2012 Motion for Leave to File Overlength Brief.
Feb. 24, 2012 Notice of Conventional Filing : Exhibits A and B to Memorandum in Support of Pfizer's Motion to Correct Memorandum in Opposition to BYU's Motion for Partial Summary Judgment Re: Defendants' (Alleged) Breach of Paragraph 4,1 of the Research Agreement.
Feb. 24, 2012 Notice of Conventional Filing of Exhibits to BYU's Reply in Support of Motion for Further Sanctions.
Feb. 24, 2012 Notice of Supplemental Authority and the following Exhibits: Exhibit 1: Falana v. Kent State Univ., 2012 U.S App, Lexis 1245 (Jan. 23. 2012) Exhibit 2: Bard Peripheral Vascular Inc. v. C.R. Bard, Inc.,, 2012 U.S. App. Lexis 2612 (Feb. 10, 2012).
Feb. 24, 2012 Pfizer's Motion to Correct Memorandum in Opposition of BYU's Motion for Partial Summary Judgment Regarding Defendants' (Alleged) Breach of Paragraph 4.1 of the Research Agreement: [Proposed] Order Granting Pfizer's Motion to Correct Memorandum in Opposition to BYU's Motion for Partial Summary Judgment Regarding Defendants' (Alleged) Breach of Paragraph 4.1 of the Reasearch Agreement.
Feb. 24, 2012 Reply in Support of Motion for Further Sanctions; Fact Appendix.
Feb. 25, 2008 Plaintiffs' Notice of Subpoenas for Production of Documents and Things to Jaime L. Masferrer, Karen Seibert, Amiram Raz and Peter C. Isakson.
Feb. 25, 2011 Notice of Conventional Filing of Memorandum in Support of Motion to Compel Production of Invention Disclosure Statements, Draft Patent Applications, Communications with New Monsanto, and Other Documents.
Feb. 26, 2009 Amended Notice of Hearing on Motion re: 179 Motion for Sanctions (Discovery) (Notice generated by chambers) Motion Hearing set for Mar. 20, 2009 09:30 AM in Room 230 before Magistrate Judge Brooke C. Wells. (DI 208).
Feb. 27, 2008 Plaintiffs' Third Set of Interrogatories to Defendant Pfizer, Inc.
Feb. 28, 2011 Order Granting Motion for Leave to File Overlength Memorandum Responding to Pfizer's Motion to Compel Production of Documents and Award Attorneys' Fees.
Feb. 29, 2012 Letter to Hon. Stewart from J. Jardine that BYU will narrow its claim to three patents for correction of inventorship.
Feb. 3, 2009 Notice of Filing of Official Transcript of Proceedings held on Jan. 30, 2009 before Judge Brooke C. Wells. Court Reporter/Transcriber Karen Murakami, CSR, RPR, Telephone No. 801-328-4800. (DI 188).
Feb. 3, 2011 Amended Subpoena for the Rule 30(b)(6) Deposition of the Monsanto Company.
Feb. 4, 1999 Industry Report from Salomon Smith Barney (BYU-PFE241790-BYU-PFE241820).
Feb. 4, 2008 Letter from L. Schneider to L.R. Williams.
Feb. 4, 2009 Defendants' Amended Notice of Taking Video Deposition of Gary Evett, Ph.D.
Feb. 4, 2009 Defendants' Amended Notice of Taking Video Deposition of Jeffrey G. Chipman, M.D.
Feb. 4, 2011 Amended Notice of Taking Video Deposition of Brigham Young University Pursuant to Fed. R. Civ. P. 30(b)(6).
Feb. 5, 2010 Order granting Motion for Extension of Time.
Feb. 8, 2011 Reply Memorandum in Support of Defendants' Motion to Strike Portions of Plaintiffs' Response in Opposition to Motion for Partial Summary Judgment, with the following exhibit: Ex. A: Jan. 28, 2011 Letter to Mr. Anderson from Ms. Owen.
Feb. 9, 2009 Memorandum in Opposition re 172 Motion to Amend/Correct for Leave From and Modification to the Protective Order filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibits 1-2) (DI 196).
Feb. 9, 2009 Memorandum in Support re 194 Motion for Suspension of Reissue Proceedings filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibits 1-2) (DI195).
Feb. 9, 2009 Motion for Suspension of Reissue Proceedings filed by Plaintiffs Brigham Young University, Daniel L. Simmons. Motions referred to Brooke C. Wells. (DI 194).
Feb. 9, 2009 Notice of Conventional Filing of Under Seal Exhibit 89 filed by Plaintiffs Brigham Young University, Daniel L. Simmons re 191 (DI 192).
Feb. 9, 2009 Notice of Errata by Brigham Young University, Daniel L. Simmons re 178 (Amended Exhibit List, Exhibits 10,13, 32, 33, 96, 104, 112, 127A, 129) (DI 191).
Feb. 9, 2009 Notice of Report to Court by Brigham Young University, Daniel L. Simmons (Exhibits 1-5) (DI 193).
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Index of marketing and financial documents from the Searle production.
Index of of Documents Cited in BYU's Supplemental Response to Interrogatory No. 4.
Isakson et al., "Discovery of a Better Aspirin." Advances in Prostaglandin, Thromboxane, and Leukotriene Research, 1995, pp. 49-5 4, vol. 23.
James Gierse Dec. 2, 2009 30(b)(6) deposition transcript.
Jan. 11, 2008 Plaintiffs' Second Set of Interrogatories to Defendant Pfizer, Inc.
Jan. 11, 2012 Order and Memorandum Decision Denying Defendants' Expedited Motion to Strike Plaintiffs' Amended Memorandum in Support of Renewed Motion for Further Discovery Sanctions.
Jan. 12, 2007 Plaintiffs' First Request for Production of Documents.
Jan. 12, 2011 Notice of Taking Video Deposition of Brigham Young University Pursuant to Fed. R. Civ. P. 30(b)(6).
Jan. 14, 2009 BYU and Dr. Simmon's Motion for Discovery Sanctions (DI179).
Jan. 14, 2009 Exhibits 1, 3-5, 9-16, 20-34, 37-47, 52-58, 63-64, 66-68, 73, 76, 82, 88, 90, 95-99, 102-106, 109, 112-116, 120, 122-131 re 178 Response to Pfizer's Third Supplemental Certification Regarding Discovery Efforts and Memorandum in Support of Motion for Discovery Sanctions filed by Plaintiffs (DI 181).
Jan. 14, 2009 Notice of Conventional Filing of Under Seal Exhibits 2, 6-8, 17-19, 35, 48-51, 59-62, 69-72, 74-75, 77-81, 83-87, 89, 91-94, 100, 101, 107-108, 110, 111, 117-119 and 121 BYU and Dr. Simmons's Response to Pfizer's Third Supplemental Certification Regarding Discovery Efforts and Memorandum in Support of Motion for Discovery Sanctions for Plaintiffs re 178) (DI 180).
Jan. 14, 2009 Plaintiffs' BYU and Dr. Simmons' Response re Pfizer's Third Supplemental Certification Regarding Discovery Efforts and Memorandum in Support of Motion for Discovery Sanctions Redacted Version (DI 178).
Jan. 14, 2011 Notice of Conventional Filing of Memorandum in Support of Defendants' Motion to Strike Portions of Plaintiff's Response in Opposition to Motion for Partial Summary Judgement.
Jan. 14, 2011 Notice of Conventional Filing of Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment on Counts I-III and V-X of the First Amended Complaint on Statute of Limitations Grounds.
Jan. 16, 2009 Notice of Taking Video Deposition of Lynn Astle, Ph.D.
Jan. 19, 2011 Motion For Admission Pro Hac Vice and Consent of Local Counsel (G. Robert Blakey) with the following Exhibits: Ex. A: Application for Admission Pro Hac Vice Ex. B: [Proposed] Order for Pro Hac Vice Admission.
Jan. 19, 2011 Notice of Conventional Filing of Defendants' Memorandum of Point and Authorities in Support of Motion to Compel Production of Documents and Award of Attorneys' Fees.
Jan. 19, 2011 Subpoena for the Deposition of Frank A. Fitzpatrick, Ph.D.
Jan. 19, 2011 Subpoena for the Deposition of Lawrence J. Marnett.
Jan. 21, 2010: Exhibits 4-22 of Defendants Memorandum in Support of Motion for a Hearing to Amend the Discovery Plan.
Jan. 21, 2011 Notice of Taking Video Deposition of Dave Thomas.
Jan. 21, 2011 Notice of Taking Video Deposition of Dr. Daniel L. Simmons.
Jan. 21, 2011 Notice of Taking Video Deposition of Steve Castle.
Jan. 22, 2009 Amended Notice of Hearing on Motion re: 113 Defendant's Motion for Extension of Time to comply with the Court's Mar. 26, 2008 Order Granting BYU's Motion to Compel Immediate Production of Documents, 179 Motion for Sanctions (Discovery): (Notice generated by chambers) Motion Hearing set for Feb. 27, 2009 01:30 PM in Room 436 before Magistrate Judge Brooke C. Wells (DI 183).
Jan. 22, 2009 Order Continuing Hearing Set for Jan. 29, 2009 and Amended Notice of Hearing. Status Conference set for Feb. 27, 2009 01:30 PM in Room 436 before Magistrate Judge Brooke C. Wells. Signed by Magistrate Judge Brooke C. Wells on Jan. 22, 2009 (DI 182).
Jan. 24, 2012 Bringham Young University and Daniel L. Simmons's Reply in Support of Motion for Patial Summary Judgment Regarding Defendants' Breach of Paragraph 4.1 of the Research Agreement and the following exibits: Exhibit A: Declaration of Randy Bell, Jan. 23, 2012 Exhibit B: P. O'Brien Dep., Dec. 18, 2009 Exhibit C: J. Mancini Dep., Nov. 7, 2011 Exhibit D: L. Astle Dep., Feb. 17, 2009 Exhibit E: M. Orme Dep., Nov. 15, 2007 Exhibit F: D. Simmons Dep., Apr. 20, 2009 Exhibit G: T. Hla Dep., Sep. 12, 2011 Exhibit H: D. Callewaert, Oct. 19, 2011 Exhibit I: K. Ricker, Jun. 2, 2011.
Jan. 24, 2012 Notice of Conventional Filing: Defendants' Memorandum in Opposition to BYU's Renewed Motion for Further Discovery Sanctions.
Jan. 24, 2012 Notice of Conventional Filing: Exhibits to Defendants' Memorandum in Opposition to BYU's Renewed Motion for Further Discovery Sanctions.
Jan. 24, 2012 Notice of Conventional Filing: Reply Memorandu in Support of Motion for Partial Summary Judgment on Plaintiffs' Claim That Defendants Have Misappropriated "Project" and "Compilation" Trade Secrets (Count VIII of the First Amended Complaint)(Defendant's Motion No. 6).
Jan. 24, 2012 Notice of Conventional Filling: Reply Memorandum in Support of Motion for Partial Summary Judgment on Plaintiffs' Claim for Correction of Inventorship (Count IV of the First Amended Complaint) (Defendants' Motion No. 5).
Jan. 24, 2012 Plaintiffs' Reply Memorandum in Support of Motion for Partial Summary Judgment Concerning Defendants' Twenty-Eighth and Twenty-Ninth Defenses.
Jan. 24, 2012 Reply in Support of Motion for Partial Summary Judgment Re: Mitigation of Damages and Failure to Patent.
Jan. 24, 2012 Reply Memorandum in Further Support of Defendants' Motion for Partial Summary judgment Dismissing Plaintiffs' Claims for Breach of Paragraph 1.6 of the Research Agreement (Defendants' Motion No. 11) Attachment 1 to Reply Memorandum in Further Support of Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Paragraph 1.6 of the Research Agreement (Defendants' Motion No. 11).
Jan. 24, 2012 Reply Memorandum in Further Support of Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Paragraph 3.1 of the Research Agreement (Defendants' Motion No. 12) Attachment 1 to Reply Memorandum in Further Support of Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Paragraph 3.1 of the Research Agreement (Defendants' Motion No. 12).
Jan. 24, 2012 Reply Memorandum in Further Support of Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims, for Breach of Paragraphs 1.3, 3.4, 3.5 and 3.7 of the research Agreement (Defendants' Motion No. 1) Attachment 1 to Reply Memorandum in Further Support of Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Paragraphs 1.3, 3.4, 3.5 and 3.7 of the Research Agreement (Defendants' Motion No. 1).
Jan. 24, 2012 Reply Memorandum in Further Support of Motion for Partial Summary Judgment on Exclusions from "Project" (Defendants' Motion No. 2) Attachment 1 to Reply Memorandum in Further Support of Motion for Partial Summary Judgment on Exclusions From "Project" (Defendants' Motion No. 2).
Jan. 24, 2012 Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment on: Count II—Implied Covenant of Good Faith and Fair Dealing, Count III—Fiduciary Duty, Count V—Unjust Enrichment, Count VI—Fraud, and Count VII—Negligent Misrepresentation, of Plaintiffs' First Amended Complaint (Defendants' Motion No. 13).
Jan. 24, 2012 Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Re: Ownership of the Cox-2 Materials (Defendants' Motion No. 10) Attachment 1 to Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Re: Ownership of the Cox-2 Materials (Defendants' Motion No. 10).
Jan. 24, 2012 Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Paragraph 3.3 of the Research Agreement (Defendants' Motion No. 3) Attachment 1 to Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Paragraph 3.3 of the Research Agreement (Defendants' Motion No. 3).
Jan. 24, 2012 Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Plaintiffs' COX-1 Trade Secret Claims (Defendants' Motion No. 7) Attachment to Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Plaintiffs' COX-1 Trade Secret Claims (Defendants' Motion No. 7).
Jan. 24, 2012 Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment That BYU's Alleged "Two-Cell Assay" Trade Secret Has Been Licensed to Defendants (Defendants' motion No. 8) Attachment to Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment that BYU's Alleged "Two-Cell Assay" Trade Secret Has Been Licensed to Defendants (Defendants' Motion No. 8).
Jan. 24, 2012 Reply Memorandum in Support of Defendants' Motion to Dismiss for Lack of Standing (Defendants' Motion No. 9).
Jan. 24, 2012 Reply Memorandum in Support of Plaintiffs' Motion Partial Summary Judgment to Discuss Defendants' Thirty-Second defense with Prejudice.
Jan. 24, 2012 Response to Pfizer's Objections to the Use of BYU's Expert Reports and the following exhibits: Exhibit 1: R. Bell Dep., Sep. 29, 2011 Exhibit 2: S. Prescott Dep., Oct. 25, 2011 Exhibit 3: R. Gering Dep., Oct. 6, 2011 Exhibit 4: E. Lentz Dep., Sep. 22, 2011.
Jan. 25, 2007 Defendants' Initial Disclosures.
Jan. 26, 2007 Plaintiffs' Initial Rule 26(a)(1) Disclosure Statement to Defendants.
Jan. 26, 2009 Order granting 184 Motion for Extension of Time to File Response/Reply re 172 Motion to Amend/Correct for Leave From and Modification to the Protective Order: Response due by Feb. 9, 2009. Signed by Magistrate Judge Brooke C. Wells on Jan. 26, 2009 (DI 185).
Jan. 26, 2009 Stipulated Motion for Extension of Times to File Response/Reply as to 172 Motion to Amend/Correct for Leave From and Modification to the Protective Order for Plaintiff (Attachments: Text of Proposed Order) (DI 184).
Jan. 26, 2011 Subpoena for the Deposition of Elizabeth Harding.
Jan. 26, 2011 Subpoena for the Deposition of Morris Robins.
Jan. 27, 1991 Department of Health and Human Services Public Health Service, Grant Application Re: Prostaglandin Synthase's Role in Transformation by v-src, submitted by Simmons BYU-12-1087-1119.
Jan. 27, 2011 Response to Defendants' Opposition to Plaintiffs' Motion for Admission Pro Hac Vice of G. Robert Blakey.
Jan. 28, 2009 Motion for Extension of Time to File Response/Reply as to 179 Motion for Discovery Sanctions (Exhibits A-B) (DI 186).
Jan. 29, 2008 Plaintiffs' Fourth Request for Production of Documents.
Jan. 3, 2012 BYU's Respnse in Opposition to Pfizer's Motion to Strike Plaintiffs' Amended Memorandum Support of Renewed Motion for Further Discovery Sanctions.
Jan. 30, 2009 Minute Order. Proceedings held before Magistrate Judge Brooke C. Wells: Motion Hearing held on Jan. 30, 2009 as to 161 Motion to Compel Production of Documents filed by Defendants and 186 Motion for Extension of Time to File Response/Reply as to 179 Motion for Sanctions (Discovery) for Pfizer. The Court hears oral argument taking under advisement 161 Motion to Compel—journals will be received by the Court for in camera review; granting 186 Motion for Extension of Time to File Response/Reply re 179 Motion for Sanctions (Discovery). Defendant will have until Feb. 16, 2009 to Reply to sanctions motion. (DI 187).
Jan. 31, 2011 Order for Pro Hac Vice Admission of G. Robert Blakey.
Jan. 31, 2012 Letter to Honorable Stewart from J. Jardine explaining urgency of expediting BYU's motion for permission to provide designated documents to Teva Pharmaceuticals (filed Feb. 2, 2012).
Jan. 31, 2012 Memorandum in Support of Motion for Permission to Provide Designated Documents to Teva Pharmaceuticals That Pfizer has Labeled as Confidential Under the Protective Order, and the following Exhibits: Exhibit 1: Agreement between Teva Pharmaceuticals USA, Inc. and Brigham Young University, Jan. 23, 2012 Exhibit 2: Affidavit of Patricia Marsh O'Brien, C.D. Searle & Co. v. NovoPharm Limited, Oct. 3, 2005 Exhibit 3: Oct. 22, 2007 Letter to L.R. Williams from L. Schneider.
Jan. 31, 2012 Memorandum in Support of Motion to Expedite Consideration of BYU's Motion for Permission to Provide Certain Documents to Teva Pharmaceuticals.
Jan. 31, 2012 Motion for Permission to Provide Certain Documents to Teva Pharmaceuticals That Pfizer Has Labeled as Confidential Under the Protective Order.
Jan. 31, 2012 Motion to Expedite Consideration of BYU's Motion for Permission to Provide Certain Documents to Teva Pharmaceuticals; Proposed Order Granting Motion to Expedite Consideration of BYU's Motion for Permission to Provide Certain Documents to Teva Pharmaceuticals.
Jan. 5, 2011 Amended Notice of Taking Video Deposition of Gary Hooper.
Jan. 5, 2011 Amended Notice of Taking Video Deposition of J. Bevan Ott.
Jan. 5, 2011 Amended Notice of Taking Video Deposition of Morris Robins.
Jan. 6, 2012 Reply Memorandum in Support of Defendants' Expedited Morion to Strike Plaintiffs' Amended Memorandom in Support of Renewed Morion for Further Discovery Sanctions.
Jan. 7, 2009 Defendant Pfizer's Motion for Leave from Protective Order DI 172.
Jan. 7, 2011 Notice of Taking Video Deposition of Gwen G. Krivi.
Jan. 7, 2011 Subpoena for the Deposition of Gwen G. Krivi.
Jan. 8, 2007 Defendants' First Request for Production of Documents.
Jan. 8, 2007 Defendants' First Set of Interrogatories.
Journal of Neurochemistry, "Evidence for Two Distinct Forms of Fatty Acid Cyclooxygenase in Brain" T. Lysz & P. Needleman vol. 38, p. 1112 dated Nov. 4, 1982.
Jul. 12, 2007 Plaintiffs' Supplemental Response to Defendants' Interrogatory No. 8.
Jul. 12, 2011 Notice of Appearance of James S. Jardine.
Jul. 13, 2011 Order Reagrding Additional Documents Submitted by Defendants for In-Camera review.
Jul. 14, 2009 letter from Joseph M. Reisman to Bryan C. Zielinski.
Jul. 14, 2011 Memorandum Decision and order Granting in Part Defendants' Motion to Compel Documents Submitted for In-Camera Review.
Jul. 16, 1991 Simmons Fax transmission sheets to Seibert BYU-14-1832-1834.
Jul. 21, 2008 Discovery Stipulation between Plaintiffs and Teva Pharmaceuticals USA, Inc.
Jul. 22, 2011 Motion and Consent of Sponsoring Local counsel for Pro Hac Vice Admission of Britton M. Worthen; Proposed Order and the following exhibits: Exhibit A: Certificate of Good Standing Exhibit B: Application for Admission Pro Hac Vice Exhibit C: Electronic Case Filing Registration Form:
Jul. 25, 2007 Plaintiffs' Request for Admission to Defendant Pfizer, Inc.
Jul. 26, 2006 Surrebuttal Expert Report of Guenter Trummlitz, Ph.D.
Jul. 26, 2011 Order for Pro Hac Vice Admission of Britton M. Worthen.
Jul. 26, 2011 Response in Opposition to Defendants' Motion to Strike Portions of Plaintiffs' Statement of Material Facts in Opposition to Defendants' Motion for Partial Summary Judgement on Paragraph 3.3 of the Research Aggreement.
Jul. 26, 2011 Response in Opposition to Defendants' Motion to Strike Portions of Plantiffs' Statement of Material Facts in Opposition to Defendants' Motion for Partial Summary Judgement on Paragraphs 3.3 and 3.4 of the Research Agreement.
Jul. 27, 2006 Surrebuttal Expert Report of Raymond Baker, Ph.D.
Jul. 28, 2009 letter from Scott A. Williams to Joseph M. Reisman.
Jul. 3, 1991 Letter from L.R. Swaney to L. Astle BYU-12-0210.
Jul. 5, 2011 Order Granting Stipulated Motion for Extension of Time to File Reply Memoranda in Support of Defendants' Motions for Summary Judgment.
Jul. 5, 2011 Stipulated Motion for Extension of Time to File Reply Memoranda in Support of Defendants' Motion for Summary Judgment and the following Exhibit: Exhibit A: Proposed Order.
Jul. 7, 2088 Letter from L. Schneider to M. Bettilyon.
Jul. 8, 2011 Memorandum in Support of Motion to Strike Portions of Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment Re: Paragraph 3.3 of the Research Agreement.
Jul. 8, 2011 Memorandum in Support of Motion to Strike Portions of Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment Regarding Breach of Contract of Paragraphs 3.3 and 3.4 of the Research Agreement.
Jul. 8, 2011 Motion to Strike Portions of Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment Re: Paragraph 3.3 of the Research Agreement.
Jul. 8, 2011 Motion to Strike Portions of Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment Regarding Breach of Contract of Paragraphs 3.3 and 3.4 of the Research Agreement.
Jul. 8, 2011 Reply Memorandum in Support of Defendants' Motion for Summary Judgment Regarding Paragraph 3.3 of the Research Agreement; Attachment 1 to Reply Memorandum in Support of Defendants' Motion for Summary Judgment Regarding Paragraph 3.3 of the Research Agreement Ex. A: Stephen Craig Dep. Tr., May 24, 2011 Ex. C: May 21, 1991 Letter to Dr. Simmons from Ms. Swaney Ex. D: Lynn Astle Dep. Tr., Feb. 17, 2009 Ex. E: Daniel Simmons Dep Tr., Jun. 20, 2009.
Jul. 8, 2011 Reply Memorandum in Support of Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Contract of Paragraphs 3.3 and 3.4 of the Research Agreement; Attachment 1 to Reply Memorandum in Support of Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Contract of Paragraphs 3.3 and 3.4 of the Research Agreement Ex. A: Stephen Craig Dep. Tr., May 24, 2011 Ex. B: May 6, 1991 Letter. to Dr. Needleman from Dr. Simmons.
Jun. 1, 2009 BYU's Opposition to Pfizer's Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 (Redacted) (DI 252).
Jun. 1, 2009 Declaration of Dr. Daniel L. Simmons re 252 Memorandum in Opposition to Motion, filed by Brigham Young University, Daniel L. Simmons. (DI 254).
Jun. 1, 2009 Notice of Conventional Filing Under Seal of Exhibits 1-77 to BYU Opposition to Pfizer Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 filed by Plaintiffs Brigham Young University, Daniel L. Simmons re 252 Memorandum in Opposition to Motion (DI 253).
Jun. 1, 2009 Plaintiff's (Alternative) Rule 56(f) Motion Opposing Defendants' Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 (DI 255).
Jun. 1, 2009 Plaintiff's Memorandum in Support of their (Alternative) Rule 56(f) Motion Opposing Defendants' Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 Redacted Version (DI 256).
Jun. 1, 2009 Rule 56(f) Affidavit of L. Richard Williams in Support of (Alternative) Rule 56(f) Motion Opposing Defendants' Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 (DI 257).
Jun. 10, 1991 Seibert Fax to Simmons BYU-08-0818-822.
Jun. 10, 2008 Deposition of Kathy Owen, Exhibits 37 (37-1 to 37-27) [37-7A to 37-7KK])-39; 44-46, 49-50.
Jun. 10, 2008 Deposition Ofscott Hauser, Exhibits 21, 22 (22A-Z; 22CC-KK), 23 (23A-23B), 24, 26, 30, 35, 36.
Jun. 11, 2008 Plaintiffs' Response to Defendants' First Set of Requests for Admission to Plaintiff Brigham Young University.
Jun. 11, 2008 Plaintiffs' Response to Defendants' First Set of Requests for Admission to Plaintiff Dr. Daniel L. Simmons.
Jun. 11, 2010 Order granting in part plaintiffs' motion for extension of time.
Jun. 12, 2008 Plaintiffs' Response to Defendants' Third Request for Production of Documents.
Jun. 14, 2010 Order granting in part plaintiffs' motion for extension of time to Amend complaint.
Jun. 15, 2010 deposition transcript of Steven Fleming.
Jun. 17, 2011 Notice of Conventional Filing of Exhibits Filed Under Seal to Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment on Plaintiffs' Claims for Breach of Paragraphs 3,3 and 3.4 of the Research Agreement as to the following exhibits: Ex. 6: Jan. 11, 1991 letter to Seibert and Masferrer from Needleman re working group Ex. 8: Jaime Masferrer Deposition, Merck Frosst litigation, Dec. 12, 2000 Ex. 17: JaimeMasferrer Deposition Teva litigation, Dec. 13, 2005 Ex. 18: Karen Seibert Deposition, Merck Frosst litigation, Oct. 17, 2000 Ex. 19: Karen Seibert Deposition, vol. 2, Jun. 2, 2010 Ex. 20: Karen Seibert Deposition, vol. 1, Jun. 1, 2010 Ex. 27: Prescott Expert Report, Feb. 18, 2011 Ex. 46: Karen Seibert Deposition, Teva litigation, Jan. 11, 2006 Ex. 47: Feb. 6, 1992 Email to D. Corley, et al. from K. Leahy Ex. 48: Len Lee notebook #21, Feb. 14, 1992 Ex. 49: Jaime Masferrer notebook 5,043,201, Feb. 5, 1992 Ex. 50: Disclosure of Invention—Lee, Jun. 24, 1992 Ex.
Jun. 17, 2011 Notice of Conventional Filing of Exhibits Filed Under Seal to Plaintiffs' Opposition to Defendants' Motion for Partial Summary Judgment re Paragraph 3.3 of the Research Agreement as to the following exhibits: Ex. 1: John Morris Expert Report, Feb. 18, 2011 Ex. 5: Needleman Univ. of Rochester deposition transcript excerpt, Aug. 9, 2002 Ex. 6: Needleman BYU v. Pfizer deposition transcript excerpt, Nov. 17, 2010 Ex. 9: Simmons' Amended and Supplemental Expert Report—Jun. 10, 2011 Ex. 11: Vern Norviel Expert Report, Feb. 18, 2011 Ex. 12: Prescott Expert Report, Feb. 18, 2011 Ex. 14: Declaration of John Talley, Apr. 9, 2002 Ex. 15: First Witness Statement of William Galbraith, Aug. 23, 1999 Ex. 16: Edward Lentz Expert Report, Feb. 18, 2011.
Jun. 2, 2009 Notice of Conventional Filing Under Seal of (1) BYU's Opposition to Pfizer's Motion for Summary Judgment for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991, and (2) Plaintiffs' Memorandum in Support of Their Alternative Rule 56(f) Motion Opposing Defendants' Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, dated Aug. 1, 1991 filed by Plaintiffs Brigham Young University, Daniel L. Simmons re 252 Memorandum in Opposition to Motion, 256 Memorandum in Support of Motion (DI 258).
Jun. 2, 2010 Reply in support of Plaintiffs' motion to extend trial date.
Jun. 21, 2010 Subpoena Served Upon Shaukat Rangwala.
Jun. 23, 2006 Expert Report of Dr. Karen Seibert.
Jun. 23, 2006 Expert Report of Dr. Peter H. Rheinstein.
Jun. 23, 2006 Expert Report of Dr. Randall M. Zusman.
Jun. 23, 2006 Expert Report of Dr. William L. Jorgensen.
Jun. 23, 2006 Expert Report of James W. McGinity, Ph.D.
Jun. 23, 2006 Expert Report of Mark J. Iannini, M.D., M.P.H.
Jun. 23, 2006 Expert Report of Thomas G. wiseman, Esq.
Jun. 23, 2006 Expert Report of Timothy Cragin Wang, M.D.
Jun. 23, 2006 rebuttal Expert Report of Dr. Henry G. Grabowski.
Jun. 23, 2006 Rebuttal Expert Report of Dr. Michael Wolfe.
Jun. 23, 2006 Rebuttal Expert Report of Dr. William Galbraith.
Jun. 23, 2006 Rebuttal Expert Report of George C. Fuller, Ph.D.
Jun. 23, 2006 Rebuttal Expert Report of Guenter Trummlitz, Ph.D.
Jun. 23, 2006 Rebuttal Expert Report of Raymond Baker, Ph.D.
Jun. 23, 2006 Rebuttal Report of Dr. Simon Helfgott.
Jun. 23, 2006 Rebuttal Report of Keith B. Leffler.
Jun. 23, 2006 Rebuttal Report of Ronald H. Smith.
Jun. 23, 2006 Second Supplement to Expert Report of William B. Schultz and Rebuttal.
Jun. 23, 2011 Memorandum Decision and Order Granting in Part Plaintiffs' Motion to Compel Documents Submitted for in Camera Review.
Jun. 24, 2010 Order granting defendants' motions in part.
Jun. 27, 2008 Plaintiffs' Supplemental Response to Defendants' Interrogatory No. 4.
Jun. 30, 2011 Memorandum Decision and Order Denying Plaintiffs' Request Regarding Materials and Deeming Moot Defendants' Motion to Strike.
Jun. 4, 2008 Defendants' Response to Plaintiffs' Fifth Requests for Production of Documents.
Jun. 4, 2008 Plaintiffs' Amended Rule 30(b)(6) Deposition Required by the Court of Pfizer, Inc.
Jun. 5, 2007 Defendant Pfizer Inc.'s Response to Plaintiffs' First Set of Interrogatories.
Jun. 7, 2011 Stipulated Motion for Extension of Time for Plaintiffs to respond to Defendants' Motions for Partial Summary Judgment Attachment: Proposed Order.
Jun. 8, 2011 Order granting Stipulated Motion for Extension of Time for Plaintiffs to respond to Defendants' Motions for Partial Summary Judgment.
Jun. 8, 2011 Reply Memorandum in Support of Motion to Strike Plaintiffs' May 16, 2011 Supplemental Memorandum Regarding Biological Materials.
Klose et al. Nichtsteroidale Entzündungshemmer. 13(1). Bis-(4-methoxy phenyl)-2-arylthiopyrimidine. Journal of Heterocyclic Chem. 1982, 1165-1167, V19, No. 4.
Leblanc et al, Synthesis & Biological Eval. of 2,3-diarylthiophenes as Select. COX-2 & COX-1 Inhibitors. Bioorganic & Medicinal Chemistry Letters, 1995, pp. 2123-2128; vol. 5; no.
Letter from A. Anderson to I. Schneider dated Jun. 11, 2007.
Letter from A. Anderson to L. Schneider dated Jul. 16, 2007 attaching spreadsheets.
Letter from A. Anderson to L. Schneider dated Jul. 16, 2007.
Letter from A. Anderson to L.R. Williams dated Oct. 3, 2007.
Letter from D. Hoscheit to E. Bramhall dated Mar. 17, 2000 (BYU-01-1426).
Letter from D. Hoscheit to E. Bramhall dated Mar. 17, 2000 (BYU-PFE 002960- BYU-PFE 002964).
Letter from D.B. Dewey to L. Schneider dated Jan. 3, 2008 (BYU-PFE 141486).
Letter from D.B. Dewey to L. Schneider dated Mar. 26, 2008.
Letter from E. Coates to A. Anderson dated May 14, 2009.
Letter from E. Coates to K. Ricker dated Feb. 19, 2009.
Letter from E. Coates to K. Ricker dated Jul. 17, 2008.
Letter from E. Coates to K. Ricker dated Mar. 18, 2008.
Letter from G. Haley to M. Bettilyon dated Feb. 9, 2009.
Letter from G. Haley to M. Bettilyon dated Jan. 29, 2009.
Letter from G. Haley to M. Bettilyon dated Mar. 10, 2009.
Letter from I. Schneider to A. Anderson dated Mar. 7, 2007.
Letter from I. Schneider to L.R. Williams dated Aug. 20, 2007.
Letter from I. Schneider to L.R. Williams dated Aug. 29, 2007.
Letter from I. Schneider to L.R. Williams dated Jan. 7, 2008 attaching invoices.
Letter from I. Schneider to L.R. Williams dated Jun. 13, 2007.
Letter from I. Schneider to L.R. Williams dated Nov. 15, 2007.
Letter from I. Schneider to L.R. Williams dated Nov. 8, 2007.
Letter from I. Schneider to L.R. Williams dated Oct. 22, 2007.
Letter from I. Schneider to L.R. Williams dated Oct. 29, 2007.
Letter from I. Schneider to L.R. Williams dated Oct. 3, 2007.
Letter from I. Schneider to L.R. Williams dated Oct. 30, 2007.
Letter from I. Schneider to L.R. Williams dated Sep. 21, 2007.
Letter from J. Spanbauer to K. Ricker dated Jul. 17, 2008.
Letter from J. Spanbauer to K. Ricker dated May 21, 2008.
Letter from J. Spanbauer to M. Bettilyon dated May 20, 2009.
Letter from J. Spanbauer v. K. Ricker dated May 11, 2009.
Letter from K. Ricker to L. Schneider dated Aug. 15, 2008.
Letter from L. Beus to L. Schneider dated Aug. 30, 2007 attaching spreadsheet.
Letter from L. Beus to L. Schneider dated Aug. 30, 2007.
Letter from L. Beus to R. O'Malley dated Jul. 31, 2007.
Letter from L. Beus to R. O'Malley. dated Feb. 28, 2007 enclosing draft of Stipulated Protective Order.
Letter from L. Dobson to L. Schneider dated Jun. 14, 2007.
Letter from L. Schneider to Adam Anderson dated Oct. 10, 2008.
Letter from L. Schneider to L.R. Williams dated Aug. 20, 2007.
Letter from L. Schneider to L.R. Williams dated Feb. 27, 2008.
Letter from L. Schneider to L.R. Williams dated Jan. 16, 2008.
Letter from L. Schneider to L.R. Williams dated Jul. 29, 2008.
Letter from L. Schneider to L.R. Williams dated May 12, 2009.
Letter from L. Schneider to L.R. Williams dated May 16, 2007.
Letter from L. Schneider to L.R. Williams dated Nov. 15, 2007.
Letter from L. Schneider to L.R. Williams dated Nov. 20, 2007.
Letter from L. Schneider to L.R. Williams dated Nov. 8, 2007.
Letter from L. Schneider to L.R. Williams dated Oct. 22, 2007.
Letter from L. Schneider to L.R. Williams dated Oct. 9, 2007.
Letter from L. Schneider to L.R. Williams dated Sep. 21, 2007.
Letter from L. Schneider to L.R. Williams dated Sep. 21, 2008.
Letter from L. Schneider to L.R: Williams dated Oct. 30, 2007.
Letter from L. Schneider to M. Bettilyon dated Apr. 18, 2008.
Letter from L. Schneider to M. Bettilyon dated Apr. 22, 2008 with indexes of production enclosed.
Letter from L. Schneider to M. Bettilyon dated Apr. 22, 2008.
Letter from L. Schneider to M. Bettilyon dated Aug. 12, 2008 and list of specific notebooks searched for or produced in response to Mar. 26, 2008 Order.
Letter from L. Schneider to M. Bettilyon dated Aug. 12, 2008 attaching List of Specific Notebooks Searched for or.
Letter from L. Schneider to M. Bettilyon dated Aug. 19, 2008.
Letter from L. Schneider to M. Bettilyon dated May 27, 2008.
Letter from L. Schneider to M. Bettilyon dated May 5, 2008.
Letter from L. Schneider to M. Bettilyon dated Oct. 22, 2008.
Letter from L. Schneider to M. Bettilyon dated Oct. 29, 2008.
Letter from L. Schneider to M. Bettilyon dated Sep. 4, 2008.
Letter from L. Schneider to Mark Bettilyon dated Aug. 12, 2008.
Letter from L.R Williams to L. Schneider dated Oct. 9, 2007.
Letter from L.R. Williams to I. Schneider dated Jan. 30, 2008.
Letter from L.R. Williams to L. Schneider dated Aug. 16, 2007.
Letter from L.R. Williams to L. Schneider dated Aug. 24, 2007.
Letter from L.R. Williams to L. Schneider dated Aug. 27, 2007.
Letter from L.R. Williams to L. Schneider dated Dec. 21, 2007.
Letter from L.R. Williams to L. Schneider dated Feb. 20, 2008.
Letter from L.R. Williams to L. Schneider dated Jan. 18, 2008.
Letter from L.R. Williams to L. Schneider dated Jan. 24, 2008 enclosing check.
Letter from L.R. Williams to L. Schneider dated Jun. 13, 2007.
Letter from L.R. Williams to L. Schneider dated Mar. 3, 2008.
Letter from L.R. Williams to L. Schneider dated Mar. 9, 2007.
Letter from L.R. Williams to L. Schneider dated Nov. 30, 2007.
Letter from L.R. Williams to L. Schneider dated Nov. 9, 2007.
Letter from L.R. Williams to L. Schneider dated Oct. 25, 2007.
Letter from L.R. Williams to L. Schneider dated Oct. 29, 2007.
Letter from L.R. Williams to L. Schneider dated Oct. 9, 2007.
Letter from L.R. Williams to L. Schneider dated Sep. 27, 2007.
Letter from L.R. Williams to L. Schneider dated Sep. 6, 2007 attaching Monsanto/Searle/Pfizer Notebook Index.
Letter from L.R. Williams to L. Schneider dated Sep. 6, 2007 enclosing Monsanto/Searle/Pfizer Notebook Index prepared by BYU.
Letter from L.R. Williams to L. Schneider dated Sep. 6, 2007.
Letter from L.R. Williams to L. Schneider dated Sep. 7, 2007.
Letter from L.R. Williams to N. Wyland dated Apr. 9, 2008.
Letter from L.R. Williams to N. Wyland dated Jul. 16, 2008.
Letter from L.R. Williams to N. Wyland dated Jun. 26, 2008.
Letter from L.R.Williams to N. Wyland dated May 2, 2008.
Letter from M. Bettilyon to G. Haley dated Mar. 4, 2009.
Letter from M. Bettilyon to G. Haley dated May 15, 2009.
Letter from N, Kopinski to L.R. Williams dated Aug. 12, 2008.
Letter from N. Kopinski to D.B. Dewey dated Jan. 7, 2008.
Letter from N. Kopinski to L.R. Williams dated Aug. 12, 2008.
Letter from N. Kopinski to L.R. Williams dated Aug. 22, 2007.
Letter from N. Kopinski to L.R. Williams dated Aug. 30, 2007 attaching Defendants' Privilege Log.
Letter from N. Kopinski to L.R. Williams dated Feb. 12, 2009 including privilege log.
Letter from N. Kopinski to L.R. Williams dated Feb. 12, 2009 with attached privilege log.
Letter from N. Kopinski to L.R. Williams dated Feb. 7, 2008.
Letter from N. Kopinski to L.R. Williams dated Jan. 23, 2008 enclosing invoices.
Letter from N. Kopinski to L.R. Williams dated Jul. 17, 2007.
Letter from N. Kopinski to L.R. Williams dated Jul. 18, 2008.
Letter from N. Kopinski to L.R. Williams dated Jul. 23, 2008.
Letter from N. Kopinski to L.R. Williams dated Jul. 24, 2008, including privilege log.
Letter from N. Kopinski to L.R. Williams dated Jul. 24, 2008.
Letter from N. Kopinski to L.R. Williams dated Jul. 28, 2008, including privilege log.
Letter from N. Kopinski to L.R. Williams dated May 23, 2008.
Letter from N. Kopinski to L.R. Williams dated Nov. 29, 2007.
Letter from N. Kopinski to L.R. Williams dated Nov. 5, 2007.
Letter from N. Kopinski to L.R. Williams dated Oct. 10, 2008.
Letter from N. Kopinski to L.R..Williams dated Oct. 23, 2007.
Letter from N. Kopinski to M. Bettilyon dated Feb. 4, 2009.
Letter from N. Kopinski to R. Williams dated Aug. 12, 2008.
Letter from N. Kopinski to R. Williams dated Aug. 19, 2008.
Letter from N. Wyland to L. Beus dated Jan. 14, 2008.
Letter from N. Wyland to L.R. Williams dated Apr. 23, 2008.
Letter from N. Wyland to L.R. Williams dated Aug. 26, 2008.
Letter from N. Wyland to L.R. Williams dated Jul. 3, 2008.
Letter from N. Wyland to L.R. Williams dated May 7, 2008.
Letter from T. Hankinson to L.R. Williams dated Aug. 15, 2008.
Letter from T. Hankinson to L.R. Williams dated Jan. 28, 2009.
Letter G. Haley to M. Bettilyon dated Feb. 6, 2009.
Letter L. Schneider to L.R. Williams dated Oct. 22, 2007.
Letter M. Bettilyon to G. Haley dated Feb. 4, 2009.
Letter to Judge Wells dated Aug. 1, 2008.
Lima et al. Current Medicinal Chemistry, 2005, 12, 23-49. *
M. Cocco et al. Il Farmaco-Ed. Sci., 40, 272 (1985).
M. Hashem et al. J. Med. Chem., 19, 229 (1976).
M.S. I. Makki et al. Chem. Abstracts, 121:11 (1994).
Makki;1994; Pyrazole derivatives.PartI.Synthesis and spectra of trisubstituted pyrazoline & pyrazole derivatives w/ possible hypoglycemic acti.;Chem.Abs.;121:11;p. 1023.
Mar. 11, 2009 Defendants' Amended Notice of Taking Video Deposition of Weilin Xie, Ph.D.
Mar. 12, 2009 Motions No Longer Referred: 194 Motion for Suspension of Reissue Proceedings, 172 Motion to Amend/Correct for Leave From and Modification to the Protective Order because these matters will be heard by Judge Kimball.
Mar. 13, 2012 Memorandum Decision and Order on Pfizer's Motions for Partial Summary Judgment Nos. 3 and 11.
Mar. 14, 2012 Pfizer's Supplemental Brief in Support of its Motion for Summary Judgment on Plaintiffs' Claim for Correction of Inventorship (Motion No. 5) and the following: Exhibit 1: Findings of Fact, Conclusions of Law and Order. Falana v. Kent State Univ., 5.08 CV 720 (N.D. Ohio), Dec. 14, 2010 Exhibit 2: U.S. Patent No. 6:803,789B2 (filed Jun. 8, 2001).
Mar. 14, 2012 Supplemental Brief re: Inventorship and the following: Appendix A Exhibit A: Declaration of Randy Bell, Mar. 14, 2012 Exhibit B: Declaration of Edward T. Lentz, Mar. 14, 2012 Exhibit C: Declaration of Rebecca Eisenberg, Mar. 14, 2012 Exhibit D: Plaintiffs' Supplemental Responses to Defendants' First Set of Interrogatories Nos. 1, 2, 9, 11, 13, 20 and 26 and to Defendants' Second Set of Interogatories No. 30. Pfizer Inc. v. Teva Pharms. USA, Inc., No. 04-754 (D.N.J.) Dec. 19, 2005 Exhibit E: Hearing Proceedings, Mar. 9, 2012.
Mar. 16, 2009 Defendant Pfizer Inc.'s Response to Plaintiffs' Sixth Request for Production of Documents.
Mar. 16, 2009 Memorandum in Support re 212 Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics filed by Defendant Pfizer (Exhibits A-L) (DI 213).
Mar. 16, 2009 Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics filed by Defendant Pfizer. (Attachments: Text of Proposed Order) Motions referred to Brooke C. Wells ( DI 212).
Mar. 17, 1992 Needleman Letter and Fax to Simmons BYU-03-0201-202.
Mar. 17, 2008 Plaintiffs' Response to Defendants' Second Request for Production of Documents.
Mar. 17, 2009 Defendants' Notice of Taking Video Deposition of Dr. Daniel L. Simmons.
Mar. 18, 2011 Notice of Status Regarding Plaintiffs' Motion to Compel Production of Sufficient Information to Allow Plaintiffs to Evaluate the Taint from Expert Rzucidlo or, in the Alternative, to Disqualify Defendants' Counsel and the following exhibit: Ex. A: Mar. 8, 2011 Email to B. Hatch from L. Beus regarding resolving the motion to disqualify.
Mar. 2, 2011 Order Re: Briefing Schedule and Striking Current Scheduling Order.
Mar. 2, 2012 Further Response to Pfizer's Objections to Use of BYU's Expert Repots and the following Exhibits: Exhibit 1: Except from R. Bell Deposition dated Sep. 29, 2011 Exhibit 2: Excerpt from D. Davis Deposition dated Sep. 20, 2011 Exhibit 3: Excerpt from J. Dellaria Deposition dated Sep. 28, 2011 Exhibit 4: Excerpt from R. Eisenberg Deposition dated Oct. 18, 2011 Exhibit 5: Excerpt from A. Fellmeth Deposition dated Sep. 13, 2011 Exhibit 6: Excerpt from M. Fraser Deposition dated Oct. 27, 2011 Exhibit 7: Excerpt from R. Gering Deposition dated Oct. 6, 2011 Exhibit 8: Excerpt from E. Lentz Deposition dated Sep. 22, 2011 Exhibit 9: Excerpt from A. Lipman Deposition dated Sep. 19, 2011 Exhibit 10: Excerpt from V. Norviel Deposition dated Oct. 26, 2011 Exhibit 11: Excerpt from S. Prescott Deposition dated Oct. 25, 2011 Exhibit 12: Excerpt from M. Robins Deposition dated Nov. 17, 2011 Exhibit 13: Excerpt from J. Severson Deposition dated Sep. 20, 2011 Exhibit 14: Excerpt from D. Simmon
Mar. 2, 2012 Response to Pfizer's Objections to the Use of BYU Expert Reports and the following Exhibits: Exhibit 1: Excerpt from R. Bell Deposition dated Sep. 29, 2011 Exhibit 2: Excerpt from Declaration of Randy Bell Exhibit 3: Excerpt from S. Prescott Deposition dated Oct. 25, 2011 Exhibit 4: Excerpt from R. Gering Deposotion dated Oct. 6, 2011.
Mar. 20, 2009 Memorandum in Support re 214 Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 filed by Defendant Pfizer. (Exhibits 1, 3-11) (DI 215).
Mar. 20, 2009 Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 filed by Defendant Pfizer. (DI 214).
Mar. 20, 2009 Notice of Conventional Filing Under Seal of Exhibit No. 2 to Defendants' Memorandum in Support of Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991 filed by Defendant Pfizer (DI 216).
Mar. 21, 2008 Dr. Peter Isakson's Objections to Plaintiffs' Mar. 7, 2008 Third-Party Subpoena.
Mar. 22, 2000 Industry Update from JPMorgan (PFC00559933-PFC00559948).
Mar. 23, 1992 Letter to Simmons from Needleman.
Mar. 25, 2011 Memorandum in Support of Defendants' Request for Attorneys' Fees and Costs.
Mar. 25, 2011 Notice of Conventional Filing of Declaration of John C. Dougherty in Support of Defendants' Request for Attorneys' Fees and Costs and Declaration of Brent O. Hatch in Support of Defendants' Request for Attorneys' Fees and Costs.
Mar. 26, 2009 Plaintiffs Motion to Amend/Correct 159 Scheduling Order, filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibits A-B) Motions referred to Brooke C. Wells. (DI 218).
Mar. 3, 2011 Letter to Magistrate Judge Wells from M. Bettilyon.
Mar. 31, 2008 Defendant Pfizer Inc.'s Response to Plaintiffs' Third Set of Interrogatories.
Mar. 4, 2008 Defendants' Response to Plaintiffs' Fourth Request for Production of Documents.
Mar. 4, 2011 Letter to Magistrate Wells from B. Hatch in Response to Letter of M. Bettilyon.
Mar. 4, 2011 Order Re: Conduct Before the Court.
Mar. 5, 2012 Reply in Support of Motion to Strike.
Mar. 6, 2012 Notice of Supplemental Authority and the following Exhibit: Exhibit 1: CDC Restoration & Construction LLC v. Trademen Contractors, LLC, 702 Utah Adv. Rep. 56 (Ut. Ct. App. 2012).
Mar. 7, 2008 Subpoena for Production of Documents and Things served upon Fish & Richardson, P.C. by Defendants.
Mar. 7, 2008 Subpoena for Production of Documents and Things served upon Harvard University by Defendants.
Mar. 7, 2008 Subpoena served upon Dr. Peter C. Isakson by Plaintiffs.
Mar. 7, 2012 Order on Hearing Structure and Pretrial Deadlines.
Mar. 8, 2011 Second Order Re: Briefing Schedule.
Mar. 9, 2009 Notice of Compliance with Court Order by Brigham Young University, Daniel L. Simmons (DI 209).
Mar. 9, 2009 Reply to Response to Motion re 194 Motion for Suspension of Reissue Proceedings filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (DI 210).
Mar. 9, 2009 Second Amended Notice of Hearing on Motion re: 179 Motion for Sanctions (Discovery) (Notice generated by BCW Chambers) Motion Hearing previously set for Mar. 20, 2009 @ 9:30 a.m. has been Reset for Apr. 7, 2009 at 01:30 PM in Room 220 before Magistrate Judge Brooke C. Wells. (jwd) (Entered: Mar. 9, 2009) (DI 211).
Mar. 9, 2011 Memorandum in Support of Plaintiffs' Motion to Compel Production of Sufficient Information to Allow Plaintiffs to Evaluate the Taint from Expert Rzucidlo Or, in the Alternative, to Disqualify Defendants' Counsel and the following exhibits: Ex. 4: Defendants' Identification of Experts Ex. 5: Mar. 2, 2011 BYU V. Pfizer Hearing Transcript Ex. 6: Declaration of Daniel L. Simmons Ex. 7: Declaration of David Thomas Ex. 8: Declaration of Leo R. Beus Ex. 9: Jul. 10, 1999 Consultancy Agreement between Dr. Simmons and Merck Ex. 10: Amended Declaration of Daniel L. Simmons Ex. 12: Declaration of John K. Morris.
Mar. 9, 2012 Memorandum Decision and Order Denying Motion for Permission to Provide Certain Documents Labeled as Confidential Under the Protective Order.
Masferrer et al., "Cyclooxygenase-2 Inhibitors: A New Approach to the Therapy of Ocular Inflammation." Survey of Ophthalmology, 1995, pp. S35-S40, vol. 41, Suppl. 2.
May 1, 1991 Draft Research Agreement between BYU and Monsanto, w/handwritten notes BYU-12-0279-0291.
May 10, 2010 Reply in support of Plaintiffs' motion to set Date to Amend Complaint.
May 10, 2011 Notice of Appearance by Phillip J. Russell.
May 10, 2011 Order Granting Pro Hac Vice Admission to Amy K Wigmore.
May 10, 2011 Order Granting Pro Hac Vice Admission to William F. Lee.
May 11, 2009 Affidavit of Leo R. Beus in Support BYU's Application for Award of Attorneys' Fees and Costs filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibits 1-9) DI 233).
May 11, 2009 Affidavit of Mark M. Bettilyon in Support of BYU's Application for Award of Attorneys' Fees and Costs filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibits 1-8) (DI 232).
May 11, 2009 Notice of Conventional Filing Under Seal of Summary of Affidavits Submitted for in Camera Review Regarding Discovery Efforts and [Proposed] Findings of Fact and Conclusions of Law Regarding BYU's Motion for Discovery Sanctions filed by Defendant Pfizer (DI 231).
May 11, 2009 Proposed Findings of Fact and Conclusions of Law Brief filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (Exhibit 1) Redacted Version ( DI 234).
May 11, 2010 Motion to seal Exhibit 5 to Reply in support of Plaintiffs' motion for Extension of Time Amend Complaint with proposed order.
May 12, 2011 Order from Apr. 7, 2011 Status Conference.
May 14, 2010 Order sealing Exhibit 5 to Reply in support of Plaintiffs' motion for Extension of Time Amend Complaint.
May 15, 2009 BYU's Opposition to Pfizer's Motion to Allow in Camera Submission (Exhibit 1) Redacted Version (DI 238).
May 16, 1991 P. Needleman to D. Simmons re grant mechanism BYU-01-1386.
May 16, 2011 Notice of Conventional Filing of Exhibit 6 to Plaintiffs' Supplemental Memorandum Regarding Biological Materials.
May 18, 2009 Notice of Hearing on Motion re: 218 Plaintiff's Motion to Amend/Correct 159 Scheduling Order, 212 Motion for Protective Order Re Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics Motion for Protective Order Re Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics : (Notice generated by chambers) Motion Hearing set for Jul. 22, 2009 09:30 AM before Magistrate Judge Brooke C. Wells. (DI 239).
May 18, 2010 Notice of Conventional Filing of Plaintiffs' Motion to Extend Trial Date and Exhibits 5 and 6 Thereto.
May 18, 2010 Plaintiff's Motion to Expedite Briefing Schedule.
May 18, 2010 Redacted Plaintiffs' motion to extend trial date.
May 18, 2011 Notice of Conventional Filing of Exhibit 4 to Response to and Motion to Strike Plaintiffs' May 16, 2011 Supplemental Memorandum Regarding Biological Materials.
May 18, 2011 Response to and Motion to Strike Plaintiffs' May 16, 2011 Supplemental Memorandum Regarding Biological Materials and the following exhibits: Ex. 1: Declaration of Michael S. Wigotsky Regarding Plaintiffs' Access to Biological Materials Stored at Lancaster Laboratories, Feb. 8-9, 2011 Ex. 2: May 21, 2008 Letter to Mr. Ricker from Mr. Spanbauer Ex. 3: May 11, 2009 Letter to Mr. Ricker from Mr. Spanbauer Ex. 5: Jun. 1, 2010 Letter to Mr. Williams from Mr. Hankinson Ex. 6: Jun. 11, 2010 Letter to Mr. Williams from Mr. Hankinson Ex. 7: Sep. 28, 2010 Letter to Mr. Anderson from Ms. Owen Ex. 8: Oct. 26, 2010 Letter to Mr. Anderson from Ms. Hamilton Ex. 9: May 11, 2011 Letter to Mr. Ricker from Ms. Owen.
May 2, 2008 Plaintiffs Fifth Requests for Production of Documents to Defendants.
May 20, 2009 Plaintiff's Expedited Motion to Preserve and Produce Evidence of COX-2 Related Documents as Described in J. Michael Warner's Affidavit (Redacted) ( DI 240).
May 20, 2009 Plaintiff's Memorandum in Support of Expedited Motion to Preserve and Produce Evidence of COX-2 Related Documents as Described in J. Michael Warner's Affidavit (Redacted) (Exhibits 1-7) (DI 241).
May 20, 2009 Plaintiffs' Notice of Taking Video Deposition of Curtis Mathis.
May 20, 2009 Plaintiffs' Notice of Taking Video Deposition of Thomas Warren.
May 20, 2010 letter from A. Anderson L. Schneider.
May 21, 1991 Swaney Letter to Simmons BYU-11-2375.
May 21, 1992 Hardman Letter to Needleman BYU-12-0189.
May 21, 2009 Notice of Hearing on Motion re: 218 Plaintiff's Motion to Amend/Correct 159 Scheduling Order ,, 240 Plaintiff's Motion to Compel Preserve and Produce Evidence, 212 Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics : (Notice generated by chambers)Motion Hearing set for Jul. 22, 2009 09:30 AM in Room 436 before Magistrate Judge Brooke C. Wells (DI 242).
May 21, 2010 Memorandum in Opposition to Plaintiff's Motion to Expedite Briefing Schedule and Hearing Concerning Plaintiffs' Motion to Extend Trial Date.
May 23, 2011 Amended Subpoena in a Civil Case to The Monsanto Company.
May 26, 2009 Amended Notice of Hearing on Motion re: 218 Plaintiff's Motion to Amend/Correct 159 Scheduling Order, 212 Motion for Protective Order Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics : (Notice generated by chambers) Motion Hearing set for Jul. 22, 2009 09:30 AM in Room 436 before Magistrate Judge Brooke C. Wells. Plaintiff's Motion to Preserve and Produce Evidence vacated and set for earlier date (Jun. 19, 2009) per Court's Order. (DI 244).
May 26, 2009 Notice of Conventional Filing Under Seal of Reply Memorandum in Support of Motion to Allow in Camera Submission of Affidavits Regarding Discovery Efforts filed by Defendant Pfizer (DI 245).
May 26, 2009 Notice of Hearing on Motion re: 240 Plaintiff's Motion to Compel Preserve and Produce Evidence : (Notice generated by chambers) Motion Hearing set for Jun. 18, 2009 01:30 PM in Room 436 before Magistrate Judge Brooke C. Wells (DI 246).
May 26, 2009 Plaintiff's Memorandum in Support re 247 Plaintiff's Motion to Strike DI 235, 236 and 243, filed by Plaintiffs Brigham Young University, Daniel L. Simmons. (DI 248).
May 26, 2009 Plaintiff's Motion to Strike DI 235, 236 and 243, filed by Plaintiff's Brigham Young University, Daniel L. Simmons. Motions referred to Brooke C. Wells. (DI 247).
May 26, 2010 Order granting in part and denying in part 419 Motion to Expedite; granting 425 Motion for Extension of Time.
May 27, 2008 Defendants' Notice of Subpoenas' for Deposition and Production of Documents and Things BYU-21-0167-0171.
May 27, 2008 Defendants' Notice of Subpoenas for Deposition and Production of Documents and Things to Weilin Xie, Jeffrey Chipman and Gary Evett.
May 27, 2008 Deposition Subpoena to Gary Evett.
May 27, 2009 Amended Notice of Hearing on Motion re: 240 Plaintiff's Motion to Compel Preserve and Produce Evidence : (Notice generated by chambers) Motion Hearing set for Jul. 2, 2009 10:00 AM in Room 436 before Magistrate Judge Brooke C. Wells. Hearing scheduled on Jun. 18, 2009 is vacated. (DI 249).
May 27, 2009 Letter from L. Schneider to M. Bettilyon.
May 27, 2009 Order: Defendant Pfizer shall preserve the evidence at issue; specifically a collection of COX-2 related documents. Motion hearing re 240 Plaintiff's Motion to Compel Preserve and Produce Evidence set for Jun. 18, 2009 01:30 PM in Room 436 before Magistrate Judge Brooke C. Wells. Signed by Magistrate Judge Brooke C. Wells on May 26, 2009. (DI 250).
May 28, 2009 Plaintiffs' Notice of Tour of Facility and of Taking Video Deposition of Judy Lewis.
May 29, 2008 Plaintiffs' Rule 30(b)(6) Deposition Required by the Court of Pfizer, Inc.
May 3, 2007 Plaintiffs' Notice of Subpoenas for Production of Documents and Things served upon Cayman Chemical Company, Oxford Biomedical Research, Inc., University of Rochester, Washington University at St. Louis, Dr. Phillip Needleman and Merck & Co., Inc./Merck Sharp & Dohme Limited.
May 4, 2007 Plaintiffs' First Set of Interrogatories to Defendant Pfizer, Inc.
May 4, 2010 Order denying Plaintiffs' Motion for Dispositive Sanctions.
May 5, 2005 Expert Report of Dr. Henry G. Grabowski.
May 5, 2005 Expert Report of Dr. William Galbraith.
May 5, 2006 Expert Report of Barry S. Cooperman, Ph.D.
May 5, 2006 Expert Report of Dr. Michael Wolfe.
May 5, 2006 Expert Report of Dr. Simon Helfgott.
May 5, 2006 Expert Report of George C. Fuller, Ph.D.
May 5, 2006 Expert Report of Gibert S. Banker, Ph.D, D.Sc.
May 5, 2006 Expert Report of Guenter Trummlitz, Ph.D.
May 5, 2006 Expert Report of Keith B. Leffler.
May 5, 2006 Expert Report of Raymond Baker, Ph.D.
May 5, 2006 Expert Report of Ronald H. Smith.
May 5, 2006 Expert Report of William B. Schultz.
May 5, 2010 Orders granting pro hac vice admissions.
May 5, 2011 Amended Scheduling Order.
May 5, 2011 Memorandum in Support of Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Contract of Paragraphs 3.3 and 3.4 of the Research Agreement, including the following Exhibits: Ex. 01. Research AgreementEx, 02: Research Proposal to the Monsanto Company by Daniel L. Simmons, Apr. 5, 1991.
May 5, 2011 Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Contract of Paragraphs 3.3 and 3.4 of the Research Agreement.
May 5, 2011 Motion for Partial Summary Judgment Re: Paragraph 3.3 of the Research Agreement.
May 5, 2011 Notice of Conventional Filing of Memorandum in Support of Motion for Partial Summary Judgment re: Paragraph 3.3 of the Research Agreement.
May 5, 2011 Order Granting Ex Parte Motion for Leave to File Supplemental Response to Memorandum.
May 6, 2010 Order regarding hearing set for May 7, 2010.
May 8, 2009 Memorandum in Support re 229 Motion for Leave to File Motion to Allow in Camera Submission of Affidavits Regarding Discovery Efforts filed by Defendant Pfizer. (Exhibit 1 and Text of Proposed Order) (DI 230).
May 8, 2009 Motion for Leave to File Motion to Allow in Camera Submission of Affidavits Regarding Discovery Efforts filed by Defendant Pfizer. Motions referred to Brooke C. Wells. (DI 229).
May 9, 2006 First Supplement to Expert Report of William B. Schultz.
May 9, 2008 Defendants' Third Request for Production of Documents.
May 9, 2008 Notice of Taking Video Deposition of Lynn Astle.
May 9, 2008 Subpoena Duces Tecum in a Civil Case to Lynn Astle.
May 9, 2011 Joint Statement of the Parties re: May 12, 2011 Status Conference.
Maybridge Chem Co./Ryan Scientific Catalog 9; 1996 USPatent No. 5,508,426; Substituted Pyrazolyl Benzenesulfonamide Compounds For The Treatment of Inflam.Compound No.BTB 06812.
Maybridge Chemical Co./ Ryan Scientific Catalog, Compound No. BTB 06812 (No date available).
Memorandum Decision and Order granting in part and denying in part Motion to Amend/Correct for Leave From and Modification to the Protective Order; denying Motion for Suspension of Reissue Proceedings; denying Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991; finding/denying as moot Motion re Memorandum in Opposition to Motion, (Alternative) Rule 56(f) Motion.
Memorandum in Opposition to Plaintiffs' motion for Extension of Time Amend Complaint dated Apr. 29, 2010.
Minute Order. Proceedings held before Magistrate Judge Brooke C. Wells. Motion Hearing held on Jul. 2, 2009 re Plaintiff's Motion to Strike Sealed Document, Motion for Leave to File Motion to Allow in Camera Submission of Affidavits Regarding Discovery Efforts filed by Pfizer and Plaintiff's Motion to Compel Preserve and Produce Evidence filed by Daniel L. Simmons, Brigham Young University.
Mokhtar, H. et al.; 1990;Synthesis of Nitrogenous Compounds Part II Pakistan Journal of Science and Industrial Research; 33;30-36.
Mokhtar, H.; 1978;Synthesis of Some Substituted Pyrazole-3-carboxylic Acids with Possible Hypoglycemic and Antimicrobial Activity; Pharmazie; 33; 649-651.
Mokhtar, H.; 1988;Synthesis of Trisubstgituted Pyrazoles With Possible Antimicrobial Activity; Pakistan Journal of Science and Industrial Research; 31; 762-767.
Mokhtar, H.; 1991;Synthesis of Nirogenous Compounds, Part III; Pakistan Journal of Science and Industrial Research; 34; 9-15.
Mokhtar, H.M; 1985; Synthesis of Trisubstituted Pyrazoles with Possible Antimicrobial Activity; Pakistan Journal of Science and Industrial Research; V.28; No. 1;85-91.
Mokhtar,H.;1988;Synthesis of Nitrogeneous Compounds from δ-Unsaturated1,3-Dicarbonyl Esters. Part I. Subst Pyrazoles, Isoxazoles; J.Chemical Society of Pakistan;10;4;414-24.
Motion and Consent of Sponsoring Local Counsel for Admission Pro Hac Vice of Mark C. Dangerfield dated Feb. 18, 2010.
Motion for Admission Pro Hac Vice of Brad D. Brian dated May 3, 2010.
Motion for Admission Pro Hac Vice of Dan K. Webb dated Feb. 10, 2010.
Motion for Admission Pro Hac Vice of John Caleb Dougherty dated Feb. 10, 2010.
Motion for Admission Pro Hac Vice of Kahty Owen dated Mar. 12, 2010.
Motion for Admission Pro Hac Vice of Kristin S. Escalante dated May 3, 2010.
Motion for Admission Pro Hac Vice of Raymond C. Perkins dated Mar. 12, 2010.
Motion for Admission Pro Hac Vice of Richard T. Mulloy dated Mar. 12, 2010.
Motion for Admission Pro Hac Vice of Stuart N. Senator dated May 3, 2010.
Needle-P 10000013599.
Nicolaus, B.J.R.; 1983; Symbiotic Approach to Drug Design; Decision Making in Drug Research; ed. Franz Gross; Raven Press; NY; 173-188.
Notes to consolidated financial statements for Pfizer (BYU-PFE 000829-BYU-PFE 000831.
Notice of conventional filing of BYU's motion to disqualify Winston & Strawn LLP and related documents dated Mar. 31, 2010.
Notice of conventional filing of Defendants' Memorandum in Support of Their Motion for a Hearing to Amend the Discovery Plan dated Jan. 22, 2010.
Notice of Conventional Filing of Defendants Reply Memorandum in Support of Their Motion for a Protective Order Regarding Post 2001 Documents dated Apr. 26, 2010.
Notice of conventional filing of Exhibits 2 and 3 to Defendants' reply memorandum in support of motion for a hearing to amend the discovery plan dated Mar. 25, 2010.
Notice of conventional filing of Plaintiffs' Memorandum in Opposition to Defendants' Motion for a Hearing to Amend the Discovery Plan dated Mar. 8, 2010.
Notice of conventional filing of Plaintiff's memorandum in Opposition to motion for Protective Order Regarding Marketing Practices Litigation dated Apr. 12, 2010.
Notice of conventional filing of Unredacted Version of Memorandum in Support of Motion for Dispositive Sanctions dated Mar. 10, 2010.
Notice of conventional filing of unredacted version of Plaintiffs' opposition to Defendants' motion for a protective order regarding post-2001 documents dated Apr. 9, 2010.
Notice of Deposition of Brigham Young University Pursuant to Fed. R. Civ. P. 30 (b)(6) dated Jan. 13, 2010.
Notice of Deposition of Brigham Young University Pursuant to Fed. R. Civ. P. 30(b)(6) dated Dec. 14, 2009.
Notice of Errata to Motion for Pro Hac Vice Admission and Consent of Local Counsel of Dan K. Webb by Pfizer dated Feb. 11, 2010.
Notice of Filing of Official Transcript of Proceedings held on Apr. 8, 2009—Motion Hearing before Judge Brooke Wells.
Notice of Filing of Official Transcript of Proceedings held on Aug. 18, 2009—Motion Hearing before Judge Dale A. Kimball.
Notice of Submission of Privilege Logs by Pfizer.
Notice of withdrawal of exhibit dated Mar. 31, 2010.
Notice of Withdrawal of Pfizer's Motion for Partial Summary Judgment That Dr. Simmons Is Not an Inventor of the Patents Listed in Count IV of Plaintiffs' Complaint dated Feb. 5, 2010.
Nov. 1, 2010 Order and Memorandum Granting Plaintiffs' Motion to Compel in Part.
Nov. 10, 2011 Amended Notice of Taking Video Deposition of Morris Robins.
Nov. 11, 1991 Needleman Letter to Simmons BYU-08-0799.
Nov. 11, 2010 Amended Notice of Taking Video Deposition of Jan Williams.
Nov. 12, 2007 Notice of Taking Video Deposition of Michael Orme.
Nov. 12, 2010 Memorandum in Support of Plaintiffs' Emergency Motion to Extend Time for Response to Defendants' Motion for Partial Summary Judgment with the following exhibits: Exhibit A: Declaration of Adam C. Anderson Exhibit B: Scott Hauser Deposition Excerpts, Oct. 27, 2010 Exhibit C: Dec. 2, 1993 Letter to Editor of Science Magazine from Dr. Seibert Exhibit D: Karen Seibert Deposition Excerpts, Jun. 2, 2010 Exhibit E: Peter Isakson Deposition Excerpts, Dec. 18, 2001 Exhibit F: Scott Hauser Deposition Excerpts, Nov. 11, 2010.
Nov. 12, 2010 Motion to Expedite Response to BYU's Motion for an Extension of Time.
Nov. 14, 2011 Certificate of Service for Defendants' Memoranda in Support of Motions for Partial Summary Judgment filed under Seal on Nov. 14, 2011.
Nov. 14, 2011 Declaration of Kevin W. Bates in Support of Defendants' Motions for Summary Judgment on Plaintiffs' Claim for Correction of Inventorship (Count IV of the First Amended Complaint) and the following Exhibits: Exhibit 1: U.S. Patent No. 5,344,991 (filed Oct. 29, 1993) Exhibit 2: U.S. Patent No. 5,380,738 (filed May 21, 1993) Exhibit 3: U.S. Patent No. 5,393,790 (filed Feb. 10, 1994) Exhibit 4: U.S. Patent No. 5,401,765 (filed Nov. 30, 1993) Exhibit 5: U.S. Patent No. 5,418,254 (filed May 4, 1994) Exhibit 6: U.S. Patent No. 5,420,287 (filed Jun. 3, 1994) Exhibit 7: U.S. Patent No. 5,420,343 (filed Aug. 31, 1994) Exhibit 8: U.S. Patent No. 5,434,178 (filed Nov. 30, 1993) Exhibit 9: U.S. Patent No. 5,466,823 (filed Nov. 30, 1993) Exhibit 10: U.S. Patent No. 5,475,018 (filed Nov. 30, 1993) Exhibit 11: U.S. Patent No. 5,476,944 (filed May 19, 1994) Exhibit 12: U.S. Patent No. 5,486,534 (filed Jul. 21, 1994) Exhibit 13: U.S. Patent No. 5,504,215 (filed Jun. 1, 1995) Exhibit 14: U.
Nov. 14, 2011 Declaration of Phillip J. Russell Filed in Support of Defendants' Motions for Partial Summary Judgment, including the following Exhibits: Exhibit 1: Research Agreement between Brigham Young University and Monsanto Company effective Aug. 1, 1991 Exhibit 3: Defendants' First Set of Interrogatories, Jan. 8, 2007 Exhibit 4: Plaintiffs' Response to Defendants' First Set of Interrogatories, Feb. 12, 2007 Exhibit 6: Plaintiffs' Supplemental Response to Defendants' Interrogatory No. 4, Jun. 27, 2008 Exhibit 7: Response to Defendants' First Set of Requests for Admissions to Brigham Young University, Jun. 11, 2008 Exhibit 9: Apr. 29, 1991 Letter to K. Seibert and Jaime Masferrer from D. Simmons Exhibit 10: Agreement between BYU and Oxford Biomedical Research, Inc. dated Aug. 1, 1991 Exhibit 13: Mar. 27, 1992 letter to P. Needleman from C. Hardman Exhibit 14: May 20, 1992 Letter to P. Needleman from D. Simmons Exhibit 15: May 21, 1992 Letter to P. Needleman from C. Hardman Exhibit 1
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claim for Breach of Paragraph 1.6 of the Research Agreement (Defendants' Motion No. 11).
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claim for Breach of Paragraph 3.1 of the Research Agreement (Defendants' Motion No. 12).
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment on Count II—Implied Covenant of Good Faith and Fair Dealing; Count III—Fiduciary Duty; Count V—Unjust Enrichment; Count VI—Fraud; Count VII—Negligent Misrepresentation of Plaintiffs' First Amended Complaint (Defendants' Motion No. 13).
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment on Exclusions from "Project" (Defendants' Motion No. 2).
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment Re: Ownership of the COX-2 Materials (Defendants' Motion No. 10).
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment Regarding Paragraph 3.3 of the Research Agreement (Defendants' Motion No. 3).
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment Regarding Plaintiffs' COX-1 Trade Secret Claims (Defendants' Motion No. 7).
Nov. 14, 2011 Defendants' Motion for Partial Summary Judgment That Plaintiffs' Alleged "Two-Cell Assay" Trade Secret Has been Licensed to Defendants (Defendants' Motion No. 8).
Nov. 14, 2011 Defendants' Motion to Dismiss for Lack of Standing (Defendants' Motion No. 9).
Nov. 14, 2011 Memorandum in Support of Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claim for Breach of Paragraph 1.6 of the Research Agreement (Defendants' Motion No. 11).
Nov. 14, 2011 Memorandum in Support of Defendants' Motion for Partial Summary Judgment Dismissing Plaintiffs' Claim for Breach of Paragraph 3.1 of the Research Agreement (Defendants' Motion No. 12).
Nov. 14, 2011 Memorandum in Support of Defendants' Motion for Partial Summary Judgment on Exclusions from "Project" (Defendants' Motion No. 2).
Nov. 14, 2011 Memorandum in Support of Defendants' Motion for Partial Summary Judgment on: Count II—Implied Covenant of Good Faith and Fair Dealing; Count III—Fiduciary Duty; Count V—Unjust Enrichment; Count VI—Fraud; Count VII—Negligent Misrepresentation of Plaintiffs' First Amended Complaint (Defendants' Motion No. 13).
Nov. 14, 2011 Memorandum in Support of Defendants' Motion for Partial Summary Judgment Re: Ownership of the COX-2 materials (Defendants' Motion No. 10).
Nov. 14, 2011 Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Paragraph 3.3 of the Research Agreement (Defendants' Motion No. 3).
Nov. 14, 2011 Memorandum in Support of Defendants' Motion to Dismiss for Lack of Standing (Defendants' Motion No. 9).
Nov. 14, 2011 Memorandum in Support of Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Paragraphs 1.3, 3.4, 3.5 and 3.7 of the Research Agreement (Defendants' Motion No. 1).
Nov. 14, 2011 Memorandum in Support of Motion for Partial Summary Judgment Re: Mitigation of Damages and Failure to Patent as Described in Special Defenses Nos. 24 and 25 in the Amended Answer, including the following Exhibits: Exhibit 1: Declaration of Michael J. Warner, Univ. of Rochester v. G.D. Searle & Co., Inc., No. 00-CV-616IL (W.D.N.Y. Jan. 13, 2003) Exhibit 2: Mar. 23, 1992 Letter to D. Simmons from P. Needleman Exhibit 3: Expert Report by Richard Gering, Ph.D., Feb. 18, 2011 Exhibit 4: Counter Report by Richard J. Gering, Ph.D., Aug. 26, 2011 Exhibit 5: Feb. 25, 2011 E-mail from B. Hatch to L. Beus Exhibit 6: Expert Report of Ashley J. Stevens Exhibit 7: Stevens Dep. 1-4, 269-280, Oct. 26, 2011 Exhibit 8: Expert Report by Edward T. Lentz, Feb. 18, 2011.
Nov. 14, 2011 Memorandum in Support of Plaintiffs' Motion for Partial Summary Judgment to Dismiss Defendants' Thirty-Second Defense with Prejudice and the following Exhibit: Exhibit A: "Special Defenses" portion of the Answer to the First Amended Complaint.
Nov. 14, 2011 Memorandum in Support of Plaintiffs' Renewed Motion for Further Discovery Sanctions.
Nov. 14, 2011 Motion for Partial Summary Judgment Dismissing Plaintiffs' Claims for Breach of Paragraphs 1.3, 3.4,3.5 and 3.7 of the Research Agreement (Defendants' Motion No. 1).
Nov. 14, 2011 Motion for Partial Summary Judgment on Plaintiffs' Claim that Defendants Have Misappropriated "Project" and "Compilation" Trade Secrets (Count VIII of the First Amended Complaint) (Defendants' Motion No. 6).
Nov. 14, 2011 Motion for Partial Summary Judgment Re: Mitigation of Damages and Failure to Patent as Described in Special Defenses Nos. 24 and 25 in the Amended Answer.
Nov. 14, 2011 Motion for Partial Summary Judgment That Plaintiffs' Hypothetical Patent claims 12-26 May Not Be Relied Upon in Support of Any Claim for Relief (Defendants' Motion No. 4).
Nov. 14, 2011 Motion for Summary Judgment on Plaintiffs' Claim for Correction of Inventorship (Count IV) of the First Amended Complaint) (Defendants' Motion No. 5).
Nov. 14, 2011 Notice of Conventional Filing of Exhibits 1-199 to Plaintiffs' Memorandum in Support of Renewed Motion for Further Discovery Sanctions.
Nov. 14, 2011 Notice of Conventional Filing of Exhibits 1-59 to BYU's Memorandum in Support of Motion for Partial Summary Judgment Regarding Defendants' Breach of Paragraph 4.1 of the Research Agreement.
Nov. 14, 2011 Notice of Conventional filing of Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Plaintiffs' COX-1 Trade Secret Claims (Defendants' Motion No. 7).
Nov. 14, 2011 Notice of Conventional Filing of Memorandum in Support of Defendants' Motion for Partial Summary Judgment that Plaintiffs' Alleged "Two-Cell Assay" Trade Secret Has been Licensed to Defendants (Defendants' Motion No. 8).
Nov. 14, 2011 Notice of Conventional filing of Memorandum in Support of Motion for Partial Summary Judgment on Plaintiffs' Claim that Defendants have Misappropriated "Project" and "Compilation" Trade Secrets (Count VIII of the First Amended Complaint)(Defendants' Motion No. 6).
Nov. 14, 2011 Notice of Conventional Filing of Memorandum in Support of Motion for Partial Summary Judgment Regarding Defendants' Breach of Paragraph 4.1 of the Research Agreement.
Nov. 14, 2011 Notice of Conventional Filing of Memorandum in Support of Motion for Partial Summary Judgment That Plaintiffs' Hypothetical Patent Claims 12-26 May Not Be Relied Upon in Support of Any Claim for Relief (Defendants' Motion No. 4).
Nov. 14, 2011 Notice of Conventional Filing of Memorandum in Support of Motion for Summary Judgment on Plaintiffs' Claim for Correction of Inventorship (Count IV) of the First Amended Complaint (Defendants' Motion No. 5).
Nov. 14, 2011 Plaintiffs' Memorandum in Support of Motion for Partial Summary Judgment Concerning Defendants' Twenty-Eighth and Twenty-Ninth Defenses and the following Exhibit: Exhibit A: "Special Defenses" portion of the Answer to the First Amended Complaint.
Nov. 14, 2011 Plaintiffs' Motion for Leave to File Overlength Memorandum in Support of its Renewed Motion for Further Sanctions.
Nov. 14, 2011 Plaintiffs' Motion for Partial Summary Judgment concerning Defendants' Twenty-Eighth and Twenty-Ninth Defenses.
Nov. 14, 2011 Plaintiffs' Motion for Partial Summary Judgment regarding Count I (Breach of Written Contract) of Plaintiffs' First Amended Complaint.
Nov. 14, 2011 Plaintiffs' Motion for Partial Summary Judgment to Dismiss Defendants' Thirty-Second Defense with Prejudice.
Nov. 14, 2011 Plaintiffs' Renewed Motion for Further Discovery Sanctions.
Nov. 14, 2011 Plaintiffs' Reply in Support of Cross Motion for Partial Summary Judgment Regarding Fiduciary Duties, including the following Exhibits: Exhibit 1: Declaration of Michael J. Warner, Univ. of Rochester v. G.D. Searle, No. 00-CV-6161L (W.D.N.Y. Jan 13, 2003) Exhibit 2: Hoffman Dep. 1, 317-324, Oct. 5, 2011 Exhibit 3: Mancini Dep. Draft 1-2, 137, Nov. 7, 2011 Exhibit 4: Declaration of Daniel L. Simmons, Jun. 17, 2011 Exhibit 5: Mar. 20, 1992 Letter to P. Needleman from D. Simmons Exhibit 6: Zmmerman Dep. 1-4, 25-32, Oct. 27, 2011.
Nov. 15, 2007 Deposition of Michael Orme, Exhibits 2, 5-17, 20.
Nov. 15, 2010 Order Granting Plaintiffs' Emergency Motion to Extend Time for Response to Defendants' Motion for Partial Summary Judgment and Denying As Moot Plaintiffs' Motion to Expedite Response.
Nov. 15, 2011 Notice of Conventional Filing of Exhibits 19 and 23 to Declaration of Phillip J. Russell filed in support of Defendatns' Motion for Partial Summary Judgment.
Nov. 15, 2011 Notice of Conventional Filing of Exhibits 2, 5, 8, 11, 12, 16, 17, 29, 33-35, 37-43, 45, 46, 48-50 and 52-58 to Declaration of Phillip J. Russell filed in support of Defendants' Motions for Partial Summary Judgment.
Nov. 15, 2011 Notice of Conventional Filing of Exhibits to Declaration of Kevin W. Bates filed in support of Defendants' Motions for Summary Judgment on Plaintiffs' Claim for Correction of Inventorship (Count IV of the First Amended Complaint).
Nov. 16, 2010 Amended Notice of Taking Video Deposition of Joe Bulock.
Nov. 16, 2010 Amended Notice of Taking Video Deposition of Philip Needleman.
Nov. 16, 2010 Amended Subpoena for the Deposition of Joseph Bulock.
Nov. 16, 2011 Request to Submit for Decision Re: Motions for Partial Summary Judgment Re: Count III (Breach of Fidiciary Duty) of Plaintiffs' First Amended Complaint.
Nov. 17, 2009 Stipulated Motion for Extension of Time to File Joint Status Update Regarding Plaintiffs' Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics; Attached proposed order.
Nov. 17, 2011 Defendants' Memorandum in Opposition to Plaintiffs' Motion for Leave to File Overlength Memorandum in Support of its Renewed Motion for Further Sanctions, and the following Exhibits: Exhibit A: Motion Hearing Transcript, Mar. 31, 2011 Exhibit B: Status Conference Transcript, Apr. 7, 2011.
Nov. 18, 2009 Order granting Motion for Extension of Time to file joint status update regarding Plaintiffs sixth request for Production and Proposed Rule 30(b)(6) Deposition Topics.
Nov. 18, 2011 Plaintiff' Reply in Support of Motion for Leave to File Overlength Memorandum in Support of its Renewed Motion for Further Sanctions.
Nov. 19, 2010 Amended Notice of Taking Video Deposition of J. Bevan Ott.
Nov. 19, 2010 Notice of Taking Video Deposition of Gary Hooper.
Nov. 19, 2010 Notice of Taking Video Deposition of Xiaojun Lu.
Nov. 20, 2007 Defendants' Notice of Subpoena for Production of Documents and Things to Plaintiffs to Merck & Co., Inc., Merck Sharp & Dohme Limited.
Nov. 21, 2011 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Hank E. Pearson and the following: Exhibit A: Application for Admission Pro Hac Vice Exhibit B: Electronic Case Filing Registration Form [Proposed] Order for Pro Hac Vice Admission.
Nov. 23, 2009 Stipulated Motion for Extension of Time to File Joint Status Update Regarding Plaintiffs' Sixth Request for Production and Proposed Rule (30)(b)(6) Deposition Topics; Attached proposed order.
Nov. 23, 2011 Order Granting Motion for Admission Pro Hac Vice of Hank E. Pearson.
Nov. 24, 2009 Order granting Motion for Extension of Time to File Joint Status Update Regarding Plaintiffs Sixth Request for Production and Proposed Rule 30(b)(6) Deposition Topics.
Nov. 25, 2009 Order of recusal by Judge Dale A. Kimbal.
Nov. 28, 2011 Order Denying Plaintiffs' Motion for Leave to File Excess Pages.
Nov. 3, 2010 Plaintiffs' Tenth Request for Production of Documents.
Nov. 30, 2009 Order of recusal by Judge Bruce S. Jenkins.
Nov. 30, 2010 Notice of Service of Subpoena for Production of Documents and Things upon Defendants.
Nov. 4, 2009 Order re: Status of Pfizer's Motion for protective order regarding Plaintiffs sixth request for production and proposed rule 30(b)(6)Deposition Topics.
Nov. 4, 2010 Defendants' Objections to Notice of Deposition of Peter Isakson.
Nov. 5, 2007 Merck & Co., Inc.'s Responses and Objections to Brigham Young University Young University's and Dr. Daniel L. Simmons's Second Amended Rule 45 Subpoena Duces Tecum Dated Oct. 9, 2007.
Nov. 5, 2010 Amended Notice of Taking Video Deposition of Brigham Young University Pursuant to Fed.R.Civ.P.30(b)(6).
Nov. 8, 2007 Plaintiffs' Notice of Subpoena for Production of Documents and Things served upon the Monsanto Company.
Nov. 8, 2010 Amended Notice of Taking Video Deposition of Peter Isakson.
Nov. 9, 2010 Amended Notice of Taking Video Deposition of Peter Isakson.
Oct. 1, 2007 Plaintiffs' Amended Subpoena for Documents served on Merck & Co., Inc., Merck Sharp & Dohme Limited.
Oct. 1, 2009 letter from Wyland to Anderson.
Oct. 1, 2010 Amended Notice of Taking Video Deposition of Harvey Herschman, Ph.D.
Oct. 1, 2010 Amended Subpoena for the Deposition of Harvey Herschman, Ph.D.
Oct. 1, 2010 Plaintiff's Response in Opposition to Motion to Dismiss Counts IX (18 U.S.C. § 1962(c)) and X (18 U.S.C. § 1962 (D)) of Plaintiffs First Amended Complaint.
Oct. 10, 2011 Notice of Taking Video Deposition of James Severson.
Oct. 10, 2011 Notice of Taking Video Deposition of Rebecca Eisenberg.
Oct. 10, 2011 Notice of Taking Video Deposition of Vern Norviel.
Oct. 11, 2007 Plaintiffs' Notice of Subpoena for Production of Documents and Things served upon Teva Pharmaceuticals USA, Inc.
Oct. 11, 2011 Ex Parte Motion for Leave to File Combined Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Count III (Breach of Fiduciary Duty) and in Opposition to Plaintiffs' Cross-Motion for Partial Summary Judgment [Proposed] Order Granting Ex Parte Motion for Leave to File Combined Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Count III (Breach of Fiduciary Duty) and in Opposition to Plaintiffs' Cross-Motion for Partial Summary Judgment.
Oct. 11, 2011 Order granting Motion for Admission pro hac vice of Abigail M. Terhune.
Oct. 12, 2007 Plaintiffs' Notice of Subpoena for Production of Documents and Things served upon University of Connecticut and the University of California, Los Angeles.
Oct. 12, 2010 Amended Notice of Taking Video Deposition of Dr. Denis Callewaert.
Oct. 12, 2010 Amended Subpoena for Deposition of Dr., Denis Callewaert.
Oct. 12, 2011 Order granting Ex Parte Motion for Leave to File Combined Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Count III (Breach of Fiduciary Duty) and in Opposition to Plaintiff's Cross-Motion for Partial Summary Judgment.
Oct. 13, 2010 Notice of Taking Video Deposition of Earl Wolley.
Oct. 13, 2010 Notice of Taking Video Deposition of Merrill Bateman.
Oct. 13, 2010 Notice of Taking Video Deposition of William Bradshaw.
Oct. 13, 2011 Notice of Taking Video Deposition of George Cunningham.
Oct. 13, 2011 Notice of Taking Video Deposition of John Ashton.
Oct. 14, 2011 Notice of Taking Video Deposition of Weilin Xie.
Oct. 14, 2011 Order Denying Plaintiffs' Motions to Limit the Scope and Time of Deposition.
Oct. 14, 2011 Order Re: Motion for Miscellaneous Relief.
Oct. 18, 2010 Defendants' Reply Memorandum in Support of Motion to Dismiss Counts IX (18 U.S.C. § 1962(c)) and X (18 U.S.C. § 1962 (D)) of Plaintiffs' First Amended Complaint.
Oct. 18, 2011 Notice of Taking Video Deposition of Jeffrey Chipman.
Oct. 18, 2011 Notice of Taking Video Deposition of Malcolm Fraser.
Oct. 18, 2011 Notice of Taking Video Deposition of Stephen Prescott.
Oct. 19, 2006 Supplemental Expert Report of Guenter Trummlitz, Ph.D.
Oct. 21, 2009 letter from Sue Eggleston to Bryan Zielinski.
Oct. 21, 2010 Notice of Substitution of Attorneys of Record—Brent O. Hatch replacing Todd L. Krause; David R. Parkinson; Lisa A. Schneider; Neil H. Wyland; Charles W. Douglas and George M. Haley as counsel on behalf of G.D. Searle, G.D. Searle & Company, Monsanto Company, Pfizer Inc. and Pharmacia.
Oct. 21, 2010 Notice of Taking Video Deposition of Richard U. DeSchutter.
Oct. 21, 2011 Amended Notice of Taking Video Deposition of Malcolm Fraser.
Oct. 21, 2011 Notice of Taking Video Deposition of Ashley Stevens.
Oct. 21, 2011 Notice of Taking Video Deposition of Francis M. Wikstrom.
Oct. 21, 2011 Notice of Taking Video Deposition of Michael D. Zimmerman.
Oct. 24, 2011 Amended Notice of Taking Video Deposition of Vern Norviel.
Oct. 25, 2011 Amended Notice of Taking Video Deposition of George Cunningham.
Oct. 27, 2010 Amended Notice of Taking Video Deposition of William Bradshaw.
Oct. 27, 2010 Request to Submit for Decision Re: Defendants' Motion to Dismiss Counts IX (18 U.S.C. § 1962(c)) and X (18 U.S.C. § 1962 (D)) of Plaintiffs First Amended Complaint (Oral Argument Requested).
Oct. 28, 2011 Combined Reply Memorandum in Support of Defendants' Motion for Partial Summary Judgment Regarding Count III (Breach of Fiduciary Duty) and in Opposition to Plaintiffs' Cross-Motion for Partial Summary Judgment.
Oct. 29, 2007 Plaintiffs' Notice of Subpoena for Production of Documents and Things served upon Dr. Harvey Herschman and Dr. Timothy Hla.
Oct. 29, 2007 Plaintiffs' Third Request for Production of Documents.
Oct. 3, 2011 Memorandum Regarding Status Conference, including the following Exhibits: Ex. A: Scheduling Order, Jul. 30, 2007 Ex. B: Jan. 28, 2011 Letter to A. Anderson from K. Owen Ex. C: Feb. 17, 2011 Letter to A. Anderson from R. Mulloy Ex. D: Expert Deposition Calendar Ex. E: Sep. 27, 2011 letter to B. Hatch from M. Dangerfield Ex. F: Subpoena to production Documents, Information, or Objects or To Permit Inspection of Premises in a Civil Action for DNA Solutions Ex. G: Subpeona to Testify at a Deposition in a Civil Action for DNA Solutions Ex. H: Jan. 21, 2011 Letter to B. Hatch from A. Anderson.
Oct. 31, 2002 Letter to Olson from Schneider.
Oct. 31, 2007 Plaintiffs' Notice of Subpoena for Production of Documents and Things served upon American Red Cross.
Oct. 4, 2011 Notice of Takin Video Deposition of Dr. G. Steven Geis.
Oct. 4, 2011 Notice of Taking Video Deposition of Dr. Joseph M. Fortunak.
Oct. 4, 2011 Notice of Taking Video Deposition of Dr. Ronald Woodard.
Oct. 4, 2011 Plaintiffs' Motion to File Sur-Reply in Support of Supplemental Briefing Regarding Defendants' Motion for Partial Summary Judgment Re Paragraph 3.3 of the Research Agreement.
Oct. 5, 2010 Defendants' Objections to Notice of Deposition of Beverly Reitz.
Oct. 5, 2010 Defendants' Objections to Notice of Deposition of Mark Currie.
Oct. 5, 2010 Subpoena for the Deposition of Mark Currie.
Oct. 7, 2011 Motion and Consent of Sponsoring Local Counsel for Pro Hac Vice Admission of Abigail M. Terhune, including the following exhibits. Ex. A: Application for Admission Pro Hac Vice Ex. B: Electronic Case Filing Registration Form Proposed Order.
Oct. 7, 2011 Notice of Taking Continued Video Deposition of Dr. Daniel L Simmons.
Oct. 8, 2007 Defendants' Response to Plaintiffs' Second Request for Production of Documents.
Off the Charts: Pay, Profits and Spending by Drug Companies, Families USA, Jul. 2001 (BYU-PFE831921-BYU-PFE831956).
Order and Memorandum Decision Granting in Part Plaintiffs' Motion for Sanctions.
Order Denying Without Prejudice Defendants Motion for a Protective Order dated Mar. 12, 2010.
Order Denying Without Prejudice Defendants Motion for a Protective Order dated Mar. 25, 2010.
Order for Pro Hac Vice Admission of Kathy J. Owen dated Mar. 16, 2010
Order for Pro Hac Vice Admission of Richard T. Mulloy dated Mar. 15, 2010.
Order granding pro hac vice admission of Raymond C. Perkins dated Mar. 22, 2010.
Order granting 336 Motion for Admission Pro Hac Vice of Dan K. Webb dated Feb. 11, 2010.
Order Granting in Part Pfizer's Motion to Allow in Camera Submission of Affidavits Regarding Discovery Efforts and Deeming Moot BYU's Motion to Strike.
Order granting Motion for Admission Pro Hac Vice of Mark C. Dangerfield dated Feb. 18, 2010.
Order granting Motion for Extension of Time dated Apr. 19, 2010.
Order granting Motion for Extension of Time dated Apr. 23, 2010.
Order granting Motion to Amend/Correct Scheduling Order.
Order granting Motion to Intervene dated May 3, 2010.
Order granting pro hac vice admission of John C. Dougherty dated Feb. 10, 2010.
Order granting stipulated motion for extension of time dated Mar. 24, 2010.
Order Re Hearing Set for July 2, 2009.
Order regarding hearing set for May 7, 2010.
Order—Request for Courtesy Copies Pertaining to Aug. 18, 2009 Hearing.
P. Needleman, From a Twinkle in the Eye to a Blockbuster Drug, Research Technology Management, Nov.-Dec. 2001m p. 38-41 BYU-PFE831913-BYU-PFE831916.
Patent Evaluations: Pulmonary-Allergy, Derm, Gastrointestinal & Arthritis Novel COX-2 inhibitors, Expert Opinion on Therap. Patents, 1995, vol. 5, No. 4, pp. 357-359.
Penning et al., "3,4-Diarylpyraloles: Potent and Selective Inhibitors of Cyclooxygenase-2." Bioorganic & Medicinal Chemistry Letters, 1997, pp. 2121-2124, vol. 7, No. 16.
Pharmacia Annual Report 10K Compensation Table (BYU-PFE831917- BYU-PFE831920).
Plaintiffs' Amended Notice of Taking Video Deposition of Beverly Reitz (Jul. 1, 2010).
Plaintiffs' Amended Notice of Taking Video Deposition of Jaime Masferrer (Jul. 22 and Jul. 23, 2010).
Plaintiffs' Amended Notice of Taking Video Deposition of Shaukat Rangwala (Jun. 23, 2010).
Plaintiffs' Apr. 1, 2011 Response to Defendants' Request for Attorneys' Fees and Costs and the following exhibits: Ex. A: Amy Miller, No More Baby Steps: Pfizer's Top Lawyer Is Out to Change All the Rules, Corp. Counsel Online, Dec. 21, 2009. Katy Hopkins, Legal Industry Faces Major Changes, U.S. News & World Rep., Sep. 9, 2010. Ex. B: Mar. 3, 2011 Letter to Judge Wells from M. Bettilyon Ex. C: Declaration of John K. Morris Ex. D: 05-04 Utah Bar Ethics Advisory Opinions, Sep. 8, 2005.
Plaintiffs' Apr. 6, 2010 Response to Defendants' Sixth Request for Production of Documents.
Plaintiffs' Aug. 9, 2010 Reply in Support of Motion for Leave to File Overlength Memorandum Exhibit 1: Letter from K. Owen to L.R. Williams, Aug. 3, 2010 Exhibit 2: Letter from K. Owen to L.R. Williams, Aug. 6, 2010.
Plaintiffs' Dec. 10, 2010 30(b)(6) Notice of Deposition to Pfizer.
Plaintiffs' Dec. 14, 2009 Notice of Taking Video Deposition of Patricia O'Brien.
Plaintiffs' Dec. 15, 2009 Amended Notice of Taking Video Deposition of Patricia O'Brien.
Plaintiffs' Dec. 18, 2010 Response in Opposition to Motion for Partial Summary Judgment on Counts I-III and V-X of the First Amended Complaint on Statute of Limitations Grounds (Redacted Version).
Plaintiffs' Dec. 9, 2009 Amended Rule 30(b)(6) Deposition Notice to Defendants—Designee(s) Pfizer, Inc.(to be determined).
Plaintiffs' Feb. 1, 2011 Response in Opposition to Defendants' Motion to Strike Portions of Plaintiffs' Response to Motion for Partial Summary Judgment, with the following exhibits: Ex. 4: Sep. 2, 1992 Letter to P. Needleman from C. Hardman, BYU-01-1418 Ex. 11: M.K. O'Banion et al., A Serum—and Glucocorticoid-regulated 4-Kilobase mRNA Encodes a Cyclooxygenase-related Protein, J.Biochem, Mar. 1993, p. 6610, PFC01194743-748 Ex. 12: E. Meade, et al, Differential Inhibition of Prostaglandin Endoperoxide Synthase (Cyclooxygenase) Isozymes by Aspirin and Other Non-steroidal Anti-inflamatory Drugs, J. Biochem., Mar. 1993, p. 6610 Ex. 13: U.S. Patent No. 5,344,991 (filed Oct. 29, 1993). Ex. 14: U.S. Patent No. 5,563,165 (filed Jun. 1, 1995). Ex. 15: U.S. Patent No. 5,633,272 (filed Jun. 7, 1995) Ex. 16: U.S. Patent No. 5,760,068 (filed Nov. 14, 1994). Ex. 20: Draft Article submitted to Science Magazine by K. Seibert titled Mediation of Acute Inflammation by Cyclooxygenase-2, Dec. 2, 2003. Ex.
Plaintiffs' Feb. 18, 2011 Response to Defendants' Seventh Request for Production of Documents.
Plaintiffs' Feb. 18, 2011 Responses to Defendants' Second Set of Interrogatories.
Plaintiffs' Feb. 18, 2011 Responses to Defendants' Second Set of Requests for Admissions.
Plaintiffs' Feb. 5, 2010 Amended Response to Defendants' Fifth Request for Production of Documents.
Plaintiffs' Feb. 5, 2010 Response to Defendants' Fourth Request for Production of Documents.
Plaintiffs' Fifth Requests for Production of Documents dated May 2, 2008.
Plaintiffs' First Request for Production of Documents dated Jan. 12, 2007.
Plaintiffs' First Request for Production of Documents.
Plaintiffs' Jan. 11, 2011 Fourth Set of Interrogatories to Defendants.
Plaintiffs' Jan. 11, 2011 Second Set of Requests for Admission to Defendants.
Plaintiffs' Jan. 11, 2011 Twelfth Request for Production of Documents.
Plaintiffs' Jan. 19, 2010 Response o Defendants' Fifth Request for Production of Documents.
Plaintiffs' Jan. 19, 2011 Notice of Subpoenas for Production of Documents and Things.
Plaintiffs' Jan. 20, 2010 Eighth Request for Production of Documents.
Plaintiffs' Jan. 25, 2011 30(b)(6) Notice of Deposition to Pfizer.
Plaintiffs' Jan. 5, 2011: (1) Disclosure of Expert Testimony Subject Areas and (2) Supplemental Disclosure of Percipient Witness Testimony Subject Areas.
Plaintiffs' Jun. 17, 2011 Opposition to Defendants' Motion for Partial Summary Judgment on Plaintiffs' Claims for Breach of Paragraphs 3.3 and 3.4 of the Research Agreement along with the following Exhibits: Ex. 1: Apr. 9, 1991 Letter to D. Simmons from P. Needleman re housekeeping details Ex. 2: Research Agreement, Aug. 1, 1991 Ex. 3: Mar. 23, 1992 Letter to Simmons from Needleman re chicken bleed and grant/award Ex. 4: Apr. 5, 1991 Research Proposal to Monsanto by Simmons Ex. 5: Ex. 7: Witness Statement of Peter Clyde Isakson, Monsanto v Merck, Aug. 23, 1999 Ex. 9: Feb. 15, 1991 Email from R. Wiegand to P. Needleman re: Karen Seibert Ex. 10: Declaration of Dr. Daniel Simmons, Jun. 1, 2009 Ex. 11: Oct. 19, 1989 Letter to E. Woolley from D. Simmons enclosing enzyme sequences Ex. 12: FDA transcript of open public hearing on Dec. 1, 1998 Ex. 14: Daniel Simmons Deposition, Univ. of Rochester, vol. 1, Jul. 16, 2002 Ex. 15: Daniel Simmons' Deposition, vol. 2, Apr. 21, 2009 Ex. 16: Apr. 1, 1
Plaintiffs' Jun. 17, 2011 Response in Opposition to Defendants' Motion for Partial Summary Judgment Re Paragraph 3.3 of the Research Agreement and the following Exhibits: Ex. 2: Michael Orme Deposition, Nov. 15, 2007 Ex. 3: Lynn Astle Deposition, Feb. 17, 2009 Ex. 4: Stephen Craig Deposition, May 24, 2011 Ex. 7: Larry Swaney, Jun. 25, 2009 Ex. 8: Research Agreement, dated Aug. 1, 1991, executed by P. Needleman Ex. 10: Declaration of Daniel Simmons with exhibits, Jun. 17, 2011 Ex. 13: U.S. Patent No. 4,820,827 (filed Feb. 10, 1984) Ex. 17: U.S. Patent No. 5,466,823 (filed Nov. 30, 1993) Ex. 18: Declaration of Vern Norviel in BYU v. Pfizer, Jun. 17, 2011.
Plaintiff's Mar. 9, 2011 Motion to Compel Production of Sufficient Information to Allow Plaintiffs to Evaluate the Taint from Expert Rzucidlo Or, in the Alternative, to Disqualify Defendants' Counsel.
Plaintiffs' May 16, 2011 Supplemental Memorandum Regarding Biological Materials and the following exhibits: Ex. 1: Sep. 24, 2010 Letter to Ms. Owen from Mr. Anderson Ex. 2: May 11, 2009 Letter to Mr. Ricker from Mr. Spanbauer Ex. 3: Oct. 2, 2010 Letter to Mr. Anderson from Ms. Hamilton Ex. 5: Jan. 18, 2011 Letter to Mr. Mulloy from Mr. Ricker.
Plaintiffs' May 18, 2010 Notice of Taking Video Deposition of Jamie Masferrer.
Plaintiffs' May 19, 2011 Amended 30(b)(6) Notice of Deposition to Pfizer.
Plaintiffs' May 24, 2010 reply in support of motion for expedited briefing schedule and hearing concerning plaintiffs' motion to extend trial date and plaintiffs' emergency motion to adjust date of expert disclosures.
Plaintiffs' May 25, 2011 Plaintiffs' Memorandum in Opposition to Defendants' Motion to Strike.
Plaintiffs' Motion for Dispositive Sanctions dated Mar. 10, 2010.
Plaintiff's motion for Extension of Time Amend Complaint dated Apr. 12, 2010.
Plaintiffs' Notice of Taking Video Deposition of Beverly Reitz (Jul. 2, 2010).
Plaintiffs' Notice of Taking Video Deposition of Karen Seibert (Jun. 1 through Jun. 3, 2010).
Plaintiffs' Notice of Taking Video Deposition of Kathleen Leahy and Subpoena (Jul. 16, 2010).
Plaintiffs' Notice of Taking Video Deposition of Shaukat Rangwala (Jun. 23, 2010).
Plaintiffs' Notice of Taking Video Deposition of Tom Warren (Jul 1, 2010).
Plaintiffs' Notice of Third Party Subpoena for Production of Documents dated Mar. 15, 2010.
Plaintiffs' Notice Regarding Jul. 22, 2009 Hearing (re 272 Order on Motion to Compel, Motion Hearing, 239 Notice of Hearing on Motion).
Plaintiffs' Nov. 12, 2010 Emergency Motion to Extend Time for Response to Defendants' Motion for Partial Summary Judgment.
Plaintiffs' Nov. 18, 2009 Amended 30 (b)(6) Notice of Deposition to Pfizer—James Gierse.
Plaintiffs' Nov. 30, 2010 Notice of Subpoena for the Production of Documents and Things, with the following exhibits: Exhibit A: Nov. 30, 2010 Subpoena for the Deposition of the University of Chicago Exhibit B: Nov. 30, 2010 Subpoena for the Deposition of R. Michael Garavito.
Plaintiffs' Request for Admission to Plaintiffs dated Jul. 25, 2007.
Plaintiffs' Second Set of Interrogatories to Defendants dated Jan. 11, 2008.
Portion of Deposition Transcript for K. Owen dated Jun. 10, 2008.
Portions of Jul. 29, 2008 hearing transcript.
Proposed amended protective order dated Mar. 19, 2010.
Proposed order granting stipulated motion for extension of time dated Mar. 23, 2010.
Prosecution history for U.S. Appl. No. 90/009,615 (including Ex Parte Reexamination Request filed on Oct. 23, 2009).
Protective Order dated Jun. 7, 2007.
Public Exhibits 1-25 to Plaintiffs' opposition to Defendants' motion for a protective order regarding post-2001 documents dated Apr. 9, 2010.
Public Exhibits 1-31 of Redacted Plaintiff's memorandum in Opposition to motion for Protective Order Regarding Marketing Practices Litigation dated Apr. 9, 2010.
Public Exhibits to Redacted Plaintiffs' Memorandum in Support of Motion for Dispositive Sanctions dated Mar. 10, 2010.
R. Hamilton, J. Heterocyclic Chem., 13, 545 (1976).
R. Soliman et al. J. Pharm. Sci., 70, (1981).
R. Soliman et al. J. Pharm. Sci., 72, 1004 (1983).
R. Soliman et al. J. Pharm. Sci., 72:999-1004 (1983).
R. Soliman et al. J. Pharm. Sci., 76, 626 (1987).
R. Soliman et al. Pharmazie, 33, (1978).
Redacted Plaintiffs' Memorandum in Opposition to Defendants' Motion for a Hearing to Amend the Discovery Plan dated Mar. 8, 2010.
Redacted Plaintiff's memorandum in Opposition to motion for Protective Order Regarding Marketing Practices Litigation dated Apr. 9, 2010.
Redacted Plaintiffs' Memorandum in Support of Motion for Dispositive Sanctions dated Mar. 10, 2010.
Redacted Plaintiffs' opposition to Defendants' motion for a protective order regarding post-2001 documents dated Apr. 9, 2010.
Redacted Reply to Response to Motion re Protective Order Regarding Post-2001 Documents dated Apr. 26, 2010.
Reid et al., "Some New β-Diketones Containing the Trifluoromethy Group." J. Amer. Chem. Soc., 1950, pp. 2948-2952, vol. 72, No. 7.
Reply to Response to Motion re motion for Protective Order Regarding Marketing Practices Litigation dated Apr. 26, 2010.
Research-Technology Management, "From a twinkle in the eye to a blockbuster drug: The story of Celebrex holds lessons for R&D leaders everywhere," P. Needleman dated Nov. 2001.
S. Hauser deposition transcript excerpts dated Jun. 10, 2008.
Schorderet, M.; 1992; Pharmacologie; 74; 56.
Second Amended Protective Order dated Apr. 19, 2010.
Seibert et al., "Pharm. & Biochem. Demonst. of the Role of Cyclooxygenase-2 in Inflammation and Pain." Proc. Natl. Acad, Sci. USA, 1994, pp. 12013-12017, vol. 1.
Seideman et al., "Naproxen and Paracetamol Compared with Naproxen only in Coxarthrosis." Acta Orthopaedica Scandinavica, 1993, pp. 285-288, vol. 64, No. 3.
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Sep 15, 2010 Defendants' Objections to Notice of Deposition of Len Lee.
Sep. 10, 2010 Subpoena for the Deposition of Len Lee.
Sep. 12, 2011 Motion for Pro Hac Vice Admission and Consent of Local Counsel of Emil R. Whelan.
Sep. 12, 2011 Order for Pro Hac Vice Admission of Emily R. Whelan.
Sep. 13, 2010 Notice of Conventional Filing of Defendants' Memorandum in Support of Motion for Partial Summary Judgment on Counts I-III and V-X of the First Amended Complaint on Statute of Limitations Grounds.
Sep. 13, 2010 Notice of Conventional Filing of Defendants' Motion for Partial Summary Judgment on Counts I-III and V-X of the First Amended Complaint on Statute of Limitations Grounds.
Sep. 13, 2010 Notice of Conventional Filing of Pfizer's Exhibits in Support of Defendants' Motion for Partial Summary Judgment on Counts I-III and V-X of the First Amended Complaint on Statute of Limitations Grounds, with Exhibits 1-33.
Sep. 14, 2010 Notice of Taking Video Deposition of Ben Zweifel.
Sep. 15, 2011 Notice of Takin•Video Deposition of Darrell Davis.
Sep. 15, 2011 Notice of Taking Video Deposition of Arthur Lipman.
Sep. 15, 2011 Notice of Taking Video Deposition of Edward T. Lentz.
Sep. 15, 2011 Notice of Taking Video Deposition of Joseph Dellaria.
Sep. 15, 2011 Notice of Taking Video Deposition of Randy Bell.
Sep. 15, 2011 Notice of Taking Video Deposition of Timothy Hia.
Sep. 15, 2011 Notice of Taking Video Deposition of William Galbraith.
Sep. 16, 2010 Defendants' Objections to Amended Notice of Deposition of Kathleen Leahy.
Sep. 19, 2011 Defendants' Supplemental Memorandum in Support of Motion for Summary Judgment Regarding Paragraph 3.3 of the Research Agreement.
Sep. 2, 1992 Hardman Letter to Needleman BYU-12-0187.
Sep. 2, 2010 Plaintiffs' Reply in Support of Motion to Compel Production Exhibit 1: Karen Seibert Deposition Excerpt, Jun. 1, 2010 Exhibit 2: Guidelines for Research Records, Apr. 2, 1985.
Sep. 2, 2011 Supplemental Memorandum in Opposition to Defendants' Motion for Partial Summary Judgment Re: Paragraph 3.3 of the Research Agreement and the following Exhibits: Exhibit A: Excerpts of deposition of Stephen Craig, May 24, 2011 Exhibit B: Excerpts of Deposition of Karen Seibert, Jun. 3, 2010.
Sep. 21, 2007 Defendants' Notice of Deposition of Michael Orme.
Sep. 22, 2011 Notice of Taking Video Deposition of Christine Botosan.
Sep. 22, 2011 Notice of Taking Video Deposition of Richard Hoffman.
Sep. 23, 2010 Defendants' Objections to Notice of Deposition Barry Haymore.
Sep. 23, 2010 Defendants' Objections to Notice of Deposition of Ben Zweifel.
Sep. 23, 2010 Notice of Taking Video Deposition of Scott Hauser.
Sep. 28, 2010 Stipulated Motion for Extension of Time to respond to Defendants' Motion for Partial Summary Judgment Exhibit A: [Proposed] Order Granting Stipulated Motion for Extension of Time.
Sep. 28, 2011 Notice of Taking Video Deposition of Judy VanDusen.
Sep. 29, 2008 letter from T. Hankinson to L.R. Williams.
Sep. 29, 2010 Amended Notice of Taking Video Deposition of Joe Bulock.
Sep. 29, 2010 Notice of Taking Video Deposition of Jan Williams.
Sep. 29, 2010 Notice of Taking Video Deposition of John Talley.
Sep. 29, 2010 Notice of Taking Video Deposition of Peter Isakson.
Sep. 29, 2010 Notice of Taking Video Deposition of Philip Needleman.
Sep. 29, 2010 Order Granting Stipulated Motion for Extension of Time to File Responses to Defendants' Motion for Partial Summary Judgment.
Sep. 29, 2011 Consolidated Memorandum in Opposition to Defendants' Motion for Partial Summary Judgment Regarding Count III (Breach of Fiduciary Duty) Plaintiffs' First Amended Complaint, And in Support of Plaintiffs' Cross Motion for Partial Summary Judgment Appendix A. Ex 1: Declaration of Daniel L. Simmons, Jun. 17, 2011 Ex. 2. Research Agreement between BYU and Monsanto Company, effective Aug. 1, 1991 Ex. 3 Dr. Philip Needleman Dep. 1; 516-523, University of Rochester v. G. D. Searle & Co., et al., Aug. 9, 2002 Ex. 4: Philip Needleman, Ph D. Dep. 1-4, 145-148. 165-172, 201-204, Nov. 17, 2010 Ex. 5: Expert Report of John Morris, Feb. 18, 2011 Ex. 6. Expert Report of James A. Severson, Ph.D., Jul. 25, 2011 Ex. 7: Lynn Astle Dep. 1; 6-17; 22-25; 54-57; 106-109; 138-141; 146-149, Feb. 17, 2009 Ex. 8: Michael Orme Dep. 1; 18-25; 42-45; 62-65; 74-77; 130-133, Nov. 15, 2007 Ex. 9: Expert Report by Edward T. Lentz, Aug. 25, 2011 Ex. 10: Oct. 19, 1989 Letter to E. Woolley from D. Simmons Ex.
Sep. 29, 2011 Notice of Issuance of Subpoenas upon DNA Solutions.
Sep. 29, 2011 Plaintiffs' Cross Motion for Partial Summary Judgment on Count III (Breach of Fiduciary Duty) of Their First Amended Complaint.
Sep. 29, 2011 Subpoena to Produce Documents. Information or Objects or to Permit Inspection of Premises in a Civil Action served upon DNA Solutions.
Sep. 29, 2011 Subpoena to Testify at a Deposition in a Civil Action served upon DNA Solutions.
Sep. 30, 2011 Notice of Taking Video Deposition of Dr. Daniel L. Simmons.
Sep. 30, 2011 Notice of Taking Video Deposition of Richard Gering.
Sep. 6, 2011 Motion for Pro Hac Vice Admission and Consent of Local Counsel Amanda L. Major.
Sep. 6, 2011 Motion for Pro Hac Vice Admission and Consent of Local Counsel Donald W. Ward.
Sep. 6, 2011 Motion for Pro Hac Vice Admission and Consent of Local Counsel James L. Quarles III.
Sep. 6, 2011 Order for Pro Hac Vice Admission of Amanda L. Major.
Sep. 6, 2011 Order for Pro Hac Vice Admission of Andrea Weiss Jeffries.
Sep. 6, 2011 Order for Pro Hac Vice Admission of Donald W. Ward.
Sep. 6, 2011 Order for Pro Hac Vice Admission of James L. Quarles III.
Sep. 6. 2011 Motion for Pro Hac Vice Admission and Consent of Local counsel of Andrea Weiss Jeffries.
Sep. 9, 2011 Notice of Appearance of Counsel Kevin W. Bates.
Series of emails between Joseph Reisman and Bryan Zielinski including Jul. 4, 2009 email from Joseph Reisman to Bryan Zielinski; Jul. 27, 2009 email from Joseph Reisman to Bryan Zielinski; and Jul. 27, 2009 email from Bryan Zielinski to Joseph Riesman.
Set/Reset Deadlines as to Plaintiff's Motion re Memorandum in Opposition to Motion, (Alternative) Rule 56(f) Motion, Motion for Suspension of Reissue Proceedings, Motion to Amend/Correct for Leave From and Modification to the Protective Order, Motion for Partial Summary Judgment Regarding Integration of the Research Agreement, Dated Aug. 1, 1991.
Set/Reset Deadlines: Amended Pleadings due by: Plaintiffs Aug. 10, 2009, Defendants Aug. 23, 2009.
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Source List for Documents Found in Pfizer's Production in re University of Rochester v. G.D. Searle.
Stipulated motion for extension of time dated Mar. 23, 2010.
Stipulated motion for Extension of Time for Defendants to file their Opposition to Plaintiffs' Motion for Dispositive Sanctions and proposed order dated Apr. 22, 2010.
Stipulated Motion for Extension of Time in which to respond to the Motion for Hearing to Amend Discovery Plan dated Feb. 5, 2010.
Stipulated motion to amend protective order dated Mar. 19, 2010.
Stipulated Motion to Intervene for a Limited Purpose filed by Movant Winston & Strawn with proposed order dated Apr. 30, 2010.
Subpoena for Deposition, dated May 27, 2008.
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