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WO2000045635A1 - Thiazole derivatives and combinatorial libraries thereof - Google Patents

Thiazole derivatives and combinatorial libraries thereof Download PDF

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Publication number
WO2000045635A1
WO2000045635A1 PCT/US2000/003475 US0003475W WO0045635A1 WO 2000045635 A1 WO2000045635 A1 WO 2000045635A1 US 0003475 W US0003475 W US 0003475W WO 0045635 A1 WO0045635 A1 WO 0045635A1
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Prior art keywords
carbamyl
substituted
ethyl
chloro
benzene
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PCT/US2000/003475
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French (fr)
Inventor
Behrouz Forood
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Lion Bioscience Ag
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Priority to EP00913425A priority Critical patent/EP1150565A1/en
Priority to AU34875/00A priority patent/AU3487500A/en
Publication of WO2000045635A1 publication Critical patent/WO2000045635A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with 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
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the present invention relates generally to the synthesis of compounds comprising heterocyclic rings.
  • the invention provides novel thiazoles as well as novel combinatorial libraries comprised of such compounds.
  • the process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure (s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional "one-at- a-time" synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional "one-at-a-time” synthesis methods, except over a time frame of years or even decades.
  • Patent 5,182,366 describes a method of preparing a mixture of peptides having known composition using three essential steps, dividing an amount of a mixture of amino acid derivatized resins, coupling a subsequent amino acid and combining a known amount of a different resin together to obtain peptide mixtures. Also described are methods to retrieve and analyze the amino acid sequence. Appel et al . in WO PCT 92/09300, describes the synthesis of complex mixtures of solid support-coupled amino acids in which the mixture contains an equimolar representation of each reacted amino acid coupled.
  • Geysen in published European Patent Application 0 138 855 describes a method of synthesizing a peptide library and detecting a peptide comprising a sequence of amino acids which has antigenic activity.
  • Pirrung et al . in U.S. Patent 5,143,854 describe polypeptide arrays synthesized using photoremovable groups. Synthesized combinatorial libraries have provided an extraordinary number of various peptides in such libraries and the availability of rapid screening of the library which can identify lead pharmaceutical peptides.
  • the present invention overcomes the known limitations to classical organic synthesis of thiazoles, for example, as well as the shortcomings of combinatorial chemistry related to heterocycles .
  • the present invention allows for rapid generation of large diverse libraries of complex heterocycles as discrete molecules or as molecules bound to a resin.
  • the present invention can utilize a readily available pool of building blocks, either from commerical sources or available through chemistries known in the art, that can be incorporated into the various regions of the molecule.
  • the method of making the present invention allows for the use of building blocks that contain a wide range of diverse functionalities. Therefore, building blocks, such as those described herein, can provide libraries that consist of large numbers as well as libraries that are extremely diverse with respect to the functionality contained within those libraries.
  • the present invention combines the techniques of solid-phase synthesis of heterocycles and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new thiazole libraries and thiazole compounds.
  • the present invention relates to novel thiazole compounds of formula (I) :
  • the invention further relates to combinatorial libraries containing two or more such compounds, and to the generation of such combinatorial libraries composed of such compounds .
  • Figure 1 provides Reaction Scheme 1 showing the steps of attachment of the amino acid, thio-urea formation, thiazole ring formation and cleavage used in the formation of the 2-aminothiazole library.
  • Figure 2 provides Reaction Scheme 2 showing the synthetic steps for the formation of the branched 2- aminothiazole library.
  • the present invention provides novel compounds, and libraries of novel compounds of Formula (I) :
  • q is an integer selected from 0, 1 or 2 ;
  • R ⁇ is a hydrogen or a functionalized resin
  • R 2 is a hydrogen atom, C ⁇ to C 6 alkyl, Ci to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, phenyl, substituted phenyl, naphthyl , substituted naphthyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or R l7 N and R 2 together is of the formula:
  • R 9 is a hydrogen or a functionalized resin
  • R 3 is Ci to C 8 alkylene, Ci to C 8 substituted alkylene, C 2 to C 7 alkenylene, C 2 to C 7 substituted alkenylene, C 2 to C 7 alkynylene, C 3 to C 7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C 3 to C 7 cycloalkylene, C 3 to C 7 substituted cycloalkylene, C 5 to C 7 cycloalkenylene, C 5 to C 7 substituted cycloalkenylene, C 4 to C 10 cycloalkylalkylene, C 4 to C 10 substituted cycloalkylalkylene, C to C 12 phenylalkylene or C 7 to C 12 substituted phenylalkylene; or
  • R 3 is of the formula:
  • R 10 and R are, independently, a hydrogen atom, C ⁇ to C 6 alkyl, Ci to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 substituted alkynyl, C x to C 7 acyl , C ⁇ to C 7 substituted acyl, C 3 to C 7 cycloalkyl, C 3 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl , C 5 to C 7 substituted cycloalkenyl , a heterocyclic ring, substituted heterocyclic ring, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C 2 to C 7 alkylene, substituted cyclic C 2 to C 7 alkylene
  • R 3 is of the formula (II) or (III) :
  • R 15 is a hydrogen atom, Cj to C 6 alkyl, Ci to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C 7 acyl, Cj to C 7 substituted acyl, Ci to C 7 alkoxycarbonyl, C to C 7 substituted alkoxycarbonyl, C x to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; and R 16 is a hydrogen atom, C a to C 6 alkyl, C to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl,
  • R 3 is of the formula (IV) or (V)
  • n is an integer selected from 1 to 8; R 13 and R 1 ⁇ is the same as described herein above;
  • R 4 is a hydrogen atom, C x to C 6 alkyl, C ⁇ to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, Ci to C 7 alkylsulfonyl, C x to C 7 substituted alkylsulfonyl, C : to C 7 acyl, C ⁇ to C 7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl, C ⁇ to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl or substituted phenylaminocarbonyl; or
  • R 3 , N and R 4 together form a heterocycle or substituted heterocycle
  • R 5 is a hydrogen atom, C x to C 6 alkyl, Ci to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C 7 acyl, Ci to C 7 substituted acyl, Cj to C 7 alkoxycarbonyl, Ci to C, substituted alkoxycarbonyl, C ⁇ to C 7 alkylaminocarbonyl, C, to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl or substituted naphthyl;
  • R 6 is a hydrogen atom, Ci to C 6 alkyl, Ci to C 6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, C x to C 7 acyl, Ci to C 7 substituted acyl, Ci to C 7 alkoxycarbonyl, Ci to C 7 substituted alkoxycarbonyl, C : to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl or substituted naphthyl; or
  • R 5 and R 6 together are fused with the thiazole ring to form a second ring which is a C 5 to C 7 cycloalkyl, C 5 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or
  • R 5 and R 6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is a C 5 to C 7 cycloalkyl, C 5 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring, and the third ring which is directly fused to the second ring is a C 5 to C 7 cycloalkyl, C 5 to C 7 substituted cycloalkyl, C 5 to C 7 cycloalkenyl, C 5 to C 7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
  • R 7 is C x to C 8 alkylene, C : to C 8 substituted alkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C 3 to C 7 cycloalkylene, C 3 to C 7 substituted cycloalkylene, heteroarylene or substituted heteroarylene ;
  • R 8 is a hydrogen atom, C, to C 6 alkyl, C x to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C x to C 7 alkylsulfonyl, C x to C 7 substituted alkylsulfonyl, C x to C 7 acyl, C x to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 7 alkylaminocarbonyl, Ci to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl or substituted phenylaminocarbonyl; or
  • the thiazole compounds and libraries are of the Formula (I) :
  • q is 0 or 1 ;
  • R 3 is of the formula:
  • Rio and R X1 are together or independently a hydrogen atom, Cj to C 6 alkyl, Cj to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C 3 to C, cycloalkyl, substituted C 3 to C 7 cycloalkyl, hydroxymethyl or protected hydroxymethyl; or
  • R 3 is of the formula (II) or (III) :
  • n is an integer selected from 1 or 2;
  • R 12 is hydrogen, halogen, hydroxy, protected hydroxy, Ci to C 7 alkyl, Ci to C 7 substituted alkyl, C x to C 7 alkoxy, C to C 7 substituted alkoxy; and
  • R 13 is a hydrogen atom, Ci to C 5 alkyl, Ci to C 6 substituted alkyl; and
  • R :4 is a hydrogen, ⁇ to C 6 alkyl, C : to C 6 substituted alkyl, Ci to C 7 acyl, Ci to C 7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl , Q x to C 7 alkylaminocarbonyl, Q ⁇ to C 7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl; or
  • R 3 is of the formula (IV) or (V)
  • R 4 is a hydrogen atom, C : to C 6 alkyl or C to C 6 substituted alkyl;
  • R 7 is phenylene or substituted phenylene
  • R 8 is a hydrogen atom, C : to C 6 alkyl or C : to C 6 substituted alkyl; or
  • q is 1 or 2.
  • R 5 and R 6 are fused with the thiazole ring of Formula (I) to form either the two or three ring systems as disclosed above .
  • R 3 is as described above, provided that the carbon to the carbonyl of Formula (I) is chiral . In another preferred embodiment of this invention, R 3 is as described above, except that it does not include methylene. In another preferred embodiment of this invention, R 3 is as described above, except that it does not include C : to C 8 alkylene. In another preferred embodiment of this invention, R 3 is as described above, except that it does not include C x to C 8 alkylene or C x to C 8 substituted alkylene.
  • the compounds are as described above, provided that provided that they are not where q is 0, R l t R 2 , R 4 and R 6 are each a hydrogen atom, R 3 is methylene and R 5 is 4-fluoromethyl .
  • the thiazole compounds and libraries are of the Formula (I) :
  • Ri is a hydrogen atom or polystyryl 4-methylbenzhydryl
  • R is a hydrogen atom, 2- (1-pyrrolidino) ethyl,
  • R 3 is methylene, 1 , 2 -ethylene, 1 , 3-propylene, 1,4- butylene, 1 , 5-pentylene, 1 , 6-hexylene, 1, 7-heptanylene, 1, 8-octanylene, cyclohexyl-4 -methylene, 1-methyl-1, 1- ethylene, D-1 , 1-butylene, D-1 , 1-ethylene, D-1,1- pentylene, D-1 , 1-propylene, D-5-amino-l , 1-pentylene, D-l- amino-1, 5-pentylene, D-2- (2-napthyl) -1, 1-ethylene, D-2- (2-thienyl) -1, 1-ethylene, D-2- (4-ethoxyphenyl) -1, 1- ethylene, D-2- (4-fluoropehnyl) -1 , 1-ethylene, D-2- (4- hydroxyphenyl ) -1, 1-ethylene, D-2- (N-formyl-indo
  • R 3 is of the formula (II), (III) , (IV) or (V) :
  • R 12 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, pentane, methoxy, ethoxy, propoxy or iso-proproxy;
  • R 13 is a hydrogen atom, 2-pyridinemethyl , allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl , 3-methylbenzyl , 4-methylbenzyl, 2-fluorobenzyl , 3-fluorobenzyl , 4 -fluorobenzyl, 3 - (1-imidazole) propyl ,
  • R i4 is a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl , 4-methylbenzyl , 2-fluorobenzyl, 3-fluorobenzyl , 4 -fluorobenzyl , 3 - (1-imidazole ) propyl , 4-aminomethylbenzyl , -methoxybenzyl , 3-chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl , piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl,
  • R 14 is acetyl, alpha-methylcinnamyl, benzoyl , crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl , 4-ethoxybenzoyl , isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl , 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3 - (3-pyridyl) acrylyl , trimethylacetyl , triphenylacetyl,
  • R i4 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl ,
  • R ⁇ 4 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3-methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2 - (carbamyl) glutarate diethyl ester, (s)
  • R 15 is hydrogen, methyl, t-butyl, carbomethoxymethyl , ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4-methylphenyl , 4- fluorophenyl, 3-fluorophenyl , 4-cyanophenyl, 2- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- chlorophenyl , 3 , 4-difluorophenyl, 4-nitrophenyl, 3,4- dihydroxyphenyl, 3-nitrophenyl, 3 -methyl -4 -chlorophenyl, adamantyl , 2 , 5-dimethoxyphenyl, 3 -chloro-4-methylphenyl, 5- (3 -carboethoxy) isoxazole, 4-phenylphenyl, 3,4- dichlorophenyl, 6- (2-oxo) -1 , 2 , 3 , 4-t
  • R 4 is a hydrogen atom, 2-pyridinemethyl , allyl, 2-methoxyethyl , benzyl, 2-methylbenzyl , 3-methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl , 3 -fluorobenzyl, 4-fluorobenzyl , 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl ,
  • R 4 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl,
  • 3-thiopheneacetyl 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl , 3 , 5-dichloro-4-hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3-lndolepropionyl, 2, 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl, succinamyl,
  • R 4 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl,
  • R 4 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - ( -) -1- (carbamyl) - (1-naphthyl) ethane, (s) - ( +) -1- (carbamyl) - (1 -naphthyl) ethane, (s) -(+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (
  • R 3 , R 4 and the attached nitrogen atom of Formula (I) together form pyrrolidine, 4- (R) -hydroxy-2- (S) - pyrrolidine, 4- (R) -hydroxy-2- (R) -pyrrolidine, 4-(S)- hydroxy-2- (S) -pyrrolidine, 4- (S) -hydroxy-2- (S) - pyrrolidine, 4- (R) -benzyloxy-2- (S) -pyrrolidine, 4-(R)- benzyloxy-2- (R) -pyrrolidine, 4- (S) -benzyloxy-2- (S) - pyrrolidine, 4- (S) -benzyloxy-2- (S) -pyrrolidine, 4- piperidino, 3- (R) -piperidino, 3 - (S) -piperidino, 2- (R) - piperidino, 2- (S) -piperidino, octahydroisoquinoline or dihydroindoy
  • R 5 is methyl, t-butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl , carboethoxy, phenyl, 4-methylphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-cyanophenyl , 2-methoxyphenyl , 3-methoxyphenyl, 4- methoxyphenyl , 4 -chlorophenyl , 3 , 4 -difluorophenyl , 4- nitrophenyl, 3 , 4-dihydroxyphenyl , 3-nitrophenyl , 3- methyl -4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, 3- chloro-4-methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4 -dichlorophenyl , 6- (2-oxo
  • bromophenyl 2- (5 -chloro-3 -methyl ) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5- [3 -(3 ',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ' , 4 ' - dichlorophenyl) ] isoxazole, 5- (3 -phenyl) isoxazole; and
  • R 6 is hydrogen, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl, 4-methylphenyl; or
  • R 7 is 1 , 3 -phenylene, 3 -methoxy- 1 , 4-phenylene, 2 -methoxy- 1, 4-phenylene, 2-chloro-l , 4-phenylene, 1 , 4-phenylene, 2- methoxy-4-chloro-l , 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l , 3 -phenylene, 2-chloro- 1, 3 -phenylene, 4-chloro-l, 3 -phenylene, 6-chloro-l, 3- phenylene, 5-carboxy- 1 , 3 -phenylene, 5-methoxycarbonyl- 1 , 3 -phenylene, 2 , 6-dimethoxy-l , 3 -phenylene, 2 , 5-dichloro- 1 , 3 -phenylene, 2-bromo-1 , 3 -phenylene, 6-bromo-l,3- phenylene, 2 , 6-d
  • R 8 is a hydrogen atom, 2-pyridinemethyl , allyl,
  • R 8 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl , hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl , p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl , tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl, nicotin
  • R 8 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl,
  • R 8 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - ( - ) -1- (carbamyl) - (1 -naphthyl) ethane, (s) - ( + ) -1- (carbamyl) - (1 -naphthyl) ethane, (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4 -methylvalerate methyl ester, (s) -
  • the present invention also provides a method of preparing libraries containing discrete compounds of Formula (I), in particular, thiazoles, by reacting a resin-bound amine with an amino containing carboxylic acid, where the amino group can be a free amino group, a protected amino group or a masked amino group, such as, for example, a nitro group; and deprotecting or unmasking the amino group, if need be, to give a new amino bound resin.
  • the amino group is preferably a protected amino group.
  • the starting resin-bound amine is preferably a commercially available resin, such as, for example, MBHA (i.e., 4-methylbenzhydrylamine) , or prepared by synthetic methods known to those skilled in the art, such as, for example, the reductive alkylation of MBHA resin with an aldehyde or ketone to give a nitrogen-substituted resin or through the use of an aldehyde-bound resin prepared from Wang resin and reductively alkylating with an amine or diamine to give a nitrogen-substituted resin or yet another method, such as, displacing an alkyl halide-bound resin with an amine or diamine.
  • MBHA i.e., 4-methylbenzhydrylamine
  • the new amino-bound resin is converted to a thiourea with thiophosgene or a thiophosgene equivalent, such as, for example, 1,1'- thiocarbonyldiimidazole, and the resulting intermediate is subsequently allowed to react with ammonia or an ammonia equivalent, to give a thiourea-bound resin.
  • thiourea-bound resin is allowed to react with an ⁇ - haloketone and after cyclization affords a thiazole library containing discrete compounds of Formula (I).
  • Another aspect of this invention is the use of an orthogonally protected amino group that can be introduced in the above mentioned amino containing carboxylic acid and can be further modified, in an dependent or independent manner, either before or after the formation of the thiazole.
  • the amino group, introduced in the amino containing carboxylic acid is masked as a nitro group and converted into the amino group through the use of any one of the different reductive methods know to one skilled in the art, such as, for example, SnCl 2 .
  • the amino group is protected by any one of the variety protecting groups known in the art, such as, for example, a benzyloxycarbonyl (i.e, Cbz), tert-butyloxycarbonyl (i.e., t-Boc) and the like.
  • the amino group either after deprotection or after reduction of a nitro group, can optionally be reacted with an aldehyde or ketone to give a substituted nitrogen.
  • the resulting substituted nitrogen can be optionally alkylated to give a disubstituted nitrogen or reacted with an electrophile such as, for example, an acyl chloride, isocyanates or sulfonyl chlorides to give an amide, carbamoyl or sulfonamide respectively.
  • an electrophile such as, for example, an acyl chloride, isocyanates or sulfonyl chlorides to give an amide, carbamoyl or sulfonamide respectively.
  • the nitrogen, either substituted or unsubstituted can be reacted, as mention above herein, with thiophosgene or a thiophosgene equivalent followed by ammonia to give a thiourea that can be converted into a thiazole library through the use of an ⁇ -haloketone .
  • the library prepared from the above mentioned method can be useful for screening the library on the resin or alternatively can be cleaved from the resin as discrete compounds and screened in absence of resin.
  • the methods described above further comprise the step of cleaving the library from the resin to give discrete compounds.
  • R 10 R 11 can independently be in the R or S configuration, or a mixture of the two.
  • the chiral centers can be further designated as R or S or R,S or d,D, 1,L or d,l, D,L.
  • C 1 to C 6 alkyl denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert -butyl, amyl, tert-amyl, hexyl and the like.
  • the preferred “Cj to C 6 alkyl” groups are methyl, iso-butyl, sec-butyl and iso-propyl .
  • C 2 to C 7 alkenyl denotes such radicals as vinyl, allyl, 2-butenyl, 3-butenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight and branched chains.
  • C 2 to C 7 alkynyl denotes such radicals as ethynyl, propynyl , 2-butynyl, 2-pentynyl, 3- pentyny1 , 2 - hexynyl , 3 -hexyny1 , 4 -hexyny1 , 2 -heptyny1 , 3-heptynyl, 4- heptynyl , 5-heptynyl as well as di- and tri-ynes of straight and branched chains.
  • Ci to C 6 substituted alkyl denotes that the above Cj to C 6 alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl groups and Ci to C 8 alkylene groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C 3 to C 7 cycloalkyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C ⁇ to C 7 alkoxy, Cj to C 7
  • Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3 -oxo-but-1-yl , cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl , trityloxymethyl , propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylammomethyl , methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl , chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4- dichloro (n-butyl) , 2-aminopropyl , 1-chloroethyl , 2- chloroethyl, 1- bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroe
  • Examples of the above substituted alkenyl groups include styrenyl, 3-chloro-propen-l-yl , 3-chloro- buten-1-yl, 3-methoxy-propen-2-yl, 3 -phenyl -buten-2 -yl , l-cyano-buten-3-yl and the like.
  • the geometrical isomerism is not critical, and all geometrical isomers for a given substituted alkenyl can be used.
  • Examples of the above substituted alkynyl groups include phenylacetylen-1-yl, 1-phenyl -2 -propyn-1- yl and the like.
  • C 2 to C 7 alkenylene denotes an alkene group that is linked by two different substitutents.
  • C 2 to C 7 alkynylene denotes an alkyne group that is linked by two different substitutents.
  • C 2 to C 7 substituted alkenylene and “C 3 to C 7 substituted alkynylene” as used herein denote, respectively, an alkene group or alkyne group that is linked by two different substitutents and is further substituted by one or two halogen, hydroxy, protected hydroxy, oxo, protected oxo, C 3 to C 7 cycloalkyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C x to C, alkoxy, C : to C acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano,
  • oxo denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety.
  • protected oxo denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety.
  • C x to C 7 alkoxy denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
  • a preferred alkoxy is methoxy.
  • d to C 7 substituted alkoxy means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Ci to C 6 substituted alkyl.
  • C 7 to C 13 phenylalkoxy as used herein means "Cj . to C 7 alkoxy" bonded to a phenyl radical .
  • C 1 to C 7 acyloxy denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.
  • C ⁇ to C 7 acyl encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like.
  • Preferred acyl groups are acetyl and benzoyl.
  • C x to C 7 substituted acyl denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C to C 7 alkoxy, C x to C 7 acyl, C ⁇ to C 7 acyloxy, nitro, Cj to C 6 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano, methylsulfonylamino, thiol, Ci to C 4 alkylthio or C x to C 7 alkyl,
  • Cj to C 7 substituted acyl groups examples include 4-phenylbutyroyl, 3-phenylbutyroyl, 3-phenylpropanoyl, 2- cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and 3 -dimethylaminobenzoyl .
  • C 3 to C 7 cycloalkyl includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
  • C 5 to C 7 cycloalkyl includes the cyclopentyl, cyclohexyl or cycloheptyl rings.
  • C 3 to C 7 substituted cycloalkyl and “C 5 to C 7 substituted cycloalkyl” indicate the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Ci to C 4 alkylthio, Ci to C 4 alkylsulfoxide, C x to C 7 alkylsulfonyl, C ⁇ to C 4 substituted alkylthio, Ci to C 4 substituted alkylsulfoxide, C ⁇ to C 7 substituted alkylsulfonyl, C ⁇ to C 6 alkyl, C x to C 7 alkoxy, Cj to C 6 substituted alkyl, C ⁇ to C 7 substituted alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, pheny
  • C 3 to C 7 cycloalkylene means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups.
  • C 3 to C 7 substituted cycloalkylene means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substitution in the same manner as in relation to C 3 to C 7 substituted cycloalkyl .
  • C 5 to C 7 cycloalkenyl indicates a 1,2, or 3- cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring
  • substituted C 5 to C 7 cycloalkenyl denotes the above C 5 to C 7 cycloalkenyl rings substituted by a C x to C 6 alkyl radical, halogen, hydroxy, protected hydroxy, C x to C 7 alkoxy, trifluoromethyl , carboxy, protected carboxy, oxo, protected oxo, (monosubstituted) amino, protected
  • C 5 to C 7 cycloalkenylene is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups.
  • substituted C 5 to C 7 cycloalkenylene means a cycloalkeneylene further substituted by halogen, hydroxy, protected hydroxy, C ⁇ to C 4 alkylthio, C a to C 4 alkylsulfoxide, C : to C 7 alkylsulfonyl, x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 7 substituted alkylsulfonyl , C ⁇ to C 6 alkyl, C : to C 7 alkoxy, C x to C 6 substituted alkyl, C ⁇ to C 7 alkoxy, oxo, protected oxo, (monosubstitute
  • heterocycle or “heterocyclic ring” denotes optionally substituted five-membered or six- membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered or six-membered rings may be saturated, fully saturated or partially unsaturated, with fully saturated rings being preferred.
  • An "amino- substituted heterocyclic ring” means any one of the above-described heterocyclic rings is substituted with at least one amino group.
  • Preferred heterocyclic rings include pyrrolidino, morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen-yl .
  • substituted heterocycle or “substituted heterocyclic ring” means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which can be the same or different.
  • the substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, Cj to C 7 alkoxy, ⁇ to C 7 substituted alkoxy, C 1 to C 7 acyl, C ⁇ to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino carboxamide, protected carboxamide or trifluoromethyl groups.
  • heteroaryl means a heterocyclic aromatic derivative which is a five-membered or six- membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms.
  • heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, phthalimido, thiazolo and the like.
  • substituted heteroaryl means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which can be the same or different.
  • the substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C : to C 7 acyl, C ⁇ to C 7 substituted acyl, C ⁇ to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl groups.
  • heteroarylene means the above described definition for “heteroaryl” wherein the heteroaryl is bonded at two positions connecting together two separate additional groups.
  • substituted heteroarylene means the above described heteroarylene is substituted with, for example, one or more, and preferably one or two, substituents which can be the same or different .
  • the substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C : to C 7 substituted alkoxy, Ci to C 7 acyl, C ⁇ to C 7 substituted acyl, Ci to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl groups.
  • heteroarylalkylene means the above described definition for “heteroaryl” wherein the heteroaryl is substituted with an alkylene and is bonded at two positions connecting together two separate additional groups.
  • the definition includes groups of the formula : -heteroaryl -alkyl- and -alkyl-heteroaryl-alkyl- where "-" represents a bond.
  • substituted heteroarylalkylene means the above described heteroarylalkylene is substituted on the heteroaryl group, alkylene group or both with, for example, one or more, and preferably one or two, substituents which can be the same or different.
  • the substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C 2 to C 7 acyl, C x to C 7 substituted acyl, Ci to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl groups .
  • C 7 to C 12 phenylalkyl denotes a C x to
  • C 6 alkyl group substituted at any position by a phenyl, substituted phenyl, heteroaryl or substituted heteroaryl.
  • a phenyl substituted phenyl, heteroaryl or substituted heteroaryl.
  • Examples of such a group include benzyl, 2-phenylethyl, 3 -phenyl (n-propyl) , 4-phenylhexyl, 3 -phenyl (n-amyl) , 3- phenyl (sec-butyl) and the like.
  • Preferred C 7 to C 12 phenylalkyl groups are the benzyl and the phenylethyl groups .
  • C 7 to C 12 substituted phenylalkyl denotes a C 7 to C 12 phenylalkyl group substituted on the Ci to C 6 alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, C 1 to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, C ⁇ to C 7 substituted alkoxy, C x to C 7 acyl, Ci to C 7 substituted acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl , carboxamide, protected carboxamide, cyano,
  • C 7 to C i2 substituted phenylalkyl examples include groups such as 2 -phenyl- 1- chloroethyl, 2- (4-methoxyphenyl) ethyl, 4- (2 , 6-dihydroxy phenyl) n-hexyl, 2- (5-cyano-3-methoxyphenyl) n-pentyl, 3- (2 , 6-dimethylphenyl) n-propyl, 4-chloro-3 -aminobenzyl, 6- (4-methoxyphenyl) -3 -carboxy (n-hexyl) , 5- (4- aminomethylphenyl) - 3- (aminomethyl) n-pentyl , 5-phenyl-3- oxo-n-pent-1-yl and the like.
  • C 7 to C 12 phenylalkylene specifies a
  • C 7 to C 12 phenylalkyl as defined above, where the phenylalkyl radical is bonded at two positions connecting together two separate additional groups.
  • the definition includes groups of the formula: -phenyl-alkyl- and - alkyl-phenyl-alkyl- where "-" represents a bond.
  • C 7 to C 12 substituted phenylalkylene means a C 7 to C 12 phenylalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, C to C 4 alkylthio, C x to C 4 alkylsulfoxide, C ⁇ to C 7 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 7 substituted alkylsulfonyl, C x to C 6 alkyl, C x to C 7 alkoxy, C to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted
  • substituted phenyl specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, C x to C 7 acyl, C x to C 7 substituted acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, trifluoromethyl and phenyl, wherein the second phenyl is substituted or unsubstituted, such that, for example, a biphenyl, wherein the second
  • substituted phenyl includes a mono- or di (halo) phenyl group such as 2 , 3 or 4 -chlorophenyl, 2 , 6 -dichlorophenyl , 2 , 5 -dichlorophenyl , 3 , 4 -dichlorophenyl, 2, 3 or 4 -bromophenyl, 3 , 4-dibromophenyl, 3 -chloro-4 -fluorophenyl, 2, 3 or 4-fluorophenyl and the like; a mono or di (hydroxy) phenyl group such as 2, 3 or 4-hydroxyphenyl,
  • substituted phenyl represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3 -chloro-4 - hydroxyphenyl , 2 -methoxy-4 -bromophenyl , 4-ethyl-2-hydroxyphenyl, 3 -hydroxy-4-nitrophenyl, 2 -hydroxy 4 -chlorophenyl and the like.
  • phenoxy denotes a phenyl bonded to an oxygen atom.
  • substituted phenoxy specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C x to C 6 alkyl, Ci to C 7 alkoxy, C x to C 7 substituted alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl .
  • substituted phenoxy examples include 2-methylphenoxy, 2-ethylphenoxy, 2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy,
  • 2-tert-butylphenoxy 2-allylphenoxy, 2-propenylphenoxy, 2 -eyelopentylphenoxy, 2 -fluorophenoxy, 2- (trifluoromethyl) phenoxy, 2-chlorophenoxy, 2-bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy, 2-isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy, 3 -isopropylphenoxy, 3 -tert-butylphenoxy, 3 -pentadecylphenoxy, 3- (trifluoromethyl) phenoxy, 3-fluorophenoxy, 3-chlorophenoxy, 3 -bromophenoxy, 3-iodophenoxy, 3 -methoxyphenoxy, 3- (trifluoromethoxy) phenoxy, 4-methylphenoxy,
  • C 7 to C 13 substituted phenylalkoxy denotes a C 7 to C 13 phenylalkoxy group wherein the C x to C 7 alkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, C x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano, thiol, C x to C 4 alkylthio and C x to C 7 alkylsulfonyl groups; and/or the phenyl group can be substituted
  • C 7 to C 13 substituted phenylalkoxy examples include groups such as 2- (4- hydroxyphenyl) ethoxy, 4- (4-methoxyphenyl) butoxy, (2R)-3- phenyl-2-amino-propoxy, (2S) -3-phenyl-2-amino-propoxy, 2-indanoxy, 6 -phenyl-1-hexanoxy, cinnamyloxy, (+/-) -2 -phenyl-1-propoxy, 2 , 2 -dimethyl-3 -phenyl-1-propoxy and the like.
  • phthalimide means a cyclic imide which is made from phthalic acid, also called 1, 2-benzenedicarboxylic acid.
  • substituted phthalimide specifies a phthalimide group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 6 alkyl, C x to C 7 alkoxy, Ci to C 7 substituted alkoxy, Cl to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • substituted phthalimides examples include 4 , 5-dichlorophthalimido, 3 -fluorophthalimido, 4-methoxyphthalimido, 3-methylphthalimido, 4-carboxyphthalimido and the like.
  • substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C 6 alkyl, Ci to C 7 alkoxy, C x to C, acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • substituted naphthyl includes a mono or di (halo) naphthyl group such as 1, 2, 3, 4, 5, 6, 7 or 8-chloronaphthyl, 2, 6-dichloronaphthyl, 2, 5-dichloronaphthyl, 3, 4-dichloronaphthyl , 1, 2, 3, 4, 5, 6, 7 or 8-bromonaphthyl, 3, 4-dibromonaphthyl, 3-chloro-4-fluoronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-fluoronaphthyl and the like; a mono or di (hydroxy) naphthyl group such as l, 2, 3, 4, 5, 6, 7 or 8-hydroxynaphthyl, 2, 4-d
  • 4-di (hydroxymethyl) naphthyl a mono- or di (amino) naphthyl or (protected amino) naphthyl such as l, 2, 3, 4, 5, 6, 7 or 8- (amino) naphthyl or 2, 4- (protected amino) -naphthyl , a mono- or di (aminomethyl) naphthyl or (protected aminomethyl) naphthyl such as 2 , 3, or 4- (aminomethyl) naphthyl or 2, 4- (protected aminomethyl)- naphthyl; or a mono- or di- (N-methylsulfonylamino) naphthyl such as l, 2, 3, 4, 5, 6, 7 or 8- (N-methylsulfonylamino) naphthyl .
  • substituted naphthyl represents disubstituted naphthyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxynaphth-l-yl, 3-chloro-4- hydroxynaphth-2-yl, 2-methoxy-4 -bromonaphth-1 -y1 , 4-ethyl-2-hydroxynaphth-l-yl, 3 -hydroxy-4 -nitronaphth-2- yl, 2 -hydroxy-4-chloronaphth- 1-yl, 2 -methoxy- 7- bromonaphth-1-yl , 4-ethyl-5-hydroxynaphth-2-yl ,
  • naphthylene means a naphthyl radical bonded at two positions connecting together two separate additional groups.
  • substituted napthylene means a naphthylene group that is further substituted by halogen, hydroxy, protected hydroxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 7 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 7 substituted alkylsulfonyl , C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phen
  • halo and halogen refer to the fluoro, chloro, bromo or iodo atoms. There can be one or more halogen, which are the same or different. Preferred halogens are chloro and fluoro.
  • (monosubstituted) amino refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, phenyl sulfonyl, substituted phenyl sulfonyl, C x to C 7 alkylsulfonyl, C x to C 7 substituted alkylsulfonyl , C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 acyl, C x to C 7 substituted acyl, C 2 to C 7 alkenyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 alkynyl, C 2 to C 7 substituted alkynyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl and heterocyclic ring.
  • the (monosubstituted) amino can additionally have an amino-protecting group as encompassed by the term
  • (disubstituted) amino refers to an amino group with two substituents chosen from the group consisting of phenyl, substituted phenyl, C x to C 6 alkyl, Ci to C 6 substituted alkyl, C x to C 7 acyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C 7 to C 12 phenylalkyl, and C 7 to C 12 substituted phenylalkyl.
  • the two substituents can be the same or different.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule.
  • protected (monosubstituted) amino means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
  • protected carboxamide means there is an amino-protecting group on the carboxamide nitrogen.
  • amino-protecting groups include the formyl ("For") group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl , and iodoacetyl groups, urethane-type blocking groups, such as t-butoxycarbonyl ("Boc”), 2- (4-biphenylyl) propyl- 2 -oxycarbonyl (“Bpoc”), 2-phenylpropyl-2-oxycarbonyl (“Poc”) , 2- (4-xenyl) isopropoxycarbonyl , 1, 1-diphenylethyl-l- oxycarbonyl, 1 , 1-diphenylpropyl-l-oxycarbonyl , 2- (3, 5- dimethoxyphenyl) propyl -2 -oxycarbonyl (“Ddz”), 2- (p- toluyl ) propyl-2 -oxycarbonyl , cycl
  • amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the compounds.
  • Preferred amino-protecting groups are Boc, Cbz and Fmoc.
  • Further examples of amino-protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 7, M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed.
  • protected guanidino refers to an "amino-protecting group" on one or two of the guanidino nitrogen atoms. Examples of “protected guanidino” groups are described by T.W. Greene and P.G.M. Wuts; M. Bodanzsky; and Stewart and Young, supra.
  • carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • carboxylic acid protecting groups include t-butyl, 4-nitrobenzyl, 4 -methoxybenzyl, 3 , 4 -dimethoxybenzyl , 2 , 4 -dimethoxybenzyl , 2,4, 6-trimethoxybenzyl , 2,4, 6-trimethylbenzyl , pentamethylbenzyl, 3 , 4-methylenedioxybenzyl , benzhydryl, 4,4' -dimethoxytrityl , 4 , 4 ' , 4 " -trimethoxytrityl , 2-phenylpropyl, trimethylsilyl , t-butyldimethylsilyl, phenacyl, 2 , 2 , 2-trichloroethyl
  • carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry, " J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapter 5, each of which is incorporated herein by reference.
  • a related term is "protected carboxy, " which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
  • protected carboxymethyl refers to a carboxy portion of the carboxymethyl substituted with one of the above carboxy-protecting groups.
  • hydroxy-protecting group refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl , methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4 , 4 ' -dimethoxytrityl, 4 , 4 ', 4 " -trimethoxytrityl , benzyl, allyl, trimethylsilyl, (t-butyl) dimethylsilyl , 2 , 2 , 2-trichloroethoxycarbonyl groups and the like.
  • hydroxy-protecting groups are not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of hydroxy-protecting groups are described by C.B. Reese and E. Haslam,
  • C x to C 4 alkylthio refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.
  • C x to C 4 alkylsulfoxide indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide and the like.
  • C x to C 7 alkylsulfonyl encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like.
  • phenylthio " "phenylsulfoxide, “ and “phenylsulfonyl” specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group.
  • substituted phenylthio " “substituted phenylsulfoxide, " and “substituted phenylsulfonyl” means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl.”
  • C to C 7 alkylaminocarbonyl means a
  • Ci to C 7 alkyl attached to a nitrogen of the aminocarbonyl group examples include methylaminocarbonyl , ethylaminocarbonyl , propylaminocarbonyl, butylaminocarbonyl .
  • the term " C x to C 7 substituted alkylaminocarbonyl” denotes a substituted alkyl bonded to a nitrogen of the aminocarbonyl group, which alkyl may be substituted as described above in relation to C x to C 7 substituted alkyl.
  • C to C 7 substituted alkylaminocarbonyl examples include, for example, methoxymethylaminocarbonyl , 2 -chloroethylaminocarbonyl , 2-oxopropylaminocarbonyl and 4-phenylbutylaminocarbonyl.
  • C x to C 7 alkoxycarbonyl means a “Ci to C 7 alkoxy” group attached to a carbonyl group.
  • C x to C 7 substituted alkoxycarbonyl denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to C x to C 6 substituted alkyl.
  • phenylaminocarbonyl means a phenyl attached to a nitrogen of the aminocarbonyl group.
  • substituted phenylaminocarbonyl denotes a substituted phenyl bonded to a nitrogen of the aminocarbonyl group, which phenyl may be substituted as described above in relation to substituted phenyl.
  • substituted phenylaminocarbonyl include 2 -chlorophenylaminocarbonyl (from 2-chlorophenylisocyanate) , 3 -chlorophenylaminocarbonyl (from 3-chlorophenylisocyanate) , 2-nitorphenylaminocarbonyl (from
  • C x to C 6 alkylaminothiocarbonyl means a Ci to C 6 alkyl attached to an aminothiocarbonyl group, wherein the alkyl has the same meaning as defined above.
  • C x to C 6 alkylaminothiocarbonyl examples include methylaminothiocarbonyl (from methylisothiocyanate) , ethylaminothiocarbonyl (from ethylisothiocyanate) , propylaminothiocarbonyl (from propylisothiocyanate) , butylaminothiocarbonyl (from butylisothiocyatate) .
  • C x to C 6 substituted alkylaminothiocarbonyl denotes a substituted alkyl bonded to an aminothiocarbonyl group, wherein the alkyl may be substituted as described above in relation to C x to C 6 substituted alkyl.
  • C x to C 5 substituted alkylaminothiocarbonyl examples include, for example, methoxymethylaminothiocarbonyl (from methoxymethylisothiocyanate) , 2 -chloroethylaminothiocarbonyl (from 2-chloroethylisothiocyanate) , 2-oxopropylaminothiocarbonyl (from 2-oxopropylisothiocyanate) , and
  • phenylaminothiocarbonyl means a phenyl attached to an aminothiocarbonyl group, wherein the phenyl has the same meaning as defined above.
  • substituted phenylaminothiocarbonyl denotes a substituted phenyl bonded to an aminothiocarbonyl group, wherein phenyl may be substituted as described above in relation to substituted phenyl.
  • substituted phenylaminothiocarbonyls include 2-chlorophenylaminothiocarbonyl (from
  • C x to C 8 alkylene or "C 2 to C 8 alkylene” means a C to C 8 or C 2 to C 8 alkyl group where the alkyl radical is bonded at two positions or, regarding a C x alkylene, at one position, connecting together two separate additional groups.
  • Examples of “ C x to C 8 alkylene” include methylene, 1,2-ethyl, 1,1-ethyl, 1, 3 -propyl .
  • C x to C e substituted alkylene means a Ci to C 8 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent.
  • n C x to C 8 substituted alkylene include aminomethylene, 1- (amino) -1, 2 -ethyl, 2- (amino) -1, 2 -ethyl, 1- (acetamido) -1, 2-ethyl, 2- (acetamido) -1 , 2-ethyl, 2- hydroxy-1, 1-ethyl, 1- (amino) -1 , 3-propyl .
  • phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups.
  • phenylene includes 1, 2 -phenylene, 1,3- phenylene, and 1 , 4-phenylene .
  • substituted phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, and wherein the phenyl is substituted as described above in relation to "substituted phenyl.”
  • substituted phenylene include thoses derived from the building blocks, namely, 3 -methyoxy-1, 4-phenylene from 4 -hydroxy- 3-methoxybenzonitrile, 2-fluoro- 1, 4-phenylene from 2- fluoro-4 -hydroxybenzonitrile , 3 , 5-Dibromo-l , 4 -phenylene from 3 , 5 -dibromo-4 -hydroxybenzonitrile, 3 , 5-diiodo-l , 4- phenylene from 3 , 5-diiodo-4-hydroxybenzonitrile, 3,4- Dihydroxy-1, 2 -phenylene from 3 , 4-dihydroxybenzonitrile, 2 ,
  • cyclic C 2 to C 7 alkylene defines such a cyclic group bonded (“fused") to the phenyl radical resulting in a bicyclic ring system.
  • the cyclic group may be saturated or contain one or two double bonds.
  • the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic C 2 to C 7 heteroalkylene.
  • the cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, Ci to C 4 acyloxy, formyl, C x to C 7 acyl, C x to C 6 alkyl, C x to C 7 alkoxy, Ci to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 7 alkylsulfonyl , halo, amino, protected amino,
  • the cyclic alkylene or heteroalkylene group fused on to the benzene radical can contain two to ten ring members, but preferably contains three to six members. Examples of such saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro- indanyl and a tetralin ring. When the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or indolyl .
  • fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl , dihydropyrrolo, or dihydropyridinyl ring.
  • fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring.
  • fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring.
  • cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring.
  • Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring.
  • Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl.
  • C 4 to C 10 cycloalkylalkylene means a cycloalkyl substituted with an alkyl group.
  • the cycloalkylalkylene radical is bonded at two positions connecting together two separate additional groups where one bond is directly to the cycloalkyl and the second bond is to the alkyl.
  • Examples of “cycloalkylalkylene” include cyclohexyl -2 -methylene, cyclohexyl -3 -methylene, and cyclohexyl -4 -methylene.
  • C 4 to C 10 substituted cycloalkylalkylene means a cycloalkylalkylene group that is substituted at the cycloalkyl group or the alkyl group or both with one or more groups but preferrably, one or two groups, such as halogen, hydroxy, protected hydroxy, Ci to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 7 alkylsulfonyl, C to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C ⁇ to C 7 substituted alkylsulfonyl, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, oxo, protected oxo, (monosubstituted) amino,
  • carbamoyl means an -NCO- group where the radical is bonded at two positions connecting two separate additional groups.
  • salt encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D- glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
  • organic or inorganic cation refers to counter- ions for the carboxylate anion of a carboxylate salt.
  • the counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium) ; ammonium and mono-, di- and tri -alkyl amines such as trimethylamine, cyclohexylamme; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.
  • the compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent.
  • the solvates and hydrates of such compounds are included within the scope of this invention.
  • One or more compounds of the invention, even when in a library, can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester- form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non- esterified forms of the compounds.
  • Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the - ⁇ C x to C 7 ) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl , isopropoxyethyl and the like; the 2-oxo-l, 3 -diooxlen-4- ylmethyl groups, such as 5-methyl-2-oxo-l , 3 -dioxolen-4- ylmethyl, 5 -phenyl -2-oxo-l , 3-dioxolen-4-ylmethyl and the like; the C x to C 4 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl and the like; the acyloxymethyl groups, for example pivaloyloxymethyl , pi
  • amino acid includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids.
  • amino acid also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally- occurring amino acids.
  • non-naturally-occurring amino acids include, for example, norleucine ("Nle”), norvaline (“Nva”), L- or D- naphthalanine, ornithine (“Orn”), homoarginine (homoArg) and others well known in the art, such as those described in M.
  • the term "functionalized resin” means any resin, crosslinked or otherwise, where functional groups have been introduced into the resin, as is common in the art. Such resins include, for example, those functionalized with amino, alkylhalo, formyl or hydroxy groups. Such resins which can serve as solid supports are well known in the art and include, for example, 4 -methylbenzhydrylamine-copoly (styrene-1% divinylbenzene) (MBHA) , 4 -hydroxymethylphenoxymethyl-copoly (styrene-1% divinylbenzene) , 4 -oxymethyl-phenyl-acetamido- copoly (stryene-1% divinylbenzene) (Wang), 4- (oxymethyl) - phenylacetamido methyl (Pam) , and TentagelTM, from Rapp Polymere Gmbh, trialkoxy-diphenyl-methyl ester- copoly (styrene-1% divinylbenzene) (
  • a "combinatorial library” is an intentionally created collection of differing molecules which can be prepared by the means provided below or otherwise and screened for biological activity in a variety of formats (e.g., libraries of soluble molecules, libraries of compounds attached to resin beads, silica chips or other solid supports) .
  • a "combinatorial library, " as defined above, involves successive rounds of chemical syntheses based on a common starting structure.
  • the combinatorial libraries can be screened in any variety of assays, such as those detailed below as well as others useful for assessing their biological activity.
  • the combinatorial libraries will generally have at least one active compound and are generally prepared such that the compounds are in equimolar quantities.
  • a combinatorial library of the invention can contain two or more of the above-described compounds.
  • the invention further provides a combinatorial library containing five or more of the above-described compounds.
  • a combinatorial library can contain ten or more of the above-described compounds.
  • a combinatorial library can contain fifty or more of the above-described compounds.
  • a combinatorial library of the invention can contain 100,000 or more, or even 1,000,000 or more, of the above-described compounds.
  • the preparation of the combinatorial libraries can use the "split resin approach.”
  • the split resin approach is described by, for example, U.S. Patent 5,010,175 to Rutter, WO PCT 91/19735 to Simon, and Gallop et al . , J. Med. Chem. , 37:1233-1251
  • amino acids are indicated herein by either their full name or by the commonly known three letter code. Further, in the naming of amino acids, "D-" designates an amino acid having the "D" configuration, as opposed to the naturally occurring L-amino acids. Where no specific configuration is indicated, one skilled in the art would understand the amino acid to be an L-amino acid.
  • the amino acids can, however, also be in racemic mixtures of the D- and L-configuration or the D-amino acid can readily be substituted for that in the L-configuration.
  • inert, pharmaceutically acceptable carriers are used.
  • the pharmaceutical carrier can be either solid or liquid.
  • Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories .
  • a solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier is generally a finely divided solid which is in a mixture with the finely divided active component.
  • the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient -sized molds and allowed to cool and solidify.
  • Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
  • Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
  • compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
  • a carrier which is thus in association with it.
  • cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration.
  • Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
  • Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
  • Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical composition is in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active thiazole.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • the compounds of the present invention are generally in a pharmaceutical composition so as to be administered to a subject at dosage levels of from 0.7 to 7000 mg per day, and preferably 1 to 500 mg per day, for a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 0.01 to 100 mg/kg of body weight per day.
  • the specific dosages employed can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
  • the compounds of Formula (I) and combinatorial libraries containing the same can be prepared as set forth in Reaction Schemes 1 and 2 as well as the description provided below.
  • the amino containing carboxylic acids could be coupled to resin- bound primary or secondary amines which can be incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • resin-bound primary or secondary amines which can be incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • These amines could be prepared by reductive amination of a primary amine to an aldehyde resin or vice-versa, by displacement of a resin-bound halide, such as chloro or bromo, by a primary amine or by any other methods known to those skilled in the art.
  • the amino containing carboxylic acid coupled to the resin-bound amine from Step 1 was converted to a thiourea through the use of thiophosgene or a thiophosgene equivalent, such as, for example, 1,1'- thiocarbonyldiimidazole, followed by treatment with ammonia (Scheme 1: Library Synthesis Scheme, 2-Amino- Thiazoles; Step 2: Thio-urea formation).
  • the resin-bound thiourea from Step 2 was converted to a thiazole through the use of a variety a- haloketones (Scheme 1: Library Synthesis Scheme, 2-Amino- Thiazoles; Step 3: Thiazole ring formation).
  • Discrete compounds from the libraries can be obtained by cleavage from the resin by treatment with hydrofluoric acid (i.e., HF) or other methods known by those skilled in the art (Scheme 1: Library Synthesis Scheme, 2-Amino-Thiazoles; Step 4: Cleavage) .
  • hydrofluoric acid i.e., HF
  • Scheme 1 Library Synthesis Scheme, 2-Amino-Thiazoles; Step 4: Cleavage
  • the amino-containing carboxylic acid can have a second amino group attached that is either orthogonally protected or masked, such a with a nitro group (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 1: Amino acid attachment).
  • the carboxylic acid was coupled directly to a resin-bound primary amine such as methyl benzhydrylamine (MBHA) , or other resins known in the art that afford a primary amide upon cleavage.
  • MBHA methyl benzhydrylamine
  • the amino-containing carboxylic acid from Step 1 was coupled to a variety of second carboxylic acids via amide bond (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 2: Acylation of the amino group).
  • the second masked amino group then was reduced using SnCl 2 to prodice the free amine (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 3: Reduction of the nitro group) .
  • the free amine was then converted to a thiourea by using thiophosgene or a thiophosgene equivalent such as 1, 1 ' -thiocarbonyldiimidazole, followed by treatment with ammonia (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 4: Thiourea formation).
  • the resulting thiourea was then converted to a thiazole by using a variety of ⁇ -haloketones (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 5: Thiazole ring formation) .
  • Discrete compounds from the libraries can then be obtained by cleavage from the resin by treatment with hydrofluoric acid (HF) or other methods known in the art (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 6: Cleavage).
  • HF hydrofluoric acid
  • amino acids can be used for the first building block of the library of the present invention.
  • Amino acids that can be used for this building block include, natural and unnatural amino acids (i.e., both D and L forms, as well as racemic mixtures) and compounds that are contain simply contain a carboxylic acid for which to couple to the resin and an amino group that can be further modified as described above herein to a substituted thiazole. This represents a very large class of compounds the basis of the first diverse building block.
  • the free amino group can be reductively alkylated with a wide range of commerically available or synthetically prepared aldehydes.
  • the primary amine or secondary amine can be reacted with thiophosgene or an equivalent to give a thiourea that is converted to a substituted thiazole to provide still another site of diversity.
  • This third diverse building block originates from a-haloketones .
  • amino containing carboxylic acid i.e., amino acid
  • a second amino group that is either orthogonally protected or masked, such as a nitro group, that can be treated in a similar manner as described above or in an independent manner to give di-substituted amines, aminothiazoles or N-substituted-aminothiazoles, providing optionally three additional building blocks respectively.
  • the nonsupport-bound combinatorial libraries can be screened as mixtures or discrete arrays of single compounds in solution in assays such as radio-receptor inhibition assays, anti-bacterial assays, anti-fungal assays, calmodulin-dependent phosphodiesterase (CaMPDE) assays and phosphodiesterase (PDE) assays, as described in detail below.
  • Deconvolution of highly active mixtures can then be carried out by iterative or positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds within the combinatorial libraries of the present invention using any one of the below-described assays or others well known in the art .
  • the compounds of the present invention can be used for a variety of purposes and indications and as medicaments for any such purposes and indications.
  • compounds of the present invention including thiazole derivatives, can be used as pesticides, acaricides, receptor agonisits and antimicrobial agents, including antibacterial and antiviral agents.
  • the subject compounds can be useful as analgesics.
  • Assays which can be used to test the biological activity of the instant compounds include antimicrobial assays, a competitive enzyme-linked immunoabsorbent assay and radio-receptor assays, as described below.
  • the ability of the compounds to inhibit bacterial growth, and therefore be useful to that infection, can be determined by methods well known in the art.
  • Compounds of the present invention were shown to have antimicrobial activity by the in vi tro antimicrobial activity assay described in Example 7 below and, therefore, are useful as antimicrobial agents.
  • the concentration of cells is established by plating 100 ⁇ l of the culture solution using serial dilutions (e.g., 10 "2 , 10 "3 and 10 "4 ) onto solid agar plates.
  • serial dilutions e.g., 10 "2 , 10 "3 and 10 "4
  • compounds, individual or in mixtures are added to the bacterial suspension at concentrations derived from serial two-fold dilutions ranging from 1500 to 2.9 ⁇ g/ml.
  • the plates are incubated overnight at 37°C and the growth determined at each concentration by OD 620 nm.
  • the IC 50 (the concentration necessary to inhibit 50% of the growth of the bacteria) can then be calculated.
  • the competitive ELISA method which can be used here is a modification of the direct ELISA technique described previously in Appel et al . , J. Immunol.
  • multi-well microplates are coated with the antigenic peptide (Ac-GASPYPNLSNQQT-NH 2 ) at a concentration of 100 pmol/50 ⁇ l .
  • MAb 125-10F3 Appel et al . , supra
  • the MAb is added at a fixed dilution in which the bicyclic guanidine in solution effectively competes for MAb binding with the antigenic peptide adsorbed to the plate.
  • the remaining steps are the same as for direct ELISA.
  • the concentration of compound necessary to inhibit 50% of the MAb binding to the control peptide on the plate (IC 50 ) is determined by serial dilutions of the compound.
  • Radio- receptor assays can be selective for any one of the ⁇ , K, or ⁇ opiate receptors.
  • Compounds of the present invention can be useful in vitro for the diagnosis of relevant opioid receptor subtypes, such as , in the brain and other tissue samples. Similarly, the compounds can be used in vivo diagnostically to localize opioid receptor subtypes.
  • radio-receptor assays are also an indication of the compounds' analgesic properties as described, for example, in Dooley et al . , Proc . Na tl .
  • these compounds can be used for therapeutic purposes to block the peripheral effects of a centrally acting pain killer.
  • morphine is a centrally acting pain killer.
  • Morphine has a number of deleterious effects in the periphery which are not required for the desired analgesic effects, such as constipation and pruritus (itching) .
  • the subject compounds can have value in blocking the periphery effects of morphine, such as constipation and pruritus.
  • the subject compounds can also be useful as drugs, namely as analgesics, or to treat pathologies associated with other compounds which interact with the opioid receptor system.
  • Ligands for the ⁇ receptor can be useful as antipsychotic agents, as described in Abou- Gharbia et al . , Annual Reports in Medicinal Chemistry,
  • Radio-receptor assays can be performed with particulate membranes prepared using a modification of the method described in Pasternak et al . , Moi . Pharmacol .
  • Rat brains frozen in liquid nitrogen can be obtained from Rockland (Gilbertsville, PA) . The brains are thawed, the cerebella removed and the remaining tissue weighed. Each brain is individually homogenized in 40 ml Tris-HCl buffer (50 mM, pH 7.4, 4°C) and centrifuged (Sorvall ® RC5C SA-600: Du Pont, Wilmington, DE) (16,000 rpm) for 10 minutes. The pellets are resuspended in fresh Tris-HCl buffer and incubated at 37°C for 40 minutes.
  • the reaction is terminated by filtration through GF-B filters on a Tomtec harvester (Orange, CT) .
  • the filters are subsequently washed with 6 ml of Tris-HCl buffer, 4°C. Bound radioactivity is counted on a Pharmacia Biotech Betaplate Liquid Scintillation Counter
  • assays selective for K receptors can be carried out using [ 3 H]-U69,593 (3 nM, specific activity 62 Ci/mmol) as radioligand.
  • Assays selective for ⁇ opiate receptors can be carried out using tritiated DSLET ([D-Ser 2 , D-Leu 5 ] -threonine-enkephalin) as radioligand.
  • Assays selective for the ⁇ opiate receptor can use radiolabeled pentazocine as ligand.
  • Screening of combinatorial libraries and compounds of the invention can be done with an anti- fungal assay.
  • Compounds of the present invention can be useful for treating fungal infections.
  • Screening of combinatorial libraries and compounds of the invention also can be done with a calmodulin-dependent phosphodiesterase (CaMPDE) assay.
  • CaMPDE calmodulin-dependent phosphodiesterase
  • Compounds of the present invention can be useful as calmodulin antagonists.
  • Calmodulin (CaM) which is the major intracellular calcium receptor, is involved in many processes that are crucial to cellular viability.
  • Calmodulin is implicated in calcium- stimulated cell proliferation.
  • Calmodulin antagonists are, therefore, useful for treating conditions associated with increased cell proliferation, for example, cancer.
  • calmodulin antagonists such as compounds of the subject invention are useful both in vitro and in vivo for identifying the role of calmodulin in other biological processes.
  • the disadvantages of known antagonists such as trifluoperazine and N- (4-aminobutyl) - 5-chloro-2-naphthalenesulfonamide (W13) include their non-specificity and toxicity.
  • advantages of the combinatorial libraries and compounds of the subject invention as calmodulin antagonists include their reduced flexibility and ability to generate broader conformational space of interactive residues as compared to their linear counterparts.
  • an assay that identifies CaM antagonists is a CaMPDE assay.
  • samples are mixed with 50 ⁇ l of assay buffer (360 mM Tris, 360 mM
  • Imidazole 45 mM Mg(CH 3 COO) 2 , pH 7.5
  • 10 ⁇ l of CaCl 2 4.5 mM
  • 25 ⁇ l of calmodulin stock solution (Boehringer Mannheim; 0.01 ⁇ g/ ⁇ l) is then added and the samples then sit at room temperature for 10 minutes.
  • adenosine 3', 5 '-cyclic monophosphate (c7AMP) (20 mM in water at pH 7.0) is added, the samples incubated for 1 hour at 30°C and then vortexed.
  • 200 ⁇ l of trichloroacetic acid (TCA) (55% in water) is added to a 200 ⁇ l sample aliquot, which is then vortexed and centrifuged for 10 minutes.
  • 80 ⁇ l of the resulting supernatants of each sample is transferred to a 96-well plate, with 2 wells each containing 80 ⁇ l of each sample.
  • 80 ⁇ l of ammonium molybdate (1.1% in 1.
  • the percent inhibition of calmodulin activity is then calculated for each sample, using as 0% inhibition a control sample containing all reagents without any test samples and as 100% inhibition a control sample containing test samples and all reagents except calmodulin.
  • the percent inhibition of phosphodiesterase activity was determined by following a similar protocol as the CaMPDE assay described above, except not adding calmodulin to the sample mixture and calculating the percent inhibition by using as 0% inhibition a control reagent without any test samples and as 100% inhibition a control sample containing test samples and all reagents except cAMP .
  • TBU 2-(lH- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate
  • TRT trityl
  • ACM acetamidomethyl
  • MTR 2, 3 , 6-trimethyl-4-methoxybenzenesulfonyl
  • MBH 4, 4 ' -dimethoxybenzyhydryl
  • ADA adamanyl
  • PMEOBZL p-methoxybenzyl
  • 2-CL-Z 2 -chlorobenzyl -oxycarbonyl
  • 2-BR-Z 2 -bromobenzyloxycarbonyl
  • TMOB 2-(lH- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate
  • TRT trityl
  • ACM acetamidomethyl
  • MTR 2, 3 , 6-trimethyl-4-methoxybenzenesulfonyl
  • Step 1 Coupling of N-Protected amino acid to MBHA resin.
  • Step 2 Thiourea formation using Thiophosgene and Ammonia .
  • the packet was shaken in a solution of Thiophosgene (1.84g, 16 mmol) and DIEA (2.02g, 16 mmol) in DCM (40 mL) at room temperature for 1 hours.
  • the packet was washed several times with anhydrous DCM (3x80 mL) and then was reacted with ammonia (80mL, 0.5M solution in dioxane) for 1 hour at RT .
  • Packet was washed with dioxane (3x80mL) and alternatively with DMF (80 mL) and MeOH (80 mL) 3 cycles followed by DCM (2x80 mL) and MeOH (3x80 mL) .
  • the packet was air-dried overnight.
  • Step 3 Reaction with halo-ketones to form thiazoles.
  • the packet was cut open and the resin was suspended DMF (50 mL) .
  • the suspension was distributed equally into 48 wells of a microtiter plate (lmLx48) .
  • N N-DIMETHYL-2-CHLOROACETOACETAMIDE 12 ETHYL 4-CHLOROACETOACETATE
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 199.27 Found (M+l) : 200.4
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 275.37 Found (M+l) : 276.2
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 185.24 Found (M+l) : 186.3
  • Halo-Ketone 3-CHLORO-2-BUTANONE Calcd. MW: 241.35 Found (M+l) : 242.3
  • Halo-Ketone N, -DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 256.32 Found (M+l) : 257
  • Halo-Ketone 1-ADAMANTYL BROMOMETHYL KETONE Calcd. MW: 305.44 Found (M+l) : 306.2
  • Step 1 Coupling of 4-amino-benzoic acid to MBHA resin.
  • Step 2 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 3 Reaction with halo-ketones to form thiazoles.
  • Halo-Ketone 2 -BROMOACETOPHENONE Calcd. MW: 295.35 Found (M+l) : 296.5
  • Step 1 Coupling of 3-Nitro-benzoic acid to MBHA resin
  • Step 2 Reduction of the nitro group to amine.
  • the packet was shaken with a 2.0 M solution of tin (II) chloride dihydrate DMF (80 mL) for 24 hours at room temperature.
  • the packet was washed with DMF (6 X 80 mL) , 10% DIEA/DCM (4 X 80 mL) , MeOH, (2 X 80 mL) , DMF (80 mL) , MeOH (80 mL) , DCM (2 X 80 mL) and MeOH (2 X 80 mL) and air- dried overnight .
  • Step 3 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 4 Reaction with halo-ketones to form thiazoles.
  • Compounds 25 represent variations at the 2, 4 and 5 position of the amino-thiazole template derived from 3- Nitrobenzoic acids, and various halo-ketones.
  • Step 1 Coupling of Boc-Lysine (Fmoc) to MBHA resin.
  • the packets were washed alternatively with DMF (3x8L) and MeOH (2x8L) followed by DCM (2x8L) and MeOH (3x8L) .
  • the packets were air-dried for 2 h.
  • the packet was shaken with 55% TFA/DCM (8L) at room temperature for 40 minutes and washed with DCM (3 X 8L) , 5% DIEA/DCM (2x8L) and MeOH (2x8L) .
  • the packets were air-dried overnight.
  • Step 2 Acylation of alpha-amino group using Carboxylic acids.
  • the packet was washed alternatively with DMF (3x80 mL) and MeOH (2x80 mL) 3 cycles followed by DCM (2x80 mL) and MeOH (3x80 mL) .
  • the packet was air-dried for 2 h.
  • the packet was then shaken with 25% PIP/DMF (80 mL) at room temperature for 40 minutes and washed with DMF (3x80 mL) , 5% DIEA/DCM (2x80 mL) and MeOH (2x80 mL) . Resin was air dried for 2 hours.
  • Step 3 Thiourea formation using Thiophosgene and Ammonia.
  • Step 4 Reaction with halo-ketones to form thiazoles.
  • the packet was cut open and the resin was suspended DMF (25 mL) .
  • the suspension was distributed equally into 24 wells of a microtiter plate (lmlx24) . Excess DMF was removed and the resin was washed several times using MeoH (3x1.5ml per well) .
  • the resin was air-dried overnight.
  • a solution of corresponding halo-ketone (see Table x) in ethoxyethanol (200 ⁇ L X 0.4 M) was added to each well.
  • the plate was tightly capped, shaken and incubated at 65° C for 15 hours. Each plate was washed alternatively with DMF (10 X 1 mL/well) and MeOH (14 xl mL/well) .
  • the plate was dried in air overnight and under vacuum for 4 hours .
  • the plate was treated with gaseous HF at room temperature for 1.5 hours. After complete removal of HF under a nitrogen stream followed by vacuum, the plate was extracted with AcOH (4 x 0.5 mL/well). The extractions were lyophilized to give the title compounds.
  • Halo-Ketone N, N-DIMETHYL-2-CHLOROACETOACETAMIDE
  • Carboxylic Acid Ethoxyacetic acid
  • Halo-Ketone N, N-DIMETHYL-2-CHLOROACETOACETAMIDE
  • Step 1 Coupling of Boc-Lysine (Fmoc) to MBHA resin.
  • the packets were washed alternatively with DMF (3x8L) and MeOH (2x8L) followed by DCM (2x8L) and MeOH (3x8L) .
  • the packets were air-dried for 2 h.
  • the packet was shaken with 25% PIP/DMF (8L) at room temperature for 40 minutes and washed with DMF (3x8L) , 5% DIEA/DCM (2x8L) and MeOH (3x8L) . Resin was air-dried overnight .
  • Step 2 Acylation of epsilon-amino group using Carboxylic acids .
  • Step 3 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 4 Reaction with halo-ketones to form thiazoles.
  • Step 1 Coupling of Boc-p-nitro-Phe to MBHA resin.
  • Step 3 Reduction of the nitro group to amine.
  • the packet was shaken with a 2.0 M solution of tin (II) chloride dihydrate DMF (80 mL) for 24 hours at room temperature.
  • the packet was washed with DMF (6 X 80 mL) , 10% DIEA/DCM (4 X 80 mL) , MeOH, (2 X 80 mL) , DMF (80 mL) , MeOH (80 mL) , DCM (2 X 80 mL) and MeOH (2 X 80 mL) and air- dried overnight .
  • Step 4 Thio-urea formation using Thiophosgene and Ammonia.
  • Step 5 Reaction with halo-ketones to form thiazoles.
  • Compounds 29-32 represent the variations at 2,4 and 5 position of the amino-thiazole template derived from Boc- p-nitro-Phe, carboxylic acids and various halo-ketones.
  • Halo-Ketone N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 519 Found (M+l) : 520

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Abstract

The present invention relates to novel thiazole compounds of formula (I): wherein q, R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings provided below. The invention further relates to combinatorial libraries containing at least two or more such compounds, and to methods of preparing combinatorial libraries composed of such compounds.

Description

THIAZOLE DERIVATIVES AND COMBINATORIAL LIBRARIES THEREOF
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates generally to the synthesis of compounds comprising heterocyclic rings. In one specific embodiment, the invention provides novel thiazoles as well as novel combinatorial libraries comprised of such compounds.
BACKGROUND INFORMATION
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure (s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional "one-at- a-time" synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional "one-at-a-time" synthesis methods, except over a time frame of years or even decades.
Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as thiazoles. Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides. The preparation and use of synthetic peptide combinatorial libraries has been described, for example, by Houghten et al., ( Proc . Na tl . Acad. Sci . USA 1985, 82, 5131; Biochemistry, 1993, 32, 11035; and U.S. Patent No. 4,631,211) utilized individual polyethylene bags, referred to "tea bags" to generate peptide libraries. The tea bags, containing C-terminal amino acids bound to a solid support, were mixed and coupled with the requisite amino acids using solid phase synthesis techniques. Common steps, such as resin washing and deprotection of α-amino groups, can be performed simultaneously in a single reaction vessel and upon completion of the synthesis, each bag contained a single peptide sequence. Dooley et al . in U.S. Patent 5,367,053, used combinatorial libraries for the determination of high affinity opioid receptors. Huebner in U.S. Patent 5,182,366, describes a method of preparing a mixture of peptides having known composition using three essential steps, dividing an amount of a mixture of amino acid derivatized resins, coupling a subsequent amino acid and combining a known amount of a different resin together to obtain peptide mixtures. Also described are methods to retrieve and analyze the amino acid sequence. Appel et al . in WO PCT 92/09300, describes the synthesis of complex mixtures of solid support-coupled amino acids in which the mixture contains an equimolar representation of each reacted amino acid coupled. Geysen in published European Patent Application 0 138 855 describes a method of synthesizing a peptide library and detecting a peptide comprising a sequence of amino acids which has antigenic activity. Pirrung et al . in U.S. Patent 5,143,854 describe polypeptide arrays synthesized using photoremovable groups. Synthesized combinatorial libraries have provided an extraordinary number of various peptides in such libraries and the availability of rapid screening of the library which can identify lead pharmaceutical peptides.
Combinatorial approaches have recently been extended to "organic," or non-peptide, libraries. Zambias et al . (U.S. Patent No. 5,712,171) describe a method of generating libraries that contain aminimides, oxazolones, sulfonylaminides and phosphonylaminides as the core structure in spatially arranged arrays. Combinatorial chemical methods have been applied to a limited number of heterocyclic compounds, as described, for example, in U.S. Patent Nos. 5,288,514; 5,324,483; and Goff et al . , J. Org . Chem. , 60:5748-5749 (1995). See also U.S. Patent Nos. 5,549,974 and 5,506,337. However, the heterocyclic libraries to date contain compounds of limited diversity and complexity.
Substituent limitations have been overcome for mixtures of peptides and peptidomimetics through the use of solid phase techniques versus solution-phase. An important step in the development of solid-phase techniques was the discovery of methods to prepare large numbers of individual compounds simultaneously, as described, for example, by Houghten in U.S. Patent No. 4,631,211. These solid phase methods, however, have not been fully applied to the syntheses of complex heterocyclic structures. In this regard, improved methods for generating therapeutically useful heterocyclic compounds, such as thiazole and thiazole derivatives, are desired. Thiazoles, for example, have been the subject of investigation in a number of different biological areas. See, for example, Bailey, et al., Bioorg . Med . Chem . Lett . , 6:1409-1414 (1996); Zaragoza, F., Tetrahedron Lett . , 37:6213-6216 (1996); Hoekstra, et al . , Tetrahedron Lett . , 38:2629-2632 (1997); Kearney et al . , J. Org . Chem. , 63:196-200 (1998); and Krchnak, et al . , Moi . Diversi ty, 1:149-164 (1996).
Therefore, a need still exists to develop more complex "organic" libraries based on thiazole-based medicinal compounds which would need less time and effort in the synthesis and testing required to bring an organic pharmaceutical product to fruition. This invention satisfies these needs and provides related advantages as well .
The present invention overcomes the known limitations to classical organic synthesis of thiazoles, for example, as well as the shortcomings of combinatorial chemistry related to heterocycles . The present invention allows for rapid generation of large diverse libraries of complex heterocycles as discrete molecules or as molecules bound to a resin. The present invention can utilize a readily available pool of building blocks, either from commerical sources or available through chemistries known in the art, that can be incorporated into the various regions of the molecule. Furthermore, the method of making the present invention allows for the use of building blocks that contain a wide range of diverse functionalities. Therefore, building blocks, such as those described herein, can provide libraries that consist of large numbers as well as libraries that are extremely diverse with respect to the functionality contained within those libraries. The present invention combines the techniques of solid-phase synthesis of heterocycles and the general techniques of synthesis of combinatorial libraries to prepare highly diverse new thiazole libraries and thiazole compounds. SUMMARY OF THE INVENTION
The present invention relates to novel thiazole compounds of formula (I) :
Figure imgf000007_0001
(I) wherein q, R: , R2, R3, R4 , R5, R6/ R7 and R8 have the meanings provided below.
The invention further relates to combinatorial libraries containing two or more such compounds, and to the generation of such combinatorial libraries composed of such compounds .
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 provides Reaction Scheme 1 showing the steps of attachment of the amino acid, thio-urea formation, thiazole ring formation and cleavage used in the formation of the 2-aminothiazole library.
Figure 2 provides Reaction Scheme 2 showing the synthetic steps for the formation of the branched 2- aminothiazole library.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel compounds, and libraries of novel compounds of Formula (I) :
Figure imgf000008_0001
( i :
wherein :
q is an integer selected from 0, 1 or 2 ;
Rα is a hydrogen or a functionalized resin;
R2 is a hydrogen atom, Cλ to C6 alkyl, Ci to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, phenyl, substituted phenyl, naphthyl , substituted naphthyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or Rl7 N and R2 together is of the formula:
Figure imgf000008_0002
Figure imgf000009_0001
wherein R9 is a hydrogen or a functionalized resin; and
R3 is Ci to C8 alkylene, Ci to C8 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, C4 to C10 cycloalkylalkylene, C4 to C10 substituted cycloalkylalkylene, C to C12 phenylalkylene or C7 to C12 substituted phenylalkylene; or
R3 is of the formula:
Figure imgf000009_0002
R10 R11 wherein:
R10 and R are, independently, a hydrogen atom, Cλ to C6 alkyl, Ci to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, Cx to C7 acyl , Cλ to C7 substituted acyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl , C5 to C7 substituted cycloalkenyl , a heterocyclic ring, substituted heterocyclic ring, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C2 to C7 alkylene, substituted cyclic C2 to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene, hydroxymethyl or protected hydroxymethyl; or
Rio and Rn together with the carbon atom in between R10 and Rn form a C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, a heterocyclic ring or substituted heterocyclic ring; or
R3 is of the formula (II) or (III) :
Figure imgf000010_0001
wherein n is an integer selected from 0 to 4; R12 is hydrogen, halogen, hydroxy, protected hydroxy, cyano, Ci to C6 alkyl, Ci to C7 alkoxy, Cλ to C7 acyl, C, to C7 acyloxy, Ct to C7 alkylaminocarbonyl , Cλ to C7 substituted alkylaminocarbonyl , phenylaminocarbonyl , substituted phenylaminocarbonyl, carboxy, protected carboxy, carboxymethyl , protected carboxymethyl , hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl ; R13 is a hydrogen atom, Cx to C6 alkyl, Ci to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl or C7 to C12 substituted phenylalkyl; and R14 is a hydrogen atom, C1 to C6 alkyl, Cλ to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cj to C7 alkylsulfonyl , Cλ to C7 substituted alkylsulfonyl , C± to C7 acyl, to C7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl, Ci to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, or substituted phenylaminocarbonyl; or R14 is of the formula:
Figure imgf000011_0001
wherein R15 is a hydrogen atom, Cj to C6 alkyl, Ci to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C7 acyl, Cj to C7 substituted acyl, Ci to C7 alkoxycarbonyl, C to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; and R16 is a hydrogen atom, Ca to C6 alkyl, C to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C7 acyl, Cj to C7 substituted acyl, C: to C7 alkoxycarbonyl, Ci to C7 substituted alkoxycarbonyl, C: to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl or substituted naphthyl; or R15 and R16 together are fused with the thiazole ring to form a second ring which is a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or R15 and R16 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring, and the third ring which is directly fused to the second ring is a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl; or
R3 is of the formula (IV) or (V)
Figure imgf000013_0001
IV) (V) wherein:
m is an integer selected from 1 to 8; R13 and R1 Δ is the same as described herein above;
R4 is a hydrogen atom, Cx to C6 alkyl, Cα to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Ci to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl, C: to C7 acyl, Cλ to C7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl, Cα to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl or substituted phenylaminocarbonyl; or
R3, N and R4 together form a heterocycle or substituted heterocycle; and
R5 is a hydrogen atom, Cx to C6 alkyl, Ci to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C7 acyl, Ci to C7 substituted acyl, Cj to C7 alkoxycarbonyl, Ci to C, substituted alkoxycarbonyl, C± to C7 alkylaminocarbonyl, C, to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl or substituted naphthyl;
R6 is a hydrogen atom, Ci to C6 alkyl, Ci to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Ci to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Ci to C7 substituted alkoxycarbonyl, C: to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl or substituted naphthyl; or
R5 and R6 together are fused with the thiazole ring to form a second ring which is a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or
R5 and R6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring, and the third ring which is directly fused to the second ring is a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl;
R7 is Cx to C8 alkylene, C: to C8 substituted alkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, heteroarylene or substituted heteroarylene ;
R8 is a hydrogen atom, C, to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl or substituted phenylaminocarbonyl; or
a pharmaceutically acceptable salt of a compound of the formula (I) .
In a preferred embodiment of this invention, the thiazole compounds and libraries are of the Formula (I) :
Figure imgf000015_0001
wherein :
q is 0 or 1 ;
R3 is of the formula:
Figure imgf000015_0002
R10 R11 wherein:
Rio and RX1 are together or independently a hydrogen atom, Cj to C6 alkyl, Cj to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C3 to C, cycloalkyl, substituted C3 to C7 cycloalkyl, hydroxymethyl or protected hydroxymethyl; or
R3 is of the formula (II) or (III) :
Figure imgf000016_0001
wherein n is an integer selected from 1 or 2; R12 is hydrogen, halogen, hydroxy, protected hydroxy, Ci to C7 alkyl, Ci to C7 substituted alkyl, Cx to C7 alkoxy, C to C7 substituted alkoxy; and R13 is a hydrogen atom, Ci to C5 alkyl, Ci to C6 substituted alkyl; and R:4 is a hydrogen, λ to C6 alkyl, C: to C6 substituted alkyl, Ci to C7 acyl, Ci to C7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl , Qx to C7 alkylaminocarbonyl, Qλ to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl; or
R3 is of the formula (IV) or (V)
Figure imgf000017_0001
(IV) (V) wherein: m is an integer selected from 1 to 5; R13 and R14 are the same as described above in this embodiment;
R4 is a hydrogen atom, C: to C6 alkyl or C to C6 substituted alkyl;
R7 is phenylene or substituted phenylene, and
R8 is a hydrogen atom, C: to C6 alkyl or C: to C6 substituted alkyl; or
a pharmaceutically acceptable salt of a compound of the formula (I) .
In another preferred embodiment of this invention, q is 1 or 2. In another preferred embodiment of this invention R5 and R6 are fused with the thiazole ring of Formula (I) to form either the two or three ring systems as disclosed above .
In another preferred embodiment of this invention, R3 is as described above, provided that the carbon to the carbonyl of Formula (I) is chiral . In another preferred embodiment of this invention, R3 is as described above, except that it does not include methylene. In another preferred embodiment of this invention, R3 is as described above, except that it does not include C: to C8 alkylene. In another preferred embodiment of this invention, R3 is as described above, except that it does not include Cx to C8 alkylene or Cx to C8 substituted alkylene. In another preferred embodiment of this invention, the compounds are as described above, provided that provided that they are not where q is 0, Rl t R2, R4 and R6 are each a hydrogen atom, R3 is methylene and R5 is 4-fluoromethyl .
In another preferred embodiment of this invention, the thiazole compounds and libraries are of the Formula (I) :
Figure imgf000018_0001
wherein:
Ri is a hydrogen atom or polystyryl 4-methylbenzhydryl;
R, is a hydrogen atom, 2- (1-pyrrolidino) ethyl,
2-pyridinemethyl, 2- (4-imidazole) ethyl, cyclopentyl, allyl, 2-methoxyethyl, (+/- ) -tetrahydrofuryl , benzyl, 2-methylbenzyl, 3 -methylbenzyl, 4-methylbenzyl , 2-fluorobenzyl, 3 -fluorobenzyl, 4-fluorobenzyl , 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4-methoxybenzyl , 3-chlorobenzyl , 3-bromobenzyl , 4-bromobenzyl, cyclopropyl, cyclopropanemethyl , 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl , 3- methoxybenzyl, piperonyl, 4-methoxyphenethyl , 2-fluorophenethyl, 2 - (4-chlorophenyl) ethyl , 2- (3 -chlorophenyl) ethyl , 2- (2 -chlorophenyl) ethyl , 2 , 3-dimethoxy-benzyl,
3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl , 3- (diethylamino) propyl, 2~ (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3-ethoxypropyl,
3 - (2 -pipecolinyl ) propyl , 3 -butoxypropyl , 3- (pyrrolidin-2-one-l-yl)propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl , 2 -methyl-2 -phenylethyl , -phenylbutyl , 3 , 3 -diphenylpropyl , isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl , 3-methoxyphenethyl, 3-phenylbenzyl, piperazine;
R3 is methylene, 1 , 2 -ethylene, 1 , 3-propylene, 1,4- butylene, 1 , 5-pentylene, 1 , 6-hexylene, 1, 7-heptanylene, 1, 8-octanylene, cyclohexyl-4 -methylene, 1-methyl-1, 1- ethylene, D-1 , 1-butylene, D-1 , 1-ethylene, D-1,1- pentylene, D-1 , 1-propylene, D-5-amino-l , 1-pentylene, D-l- amino-1, 5-pentylene, D-2- (2-napthyl) -1, 1-ethylene, D-2- (2-thienyl) -1, 1-ethylene, D-2- (4-ethoxyphenyl) -1, 1- ethylene, D-2- (4-fluoropehnyl) -1 , 1-ethylene, D-2- (4- hydroxyphenyl ) -1, 1-ethylene, D-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, D-2-carboxamide-l, 1-ethylene, D-2- carboxamide-1 , 2 -ethylene, D-2-carboxy-l , 2-ethylene, D-2- cyclohexyl-1, 1-ethylene, D-2 -hydroxy-1 , 1-ethylene, D-2- hydroxy-1, 1-ethylene, D-2 -hydroxy-1, 1-propylene, D-2- mercapto-1, 1-ethylene, D-2-methyl-l, 1-butylene, D-2- methyl-1 , 1-propylene, D-2 -phenyl-1 , 1-ethylene, D-3- carboxamido-1 , 1-propylene, D-3-carboxamido-l , 3 -propylene, D-3 -carboxy- 1, 1-propylene, D-3-carboxyl -1 , 3-propylene, D- 3-methyl-l, 1-butylene, D-4-ureido-l , 1-butylene, D-5- (9- fluorenylmethoxycarboxamido) -1 , 1-pentylene, D-5- acetamiode-1 , 1-pentylene, D-5-amino-l , 1-pentylene, D- methylthio-1 , 1-propylene, phenylmethylene, D- t- butylmethylene, 1, 2 -ethylene, 1 , 3-propylene, 1,4- butylene, 1, 5-pentylene, 1 , 6-hexylene, 1-methyl -1, 1- ethylene, L-l, 1-butylene, L-l, 1-ethylene, L-1,1- pentylene, 1, 1-propylene, L-5-amino-l, 1-pentylene, L-l- amino-1, 5-pentylene, L-2- (2-napthyl) -1, 1-ethylene, L-2- (2-thienyl) -1, 1-ethylene, L-2- (4-ethoxyphenyl) -1, 1- ethylene, L-2- (4-fluoropehnyl) -1, 1-ethylene, L-2- (4- hydroxyphenyl) -1, 1-ethylene, L-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, L-2 -carboxamide-1 , 1-ethylene, L-2- carboxamide-1 , 2 -ethylene, L-2-carboxy-1, 2 -ethylene, L-2- cyclohexyl-1, 1-ethylene, L-2-hydroxy-1 , 1-ethylene, L-2- hydroxy-1, 1-ethylene, L-2-hydroxy-l, 1-propylene, L-2- mercapto-1, 1-ethylene, L-2-methyl-l, 1-butylene, L-2- methyl-1, 1-propylene, L-2-phenyl-l, 1-ethylene, L-3- carboxamido-1, 1-propylene, L-3 -carboxamido-1, 3-propylene, L-3-carboxy- 1, 1-propylene, L-3 -carboxyl-1 , 3-propylene, L- 3 -methyl-1, 1-butylene, L-4-ureido-l , 1-butylene, L-5- (9- fluorenylmethoxycarboxamido) -1 , 1-pentylene, L-5- acetamiode-1 , 1-pentylene, L-5-amino-1 , 1-pentylene, methylthio-1 , 1-propylene, L-phenylmethylene, L- t- butylmethylene, 3 -methoxy-1, -phenylene, 2 -methoxy-1, 4- phenylene, 2 -chloro-1, 4 -phenylene, 1 , 4 -phenylene, 2- methoxy-4-chloro-l, 4 -phenylene, 4 -methoxy-1, 3 -phenylene, 2 -chloro-1, 3 -phenylene, 4 -chloro-1 , 3 -phenylene, 6-chloro- 1, 3 -phenylene, 5-carboxy-1, 3 -phenylene, 5- methoxycarbonyl -1,3 -phenylene , 2 , 6 -dimethoxy-1,3- phenylene, 2 , 5-dichloro-l , 3 -phenylene, 2-bromo-l,3- phenylene, 6 -bromo-1, 3 -phenylene, 2 , 6-dimethoxy-5-chloro-
1, 3-phenylene or methylene; or R3 is of the formula (II), (III) , (IV) or (V) :
Figure imgf000021_0001
R 14
ID ; 111 '
Figure imgf000021_0002
(IV) (V) wherein n is 1 ; m is 3 or 4 ;
R12 is hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, pentane, methoxy, ethoxy, propoxy or iso-proproxy; and
R13 is a hydrogen atom, 2-pyridinemethyl , allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl , 3-methylbenzyl , 4-methylbenzyl, 2-fluorobenzyl , 3-fluorobenzyl , 4 -fluorobenzyl, 3 - (1-imidazole) propyl ,
4-aminomethylbenzyl, 4 -methoxybenzyl , 3 -chlorobenzyl , 3-bromobenzyl, 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl , 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl, 2 - (3 -chlorophenyl ) ethyl , 2 - (2 -chlorophenyl ) ethyl , 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl , 2,4- dichlorophenethyl, 2- (diethylamino) ethyl,
2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) ropyl,
2- (5-nitro-2-pyridyl) ethyl,
3- (dimethylamino) -2 , 2-dimethylpropyl,
3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl , isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl)propyl, 3- (morpholino) propyl, 2- (N-ethyl -3 -methylanilino) ethyl , 3 -phenyl-1-propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl , isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3 -phenylbenzyl ; and
Ri4 is a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl , 4-methylbenzyl , 2-fluorobenzyl, 3-fluorobenzyl , 4 -fluorobenzyl , 3 - (1-imidazole ) propyl , 4-aminomethylbenzyl , -methoxybenzyl , 3-chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl , piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl,
2 - (3 -chlorophenyl) ethyl , 2 - (2 -chlorophenyl) ethyl ,
2 , 3 -dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl , 2,4- dichlorophenethyl, 2- (diethylamino) ethyl ,
2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl,
2- (5-nitro-2-pyridyl) ethyl,
3- (dimethylamino) -2 , 2-dimethylpropyl,
3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl , isoamyl, 3 -ethoxypropyl ,
3 - ( 2 -pipecolinyl ) propyl , 3 -butoxypropyl , 3- (pyrrolidin-2 -one-1-yl) propyl, 3- (morpholino) propyl , 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2 -methyl -2 -phenylethyl , -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl; or
R14 is acetyl, alpha-methylcinnamyl, benzoyl , crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl , 4-ethoxybenzoyl , isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl , 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3 - (3-pyridyl) acrylyl , trimethylacetyl , triphenylacetyl, nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl , 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl , 4 -methyl-1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl , 1 , 3 -phenylene diacetyl, 2-norbornaneacetyl , 2-pyrazinecarbonyl , 2-pyridylacetyl , 2-thiopheneacetyl , 3,4,5- triethoxybenzoyl ,
3 , 4-methylenedioxyphenylacetyl , 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -1ert-butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5, 5-trimethylhexanoyl, 3,5-bis (trifluoromethyl) -benzoyl,
5-bromo-2 -chlorobenzoyl , 5 -bromonicotinyl , 6-chloronicotinyl , 3 , 5 -dimethyl -p-anisyl , 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl , 3-benzoylpropionyl , 3 , 5-dichlorobenzoyl , 3-cyanobenzoyl , 3 -fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl , 3 -methyl-2-thiophenecarbonyl , 3 -phenoxybenzoyl, 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl, 3 , 5-dichloro-4-hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3-lndolepropionyl, 2 , 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl , succinamyl , 4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r (-) -2-oxothiazolidine-4-carbonyl , 4-nitrophenylacetyl, coumarin-3 -carbonyl, 1-cyano-l-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl , 2- (2 -cyanophenylthio) benzoyl ; or
Ri4 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl ,
2 -1hiophenesulfonyl , 4 -chlorobenzenesulfonyl , 4-fluorobenzenesulfonyl , 4-methoxybenzenesulfonyl,
4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl ,
2-acetamido-4-methyl-5-thiazolesulfonyl ,
4- (trifluoromethoxy) benzenesulfonyl, 4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl ,
2 , 3 -dichlorothiophene-5-sulfonyl ,
3 , 4 -dimethoxybenzenesulfonyl ,
3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 - fluorobenzenesulfonyl , 3-trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl, pentamethylbenzenesulfonyl ,
2,3, 4 -trifluorobenzenesulfonyl,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5-dichlorothiophene-3 -sulfonyl , 2 , 6-dichlorobenzenesulfonyl, 2 , 6-difluorobenzenesulfonyl,
2 -chloro-4 - (trifluoromethyl ) benzenesulfonyl ,
2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2-chloro-6-methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl , 3 , 5-dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl,
4- (n-butoxy) benzenesul onyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4 -sulfonyl,
2 - (methoxycarbonyl) thiophene-3 -sulfonyl ,
4 -acetamido-3 -chlorobenzene sulfonyl ,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5 -sulfonyl,
3 -methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl,
5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4 -difluorobenzenesulfonyl , 2 - fluorobenzenesulfonyl ,
4-isopropylbenzene sulfonyl,
2, 5-dimethoxybenzenesulfonyl,
3 , 4-dichlorobenzenesulfonyl ; or
Rι4 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3-methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2 - (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester, (s) -2- (carbamyl) -3- phenylpropionate methyl ester, 1- (carbamyl) -tridecafluoro-1-hexane,
1- (carbamyl) -1,1,3,3 -tetramethylbutane, 1- (carbamyl) - (1 -naphthyl) ethane, 1- (carbamyl) - (4 -bromophenyl) ethane, 1- (carbamyl) -adamantane, 1- (carbamyl) naphthalene, 1- (carbamyl) -2,3, 4-trifluorobenzene, 1- (carbamyl) -2 , 3-dichlorobenzene, 1- (carbamyl) -2 , 3-dimethylbenzene, 1- (carbamyl) -2,4, 5-trichlorobenzene, - (carbamyl) -2,4, 5-trimethylbenzene, - (carbamyl) -2,4, 6-trichlorobenzene, - (carbamyl) -2 , 4-dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene,
1- (carbamyl -2, 4-dimethylbenzene,
1- (carbamyl -2 , 5-dichlorobenzene,
1- (carbamyl -2, 5-difluorobenzene,
1- (carbamyl -2, 5-dimethoxybenzene,
1- (carbamyl -2,5- dimethylbenzene,
1- (carbamyl -2 , 6-dibromo-4-fluorobenzene,
1- (carbamyl -2 , 6-dibromo-4-isopropylbenzene,
1- (carbamyl -2 , 6-dichlorobenzene,
1- (carbamyl -2 , 6-diethylbenzene,
1- (carbamyl -2 , 6-difluorobenzoyl,
1- (carbamyl -2 , 6-difluorobenzene,
1- (carbamyl -2 , 6-diisopropylbenzene,
1- (carbamyl -2 , 6 -dimethylbenzene,
1- (carbamyl -2- (chloromethyl) benzene,
1- (carbamyl -2- (difluoromethoxy) benzene,
1- (carbamyl -2- (methylthio) benzene,
1- (carbamyl -2- (trifluoromethoxy) benzene, - (carbamyl -2- (trifluoromethyl) benzene,
1- (carbamyl -2-biphenyl, - (carbamyl -2-bromo-4 , 6-difluorobenzene, - (carbamyl -2-bromoethane, 1- (carbamyl) -2-bromobenzene, - (carbamyl -2 -chloro-4 -nitrobenzene , - (carbamyl -2-chloro-5- (trifluoromethyl) benzene, - (carbamyl -2 -chloro-5 -nitrobenzene, - (carbamyl -2 -chloro- 6 -methylbenzene , - (carbamyl -2-chlorobenzyl, 1- (carbamyl) -2-chloroethane, - (carbamyl -2 -chlorobenzene , - (carbamyl -2 -cyanobenzene , - (carbamyl -2-ethoxybenzene, - (carbamyl -2 -ethyl-6 -methylbenzene , - (carbamyl -2-ethylbenzene, - (carbamyl -2-fluoro-3- (trifluoromethyl) benzene, - (carbamyl -2-fluoro-5- (trifluoromethyl) benzene, - (carbamyl -2 - fluoro- 5 -methylbenzene , - (carbamyl -2-fluoro-5 -nitrobenzene, - (carbamyl -2-fluoro-6- (trifluoromethyl) benzene, 1- (carbamyl -2-fluorobenzene, 1- (carbamyl; -2-iodobenzene, 1- (carbamyl -2 -isopropyl-6 -methylbenzene , 1- (carbamyl -2 -isopropylbenzene , 1- (carbamyl -2 -methoxy- 5-chloro benzene, 1- (carbamyl -2 -methoxy-5-methylbenzene, 1- (carbamyl -2 -methoxy-5-nitrobenzene, 1- (carbamyl -2-methoxybenzene, 1- (carbamyl -2 -methyl-3 -nitrobenzene , 1- (carbamyl -2-methyl-5-nitrobenzene, 1- (carbamyl -2 -methyl- 6 -1-butylbenzene , 1- (carbamyl -1 - (2 -methylphenyl) methane , 1- (carbamyl -2 -n-propylbenzene , 1- (carbamyl -2 -naphthalene, 1- (carbamyl) -2 -nitrobenzene, 1- (carbamyl -2-phenoxybenzene, 1- (carbamyl -2 -tert-butylbenzene , 1- (carbamyl -3,4,5-1rimethoxybenzene , 1- (carbamyl -1- (3 , 4-dichlorophenyl) methane, 1- (carbamyl -3 , 4-dichlorobenzene, 1- (carbamyl -3 , 4 -difluorobenzene, 1- (carbamyl -3 , 4 -dimethylbenzene , 1- (carbamyl -3 , 5 -bis (trifluoromethyl) benzene, 1- (carbamyl -3,5- dichlorobenzene, 1- (carbamyl -3,5-dimethoxybenzene , 1- (carbamyl -3 , 5 -dimethylbenzene, 1- (carbamyl) -3,5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
1- carbamyl -3- (trifluoromethyl) benzene, 1- carbamyl -3- (trifluoromethylthio) benzene, 1- carbamyl -3 -acetylbenzene, 1- carbamyl -3 -bromobenzene, 1- (carbamyl) -3-bromopropane, 1- carbamyl -3 -carbomethoxybenzene , 1- carbamyl -3 -chloro-2-methoxybenzene, 1- carbamyl -3 -chloro-2 -methylbenzene, 1- carbamyl -3 -chloro-4 -fluorobenzene, 1- carbamyl -3 -chloro-4 -methylbenzene , 1- carbamyl -3-chlorobenzene, 1- carbamyl -3 -chloropropane , 1- carbamyl - 3 -cyanobenzene , - (carbamyl) -3-cyclopentoxy-4-methoxybenzene, - (carbamyl) -3-ethylbenzene, - (carbamyl) -3 -fluoro-4 -methylbenzene , - (carbamyl) -3 -fluorobenzene, 1- (carbamyl) -3 -iodopropane, - (carbamyl) benzoyl chloride, - (carbamyl) -3-methoxybenzene, - (carbamyl) - (3 -methylphenyl) methane, - (carbamyl) -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, ' - (carbamyl) -5 ' -nitrobenzo-15-crown-5, - - (carbamyl) benzo-15-crown-5, ' - (carbamyl) benzo-18 -crown- 6, - (carbamyl -4 , 5-dimethyl-2 -nitrobenzene, - (carbamyl -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert-butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) benzene, - (carbamyl -4- (trifluoromethylthio) benzene, - (carbamyl -4-acetylbenzene, - (carbamyl -4-benzyloxybenzene, - (carbamyl -4-bromo-2, 6 -dimethylbenzene, - (carbamyl -4-bromo-2- (trifluoromethyl) benzene, - (carbamyl -4 -bromo-2 -chlorobenzene , - (carbamyl -4 -bromo-2-fluorobenzene, - (carbamyl -4 -bromo-2 -methylbenzene , - (carbamyl -4 -bromobenzene , - (carbamyl -4-chloro-2- (trifluoromethyl) benzene, - (carbamyl -4 -chloro-2 -methoxybenzene , - (carbamyl -4 -chloro-2 -methylbenzene, - (carbamyl -4 -chloro-2 -nitrobenzene, - (carbamyl -4 -chloro-3- (trifluoromethyl) benzene, - (carbamyl -4 -chloro-3 -nitrobenzene , - (carbamyl -4 -chlorobenzene , - (carbamyl -4 -dimethylaminobenzene , 1- (carbamyl -4-ethoxybenzene, 1- (carbamyl -4-ethylbenzene, 1- (carbamyl -4-fluoro-2- (trifluoromethyl) benzene, 1- (carbamyl -4 -fluoro-2 -nitrobenzene , 1- (carbamyl -4-fluoro-3- (trifluoromethyl) benzene, 1- (carbamyl -4 -fluoro-3 -nitrobenzene , 1- (carbamyl -4 -fluorobenzoyl , 1- (carbamyl -4-fluorobenzyl, 1- (carbamyl -4 - fluorobenzene , 1- (carbamyl -4 -heptyloxybenzene , 1- (carbamyl -4-iodobenzene, 1- (carbamyl -4 - isopropylbenzene , 1- (carbamyl -4 -methoxy-2 -methylbenzene , 1- (carbamyl - (4 -methoxyphenyl) methane, 1- (carbamyl -4-methoxybenzene, 1- (carbamyl -4 -methyl-2 -nitrobenzene, 1- (carbamyl -4 -methyl-3 -nitrobenzene, 1- (carbamyl - (4 -methylphenyl) methane, 1- (carbamyl -4 -n-butoxycarbonylbenzene , 1- (carbamyl -4-n-butoxybenzene, 1- (carbamyl -4 -n-butyl -2 -methylbenzene , 1- (carbamyl -4 -n-butylbenzene , 1- (carbamyl -4 -nitrobenzene , 1- (carbamyl -4 -phenoxybenzene , 1- (carbamyl - 5-bromopenane , 1- (carbamyl -5-chloro-2 , 4-dimethoxybenzene, 1- (carbamyl -5 -chloro-2 -methylbenzene , 1- (carbamyl -5 - fluoro-2 -methylbenzene , 1- (carbamyl • 5-iodopentane , 1- (carbamyl) -2 -propene benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl -cyclohexane, carboxyethylcarbamyl, ethyl 2- (carbamyl -3 -methylbutyrate, ethyl 2- (carbamyl -3-phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio butyrate, ethyl 2- (carbamyl -4-methylvalerate, ethyl 2- (carbamyl benzoate, ethyl 2- (carbamyl) propionate, ethyl 3 - (carbamyl benzoate, ethyl 3 - (carbamyl) propionate, ethyl 4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate, 1- (carbamyl) -ethyl, ethyl (carbamyl) acetate, 1- (carbamyl) -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2-methylethane, methyl 2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl (carbamyl) acetate, 1- (carbamyl) -propane , 1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane, 1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate, carbamyltrichloromethane; or
Ri, is of the formula
Figure imgf000030_0001
wherein R15 is hydrogen, methyl, t-butyl, carbomethoxymethyl , ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4-methylphenyl , 4- fluorophenyl, 3-fluorophenyl , 4-cyanophenyl, 2- methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- chlorophenyl , 3 , 4-difluorophenyl, 4-nitrophenyl, 3,4- dihydroxyphenyl, 3-nitrophenyl, 3 -methyl -4 -chlorophenyl, adamantyl , 2 , 5-dimethoxyphenyl, 3 -chloro-4-methylphenyl, 5- (3 -carboethoxy) isoxazole, 4-phenylphenyl, 3,4- dichlorophenyl, 6- (2-oxo) -1 , 2 , 3 , 4-tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4 -bromophenyl , 2-(5-chloro- 3 -methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) - 1 , 2 , 3 , 4-tetrahydronaphthalene, 4 -chlorophenyl , 1-pyrene, 5- [3- (3 ' ,4 ' -dichlorophenyl) ] isoxazole, 5- [3- (2 ',4'- dichlorophenyl) ] isoxazole, 5- (3-phenyl) isoxazole; and Ri6 is hydrogen, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl, 4-methylphenyl ; or Rι4, R15 and R16 together form the structure
Figure imgf000031_0001
or the structure
Figure imgf000031_0002
R4 is a hydrogen atom, 2-pyridinemethyl , allyl, 2-methoxyethyl , benzyl, 2-methylbenzyl , 3-methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl , 3 -fluorobenzyl, 4-fluorobenzyl , 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl ,
2 - (3 -chlorophenyl ) ethyl , 2 - (2 -chlorophenyl ) ethyl ,
2 , 3 -dimethoxy-benzyl , 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl ,
2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl,
3- (dimethylamino) -2 , 2-dimethylpropyl ,
3- (dimethylamino) propyl, 2-aminoethyl,
2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl ,
3- (2 -pipecolinyl) propyl, 3 -butoxypropyl , 3- (pyrrolidin-2-one-l-yl) propyl, 3 - (morpholino) propyl , 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl -1-propyl,
2 -methyl-2 -phenylethyl , 4 -phenylbutyl ,
3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl; or
R4 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl,
4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl , trimethylacetyl, triphenylacetyl, nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl , (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl , 2 , 4-dichlorobenzoyl, 4 -methyl-1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl , 2-pyridylacetyl, 2-thiopheneacetyl , 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl , 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert-butyl -cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5,5-trimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl , 5-bromo-2-chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl , 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3-benzoylpropionyl , 3 , 5-dichlorobenzoyl , 3 -cyanobenzoyl, 3 -fluoro-4 -methylbenzoyl , 1-isoquinolinecarbonyl, 3-methyl-2-thiophenecarbonyl , 3-phenoxybenzoyl ,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl , 3 , 5-dichloro-4-hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3-lndolepropionyl, 2, 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl, succinamyl,
4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r (-) -2-oxothiazolidine-4-carbonyl, 4 -nitrophenylacetyl , coumarin-3 -carbonyl , 1-cyano-l-cyclopropane carbonyl, 2-chloro-5- (methylthio) benzoyl , theophylline- 7 -acetyl, 2- (2-cyanophenylthio) benzoyl ; or
R4 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl,
2-thiophenesulfonyl, 4-chlorobenzenesulfonyl ,
4 - fluorobenzenesulfonyl , 4 -methoxybenzenesulfonyl , 4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2-acetamido-4-methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl , 2 , 3 -dichlorothiophene- 5 -sulfonyl ,
3 , 4 -dimethoxybenzenesulfonyl ,
3 , 5 -bis (trifluoromethyl) benzenesulfonyl ,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl,
2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5 -dichlorothiophene-3- sulfonyl,
2 , 6-dichlorobenzenesulfonyl , 2 , 6-difluorobenzenesulfonyl, 2-chloro-4- (trifluoromethyl) enzenesulfonyl ,
2 -chloro-5- (trifluoromethyl) benzenesulfonyl ,
2 -chloro-6 -methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl , 3 -chlorobenzenesulfonyl , 4- (n-butoxy) benzenesulfonyl , 4 -trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4 -sulfonyl , 2- (methoxycarbonyl) thiophene-3 -sulfonyl, 4 -acetamido-3 -chlorobenzene sulfonyl ,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5 -s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl, 5- (isoxazol-3-yl) thiophene-2-sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4-methylbenzenesulfonyl , 2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl, 4-isopropylbenzene sulfonyl, 2 , 5 -dimethoxybenzenesulfonyl, 3 , -dichlorobenzenesulfonyl ; or
R4 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - ( -) -1- (carbamyl) - (1-naphthyl) ethane, (s) - ( +) -1- (carbamyl) - (1 -naphthyl) ethane, (s) -(+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester,
(s) -2- (carbamyl) -3- phenylpropionate methyl ester,
1- (carbamyl) -tridecafluoro-1-hexane,
1- (carbamyl) -1,1,3, 3-tetramethylbutane,
1- (carbamyl) - (1 -naphthyl) ethane, 1- (carbamyl) - (4 -bromophenyl) ethane,
1- (carbamyl) -adamantane, 1- (carbamyl) naphthalene,
1- (carbamyl) -2,3, 4-trifluorobenzene,
1- (carbamyl) -2 , 3-dichlorobenzene,
1- (carbamyl) -2 , 3 -dimethylbenzene, 1- (carbamyl) -2,4, 5-trichlorobenzene,
1- (carbamyl) -2,4, 5 -tri ethylbenzene,
1- (carbamyl) -2,4, 6-trichlorobenzene,
1- (carbamyl) -2 , 4-dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene, 1- (carbamyl) -2 , 4 -dimethylbenzene,
1- (carbamyl) -2 , 5 -dichlorobenzene, -2 , 5-difluorobenzene,
-2 , 5-dimethoxybenzene,
-2,5- dimethylbenzene,
-2 , 6 -dibromo-4-fluorobenzene,
-2 , 6-dibromo-4-isopropylbenzene,
-2, 6-dichlorobenzene,
-2, 6-diethylbenzene,
-2 , 6-difluorobenzoyl,
-2, 6-difluorobenzene,
-2 , 6-diisopropylbenzene,
-2 , 6 -dimethylbenzene,
-2- (chloromethyl) benzene,
-2- (difluoromethoxy) benzene,
-2- (methylthio) benzene,
-2- (trifluoromethoxy) benzene,
-2- (trifluoromethyl) benzene,
-2-biphenyl,
-2 -bromo-4 , 6-difluorobenzene,
-2-bromoethane, 1- (carbamyl) -2-bromobenzene,
-2 -chloro-4 -nitrobenzene ,
-2 -chloro-5- (trifluoromethyl) benzene,
-2 -chloro-5 -nitrobenzene,
-2 -chloro-6-methylbenzene ,
-2 -chlorobenzyl , 1 - (carbamyl ) -2 -chloroethane ,
-2 -chlorobenzene ,
-2 -cyanobenzene ,
-2 -ethoxybenzene ,
-2 -ethyl-6 -methylbenzene,
-2-ethylbenzene,
-2-fluoro-3- (trifluoromethyl) benzene,
-2-fluoro-5- (trifluoromethyl) benzene,
-2-fluoro-5-methylbenzene, 2 - fluoro-5-nitrobenzene , 2-fluoro-6- (trifluoromethyl) benzene, 2-fluorobenzene, 1- (carbamyl) -2-iodobenzene, 2 - isopropyl - 6 -methylbenzene ,
Figure imgf000035_0001
2 -isopropylbenzene, -2-methoxy-5-chloro benzene, -2 -methoxy-5 -methylbenzene , -2 -methoxy-5 -nitrobenzene , -2-methoxybenzene , -2 -methyl-3 -nitrobenzene, -2 -methyl- 5-nitrobenzene, -2 -methyl-6 -1-butylbenzene , -1- (2 -methylphenyl) methane, -2-n-propylbenzene,
-2-naphthalene, 1- (carbamyl) -2 -nitrobenzene, -2 -phenoxybenzene , -2 -tert-butylbenzene, -3,4, 5-trimethoxybenzene, -1- (3 , 4 -dichlorophenyl) methane, -3 , 4 -dichlorobenzene, -3 , 4 -difluorobenzene, -3 , 4 -dimethylbenzene, -3 , 5 -bis (trifluoromethyl) benzene, -3,5- dichlorobenzene, -3 , 5-dimethoxybenzene,
-3 , 5 -dimethylbenzene, 1- (carbamyl) -3,5- ne, 1- (carbamyl) -3- (methylthio) benzene, -3- (trifluoromethyl) benzene, -3- (trifluoromethylthio) benzene, -3 -acetylbenzene,
-3 -bromobenzene, 1- (carbamyl) -3-bromopropane, -3 -carbomethoxybenzene , -3 -chloro-2 -methoxybenzene , -3 -chloro-2 -methylbenzene , -3 -chloro-4 -fluorobenzene, -3 -chloro-4 -methylbenzene, -3 -chlorobenzene , - 3 -chloropropane , -3 -cyanobenzene ,
-3 -cyclopentoxy-4 -methoxybenzene , 3 -ethylbenzene ,
Figure imgf000036_0001
3 -fluoro-4 -methylbenzene, - (carbamyl) -3-fluorobenzene, 1- (carbamyl) -3-iodopropane, - (carbamyl) benzoyl chloride, - (carbamyl) -3 -methoxybenzene, - (carbamyl) - (3 -methylphenyl) methane, - (carbamyl) -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, ■ - (carbamyl) -5 ' -nitrobenzo-15-crown-5 , ' - (carbamyl) benzo-15-crown-5 , ' - (carbamyl) benzo-18-crown-6, - (carbamyl -4 , 5 -dimethyl-2 -nitrobenzene, - (carbamyl -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert-butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) enzene, - (carbamyl -4 - (trifluoromethylthio) benzene , - (carbamyl -4-acetylbenzene, - (carbamyl -4-benzyloxybenzene, - (carbamyl -4 -bromo-2 , 6 -dimethylbenzene , - (carbamyl -4 -bromo-2- (trifluoromethyl) benzene, - (carbamyl -4 -bromo-2 -chlorobenzene, - (carbamyl -4 -bromo-2 -fluorobenzene, - (carbamyl -4 -bromo-2 -methylbenzene , - (carbamyl -4 -bromobenzene , - (carbamyl -4 -chloro-2- (trifluoromethyl) benzene, - (carbamyl -4 -chloro-2 -methoxybenzene , - (carbamyl -4 -chloro-2 -methylbenzene , - (carbamyl -4 -chloro-2 -nitrobenzene, - (carbamyl -4 -chloro-3- (trifluoromethyl) benzene, - (carbamyl -4 -chloro- 3 -nitrobenzene, - (carbamyl -4 -chlorobenzene, - (carbamyl -4 -dimethylaminobenzene , - (carbamyl -4 -ethoxybenzene , - (carbamyl -4 -ethylbenzene, - (carbamyl -4-fluoro-2- (trifluoromethyl) benzene, 1- (carbamyl) -4-fluoro-2 -nitrobenzene,
1- (carbamyl) -4-fluoro-3- (trifluoromethyl) benzene,
1- (carbamyl) -4-fluoro-3 -nitrobenzene,
1- (carbamyl) -4-fluorobenzoyl, 1- (carbamyl) -4-fluorobenzyl,
1- (carbamyl) -4-fluorobenzene,
1- (carbamyl) -4-heptyloxybenzene,
1- (carbamyl) -4-iodobenzene,
1- (carbamyl) -4-isopropylbenzene, 1- (carbamyl) -4 -methoxy-2 -methylbenzene,
1- (carbamyl) - (4 -methoxyphenyl) methane,
1- (carbamyl) -4-methoxybenzene,
1- (carbamyl) -4-methyl-2-nitrobenzene,
1- (carbamyl) -4-methyl-3-nitrobenzene, 1- (carbamyl) - (4 -methylphenyl) methane,
1- (carbamyl) -4-n-butoxycarbonylbenzene,
1- (carbamyl) -4-n-butoxybenzene,
1- (carbamyl) -4-n-butyl-2-methylbenzene,
1- (carbamyl) -4-n-butylbenzene, 1- (carbamyl) -4-nitrobenzene,
1- (carbamyl) -4-phenoxybenzene,
1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (carbamyl) -5 -chloro-2 -methylbenzene, 1- (carbamyl) -5 -fluoro-2 -methylbenzene,
1- (carbamyl) -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl
2- (carbamyl) -3-methylbutyrate, ethyl 2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4-
(methylthio) butyrate, ethyl
2- (carbamyl) -4-methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3 - (carbamyl) benzoate, ethyl 3 - (carbamyl) propionate, ethyl 4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate,
1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl 2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl (carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane, 1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate, carbamyltrichloromethane; and
R3, R4 and the attached nitrogen atom of Formula (I) together form pyrrolidine, 4- (R) -hydroxy-2- (S) - pyrrolidine, 4- (R) -hydroxy-2- (R) -pyrrolidine, 4-(S)- hydroxy-2- (S) -pyrrolidine, 4- (S) -hydroxy-2- (S) - pyrrolidine, 4- (R) -benzyloxy-2- (S) -pyrrolidine, 4-(R)- benzyloxy-2- (R) -pyrrolidine, 4- (S) -benzyloxy-2- (S) - pyrrolidine, 4- (S) -benzyloxy-2- (S) -pyrrolidine, 4- piperidino, 3- (R) -piperidino, 3 - (S) -piperidino, 2- (R) - piperidino, 2- (S) -piperidino, octahydroisoquinoline or dihydroindoyl ;
R5 is methyl, t-butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl , carboethoxy, phenyl, 4-methylphenyl, 4-fluorophenyl, 3 -fluorophenyl, 4-cyanophenyl , 2-methoxyphenyl , 3-methoxyphenyl, 4- methoxyphenyl , 4 -chlorophenyl , 3 , 4 -difluorophenyl , 4- nitrophenyl, 3 , 4-dihydroxyphenyl , 3-nitrophenyl , 3- methyl -4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, 3- chloro-4-methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4 -dichlorophenyl , 6- (2-oxo) -1 , 2 , 3 , 4- tetrahydroquinoline, 4 - (5-methyl -3 -phenyl) isoxazole, 4-. bromophenyl, 2- (5 -chloro-3 -methyl ) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5- [3 -(3 ',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ' , 4 ' - dichlorophenyl) ] isoxazole, 5- (3 -phenyl) isoxazole; and
R6 is hydrogen, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl, 4-methylphenyl; or
R5 and R6 together with the triazole ring of Formula (I) form the structure
Figure imgf000040_0001
or the structure
Figure imgf000040_0002
R7 is 1 , 3 -phenylene, 3 -methoxy- 1 , 4-phenylene, 2 -methoxy- 1, 4-phenylene, 2-chloro-l , 4-phenylene, 1 , 4-phenylene, 2- methoxy-4-chloro-l , 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l , 3 -phenylene, 2-chloro- 1, 3 -phenylene, 4-chloro-l, 3 -phenylene, 6-chloro-l, 3- phenylene, 5-carboxy- 1 , 3 -phenylene, 5-methoxycarbonyl- 1 , 3 -phenylene, 2 , 6-dimethoxy-l , 3 -phenylene, 2 , 5-dichloro- 1 , 3 -phenylene, 2-bromo-1 , 3 -phenylene, 6-bromo-l,3- phenylene, 2 , 6-dimethoxy-5-chloro-l, 3-phenylene; and
R8 is a hydrogen atom, 2-pyridinemethyl , allyl,
2-methoxyethyl, benzyl, 2-methylbenzyl , 3 -methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3 -fluorobenzyl, 4-fluorobenzyl, 3- (1-imidazole) propyl , 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2-chlorophenyl) ethyl, 2, 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl , 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3 - (diethylamino) propyl , 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl,
3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl -1 -propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl; or
R8 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl , hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl , p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl , tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl, nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl , (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl , 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl , 2 , 4 -dichlorobenzoyl , 4 -methyl -1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl , 1, 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl , 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4-tert-butyl-cyclohexanecarbonyl, 4-sulfonamidobenzoyl, 3,5, 5-trimethylhexanoyl, 3 , 5-bis (trifluoromethyl) -benzoyl , 5-bromo-2-chlorobenzoyl, 5-bromonicotinyl , 6-chloronicotinyl, 3 , 5-dimethyl -p-anisyl , 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl , 3-cyanobenzoyl , 3 -fluoro-4 -methylbenzoyl , 1 - isoquinolinecarbonyl , 3 -methyl-2-thiophenecarbonyl , 3 -phenoxybenzoyl,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl , 3 , 5-dichloro-4-hydroxybenzoyl , 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3 -lndolepropionyl , 2 , 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl , succinamyl , 4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r (-) -2-oxothiazolidine-4-carbonyl , -nitrophenylacetyl , coumarin-3 -carbonyl , 1-cyano-l-cyclopropane carbonyl, -chloro-5- (methylthio) benzoyl , theophylline-7-acetyl, - (2 -cyanophenylthio) benzoyl ; or
R8 is 2-mesitylenesulfonyl, 2-naphthalenesulfonyl,
2-thiophenesulfonyl, 4-chlorobenzenesulfonyl ,
4 -fluorobenzenesulfonyl, 4-methoxybenzenesulfonyl ,
4-methylsulfonylbenzenesul onyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2-acetamido-4-methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl,
2 , 3 -dichlorothiophene-5-sulfonyl , 3 , 4 -dimethoxybenzenesulfonyl,
3 , 5 -bis (trifluoromethyl) benzenesulfonyl ,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5-dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl , 2 , 6-difluorobenzenesulfonyl,
2-chloro-4- (trifluoromethyl) benzenesulfonyl, 2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro-6 -methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3-chlorobenzenesulfonyl,
4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl ,
2- (methoxycarbonyl) thiophene-3 -sulfonyl,
4 -acetamido-3 -chlorobenzene sulfonyl ,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl ,
5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4 -difluorobenzenesulfonyl , 2-fluorobenzenesulfonyl ,
4 -isopropylbenzene sulfonyl, 2 , 5 -dimethoxybenzenesulfonyl ,
3 , 4 -dichlorobenzenesulfonyl ; or R8 is (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - ( - ) -1- (carbamyl) - (1 -naphthyl) ethane, (s) - ( + ) -1- (carbamyl) - (1 -naphthyl) ethane, (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4 -methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester,
(s •(-) -2- (carbamyl) propionate methyl ester, (s ■2- (carbamyl) -3- phenylpropionate methyl ester, 1- carbamyl -tridecafluoro- 1 -hexane , 1- carbamyl -1,1,3, 3 -tetramethylbutane , 1- carbamyl - (1 -naphthyl) ethane, 1- carbamyl - (4 -bromophenyl) ethane, 1- carbamyl -adamantane, 1- (carbamyl) naphthalene, 1- carbamyl -2,3, 4-trifluorobenzene, 1- carbamyl -2 , 3 -dichlorobenzene , 1- carbamyl 2.3 -dimethylbenzene , 1- carbamyl -2,4, 5-trichlorobenzene, 1- carbamyl 2,4, 5-trimethylbenzene, 1- carbamyl 2,4, 6-trichlorobenzene, 1- carbamyl 2, 4 -dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene,
1- carbamyl -2 4 -dimethylbenzene , 1- carbamyl -2 5 -dichlorobenzene , 1- carbamyl -2 5 -difluorobenzene, 1- carbamyl -2 5 -dimethoxybenzene , 1- carbamyl -2 5- dimethylbenzene, 1- carbamyl -2 6 -dibromo-4 -fluorobenzene , 1- carbamyl -2 6 -dibromo-4 -isopropylbenzene , 1- carbamyl -2 6 -dichlorobenzene, 1- carbamyl -2 6-diethylbenzene, 1- carbamyl -2 6-difluorobenzoyl , 1- carbamyl -2 6-difluorobenzene, 1- carbamyl -2 6 -diisopropylbenzene , - carbamyl -2 6 -dimethylbenzene, - carbamyl -2 ( chloromethyl ) benzene , -2- (difluoromethoxy) benzene,
-2- (methylthio) benzene,
-2- (trifluoromethoxy) benzene,
-2- (trifluoromethyl) benzene,
-2-biphenyl,
-2-bromo-4 , 6-difluorobenzene,
-2-bromoethane, 1- (carbamyl) -2-bromobenzene,
-2 -chloro-4 -nitrobenzene ,
-2 -chloro-5- (trifluoromethyl) benzene,
-2 -chloro-5-nitrobenzene,
-2 -chloro-6 -methylbenzene,
-2-chlorobenzyl, 1- (carbamyl) -2-chloroethane,
-2 -chlorobenzene ,
-2 -cyanobenzene ,
-2-ethoxybenzene,
-2 -ethyl - 6 -methylbenzene ,
-2-ethylbenzene,
-2-fluoro-3- (trifluoromethyl) benzene,
-2-fluoro-5- (trifluoromethyl) benzene,
-2 - fluoro-5-methylbenzene ,
-2 -fluoro-5-nitrobenzene ,
-2-fluoro-6- (trifluoromethyl) benzene,
-2-fluorobenzene, 1- (carbamyl) -2-iodobenzene,
-2 - isopropyl- 6 -methylbenzene ,
-2 - isopropylbenzene ,
-2-methoxy-5-chloro benzene,
-2 -methoxy-5-methylbenzene,
-2 -methoxy-5-nitrobenzene,
-2 -methoxybenzene ,
-2 -methyl-3 -nitrobenzene ,
-2 -methyl-5-nitrobenzene,
-2 -methyl-6-t -butylbenzene,
-1- (2 -methylphenyl) methane,
-2 -n-propylbenzene , 2-naphthalene, 1- (carbamyl) -2-nitrobenzene, 2 -phenoxybenzene ,
Figure imgf000045_0001
2 -tert-butylbenzene, 1- carbamyl -3,4,5 - 1rimethoxybenzene , 1- carbamyl -1- (3 , 4 -dichlorophenyl) methane, 1- carbamyl -3 , 4 -dichlorobenzene, 1- carbamyl -3 , 4 -difluorobenzene, 1- carbamyl -3 4 -dimethylbenzene , 1- carbamyl -3 5-bis (trifluoromethyl) benzene, 1- carbamyl -3 5- dichlorobenzene, 1- carbamyl -3 5-dimethoxybenzene, 1- carbamyl -3 5 -dimethylbenzene, 1- (carbamyl) -3,5- dinitrobenzene 1- (carbamyl) -3- (methylthio) benzene,
1- carbamyl -3- (trifluoromethyl) benzene, 1- carbamyl -3- (trifluoromethylthio) benzene, 1- carbamyl -3 -acetylbenzene, 1- carbamyl -3 -bromobenzene, 1- (carbamyl) -3-bromopropane,
11-- (carbamyl - 3 - carbomethoxybenzene , 1- carbamyl -3 -chloro-2 -methoxybenzene , 1- carbamyl -3 -chloro-2 -methylbenzene , 1- carbamyl -3 -chloro-4 -fluorobenzene, 1- carbamyl - 3 -chloro-4 -methylbenzene , 1- carbamyl -3 -chlorobenzene , 1- carbamyl -3 -chloropropane , 1- carbamyl - 3 -cyanobenzene , 1- carbamyl -3 -cyclopentoxy-4 -methoxybenzene, 1- carbamyl -3 -ethylbenzene ,
11-- (carbamyl -3 -fluoro-4 -methylbenzene , 1- carbamyl -3-fluorobenzene, 1- (carbamyl) -3-iodopropane, 3- carbamyl benzoyl chloride, - carbamyl -3 -methoxybenzene , - carbamyl - ( 3 -methylphenyl) methane, -- (carbamyl -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, ' - (carbamyl ) -5 ' -nitrobenzo-15-crown-5 , ' - (carbamyl) benzo-15-crown-5, ' - (carbamyl) benzo-18-crown-6 , - (carbamyl) -4 , 5 -dimethyl -2 -nitrobenzene, - (carbamyl) -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl) -4- (chloromethyl) benzene, - (carbamyl) -4- (chlorosulfonyl) benzene, -4- (difluoromethoxy) benzene,
-4- (methylthio) benzene,
-4- (tert -butyl) benzene,
-4- (trifluoromethoxy) benzene,
-4- (trifluoromethyl) benzene,
-4- (trifluoromethylthio) benzene,
-4 -acetylbenzene ,
-4-benzyloxybenzene,
-4 -bromo-2 , 6 -dimethylbenzene,
-4 -bromo-2- (trifluoromethyl) benzene,
-4 -bromo-2 -chlorobenzene ,
-4 -bromo-2 -fluorobenzene ,
-4 -bromo-2 -methylbenzene,
-4 -bromobenzene ,
-4 -chloro-2 - (trifluoromethyl) benzene ,
-4 -chloro-2 -methoxybenzene ,
-4 -chloro-2 -methylbenzene ,
-4 -chloro-2 -nitrobenzene,
-4 -chloro-3- (trifluoromethyl) benzene,
-4 -chloro-3 -nitrobenzene,
-4 -chlorobenzene ,
-4 -dimethylaminobenzene ,
-4 -ethoxybenzene ,
-4-ethylbenzene,
-4 -fluoro-2- (trifluoromethyl) benzene,
-4-fluoro-2 -nitrobenzene,
-4-fluoro-3- (trifluoromethyl) benzene,
-4-fluoro-3 -nitrobenzene,
-4 - fluorobenzoyl ,
-4 - fluorobenzyl ,
-4 - fluorobenzene ,
-4 -heptyloxybenzene ,
-4-iodobenzene,
-4 - isopropylbenzene ,
-4 -methoxy-2 -methylbenzene ,
- (4 -methoxyphenyl) methane,
Figure imgf000047_0001
-4 -methoxybenzene , 1- (carbamyl) -4-methyl-2-nitrobenzene,
1- (carbamyl) -4 -methyl-3 -nitrobenzene,
1- (carbamyl) - (4 -methylphenyl) methane,
1- (carbamyl) -4-n-butoxycarbonylbenzene, 1- (carbamyl) -4-n-butoxybenzene,
1- (carbamyl) -4 -n-butyl-2 -methylbenzene,
1- (carbamyl) -4-n-butylbenzene,
1- (carbamyl) -4 -nitrobenzene,
1- (carbamyl) -4-phenoxybenzene, 1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (carbamyl) -5-chloro-2-methylbenzene,
1- (carbamyl) -5-fluoro-2 -methylbenzene,
1- (carbamyl) -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl
2- (carbamyl) -3-methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4-
(methylthio) butyrate, ethyl 2- (carbamyl) -4 -methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate,
1- (carbamyl) -ethyl , ethyl (carbamyl) acetate, 1- (carbamyl) -heptane, 1- (carbamyl) -hexane,
1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl
2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl (carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane,
1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane,
1- (carbamyl) -tetrahydro-2-pyran,
1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate, carbamyltrichloromethane. The present invention also provides a method of preparing libraries containing discrete compounds of Formula (I), in particular, thiazoles, by reacting a resin-bound amine with an amino containing carboxylic acid, where the amino group can be a free amino group, a protected amino group or a masked amino group, such as, for example, a nitro group; and deprotecting or unmasking the amino group, if need be, to give a new amino bound resin. In one aspect of the invention, the amino group is preferably a protected amino group.
The starting resin-bound amine is preferably a commercially available resin, such as, for example, MBHA (i.e., 4-methylbenzhydrylamine) , or prepared by synthetic methods known to those skilled in the art, such as, for example, the reductive alkylation of MBHA resin with an aldehyde or ketone to give a nitrogen-substituted resin or through the use of an aldehyde-bound resin prepared from Wang resin and reductively alkylating with an amine or diamine to give a nitrogen-substituted resin or yet another method, such as, displacing an alkyl halide-bound resin with an amine or diamine. In the instance where a diamine is used, further reaction on the resin by the above mentioned carboxylic acid can take place at the available nitrogen (i.e., primary or secondary nitrogen), such as, for example, the displacement of an alkyl-bound resin with piperazine will result in both a secondary and tertiary nitrogen where only the secondary nitrogen is available for subsequent reaction, such as, coupling, with the carboxylic acid to form an amide.
Once the amino containing carboxylic acid is reacted with the resin-bound amine, the new amino-bound resin is converted to a thiourea with thiophosgene or a thiophosgene equivalent, such as, for example, 1,1'- thiocarbonyldiimidazole, and the resulting intermediate is subsequently allowed to react with ammonia or an ammonia equivalent, to give a thiourea-bound resin. The thiourea-bound resin is allowed to react with an α- haloketone and after cyclization affords a thiazole library containing discrete compounds of Formula (I).
Another aspect of this invention is the use of an orthogonally protected amino group that can be introduced in the above mentioned amino containing carboxylic acid and can be further modified, in an dependent or independent manner, either before or after the formation of the thiazole. Preferably the amino group, introduced in the amino containing carboxylic acid, is masked as a nitro group and converted into the amino group through the use of any one of the different reductive methods know to one skilled in the art, such as, for example, SnCl2. In another preferred embodiment, the amino group is protected by any one of the variety protecting groups known in the art, such as, for example, a benzyloxycarbonyl (i.e, Cbz), tert-butyloxycarbonyl (i.e., t-Boc) and the like. The amino group, either after deprotection or after reduction of a nitro group, can optionally be reacted with an aldehyde or ketone to give a substituted nitrogen. The resulting substituted nitrogen can be optionally alkylated to give a disubstituted nitrogen or reacted with an electrophile such as, for example, an acyl chloride, isocyanates or sulfonyl chlorides to give an amide, carbamoyl or sulfonamide respectively. Alternatively, the nitrogen, either substituted or unsubstituted, can be reacted, as mention above herein, with thiophosgene or a thiophosgene equivalent followed by ammonia to give a thiourea that can be converted into a thiazole library through the use of an α-haloketone . The library prepared from the above mentioned method can be useful for screening the library on the resin or alternatively can be cleaved from the resin as discrete compounds and screened in absence of resin. Preferably, the methods described above further comprise the step of cleaving the library from the resin to give discrete compounds.
In the above Formula (I), the stereochemistry of chiral centers associated with R3 is of the formula:
Figure imgf000051_0001
R10 R11 can independently be in the R or S configuration, or a mixture of the two. The chiral centers can be further designated as R or S or R,S or d,D, 1,L or d,l, D,L.
In the above Formula (I) , the term " C1 to C6 alkyl" denotes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert -butyl, amyl, tert-amyl, hexyl and the like. The preferred "Cj to C6 alkyl" groups are methyl, iso-butyl, sec-butyl and iso-propyl .
The term "C2 to C7 alkenyl" denotes such radicals as vinyl, allyl, 2-butenyl, 3-butenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight and branched chains.
The term "C2 to C7 alkynyl" denotes such radicals as ethynyl, propynyl , 2-butynyl, 2-pentynyl, 3- pentyny1 , 2 - hexynyl , 3 -hexyny1 , 4 -hexyny1 , 2 -heptyny1 , 3-heptynyl, 4- heptynyl , 5-heptynyl as well as di- and tri-ynes of straight and branched chains. The terms "Ci to C6 substituted alkyl," "C2 to C7 substituted alkenyl," "C2 to C7 substituted alkynyl," and "Ci to C8 substituted alkylene" denote that the above Cj to C6 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl groups and Ci to C8 alkylene groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, C3 to C7 cycloalkyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Cλ to C7 alkoxy, Cj to C7 acyl, Cx to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano, methylsulfonylamino, thiol, Cj to C4 alkylthio or Cx to C7 alkylsulfonyl groups. The substituted alkyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents.
Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3 -oxo-but-1-yl , cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl , trityloxymethyl , propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylammomethyl , methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl , chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4- dichloro (n-butyl) , 2-aminopropyl , 1-chloroethyl , 2- chloroethyl, 1- bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 1- iodoethyl, 2-iodoethyl, 1-chloropropyl, 2-chloropropyl, 3- chloropropyl , 1-bromopropyl , 2- bromopropyl , 3 -bromopropyl, 1-fluoropropyl , 2- fluoropropyl, 3 -fluoropropyl , 1- iodopropyl, 2- iodopropyl, 3 -iodopropyl, 2-aminoethyl, 1- aminoethyl, N- benzoyl-2-aminoethyl , N-acetyl-2-aminoethyl , N-benzoyl-1- aminoethyl, N-acetyl-l-aminoethyl and the like. Examples of the above substituted alkenyl groups include styrenyl, 3-chloro-propen-l-yl , 3-chloro- buten-1-yl, 3-methoxy-propen-2-yl, 3 -phenyl -buten-2 -yl , l-cyano-buten-3-yl and the like. The geometrical isomerism is not critical, and all geometrical isomers for a given substituted alkenyl can be used.
Examples of the above substituted alkynyl groups include phenylacetylen-1-yl, 1-phenyl -2 -propyn-1- yl and the like.
The term "C2 to C7 alkenylene" as used herein denotes an alkene group that is linked by two different substitutents. Similarly, the term "C2 to C7 alkynylene" as used herein denotes an alkyne group that is linked by two different substitutents. The terms "C2 to C7 substituted alkenylene" and "C3 to C7 substituted alkynylene" as used herein denote, respectively, an alkene group or alkyne group that is linked by two different substitutents and is further substituted by one or two halogen, hydroxy, protected hydroxy, oxo, protected oxo, C3 to C7 cycloalkyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Cx to C, alkoxy, C: to C acyl, Cx to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano, methylsulfonylamino, thiol, Ci to C4 alkylthio or C: to C7 alkylsulfonyl groups.
The term "oxo" denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety. The term "protected oxo" denotes a carbon atom bonded to two additional carbon atoms substituted with two alkoxy groups or twice bonded to a substituted diol moiety, thereby forming an acyclic or cyclic ketal moiety.
The term "Cx to C7 alkoxy" as used herein denotes groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. A preferred alkoxy is methoxy. The term "d to C7 substituted alkoxy" means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Ci to C6 substituted alkyl. Similarly, the term "C7 to C13 phenylalkoxy" as used herein means "Cj. to C7 alkoxy" bonded to a phenyl radical .
The term " C1 to C7 acyloxy" denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.
Similarly, the term " Cλ to C7 acyl" encompasses groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like. Preferred acyl groups are acetyl and benzoyl.
The term " Cx to C7 substituted acyl" denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, oxo, protected oxo, cyclohexyl, naphthyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C to C7 alkoxy, Cx to C7 acyl, Cα to C7 acyloxy, nitro, Cj to C6 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano, methylsulfonylamino, thiol, Ci to C4 alkylthio or Cx to C7 alkylsulfonyl groups. The substituted acyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents.
Examples of Cj to C7 substituted acyl groups include 4-phenylbutyroyl, 3-phenylbutyroyl, 3-phenylpropanoyl, 2- cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and 3 -dimethylaminobenzoyl .
The term "C3 to C7 cycloalkyl" includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. Similarly, the term "C5 to C7 cycloalkyl" includes the cyclopentyl, cyclohexyl or cycloheptyl rings. The terms "C3 to C7 substituted cycloalkyl" and "C5 to C7 substituted cycloalkyl" indicate the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Ci to C4 alkylthio, Ci to C4 alkylsulfoxide, Cx to C7 alkylsulfonyl, Cλ to C4 substituted alkylthio, Ci to C4 substituted alkylsulfoxide, Cλ to C7 substituted alkylsulfonyl, Cλ to C6 alkyl, Cx to C7 alkoxy, Cj to C6 substituted alkyl, Cλ to C7 substituted alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino groups.
The term "C3 to C7 cycloalkylene" means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups. Similarly, the term "C3 to C7 substituted cycloalkylene" means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substitution in the same manner as in relation to C3 to C7 substituted cycloalkyl .
The term "C5 to C7 cycloalkenyl" indicates a 1,2, or 3- cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring, while the term "substituted C5 to C7 cycloalkenyl" denotes the above C5 to C7 cycloalkenyl rings substituted by a Cx to C6 alkyl radical, halogen, hydroxy, protected hydroxy, Cx to C7 alkoxy, trifluoromethyl , carboxy, protected carboxy, oxo, protected oxo, (monosubstituted) amino, protected
(monosubstituted) amino, (disubstituted) amino, phenyl, substituted phenyl, amino or protected amino.
The term "C5 to C7 cycloalkenylene" is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted C5 to C7 cycloalkenylene" means a cycloalkeneylene further substituted by halogen, hydroxy, protected hydroxy, Cλ to C4 alkylthio, Ca to C4 alkylsulfoxide, C: to C7 alkylsulfonyl, x to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cx to C7 substituted alkylsulfonyl , Cλ to C6 alkyl, C: to C7 alkoxy, Cx to C6 substituted alkyl, Cα to C7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl , amino, or protected amino group .
The term "heterocycle" or "heterocyclic ring" denotes optionally substituted five-membered or six- membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered or six-membered rings may be saturated, fully saturated or partially unsaturated, with fully saturated rings being preferred. An "amino- substituted heterocyclic ring" means any one of the above-described heterocyclic rings is substituted with at least one amino group. Preferred heterocyclic rings include pyrrolidino, morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen-yl .
The term "substituted heterocycle" or "substituted heterocyclic ring" means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which can be the same or different. The substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Cj to C7 alkoxy, λ to C7 substituted alkoxy, C1 to C7 acyl, Cλ to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino carboxamide, protected carboxamide or trifluoromethyl groups.
The term "heteroaryl" means a heterocyclic aromatic derivative which is a five-membered or six- membered ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. Examples of heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolo, furano, oxazolo, isoxazolo, phthalimido, thiazolo and the like.
The term "substituted heteroaryl" means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which can be the same or different. The substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C7 substituted alkoxy, C: to C7 acyl, Cλ to C7 substituted acyl, Cλ to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl groups.
The term "heteroarylene" means the above described definition for "heteroaryl" wherein the heteroaryl is bonded at two positions connecting together two separate additional groups.
The term "substituted heteroarylene" means the above described heteroarylene is substituted with, for example, one or more, and preferably one or two, substituents which can be the same or different . The substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Cx to C7 alkoxy, C: to C7 substituted alkoxy, Ci to C7 acyl, Cα to C7 substituted acyl, Ci to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl groups.
The term "heteroarylalkylene" means the above described definition for "heteroaryl" wherein the heteroaryl is substituted with an alkylene and is bonded at two positions connecting together two separate additional groups. The definition includes groups of the formula : -heteroaryl -alkyl- and -alkyl-heteroaryl-alkyl- where "-" represents a bond. The term "substituted heteroarylalkylene" means the above described heteroarylalkylene is substituted on the heteroaryl group, alkylene group or both with, for example, one or more, and preferably one or two, substituents which can be the same or different. The substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C7 substituted alkoxy, C2 to C7 acyl, Cx to C7 substituted acyl, Ci to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl groups .
The term "C7 to C12 phenylalkyl" denotes a Cx to
C6 alkyl group substituted at any position by a phenyl, substituted phenyl, heteroaryl or substituted heteroaryl. Examples of such a group include benzyl, 2-phenylethyl, 3 -phenyl (n-propyl) , 4-phenylhexyl, 3 -phenyl (n-amyl) , 3- phenyl (sec-butyl) and the like. Preferred C7 to C12 phenylalkyl groups are the benzyl and the phenylethyl groups .
The term "C7 to C12 substituted phenylalkyl" denotes a C7 to C12 phenylalkyl group substituted on the Ci to C6 alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, protected guanidino, heterocyclic ring, substituted heterocyclic ring, C1 to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 alkoxy, Cλ to C7 substituted alkoxy, Cx to C7 acyl, Ci to C7 substituted acyl, Cx to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl , carboxamide, protected carboxamide, cyano, thiol, Cx to C4 alkylthio or C1 to C7 alkylsulfonyl groups; and/or the phenyl group may be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Cλ to C6 substituted alkyl, Ci to C7 alkoxy, Ci to C7 substituted alkoxy, Cλ to C7 acyl, Cx to C7 substituted acyl, Cx to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, trifluoromethyl, cyclic C2 to C7 alkylene or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl or phenyl groups can be substituted with one or more, and preferably one or two, substituents which can be the same or different.
Examples of the term "C7 to Ci2 substituted phenylalkyl" include groups such as 2 -phenyl- 1- chloroethyl, 2- (4-methoxyphenyl) ethyl, 4- (2 , 6-dihydroxy phenyl) n-hexyl, 2- (5-cyano-3-methoxyphenyl) n-pentyl, 3- (2 , 6-dimethylphenyl) n-propyl, 4-chloro-3 -aminobenzyl, 6- (4-methoxyphenyl) -3 -carboxy (n-hexyl) , 5- (4- aminomethylphenyl) - 3- (aminomethyl) n-pentyl , 5-phenyl-3- oxo-n-pent-1-yl and the like.
The term "C7 to C12 phenylalkylene" specifies a
C7 to C12 phenylalkyl, as defined above, where the phenylalkyl radical is bonded at two positions connecting together two separate additional groups. The definition includes groups of the formula: -phenyl-alkyl- and - alkyl-phenyl-alkyl- where "-" represents a bond.
Substitutions on the phenyl ring can be 1,2, 1,3 or 1,4. The term "C7 to C12 substituted phenylalkylene" means a C7 to C12 phenylalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, C to C4 alkylthio, Cx to C4 alkylsulfoxide, Cλ to C7 alkylsulfonyl, Cx to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cx to C7 substituted alkylsulfonyl, Cx to C6 alkyl, Cx to C7 alkoxy, C to C6 substituted alkyl, Cx to C7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group on the phenyl ring or on the alkyl group.
The term "substituted phenyl" specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 alkoxy, Cx to C7 substituted alkoxy, Cx to C7 acyl, Cx to C7 substituted acyl, Cx to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, trifluoromethyl and phenyl, wherein the second phenyl is substituted or unsubstituted, such that, for example, a biphenyl results .
Examples of the term "substituted phenyl" includes a mono- or di (halo) phenyl group such as 2 , 3 or 4 -chlorophenyl, 2 , 6 -dichlorophenyl , 2 , 5 -dichlorophenyl , 3 , 4 -dichlorophenyl, 2, 3 or 4 -bromophenyl, 3 , 4-dibromophenyl, 3 -chloro-4 -fluorophenyl, 2, 3 or 4-fluorophenyl and the like; a mono or di (hydroxy) phenyl group such as 2, 3 or 4-hydroxyphenyl,
2 , 4-dihydroxyphenyl , the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2, 3 or 4-nitrophenyl ; a cyanophenyl group, for example, 2, 3 or 4-cyanophenyl; a mono- or di (alkyl) phenyl group such as 2, 3 or 4-methylphenyl, 2 , 4-dimethylphenyl , 2 , 3 or 4- (iso-propyl) phenyl, 2, 3 or 4-ethylphenyl, 2, 3 or 4- (n-propyl) phenyl and the like; a mono or di (alkoxyl) phenyl group, for example, 2 , 6-dimethoxyphenyl, 2, 3 or 4-methoxyphenyl, 2, 3 or 4-ethoxyphenyl, 2, 3 or 4- (isopropoxy) phenyl, 2, 3 or 4- (t-butoxy) phenyl, 3 -ethoxy-4-methoxyphenyl and the like; 2, 3 or 4-trifluoromethylphenyl ; a mono- or dicarboxyphenyl or (protected carboxy) phenyl group such as 2 , 3 or 4-carboxyphenyl or 2 , 4-di (protected carboxy) phenyl; a mono-or di (hydroxymethyl) phenyl or (protected hydroxymethyl) phenyl such as 2 , 3, or 4- (protected hydroxymethyl) phenyl or 3 , 4-di (hydroxymethyl) phenyl; a mono- or di (aminomethyl) henyl or (protected aminomethyl) phenyl such as 2, 3 or 4- (aminomethyl) phenyl or 2 , 4- (protected aminomethyl) phenyl ; or a mono- or di (N- (methylsulfonylamino) ) phenyl such as 2 , 3 or 4- (N- (methylsulfonylamino) ) phenyl . Also, the term "substituted phenyl" represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3 -chloro-4 - hydroxyphenyl , 2 -methoxy-4 -bromophenyl , 4-ethyl-2-hydroxyphenyl, 3 -hydroxy-4-nitrophenyl, 2 -hydroxy 4 -chlorophenyl and the like.
The term "phenoxy" denotes a phenyl bonded to an oxygen atom. The term "substituted phenoxy" specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Ci to C7 alkoxy, Cx to C7 substituted alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl .
Examples of substituted phenoxy include 2-methylphenoxy, 2-ethylphenoxy, 2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy,
2-tert-butylphenoxy, 2-allylphenoxy, 2-propenylphenoxy, 2 -eyelopentylphenoxy, 2 -fluorophenoxy, 2- (trifluoromethyl) phenoxy, 2-chlorophenoxy, 2-bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy, 2-isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy, 3 -isopropylphenoxy, 3 -tert-butylphenoxy, 3 -pentadecylphenoxy, 3- (trifluoromethyl) phenoxy, 3-fluorophenoxy, 3-chlorophenoxy, 3 -bromophenoxy, 3-iodophenoxy, 3 -methoxyphenoxy, 3- (trifluoromethoxy) phenoxy, 4-methylphenoxy,
4-ethylphenoxy, 4 -propylphenoxy, 4-isopropylphenoxy, 4 -sec-butylphenoxy, 4 -1ert-butylphenoxy, 4-tert-amylphenoxy, 4 -nonylphenoxy, 4-dodecylphenoxy, 4-cyclopenylphenoxy, 4- (trifluoromethyl) phenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 4 -bromophenoxy, 4 -iodophenoxy, 4 -methoxyphenoxy, 4- (trifluoromethoxy) phenoxy, 4-ethoxyphenoxy, 4-propoxyphenoxy, 4-butoxyphenoxy, 4-hexyloxyphenoxy, 4-heptyloxyphenoxy, 2 , 3-dimethylphenoxy, 5, 6 , 7, 8-tetrahydro-l-naphthoxy, 2 , 3-dichlorophenoxy, 2, 3-dihydro-2 , 2 -dimethyl- 7 -benzofuranoxy, 2,3-dimethoxyphenoxy, 2,6-dimethylphenoxy, 2 , 6-diisopropylphenoxy, 2 , 6-di-sec-butylphenoxy, 2-tert- butyl-6-methylphenoxy, 2 , 6-di-tert-butylphenoxy, 2-allyl- 6 -methylphenoxy, 2 , 6-difluorophenoxy,
2 , 3 -difluorophenoxy, 2 , 6-dichlorophenoxy,
2 , 6-dibromophenoxy, 2-fluoro-6 -methoxyphenoxy,
2, 6 -dimethoxyphenoxy, 3 , 5 -dimethylphenoxy, 5-isopropyl-
3-methylphenoxy, 3 , 5 -di-tert-butylphenoxy, 3 , 5-bis (trifluoromethyl) phenoxy, 3 , 5-difluorophenoxy, 3 , 5-dichlorophenoxy, 3 , 5-dimethoxyphenoxy, 3 -chloro- 5- methoxyphenoxy, 3 , 4 -dimethylphenoxy, 5-indanoxy, 5,6,7, 8-tetrahydro-2-naphthoxy, 4 -chloro-3 -methylphenoxy, 2 , 4-dimethylphenoxy, 2 , 5 -dimethylphenoxy, 2-isopropyl- 5 -methylphenoxy, 4 -isopropyl -3 -methylphenoxy, 5-isopropyl-2-methylphenoxy, 2-tert-butyl-
5-methylphenoxy, 2 -1ert -butyl-4 -methylphenoxy, 2 , 4 -di-tert-butylphenoxy, 2 , 4 -di-1ert-amylphenoxy, 4 - fluoro-2 -methylphenoxy, 4 - fluoro-3 -methylphenoxy, 2 -chloro-4 -methylphenoxy, 2 -chloro-5 -methylphenoxy, 4 -chloro-2 -methylphenoxy, 4-chloro-3-ethylphenoxy, 2 -bromo-4 -methylphenoxy, 4 - iodo-2 -methylphenoxy, 2-chloro-5- (trifluoromethyl) phenoxy, 2 , 4-difluorophenoxy, 2 , 5-difluorophenoxy, 3 , 4-difluorophenoxy, 4-chloro-2- fluorophenoxy, 3 -chloro-4 -fluorophenoxy, 4 -chloro-3- fluorophenoxy, 2 -bromo-4-fluorophenoxy, 4 -bromo-2 - fluorophenoxy, 2 -bromo- 5-fluorophenoxy, 2 , 4-dichlorophenoxy, 3 , 4-dichlorophenoxy,
2 , 5-dichlorophenoxy, 2-bromo-4-chlorophenoxy, 2-chloro-4- fluorophenoxy, 4-bromo-2-chlorophenoxy, 2 , 4 -dibromophenoxy, 2 -methoxy-4 -methylphenoxy, 4-allyl-2- methylphenoxy, trans-2-ethoxy-5- (1-propenyl) phenoxy, 2 -methoxy-4 -propenylphenoxy, 3 , 4-dimethoxyphenoxy, 3 -ethoxy-4 -methoxyphenoxy, 4-allyl-2 , 6 -dimethoxyphenoxy, 3 , 4-methylenedioxyphenoxy, 2,3, 6-trimethylphenoxy, 2, 4 -dichloro-3 -methylphenoxy, 2 , 3 , 4-trifluorophenoxy, 2,3, 6 -trifluorophenoxy, 2,3, 5 -trifluorophenoxy, 2,3, 4-trichlorophenoxy, 2,3, 6-trichlorophenoxy, 2 , 3 , 5-trimethylphenoxy, 3 , 4 , 5-trimethylphenoxy, 4-chloro- 3 , 5-dimethylphenoxy, 4-bromo-3 , 5-dimethylphenoxy, 2 , 4 , 6-trimethylphenoxy, 2 , 6-bis (hydroxymethyl) -4- methylphenoxy, 2 , 6 -di-tert-butyl-4 -methylphenoxy, 2,6- di-tert-butyl-4-methoxyphenoxy, 2,4,5- trifluorophenoxy, 2 -chloro-3 , 5-difluorophenoxy, 2,4, 6-trichlorophenoxy, 3 , 4 , 5-trimethoxyphenoxy, 2 , 3 , 5-trichlorophenoxy, 4-bromo- 2 , 6-dimethylphenoxy, 4-bromo-6-chloro-2-methylphenoxy, 2 , 6 -dibromo-4 -methylphenoxy, 2 , 6 -dichloro-4- fluorophenoxy, 2 , 6 -dibromo-4-fluorophenoxy, 2 , 4 , 6-tribromophenoxy, 2 , 4 , 6-triiodophenoxy, 2-chloro- 4 , 5-dimethylphenoxy, 4 -chloro-2 -isopropyl-5- methylphenoxy, 2-bromo-4, 5-difluorophenoxy, 2 , 4 , 5-trichlorophenoxy, 2 , 3 , 5 , 6-tetrafluorophenoxy and the like.
The term "C7 to C13 substituted phenylalkoxy" denotes a C7 to C13 phenylalkoxy group wherein the Cx to C7 alkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, protected oxo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, heterocyclic ring, substituted heterocyclic ring, Cx to C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, cyano, thiol, Cx to C4 alkylthio and Cx to C7 alkylsulfonyl groups; and/or the phenyl group can be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Ci to C7 alkoxy, Ci to C7 acyl, Cx to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide, N- ( Cx to C6 alkyl) carboxamide, protected N- ( Cx to C6 alkyl) carboxamide, trifluoromethyl or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
Examples of the term "C7 to C13 substituted phenylalkoxy" include groups such as 2- (4- hydroxyphenyl) ethoxy, 4- (4-methoxyphenyl) butoxy, (2R)-3- phenyl-2-amino-propoxy, (2S) -3-phenyl-2-amino-propoxy, 2-indanoxy, 6 -phenyl-1-hexanoxy, cinnamyloxy, (+/-) -2 -phenyl-1-propoxy, 2 , 2 -dimethyl-3 -phenyl-1-propoxy and the like.
The term "phthalimide" means a cyclic imide which is made from phthalic acid, also called 1, 2-benzenedicarboxylic acid. The term "substituted phthalimide" specifies a phthalimide group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C6 alkyl, Cx to C7 alkoxy, Ci to C7 substituted alkoxy, Cl to C7 acyl, Cx to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide and trifluoromethyl .
Examples of substituted phthalimides include 4 , 5-dichlorophthalimido, 3 -fluorophthalimido, 4-methoxyphthalimido, 3-methylphthalimido, 4-carboxyphthalimido and the like.
The term "substituted naphthyl" specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, Ci to C6 alkyl, Ci to C7 alkoxy, Cx to C, acyl, Cx to C7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide or trifluoromethyl . Examples of the term "substituted naphthyl" includes a mono or di (halo) naphthyl group such as 1, 2, 3, 4, 5, 6, 7 or 8-chloronaphthyl, 2, 6-dichloronaphthyl, 2, 5-dichloronaphthyl, 3, 4-dichloronaphthyl , 1, 2, 3, 4, 5, 6, 7 or 8-bromonaphthyl, 3, 4-dibromonaphthyl, 3-chloro-4-fluoronaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-fluoronaphthyl and the like; a mono or di (hydroxy) naphthyl group such as l, 2, 3, 4, 5, 6, 7 or 8-hydroxynaphthyl, 2, 4-dihydroxynaphthyl, the protected- hydroxy derivatives thereof and the like; a nitronaphthyl group such as 3- or 4 -nitronaphthyl ; a cyanonaphthyl group, for example, 1, 2, 3, 4, 5, 6, 7 or 8 -cyanonaphthyl; a mono- or di (alkyl) naphthyl group such as 2, 3, 4, 5, 6, 7 or 8-methylnaphthyl, 1, 2, 4-dimethylnaphthyl, 1, 2, 3, 4, 5, 6, 7 or
8- (isopropyl) naphthyl , 1, 2, 3, 4, 5, 6, 7 or 8-ethylnaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8- (n-propyl) naphthyl and the like; a mono or di (alkoxy) naphthyl group, for example, 2, 6-dimethoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-methoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8-ethoxynaphthyl, 1, 2, 3, 4, 5, 6, 7 or 8- (isopropoxy) naphthyl, 1, 2, 3, 4, 5, 6, 7 or 8- (t-butoxy) naphthyl, 3 -ethoxy-4 -methoxynaphthyl and the like; 1, 2, 3, 4, 5, 6, 7 or 8-trifluoromethylnaphthyl ; a mono- or dicarboxynaphthyl or (protected carboxy) naphthyl group such as l, 2, 3, 4, 5, 6, 7 or 8-carboxynaphthyl or 2, 4-di ( -protected carboxy) naphthyl ; a mono-or di (hydroxymethyl) naphthyl or (protected hydroxymethyl) naphthyl such as l, 2, 3, 4, 5, 6, 7 or 8- (protected hydroxymethyl) naphthyl or 3,
4-di (hydroxymethyl) naphthyl ; a mono- or di (amino) naphthyl or (protected amino) naphthyl such as l, 2, 3, 4, 5, 6, 7 or 8- (amino) naphthyl or 2, 4- (protected amino) -naphthyl , a mono- or di (aminomethyl) naphthyl or (protected aminomethyl) naphthyl such as 2 , 3, or 4- (aminomethyl) naphthyl or 2, 4- (protected aminomethyl)- naphthyl; or a mono- or di- (N-methylsulfonylamino) naphthyl such as l, 2, 3, 4, 5, 6, 7 or 8- (N-methylsulfonylamino) naphthyl . Also, the term "substituted naphthyl" represents disubstituted naphthyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxynaphth-l-yl, 3-chloro-4- hydroxynaphth-2-yl, 2-methoxy-4 -bromonaphth-1 -y1 , 4-ethyl-2-hydroxynaphth-l-yl, 3 -hydroxy-4 -nitronaphth-2- yl, 2 -hydroxy-4-chloronaphth- 1-yl, 2 -methoxy- 7- bromonaphth-1-yl , 4-ethyl-5-hydroxynaphth-2-yl ,
3 -hydroxy- 8 -nitronaphth-2 -yl , 2 -hydroxy- 5-chloronaphth- 1- yl and the like.
The term "naphthylene" means a naphthyl radical bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted napthylene" means a naphthylene group that is further substituted by halogen, hydroxy, protected hydroxy, Cx to C4 alkylthio, Cx to C4 alkylsulfoxide, Cx to C7 alkylsulfonyl, Cx to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cx to C7 substituted alkylsulfonyl , Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C6 substituted alkyl, Cx to C7 alkoxy, oxo, protected oxo, (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group.
The terms "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo atoms. There can be one or more halogen, which are the same or different. Preferred halogens are chloro and fluoro.
The term " (monosubstituted) amino" refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, phenyl sulfonyl, substituted phenyl sulfonyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl , Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 acyl, Cx to C7 substituted acyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkynyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl and heterocyclic ring. The (monosubstituted) amino can additionally have an amino-protecting group as encompassed by the term "protected (monosubstituted) amino . "
The term " (disubstituted) amino" refers to an amino group with two substituents chosen from the group consisting of phenyl, substituted phenyl, Cx to C6 alkyl, Ci to C6 substituted alkyl, Cx to C7 acyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C7 to C12 phenylalkyl, and C7 to C12 substituted phenylalkyl. The two substituents can be the same or different.
The term "amino-protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule. The term "protected (monosubstituted) amino" means there is an amino-protecting group on the monosubstituted amino nitrogen atom. In addition, the term "protected carboxamide" means there is an amino-protecting group on the carboxamide nitrogen.
Examples of such amino-protecting groups include the formyl ("For") group, the trityl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl , and iodoacetyl groups, urethane-type blocking groups, such as t-butoxycarbonyl ("Boc"), 2- (4-biphenylyl) propyl- 2 -oxycarbonyl ("Bpoc"), 2-phenylpropyl-2-oxycarbonyl ("Poc") , 2- (4-xenyl) isopropoxycarbonyl , 1, 1-diphenylethyl-l- oxycarbonyl, 1 , 1-diphenylpropyl-l-oxycarbonyl , 2- (3, 5- dimethoxyphenyl) propyl -2 -oxycarbonyl ("Ddz"), 2- (p- toluyl ) propyl-2 -oxycarbonyl , cyclopentanyloxycarbonyl , 1-methylcyclopentanyloxycarbonyl , cyclohexanyloxy- carbonyl , 1-methylcyclohexanyloxycarbonyl , 2 -methylcyclohexanyloxycarbonyl, 2- (4-toluylsulfonyl) - ethoxycarbonyl , 2 - (methylsulfonyl) ethoxycarbonyl , 2- (triphenylphosphino) -ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("Fmoc") , 2- (trimethylsilyl) ethoxycarbonyl , allyloxycarbonyl, 1- (trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl , 4-acetoxybenzyl- oxycarbonyl, 2 , 2 , 2-trichloroethoxycarbonyl, 2-ethynyl-2- propoxycarbonyl , cyclopropylmethoxycarbonyl , isobornyloxycarbonyl , 1-piperidyloxycarbonyl, benzyloxycarbonyl ("Cbz"), 4-phenylbenzyloxycarbonyl, 2 -methylbenzyloxy-carbonyl, - 2,4,5,- tetramethylbenzyloxycarbonyl ("Tmz") ,
4 -methoxybenzyloxycarbonyl , 4 - fluorobenzyloxycarbonyl , 4 -chlorobenzyloxycarbonyl , 3 -chlorobenzyloxycarbonyl , 2 -chlorobenzyloxycarbonyl , 2 , 4-dichlorobenzyl- oxycarbonyl , 4 -bromobenzyloxycarbonyl , 3 -bromobenzyloxycarbonyl , 4 -nitrobenzyloxy-carbonyl , 4 -cyanobenzyloxycarbonyl , 4 - (decyloxy) benzyloxycarbonyl and the like; the benzoylmethylsulfonyl group, dithiasuccinoyl ("Dts"), the 2- (nitro) phenylsulfenyl group ("Nps"), the diphenyl-phosphine oxide group and like amino-protecting groups. The species of amino- protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the compounds. Preferred amino-protecting groups are Boc, Cbz and Fmoc. Further examples of amino-protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapter 7, M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed. , Springer-Verlag, New York, NY, 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, IL, 1984, each of which is incorporated herein by reference. The related term "protected amino" defines an amino group substituted with an amino-protecting group discussed above.
The term "protected guanidino" as used herein refers to an "amino-protecting group" on one or two of the guanidino nitrogen atoms. Examples of "protected guanidino" groups are described by T.W. Greene and P.G.M. Wuts; M. Bodanzsky; and Stewart and Young, supra.
The term "carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include t-butyl, 4-nitrobenzyl, 4 -methoxybenzyl, 3 , 4 -dimethoxybenzyl , 2 , 4 -dimethoxybenzyl , 2,4, 6-trimethoxybenzyl , 2,4, 6-trimethylbenzyl , pentamethylbenzyl, 3 , 4-methylenedioxybenzyl , benzhydryl, 4,4' -dimethoxytrityl , 4 , 4 ' , 4 " -trimethoxytrityl , 2-phenylpropyl, trimethylsilyl , t-butyldimethylsilyl, phenacyl, 2 , 2 , 2-trichloroethyl , - (trimethylsilyl) ethyl , - (di (n-butyl) methylsilyl) ethyl , p- toluenesulfonylethyl , 4-nitrobenzylsulfonylethyl , allyl, cinnamyl, 1- (trimethylsilylmethyl) -propenyl and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in E. Haslam, "Protective Groups in Organic Chemistry, " J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed. , John Wiley and Sons, New York, NY, 1991, Chapter 5, each of which is incorporated herein by reference. A related term is "protected carboxy, " which refers to a carboxy group substituted with one of the above carboxy-protecting groups. Similarly, the term "protected carboxymethyl" refers to a carboxy portion of the carboxymethyl substituted with one of the above carboxy-protecting groups.
The term "hydroxy-protecting group" refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxypropyl, 1-ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl , methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4 , 4 ' -dimethoxytrityl, 4 , 4 ', 4 " -trimethoxytrityl , benzyl, allyl, trimethylsilyl, (t-butyl) dimethylsilyl , 2 , 2 , 2-trichloroethoxycarbonyl groups and the like. The species of hydroxy-protecting groups is not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of hydroxy-protecting groups are described by C.B. Reese and E. Haslam,
"Protective Groups in Organic Chemistry," J.G.W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapters 3 and 4, respectively, and T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, NY, 1991, Chapters 2 and 3. Related terms are "protected hydroxy, " and "protected hydoxymethyl " which refer to a hydroxy or hydroxymethyl substituted with one of the above hydroxy-protecting groups . The term " Cx to C4 alkylthio" refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups.
The term " Cx to C4 alkylsulfoxide" indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide and the like.
The term " Cx to C7 alkylsulfonyl" encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like.
The terms "O. to C4 substituted alkylthio, " "Ci to C4 substituted alkylsulfoxide, " and " Cx to C7 substituted alkylsulfonyl, " denote the Cx to C4 alkyl portion of these groups may be substituted as described above in relation to "substituted alkyl."
The terms "phenylthio, " "phenylsulfoxide, " and "phenylsulfonyl" specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group. The terms "substituted phenylthio, " "substituted phenylsulfoxide, " and "substituted phenylsulfonyl" means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl."
The term " C to C7 alkylaminocarbonyl" means a
Ci to C7 alkyl attached to a nitrogen of the aminocarbonyl group. Examples of Cx to C7 alkylaminocarbonyl include methylaminocarbonyl , ethylaminocarbonyl , propylaminocarbonyl, butylaminocarbonyl . The term " Cx to C7 substituted alkylaminocarbonyl" denotes a substituted alkyl bonded to a nitrogen of the aminocarbonyl group, which alkyl may be substituted as described above in relation to Cx to C7 substituted alkyl. Examples of C to C7 substituted alkylaminocarbonyl include, for example, methoxymethylaminocarbonyl , 2 -chloroethylaminocarbonyl , 2-oxopropylaminocarbonyl and 4-phenylbutylaminocarbonyl.
The term " Cx to C7 alkoxycarbonyl" means a "Ci to C7 alkoxy" group attached to a carbonyl group. The term " Cx to C7 substituted alkoxycarbonyl" denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to Cx to C6 substituted alkyl.
The term "phenylaminocarbonyl" means a phenyl attached to a nitrogen of the aminocarbonyl group. The term "substituted phenylaminocarbonyl" denotes a substituted phenyl bonded to a nitrogen of the aminocarbonyl group, which phenyl may be substituted as described above in relation to substituted phenyl. Examples of substituted phenylaminocarbonyl include 2 -chlorophenylaminocarbonyl (from 2-chlorophenylisocyanate) , 3 -chlorophenylaminocarbonyl (from 3-chlorophenylisocyanate) , 2-nitorphenylaminocarbonyl (from
2-nitrophenylisocyanate) , 4-biphenylaminocarbonyl (from 4-biphenylisocyanate) , and 4-methoxyphenylaminocarbonyl (from 4-methoxyphenylisocyanate) .
The term "Cx to C6 alkylaminothiocarbonyl" means a Ci to C6 alkyl attached to an aminothiocarbonyl group, wherein the alkyl has the same meaning as defined above.
Examples of Cx to C6 alkylaminothiocarbonyl include methylaminothiocarbonyl (from methylisothiocyanate) , ethylaminothiocarbonyl (from ethylisothiocyanate) , propylaminothiocarbonyl (from propylisothiocyanate) , butylaminothiocarbonyl (from butylisothiocyatate) .
The term " Cx to C6 substituted alkylaminothiocarbonyl" denotes a substituted alkyl bonded to an aminothiocarbonyl group, wherein the alkyl may be substituted as described above in relation to Cx to C6 substituted alkyl. Examples of Cx to C5 substituted alkylaminothiocarbonyl include, for example, methoxymethylaminothiocarbonyl (from methoxymethylisothiocyanate) , 2 -chloroethylaminothiocarbonyl (from 2-chloroethylisothiocyanate) , 2-oxopropylaminothiocarbonyl (from 2-oxopropylisothiocyanate) , and
4 -phenylbutylaminothiocarbonyl ( from phenylbutylisothiocyanate) .
The term "phenylaminothiocarbonyl" means a phenyl attached to an aminothiocarbonyl group, wherein the phenyl has the same meaning as defined above.
The term "substituted phenylaminothiocarbonyl" denotes a substituted phenyl bonded to an aminothiocarbonyl group, wherein phenyl may be substituted as described above in relation to substituted phenyl. Examples of substituted phenylaminothiocarbonyls include 2-chlorophenylaminothiocarbonyl (from
2-chlorophenylisothiocyanate) ,
3-chlorophenylaminothiocarbonyl (from
3-chlorophenylisothiocyanate) , 2nitorphenylaminothiocarbonyl (from
2-nitrophenylisothiocyanate) , 4-biphenylaminothiocarbonyl
(from 4-biphenylisothiocyanate) , and
4 -methoxyphenylaminothiocarbonyl ( from
4-methoxyphenylisothiocyanate) .
The term " Cx to C8 alkylene" or "C2 to C8 alkylene" means a C to C8 or C2 to C8 alkyl group where the alkyl radical is bonded at two positions or, regarding a Cx alkylene, at one position, connecting together two separate additional groups. Examples of " Cx to C8 alkylene" include methylene, 1,2-ethyl, 1,1-ethyl, 1, 3 -propyl .
The term " Cx to Ce substituted alkylene" means a Ci to C8 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent. Examples of n Cx to C8 substituted alkylene" include aminomethylene, 1- (amino) -1, 2 -ethyl, 2- (amino) -1, 2 -ethyl, 1- (acetamido) -1, 2-ethyl, 2- (acetamido) -1 , 2-ethyl, 2- hydroxy-1, 1-ethyl, 1- (amino) -1 , 3-propyl .
The term "phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups. Examples of "phenylene" includes 1, 2 -phenylene, 1,3- phenylene, and 1 , 4-phenylene . The term "substituted phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, and wherein the phenyl is substituted as described above in relation to "substituted phenyl." Examples of "substituted phenylene" include thoses derived from the building blocks, namely, 3 -methyoxy-1, 4-phenylene from 4 -hydroxy- 3-methoxybenzonitrile, 2-fluoro- 1, 4-phenylene from 2- fluoro-4 -hydroxybenzonitrile , 3 , 5-Dibromo-l , 4 -phenylene from 3 , 5 -dibromo-4 -hydroxybenzonitrile, 3 , 5-diiodo-l , 4- phenylene from 3 , 5-diiodo-4-hydroxybenzonitrile, 3,4- Dihydroxy-1, 2 -phenylene from 3 , 4-dihydroxybenzonitrile, 2 , 3 , 5 , 6-tetrafluoro-1 , 4-phenylene from 4- hydroxytetrafluorobenzonitrile, 3 -bromo-4 -hydroxy-1 , 2- phenylene from 3-bromo-4-hydroxy-benzonitrile, 3,5-di- tert -butyl -1, 4 -phenylene from 3 , 5-di-tert-butyl-4- hydroxybenzonitrile, 4 -hydroxy-3 -nitro- 1 , 2 -phenylene from 4 -hydroxy-3 -nitrobenzonitrile, 5 -hydroxy-1, 3 -phenylene form 3 , 5-dihydroxybenzonitrile, 2-chloro-4 -hydroxy-1 , 4- phenylene from 2 -chloro-4 -hydroxybenzonitrile, 2-fluoro- 1, 4-phenylene from 4-cyano-2-fluorophenol, 3 , 5-dimethyl- 1 , 4-phenylene from 3 , 5-dimethyl-4-hydroxybenzonitrile, 2, 6 -dimethyl-1, 4-phenylene from 2 , 6 -dimethyl-4- hydroxybenzonitrile, 2,6 dichloro-1, 4-phenylene from 2,6- dichloro-4 -hydroxybenzonitrile, 4-chloro-l , 2- phenylene from 4 -chloro-2 -hydroxybenzonitrile, 6-nitro-l,2- phenylene from 2-cyano-6-nitro-phenol , 5-nitro-1,2- phenylene from 2-hydroxy-5-nitrobenzonitrile, 2-amino- 1 , 4-phenylene from 2-amino-4-cyanophenol, 2- carboxymethyl- 1, 4-phenylene from methyl-2 -hydroxy-5- cyano-benzoate, 2 -iodo-6 -nitro- 1, 4-phenylene from 4- cyano-2-iodo-6-nitrophenol .
The terms "cyclic C2 to C7 alkylene," "substituted cyclic C2 to C7 alkylene, " "cyclic C2 to C7 heteroalkylene, " and "substituted cyclic C2 to C7 heteroalkylene, " defines such a cyclic group bonded ("fused") to the phenyl radical resulting in a bicyclic ring system. The cyclic group may be saturated or contain one or two double bonds. Furthermore, the cyclic group may have one or two methylene or methine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic C2 to C7 heteroalkylene.
The cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, Ci to C4 acyloxy, formyl, Cx to C7 acyl, Cx to C6 alkyl, Cx to C7 alkoxy, Ci to C4 alkylthio, Cx to C4 alkylsulfoxide, Cx to C7 alkylsulfonyl , halo, amino, protected amino,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, hydroxymethyl or a protected hydroxymethyl . The cyclic alkylene or heteroalkylene group fused on to the benzene radical can contain two to ten ring members, but preferably contains three to six members. Examples of such saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro- indanyl and a tetralin ring. When the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or indolyl . Examples of fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridino, pyrano, pyrrolo, pyridinyl , dihydropyrrolo, or dihydropyridinyl ring. Examples of fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a furo, pyrano, dihydrofurano, or dihydropyrano ring. Examples of fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrothiopyrano ring. Examples of cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolo, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring. Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl.
The term "C4 to C10 cycloalkylalkylene" means a cycloalkyl substituted with an alkyl group. The cycloalkylalkylene radical is bonded at two positions connecting together two separate additional groups where one bond is directly to the cycloalkyl and the second bond is to the alkyl. Examples of "cycloalkylalkylene" include cyclohexyl -2 -methylene, cyclohexyl -3 -methylene, and cyclohexyl -4 -methylene.
The term "C4 to C10 substituted cycloalkylalkylene" means a cycloalkylalkylene group that is substituted at the cycloalkyl group or the alkyl group or both with one or more groups but preferrably, one or two groups, such as halogen, hydroxy, protected hydroxy, Ci to C4 alkylthio, Cx to C4 alkylsulfoxide, Cx to C7 alkylsulfonyl, C to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cα to C7 substituted alkylsulfonyl, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 alkoxy, oxo, protected oxo, (monosubstituted) amino,
(disubstituted) amino, trifluoromethyl , carboxy, protected carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl , amino, or protected amino group .
The term "carbamoyl" means an -NCO- group where the radical is bonded at two positions connecting two separate additional groups.
One or more of the compounds of the invention, even within a given library, may be present as a salt. The term "salt" encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D- glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
The term "organic or inorganic cation" refers to counter- ions for the carboxylate anion of a carboxylate salt. The counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium) ; ammonium and mono-, di- and tri -alkyl amines such as trimethylamine, cyclohexylamme; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations. See, for example, "Pharmaceutical Salts," Berge et al . , J. Pharm. Sci., 66:1-19 (1977), which is incorporated herein by reference. Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycme, lysine and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. For example, a cation for a carboxylate anion will exist when R2 or R3 is substituted with a (quaternary ammonium) methyl group. A preferred cation for the carboxylate anion is the sodium cation.
The compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention. One or more compounds of the invention, even when in a library, can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester- form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non- esterified forms of the compounds. Ester groups which can be used include the lower alkoxymethyl groups, for example, methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; the - { Cx to C7) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propoxyethyl , isopropoxyethyl and the like; the 2-oxo-l, 3 -diooxlen-4- ylmethyl groups, such as 5-methyl-2-oxo-l , 3 -dioxolen-4- ylmethyl, 5 -phenyl -2-oxo-l , 3-dioxolen-4-ylmethyl and the like; the Cx to C4 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, iso-propylthiomethyl and the like; the acyloxymethyl groups, for example pivaloyloxymethyl , pivaloyloxyethyl, -acetoxymethyl and the like; the ethoxycarbonyl-1-methyl group; the -acetoxyethyl ; the 1- ( Cx to C7 alkyloxycarbonyloxy) ethyl groups such as the 1- (ethoxycarbonyloxy) ethyl group; and the 1- ( Cx to C7 alkylaminocarbonyloxy) ethyl groups such as the 1- (methylaminocarbonyloxy) ethyl group.
The term "amino acid" includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids. In addition, the term "amino acid" also includes other non- naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally- occurring amino acids. Such non-naturally-occurring amino acids include, for example, norleucine ("Nle"), norvaline ("Nva"), L- or D- naphthalanine, ornithine ("Orn"), homoarginine (homoArg) and others well known in the art, such as those described in M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer-Verlag, New York, NY, 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis, " 2nd ed., Pierce Chemical Co., Rockford, IL, 1984, both of which are incorporated herein by reference. Amino acids and amino acid analogs can be purchased commercially (Sigma Chemical Co.; Advanced Chemtech) or synthesized using methods known in the art. Further examples of amino acids that are embaced by the above term are well known in organic synthesis and examples can be found in the Nova Biochem Catalog and Aldrich Catalog Handbook of Fine Chemicals .
The term "functionalized resin" means any resin, crosslinked or otherwise, where functional groups have been introduced into the resin, as is common in the art. Such resins include, for example, those functionalized with amino, alkylhalo, formyl or hydroxy groups. Such resins which can serve as solid supports are well known in the art and include, for example, 4 -methylbenzhydrylamine-copoly (styrene-1% divinylbenzene) (MBHA) , 4 -hydroxymethylphenoxymethyl-copoly (styrene-1% divinylbenzene) , 4 -oxymethyl-phenyl-acetamido- copoly (stryene-1% divinylbenzene) (Wang), 4- (oxymethyl) - phenylacetamido methyl (Pam) , and Tentagel™, from Rapp Polymere Gmbh, trialkoxy-diphenyl-methyl ester- copoly (styrene-1% divinylbenzene) (RINK) all of which are commercially available. Other functionalized resins are known in the art and can be use without departure from the scope of the current invention. Such resins may include those described in Jung, G. , Combinatorial Peptide and Nonpeptide Libraties, A Handbook (VCH Verlag, 1996) or Bunin, B. A., The Combinatorial Index (Academic Press, 1998) and are incorporated herein by reference.
As used herein, a "combinatorial library" is an intentionally created collection of differing molecules which can be prepared by the means provided below or otherwise and screened for biological activity in a variety of formats (e.g., libraries of soluble molecules, libraries of compounds attached to resin beads, silica chips or other solid supports) . A "combinatorial library, " as defined above, involves successive rounds of chemical syntheses based on a common starting structure. The combinatorial libraries can be screened in any variety of assays, such as those detailed below as well as others useful for assessing their biological activity. The combinatorial libraries will generally have at least one active compound and are generally prepared such that the compounds are in equimolar quantities.
Compounds disclosed in previous work that are not in an intentially created collection are not part of a "combinatorial library" of the invention. In addition, compounds that are in an unintentional or undesired mixture are not part of a "combinatorial library" of the invention.
A combinatorial library of the invention can contain two or more of the above-described compounds. The invention further provides a combinatorial library containing five or more of the above-described compounds. In another embodiment of the invention, a combinatorial library can contain ten or more of the above-described compounds. In yet another embodiment of the invention, a combinatorial library can contain fifty or more of the above-described compounds. If desired, a combinatorial library of the invention can contain 100,000 or more, or even 1,000,000 or more, of the above-described compounds.
By way of example, the preparation of the combinatorial libraries can use the "split resin approach." The split resin approach is described by, for example, U.S. Patent 5,010,175 to Rutter, WO PCT 91/19735 to Simon, and Gallop et al . , J. Med. Chem. , 37:1233-1251
(1994), all of which are incorporated herein by reference . The amino acids are indicated herein by either their full name or by the commonly known three letter code. Further, in the naming of amino acids, "D-" designates an amino acid having the "D" configuration, as opposed to the naturally occurring L-amino acids. Where no specific configuration is indicated, one skilled in the art would understand the amino acid to be an L-amino acid. The amino acids can, however, also be in racemic mixtures of the D- and L-configuration or the D-amino acid can readily be substituted for that in the L-configuration.
For preparing pharmaceutical compositions containing compounds of the invention, inert, pharmaceutically acceptable carriers are used. The pharmaceutical carrier can be either solid or liquid. Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories .
A solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is generally a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing pharmaceutical composition in the form of suppositories, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient -sized molds and allowed to cool and solidify.
Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient. Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
The pharmaceutical compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it. In a similar manner, cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration. Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions. Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
Preferably, the pharmaceutical composition is in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active thiazole. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
As pharmaceutical compositions for treating infections, pain, or any other indication the compounds of the present invention are generally in a pharmaceutical composition so as to be administered to a subject at dosage levels of from 0.7 to 7000 mg per day, and preferably 1 to 500 mg per day, for a normal human adult of approximately 70 kg of body weight, this translates into a dosage of from 0.01 to 100 mg/kg of body weight per day. The specific dosages employed, however, can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art. The compounds of Formula (I) and combinatorial libraries containing the same can be prepared as set forth in Reaction Schemes 1 and 2 as well as the description provided below.
Several variant thiazole combinatorial libraries have been prepared in order to achieve a high level of diversity. Different types of amine containing substrates were attached to solid support. Among the available amines, those containing a carboxylic acid moiety were coupled to a resin-bound amine via an amide bond (Scheme 1: Library Synthesis Scheme, 2-Amino- Thiazoles; Step 1: Attach amino acid). The carboxylic acid was coupled directly to a resin-bound primary amine, such as, for example, methyl benzhydrylamine (i.e., MBHA) , or other resins known in the art which afford a primary amide upon cleavage. Alternatively, the amino containing carboxylic acids could be coupled to resin- bound primary or secondary amines which can be incorporated into the product as secondary or tertiary amides after cleavage from the resin. These amines could be prepared by reductive amination of a primary amine to an aldehyde resin or vice-versa, by displacement of a resin-bound halide, such as chloro or bromo, by a primary amine or by any other methods known to those skilled in the art.
The amino containing carboxylic acid coupled to the resin-bound amine from Step 1 was converted to a thiourea through the use of thiophosgene or a thiophosgene equivalent, such as, for example, 1,1'- thiocarbonyldiimidazole, followed by treatment with ammonia (Scheme 1: Library Synthesis Scheme, 2-Amino- Thiazoles; Step 2: Thio-urea formation). The resin-bound thiourea from Step 2 was converted to a thiazole through the use of a variety a- haloketones (Scheme 1: Library Synthesis Scheme, 2-Amino- Thiazoles; Step 3: Thiazole ring formation). Discrete compounds from the libraries can be obtained by cleavage from the resin by treatment with hydrofluoric acid (i.e., HF) or other methods known by those skilled in the art (Scheme 1: Library Synthesis Scheme, 2-Amino-Thiazoles; Step 4: Cleavage) .
In addition, the amino-containing carboxylic acid can have a second amino group attached that is either orthogonally protected or masked, such a with a nitro group (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 1: Amino acid attachment). The carboxylic acid was coupled directly to a resin-bound primary amine such as methyl benzhydrylamine (MBHA) , or other resins known in the art that afford a primary amide upon cleavage.
The amino-containing carboxylic acid from Step 1 was coupled to a variety of second carboxylic acids via amide bond (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 2: Acylation of the amino group). The second masked amino group then was reduced using SnCl2 to prodice the free amine (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 3: Reduction of the nitro group) .
The free amine was then converted to a thiourea by using thiophosgene or a thiophosgene equivalent such as 1, 1 ' -thiocarbonyldiimidazole, followed by treatment with ammonia (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 4: Thiourea formation). The resulting thiourea was then converted to a thiazole by using a variety of α-haloketones (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 5: Thiazole ring formation) . Discrete compounds from the libraries can then be obtained by cleavage from the resin by treatment with hydrofluoric acid (HF) or other methods known in the art (Scheme 2: Library Synthesis Scheme, branched 2-Amino-Thiazoles; Step 6: Cleavage).
Many types of amino containing carboxylic acids, also referred to as amino acids, can be used for the first building block of the library of the present invention. Amino acids that can be used for this building block include, natural and unnatural amino acids (i.e., both D and L forms, as well as racemic mixtures) and compounds that are contain simply contain a carboxylic acid for which to couple to the resin and an amino group that can be further modified as described above herein to a substituted thiazole. This represents a very large class of compounds the basis of the first diverse building block.
In order to provide further diversity the free amino group can be reductively alkylated with a wide range of commerically available or synthetically prepared aldehydes. Thus, providing a second diverse building block. The primary amine or secondary amine can be reacted with thiophosgene or an equivalent to give a thiourea that is converted to a substituted thiazole to provide still another site of diversity. This third diverse building block originates from a-haloketones . Furthermore, the amino containing carboxylic acid (i.e., amino acid) can have a second amino group that is either orthogonally protected or masked, such as a nitro group, that can be treated in a similar manner as described above or in an independent manner to give di-substituted amines, aminothiazoles or N-substituted-aminothiazoles, providing optionally three additional building blocks respectively.
In general, large diverse combinatorial libraries of thiazole compounds were prepared by assembling three building blocks with the option of extending the diversity with the incorporation of three additional building blocks.
The nonsupport-bound combinatorial libraries can be screened as mixtures or discrete arrays of single compounds in solution in assays such as radio-receptor inhibition assays, anti-bacterial assays, anti-fungal assays, calmodulin-dependent phosphodiesterase (CaMPDE) assays and phosphodiesterase (PDE) assays, as described in detail below. Deconvolution of highly active mixtures can then be carried out by iterative or positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds within the combinatorial libraries of the present invention using any one of the below-described assays or others well known in the art .
The iterative approach is well-known and is set forth in general in Houghten et al . , Nature, 354, 84-86
(1991) and Dooley et al . , Science, 266, 2019-2022 (1994), both of which are incorporated herein by reference. In the iterative approach, for example, sub-libraries of a molecule having three variable groups are made wherein the first variable is defined. Each of the compounds with the defined variable group is reacted with all of the other possibilities at the other two variable groups. These sub-libraries are each tested to define the identity of the second variable in the sub- library having the highest activity in the screen of choice. A new sub- library with the first two variable positions defined is reacted again with all the other possibilities at the remaining undefined variable position. As before, the identity of the third variable position in the sub- library having the highest activity is determined. If more variables exist, this process is repeated for all variables, yielding the compound with each variable contributing to the highest desired activity in the screening process. Promising compounds from this process can then be synthesized on larger scale in traditional single-compound synthetic methods for further biological investigation .
The positional-scanning approach has been described for various combinatorial libraries as described, for example, in R. Houghten et al .
PCT/US91/08694 and U.S. Patent 5,556,762, both of which are incorporated herein by reference. In the positional scanning approach, sublibraries are made defining only one variable with each set of sublibraries and all possible sublibraries with each single variable defined (and all other possibilities at all of the other variable positions) , made and tested. From the instant description one skilled in the art could synthesize combinatorial libraries wherein two fixed positions are defined at a time. From the testing of each single- variable defined combinatorial library, the optimum substituent at that position can be determined, pointing to the optimum or at least a series of compounds having a maximum of the desired biological activity. Thus, the number of sublibraries for compounds with a single position defined will be the number of different substituents desired at that position, and the number of all the compounds in each sublibrary will be the product of the number of substituents at each of the other variables .
Individual compounds and pharmaceutical compositions containing the compounds, as well as methods of using the same, are included within the scope of the present invention. The compounds of the present invention can be used for a variety of purposes and indications and as medicaments for any such purposes and indications. For example, as described above, compounds of the present invention, including thiazole derivatives, can be used as pesticides, acaricides, receptor agonisits and antimicrobial agents, including antibacterial and antiviral agents. Additionally, the subject compounds can be useful as analgesics. Assays which can be used to test the biological activity of the instant compounds include antimicrobial assays, a competitive enzyme-linked immunoabsorbent assay and radio-receptor assays, as described below.
The ability of the compounds to inhibit bacterial growth, and therefore be useful to that infection, can be determined by methods well known in the art. Compounds of the present invention were shown to have antimicrobial activity by the in vi tro antimicrobial activity assay described in Example 7 below and, therefore, are useful as antimicrobial agents.
In addition, an exemplary in vi tro antimicrobial activity assay is described in Blondelle and Houghten, Biochemistry 30:4671-4678 (1991), which is incorporated herein by reference. In brief, Staphylococcus aureus ATCC 29213 (Rockville, MD) is grown overnight at 37°C in Mueller-Hinton broth, then re- inoculated and incubated at 37°C to reach the exponential phase of bacterial growth (i.e., a final bacterial suspension containing 105 to 5 x 105 colony-forming units/ml) . The concentration of cells is established by plating 100 μl of the culture solution using serial dilutions (e.g., 10"2, 10"3 and 10"4) onto solid agar plates. In 96 -well tissue culture plates, compounds, individual or in mixtures, are added to the bacterial suspension at concentrations derived from serial two-fold dilutions ranging from 1500 to 2.9 μg/ml. The plates are incubated overnight at 37°C and the growth determined at each concentration by OD620 nm. The IC50 (the concentration necessary to inhibit 50% of the growth of the bacteria) can then be calculated.
The competitive ELISA method which can be used here is a modification of the direct ELISA technique described previously in Appel et al . , J. Immunol.
144:976-983 (1990), which is incorporated herein by reference. It differs only in the MAb addition step. Briefly, multi-well microplates are coated with the antigenic peptide (Ac-GASPYPNLSNQQT-NH2) at a concentration of 100 pmol/50 μl . After blocking, 25 μl of a 1.0 mg/ml solution of each mixture of a synthetic combinatorial library (or individual compound) is added, followed by MAb 125-10F3 (Appel et al . , supra) (25 μl per well) . The MAb is added at a fixed dilution in which the bicyclic guanidine in solution effectively competes for MAb binding with the antigenic peptide adsorbed to the plate. The remaining steps are the same as for direct ELISA. The concentration of compound necessary to inhibit 50% of the MAb binding to the control peptide on the plate (IC50) is determined by serial dilutions of the compound.
Alternative screening can be done with radio- receptor assays. The radio-receptor assay, can be selective for any one of the μ, K, or δ opiate receptors. Compounds of the present invention can be useful in vitro for the diagnosis of relevant opioid receptor subtypes, such as , in the brain and other tissue samples. Similarly, the compounds can be used in vivo diagnostically to localize opioid receptor subtypes.
The radio-receptor assays are also an indication of the compounds' analgesic properties as described, for example, in Dooley et al . , Proc . Na tl .
Acad. Sci . , 90:10811-10815 (1993). For example, it can be envisioned that these compounds can be used for therapeutic purposes to block the peripheral effects of a centrally acting pain killer. For instance, morphine is a centrally acting pain killer. Morphine, however, has a number of deleterious effects in the periphery which are not required for the desired analgesic effects, such as constipation and pruritus (itching) . While it is known that the many compounds do not readily cross the blood- brain barrier and, therefore, elicit no central effect, the subject compounds can have value in blocking the periphery effects of morphine, such as constipation and pruritus. Accordingly, the subject compounds can also be useful as drugs, namely as analgesics, or to treat pathologies associated with other compounds which interact with the opioid receptor system.
Additionally, such compounds can be tested in a σ receptor assay. Ligands for the σ receptor can be useful as antipsychotic agents, as described in Abou- Gharbia et al . , Annual Reports in Medicinal Chemistry,
28:1-10 (1993) .
Radio-receptor assays can be performed with particulate membranes prepared using a modification of the method described in Pasternak et al . , Moi . Pharmacol .
11:340-351 (1975), which is incorporated herein by reference. Rat brains frozen in liquid nitrogen can be obtained from Rockland (Gilbertsville, PA) . The brains are thawed, the cerebella removed and the remaining tissue weighed. Each brain is individually homogenized in 40 ml Tris-HCl buffer (50 mM, pH 7.4, 4°C) and centrifuged (Sorvall® RC5C SA-600: Du Pont, Wilmington, DE) (16,000 rpm) for 10 minutes. The pellets are resuspended in fresh Tris-HCl buffer and incubated at 37°C for 40 minutes. Following incubation, the suspensions are centrifuged as before, the resulting pellets resuspended in 100 volumes of Tris buffer and the suspensions combined. Membrane suspensions are prepared and used in the same day. Protein content of the crude homogenates generally range from 0.15-0.2 mg/ml as determined using the method described in Bradford, M.M., Anal. Biochem . 72:248-254 (1976), which is incorporated herein by reference.
Binding assays are carried out in polypropylene tubes, each tube containing 0.5 ml of membrane suspension. 8 nM of 3H- [D-Ala2, Me-Phe4, Gly-ol5] enkephalin (DAMGO) (specific activity = 36 Ci/mmol, 160,000 cpm per tube; which can be obtained from Multiple Peptide Systems, San Diego, CA, through NIDA drug distribution program 271-90-7302) and 80 μg/ml of bicyclic guanidine, individual or as a mixture and Tris-HCl buffer in a total volume of 0.65 ml. Assay tubes are incubated for 60 mins . at 25°C. The reaction is terminated by filtration through GF-B filters on a Tomtec harvester (Orange, CT) . The filters are subsequently washed with 6 ml of Tris-HCl buffer, 4°C. Bound radioactivity is counted on a Pharmacia Biotech Betaplate Liquid Scintillation Counter
(Piscataway, NJ) and expressed in cpm. To determine inter- and intra-assay variation, standard curves in which 3H-DAMGO is incubated in the presence of a range of concentrations of unlabeled DAMGO (0.13-3900 nM) are generally included in each plate of each assay (a 96-well format) . Competitive inhibition assays are performed as above using serial dilutions of the bicyclic guanidines, individually or in mixtures. IC50 values (the concentration necessary to inhibit 50% of 3H-DAMGO binding) are then calculated. IC50 values of less than 1000 nM are indicative of highly active opioid compounds which bind to the μ receptor, with particularly active compounds having IC50 values of 100 nM or less and the most active compounds with values of less than 10 nM.
As opposed to this μ receptor selective assay, which can be carried out using 3H-DAMG0 as radioligand, as described above, assays selective for K receptors can be carried out using [3H]-U69,593 (3 nM, specific activity 62 Ci/mmol) as radioligand. Assays selective for δ opiate receptors can be carried out using tritiated DSLET ([D-Ser2, D-Leu5] -threonine-enkephalin) as radioligand. Assays selective for the σ opiate receptor can use radiolabeled pentazocine as ligand.
Screening of combinatorial libraries and compounds of the invention can be done with an anti- fungal assay. Compounds of the present invention can be useful for treating fungal infections.
Screening of combinatorial libraries and compounds of the invention also can be done with a calmodulin-dependent phosphodiesterase (CaMPDE) assay. Compounds of the present invention can be useful as calmodulin antagonists.
Calmodulin (CaM) , which is the major intracellular calcium receptor, is involved in many processes that are crucial to cellular viability. In particular, calmodulin is implicated in calcium- stimulated cell proliferation. Calmodulin antagonists are, therefore, useful for treating conditions associated with increased cell proliferation, for example, cancer. In addition, calmodulin antagonists such as compounds of the subject invention are useful both in vitro and in vivo for identifying the role of calmodulin in other biological processes. The disadvantages of known antagonists such as trifluoperazine and N- (4-aminobutyl) - 5-chloro-2-naphthalenesulfonamide (W13) include their non-specificity and toxicity. In contrast, advantages of the combinatorial libraries and compounds of the subject invention as calmodulin antagonists include their reduced flexibility and ability to generate broader conformational space of interactive residues as compared to their linear counterparts.
An example of an assay that identifies CaM antagonists is a CaMPDE assay. In brief, samples are mixed with 50 μl of assay buffer (360 mM Tris, 360 mM
Imidazole, 45 mM Mg(CH3COO)2, pH 7.5) and 10 μl of CaCl2 (4.5 mM) to a final volume of 251 μl . 25 μl of calmodulin stock solution (Boehringer Mannheim; 0.01 μg/μl) is then added and the samples then sit at room temperature for 10 minutes. 14 μl of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/μl) is then added, followed by 50 μl of 5 ' -nucleotidase (Sigma; 100 Units dissolved in 10 ml of 10 mM Tris-HCl containing 0.5 mM Mg(CH3COO)2, pH 7.0; stock concentration: 10 Units/ml) . The samples are then incubated for 10 minutes at 30°C. 50 μl of adenosine 3', 5 '-cyclic monophosphate (c7AMP) (20 mM in water at pH 7.0) is added, the samples incubated for 1 hour at 30°C and then vortexed. 200 μl of trichloroacetic acid (TCA) (55% in water) is added to a 200 μl sample aliquot, which is then vortexed and centrifuged for 10 minutes. 80 μl of the resulting supernatants of each sample is transferred to a 96-well plate, with 2 wells each containing 80 μl of each sample. 80 μl of ammonium molybdate (1.1% in 1. IN H2S04) is then added to all the wells, and the OD of each were determined at 730nm, with the values later subtracted to the final OD reading. 16 μl of reducing agent (6g sodium bisulfite, 0.6g sodium sulfite and 125mg of l-amino-2-naphtol-4-sulfonic acid in 50ml of water) is then added to one of each sample duplicate and 16 μl of water is added to the other duplicate. After sitting for 1 hour at room temperature, the OD of each well is determined at 730nm. The percent inhibition of calmodulin activity is then calculated for each sample, using as 0% inhibition a control sample containing all reagents without any test samples and as 100% inhibition a control sample containing test samples and all reagents except calmodulin. In addition, the percent inhibition of phosphodiesterase activity was determined by following a similar protocol as the CaMPDE assay described above, except not adding calmodulin to the sample mixture and calculating the percent inhibition by using as 0% inhibition a control reagent without any test samples and as 100% inhibition a control sample containing test samples and all reagents except cAMP .
EXAMPLES
Experimental Procedures
The following Examples are intended to illustrate but not limit the present invention. The following abbreviations are used the following experimental procedures and examples: 3 -ABA, 3- aminobenzoic acid; 4 -ABA, 4-aminobenzoic acid; 3 -NBA, 3- nitrobenzoic acid; 4 -NBA, 4-nitrobenzoic acid; DMA, dimethyl acetamide; RT, room temperature; DMF, dimethylforamide; IPA, isopropyl alcohol; Wang resin, p-benzyloxybenzylalcohol-polystyrene; DCM, dichloromethane; MTBE, methyl -tert-butyl ether; MBHA-HCl resin, methyl -benzhydrylamine hydrochloride ; PP, polypropylene; DIEA, diisopropylethylamine ; HOBT, 1-hydroxybenzotriazole; DIC, N,N' -diisopropylcarbodiimide; DMAP, 4 -dimethylamino- pyridine; KotBu, potassium tert-butoxide; Boc, tert-butoxycarbonyl; FMOC, 9-fluorenyl-methoxycarbonyl ; Tos, p- toluenesulfonyl; Bzl, benzyl; For, formyl; PMC,
2, 2, 5, 7, 8 -pentamethylchro an- 6 -sulfonyl; TBU, 2-(lH- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate; TRT, trityl; ACM, acetamidomethyl ; MTR, 2, 3 , 6-trimethyl-4-methoxybenzenesulfonyl; MBH, 4, 4 ' -dimethoxybenzyhydryl; ADA, adamanyl; PMEOBZL, p-methoxybenzyl; 2-CL-Z, 2 -chlorobenzyl -oxycarbonyl ; 2-BR-Z, 2 -bromobenzyloxycarbonyl; TMOB,
2,4, 6-trimethoxybenzyl; MTT, 4 -methyltrityl ; PBF, 2,2,4,6,7- pentamethyldihydrobenzofuran-5 -sulfonyl; DDE, l-(4,4- dimethyl-2, 6-dioxocyclohex-l-ylidene) ethyl; DMAB, 4- [N- (1- [4 , 4-diemthyl-2 , 6-dioxocyclhexylidene] -3- methylbutyl) -amino] benzzyl; TFA, trifluoroacetic acid; BOP, benzotriazol- 1-yl-oxy-tris (dimethylamino) - phosphonium hexafluoro-phosphate ; PyBOP, benzotriazol- 1- yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; HATU, azabenzotriazolyl-N,N,N' ,N' -tetramethyluronium hexafluorophosphate; HBTU, 2- (lH-benzotriazole-1-yl) - 1, 1, 3 , 3-tetramethyluronium hexafluorophosphate; MeOH, methanol; ACN, acetonitrile; DCE, 1 , 2-dichloroethane; THF, tetrahydrofuran; HF, hydrogen fluoride; HPLC/MS, high performance liquid chromatography - mass spectrometry; FIA-MS, flow injection analysis - mass spectrometry; ELSD, evaporative light scattering detector; THB, Todd Hewitt Broth; OD, optical density; DMSO, dimethylsulfoxide .
Example 1 TRG 4100 General procedure for Preparation of N-Alkyl-2 -Amino
Thiazoles
Step 1: Coupling of N-Protected amino acid to MBHA resin.
2.0 g of MBHA resin (1.3 meq/g ) was placed in a porous polypropylene packets (Tea-bag, 60mm x 60mm, 65μ) .
Each packet was washed with 5% DIEA/DCM (2x60 mL) in a 125 mL plastic bottle. N-protected amino acids (16 mmol, 6.2eq, 0.4M) (Table x) , DMF (40 mL) , DIC (2.1g, 16 mmol), HOBt
(2.16g, 16 mmol) were added sequentially. After shaking for
24 hours, the packet was washed alternatively with DMF
(3x80 mL) and MeOH (2x80 mL) followed by DCM (2x80 mL) and
MeOH (3x80 mL) . The packet was dried in air for 2 h. The packet was shaken with 55% TFA/DCM (80 mL) at room temperature for 40 minutes and washed with DCM (3x80 mL) ,
5% DIEA/DCM (2x80 mL) and MeOH (2x80 mL) . The packet was air-dried overnight.
ottle# Protected Amine
1 BOC-L-ALA
2 BOC-L-ASP(Bzl)
3 BOC-L-PHE
4 BOC-GLY
5 BOC-L-HIS(DNP)
6 BOC-L-ILE
7 BOC-L-LYS(CBZ)
8 BOC-L-LEU
9 BOC-L-MET(O)
10 BOC-L-ASN
11 BOC-L-PRO
12 BOC-L-GLN
13 BOC-L-ARG(Tos)
14 BOC-L-SER(Bzl)
15 BOC-L-THR(Bzl)
16 BOC-L-VAL
17 BOC-L-TRP(CHO)
18 BOC-L-TYR(BrZ) 19 BOC-D-ALA
20 BOC-L-Ala-3-ABA
21 BOC-D-ASP(Bzl)
22 BOC-D-PHE 23 BOC-D-HIS(DNP)
24 BOC-L-Phe-3-ABA
25 BOC-D-LYS(CBZ)
26 BOC-D-LEU
27 BOC-D-MET 28 BOC-D-ASN
29 BOC-D-PRO
30 BOC-D-GLN
31 BOC-D-ARG(Tos)
32 BOC-D-SER(Bzl) 33 BOC-D-THR(Bzl)
34 BOC-D-VAL
35 BOC-L-Pro-3-ABA
36 BOC-D-TYR(BrZ)
37 BOC-L-a-AMINOBUTYRIC ACID 38 BOC-L-g-AMINOBUTYRIC ACID
39 BOC-L-a-AMINOISOBUTYRIC ACID
40 BOC-L-NORVALINE
41 BOC-L-NORLEUCINE
42 Fmoc-Tranexamic acid 43 BOC-e-AMINOCAPROIC ACID
44 BOC-7-AMINOHEPTANOIC ACID
45 Fmoc-e AMINO-HEXANOIC ACID
46 BOC-L-ORNITHINE(CBZ)
47 BOC-L-PROLINE-4-ABA 48 BOC-L-PHENYLGLYCINE
49 BOC-L-NAPHTHYLALANINE
50 BOC-D-NAPHTHYLALANINE
51 BOC-b-ALANINE
52 BOC-L-CYCLOHEXYLALANINE 53 BOC-L-LYSINE(e-ISONICOTINYL) iso
54 BOC-L-METHIONINE SULFONE
55 BOC-L-p-NITRO-PHENYLALANINE
56 BOC-D-p-NITRO-PHENYLALANINE
57 BOC-L-4-CHLOROPHENYLALANINE 58 BOC-D-4-CHLOROPHENYLALANINE
59 BOC-L-LYSINE(eAcetyl)
60 BOC-L- (3 -PYRIDYL) ALANINE
61 BOC-D- (3 -PYRIDYL) ALANINE
62 BOC-L-a-tBUTYLGLYCINE 63 BOC-L-LYSINE(e-P-ANISYL)
64 BOC-L-LYSINE(e-2 -THIOPHENE CARBOXYL)
65 BOC-L-HIS(TOS)
66 Boc-L-3-Benzothienylalanine
67 Boc-L-Biphenylalanine 68 Boc-L-4-Bromophenylalanine 69 Boc-L-3-chlorophenylalanine
70 Boc-3 , 3-Diphenylalanine
71 BOC-L-2-FLUOROPHENYLALANINE
72 BOC-L-3-FLUOROPHENYLALANINE 73 BOC-L-Homophenylalanine
74 Boc-L-2-thienylalanine
Step 2 : Thiourea formation using Thiophosgene and Ammonia .
The packet was shaken in a solution of Thiophosgene (1.84g, 16 mmol) and DIEA (2.02g, 16 mmol) in DCM (40 mL) at room temperature for 1 hours. The packet was washed several times with anhydrous DCM (3x80 mL) and then was reacted with ammonia (80mL, 0.5M solution in dioxane) for 1 hour at RT . Packet was washed with dioxane (3x80mL) and alternatively with DMF (80 mL) and MeOH (80 mL) 3 cycles followed by DCM (2x80 mL) and MeOH (3x80 mL) . The packet was air-dried overnight.
Step 3: Reaction with halo-ketones to form thiazoles.
The packet was cut open and the resin was suspended DMF (50 mL) . The suspension was distributed equally into 48 wells of a microtiter plate (lmLx48) .
Excess DMF was removed and the resin was washed several times using MeOH (3x1.5mL per well) . The plate was dried in air overnight . A solution of corresponding halo-ketone (see Table 2) in ethoxyethanol (200 μh X 0.4 M) was added to each well. The plate was tightly capped, shaken and incubated at 65 °C for 15 hours. Each plate was washed alternatively with DMF (10 X 1 mL/well) and MeOH (14 xl mL/well) . The plate was dried in air overnight and under vacuum for 4 hours. The plate was treated with gaseous HF at room temperature for 1.5 hours . After complete removal of HF under a nitrogen stream followed by vacuum, the plate was extracted with AcOH (4 x 0.5 mL/well) . The extractions were lyophilized to give the title compounds.
Well # Halo-ketones
1 CHLOROACETONE 2 3-CHLORO-2-BUTANONE
3 2-CHL0R0CYCL0HEXAN0NE
4 3-CHL0R0ACETYLACET0NE
5 l-CHLOROPINACOLONE
6 2-CHLORO-N-METHYLACETOACETAMIDE 7 METHYL 4-CHLOROACETOACETATE
8 METHYL 2-CHLOROACETOACETATE
9 1-BROMO-2-BUTANONE
10 2-BROMOACETOPHENONE
11 N, N-DIMETHYL-2-CHLOROACETOACETAMIDE 12 ETHYL 4-CHLOROACETOACETATE
13 ETHYL 2-CHLOROACETOACETATE
14 3-BROMOPYRUVIC ACID
15 3-BROMO-l, 1, 1-TRIFLUOROACETONE
16 ETHYL BROMOPYRUVATE 17 2-BROMO-l-INDANONE
18 ALPHA-BROMOPROPIOPHENONE
19 2-BROMO-4 ' -METHYLACETOPHENONE
20 4-FLUOROPHENACYL BROMIDE
21 3-FLUOROPHENACYL BROMIDE 22 4-CYANOPHENACYL BROMIDE
23 2-BROMO-2 ' -METHOXYACETOPHENONE
24 3-METHOXYPHENACYL BROMIDE
25 2-BROMO-4 ' -METHOXYACETOPHENONE 26 4-CHLOROPHENACYL BROMIDE
27 3, -DIFLUOROPHENACYL BROMIDE
28 2-BROMO-4'-NITROACETOPHENONE 29 - ( CHLOROACETYL) CATECHOL 30 3-NITROPHENACYL BROMIDE
31 4-CHLORO-3-METHYLPHENACYL BROMIDE
32 ALPHA-BROMO-2 ' -ACETONAPHTHONE
33 1-ADAMANTYL BROMOMETHYL KETONE
34 2-BROMO-2 ' , 5 ' -DIMETHOXYACETOPHENONE 35 2-BROMO-3' -CHLORO-4 ' ETHYLPROPIOPHENONE
36 ETHYL
5- (BROMOACETYL) ISOXAZOLE-3-CARBOXYLATE,
37 2-CHLORO- ' -PHENYLACETOPHENONE
38 3,4-DICHLOROPHENACYL BROMIDE
39 6- (BROMOACETYL) -2-OXO-l , 2 , 3.4-TETRA HYDROQUINOLINE, 40 4- (BROMOACETYL) -5-METHYL-3-PHENYL
ISOXAZOLE,
41 2,4' -DIBROMOPROPIOPHENONE
42 2- (BROMOACETYL) -5-CHLORO-3-METHYL BENZO [2] THIOPHENE,
43 6- (Bromoacetyl) -1,2,3, 4-tetrahydro-l, 1, , -tetramethyl napthalene
44 2-BROMO-l- (4-CHLOROPHENYL) -2 ' PHENYLETHA N-l-ONE, 45 1- (BROMOACETYL) PYRENE
46 2-BROMO-l- (4-CHLOROPHENYL) 2-4-METHYLPHE NYL) ETHAN-1-ONE,
47 5- (BROMOACETYL) 3- (3, -DICHLOROPHANYL) IS OXAZOLE
48 5- (BROMOACETYL) 3- (2 , -DICHLOROPHANYL) IS OXAZOLE Compounds 1-20 represent variations at the 2, 4 and
5 position of the amino-thiazole template derived from protected amino acids, and various halo-ketones.
Compound: Compound 1 Protected AA: BOC-L-ALA
Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 199.27 Found (M+l) : 200.4
Compound: Compound 2 Protected AA: BOC-L-PHE
Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 275.37 Found (M+l) : 276.2
Compound: Compound 3 Protected AA: BOC-GLY
Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 185.24 Found (M+l) : 186.3
Compound: Compound 4 Protected AA: BOC-L-ILE
Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 241.35 Found (M+l) : 242.3
Compound: Compound 5 Protected AA: BOC-L-PRO
Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 225.31 Found (M+l) : 226.5 Compound: Compound 6
Protected AA: BOC-L-g-AMINOBUTYRIC ACID Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 213.3 Found (M+l) : 214.6
Compound: Compound 7 Protected AA: BOC-b-ALANINE Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 199.27 Found (M+l) : 200.4
Compound: Compound 8 Protected AA: BOC-L-PHENYLGLYCINE Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 261.34 Found (M+l) : 262.2
Compound: Compound 9
Protected AA: BOC-L-CYCLOHEXYLALANINE Halo-Ketone: 3-CHLORO-2-BUTANONE Calcd. MW: 281.43 Found (M+l) : 282.2
Compound: Compound 10 Protected AA: BOC-b-ALANINE Halo-Ketone: CHLOROACETONE Calcd. MW: 185.24 Found (M+l) : 186.3
Compound: Compound 11 Protected AA: BOC-b-ALANINE Halo-Ketone : 2-CHLOROCYCLOHEXANONE Calcd. MW: 225.31 Found (M+l) : 226.2 Compound: Compound 12 Protected AA: BOC-b-ALANINE Halo-Ketone: METHYL 2-CHLOROACETOACETATE Calcd. MW: 243.28 Found (M+l) : 244
Compound: Compound 13 Protected AA: BOC-b-ALANINE Halo-Ketone : 2-BROMOACETOPHENONE Calcd. MW: 247.31 Found (M+l) : 248.2
Compound: Compound 14 Protected AA: BOC-b-ALANINE
Halo-Ketone : N, -DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 256.32 Found (M+l) : 257
Compound: Compound 15 Protected AA: BOC-b-ALANINE Halo-Ketone: 3-BROMOPYRUVIC ACID Calcd. MW: 215.23 Found (M+l) : 216
Compound: Compound 16 Protected AA: BOC-b-ALANINE Halo-Ketone: 4-CYANOPHENACYL BROMIDE Calcd. MW: 272.32 Found (M+l) : 273
Compound: Compound 17 Protected AA: BOC-b-ALANINE Halo-Ketone: 3,4-DIFLUOROPHENACYL BROMIDE Calcd. MW: 283.3 Found (M+l) : 284.1
Compound: Compound 18 Protected AA: BOC-b-ALANINE Halo-Ketone: 3-NITROPHENACYL BROMIDE Calcd. MW: 292.31 Found (M+l) : 292.9
Compound: Compound 19 Protected AA: BOC-b-ALANINE
Halo-Ketone: 1-ADAMANTYL BROMOMETHYL KETONE Calcd. MW: 305.44 Found (M+l) : 306.2
Compound: Compound 20 Protected AA: BOC-b-ALANINE
Halo-Ketone : 2-BROMO-2 ' , 5 ' -DIMETHOXYACETOPHENONE Calcd. MW: 307.37 Found (M+l) : 308
Example 2
General procedure for Preparation of N- (4- CarboxamidoPhenyl) -2 -Aminothiazoles
Step 1: Coupling of 4-amino-benzoic acid to MBHA resin.
2.0 g of MBHA resin (1.3 meq/g ) was placed in a porous polypropylene packets (Tea-bag, 60mm x 60mm, 65μ) . Each packet was washed with 5% DIEA/DCM (2x60 mL) in a 125 mL plastic bottle. 4-aminobenzoic acids (16 mmol, 6.2eq, 0.4M) (Tablex) , DMF (40 mL) , DIC (2.1g, 16 mmol), HOBt (2.16g, 16 mmol) were added sequentially. After shaking for 24 hours, the packet was washed alternatively with DMF (3x80 mL) and MeOH (2x80 mL) followed by DCM (2x80 mL) and MeOH (3x80 mL) . The packet was air-dried overnight.
Bottle # 4-Aminobenzoic acids
1 4-AminoBenzoic Acid 2 4-Amino-5-Chloro-2-methoxy-Benzoic Acid 4-Aminohippric acid
Step 2: Thio-urea formation using Thiophosgene and Ammonia.
The procedure is similar to step 2 as described in Example 1 for the preparation of N-alkyl-2 -amino thiazoles.
Step 3: Reaction with halo-ketones to form thiazoles.
The procedure is similar to step 3 as described in Example 1 for the preparation of N-alkyl-2 -amino thiazoles. Compounds 21-24 represent variations at the 2, 4 and 5 position of the amino-thiazole template derived from 4- Aminobenzoic acids, and halo-ketones.
Compound : 21 4-ABA: 4-AminoBenzoic Acid Halo-Ketone: 3 -CHLORO-2 -BUTANONE Calcd. MW: 247.31 Found (M+l) : 248.5
Compound: 22 4-ABA: 4-AminoBenzoic Acid Halo-Ketone 2 -CHLOROCYCLOHEXANONE Calcd. MW: 273.35 Found (M+l) : 274.5 Compound: 23 4-ABA: 4-AminoBenzoic Acid Halo-Ketone CHLOROACETONE Calcd. MW: 233.29 Found (M+l) : 234.6
Compound: 24 4-ABA: 4-AminoBenzoic Acid
Halo-Ketone: 2 -BROMOACETOPHENONE Calcd. MW: 295.35 Found (M+l) : 296.5
Example 3
General procedure for Preparation of N- (4- CarboxamidoPhenyl) -2 -Aminothiazoles
Step 1: Coupling of 3-Nitro-benzoic acid to MBHA resin,
2.0 g of MBHA resin (1.3 meq/g ) was placed in a porous polypropylene packets (Tea-bag, 60mm x 60mm, 65μ) . Each packet was washed with 5% DIEA/DCM (2x60 mL) in a 125 mL plastic bottle. 3-nitrobenzoic acids (16 mmol, 6.2eq, 0.4M) (Tablex) , DMF (40 mL) , DIC (2.1g, 16 mmol), HOBt (2.16g, 16 mmol) were added sequentially. After shaking for 24 hours, the packet was washed alternatively with DMF (3x80 mL) and MeOH (2x80 mL) followed by DCM (2x80 mL) and MeOH (3x80 mL) . The packet was dried in air for 2 h. Bottle # 3-Nitrobenzoic acids
1 3 -Methoxy-4 -Nitrobenzoic Acid
2 2 -Methoxy-4 -Nitrobenzoic Acid 3 2-Chloro-4-Nitrobenzoic Acid
4 4-Methoxy-3-NitroBenzoic Acids
5 2-Chloro-3-NitroBenzoic Acids
6 4-Chloro-3-NitroBenzoic Acids
7 2-Chloro-5-NitroBenzoic Acids
8 Mono-methyl-5-Nitroisophthalate
9 2 , 6-Dimethoxy-3-NitroBenzoic Acid
10 2, 5-Dichlro-3-NitroBenzoic Acid
11 2-Bromo-3-NitroBenzoic Acid
12 2-Bromo-5-NitroBenzoic Acid
13 3 -Chloro-2, 6-Dimethoxy-5-NitroBenzoic Acid
14 2- (2 , 6-Dimethylmorpholino) -5-nitro benzoic acid
Step 2: Reduction of the nitro group to amine.
The packet was shaken with a 2.0 M solution of tin (II) chloride dihydrate DMF (80 mL) for 24 hours at room temperature. The packet was washed with DMF (6 X 80 mL) , 10% DIEA/DCM (4 X 80 mL) , MeOH, (2 X 80 mL) , DMF (80 mL) , MeOH (80 mL) , DCM (2 X 80 mL) and MeOH (2 X 80 mL) and air- dried overnight .
Step 3: Thio-urea formation using Thiophosgene and Ammonia.
The procedure is similar to step 2 as described in Example 2 for the preparation of N- (4-carboxamidophenyl) -2- aminothiazoles . Step 4: Reaction with halo-ketones to form thiazoles.
The procedure is similar to step 3 as described in Example 2 for the preparation of N- (4-carboxamidophenyl) - 2-aminothiazoles .
Compounds 25 represent variations at the 2, 4 and 5 position of the amino-thiazole template derived from 3- Nitrobenzoic acids, and various halo-ketones.
Compound: 25
3 -NBA: 3 -Amino Benzoic Acid Halo-Ketone: 3 -CHLORO-2 -BUTANONE
Calcd. MW: 247.31
Found (M+l) : 248.5
Example 4 General procedure for Preparation of Branched N-Alkyl-2- Amino Thiazoles
Acylation of the alpha-amino group
Step 1: Coupling of Boc-Lysine (Fmoc) to MBHA resin.
216. Og of MBHA resin (1.3 meq/g ) was placed in 108 porous polypropylene packets (2.0g resin/Tea-bag packet, 60mm x 60mm, 65μ) . The packets (108 bags) were washed with 5% DIEA/DCM (2x6.5L) in a plastic bottle. DMF (4.32L), Boc- Lysine (Fmoc) , 1.73mol, 6.2eq, 0.4M), DIC (227. Og, 1.73mol), HOBt (233.3g, 1.73mol) were added sequentially. After shaking for 24 hours, the packets were washed alternatively with DMF (3x8L) and MeOH (2x8L) followed by DCM (2x8L) and MeOH (3x8L) . The packets were air-dried for 2 h. The packet was shaken with 55% TFA/DCM (8L) at room temperature for 40 minutes and washed with DCM (3 X 8L) , 5% DIEA/DCM (2x8L) and MeOH (2x8L) . The packets were air-dried overnight.
Step 2: Acylation of alpha-amino group using Carboxylic acids.
2. Og of amino acid bound resin (1.3 meq/g ) in porous polypropylene packets (Tea-bag, 60mm x 60mm, 65μ) was washed with 5% DIEA/DCM (2 X 60 mL) in a 125 plastic bottle. Carboxylic acids (16mmol, 6.2eq, 0.4M) (table x) , DMF (40 mL) , DIC (2.1g, 16 mmol), HOBt (2.16g, 16 mmol) were added sequentially. After shaking for 24 hours, the packet was washed alternatively with DMF (3x80 mL) and MeOH (2x80 mL) 3 cycles followed by DCM (2x80 mL) and MeOH (3x80 mL) . The packet was air-dried for 2 h. The packet was then shaken with 25% PIP/DMF (80 mL) at room temperature for 40 minutes and washed with DMF (3x80 mL) , 5% DIEA/DCM (2x80 mL) and MeOH (2x80 mL) . Resin was air dried for 2 hours.
Bottle # Carboxylic Acids
1 Acetic acid 2 alpha-Methylcinnamic acid
3 alpha, alpha, alpha-Trifluoro-m-toluic acid
4 alpha, alpha, alpha-Trifluoro-p-toluic acid
5 Benzoic acid
6 Cyclobutanecarboxylic acid 7 Cycloheptanecarboxylic acid
8 Cyclohexanepropionic acid
9 Cyclopentylacetic acid
10 Ethoxyacetic acid
11 Hydrocinnamic acid 12 4-Dimethylaminobenzoic acid 4-Ethoxybenzoic acid Isobutyric acid Isonicotinic acid 4-Ethoxyphenylacetic acid m-Tolylacetic acid m-Anisic acid m-Toluic acid N-Acetylanthranilic acid Niflumic acid p-Anisic acid p-Toluic acid p-Tolylacetic acid Phenoxyacetic acid Phenylacetic acid Picolinic acid Piperonylic acid Propionic acid ' -Ethyl-4-biphenylcarboxylic acid 4-Fluorobenzoic acid 4-Fluorophenylacetic acid Tetrahydro-3-furoic acid trans-Cinnamic acid Trimethylacetic acid 4-Isobutyl-alpha-Methylphenylacetic acid Xanthene-9-carboxylic acid (3, -Dimethoxyphenyl ) cetic acid (alpha-alpha-alpha-Trifluoro-m-Tolyl) acetic acid (Methylthio) acetic acid (Phenylthio) acetic acid 1-Adamantaneacetic acid 1-Naphthylacetic acid 4-Iodobenzoic acid 4-Isopropylbenzoic acid 4-Methoxyphenylacetic acid 4-Isopropoxybenzoic acid 4-Methyl-l-Cyclohexanecarboxylic acid 4-Methylcyclohexaneacetic acid 2-Bromobenzoic acid Theophylline-7-acetic acid 2-Ethyl-2-Hexenoic acid 2-Ethylbutyric acid 2-Fluorobenzoic acid 2-Furoic acid 2-Methylcyclopropanecarboxylic acid Coumarin-3-carboxylic acid 2-Norbornaneacetic acid 2-Phenylbutyric acid 2-Pyrazinecarboxylic acid 2-Thiopheneacetic acid 2-Thiophenecarboxylic acid 3,4,5 trimethoxycinnamic acid 3, 4- (Methylenedioxy) -Phenylacetic acid 3, 4-Dichlorophenylacetic acid Oleic acid 4-tert-Butyl-cyclohexanecarboxylic acid 3, -Dimethylbenzoic acid 3, 5, 5-Trimethylhexanoic acid 3, 5-Bis (Trifluoromethyl) -Benzoic acid 5-Bromonicotinic acid 5-Phenylvaleric acid 73 3, 5-Dichlorobenzoic acid
74 6-Chloronicotinic acid
75 3, 5-Dimethyl-p-anisic acid
76 3,4, 5-Trimethoxyphenylacetic acid
77 Heptanoic acid
78 3-Benzoylpropionic acid
79 3-Bromo-4-Methylbenzoic acid
80 3-Bromobenzoic acid
81 3-Bromophenylacetic acid 8 822 3-Chlorobenzoic acid
83 3-Cyanobenzoic acid
84 3-Cyclopentylpropionic acid
85 3-Dimethylaminobenzoic acid
86 4-carboxybenzesulfonmide 8 877 3-Fluorobenzoic acid
88 3-Iodo-4-Methylbenzoic acid
89 Formic acid
90 1-Isoquinolinecarboxylic acid
91 3-Methoxyphenylacetic acid 9 922 3-Methyl-2-thiophenecarboxaldehyde
93 3-Phenoxybenzoic acid
94 3-Phenylbutyric acid
95 3-Thiopheneacetic acid
96 4- (Diethylamino) benzoic acid 9 977 4-Biphenylacetic acid
98 4-Bromobenzoic acid
99 4-Bromophenylacetic acid
100 L-Mandelic acid
101 5-Methoxyindole-2-carboxylic acid 1 10022 Succinamic acid 103 4- (methylthio) benzoic acid
104 2- (methylthio) nicotinic acid
105 Diphenylacetic acid
106 3, 4 , 5-Triethoxybenzoic acid 107 2, 4-Dichlorobenzoic acid
108 Crotonic acid
Step 3: Thiourea formation using Thiophosgene and Ammonia.
The procedure is similar to step 2 as described in Example 2 for the preparation of N- (4-carboxamidophenyl) -2- aminothiazoles .
Step 4: Reaction with halo-ketones to form thiazoles.
The packet was cut open and the resin was suspended DMF (25 mL) . The suspension was distributed equally into 24 wells of a microtiter plate (lmlx24) . Excess DMF was removed and the resin was washed several times using MeoH (3x1.5ml per well) . The resin was air-dried overnight. A solution of corresponding halo-ketone (see Table x) in ethoxyethanol (200 μL X 0.4 M) was added to each well. The plate was tightly capped, shaken and incubated at 65° C for 15 hours. Each plate was washed alternatively with DMF (10 X 1 mL/well) and MeOH (14 xl mL/well) . The plate was dried in air overnight and under vacuum for 4 hours . The plate was treated with gaseous HF at room temperature for 1.5 hours. After complete removal of HF under a nitrogen stream followed by vacuum, the plate was extracted with AcOH (4 x 0.5 mL/well). The extractions were lyophilized to give the title compounds.
Well # Halo-Ketones
1 3-CHLOROACETYLACETONE 1-CHLOROPINACOLONE 2-CHLORO-N-METHYLACETOACETAMIDE METHYL 4-CHLOROACETOACETATE METHYL 2-CHLOROACETOACETATE N,N-DIMETHYL-2-CHLOROACETOACETAMIDE ETHYL 4-CHLOROACETOACETATE ETHYL 2-CHLOROACETOACETATE ETHYL BROMOPYRUVATE ALPHA-BROMOPROPIOPHENONE 4-CYANOPHENACYL BROMIDE 2-CHLORO-4 ' -PHENYLACETOPHENONE 2-BROMO-4 ' -NITROACETOPHENONE ALPHA-BROMO-2 ' -ACETONAPHTHONE 1-ADAMANTYL BROMOMETHYL KETONE 2-BROMO-3' -CHLORO-4 ' METHYLPROPIOPHENONE 5- (BROMOACETYL) -3-PHENYLISOXAZOLE, 4- (BROMOACETYL) -5-METHYL-3-PHENYL ISOXAZOLE 2, 4 '-DIBROMOPROPIOPHENONE 6- (Bromoacetyl) -1,2, 3, -tetrahydro-l, 1, 4, -tetr amethyl napthalene 2-BROMO-l- (4-CHLOROPHENYL) -2 'PHENYLETHAN-1-ONE 2-BROMO-l- (4-CHLOROPHENYL) 2-4-METHYLPHENYL) ETHA N-l-ONE 5- (BROMOACETYL) 3- (2, 4-DICHLOROPHANYL) ISOXAZOLE 5- (BROMOACETYL) 3- (3, -DICHLOROPHANYL) ISOXAZOLE Compounds 25-28 represent the variations at 2,4 and 5 position of the amino-thiazole template derived from Boc- Lysine (Fmoc) , carboxylic acids and various halo-ketones.
Compound: 25 Carboxylic Acid: Acetic acid Halo-Ketone: N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 355 Found (M+l) : 356.1
Compound: 26 Carboxylic Acid: alpha, alpha, alpha-Trifluoro-m-toluic acid
Halo-Ketone: N, N-DIMETHYL-2-CHLOROACETOACETAMIDE
Calcd. MW: 485
Found (M+l) : 486.1
Compound: 27 Carboxylic Acid: Cyclohexanepropionic acid Halo-Ketone : N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 451 Found (M+l) : 452.1
Compound: 28
Carboxylic Acid: Ethoxyacetic acid
Halo-Ketone : N, N-DIMETHYL-2-CHLOROACETOACETAMIDE
Calcd. MW: 399
Found (M+l) : 400.1 Example 5
General procedure for Preparation of Branched N-Alkyl-2-
Amino Thiazoles
Acylation of the epsilon-amino group
Step 1: Coupling of Boc-Lysine (Fmoc) to MBHA resin.
216. Og of MBHA resin (1.3 meq/g ) was placed in 108 porous polypropylene packets (2.0g resin/Tea-bag packet, 60mm x 60mm, 65μ) . The packets (108 bags) were washed with 5% DIEA/DCM (2x6.5L) in a plastic bottle. DMF (4.32L), L- Boc-Lysine (Fmoc) , 1.73mol, 6.2eq, 0.4M), DIC (227. Og, 1.73mol), HOBt (233.3g, 1.73mol) were added sequentially. After shaking for 24 hours, the packets were washed alternatively with DMF (3x8L) and MeOH (2x8L) followed by DCM (2x8L) and MeOH (3x8L) . The packets were air-dried for 2 h. The packet was shaken with 25% PIP/DMF (8L) at room temperature for 40 minutes and washed with DMF (3x8L) , 5% DIEA/DCM (2x8L) and MeOH (3x8L) . Resin was air-dried overnight .
Step 2: Acylation of epsilon-amino group using Carboxylic acids .
2. Og of amino acid bound resin (1.3 meq/g ) in porous polypropylene packets (Tea-bag, 60mm x 60mm, 65μ) was washed with 5% DIEA/DCM (2 X 60 mL) in a 125 plastic bottle. Carboxylic acids (16mmol, 6.2eq, 0.4M) (table x) ,
DMF (40 mL) , DIC (2.1g, 16 mmol), HOBt (2.16g, 16 mmol) were added sequentially. After shaking for 24 hours, the packet was washed alternatively with DMF (3x80 mL) and MeOH
(2x80 mL) 3 cycles followed by DCM (2x80 mL) and MeOH (3x80 mL) . The packet was air-dried for 2 h. The packet was shaken with 55% TFA/DCM (80 mL) at room temperature for 40 minutes and washed with DCM (3x80 mL) , 5% DIEA/DCM (2x80 mL) and MeOH (2x80 mL) . Resin was air-dried overnight.
Step 3: Thio-urea formation using Thiophosgene and Ammonia.
The procedure is similar to step 2 as described in Example 2 for the preparation of N- (4-carboxamidophenyl) -2- aminothiazoles .
Step 4: Reaction with halo-ketones to form thiazoles.
The procedure is similar to step 3 as described in Example 2 for the preparation of N- (4-carboxamidophenyl) -2- aminothiazoles .
Example 6
General procedure for Preparation of Branched N-Aryl-2-
Amino Thiazoles
Step 1: Coupling of Boc-p-nitro-Phe to MBHA resin.
216. Og of MBHA resin (1.3 meq/g) was placed in 108 porous polypropylene packets (2.0g resin/Tea-bag packet, 60mm x 60mm, 65 ) . The packets (108 bags) were washed with 5% DIEA/DCM (2x6.5L) in a plastic bottle. DMF (4.32L), Boc-p-nitro-Phe, (1.73mol, 6.2eq, 0.4M), DIC (227. Og, 1.73mol), HOBt (233.3g, 1.73mol) were added sequentially. After shaking for 24 hours, the packets were washed alternatively with DMF (3x8L) and MeOH (2x8L) followed by DCM (2x8L) and MeOH (3x8L) . The packets were air-dried for 2 h. The packet was shaken with 55% TFA/DCM (8L) at room temperature for 40 minutes and washed with DCM (3 X 8L) , 5% DIEA/DCM (2x8L) and MeOH (2x8L) . The packets were air- dried overnight . Step 2: Acylation of alpha-amino group using Carboxylic acids.
The procedure is similar to step 2 as described in Example 4 for the preparation branched N-alkyl-2 -amino thiazoles.
Step 3: Reduction of the nitro group to amine.
The packet was shaken with a 2.0 M solution of tin (II) chloride dihydrate DMF (80 mL) for 24 hours at room temperature. The packet was washed with DMF (6 X 80 mL) , 10% DIEA/DCM (4 X 80 mL) , MeOH, (2 X 80 mL) , DMF (80 mL) , MeOH (80 mL) , DCM (2 X 80 mL) and MeOH (2 X 80 mL) and air- dried overnight .
Step 4: Thio-urea formation using Thiophosgene and Ammonia.
The procedure is similar to step 2 as described in Example 2 for the preparation of N- (4-carboxamidophenyl) -2- aminothiazoles .
Step 5: Reaction with halo-ketones to form thiazoles.
The procedure is similar to step 3 as described in Example 2 for the preparation of N- (4-carboxamidophenyl) -2- aminothiazoles .
Compounds 29-32 represent the variations at 2,4 and 5 position of the amino-thiazole template derived from Boc- p-nitro-Phe, carboxylic acids and various halo-ketones.
Compound: 29 Carboxylic Acid: alpha, alpha, alpha-Trifluoro-m-toluic acid
Halo-Ketone: N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 519 Found (M+l) : 520
Compound : 30 Carboxylic Acid: Cyclohexanepropionic acid Halo-Ketone : N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 485 Found (M+l) : 486.1
Compound : 31 Carboxylic Acid: Ethoxyacetic acid Halo-Ketone : N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 433 Found (M+l) : 434
Compound : 32 Carboxylic Acid: Isobutyric acid Halo-Ketone : N,N-DIMETHYL-2-CHLOROACETOACETAMIDE Calcd. MW: 417 Found (M+l) : 418
Example 7 Anti-microbial Screen
Streptococcus pyogenes (ATCC# 97-03 14289) were grown in Todd Hewitt Broth (THB) (Difco Laboratories #0492-17-6) overnight until they reached an optical density of ( OD = 0.636® 570 nm) by reading 0.1 ml in a 96 well microtiter plate in a Molecular Devices Thermomax. This preparation was kept frozen as stocks in 30% v/v glycerol in 1.5 ml aliquots at -70°C until use. Prior to experiments 1.5 ml aliquots were thawed and diluted into 50 ml THB. 200 ul of this dilution was added to 92 wells of microtiter plate. To three wells THB (200 ul) was added to serve as a blank and a sterility control . Test compounds in DMSO and appropriate concentrations of DMSO were added to Growth/Solvent
Controls at 0 time. Plates were read at 0 time at 570 nm in the Molecular Devices plate reader to obtain compounds correction factors for insoluble or colored compounds. Plates were read again at 4 hrs .
Percent inhibition was calculated with the following formulae :
Color correct =
(O.D. 0 hr - Blank 0 hr) - (Solvent Control Ohr - Blank 0 hr)
% Inhibition =
100 - P.P. test compound 4 hr - Blank 4 hr - color correct
O.D. growth/solvent control 4 hr - Blank 4 hr
Percent inhibition for compounds of the subject invention are listed in the table below.
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
150
Figure imgf000152_0001
151
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
155
Figure imgf000157_0001
156
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
162
Figure imgf000164_0001
Although the invention has been described with reference to the examples provided above, it should be understood that various modifications can be made by those skilled in the art without departing from the invention. Accordingly, the invention is set out in the following claims.

Claims

I claim :
1. A combinatorial library of two or more compounds of the structure :
Figure imgf000166_0001
wherein:
q is an integer selected from 0, 1 or 2 ;
Rx is selected from the group consisting of a hydrogen atom and a functionalized resin;
R2 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; or Rl7 N and R2 together is one of the following formulae :
Figure imgf000167_0001
Figure imgf000167_0002
wherein R9 is selected from the group consisting of a hydrogen atom and a functionalized resin; and
R3 is selected from the group consisting of C2 to C8 alkylene, Cx to C8 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, C4 to C10 cycloalkylalkylene, C4 to C10 substituted cycloalkylalkylene, C7 to C12 phenylalkylene and C7 to C12 substituted phenylalkylene; or R3 is of the formula:
Figure imgf000168_0001
R10 R^
wherein :
R10 and Rn are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, Cx to C7 acyl, Cx to C7 substituted acyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C7 to
C12 phenylalkyl, C7 to C12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C2 to C7 alkylene, substituted cyclic C2 to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene, hydroxymethyl and protected hydroxymethyl, provided that both R10 and R:ι are not hydrogen atoms; or
R10 and Rn together with the carbon atom in between R10 and Rn form a ring selected from the group consisting of a C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, a heterocyclic ring and substituted heterocyclic ring; or R3 is of the formula ( I I ) or ( I I I )
Figure imgf000169_0001
wherein n is an integer selected from 0 to 4; R12 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, cyano, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide and trifluoromethyl; R13 is selected from the group consisting of a hydrogen atom, C: to C6 alkyl, C: to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl and C7 to C12 substituted phenylalkyl; and R14 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C- to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl , Cx to C7 acyl, Cx to C. substituted acyl, phenylsulfonyl, substituted phenylsulfonyl , Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or R14 is of the formula:
Figure imgf000170_0001
wherein R15 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Cx to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Ci to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; and R16 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Cx to C7 substituted acyl, Cx to C7 alkoxycarbonyl, Ci to C7 substituted alkoxycarbonyl , Ci to C7 alkylaminocarbonyl , Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; or R15 and R16 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or R15 and R16 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; or
R3 is of the formula (IV) or (V)
Figure imgf000171_0001
Figure imgf000171_0002
(IV) (V) wherein:
m is an integer selected from 1 to 8; R13 and R14 are each the same as described herein above;
R4 is selected from the group consisting of a hydrogen atom, Ci to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or R3 and R4 together with nitrogen atom in between R3 and R4 form a ring selected from the group consisting of a heterocycle and substituted heterocycle;
R5 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C7 acyl, Ci to C7 substituted acyl, Cx to C7 alkoxycarbonyl, C: to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; R6 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Cx to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl , Cx to C7 alkylaminocarbonyl , Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; or
R5 and R6 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or
R5 and R6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl;
R7 is selected from the group consisting of Cx to C8 alkylene, Ci to C8 substituted alkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, heteroarylene and substituted heteroarylene; and
R8 is selected from the group consisting of a hydrogen atom, Ci to C6 alkyl, C to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl , Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl , Cx to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or
a pharmaceutically acceptable salt thereof.
2. The combinatorial library of claim 1, wherein R3 is of the formula (II) or (III) :
Figure imgf000174_0001
R 13 \
R 14 :ιi) ; ni )
wherein n is an integer selected from 0 to 4; R12 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, cyano, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, Cx to C alkylaminocarbonyl, C: to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide and trifluoromethyl; Ri3 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl and C7 to C12 substituted phenylalkyl; and Ri4 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl, Ci to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl , Cx to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or R14 is of the formula:
Figure imgf000175_0001
wherein R15 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Cx to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; and R16 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Cx to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; or R15 and R16 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or R15 and R16 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; or
R3 is of the formula (IV) or (V) :
Figure imgf000176_0001
(IV) (V)
wherein:
m is an integer selected from 1 to 8; R13 and Ri4 are each the same as described herein above; and
R4 is selected from the group consisting of a hydrogen atom, Cj to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl, Cx to C7 acyl, Cj to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or
R3 and R4 together with nitrogen atom in between R3 and R4 form a ring selected from the group consisting of a heterocycle and substituted heterocycle.
3. The combinatorial library of claim 1, wherein R3 is selected from the group consisting of Cx to C8 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, C4 to C10 cycloalkylalkylene, C4 to C10 substituted cycloalkylalkylene, C7 to C12 phenylalkylene and C7 to C12 substituted phenylalkylene; or R3 is of the formula:
Figure imgf000177_0001
R10 R11 wherein:
Rio and Rn are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, Cx to C7 acyl, Cx to C7 substituted acyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C2 to C7 alkylene, substituted cyclic C2 to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene, hydroxymethyl and protected hydroxymethyl, provided that R10 and Rn are not both hydrogen atoms; or
Rio and Ru together with the carbon atom in between R10 and Rn form a ring selected from the group consisting of a C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, a heterocyclic ring and substituted heterocyclic ring.
4. The combinatorial library of claim 1, wherein R3 is selected from the group consisting of C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, C4 to C10 cycloalkylalkylene, C4 to C10 substituted cycloalkylalkylene, C7 to Cι2 phenylalkylene and C to C12 substituted phenylalkylene.
5. The combinatorial library of claim 1, wherein q is 1 or 2.
6. The combinatorial library of claim 1, wherein R5 and R6 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or R5 and R6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl.
7. The combinatorial library of claim 1, wherein q is 0 or 1;
R3 is of the formula:
Figure imgf000179_0001
R10 R11
wherein:
Rio and Rn are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to CX2 phenylalkyl, C7 to C12 substituted phenylalkyl, C3 to C7 cycloalkyl, substituted C3 to C7 cycloalkyl, hydroxymethyl and protected hydroxymethyl, provided that both R10 and Rn are not hydrogen atoms; or Rio and Ru together with the carbon atom in between Ri0 and Rn form a ring selected from the group consisting of C3 to C7 cycloalkyl and substituted C3 to C7 cycloalkyl; or
R3 is of the formula (II) or (III) :
Figure imgf000180_0001
wherein n is an integer selected from 1 or 2; R12 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, Cx to C7 alkyl, Cx to C7 substituted alkyl, Cx to C7 alkoxy and Cx to C7 substituted alkoxy; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl; and R14 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 Oubstituted alkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C7 alkylaminocarbonyl, C to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl ; or
R3 is of the formula (IV) or (V)
Figure imgf000180_0002
( IV) (V ) wherein : m is an integer selected from 1 to 5; and R13 and R14 are the same as described herein;
R4 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl;
R7 is selected from the group consisting of phenylene and substituted phenylene; and
R8 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Ci to C6 substituted alkyl.
8. The combinatorial library of claim 1, wherein q is 0 or 1.
9. The combinatorial library of claim 1, wherein R3 is of the formula:
Figure imgf000181_0001
R10 R^
wherein: R10 and Rn are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C3 to C7 cycloalkyl, substituted C3 to C7 cycloalkyl, hydroxymethyl and protected hydroxymethyl, provided that both R10 and Rn are not hydrogen atoms; or
R10 and Rn together with the carbon atom in between R10 and Rn form a ring selected from the group consisting of C3 to C7 cycloalkyl and substituted C3 to C7 cycloalkyl.
10. The combinatorial library of claim 1, wherein R3 is of the formula (II) or (III) :
Figure imgf000182_0001
wherein n is an integer selected from 1 or 2; R12 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, Cx to C7 alkyl, Cx to C7 substituted alkyl, Ci to C7 alkoxy and Ci to C7 substituted alkoxy; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl; and RX4 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C: to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl .
11. The combinatorial library of claim 1, wherein R3 is of the formula (IV) or (V) :
Figure imgf000182_0002
CH2 m N R14
N R14 R13
R13
:ιv; (V) wherein : m is an integer selected from 1 to 5; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl; and R14 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Ci to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl.
12. The combinatorial library of claim 1, wherein R4 is selected from the group consisting of a hydrogen atom, Cj to C6 alkyl and Cx to C6 substituted alkyl.
13. The combinatorial library of claim 1, wherein R7 is selected from the group consisting of phenylene and substituted phenylene.
14. The combinatorial library of claim 1, wherein R8 is selected from the group consisting of a hydrogen atom, Ci to C6 alkyl and Cx to C6 substituted alkyl.
15. The combinatorial library of claim 1, wherein q is 0 or 1;
Ri is selected from the group consisting of a hydrogen atom and polystyryl 4-methylbenzhydryl;
R2 is selected from the group consisting of a hydrogen atom, 2- (1-pyrrolidino) ethyl , 2-pyridinemethyl,
2- (4-imidazole) ethyl, cyclopentyl, allyl, 2-methoxyethyl , (+/-) -tetrahydrofuryl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-fluorobenzyl , 3-fluorobenzyl, 4-fluorobenzyl , 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl , 3 -chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl , 2 - (3 -chlorophenyl) ethyl , 2 - (2 -chlorophenyl ) ethyl , 2, 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl , 2,4- dichlorophenethyl, 2- (diethylamino) ethyl,
2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl , 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl , 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl)propyl, 3- (morpholino) propyl , 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2 -methyl -2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl and piperazine;
R3 is selected from the group consisting of 1,2-ethylene, 1, 3-propylene, 1 , 4-butylene, 1 , 5-pentylene, 1 , 6-hexylene, 1 , 7-heptanylene, 1 , 8-octanylene, cyclohexyl-4 -methylene, 1-methyl-l, 1-ethylene, D-1, 1-butylene, D-1, 1-ethylene, D- 1 , 1-pentylene, D-1, 1-propylene, D-5-amino-l , 1-pentylene, D-1 -amino-1, 5-pentylene, D-2- (2-napthyl) -1 , 1-ethylene, D- 2- (2-thienyl) -1, 1-ethylene, D-2- (4-ethoxyphenyl) -1, 1- ethylene, D-2- (4-fluoropehnyl) -1, 1-ethylene, D-2- (4- hydroxyphenyl) -1, 1-ethylene, D-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, D-2 -carboxamide-1, 1-ethylene, D-2- carboxamide-1, 2 -ethylene, D-2 -carboxy-1 , 2 -ethylene, D-2- cyclohexyl-1, 1-ethylene, D-2 -hydroxy- 1 , 1-ethylene, D-2- hydroxy-1, 1-ethylene, D-2 -hydroxy-1, 1-propylene, D-2- mercapto-1, 1-ethylene, D-2-methyl-l, 1-butylene, Dimethyl-1, 1-propylene, D-2-phenyl-l, 1-ethylene, D-3- carboxamido-1, 1-propylene, D-3 -carboxamido-1 , 3 -propylene, D-3 -carboxy-1, 1-propylene, D-3 -carboxyl -1 , 3 -propylene, D- 3 -methyl -1, 1-butylene, D-4-ureido-l , 1-butylene, D-5- (9- fluorenylmethoxycarboxamido) -1 , 1-pentylene, D-5- acetamiode-1, 1-pentylene, D-5-amino-l, 1-pentylene, D- methylthio-1, 1-propylene, phenylmethylene, D-t- butylmethylene, 1,2-ethylene, 1 , 3-propylene, 1,4- butylene, 1, 5-pentylene, 1, 6-hexylene, 1-methyl-l, 1- ethylene, L-l, 1-butylene, L-l, 1-ethylene, L-l.l- pentylene, 1, 1-propylene, L-5-amino-l , 1-pentylene, L-l- amino-1 , 5-pentylene, L-2- (2-napthyl) -1, 1-ethylene, L-2- (2-thienyl) -1, 1-ethylene, L-2- (4-ethoxyphenyl) -1, 1- ethylene, L-2- (4-fluoropehnyl) -1, 1-ethylene, L-2- (4- hydroxyphenyl ) -1, 1-ethylene, L-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, L-2 -carboxamide-1 , 1-ethylene, L-2- carboxamide-1 , 2 -ethylene, L-2 -carboxy-1 , 2-ethylene, L-2- cyclohexyl-1, 1-ethylene, L-2 -hydroxy- 1 , 1-ethylene, L-2- hydroxy-1, 1-ethylene, L-2-hydroxy-1, 1-propylene, L-2- mercapto-1, 1-ethylene, L-2 -methyl-1, 1-butylene, L-2- methyl-1, 1-propylene, L-2-phenyl-l, 1-ethylene, L-3- carboxamido-1 , 1-propylene, L-3 -carboxamido-1 , 3-propylene, L-3 -carboxy-1 , 1-propylene, L-3-carboxyl-1, 3-propylene, L- 3 -methyl -1, 1-butylene, L-4-ureido-l , 1-butylene, L-5- (9- fluorenylmethoxycarboxamido) -1 , 1-pentylene, L-5- acetamiode-1 , 1-pentylene, L-5-amino-1, 1-pentylene, methylthio-1 , 1-propylene, L-phenylmethylene, L- - butylmethylene, 3 -methoxy-1 , 4-phenylene, 2-methoxy-l, 4- phenylene, 2 -chloro-1, 4-phenylene, 1, 4-phenylene, 2- methoxy-4 -chloro-1, 4-phenylene, 4-methoxy-l, 3 -phenylene, 2-chloro-l , 3 -phenylene, 4-chloro-l, 3 -phenylene, 6-chloro- 1 , 3 -phenylene, 5-carboxy-1 , 3 -phenylene, 5- methoxycarbonyl-1, 3 -phenylene, 2 , 6-dimethoxy-l , 3- phenylene, 2 , 5-dichloro-l, 3 -phenylene, 2 -bromo- 1, 3- phenylene, 6-bromo-l , 3 -phenylene and 2 , 6-dimethoxy-5- chloro-1 , 3 -phenylene;
R4 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl , allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl, 3 -methylbenzyl, 4 -methylbenzyl , 2-fluorobenzyl , 3 -fluorobenzyl , 4-fluorobenzyl , 3- (1-imidazole) propyl , 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2 - (4 -chlorophenyl ) ethyl , 2 - (3 -chlorophenyl) ethyl , 2- (2 -chlorophenyl) ethyl, 2 , 3 -dimethoxy-benzyl , 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl,
2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl , 3- (pyrrolidin-2-one-1-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3 -diphenylpropyl, isobutyl, 2- (2 -pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl , benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl , 4-dimethylaminobenzoyl , 4-ethoxybenzoyl , isobutyryl, 4-ethoxyphenylacetyl , isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl , trans-3- (3-pyridyl) acrylyl, trimethylacetyl , triphenylacetyl , nicotinyl,
(3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl , (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl -1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl , 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert-butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5,5-1rimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl, 5 -bromo-2 -chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3-benzoylpropionyl, 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl, 3-fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl, 3-methyl-2-thiophenecarbonyl, 3-phenoxybenzoyl,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl, 3 , 5 -dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3-lndolepropionyl, 2 , 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl , succinamyl , 4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r (-) -2 -oxothiazolidine-4 -carbonyl , 4 -nitrophenylacetyl , coumarin-3 -carbonyl , 1 -cyano-1-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl , 2- (2 -cyanophenylthio) benzoyl, 2-mesitylenesulfonyl, 2 -naphthalenesulfonyl , 2 -thiophenesulfonyl , 4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl , 4-methoxybenzenesulfonyl,
4 -methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2 -acetamido-4 -methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl, 4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl , 2 , 3 -dichlorothiophene- 5 -sulfonyl, 3 , 4 -dimethoxybenzenesulfonyl , 3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2, 5 -dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl , 2 , 6 -difluorobenzenesulfonyl ,
2-chloro-4- (trifluoromethyl) benzenesulfonyl, 2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro- 6 -methylbenzenesulfonyl,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3-chlorobenzenesulfonyl,
4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl,
2- (methoxycarbonyl) thiophene-3 -sulfonyl ,
4 -acetamido-3 -chlorobenzene sulfonyl ,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl,
5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl,
4-isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl,
3 , 4 -dichlorobenzenesulfonyl ,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester,
(r) - (-) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -1- (carbamyl) - (1 -naphthyl) ethane, (s) -(+) -2- (carbamyl) -3-tert -butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester,
(s) -2- (carbamyl) -3- phenylpropionate methyl ester,
1- (carbamyl) -tridecafluoro- 1-hexane, 1- (carbamyl) -1,1,3, 3-tetramethylbutane,
1- (carbamyl) - (1-naphthyl) ethane,
1- (carbamyl) - (4 -bromophenyl) ethane,
1- (carbamyl) -adamantane , 1- (carbamyl) naphthalene ,
1- (carbamyl) -2,3, 4-trifluorobenzene,
1- (carbamyl) -2 , 3 -dichlorobenzene,
1- (carbamyl) -2 , 3 -dimethylbenzene,
1- (carbamyl) -2 , 4 , 5-trichlorobenzene ,
1- (carbamyl) -2 , 4 , 5-trimethylbenzene ,
1- (carbamyl) -2,4, 6-trichlorobenzene,
1- (carbamyl) -2 , 4 -dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene,
1- (carbamyl) -2,4-dimethylbenzene ,
1- (carbamyl) -2 , 5 -dichlorobenzene,
1- (carbamyl) -2 , 5-difluorobenzene,
1- (carbamyl) -2 , 5-dimethoxybenzene,
1- (carbamyl) -2 , 5- dimethylbenzene,
1- (carbamyl) -2 , 6 -dibromo-4-fluorobenzene,
1- (carbamyl) -2 , 6 -dibromo-4- isopropylbenzene,
1- (carbamyl) -2 , 6 -dichlorobenzene,
1- (carbamyl) -2 , 6-diethylbenzene,
1- (carbamyl) -2 , 6-difluorobenzoyl,
1- (carbamyl) -2 , 6-difluorobenzene,
1- (carbamyl) -2 , 6-diisopropylbenzene,
1- (carbamyl) -2 , 6 -dimethylbenzene,
1- (carbamyl) -2- (chloromethyl) benzene,
1- (carbamyl) -2- (difluoromethoxy) benzene,
1- (carbamyl) -2- (methylthio) benzene, - (carbamyl) -2- (trifluoromethoxy) benzene, - (carbamyl) -2- (trifluoromethyl) benzene, - ( carbamyl ) -2 -biphenyl , - (carbamyl) -2 -bromo-4 , 6-difluorobenzene, - (carbamyl) -2-bromoethane, 1- (carbamyl) -2-bromobenzene, - (carbamyl) -2 -chloro-4 -nitrobenzene, - (carbamyl) -2-chloro-5- (trifluoromethyl) benzene, - (carbamyl ) -2 -chloro-5-nitrobenzene , - (carbamyl ) -2 -chloro- 6 -methylbenzene , 1- (carbamyl ) -2--chlorobenzyl, 1- (carbamyl) -2-chloroethane,
1- (carbamyl ) -2- -chlorobenzene ,
1- (carbamyl ) -2- -cyanobenzene ,
1- (carbamyl ) -2- -ethoxybenzene,
1- (carbamyl ) -2- -ethyl-6 -methylbenzene ,
1- (carbamyl ) -2- -ethylbenzene ,
1- (carbamyl ) -2- -fluoro-3- (trifluoromethyl) benzene,
1- (carbamyl ) -2- •fluoro-5- (trifluoromethyl) benzene,
1- (carbamyl ) -2- ■fluoro-5-methylbenzene,
1- (carbamyl -2- ■fluoro-5-nitrobenzene,
1- (carbamyl -2- ■fluoro-6- (trifluoromethyl) benzene,
1- (carbamyl -2- •fluorobenzene, 1- (carbamyl) -2-iodobenzene,
1- (carbamyl -2- ■isopropyl-6 -methylbenzene ,
1- (carbamyl -2- •isopropylbenzene,
1- carbamyl -2- •methoxy-5-chloro benzene,
1- 'carbamyl -2-methoxy-5 -methylbenzene ,
1- carbamyl) -2-methoxy-5 -nitrobenzene ,
1- carbamyl) -2-methoxybenzene ,
1- carbamyl) -2-methyl -3 -nitrobenzene ,
1- carbamyl) -2-methyl -5-nitrobenzene ,
1- carbamyl) -2-methyl- 6-1-butylbenzene ,
1- carbamyl) -1- (2 -methylphenyl ) methane ,
1- carbamyl) -2-n-propylbenzene ,
1- carbamyl) -2-naphthalene, 1- (carbamyl) -2-nitrobenzene,
1- ( carbamyl ) -2-phenoxybenzene ,
1- ( carbamyl) -2-tert-butylbenzene ,
1- (carbamyl) -3, 4 , 5-trimethoxybenzene,
1- (carbamyl) -1- (3 , 4 -dichlorophenyl) methane,
1- (carbamyl) -3, 4 -dichlorobenzene,
1- (carbamyl) -3, 4-difluorobenzene,
1- (carbamyl) -3, 4 -dimethylbenzene ,
1- (carbamyl) -3, 5-bis (trifluoromethyl) benzene,
1- (carbamyl ) -3, 5- dichlorobenzene,
1- (carbamyl ) -3, 5-dimethoxybenzene,
1- (carbamyl) -3, 5-dimethylbenzene , 1- (carbamyl) -3,5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene, l-(carbamyl) -3- (trifluoromethyl) benzene, - (carbamyl) -3- (trifluoromethylthio) benzene, - (carbamyl) -3-acetylbenzene, - (carbamyl) -3 -bromobenzene, 1- (carbamyl] •3 -bromopropane , - (carbamyl) -3 -carbomethoxybenzene , - (carbamyl) -3 -chloro-2 -methoxybenzene , - (carbamyl) -3 -chloro-2-methylbenzene, - (carbamyl) -3 -chloro-4 -fluorobenzene , - (carbamyl) -3 -chloro-4 -methylbenzene, - (carbamyl) -3 -chlorobenzene, - (carbamyl) -3 -chloropropane, - (carbamyl) -3-cyanobenzene, - (carbamyl) -3 -eyelopentoxy-4 -methoxybenzene , - (carbamyl) -3-ethylbenzene, - (carbamyl) -3-fluoro-4 -methylbenzene, - (carbamyl) -3-fluorobenzene, 1- (carbamyl] ■3 - iodopropane , - (carbamyl) benzoyl chloride, - (carbamyl) -3 -methoxybenzene, - (carbamyl) - (3 -methylphenyl) methane, - (carbamyl) -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, ' - (carbamyl) -5 ' -nitrobenzo-15-crown-5 , ' - (carbamyl) benzo-15-crown-5 , ' - (carbamyl) benzo-18-crown-6 , - (carbamyl -4 , 5 -dimethyl-2 -nitrobenzene, - (carbamyl -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert-butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) benzene, - (carbamyl -4- (trifluoromethylthio) benzene, - (carbamyl -4 -acetylbenzene , - (carbamyl -4 -benzyloxybenzene , - (carbamyl -4 -bromo-2 , 6 -dimethylbenzene, - (carbamyl -4 -bromo-2- (trifluoromethyl) benzene, - (carbamyl -4 -bromo-2 -chlorobenzene , - -bromo-2 -fluorobenzene ,
-4 -bromo-2 -methylbenzene,
-4 -bromobenzene,
-4-chloro-2- (trifluoromethyl) benzene,
-4 -chloro-2 -methoxybenzene,
-4 -chloro-2 -methylbenzene,
-4 -chloro-2 -nitrobenzene,
-4-chloro-3- (trifluoromethyl) benzene,
-4 -chloro-3 -nitrobenzene,
-4 -chlorobenzene ,
-4 -dimethylaminobenzene ,
-4 -ethoxybenzene ,
-4-ethylbenzene,
-4-fluoro-2- (trifluoromethyl) benzene,
-4 -fluoro-2 -nitrobenzene ,
-4-fluoro-3- (trifluoromethyl) benzene,
-4-fluoro-3 -nitrobenzene,
-4 - fluorobenzoyl ,
-4 - fluorobenzyl ,
-4-fluorobenzene,
-4 -heptyloxybenzene ,
-4-iodobenzene,
-4 - isopropylbenzene ,
-4 -methoxy-2 -methylbenzene ,
- (4-methoxyphenyl) methane,
-4 -methoxybenzene ,
-4 -methyl-2 -nitrobenzene ,
-4-methyl-3 -nitrobenzene,
- (4 -methylphenyl) methane,
-4-n-butoxycarbonylbenzene,
-4 -n-butoxybenzene ,
-4 -n-butyl -2 -methylbenzene ,
-4 - -butylbenzene,
-4 -nitrobenzene,
-4-phenoxybenzene,
-5-bromopenane ,
Figure imgf000192_0001
-5-chloro-2 , 4-dimethoxybenzene, 1- (carbamyl) -5 -chloro-2 -methylbenzene,
1- (carbamyl) -5-fluoro-2 -methylbenzene,
1- (carbamyl ) - 5 - iodopentane , 1 - (carbamyl ) -2 -propene , benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane, 1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl
2- (carbamyl) -3-methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4-
(methylthio) butyrate, ethyl
2- (carbamyl) -4-methylvalerate, ethyl 2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate,
1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2 -methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane , methyl
2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl
(carbamyl) acetate , 1 - (carbamyl ) -propane , 1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane,
1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane,
1- (carbamyl) -tetrahydro-2-pyran,
1- (carbamyl) -trans-2-benzenecyclopropane,
1- (carbamyl) -trichloroacetate and carbamyltrichloromethane; or
R3, R4 together with the nitrogen atom of Formula (I) form a ring selected from the group consisting of pyrrolidine, 4- (R) -hydroxy-2- (S) -pyrrolidine, 4-(R)- hydroxy-2- (R) -pyrrolidine, 4- (S) -hydroxy-2- (S) - pyrrolidine, 4- (S) -hydroxy-2- (S) -pyrrolidine, 4- (R) - benzyloxy-2- (S) -pyrrolidine, 4- (R) -benzyloxy-2- (R) - pyrrolidine, 4- (S) -benzyloxy-2- (S) -pyrrolidine, 4-(S)- benzyloxy-2- (S) -pyrrolidine , 4-piperidino, 3-(R)- piperidino, 3- (S) -piperidino, 2- (R) -piperidino, 2-(S)- piperidino, octahydroisoquinoline and dihydroindoyl ; R5 is selected from the group consisting of methyl, t- butyl , carbomethoxymethyl , ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4- methylphenyl, 4-fluorophenyl, 3-fluorophenyl , 4- cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 4 -chlorophenyl, 3 , 4-difluorophenyl, 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl, 3- methyl-4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, chloro-4 -methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4 -dichlorophenyl , 6- (2-oxo) -1, 2 , 3 , 4- tetrahydroquinoline, 4- (5 -methyl-3 -phenyl) isoxazole, 4- bromophenyl, 2- (5-chloro-3-methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5-[3-(3',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ' , 4 ' - dichlorophenyl) ] isoxazole and 5- (3 -phenyl) isoxazole;
R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or
R5 and R6 together with the triazole ring of Formula (I) form a ring structure selected from the group consisting of the structure
Figure imgf000194_0001
and the structure
Figure imgf000194_0002
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1 , 4-phenylene, 2-methoxy-l , 4- phenylene, 2-chloro-l, 4-phenylene, 1, 4-phenylene, 2- methoxy-4 -chloro-1, 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l, 3 -phenylene, 2-chloro- 1, 3 -phenylene, 4-chloro-l, 3 -phenylene, 6 -chloro-1, 3- phenylene, 5-carboxy-1, 3 -phenylene, 5 -methoxycarbonyl- 1 , 3 -phenylene, 2 , 6-dimethoxy-l, 3 -phenylene, 2 , 5-dichloro- 1, 3 -phenylene, 2 -bromo-1, 3 -phenylene, 6 -bromo- 1,3- phenylene and 2 , 6-dimethoxy-5-chloro-l , 3 -phenylene; and
R8 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl , benzyl, 2 -methylbenzyl, 3 -methylbenzyl, 4 -methylbenzyl , 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3- (1-imidazole) propyl, 4-aminomethylbenzyl,
4 -methoxybenzyl , 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl , cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2 - (4 -chlorophenyl ) ethyl , 2 - ( 3 -chlorophenyl ) ethyl , 2- (2 -chlorophenyl) ethyl, 2, 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl , 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl , 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl , 3 -butoxypropyl , 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl , 2- (N-ethyl-3 -methylanilino) ethyl, 3 -phenyl -1-propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl , benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl , 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl,
4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl, nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl , (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl , 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl-1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl , 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl , 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -1ert -butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5,5 -1rimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl, 5-bromo-2-chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl , 3-benzoylpropionyl, 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl , 3-fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl , 3-methyl-2-thiophenecarbonyl , 3 -phenoxybenzoyl ,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5 -di-tert-butyl-4 -hydroxybenzoyl , 3 , 5-dichloro-4 -hydroxybenzoyl , 4- hydroxybenzoyl, 5-methylsalicylyl, 2-methylcyclopropanecarbonyl, 3-lndolepropionyl, 2 , 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl , succinamyl , 4-dimethylaminobutyryl, 4- methylthiobenzoyl , 2-methylthionicotinyl, r (-) -2-oxothiazolidine-4-carbonyl,
4 -nitrophenylacetyl , coumarin-3 -carbonyl ,
1-cyano-l-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl , theophylline-7-acetyl , 2- (2-cyanophenylthio) benzoyl, 2-mesitylenesulfonyl,
2 -naphthalenesulfonyl , 2 -thiophenesulfonyl ,
4 -chlorobenzenesulfonyl , 4 - fluorobenzenesulfonyl ,
4-methoxybenzenesulfonyl ,
4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2 -acetamido-4 -methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4 -tert -butylbenzenesulfonyl , 8 -quinolinesulfonyl ,
2 , 3 -dichlorothiophene- 5 -sulfonyl, 3 , 4 -dimethoxybenzenesulfonyl,
3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4-trifluorobenzenesulfonyl,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5 -dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl, 2 , 6-difluorobenzenesulfonyl ,
2-chloro-4- (trifluoromethyl) benzenesulfonyl, 2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro- 6 -methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl,
4- (n-butoxy) benzenesulfonyl , 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl,
2- (methoxycarbonyl) thiophene-3 -sulfonyl ,
4-acetamido-3 -chlorobenzene sulfonyl,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene- 5 -sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl ,
5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl, 3 -chloro-4 -methylbenzenesulfonyl , 2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl, 4 -isopropylbenzene sulfonyl, 2 , 5 -dimethoxybenzenesulfonyl, 3 , 4 -dichlorobenzenesulfonyl ,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -1- (carbamyl) - (1-naphthyl) ethane , (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester,
(s -(-) -2- (carbamyl) propionate methyl ester,
(s -2- (carbamyl) -3 - phenylpropionate methyl ester,
1- carbamyl ) -tridecafluoro-1-hexane ,
1- carbamyl) -1,1,3, 3-tetramethylbutane,
1- carbamyl) - (1-naphthyl) ethane,
1- carbamyl) - (4 -bromophenyl) ethane,
1- carbamyl) -adamantane , 1- (carbamyl ) naphthalene ,
1- carbamyl) -2,3, 4-trifluorobenzene,
1- carbamyl) -2 , 3 -dichlorobenzene,
1- carbamyl) -2 , 3 -dimethylbenzene,
1- carbamyl) -2,4, 5-trichlorobenzene,
1- carbamyl) -2,4, 5-trimethylbenzene,
1- carbamyl) -2,4, 6-trichlorobenzene,
1- carbamyl) -2 , 4 -dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene,
1- carbamyl) -2,4-dimethylbenzene ,
1- carbamyl) -2 , 5 -dichlorobenzene ,
1- carbamyl) -2 , 5-difluorobenzene,
1- carbamyl) -2 , 5 -dimethoxybenzene ,
1- carbamyl) -2 , 5- dimethylbenzene,
1- carbamyl) -2 , 6 -dibromo-4-fluorobenzene,
1- carbamyl) -2 , 6 -dibromo-4 -isopropylbenzene,
1- carbamyl) -2 , 6 -dichlorobenzene,
1- carbamyl) -2 , 6-diethylbenzene, -2 , 6-difluorobenzoyl,
-2 , 6-difluorobenzene,
-2, 6-diisopropylbenzene,
-2 , 6 -dimethylbenzene,
-2- (chloromethyl) benzene,
-2- (difluoromethoxy) benzene,
-2- (methylthio) benzene,
-2- (trifluoromethoxy) benzene,
-2- (trifluoromethyl) benzene,
-2-biphenyl,
-2-bromo-4 , 6-difluorobenzene,
-2-bromoethane, 1- (carbamyl) -2-bromobenzene,
-2 -chloro-4 -nitrobenzene,
-2 -chloro-5- (trifluoromethyl) benzene,
-2 -chloro-5-nitrobenzene,
-2 -chloro-6 -methylbenzene ,
-2 -chlorobenzyl , 1- (carbamyl) -2 -chloroethane ,
-2 -chlorobenzene ,
-2 -cyanobenzene ,
-2 -ethoxybenzene ,
-2 -ethyl-6 -methylbenzene,
-2 -ethylbenzene ,
-2-fluoro-3- (trifluoromethyl) benzene,
-2-fluoro-5- (trifluoromethyl) benzene,
-2-fluoro-5-methylbenzene,
-2 -fluoro-5-nitrobenzene ,
-2-fluoro-6- (trifluoromethyl) benzene,
-2 - fluorobenzene , 1 - (carbamyl) -2 - iodobenzene ,
-2 - isopropyl - 6 -methylbenzene ,
-2 - isopropylbenzene ,
-2 -methoxy-5 -chloro benzene, 2 -methoxy-5 -methylbenzene , 2 -methoxy-5-nitrobenzene, 2-methoxybenzene , 2 -methyl -3 -nitrobenzene , 2 -methyl-5-nitrobenzene,
Figure imgf000199_0001
2 -methyl- 6 -1 -butylbenzene , 1- (carbamyl -1- (2 -methylphenyl) methane, 1- (carbamyl -2 -n-propylbenzene , 1- (carbamyl -2-naphthalene, 1- (carbamyl) -2-nitrobenzene, 1- (carbamyl -2 -phenoxybenzene , 1- (carbamyl -2-1ert-butylbenzene, 1- (carbamyl -3,4, 5-trimethoxybenzene, 1- (carbamyl -1- (3 , 4 -dichlorophenyl) methane, 1- (carbamyl -3 , 4 -dichlorobenzene, 1- (carbamyl -3 , 4-difluorobenzene, 1- (carbamyl -3 , 4 -dimethylbenzene, 1- (carbamyl -3 , 5-bis (trifluoromethyl) benzene, 1- (carbamyl -3,5- dichlorobenzene, 1- (carbamyl -3 , 5-dimethoxybenzene, 1- (carbamyl -3,5-dimethylbenzene , 1- (carbamyl) -3,5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
(carbamyl -3- (trifluoromethyl) benzene, (carbamyl -3- (trifluoromethylthio) benzene, (carbamyl -3-acetylbenzene, (carbamyl -3 -bromobenzene, 1- (carbamyl) -3-bromopropane, (carbamyl -3 -carbomethoxybenzene , (carbamyl -3 -chloro-2 -methoxybenzene , (carbamyl -3 -chloro-2 -methylbenzene , (carbamyl -3 -chloro-4 -fluorobenzene , (carbamyl -3 -chloro-4 -methylbenzene , (carbamyl -3 -chlorobenzene , (carbamyl -3 -chloropropane , (carbamyl -3 -cyanobenzene , (carbamyl -3 -cyclopentoxy-4 -methoxybenzene , (carbamyl -3 -ethylbenzene , (carbamyl -3 -fluoro-4 -methylbenzene, (carbamyl -3 -fluorobenzene, 1- (carbamyl) -3-iodopropane, (carbamyl benzoyl chloride, (carbamyl -3 -methoxybenzene , (carbamyl - (3 -methylphenyl) methane , (carbamyl -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, - (carbamyl) -5 ' -nitrobenzo-15-crown-5 , ' - (carbamyl) benzo-15-crown-5 , ' - (carbamyl) benzo-18-crown-6, - (carbamyl) -4 , 5-dimethyl-2-nitrobenzene, - (carbamyl) -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl) -4- (chloromethyl) benzene, - (carbamyl) -4- (chlorosulfonyl) benzene, - (carbamyl) -4- (difluoromethoxy) benzene, - (carbamyl) -4- (methylthio) benzene, - (carbamyl) -4- (tert-butyl) benzene, - (carbamyl) -4- (trifluoromethoxy) benzene, - (carbamyl) -4- (trifluoromethyl) benzene, - (carbamyl) -4- (trifluoromethylthio) benzene, - (carbamyl) -4-acetylbenzene, - (carbamyl) -4 -benzyloxybenzene , - (carbamyl) -4 -bromo-2 , 6 -dimethylbenzene, - (carbamyl) -4-bromo-2- (trifluoromethyl) benzene, - (carbamyl) -4 -bromo-2 -chlorobenzene , - carbamyl) -4 -bromo-2 -fluorobenzene , - carbamyl) -4 -bromo-2 -methylbenzene , - carbamyl ) -4 -bromobenzene, - carbamyl) -4-chloro-2- (trifluoromethyl) benzene, - carbamyl) -4 -chloro-2 -methoxybenzene, - carbamyl) -4 -chloro-2 -methylbenzene, - < carbamyl ) -4 -chloro-2 -nitrobenzene , - ( carbamyl) -4 -chloro-3- (trifluoromethyl) benzene, - ( carbamyl) -4 -chloro-3 -nitrobenzene, - ( carbamyl) -4 -chlorobenzene, - ( carbamyl ) -4-dimethylaminobenzene, - (carbamyl) - -4-ethoxybenzene, - (carbamyl) - -4-ethylbenzene, - (carbamyl) - -4-fluoro-2- (trifluoromethyl) benzene, - (carbamyl) - -4 - fluoro-2 -nitrobenzene , - (carbamyl) - -4-fluoro-3- (trifluoromethyl) benzene, - (carbamyl) - -4-fluoro-3 -nitrobenzene, - (carbamyl) - -4 - fluorobenzoyl , - (carbamyl) - -4-fluorobenzyl, - (carbamyl) - -4-fluorobenzene , 1- (carbamyl) -4-heptyloxybenzene,
1- (carbamyl) -4-iodobenzene,
1- (carbamyl) -4 -isopropylbenzene,
1- (carbamyl) -4 -methoxy-2 -methylbenzene, 1- (carbamyl) - (4-methoxyphenyl) methane,
1- (carbamyl) -4 -methoxybenzene,
1- (carbamyl) -4-methyl-2-nitrobenzene,
1- (carbamyl) -4 -methyl-3 -nitrobenzene,
1- (carbamyl) - (4 -methylphenyl) methane, 1- (carbamyl) -4-n-butoxycarbonylbenzene,
1- (carbamyl) -4-n-butoxybenzene,
1- (carbamyl) -4-n-butyl-2-methylbenzene,
1- (carbamyl) -4-n-butylbenzene,
1- (carbamyl) - -nitrobenzene, 1- (carbamyl) -4-phenoxybenzene,
1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (carbamyl) -5-chloro-2-methylbenzene,
1- (carbamyl) -5-fluoro-2 -methylbenzene, 1- (carbamyl) -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl
2- (carbamyl) -3-methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio) butyrate, ethyl
2- (carbamyl) -4-methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3- (carbamyl) benzoate, ethyl 3 - (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate, 1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane,
1- (carbamyl) -2 -methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl
2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl
(carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane, 1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate and carbamyltrichloromethane.
16. The combinatorial library of claim 1, wherein q is 0 or 1;
Rx is selected from the group consisting of a hydrogen atom and polystyryl 4-methylbenzhydryl ;
R2 is selected from the group consisting of a hydrogen atom, 2- (1-pyrrolidino) ethyl, 2-pyridinemethyl, 2- (4-imidazole) ethyl, cyclopentyl, allyl, 2-methoxyethyl, (+/-) -tetrahydrofuryl, benzyl, 2 -methylbenzyl , 3 -methylbenzyl , 4 -methylbenzyl, 2-fluorobenzyl,
3-fluorobenzyl, 4-fluorobenzyl, 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl, 3 -bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonyl, 4-methoxyphenethyl, 2-fluorophenethyl , 2- (4 -chlorophenyl) ethyl , 2 - ( 3 -chlorophenyl ) ethyl , 2 - (2 -chlorophenyl ) ethyl , 2 , 3-dimethoxy-benzyl , 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl,
2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl ,
2- (5-nitro-2-pyridyl) ethyl,
3- (dimethylamino) -2 , 2-dimethylpropyl,
3- (dimethylamino) propyl , 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl , 3- (2 -pipecolinyl) propyl, 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl -1-propyl , 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2 -pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl and piperazine;
R3 is of the formula (II), (III), (IV) or (V):
Figure imgf000204_0001
— - N 3 \
Figure imgf000204_0002
(IV) (V) wherein n is 1; m is 3 or 4 ;
R12 is selected from the group consisting of a hydrogen atom, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, pentane, methoxy, ethoxy, propoxy and iso-proproxy;
R13 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl , 4 -methylbenzyl , 2-fluorobenzyl, 3 -fluorobenzyl , 4-fluorobenzyl , 3 - (1-imidazole) propyl , 4-aminomethylbenzyl , 4 -methoxybenzyl, 3 -chlorobenzyl , 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl , 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl,
3- (pyrrolidin-2-one-l-yl)propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl -1 -propyl , 2-methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl and 3-phenylbenzyl; and
Ri4 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl , 4 -methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3 - ( 1 - imidazole) propyl , 4 -aminomethylbenzyl , 4 -methoxybenzyl , 3 -chlorobenzyl , 3 -bromobenzyl , 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl , 2- (4 -chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2-chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl , 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5 -nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl,
3- (dimethylamino) propyl, 2-aminoethyl,
2- (piperidino) ethyl , isoamyl, 3 -ethoxypropyl,
3 - (2 -pipecolinyl ) propyl , 3 -butoxypropyl , 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl , 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl,
4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl, nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl , 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl-1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl , 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl , 2-thiopheneacetyl , 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl ,
4 -1ert -butyl-cyclohexanecarbonyl , 4 -sulfona idobenzoyl , 3,5,5-trimethylhexanoyl ,
3 , 5-bis (trifluoromethyl) -benzoyl, 5-bromo-2-chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5 -dimethyl -p-anisyl , 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3-benzoylpropionyl, 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl, 3 -fluoro-4 -methylbenzoyl , 1-isoquinolinecarbonyl , 3 -methyl-2 -thiophenecarbonyl , 3 -phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl, 3 , 5-dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5-methylsalicylyl, 2-methylcyclopropanecarbonyl,
3 - lndolepropionyl , 2 , 2 -diphenylacetyl , 5 -methoxyindole-2 -carbonyl, succinamyl, 4-dimethylaminobutyryl, 4- methylthiobenzoyl,
2-methylthionicotinyl, r(-) -2-oxothiazolidine-4-carbonyl,
4 -nitrophenylacetyl , coumarin-3 -carbonyl ,
1-cyano-l-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl , 2- (2-cyanophenylthio) benzoyl, 2-mesitylenesulfonyl,
2 -naphthalenesulfonyl , 2 -thiophenesulfonyl ,
4 -chlorobenzenesulfonyl , 4 - fluorobenzenesulfonyl ,
4-methoxybenzenesulfonyl,
4-methylsulfonylbenzenesulfonyl , benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2-acetamido-4-methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4 -tert -butylbenzenesulfonyl , 8 -quinolinesulfonyl , 2 , 3 -dichlorothiophene-5-sulfonyl , 3 , 4 -dimethoxybenzenesulfonyl,
3 , 5-bis (trifluoromethyl) benzenesulfonyl ,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4-trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2, 5 -dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl, 2 , 6-difluorobenzenesulfonyl ,
2-chloro-4- (trifluoromethyl) benzenesulfonyl, 2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro- 6-methylbenzenesulfonyl,
3 , 4 -difluorobenzenesulphonyl , 3 , 5-dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl, 4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl , 2- (methoxycarbonyl) thiophene-3 -sulfonyl, 4 -acetamido-3 -chlorobenzene sulfonyl,
2- [l-methyl-5- (trifluoromethyl) yrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl, 5- (isoxazol-3-yl) thiophene-2-sulfonyl , 4-cyanobenzene sulfonyl, 3 -chloro-4 -methylbenzenesulfonyl,
2 , 4 -difluorobenzenesulfonyl , 2 - fluorobenzenesulfonyl , 4 -isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl, 3 , 4 -dichlorobenzenesulfonyl , (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -2- (carbamyl) -3-tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester, (s) -2- (carbamyl) -3- phenylpropionate methyl ester, 1- (carbamyl) -tridecafluoro- 1-hexane,
1- (carbamyl) -1 , 1 , 3 , 3 -1etramethylbutane ,
1- (carbamyl) - (1-naphthyl) ethane,
1- (carbamyl) - (4 -bromophenyl) ethane,
1- (carbamyl) -adamantane, 1- (carbamyl) naphthalene, 1- (carbamyl) -2,3, 4-trifluorobenzene, 1- (carbamyl) -2 , 3 -dichlorobenzene, 1- (carbamyl) -2 , 3 -dimethylbenzene, 1- (carbamyl) -2,4, 5-trichlorobenzene, 1- (carbamyl) -2,4, 5-trimethylbenzene, 1- (carbamyl) -2,4, 6-trichlorobenzene,
1- (carbamyl) -2, 4 -dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene, -2, 4 -dimethylbenzene,
-2 , 5 -dichlorobenzene,
-2 , 5-difluorobenzene,
-2 , 5-dimethoxybenzene,
-2,5- dimethylbenzene,
-2 , 6 -dibromo-4-fluorobenzene,
-2 , 6-dibromo-4 -isopropylbenzene,
-2 , 6-dichlorobenzene,
-2 , 6-diethylbenzene,
-2 , 6-difluorobenzoyl ,
-2 , 6-difluorobenzene,
-2, 6-diisopropylbenzene,
-2, 6 -dimethylbenzene,
-2- (chloromethyl) benzene,
-2- (difluoromethoxy) benzene,
-2- (methylthio) benzene,
-2- (trifluoromethoxy) benzene,
-2- (trifluoromethyl) benzene,
-2-biphenyl,
-2-bromo-4 , 6-difluorobenzene,
-2-bromoethane, 1- (carbamyl) -2-bromobenzene,
-2 -chloro-4 -nitrobenzene ,
-2-chloro-5- (trifluoromethyl) benzene,
-2 -chloro-5 -nitrobenzene ,
-2 -chloro-6 -methylbenzene ,
-2-chlorobenzyl , 1- (carbamyl) -2 -chloroethane ,
-2 -chlorobenzene,
-2 -cyanobenzene ,
-2-ethoxybenzene,
-2 -ethyl-6 -methylbenzene,
-2-ethylbenzene, 2-fluoro-3- (trifluoromethyl) benzene, 2-fluoro-5- (trifluoromethyl) benzene, 2 - fluoro-5 -methylbenzene , 2-fluoro-5 -nitrobenzene, 2-fluoro-6- (trifluoromethyl) benzene,
Figure imgf000209_0001
2-fluorobenzene, 1- (carbamyl) -2-iodobenzene, 1- (carbamyl) -2 -isopropyl-6 -methylbenzene,
1- (carbamyl) -2 -isopropylbenzene,
1- (carbamyl) -2 -methoxy-5-chloro benzene,
1- (carbamyl) -2 -methoxy-5 -methylbenzene,
1- (carbamyl) -2 -methoxy-5 -nitrobenzene,
1- (carbamyl) -2-methoxybenzene,
1- (carbamyl) -2 -methyl-3 -nitrobenzene,
1- (carbamyl) -2 -methyl-5-nitrobenzene,
1- (carbamyl) -2 -methyl -6 -t -butylbenzene,
1- (carbamyl) -1- (2-methylphenyl) methane,
1- (carbamyl) -2-n-propylbenzene,
1- (carbamyl) -2-naphthalene, 1- (carbamyl: -2-nitrobenzene,
1- (carbamyl) -2-phenoxybenzene,
1- (carbamyl) -2 -tert -butylbenzene,
1- (carbamyl) -3,4, 5-trimethoxybenzene,
1- (carbamyl) -1- (3 , 4 -dichlorophenyl) methane,
1- (carbamyl) -3 , 4 -dichlorobenzene,
1- (carbamyl) -3 , 4-difluorobenzene,
1- (carbamyl) -3 , 4 -dimethylbenzene,
1- (carbamyl) -3 , 5-bis (trifluoromethyl) benzene,
1- (carbamyl) -3,5- dichlorobenzene ,
1- (carbamyl) -3 , 5-dimethoxybenzene,
1- (carbamyl) -3 , 5 -dimethylbenzene, 1- (carbamyl) -3,5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
1- (carbamyl) -3- (trifluoromethyl) benzene,
1- (carbamyl) -3- (trifluoromethylthio) benzene,
1- (carbamyl) -3-acetylbenzene,
1- (carbamyl) -3 -bromobenzene, 1- (carbamyl) -3-bromopropane,
1- (carbamyl) -3-carbomethoxybenzene,
1- (carbamyl) -3-chloro-2-methoxybenzene,
1- (carbamyl) -3-chloro-2-methylbenzene,
1- (carbamyl) -3 -chloro-4-fluorobenzene,
1- (carbamyl) -3 -chloro-4 -methylbenzene,
1- (carbamyl) -3 -chlorobenzene,
1- (carbamyl) -3-chloropropane,
1- (carbamyl) -3-cyanobenzene,
1- (carbamyl) -3 -cyclopentoxy-4 -methoxybenzene, ■ (carbamyl ) -3 -ethylbenzene ,
■ (carbamyl) -3-fluoro-4 -methylbenzene,
■ (carbamyl) -3-fluorobenzene, 1- (carbamyl) -3-iodopropane, • (carbamyl) benzoyl chloride,
■ (carbamyl) -3 -methoxybenzene, (carbamyl) - (3 -methylphenyl) methane,
■ (carbamyl) -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, - (carbamyl) -5 ' -nitrobenzo-15-crown-5,
- (carbamyl) benzo-15-crown-5, - (carbamyl) benzo-18 -crown-6, - (carbamyl -4 , 5-dimethyl-2 -nitrobenzene, - (carbamyl -4- (6 -methyl -2 -benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert-butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) benzene, - (carbamyl -4- (trifluoromethylthio) benzene, - (carbamyl -4 -acetylbenzene , - (carbamyl -4 -benzyloxybenzene , - (carbamyl -4 -bromo-2 , 6 -dimethylbenzene, - (carbamyl -4 -bromo-2- (trifluoromethyl) benzene, - (carbamyl -4 -bromo-2 -chlorobenzene, - (carbamyl -4-bromo-2- fluorobenzene, - (carbamyl -4 -bromo-2 -methylbenzene , - (carbamyl -4 -bromobenzene , - (carbamyl -4-chloro-2- (trifluoromethyl) benzene, - (carbamyl -4 -chloro-2 -methoxybenzene, - (carbamyl -4 -chloro-2 -methylbenzene, - (carbamyl -4 -chloro-2-nitrobenzene, - (carbamyl -4 -chloro-3- (trifluoromethyl) benzene, - (carbamyl -4 -chloro-3 -nitrobenzene, - (carbamyl -4 -chlorobenzene, - (carbamyl -4 -dimethylaminobenzene , - (carbamyl -4-ethoxybenzene, 1- (carbamyl -4-ethylbenzene, 1- (carbamyl -4-fluoro-2- (trifluoromethyl) benzene, 1- (carbamyl -4 -fluoro-2 -nitrobenzene , 1- (carbamyl -4-fluoro-3- (trifluoromethyl) benzene, 1- (carbamyl -4 -fluoro-3 -nitrobenzene , 1- (carbamyl -4-fluorobenzoyl, 1- (carbamyl -4-fluorobenzyl, 1- (carbamyl -4 -fluorobenzene , 1- (carbamyl -4 -heptyloxybenzene , 1- (carbamyl -4-iodobenzene, 1- (carbamyl -4 -isopropylbenzene , 1- (carbamyl -4 -methoxy-2 -methylbenzene , 1- (carbamyl - (4-methoxyphenyl) methane, 1- (carbamyl -4 -methoxybenzene, 1- (carbamyl -4 -methyl-2 -nitrobenzene , 1- (carbamyl -4 -methyl-3 -nitrobenzene , 1- (carbamyl - (4 -methylphenyl) methane, 1- (carbamyl -4 -n-butoxycarbonylbenzene , 1- (carbamyl -4 -n-butoxybenzene , 1- (carbamyl -4 -n-butyl-2 -methylbenzene , 1- (carbamyl -4 -n-butylbenzene , 1- (carbamyl -4 -nitrobenzene, 1- (carbamyl -4 -phenoxybenzene , 1- (carbamyl -5 -bromopenane , 1- (carbamyl -5 -chloro-2 , 4-dimethoxybenzene, 1- (carbamyl -5 -chloro-2 -methylbenzene , 1- (carbamyl -5- fluoro-2 -methylbenzene , 1- (carbamyl -5-iodopentane , 1- (carbamyl) -2 -propene , benzoyl carbamyl 1- (carbamyl) -1-phenylmethane, 1- (carbamyl -cyclohexane, carboxyethylcarbamyl, ethyl 2- (carbamyl -3-methylbutyrate, ethyl 2- (carbamyl -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio butyrate, ethyl 2- (carbamyl -4-methylvalerate, ethyl 2- (carbamyl benzoate, ethyl 2- (carbamyl) propionate, ethyl 3 - (carbamyl benzoate, ethyl 3- (carbamyl) propionate, ethyl 4- (carbamyl -benzoate, ethyl 6- (carbamyl) hexanoate, 1- (carbamyl) -ethyl , ethyl (carbamyl) acetate, 1- (carbamyl) -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl 2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl (carbamyl) acetate, 1- (carbamyl) -propane, 1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane, 1- (carbamyl) -tetrahydro-2-pyran,
1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate and carbamyltrichloromethane; or
R1 is of the formula :
Figure imgf000213_0001
wherein Rn is selected from the group consisting of a hydrogen atom, methyl, t-butyl, carbomethoxymethyl, ethyl, carboethoxymethyl , carboxy, trifluormethyl, carboethoxy, phenyl, 4 -methylphenyl , 4 -fluorophenyl, 3- fluorophenyl, 4-cyanophenyl, 2-methoxyphenyl, 3- methoxyphenyl , 4 -methoxyphenyl , 4 -chlorophenyl , 3,4- difluorophenyl, 4-nitrophenyl , 3 , 4-dihydroxyphenyl, 3- nitrophenyl, 3 -methyl-4-chlorophenyl , adamantyl, 2,5- dimethoxyphenyl, 3 -chloro-4 -methylphenyl, 5- (3- carboethoxy) isoxazole, 4-phenylphenyl, 3,4- dichlorophenyl, 6- (2-oxo) -1 , 2 , 3 , 4-tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4 -bromophenyl , 2-(5-chloro- 3 -methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) - 1, 2 , 3 , 4-tetrahydronaphthalene, 4 -chlorophenyl, 1-pyrene, 5- [3- (3 ' ,4 ' -dichlorophenyl) ] isoxazole, 5- [3- (2 ',4'- dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole; and Ri6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl ; or R14, Ri5 and Ri6 together form a ring structure selected from the group consisting of the structure
Figure imgf000214_0001
and the structure
Figure imgf000214_0002
R4 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl , 4 -methylbenzyl, 2-fluorobenzyl, 3 -fluorobenzyl, 4-fluorobenzyl, 3- (1- imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl , 3 -bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl,
4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl , 2 - (4 -chlorophenyl) ethyl , 2 - ( 3 -chlorophenyl ) ethyl , 2- (2 -chlorophenyl) ethyl , 2 , 3-dimethoxy-benzyl , 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl , 3- (diethylamino) propyl, 2- (5 -nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl , 3 - (dimethylamino) propyl, 2-aminoethyl,
2- (piperidino) ethyl , isoamyl, 3 -ethoxypropyl , 3- ( 2 -pipecolinyl) ropyl , 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl , 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl -1-propyl , 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl , picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl , nicotinyl, (3 , 4 -dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl- 1-cyclohexanecarbonyl , pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl, 2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl , 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl,
3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert-buty1-cyclohexanecarbonyl , 4-sulfonamidobenzoyl , 3,5,5-trimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl ,
5-bromo-2-chlorobenzoyl , 5-bromonicotinyl, 6-chloronicotinyl , 3 , 5 -dimethyl -p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl , 3-benzoylpropionyl, 3 , 5-dichlorobenzoyl , 3-cyanobenzoyl, 3-fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl , 3 -methyl -2 -thiophenecarbonyl , 3 -phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5 -di-tert-butyl-4 -hydroxybenzoyl,
3 , 5 -dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl,
5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl ,
3-lndolepropionyl, 2, 2-diphenylacetyl, 5-methoxyindole-2 -carbonyl, succinamyl,
4-dimethylaminobutyryl, 4- methylthiobenzoyl,
2-methylthionicotinyl, r(-) -2-oxothiazolidine-4-carbonyl,
4 -nitrophenylacetyl , coumarin-3 -carbonyl ,
1-cyano-l-cyclopropane carbonyl, 2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl,
2- (2 -cyanophenylthio) benzoyl, 2-mesitylenesulfonyl,
2 -naphthalenesulfonyl , 2 -thiophenesulfonyl ,
4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl ,
4-methoxybenzenesulfonyl, 4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2 -acetamido-4 -methyl- 5-thiazolesulfonyl ,
4- (trifluoromethoxy) benzenesulfonyl,
4 -tert -butylbenzenesulfonyl , 8 -quinolinesulfonyl , 2 , 3-dichlorothiophene-5-sulfonyl,
3 , -dimethoxybenzenesulfonyl ,
3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl,
2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5-dichlorothiophene-3 -sulfonyl ,
2 , 6-dichlorobenzenesulfonyl , 2 , 6 -difluorobenzenesulfonyl , 2 -chloro-4- (trifluoromethyl) benzenesulfonyl,
2 -chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro-6 -methylbenzenesulfonyl,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl , 4- (n-butoxy) benzenesulfonyl , 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4 -sulfonyl , 2- (methoxycarbonyl) thiophene-3 -sulfonyl,
4 -acetamido-3 -chlorobenzene sulfonyl,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3 -methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl,
5- (isoxazol-3 -yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4 -difluorobenzenesulfonyl , 2 -fluorobenzenesulfonyl ,
4 -isopropylbenzene sulfonyl, 2 , 5 -dimethoxybenzenesulfonyl,
3 , 4 -dichlorobenzenesulfonyl ,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester,
(r) - (-) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) -(+) -2- (carbamyl) -3 -tert -butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester,
(s) -2- (carbamyl) -3- phenylpropionate methyl ester,
1- (carbamyl) -tridecafluoro- 1-hexane,
1- (carbamyl ) -1,1,3,3 -1etramethylbutane ,
1- (carbamyl) - (1-naphthyl) ethane, 1 - (carbamyl ) - (4 -bromophenyl ) ethane,
1- (carbamyl) -adamantane, 1- (carbamyl) naphthalene,
1- (carbamyl) -2,3, 4-trifluorobenzene,
1- (carbamyl) -2 , 3 -dichlorobenzene,
1- (carbamyl) -2 , 3 -dimethylbenzene, 1- (carbamyl) -2,4, 5-trichlorobenzene,
1- (carbamyl) -2,4, 5-trimethylbenzene,
1- (carbamyl) -2,4, 6-trichlorobenzene,
1 - (carbamyl ) -2,4-dichlorobenzene , 1- (carbamyl ) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene, 1- (carbamyl) -2 , 4 -dimethylbenzene,
1- (carbamyl) -2 , 5 -dichlorobenzene, -2 , 5-difluorobenzene,
-2 , 5-dimethoxybenzene,
-2,5- dimethylbenzene,
-2 , 6 -dibromo-4-fluorobenzene,
-2, 6 -dibromo-4-isopropylbenzene,
-2 , 6 -dichlorobenzene,
-2 , 6-diethylbenzene,
-2 , 6-difluorobenzoyl,
-2 , 6-difluorobenzene,
-2 , 6-diisopropylbenzene,
-2 , 6 -dimethylbenzene,
-2- (chloromethyl) benzene,
-2- (difluoromethoxy) benzene,
-2- (methylthio) benzene,
-2- (trifluoromethoxy) benzene,
-2- (trifluoromethyl) benzene,
-2-biphenyl,
-2 -bromo-4 , 6-difluorobenzene,
-2-bromoethane, 1- (carbamyl) -2-bromobenzene,
-2 -chloro-4 -nitrobenzene,
-2-chloro-5- (trifluoromethyl) benzene,
-2 -chloro-5 -nitrobenzene,
-2 -chloro- 6 -methylbenzene ,
-2 -chlorobenzyl , 1- (carbamyl) -2 -chloroethane ,
-2 -chlorobenzene ,
-2 -cyanobenzene , 2 -ethoxybenzene ,
-2 -ethyl-6 -methylbenzene, 2 -ethylbenzene , 2-fluoro-3- (trifluoromethyl) benzene, 2-fluoro-5- (trifluoromethyl) benzene, 2 - fluoro-5-methylbenzene , 2 - fluoro- 5 -nitrobenzene , 2-fluoro-6- (trifluoromethyl) benzene, 2-fluorobenzene, 1- (carbamyl) -2-iodobenzene, 2 - isopropyl - 6 -methylbenzene ,
Figure imgf000218_0001
2 - isopropylbenzene , 1- carbamyl -2 -methoxy-5-chloro benzene, 1- carbamyl -2 -methoxy-5-methylbenzene , 1- carbamyl -2 -methoxy- 5-nitrobenzene, 1- carbamyl -2-methoxybenzene , 1- carbamyl -2 -methyl-3 -nitrobenzene , 1- carbamyl -2 -methyl-5-nitrobenzene, 1- carbamyl -2-methyl-6-t-butylbenzene , 1- carbamyl -1- (2 -methylphenyl ) methane , 1- carbamyl -2-n-propylbenzene, 1- carbamyl -2-naphthalene, 1- (carbamyl) -2-nitrobenzene, 1- carbamyl -2 -phenoxybenzene , 1- carbamyl -2 -tert-butylbenzene, 1- carbamyl -3,4,5-trimethoxybenzene , 1- carbamyl - 1- (3,4-dichlorophenyl) methane , 1- carbamyl -3 , 4 -dichlorobenzene, 1- carbamyl -3 , 4-difluorobenzene, 1- carbamyl -3 , 4 -dimethylbenzene, 1- carbamyl -3 , 5-bis (trifluoromethyl) benzene, 1- carbamyl -3,5- dichlorobenzene, 1- carbamyl -3 , 5-dimethoxybenzene, 1- carbamyl -3 , 5 -dimethylbenzene, 1- (carbamyl) -3,5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
1- carbamyl -3- (trifluoromethyl) benzene, 1- carbamyl -3- (trifluoromethylthio) benzene, 1- carbamyl -3-acetylbenzene, 1- carbamyl -3 -bromobenzene, 1- (carbamyl) -3-bromopropane, 1- carbamyl -3 -carbomethoxybenzene , 1- carbamyl -3 -chloro-2 -methoxybenzene , 1- carbamyl -3 -chloro-2 -methylbenzene , 1- carbamyl -3 -chloro-4-fluorobenzene, 1- carbamyl -3 -chloro-4 -methylbenzene, 1- carbamyl -3 -chlorobenzene, 1- carbamyl -3 -chloropropane , 1- carbamyl -3 -cyanobenzene , 1- carbamyl -3 -cyclopentoxy-4 -methoxybenzene, 1- carbamyl -3 -ethylbenzene , 1- carbamyl -3-fluoro-4 -methylbenzene, - (carbamyl) -3-fluorobenzene, 1- (carbamyl) -3-iodopropane, - (carbamyl) benzoyl chloride , - (carbamyl) -3 -methoxybenzene, - (carbamyl) - (3 -methylphenyl) methane, - (carbamyl) -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, ' - (carbamyl) -5 ' -nitrobenzo-15-crown-5, ' - (carbamyl) benzo-15-crown-5, ' - (carbamyl) benzo-18-crown-6,
4 , 5 -dimethyl-2 -nitrobenzene, -4- (6-methyl-2-benzothiazolyl) benzene,
-4- (chloromethyl) benzene, -4- (chlorosulfonyl) benzene, -4- (difluoromethoxy) benzene, -4- (methylthio) benzene, -4- (tert-butyl) benzene,
-4- (trifluoromethoxy) benzene, -4- (trifluoromethyl) benzene, -4- (trifluoromethylthio) benzene, -4-acetylbenzene, -4-benzyloxybenzene,
-4 -bromo-2 , 6-dimethylbenzene, -4 -bromo-2- (trifluoromethyl) benzene, -4 -bromo-2 -chlorobenzene, -4 -bromo-2 -fluorobenzene, -4 -bromo-2 -methylbenzene,
4 -bromobenzene ,
4 -chloro-2- (trifluoromethyl) benzene, 4 -chloro-2 -methoxybenzene , 4 -chloro-2 -methylbenzene , -4-chloro-2-nitrobenzene,
-4 -chloro-3 - (trifluoromethyl) benzene, -4 -chloro-3 -nitrobenzene, -4 -chlorobenzene , -4-dimethylaminobenzene, -4 -ethoxybenzene ,
-4 -ethylbenzene ,
Figure imgf000220_0001
-4-fluoro-2- (trifluoromethyl) benzene, (carbamyl -4-fluoro-2 -nitrobenzene, (carbamyl -4-fluoro-3- (trifluoromethyl) benzene, (carbamyl -4 -fluoro-3 -nitrobenzene , (carbamyl -4 -fluorobenzoyl , (carbamyl -4 -fluorobenzyl , (carbamyl -4 -fluorobenzene , (carbamyl -4 -heptyloxybenzene, (carbamyl -4 - iodobenzene , (carbamyl -4 -isopropylbenzene, (carbamyl -4 -methoxy-2 -methylbenzene , (carbamyl - (4-methoxyphenyl) methane, (carbamyl -4 -methoxybenzene , (carbamyl -4 -methyl-2 -nitrobenzene , (carbamyl -4 -methyl-3 -nitrobenzene , (carbamyl - (4 -methylphenyl) methane, (carbamyl -4-n-butoxycarbonylbenzene, (carbamyl -4 -n-butoxybenzene , (carbamyl -4 -n-butyl-2 -methylbenzene , (carbamyl -4-n-butylbenzene, (carbamyl -4 -nitrobenzene , (carbamyl -4-phenoxybenzene, (carbamyl -5 -bromopenane , (carbamyl -5-chloro-2 , 4-dimethoxybenzene, (carbamyl -5-chloro-2 -methylbenzene, (carbamyl -5-fluoro-2-methylbenzene, (carbamyl -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl -cyclohexane, carboxyethylcarbamyl, ethyl 2- (carbamyl -3-methylbutyrate, ethyl 2- (carbamyl -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio butyrate, ethyl 2- (carbamyl -4-methylvalerate, ethyl 2- (carbamyl benzoate, ethyl 2- (carbamyl) propionate, ethyl 3- (carbamyl benzoate, ethyl 3- (carbamyl) propionate, ethyl 4- (carbamyl -benzoate, ethyl 6- (carbamyl) hexanoate, 1- (carbamyl -ethyl, ethyl (carbamyl) acetate, 1- (carbamyl -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2-methylethane, methyl 2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) ropionate, 1- (carbamyl) butane, n-butyl (carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane, 1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate and carbamyltrichloromethane; or
R3, R4 together with the nitrogen atom of Formula (I) form a ring selected from the group consisting of pyrrolidine, 4- (R) -hydroxy-2- (S) -pyrrolidine, 4- (R) - hydroxy-2- (R) -pyrrolidine, 4- (S) -hydroxy-2- (S) - pyrrolidine, 4- (S) -hydroxy-2- (S) -pyrrolidine, 4- (R) - benzyloxy-2- (S) -pyrrolidine, 4- (R) -benzyloxy-2- (R) - pyrrolidine, 4- (S) -benzyloxy-2- (S) -pyrrolidine, 4-(S)- benzyloxy-2- (S) -pyrrolidine, 4-piperidino, 3-(R)- piperidino, 3- (S) -piperidino, 2- (R) -piperidino, 2- (S) - piperidino, octahydroisoquinoline and dihydroindoyl ;
R5 is selected from the group consisting of methyl, t- butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl , carboethoxy, phenyl, 4- methylphenyl, 4-fluorophenyl , 3 -fluorophenyl , 4- cyanophenyl , 2 -methoxyphenyl , 3 -methoxyphenyl , 4 - methoxyphenyl, 4 -chlorophenyl, 3 , 4-difluorophenyl , 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl, 3- methyl -4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl , 3- chloro-4-methylphenyl , 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4 -dichlorophenyl, 6- (2-oxo) -1 , 2 , 3 , 4- tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4- bromophenyl, 2- (5-chloro-3-methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5-[3-(3',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ' , 4 ' - dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole;
R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N,N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl ; or
R5 and R6 together with the triazole ring of Formula (I)
form a ring structure selected from the group consisting of the structure
Figure imgf000224_0001
and the structure
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1 , 4-phenylene, 2-methoxy-l, 4- phenylene, 2 -chloro-1, 4-phenylene, 1 , 4-phenylene, 2- methoxy-4 -chloro-1 , 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l, 3 -phenylene, 2-chloro- 1, 3 -phenylene, 4-chloro-l, 3 -phenylene, 6 -chloro-1, 3- phenylene, 5 -carboxy-1, 3 -phenylene, 5 -methoxycarbonyl - 1, 3 -phenylene, 2 , 6-dimethoxy-l , 3 -phenylene, 2 , 5-dichloro- 1 , 3 -phenylene, 2 -bromo-1 , 3 -phenylene, 6 -bromo- 1,3- phenylene and 2 , 6-dimethoxy-5-chloro-l, 3 -phenylene; and
R8 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl, 4 -methylbenzyl , 2-fluorobenzyl, 3-fluorobenzyl , 4-fluorobenzyl, 3 - ( 1- imidazole) propyl , 4 -aminomethylbenzyl , 4 -methoxybenzyl , 3 -chlorobenzyl , 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4 -pyridinemethyl , 3 -pyridinemethyl , 2 -1hiophenemethyl , phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl , 2 - (4 -chlorophenyl ) ethyl , 2 - (3 -chlorophenyl ) ethyl , 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl , 3- (2 -pipecolinyl) propyl, 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl -1 -propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl , benzoyl, crotonyl, cyclobutanecarbonyl, cyclohexanepropionyl,
4-cyanobenzoyl, hydrocinnamyl , 4-dimethylaminobenzoyl , 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl , p-tolylacetyl , picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl , tetrahydro-3-furoyl, trans-3- (3 -pyridyl) acrylyl, trimethylacetyl, triphenylacetyl, nicotinyl, (3 , 4 -dimethoxyphenyl) acetyl , boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl , (methylthio) acetyl, (phenylthio) acetyl ,
1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl-1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1 , 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl , 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl , 3 , 4-dichlorobenzoyl , 4- isopropylbenzoyl, 3 , 4-dichlorophenylacetyl ,
4 -tert-butyl -cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5, 5-trimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl,
5-bromo-2-chlorobenzoyl, 5-bromonicotinyl ,
6-chloronicotinyl , 3 , 5-dimethyl-p-anisyl,
3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl , 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl,
3-fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl,
3 -methyl-2 -thiophenecarbonyl , 3 -phenoxybenzoyl ,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert -butyl -4 -hydroxybenzoyl, 3 , 5 -dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl,
5-methylsalicylyl , 2 -methylcyclopropanecarbonyl ,
3-lndolepropionyl , 2 , 2-diphenylacetyl ,
5 -methoxyindole-2 -carbonyl, succinamyl ,
4 -dimethylaminobutyryl , 4- methylthiobenzoyl, 2-methylthionicotinyl, r ( - ) -2-oxothiazolidine-4-carbonyl ,
4 -nitrophenylacetyl , coumarin-3 -carbonyl ,
1-cyano-1-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl,
2- (2 -cyanophenylthio) benzoyl, 2-mesitylenesulfonyl, 2-naphthalenesulfonyl, 2-thiophenesulfonyl ,
4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl ,
4 -methoxybenzenesulfonyl ,
4 -methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl , 2-acetamido-4-methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl,
2 , 3 -dichlorothiophene-5-sulfonyl ,
3 , 4 -dimethoxybenzenesulfonyl , 3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl ,
2,3, 4-trifluorobenzenesulfonyl, 2 , 4 -dichlorobenzenesulfonyl,
2, 5 -dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl, 2 , 6-difluorobenzenesulfonyl , 2 -chloro-4- (trifluoromethyl) benzenesulfonyl, 2 -chloro-5- (trifluoromethyl) benzenesulfonyl, 2 -chloro- 6 -methylbenzenesulfonyl , 3 , 4 -difluorobenzenesulphonyl , 3 , 5 -dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl, 4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl, 2- (methoxycarbonyl) thiophene-3 -sulfonyl, 4 -acetamido-3 -chlorobenzene sulfonyl , 2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl , 5- (isoxazol-3-yl) thiophene-2 -sulfonyl , 4-cyanobenzene sulfonyl, 3 -chloro-4 -methylbenzenesulfonyl, 2 , 4-difluorobenzenesulfonyl , 2-fluorobenzenesulfonyl, 4-isopropylbenzene sulfonyl, 2 , 5 -dimethoxybenzenesulfonyl , 3 , 4 -dichlorobenzenesulfonyl , (2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -2- (carbamyl) -3 -tert -butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3-methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester, (s) -2- (carbamyl) -3 - phenylpropionate methyl ester, 1- (carbamyl) -tridecafluoro- 1-hexane, 1 - (carbamyl) -1,1,3,3 -1etramethylbutane , 1- (carbamyl) - (1-naphthyl) ethane, 1- (carbamyl) - (4 -bromophenyl) ethane, 1- (carbamyl) -adamantane, 1- (carbamyl) naphthalene, 1- (carbamyl) -2,3, 4-trifluorobenzene, 1- (carbamyl) -2 , 3 -dichlorobenzene, 1- (carbamyl) -2 , 3 -dimethylbenzene, 1 - (carbamyl ) -2,4,5 -1richlorobenzene , -2,4, 5-trimethylbenzene, -2,4, 6-trichlorobenzene,
-2, 4 -dichlorobenzene, 1- (carbamyl) -2,4- ene, 1- (carbamyl) -2 , 4-dimethoxybenzene, -2, 4 -dimethylbenzene, -2, 5-dichlorobenzene, -2 , 5-difluorobenzene, -2 , 5-dimethoxybenzene, -2,5- dimethylbenzene, -2 , 6-dibromo-4-fluorobenzene, -2 , 6 -dibromo-4-isopropylbenzene, -2 , 6 -dichlorobenzene, -2 , 6-diethylbenzene, -2 , 6-difluorobenzoyl, -2 , 6-difluorobenzene, -2 , 6-diisopropylbenzene, -2 , 6-dimethylbenzene , -2- (chloromethyl) benzene, -2- (difluoromethoxy) benzene, -2- (methylthio) benzene, -2- (trifluoromethoxy) benzene, -2- (trifluoromethyl) enzene, -2-biphenyl,
-2-bromo-4 , 6-difluorobenzene, -2-bromoethane, 1- (carbamyl) -2-bromobenzene, -2-chloro-4 -nitrobenzene, -2-chloro-5- (trifluoromethyl) benzene, -2 -chloro-5 -nitrobenzene , -2 -chloro- 6 -methylbenzene ,
-2 -chlorobenzyl , 1- (carbamyl) -2 -chloroethane , -2 -chlorobenzene , -2 -cyanobenzene , -2 -ethoxybenzene , -2-ethyl - 6 -methylbenzene , -2 -ethylbenzene , 2-fluoro-3 - (trifluoromethyl) benzene,
Figure imgf000228_0001
2-fluoro-5- (trifluoromethyl) benzene, -2 - fluoro-5 -methylbenzene , -2 - fluoro-5 -nitrobenzene , -2-fluoro-6- (trifluoromethyl) benzene, -2-fluorobenzene, 1- (carbamyl) -2-iodobenzene, -2 -isopropyl-6-methylbenzene, -2- isopropylbenzene, -2 -methoxy-5-chloro benzene, -2 -methoxy-5-methylbenzene , -2-methoxy- 5-nitrobenzene , -2-methoxybenzene, -2 -methyl-3 -nitrobenzene, -2-methyl-5-nitrobenzene , -2 -methyl - 6 -1-butylbenzene , -1- (2 -methylphenyl) methane, -2-n-propylbenzene,
-2-naphthalene, 1- (carbamyl) -2-nitrobenzene, -2 -phenoxybenzene , -2 -tert -butylbenzene , -3,4, 5-trimethoxybenzene, -1- (3 , 4 -dichlorophenyl) methane, -3 , 4 -dichlorobenzene, -3 , 4-difluorobenzene, -3 , 4 -dimethylbenzene, -3 , 5-bis (trifluoromethyl) benzene, -3,5- dichlorobenzene, -3 , 5-dimethoxybenzene,
-3,5-dimethylbenzene , 1 - (carbamyl) -3,5- e, 1- (carbamyl) -3- (methylthio) benzene, -3- (trifluoromethyl) benzene, -3- (trifluoromethylthio) benzene, -3-acetylbenzene,
-3 -bromobenzene, 1- (carbamyl) -3-bromopropane, -3 -carbomethoxybenzene , -3 -chloro-2 -methoxybenzene, -3 -chloro-2 -methylbenzene , -3 -chloro-4 - fluorobenzene ,
Figure imgf000229_0001
-3 -chloro-4 -methylbenzene , - (carbamyl) -3 -chlorobenzene, - (carbamyl) -3 -chloropropane, - (carbamyl) -3-cyanobenzene, - (carbamyl) -3 -cyclopentoxy-4 -methoxybenzene , - (carbamyl) -3 -ethylbenzene, - (carbamyl) -3-fluoro-4 -methylbenzene, - (carbamyl) -3-fluorobenzene, 1- (carbamyl) -3-iodopropane, - (carbamyl) benzoyl chloride, - (carbamyl) -3 -methoxybenzene, - (carbamyl) - (3 -methylphenyl) methane, - (carbamyl) -3 -nitrobenzene, 1- (carbamyl) -3-pyridine, ' - (carbamyl) -5 ' -nitrobenzo-15-crown-5, ' - (carbamyl) benzo-15-crown-5, ' - (carbamyl) benzo-18-crown-6 , - (carbamyl -4 , 5 -dimethyl -2 -nitrobenzene, - (carbamyl -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert-butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) benzene, - (carbamyl -4- (trifluoromethylthio) benzene, - (carbamyl -4-acetylbenzene, - (carbamyl -4 -benzyloxybenzene , - (carbamyl -4 -bromo-2 , 6 -dimethylbenzene, - (carbamyl -4-bromo-2- (trifluoromethyl) benzene, - (carbamyl -4 -bromo-2 -chlorobenzene , - (carbamyl -4 -bromo-2 -fluorobenzene, - (carbamyl -4 -bromo-2 -methylbenzene , - (carbamyl -4 -bromobenzene , - (carbamyl -4 -chloro-2- (trifluoromethyl) benzene, - (carbamyl -4 -chloro-2 -methoxybenzene , - (carbamyl -4 -chloro-2 -methylbenzene, - (carbamyl -4 -chloro-2 -nitrobenzene , - (carbamyl -4 -chloro-3- (trifluoromethyl) benzene, 1- -4 -chloro-3 -nitrobenzene ,
1- -4 -chlorobenzene ,
1- -4 -dimethylaminobenzene ,
1- -4-ethoxybenzene,
1- -4-ethylbenzene,
1- -4-fluoro-2- (trifluoromethyl) benzene,
1- -4 -fluoro-2 -nitrobenzene,
1- -4-fluoro-3- (trifluoromethyl) benzene,
1- -4-fluoro-3 -nitrobenzene,
1- -4-fluorobenzoyl,
1- -4-fluorobenzyl,
1- -4 - fluorobenzene ,
1- -4-heptyloxybenzene,
1- -4-iodobenzene,
1- -4 -isopropylbenzene ,
1- -4 -methoxy-2 -methylbenzene ,
1- - (4 -methoxyphenyl ) methane ,
1- -4 -methoxybenzene,
1- -4 -methyl-2-nitrobenzene ,
1- -4 -methyl-3 -nitrobenzene,
1- - (4 -methylphenyl) methane,
1- -4-n-butoxycarbonylbenzene,
1- -4-n-butoxybenzene,
1- -4 -n-butyl-2 -methylbenzene ,
1- -4-n-butylbenzene,
1- -4 -nitrobenzene ,
1- -4-phenoxybenzene,
1- -5 -bromopenane ,
1- -5-chloro-2 , 4-dimethoxybenzene,
1- -5 -chloro-2 -methylbenzene,
1- -5 -fluoro-2 -methylbenzene ,
1- -5-iodopentane, 1- (carbamyl) -2-propene, ben
1- carbamyl -cyclohexane, carboxyethylcarbamyl, ethyl
2- carbamyl -3-methylbutyrate, ethyl
2- carbamyl -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio butyrate, ethyl 2- (carbamyl) -4-methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl 3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl 4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate, 1- (carbamyl) -ethyl, ethyl (carbamyl) acetate, 1- (carbamyl) -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2-methylethane, methyl 2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl (carbamyl) acetate, 1- (carbamyl) -propane, 1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene , 1 - (carbamyl ) -2,2-dimethylpropane , 1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate and carbamyltrichloromethane .
17. The combinatorial library of claim 1, wherein q is 0 or 1;
Rx is a hydrogen atom;
R2 is a hydrogen atom;
R3 is selected from the group consisting of 1,2-ethylene, 1, 3-propylene, 1, 4-butylene, 1, 5-pentylene, 1 , 6-hexylene, 1, 7-heptanylene, 1 , 8-octanylene, cyclohexyl -4 -methylene, 1 -methyl-1, 1-ethylene, D-1 , 1-butylene, D-1, 1-ethylene, D- 1, 1-pentylene, D-1, 1-propylene, D-5-amino-l, 1-pentylene, D-l-amino-1, 5-pentylene, D-2- (2-napthyl) -1 , 1-ethylene, D- 2- (2-thienyl) -1, 1-ethylene, D-2- (4-ethoxyphenyl) -1, 1- ethylene, D-2- (4-fluoropehnyl) -1 , 1-ethylene, D-2- (4- hydroxyphenyl) -1, 1-ethylene, D-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, D-2 -carboxamide-1 , 1-ethylene, D-2- carboxamide-1, 2 -ethylene, D-2 -carboxy-1, 2-ethylene, D-2- cyclohexyl-1, 1-ethylene, D-2 -hydroxy-1, 1-ethylene, D-2- hydroxy-1, 1-ethylene, D-2 -hydroxy-1, 1-propylene, D-2- mercapto-1, 1-ethylene, D-2-methyl-l, 1-butylene, Dimethyl-1, 1-propylene, D-2-phenyl-l, 1-ethylene, D-3- carboxamido-1, 1-propylene, D-3 -carboxamido-1, 3-propylene, D-3 -carboxy-1, 1-propylene, D-3 -carboxyl-1, 3-propylene, D- 3 -methyl-1, 1-butylene, D-4-ureido-l, 1-butylene, D-5- (9- fluorenylmethoxycarboxamido) -1, 1-pentylene, D-5- acetamiode-1, 1-pentylene, D-5-amino-l, 1-pentylene, D- methylthio-1, 1-propylene, phenylmethylene, D- - butylmethylene, 1,2-ethylene, 1, 3-propylene, 1,4- butylene, 1 , 5-pentylene, 1 , 6-hexylene, 1-methyl-1, 1- ethylene, L-l, 1-butylene, L-l, 1-ethylene, L-1,1- pentylene, 1, 1-propylene, L-5-amino-l , 1-pentylene, L-l- amino-1, 5-pentylene, L-2- (2-napthyl) -1, 1-ethylene, L-2- (2-thienyl) -1, 1-ethylene, L-2- (4-ethoxyphenyl) -1, 1- ethylene, L-2- (4-fluoropehnyl) -1 , 1-ethylene, L-2- (4- hydroxyphenyl) -1 , 1-ethylene, L-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, L-2 -carboxamide-1, 1-ethylene, L-2- carboxamide-1, 2 -ethylene, L-2 -carboxy-1, 2-ethylene, L-2- cyclohexyl-1, 1-ethylene, L-2 -hydroxy-1, 1-ethylene, L-2- hydroxy-1, 1-ethylene, L-2 -hydroxy-1, 1-propylene, L-2- mercapto-1, 1-ethylene, L-2-methyl-l , 1-butylene, L-2- methyl-1 , 1-propylene, L-2-phenyl-l, 1-ethylene, L-3- carboxamido-1 , 1-propylene, L-3 -carboxamido-1, 3 -propylene, L-3 -carboxy-1 , 1-propylene, L-3 -carboxyl-1, 3 -propylene, L- 3 -methyl -1, 1-butylene, L-4-ureido-l , 1-butylene, L-5- (9- fluorenylmethoxycarboxamido) -1, 1-pentylene, L-5- acetamiode-1, 1-pentylene, L-5-amino-1, 1-pentylene, methylthio- 1 , 1-propylene, L-phenylmethylene, L-t- butylmethylene, 3 -methoxy-1, 4-phenylene, 2-methoxy-l, 4- phenylene, 2 -chloro-1, 4-phenylene, 1, 4-phenylene, 2- methoxy-4 -chloro-1 , 4-phenylene, 4-methoxy-l , 3 -phenylene, 2 -chloro-1, 3 -phenylene, 4-chloro-l , 3 -phenylene, 6-chloro- 1 , 3 -phenylene, 5 -carboxy-1, 3 -phenylene, 5- methoxycarbonyl -1 , 3 -phenylene, 2 , 6-dimethoxy-l, 3 - phenylene, 2 , 5-dichloro-l, 3 -phenylene, 2 -bromo-1,3- phenylene, 6 -bromo-1, 3 -phenylene and 2 , 6-dimethoxy-5- chloro-1, 3 -phenylene; or
R3 is of the formula (II), (III), (IV) or (V):
Figure imgf000234_0001
^ N 3 \
Figure imgf000234_0002
R 13
(IV) (V) wherein n is 1 ; m is 3 or 4 ;
Ri2 is a hydrogen atom;
RX 3 is a hydrogen atom; and
R14 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl , 4 -methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl , 4-fluorobenzyl, 3 - ( 1 - imidazole) propyl , 4 -aminomethylbenzyl , 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4 -pyridinemethyl , 3 -pyridinemethyl , 2 -1hiophenemethyl , phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2 - (4 -chlorophenyl) ethyl , 2 - (3 -chlorophenyl ) ethyl , 2- (2 -chlorophenyl) ethyl, 2, 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl,
2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl , 3- (diethylamino) propyl, 2- (5-nitro-2 -pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl , 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl , 3- (pyrrolidin-2 -one-1-yl) propyl , 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2-methyl-2-phenylethyl, 4-phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl , benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl , isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl , nicotinyl,
(3 , 4 -dimethoxyphenyl) acetyl , boc-isonipecotyl , (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl , (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl , 1-adamantaneacetyl, 1-naphthylacetyl, l-phenyl-1- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl , 4 -methyl -1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4-dichlorophenylacetyl , 4 -tert-butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5,5-trimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl, 5 -bromo-2 -chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl , 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl, 3 -fluoro-4 -methylbenzoyl , 1- isoquinolinecarbonyl , 3-methyl-2-thiophenecarbonyl, 3-phenoxybenzoyl,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl, 3 , 5-dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3-lndolepropionyl , 2 , 2-diphenylacetyl, 5-methoxyindole-2-carbonyl, succinamyl , 4 -dimethylaminobutyryl , 4 -methylthiobenzoyl , 2-methylthionicotinyl, r (-) -2-oxothiazolidine-4-carbonyl , 4 -nitrophenylacetyl , coumarin-3 -carbonyl , 1-cyano-l-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl , 2- (2-cyanophenylthio) benzoyl, 2-mesitylenesulfonyl, 2 -naphthalenesulfonyl , 2 -thiophenesulfonyl , 4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl , 4-methoxybenzenesulfonyl,
4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2-acetamido-4-methyl-5-thiazolesulfonyl, 4- (trifluoromethoxy) benzenesulfonyl , 4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl, 2 , 3 -dichlorothiophene-5-sulfonyl, 3 , 4 -dimethoxybenzenesulfonyl , 3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5-dichlorothiophene-3-sulfonyl,
2 , 6-dichlorobenzenesulfonyl , 2 , 6 -difluorobenzenesulfonyl ,
2-chloro-4- (trifluoromethyl) benzenesulfonyl, 2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro- 6 -methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5-dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl,
4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl,
2- (methoxycarbonyl) thiophene-3 -sulfonyl,
4 -acetamido-3 -chlorobenzene sulfonyl ,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl , 3-methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl,
5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl,
4 -isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl and 3 , 4 -dichlorobenzenesulfonyl ; or
Ri4 is of the formula:
Figure imgf000237_0001
wherein R15 is selected from the group consisting of a hydrogen atom, methyl, t-butyl, carbomethoxymethyl, ethyl, carboethoxymethyl , carboxy, trifluormethyl, carboethoxy, phenyl, 4 -methylphenyl, 4-fluorophenyl, 3- fluorophenyl, 4-cyanophenyl, 2 -methoxyphenyl , 3- methoxyphenyl, 4-methoxyphenyl, 4 -chlorophenyl , 3,4- difluorophenyl, 4-nitrophenyl, 3 , 4-dihydroxyphenyl, 3- nitrophenyl, 3-methyl-4-chlorophenyl, adamantyl, 2,5- dimethoxyphenyl , 3 -chloro-4 -methylphenyl, 5- (3- carboethoxy) isoxazole, 4-phenylphenyl, 3,4- dichlorophenyl, 6- (2-oxo) -1, 2, 3 , 4-tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4 -bromophenyl, 2-(5-chloro- 3 -methyl ) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) - 1, 2, 3 , 4-tetrahydronaphthalene, 4 -chlorophenyl, 1-pyrene, 5- [3- (3 ' ,4 ' -dichlorophenyl) ] isoxazole, 5- [3- (2 ',4'- dichlorophenyl) ] isoxazole and 5- (3 -phenyl) isoxazole; and Ri6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N,N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or Ri4, RX5 and R16 together form a ring structure selected from the group consisting of the structure
Figure imgf000238_0001
and the structure
Figure imgf000238_0002
R4 is selected from the group consisting of a hydrogen atom and acetyl ; or
R3, R4 together with the nitrogen atom of Formula (I form a pyrrolidine ring; R5 is selected from the group consisting of methyl, t- butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl , carboethoxy, phenyl, 4- methylphenyl, 4-fluorophenyl, 3-fluorophenyl , 4- cyanophenyl, 2 -methoxyphenyl, 3 -methoxyphenyl, 4- methoxyphenyl , 4 -chlorophenyl, 3 , 4-difluorophenyl, 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl, 3- methyl-4 -chlorophenyl , adamantyl, 2 , 5-dimethoxyphenyl, : chloro-4 -methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4-dichlorophenyl , 6- (2-oxo) -1, 2 , 3 , 4- tetrahydroquinoline, 4- (5-methyl -3 -phenyl) isoxazole, 4- bromophenyl, 2- (5 -chloro-3 -methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5-[3-(3',4'- dichlorophenyl ) ] isoxazole , 5- [3 - (2 ' , 4 ' - dichlorophenyl) ] isoxazole and 5- (3 -phenyl) isoxazole;
R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N,N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or
R5 and R6 together with the triazole ring of Formula (I) form a ring structure selected from the group consisting of the structure
Figure imgf000239_0001
and the structure
Figure imgf000239_0002
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1, 4-phenylene, 2-methoxy-l, 4- phenylene, 2 -chloro-1, 4-phenylene, 1, 4-phenylene, 2- methoxy-4-chloro-l, 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l, 3 -phenylene, 2-chloro- 1, 3 -phenylene, 4-chloro-l, 3 -phenylene, 6-chloro- 1, 3- phenylene, 5-carboxy-1, 3 -phenylene, 5-methoxycarbonyl- 1, 3 -phenylene, 2 , 6-dimethoxy-l , 3 -phenylene, 2 , 5-dichloro- 1, 3 -phenylene, 2 -bromo-1, 3 -phenylene, 6 -bromo- 1,3- phenylene and 2 , 6-dimethoxy-5 -chloro-1, 3 -phenylene; and
R8 is selected from the group consisting of a hydrogen atom and acetyl .
18. The combinatorial library of claim 1, wherein q is 0 or 1;
Rx is a hydrogen atom;
R2 is a hydrogen atom;
R3 is of the formula (II), (III), (IV) or (V):
Figure imgf000240_0001
14 (ID (III)
Figure imgf000241_0001
R13
(IV) (V)
wherein n is 1; m is 3 or 4;
R12 is a hydrogen atom;
R13 is a hydrogen atom; and
R1 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl , 4 -methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3 - (1 - imidazole) propyl , 4 -aminomethylbenzyl , 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl , 4-bromobenzyl, cyclopropyl, cyclopropanemethyl,
4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl , 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5 -nitro-2 -pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2-pipecolinyl) propyl, 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl, cyclohexanepropionyl,
4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl , 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3 -pyridyl) acrylyl, trimethylacetyl , triphenylacetyl, nicotinyl, (3 , 4 -dimethoxyphenyl) acetyl, boc-isonipecotyl , (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl, (phenylthio) acetyl,
1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-1- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl- 1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl , 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl, 3 , 4-dichlorophenylacetyl,
4 -tert-butyl-cyclohexanecarbonyl , 4-sulfonamidobenzoyl, 3,5,5-trimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl, 5-bromo-2-chlorobenzoyl , 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl,
3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl , 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl , 3-cyanobenzoyl, 3 -fluoro-4 -methylbenzoyl , 1 - isoquinolinecarbonyl ,
3 -methyl-2 -thiophenecarbonyl , 3 -phenoxybenzoyl ,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4 -hydroxybenzoyl, 3 , 5 -dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl,
5-methylsalicylyl, 2-methylcyclopropanecarbonyl,
3 - lndolepropionyl , 2 , 2-diphenylacetyl ,
5-methoxyindole-2 -carbonyl, succinamyl,
4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r ( - ) -2-oxothiazolidine-4-carbonyl,
4 -nitrophenylacetyl , coumarin-3 -carbonyl ,
1-cyano- 1-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl,
2- (2-cyanophenylthio) benzoyl, 2-mesitylenesulfonyl, 2-naphthalenesulfonyl , 2-thiophenesulfonyl,
4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl ,
4 -methoxybenzenesulfonyl ,
4 -methylsulfonylbenzenesulfonyl, benzenesulfonyl , dansyl, n-acetylsulfanilyl , 2 -acetamido-4 -methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl ,
2 , 3 -dichlorothiophene-5 -sulfonyl,
3 , 4 -dimethoxybenzenesulfonyl , 3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 - fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl ,
2,3, 4 -trifluorobenzenesulfonyl , 2 , 4 -dichlorobenzenesulfonyl ,
2 , 5-dichlorothiophene-3-sulfonyl,
2 , 6-dichlorobenzenesulfonyl, 2 , 6-difluorobenzenesulfonyl,
2 -chloro-4- (trifluoromethyl) benzenesulfonyl ,
2-chloro-5- (trifluoromethyl) benzenesulfonyl , 2 -chloro-6-methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl , 3 , 5-dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl , 4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl, 2- (methoxycarbonyl) thiophene-3 -sulfonyl, 4 -acetamido-3 -chlorobenzene sulfonyl,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3 -methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl, 5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl, 3 -chloro-4 -methylbenzenesulfonyl,
2 , 4 -difluorobenzenesulfonyl , 2 -fluorobenzenesulfonyl ,
4 -isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl and 3 , 4 -dichlorobenzenesulfonyl ;
R4 is selected from the group consisting of a hydrogen atom and acetyl; or
R3, R4 together with the nitrogen atom of Formula (I) form a pyrrolidine ring;
R5 is selected from the group consisting of methyl, t- butyl, carbomethoxymethyl , ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4- methylphenyl, 4-fluorophenyl , 3-fluorophenyl , 4- cyanophenyl, 2-methoxyphenyl , 3 -methoxyphenyl, 4- methoxyphenyl , 4 -chlorophenyl, 3 , 4-difluorophenyl, 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl, 3- methyl-4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, 3- chloro-4 -methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4-dichlorophenyl, 6- (2-oxo) -1 , 2 , 3 , 4- tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4- bromophenyl, 2- (5-chloro-3-methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, .4- chlorophenyl , 1-pyrene, 5-[3-(3',4'- dichlorophenyl) ] isoxazole, 5-[3-(2',4'- dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole; R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N,N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or
R5 and R6 together with the triazole ring of Formula (I) form a ring structure selected from the group consisting of the structure
Figure imgf000245_0001
and the structure
Figure imgf000245_0002
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1, 4-phenylene, 2-methoxy-l , 4- phenylene, 2 -chloro-1 , 4-phenylene, 1, 4-phenylene, 2- methoxy-4 -chloro-1, 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l, 3 -phenylene, 2-chloro- 1, 3-phenylene, 4-chloro-l, 3 -phenylene, 6-chloro-l, 3- phenylene, 5 -carboxy-1, 3-phenylene, 5 -methoxycarbonyl- 1, 3-phenylene, 2 , 6-dimethoxy-l, 3-phenylene, 2 , 5-dichloro- 1, 3-phenylene, 2 -bromo-1 , 3-phenylene, 6 -bromo-1,3- phenylene and 2 , 6-dimethoxy-5-chloro-l, 3-phenylene ; and
R8 is selected from the group consisting of a hydrogen atom and acetyl .
19. A single compound of the structure:
Figure imgf000246_0001
( i )
wherein :
q is an integer selected from 0, 1 or 2 ;
Rx is selected from the group consisting of a hydrogen atom and a functionalized resin;
R2 is selected from the group consisting of a hydrogen atom, Ci to C6 alkyl, Cj to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle;
or Rlf N and R2 together is one of the following formulae :
Figure imgf000247_0001
Figure imgf000247_0002
wherein R9 is selected from the group consisting of a hydrogen atom and a functionalized resin; and
R3 is selected from the group consisting of C2 to C8 alkylene, Cx to C8 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, C4 to C10 cycloalkylalkylene, C4 to C10 substituted cycloalkylalkylene, C7 to C12 phenylalkylene and C7 to C12 substituted phenylalkylene; or R3 is of the formula:
Figure imgf000248_0001
R10 R11
wherein:
Rio and Rn are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, Cj to C7 acyl, Cx to C7 substituted acyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C7 to
C12 phenylalkyl, C7 to C12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C2 to C7 alkylene, substituted cyclic C2 to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene, hydroxymethyl and protected hydroxymethyl, provided that R10 and Rn are not both hydrogen atoms; or
Rio and Rn together with the carbon atom in between R10 and Rn form a ring selected from the group consisting of a C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, a heterocyclic ring and substituted heterocyclic ring; or
R3 is of the formula ( I I ) or ( I I I ]
Figure imgf000249_0001
N
R 13 \
Figure imgf000249_0002
wherein n is an integer selected from 0 to 4; R12 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, cyano, Cx to C6 alkyl, C to C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, Cx to C7 alkylaminocarbonyl, C to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide and trifluoromethyl; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C substituted alkenyl, C7 to C12 phenylalkyl and C7 to C12 substituted phenylalkyl; and R14 is selected from the group consisting of a hydrogen atom, C: to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl , Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or R14 is of the formula:
Figure imgf000250_0001
wherein R15 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, C: to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, C: to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; and R16 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, C: to C7 acyl, Cx to C7 substituted acyl, Cx to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; or R15 and R16 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or R15 and R16 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; or
R3 is of the formula (IV) or (V)
Figure imgf000251_0001
Figure imgf000251_0002
Figure imgf000251_0003
IV) (V)
wherein :
m is an integer selected from 1 to 8; R13 and R14 are each the same as described herein above;
R is selected from the group consisting of a hydrogen atom, C: to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, C: to C7 substituted alkylsulfonyl , Cα to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl , substituted phenylsulfonyl , Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or
R3 and R4 together with nitrogen atom in between R3 and R4 form a ring selected from the group consisting of a heterocycle and substituted heterocycle;
R5 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C7 acyl, Cx to C7 substituted acyl, Cx to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl;
R6 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Cx to C7 substituted acyl, Cx to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; or R5 and R6 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or
R5 and R6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl;
R7 is selected from the group consisting of Cx to C8 alkylene, Cx to C8 substituted alkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, heteroarylene and substituted heteroarylene; and
R8 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl, Cx to C7 acyl, Ci to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C: to C7 alkylaminocarbonyl, Ci to C substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or
a pharmaceutically acceptable salt thereof.
20. The single compound of claim 19, wherein R3 is of the formula (II) or (III) :
Figure imgf000254_0001
wherein n is an integer selected from 0 to 4; Ri2 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, cyano, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, C: to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, carboxamide, protected carboxamide and trifluoromethyl ; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C: to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl and C7 to Ci2 substituted phenylalkyl; and Ri4 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to Ci2 phenylalkyl, C7 to C12 substituted phenylalkyl, Cα to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl, Ci to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl , Cx to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or R14 is of the formula:
Figure imgf000255_0001
wherein R15 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Cx to C7 acyl, Cx to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Ci to C7 substituted alkoxycarbonyl, C: to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; and Ri6 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, carboxy, protected carboxy, cyano,
(monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, Ci to C7 acyl, Cx to C7 substituted acyl, Ci to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, C: to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, heterocycle, substituted heterocycle, naphthyl and substituted naphthyl; or Ri5 and Ri6 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or Ri5 and Rx 6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; or R3 is of the formula (IV) or (V) :
Figure imgf000256_0001
(IV) (V)
wherein:
m is an integer selected from 1 to 8; R13 and Ri4 are each the same as described herein above; and
R4 is selected from the group consisting of a hydrogen atom, Ci to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 alkylsulfonyl, Cx to C7 substituted alkylsulfonyl , C to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C to C7 alkylaminocarbonyl, Ci to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl; or R3 and R4 together with nitrogen atom in between R3 and R4 form a ring selected from the group consisting of a heterocycle and substituted heterocycle.
21. The single compound of claim 19, wherein R3 is selected from the group consisting of Cx to C8 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, C4 to C10 cycloalkylalkylene, C4 to C10 substituted cycloalkylalkylene, C7 to C12 phenylalkylene and C7 to C12 substituted phenylalkylene; or R3 is of the formula:
Figure imgf000257_0001
R10 Rπ1
wherein :
Rio and Rn are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, Cx to C7 acyl, Cx to C7 substituted acyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, C to
C12 phenylalkyl, C7 to C12 substituted phenylalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C2 to C7 alkylene, substituted cyclic C2 to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene, hydroxymethyl and protected hydroxymethyl, provided that R10 and Rn are not both hydrogen atoms ; or
Rio and Rn together with the carbon atom in between R10 and Rn form a ring selected from the group consisting of a C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, a heterocyclic ring and substituted heterocyclic ring.
22. The single compound of claim 19, wherein R3 is selected from the group consisting of C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 substituted alkynylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, heteroarylene, substituted heteroarylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, C4 to C10 cycloalkylalkylene, C4 to C10 substituted cycloalkylalkylene, C7 to C12 phenylalkylene and C7 to C12 substituted phenylalkylene.
23. The single compound of claim 19, wherein q is 1 or 2.
24. The single compound of claim 19, wherein R5 and R6 together are fused with the thiazole ring to form a second ring which is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring or substituted heterocyclic ring; or R5 and R6 together are fused with the thiazole ring to form a fused tricyclic system, where the second ring which is directly fused to the thiazole ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring and substituted heterocyclic ring, and the third ring which is directly fused to the second ring is selected from the group consisting of a C5 to C7 cycloalkyl, C5 to C7 substituted cycloalkyl, C5 to C7 cycloalkenyl, C5 to C7 substituted cycloalkenyl, heterocyclic ring, substituted heterocyclic ring, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl.
25. The single compound of claim 19, wherein q is 0 or 1;
R is of the formula:
Figure imgf000259_0001
R10 R11
wherein:
R10 and RX1 are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C3 to C7 cycloalkyl, substituted C3 to C7 cycloalkyl, hydroxymethyl and protected hydroxymethyl, provided that both R10 and Rn are not hydrogen atoms ; or
R10 and Rn together with the carbon atom in between R10 and Rn form a ring selected from the group consisting of
C3 to C7 cycloalkyl and substituted C3 to C7 cycloalkyl; or
R3 is of the formula (II) or (III) :
Figure imgf000260_0001
wherein n is an integer selected from 1 or 2; R12 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, Cx to C7 alkyl, Cx to C substituted alkyl, Cx to C7 alkoxy and Cx to C7 substituted alkoxy; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl; and R14 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C to C6 substituted alkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl ; or R3 is of the formula (IV) or (V)
Figure imgf000261_0001
Figure imgf000261_0002
(IV) (V) wherein: m is an integer selected from 1 to 5; and R13 and R14 are the same as described herein;
R4 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl;
R7 is selected from the group consisting of phenylene and substituted phenylene; and
R8 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl; or
a pharmaceutically acceptable salt thereof.
26. The single compound of claim 19, wherein q is 0 or 1
27. The single compound of claim 19, wherein R3 is of the formula:
Figure imgf000261_0003
R10 R11 wherei : R:o and Ru are, independently, selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C3 to C7 cycloalkyl, substituted C3 to C7 cycloalkyl, hydroxymethyl and protected hydroxymethyl, provided that both R10 and Rn are not hydrogen atoms; or
R10 and Ru together with the carbon atom in between R10 and Rn form a ring selected from the group consisting of C3 to C7 cycloalkyl and substituted C3 to C7 cycloalkyl .
28. The single compound of claim 19, wherein R3 is of the formula (II) or (III) :
Figure imgf000262_0001
wherein n is an integer selected from 1 or 2; R12 is selected from the group consisting of a hydrogen atom, halogen, hydroxy, protected hydroxy, Cx to C7 alkyl, Cx to C7 substituted alkyl, Cx to C7 alkoxy and Cx to C7 substituted alkoxy; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cj to C6 substituted alkyl; and R14 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C: to C6 substituted alkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C7 alkylaminocarbonyl, Cx to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl .
29. The single compound of claim 19, wherein R3 is of the formula (IV) or (V) :
Figure imgf000263_0001
Figure imgf000263_0002
(IV) (V) wherein: m is an integer selected from 1 to 5; R13 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl; and R14 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, Ci to C6 substituted alkyl, Cx to C7 acyl, C: to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C: to C alkylaminocarbonyl, C: to C7 substituted alkylaminocarbonyl, phenylaminocarbonyl and substituted phenylaminocarbonyl.
30. The single compound of claim 19, wherein R4 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl.
31. The single compound of claim 19, wherein R7 is selected from the group consisting of phenylene and substituted phenylene.
32. The single compound of claim 19, wherein R8 is selected from the group consisting of a hydrogen atom, Cx to C6 alkyl and Cx to C6 substituted alkyl .
33. The single compound of claim 19, wherein q is 0 or 1 ;
Rx is selected from the group consisting of a hydrogen atom and polystyryl 4-methylbenzhydryl ;
R2 is selected from the group consisting of a hydrogen atom, 2- (1-pyrrolidino) ethyl, 2-pyridinemethyl, 2- (4-imidazole) ethyl, cyclopentyl, allyl, 2-methoxyethyl, (+/- ) -tetrahydrofuryl, benzyl, 2 -methylbenzyl , 3 -methylbenzyl, 4 -methylbenzyl, 2-fluorobenzyl , 3 -fluorobenzyl, 4-fluorobenzyl, 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl , 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl , piperonyl, 4-methoxyphenethyl, 2-fluorophenethyl , 2- (4 -chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl , 2,4- dichlorophenethyl, 2- (diethylamino) ethyl ,
2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl , 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) ropyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1 -propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl and piperazine; R3 is selected from the group consisting of 1,2-ethylene, 1, 3-propylene, 1, 4-butylene, 1, 5-pentylene, 1, 6-hexylene, 1, 7-heptanylene, 1, 8-octanylene, cyclohexyl-4 -methylene, 1-methyl-l, 1-ethylene, D-1, 1-butylene, D-1, 1-ethylene, D- 1, 1-pentylene, D-1, 1-propylene, D-5-amino-1, 1-pentylene, D-1-amino-1, 5-pentylene, D-2- (2-napthyl) -1, 1-ethylene, D- 2- (2-thienyl) -1, 1-ethylene, D-2- (4-ethoxyphenyl) -1, 1- ethylene, D-2- (4-fluoropehnyl) -1, 1-ethylene, D-2- (4- hydroxyphenyl) -1, 1-ethylene, D-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, D-2 -carboxamide-1 , 1-ethylene, D-2- carboxamide-1, 2 -ethylene, D-2 -carboxy-1, 2 -ethylene, D-2- cyclohexyl-1, 1-ethylene, D-2 -hydroxy-1, 1-ethylene, D-2- hydroxy-1, 1-ethylene, D-2-hydroxy-l , 1-propylene, D-2- mercapto-1, 1-ethylene, D-2-methyl-l, 1-butylene, D-2- methyl-1, 1-propylene, D-2-phenyl-l , 1-ethylene, D-3- carboxamido-1, 1-propylene, D-3 -carboxamido-1, 3 -propylene, D-3 -carboxy-1, 1-propylene, D-3 -carboxyl-1, 3-propylene, D- 3 -methyl -1, 1-butylene, D-4-ureido-l , 1-butylene, D-5- (9- fluorenylmethoxycarboxamido) -1, 1-pentylene, D-5- acetamiode-1, 1-pentylene, D-5-amino-l, 1-pentylene, D- methylthio-1, 1-propylene, phenylmethylene, D- t- butylmethylene, 1,2-ethylene, 1 , 3 -propylene, 1,4- butylene, 1 , 5-pentylene, 1 , 6-hexylene, 1-methyl-l, 1- ethylene, L-l , 1-butylene, L-l, 1-ethylene, L-1,1- pentylene, 1, 1-propylene, L-5-amino-l, 1-pentylene, L-l- amino-1, 5-pentylene, L-2- (2-napthyl) -1 , 1-ethylene, L-2- (2-thienyl) -1 , 1-ethylene, L-2- (4-ethoxyphenyl) -1,1- ethylene, L-2- (4-fluoropehnyl) -1 , 1-ethylene, L-2-(4- hydroxyphenyl ) -1, 1-ethylene, L-2- (N-formyl-indol-3 -yl) - 1, 1-ethylene, L-2 -carboxamide-1 , 1-ethylene, L-2- carboxamide-1 , 2 -ethylene, L-2-carboxy-l , 2-ethylene, L-2- cyclohexyl-1, 1-ethylene, L-2 -hydroxy-1, 1-ethylene, L-2- hydroxy-1, 1-ethylene, L-2 -hydroxy-1, 1-propylene, L-2- mercapto-1, 1-ethylene, L-2-methyl-l , 1-butylene, L-2- methyl-1, 1-propylene, L-2-phenyl-l, 1-ethylene, L-3- carboxamido-1, 1-propylene, L-3 -carboxamido-1, 3 -propylene, L-3 -carboxy-1, 1-propylene, L-3 -carboxyl-1, 3-propylene, L- 3 -methyl -1, 1-butylene, L-4-ureido-l, 1-butylene, L-5- (9- fluorenylmethoxycarboxamido) -1 , 1-pentylene, L-5- acetamiode-1, 1-pentylene, L-5-amino- 1, 1-pentylene, methylthio- 1, 1-propylene, L-phenylmethylene, L- t- butylmethylene, 3 -methoxy-1, 4-phenylene, 2-methoxy-l, 4- phenylene, 2-chloro-l , 4-phenylene, 1, 4-phenylene, 2- methoxy-4-chloro-l, 4-phenylene, 4-methoxy-l, 3-phenylene, 2-chloro-l, 3-phenylene, 4-chloro-l, 3-phenylene, 6-chloro- 1, 3-phenylene, 5 -carboxy-1 , 3-phenylene, 5- methoxycarbonyl-1, 3-phenylene, 2 , 6-dimethoxy-l , 3- phenylene, 2 , 5-dichloro-l, 3-phenylene, 2 -bromo- 1,3- phenylene, 6-bromo-l , 3 -phenylene and 2 , 6-dimethoxy-5- chloro-1 , 3 -phenylene;
R4 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl, 4 -methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl , 4-fluorobenzyl , 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl , 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl,
4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl , 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl , 2 - (4 -chlorophenyl ) ethyl , 2 - (3 -chlorophenyl ) ethyl , 2- (2 -chlorophenyl) ethyl , 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl , 2- (l-methylpyrrolidin-2-yl) ethyl , 3- (diethylamino) propyl, 2- (5 -nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3 - (dimethylamino) propyl , 2-aminoethyl,
2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl,
3- (2 -pipecolinyl) propyl , 3 -butoxypropyl ,
3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl,
2- (N-ethyl-3 -methylanilino) ethyl, 3 -phenyl-1-propyl , 2-methyl-2-phenylethyl, 4-phenylbutyl,
3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl , trans-3- (3-pyridyl) acrylyl , trimethylacetyl, triphenylacetyl, nicotinyl,
(3 , 4 -dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl , 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl-1-cyclohexanecarbonyl , pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl , 1, 3-phenylene diacetyl, 2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl , 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl , 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert -butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3 , 5 , 5-trimethylhexanoyl,
3 , 5-bis (trifluoromethyl) -benzoyl ,
5 -bromo-2 -chlorobenzoyl , 5 -bromonicotinyl ,
6-chloronicotinyl, 3 , 5 -dimethyl -p-anisyl,
3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl , 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl, 3 -fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl, 3 -methyl -2 -thiophenecarbonyl , 3 -phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4 -hydroxybenzoyl , 3 , 5-dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5-methylsalicylyl , 2 -methylcyclopropanecarbonyl , 3 - lndolepropionyl , 2 , 2-diphenylacetyl , 5-methoxyindole-2 -carbonyl, succinamyl,
4-dimethylaminobutyryl, 4- methylthiobenzoyl,
2-methylthionicotinyl, r (-) -2-oxothiazolidine-4-carbonyl,
4 -nitrophenylacetyl , coumarin-3 -carbonyl , 1-cyano-1-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl,
2- (2 -cyanophenylthio) benzoyl, 2-mesitylenesulfonyl,
2 -naphthalenesulfonyl , 2 -thiophenesulfonyl ,
4 -chlorobenzenesulfonyl , 4 - fluorobenzenesulfonyl , 4-methoxybenzenesulfonyl,
4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2-acetamido-4-methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl, 4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl,
2 , 3 -dichlorothiophene-5 -sulfonyl ,
3 , 4 -dimethoxybenzenesulfonyl,
3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl, 3-trifluoromethylbenzenesulfonyl, 4-ethylbenzenesulfonyl, pentamethylbenzenesulfonyl ,
2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5-dichlorothiophene-3 -sulfonyl, 2 , 6-dichlorobenzenesulfonyl , 2 , 6-difluorobenzenesulfonyl ,
2 -chloro-4- (trifluoromethyl) benzenesulfonyl,
2 -chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro- 6 -methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl , 3 , 5 -dichlorobenzenesulfonyl , 3 -chlorobenzenesulfonyl,
4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole- -sulfonyl,
2- (methoxycarbonyl) thiophene-3 -sulfonyl,
4 -acetamido-3 -chlorobenzene sulfonyl , 2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene- 5- s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl,
3-methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl , 5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl, 4 -isopropylbenzene sulfonyl,
2 , 5-dimethoxybenzenesulfonyl,
3 , 4 -dichlorobenzenesulfonyl ,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester,
(r) - (-) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3-methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester,
(s -(-) -2- (carbamyl) propionate methyl ester,
(s -2- (carbamyl) -3- phenylpropionate methyl ester, 1- carbamyl - tridecafluoro- 1 -hexane , 1- carbamyl -1,1,3, 3-tetramethylbutane, 1- carbamyl - (1-naphthyl) ethane, 1- carbamyl - (4 -bromophenyl) ethane, 1- carbamyl -adamantane, 1- (carbamyl) naphthalene, 1- carbamyl -2,3, 4-trifluorobenzene, 1- carbamyl -2 , 3 -dichlorobenzene , 1- carbamyl -2 , 3 -dimethylbenzene, 1- carbamyl -2,4, 5-trichlorobenzene, 1- carbamyl -2,4, 5-trimethylbenzene, 1- carbamyl -2,4, 6-trichlorobenzene, 1- carbamyl -2 , 4 -dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene,
1- carbamyl) -2 , 4 -dimethylbenzene, 1- carbamyl) -2 , 5 -dichlorobenzene, 1- carbamyl) -2 , 5-difluorobenzene, 1- carbamyl) -2 , 5-dimethoxybenzene, 1- carbamyl ) -2,5- dimethylbenzene , 1- carbamyl) -2, 6 -dibromo-4-fluorobenzene, 1- carbamyl) -2 , 6 -dibromo-4 -isopropylbenzene, 1- carbamyl) -2 , 6 -dichlorobenzene, -2 , 6-diethylbenzene,
-2 , 6-difluorobenzoyl,
-2 , 6-difluorobenzene,
-2, 6-diisopropylbenzene,
-2 , 6 -dimethylbenzene,
-2- (chloromethyl) benzene,
-2- (difluoromethoxy) benzene,
-2- (methylthio) benzene,
-2- (trifluoromethoxy) benzene,
-2- (trifluoromethyl) benzene,
-2-biphenyl,
-2-bromo-4 , 6-difluorobenzene,
-2-bromoethane, 1- (carbamyl) -2-bromobenzene,
-2 -chloro-4 -nitrobenzene ,
-2 -chloro-5- (trifluoromethyl) benzene,
-2 -chloro-5 -nitrobenzene ,
-2 -chloro-6-methylbenzene,
-2 -chlorobenzyl , 1- (carbamyl) -2 -chloroethane ,
-2 -chlorobenzene ,
-2 -cyanobenzene ,
-2 -ethoxybenzene ,
-2 -ethyl- 6 -methylbenzene ,
-2 -ethylbenzene ,
-2-fluoro-3- (trifluoromethyl) benzene,
-2-fluoro-5- (trifluoromethyl) benzene,
-2 - fluoro-5 -methylbenzene ,
-2 - fluoro- 5-nitrobenzene ,
-2-fluoro-6- (trifluoromethyl) benzene,
-2-fluorobenzene, 1- (carbamyl) -2-iodobenzene,
-2 -isopropyl- 6 -methylbenzene ,
-2 -isopropylbenzene ,
-2-methoxy-5-chloro benzene,
-2 -methoxy-5 -methylbenzene ,
-2 -methoxy-5 -nitrobenzene ,
-2-methoxybenzene , 2 -methyl -3 -nitrobenzene,
Figure imgf000270_0001
2 -methyl -5 -nitrobenzene, 1- (carbamyl) -- 22 --methyl - 6 -1 -butylbenzene ,
1- (carbamyl) -- 11-- (2 -methylphenyl) methane ,
1- (carbamyl) -- 22 --n-propylbenzene ,
1- (carbamyl) --22--naphthalene, 1- (carbamyl) -2-nitrobenzene,
1- ( carbamyl) -- 22 --phenoxybenzene ,
1- (carbamyl) -- 22 -- ert -butylbenzene ,
1- (carbamyl) --33,,4,5 -1rimethoxybenzene ,
1- (carbamyl) --11-- (3 , 4-dichlorophenyl) methane,
1- (carbamyl) --33 ,, 4 -dichlorobenzene,
1- (carbamyl) --33 ,, 4-difluorobenzene,
1- (carbamyl) --33,,4-dimethylbenzene ,
1- (carbamyl) --33 ,, 5-bis (trifluoromethyl) benzene,
1- (carbamyl) --33,,5- dichlorobenzene,
1- (carbamyl) --33 ,, 5-dimethoxybenzene,
1- (carbamyl) --33 ,, 5 -dimethylbenzene, 1- (carbamyl) -3 , 5- dirlitrobenzeennee,, 1- (carbamyl) -3- (methylthio) benzene,
1- 'carbamyl) --33-- (trifluoromethyl) benzene,
1- carbamyl) --33-- (trifluoromethylthio) benzene,
1- carbamyl) --33--acetylbenzene,
1- carbamyl) --33 --bromobenzene, 1- (carbamyl) -3-bromopropane,
1- carbamyl) --33--carbomethoxybenzene,
1- carbamyl) -- 33 --chloro-2 -methoxybenzene ,
1- carbamyl) --33 --chloro-2 -methylbenzene,
1- carbamyl) --33 --chloro-4 -fluorobenzene ,
1- ( carbamyl) --33 --chloro-4 -methylbenzene ,
1- ( carbamyl) --33 --chlorobenzene,
1- ( carbamyl) -- 33 --chloropropane ,
1- ( carbamyl) -- 33 --cyanobenzene ,
1- ( carbamyl) --33 --eyelopentoxy-4 -methoxybenzene,
1- ( carbamyl) -- 33 --ethylbenzene ,
1- (carbamyl) --33--fluoro-4 -methylbenzene, - (carbamyl) --33 --fluorobenzene , 1 - (carbamyl ) -3 - iodopropane , - ( carbamyl) bbeennzoyl chloride, - (carbamyl) -- 33 --methoxybenzene , - (carbamyl) -- ((33 -methylphenyl ) methane , - ( carbamyl) --33 --nitrobenzene, 1- (carbamyl) -3-pyridine, ' - (carbamyl) -5 -nitrobenzo-15-crown-5 , ' - (carbamyl) benzo-15-crown-5, ' - (carbamyl ) benzo-18-crown-6 , - (carbamyl) -4 , 5 -dimethyl-2 -nitrobenzene, - (carbamyl) -4- (6 -methyl -2 -benzothiazolyl) benzene, - (carbamyl) -4- (chloromethyl) benzene, - (carbamyl) -4- (chlorosulfonyl) benzene, - (carbamyl) -4- (difluoromethoxy) benzene, - (carbamyl) -4- (methylthio) benzene, - (carbamyl) -4- (tert-butyl) benzene, - (carbamyl) -4- (trifluoromethoxy) benzene, - (carbamyl) -4- (trifluoromethyl) benzene, - (carbamyl) -4- (trifluoromethylthio) benzene, - (carbamyl) -4-acetylbenzene, - (carbamyl) -4 -benzyloxybenzene , - (carbamyl) -4 -bromo-2 , 6 -dimethylbenzene, - (carbamyl) -4-bromo-2- (trifluoromethyl) benzene, - (carbamyl) -4 -bromo-2 -chlorobenzene, - (carbamyl) -4 -bromo-2 -fluorobenzene, - 'carbamyl) -4 -bromo-2 -methylbenzene, - 'carbamyl) -4 -bromobenzene , - carbamyl) -4-chloro-2- (trifluoromethyl) benzene, - carbamyl ) - -chloro-2 -methoxybenzene , - carbamyl ) -4 -chloro-2 -methylbenzene , - carbamyl) -4 -chloro-2-nitrobenzene, - carbamyl ) -4-chloro-3- (trifluoromethyl) benzene, - carbamyl) - -4 -chloro-3 -nitrobenzene , - carbamyl) - -4 -chlorobenzene , - ( carbamyl) - -4 -dimethylaminobenzene , - ( carbamyl) - -4 -ethoxybenzene , - ( carbamyl) - -4-ethylbenzene, - ( carbamyl) - -4-fluoro-2- (trifluoromethyl) benzene, - (carbamyl) - -4-fluoro-2-nitrobenzene, - (carbamyl) - -4-fluoro-3- (trifluoromethyl) benzene, - (carbamyl) - -4 -fluoro-3 -nitrobenzene , - (carbamyl) - -4-fluorobenzoyl, - (carbamyl) - -4 - fluorobenzyl , - (carbamyl) - -4 - fluorobenzene , 1- (carbamyl) -4-heptyloxybenzene,
1- (carbamyl) -4-iodobenzene,
1- (carbamyl) -4 -isopropylbenzene,
1- (carbamyl) -4 -methoxy-2 -methylbenzene, 1- (carbamyl) - (4-methoxyphenyl) methane,
1- (carbamyl) -4 -methoxybenzene,
1- (carbamyl) -4-methyl-2-nitrobenzene,
1- (carbamyl) -4-methyl-3-nitrobenzene,
1- (carbamyl) - (4 -methylphenyl) methane, 1- (carbamyl) -4-n-butoxycarbonylbenzene,
1- (carbamyl) -4-n-butoxybenzene,
1- (carbamyl) -4-n-butyl-2-methylbenzene,
1- (carbamyl) -4-n-butylbenzene,
1- (carbamyl) -4 -nitrobenzene, 1- (carbamyl) -4-phenoxybenzene,
1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (carbamyl) -5-chloro-2-methylbenzene,
1- (carbamyl) -5-fluoro-2 -methylbenzene, 1- (carbamyl) -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl
2- (carbamyl) -3-methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio) butyrate, ethyl
2- (carbamyl) -4 -methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate, 1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane,
1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl
2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl
(carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane, 1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate and carbamyltrichloromethane; or
R3, R4 together with the nitrogen atom of Formula (I) form a ring selected from the group consisting of pyrrolidine, 4- (R) -hydroxy-2- (S) -pyrrolidine, 4-(R)- hydroxy-2- (R) -pyrrolidine, 4- (S) -hydroxy-2- (S) - pyrrolidine, 4- (S) -hydroxy-2- (S) -pyrrolidine, 4- (R) - benzyloxy-2- (S) -pyrrolidine, 4- (R) -benzyloxy-2- (R) - pyrrolidine, 4- (S) -benzyloxy-2- (S) -pyrrolidine, 4-(S)~ benzyloxy-2- (S) -pyrrolidine, 4-piperidino, 3-(R)- piperidino, 3 - (S) -piperidino, 2- (R) -piperidino, 2- (S) - piperidino, octahydroisoquinoline and dihydroindoyl;
R5 is selected from the group consisting of methyl, t- butyl, carbomethoxymethyl , ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4- methylphenyl , 4-fluorophenyl, 3-fluorophenyl, 4- cyanophenyl , 2 -methoxyphenyl , 3 -methoxyphenyl , 4 - methoxyphenyl, 4 -chlorophenyl , 3 , 4-difluorophenyl, 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl, 3- methyl-4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, 3- chloro-4 -methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl, 3 , 4-dichlorophenyl , 6- (2-oxo) -1, 2 , 3 , 4- tetrahydroquinoline, 4- (5 -methyl-3 -phenyl) isoxazole, 4- bromophenyl, 2- (5-chloro-3-methyl) benzo [2] thiophene, 6- (1, 1,4, 4-tetramethyl) -1,2, 3 , 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5-[3-(3',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ',4'- dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole;
R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N,N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or
R5 and R6 together with the triazole ring of Formula (I) form a ring structure selected from the group consisting of the structure
Figure imgf000276_0001
and the structure
Figure imgf000276_0002
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1, 4-phenylene, 2-methoxy-l , 4- phenylene, 2-chloro-l, 4-phenylene, 1 , 4-phenylene, 2- methoxy-4 -chloro-1, 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l , 3 -phenylene, 2-chloro- 1 , 3-phenylene, 4-chloro-l , 3-phenylene, 6-chloro-l , 3- phenylene, 5-carboxy-1, 3 -phenylene, 5 -methoxycarbonyl- 1, 3-phenylene, 2 , 6-dimethoxy-l, 3 -phenylene, 2 , 5-dichloro- 1, 3-phenylene, 2 -bromo-1, 3-phenylene, 6 -bromo- 1,3- phenylene and 2 , 6-dimethoxy-5-chloro-l, 3-phenylene; and
R8 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl , 3 -methylbenzyl, 4 -methylbenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3 - ( 1-imidazole) propyl , 4 -aminomethylbenzyl , 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2 - (4 -chlorophenyl ) ethyl , 2 - (3 -chlorophenyl ) ethyl , 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl,
2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2-pipecolinyl)propyl, 3-butoxypropyl , 3- (pyrrolidin-2-one-l-yDpropyl, 3- (morpholino) propyl, 2- (N-ethyl-3 -methylanilino) ethyl , 3 -phenyl-1-propyl , 2-methyl-2-phenylethyl , 4-phenylbutyl, 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl , 4-dimethylaminobenzoyl , 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl , p-tolylacetyl , picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl , tetrahydro-3-furoyl, trans-3- (3 -pyridyl) acrylyl , trimethylacetyl, triphenylacetyl , nicotinyl,
(3 , 4 -dimethoxyphenyl) acetyl , boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl , 4 -methyl- 1 -cyclohexanecarbonyl , pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1 , 3-phenylene diacetyl, 2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl , 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl , 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert-butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoy1 , 3,5, 5-trimethylhexanoyl, 3 , 5-bis (trifluoromethyl) -benzoyl , 5-bromo-2-chlorobenzoyl, 5-bromonicotinyl , 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl, 3 -bromo-4 -methylbenzoyl , 3,4,5- trimethoxyphenylacetyl , 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl , 3-cyanobenzoyl, 3 - fluoro-4 -methylbenzoyl , 1- isoquinolinecarbonyl , 3-methyl-2-thiophenecarbonyl, 3-phenoxybenzoyl,
3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4 -hydroxybenzoyl, 3 , 5-dichloro- -hydroxybenzoyl, 4- hydroxybenzoyl, 5-methylsalicylyl, 2-methylcyclopropanecarbonyl, 3-lndolepropionyl, 2 , 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl , succinamyl , 4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r(-) -2-oxothiazolidine-4-carbonyl, 4 -nitrophenylacetyl , coumarin-3 -carbonyl , 1-cyano-l-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl, 2- (2 -cyanophenylthio) benzoyl, 2-mesitylenesulfonyl, 2-naphthalenesulfonyl , 2 -thiophenesulfonyl , 4 -chlorobenzenesulfonyl , 4 - fluorobenzenesulfonyl , 4-methoxybenzenesulfonyl,
4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl,
2 -acetamido-4 -methyl- 5-thiazolesulfonyl ,
4- (trifluoromethoxy) benzenesulfonyl, 4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl, 2 , 3 -dichlorothiophene-5-sulfonyl , 3 , 4 -dimethoxybenzenesulfonyl , 3 , 5-bis (trifluoromethyl) benzenesulfonyl, 3 -chloro-4 -fluorobenzenesulfonyl, 3 -trifluoromethylbenzenesulfonyl, 4-ethylbenzenesulfonyl, pentamethylbenzenesulfonyl , 2,3, 4 -trifluorobenzenesulfonyl , 2 , 4-dichlorobenzenesulfonyl ,
2, 5-dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl , 2 , 6-difluorobenzenesulfonyl ,
2 -chloro-4- (trifluoromethyl) benzenesulfonyl, 2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro- 6-methylbenzenesulfonyl ,
3 , 4-difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl,
4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl,
2- (methoxycarbonyl) thiophene-3 -sulfonyl,
4-acetamido-3 -chlorobenzene sulfonyl,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5 -sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl ,
5- (isoxazol-3-yl) thiophene-2-sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , -difluorobenzenesulfonyl , 2 -fluorobenzenesulfonyl ,
4 -isopropylbenzene sulfonyl, 2, 5-dimethoxybenzenesulfonyl,
3 , 4 -dichlorobenzenesulfonyl ,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester,
(r) - (-) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3-methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4 -methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester,
(s) -2- (carbamyl) -3- phenylpropionate methyl ester,
1- (carbamyl) -tridecafluoro-1-hexane,
1- (carbamyl) -1,1,3, 3-tetramethylbutane,
1- (carbamyl) - (1-naphthyl) ethane, 1- (carbamyl) - (4 -bromophenyl) ethane,
1- (carbamyl) -adamantane, 1- (carbamyl) naphthalene,
1- (carbamyl) -2,3, 4-trifluorobenzene, 1- carbamyl) -2 , 3 -dichlorobenzene,
1- carbamyl) -2 , 3 -dimethylbenzene,
1- carbamyl) -2,4, 5-trichlorobenzene,
1- carbamyl) -2,4, 5-trimethylbenzene,
1- carbamyl) -2,4, 6-trichlorobenzene,
1- carbamyl) -2, 4 -dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2, 4-dimethoxybenzene,
1- carbamyl -2 , 4 -dimethylbenzene,
1- carbamyl -2 , 5-dichlorobenzene,
1- carbamyl -2 , 5-difluorobenzene,
1- carbamyl -2,5-dimethoxybenzene ,
1- carbamyl -2,5- dimethylbenzene,
1- carbamyl -2 , 6-dibromo-4-fluorobenzene,
1- carbamyl -2 , 6 -dibromo-4 -isopropylbenzene,
1- carbamyl -2 , 6-dichlorobenzene,
1- carbamyl -2 , 6-diethylbenzene,
1- carbamyl -2 , 6-difluorobenzoyl,
1- carbamyl -2 , 6-difluorobenzene,
1- carbamyl -2 , 6-diisopropylbenzene,
1- carbamyl -2 , 6-dimethylbenzene ,
1- carbamyl -2- (chloromethyl) benzene,
1- carbamyl -2- (difluoromethoxy) benzene,
1- carbamyl -2- (methylthio) benzene, - carbamyl -2- (trifluoromethoxy) benzene, - carbamyl -2- (trifluoromethyl) benzene, - carbamyl -2-biphenyl, - carbamyl -2 -bromo-4 , 6-difluorobenzene, - carbamyl -2-bromoethane, 1- (carbamyl) -2-bromobenzene, - carbamyl -2 -chloro-4 -nitrobenzene, - carbamyl -2-chloro-5- (trifluoromethyl) benzene, - carbamyl -2 -chloro-5-nitrobenzene, - carbamyl -2 -chloro- 6 -methylbenzene, - carbamyl -2-chlorobenzyl, 1- (carbamyl) -2-chloroethane, - carbamyl -2 -chlorobenzene , - carbamyl -2 -cyanobenzene , - carbamyl -2 -ethoxybenzene , - carbamyl -2-ethyl - 6 -methylbenzene , 1- carbamyl -2 -ethylbenzene , 1- carbamyl -2-fluoro-3- (trifluoromethyl) benzene, 1- carbamyl -2-fluoro-5- (trifluoromethyl) benzene, 1- carbamyl -2 -fluoro-5-methylbenzene , 1- carbamyl -2 -fluoro-5-nitrobenzene , 1- carbamyl -2-fluoro-6- (trifluoromethyl) benzene, 1- carbamyl -2-fluorobenzene, 1- (carbamyl) -2-iodobenzene, 1- carbamyl -2 -isopropyl-6-methylbenzene , 1- carbamyl -2 -isopropylbenzene , 1- carbamyl -2 -methoxy-5 -chloro benzene, 1- carbamyl -2 -methoxy-5 -methylbenzene , 1- carbamyl -2 -methoxy-5-nitrobenzene, 1- carbamyl -2-methoxybenzene , 1- carbamyl -2 -methyl-3 -nitrobenzene , 1- carbamyl -2-methyl-5-nitrobenzene, 1- carbamyl -2 -methyl-6 -1-butylbenzene , 1- carbamyl -1- (2 -methylphenyl ) methane , 1- carbamyl -2-n-propylbenzene, 1- carbamyl -2-naphthalene, 1- (carbamyl) -2-nitrobenzene, 1- carbamyl -2 -phenoxybenzene , 1- carbamyl -2-tert-butylbenzene, 1- carbamyl -3,4,5-trimethoxybenzene , 1- carbamyl -1- (3 , 4-dichlorophenyl) methane, 1- carbamyl -3 , 4-dichlorobenzene, 1- carbamyl -3 , 4-difluorobenzene, 1- carbamyl -3 , 4 -dimethylbenzene, 1- carbamyl -3 , 5-bis (trifluoromethyl) benzene, 1- carbamyl -3,5- dichlorobenzene, 1- carbamyl -3 , 5-dimethoxybenzene, 1- carbamyl -3 , 5 -dimethylbenzene, 1- (carbamyl) -3 , 5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
1- carbamyl -3- (trifluoromethyl) benzene, 1- carbamyl -3 - (trifluoromethylthio) benzene , 1- carbamyl -3-acetylbenzene, 1- carbamyl -3 -bromobenzene, 1- (carbamyl) -3-bromopropane, 1- carbamyl -3 -carbomethoxybenzene, 1- carbamyl ■3 -chloro-2 -methoxybenzene , - (carbamyl) -3 -chloro-2 -methylbenzene, - (carbamyl) -3 -chloro-4 -fluorobenzene,
- (carbamyl) -3 -chloro-4 -methylbenzene, ■ (carbamyl) -3 -chlorobenzene,
- (carbamyl) -3-chloropropane,
■ (carbamyl) -3-cyanobenzene,
■ (carbamyl) -3 -cyclopentoxy-4 -methoxybenzene,
- (carbamyl) -3-ethylbenzene,
■ (carbamyl) -3 -fluoro-4 -methylbenzene,
■ (carbamyl) -3 -fluorobenzene, 1- (carbamyl) -3-iodopropane,
■ (carbamyl) benzoyl chloride, ' • (carbamyl) -3 -methoxybenzene,
■ (carbamyl) - (3 -methylphenyl) methane,
• (carbamyl) -3-nitrobenzene, 1- (carbamyl! •3-pyridine,
- (carbamyl) -5 ' -nitrobenzo-15-crown-5 ,
- (carbamyl) benzo-15-crown-5,
- (carbamyl) benzo-18-crown-6, - (carbamyl -4, 5-dimethyl-2 -nitrobenzene, - (carbamyl -4- (6 -methyl -2 -benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert-butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) benzene, - (carbamyl -4- (trifluoromethylthio) benzene, - (carbamyl -4 -acetylbenzene , - (carbamyl -4 -benzyloxybenzene , - (carbamyl -4 -bromo-2 , 6 -dimethylbenzene, - (carbamyl -4-bromo-2- (trifluoromethyl) benzene, - (carbamyl -4 -bromo-2 -chlorobenzene , - (carbamyl -4 -bromo-2 -fluorobenzene , - (carbamyl -4 -bromo-2 -methylbenzene , - (carbamyl -4 -bromobenzene , - (carbamyl -4-chloro-2- (trifluoromethyl) benzene, - (carbamyl -4 -chloro-2 -methoxybenzene , 1- (carbamyl) -4-chloro-2-methylbenzene,
1- (carbamyl) -4-chloro-2-nitrobenzene,
1- (carbamyl) -4-chloro-3- (trifluoromethyl) benzene,
1- (carbamyl) -4-chloro-3-nitrobenzene,
1- (carbamyl) -4 -chlorobenzene,
1- (carbamyl) -4-dimethylaminobenzene,
1- (carbamyl) -4-ethoxybenzene,
1- (carbamyl) -4-ethylbenzene,
1- (carbamyl) -4-fluoro-2- (trifluoromethyl) benzene,
1- (carbamyl) -4-fluoro-2-nitrobenzene,
1- (carbamyl) -4-fluoro-3- (trifluoromethyl) benzene,
1- (carbamyl) -4-fluoro-3 -nitrobenzene,
1- (carbamyl) -4-fluorobenzoyl ,
1- (carbamyl) -4-fluorobenzyl,
1- (carbamyl) -4-fluorobenzene,
1- (carbamyl) -4-heptyloxybenzene,
1- (carbamyl) -4-iodobenzene,
1- (carbamyl) -4 -isopropylbenzene,
1- (carbamyl) -4 -methoxy-2-methylbenzene,
1- (carbamyl) - (4-methoxyphenyl) methane,
1- (carbamyl) -4 -methoxybenzene,
1- (carbamyl) -4-methyl-2-nitrobenzene,
1- (carbamyl) -4 -methyl-3 -nitrobenzene,
1- (carbamyl) - (4 -methylphenyl) methane,
1- (carbamyl) -4-n-butoxycarbonylbenzene,
1- (carbamyl) -4-n-butoxybenzene,
1- (carbamyl) -4-n-butyl-2-methylbenzene,
1- (carbamyl) -4-n-butylbenzene,
1- (carbamyl) -4 -nitrobenzene,
1- (carbamyl) -4-phenoxybenzene,
1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (carbamyl) -5-chloro-2-methylbenzene,
1- (carbamyl) -5-fluoro-2 -methylbenzene,
1- (carbamyl) -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl 2- (carbamyl) -3 -methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio) butyrate, ethyl
2- (carbamyl) -4 -methylvalerate, ethyl 2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate,
1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2 -methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl
2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl
(carbamyl) acetate, 1- (carbamyl) -propane, 1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane,
1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2-dimethylpropane,
1- (carbamyl) -tetrahydro-2-pyran,
1- (carbamyl) -trans-2-benzenecyclopropane,
1- (carbamyl) -trichloroacetate and carbamyltrichloromethane.
34. The single compound of claim 19, wherein q is 0 or 1;
Rx is selected from the group consisting of a hydrogen atom and polystyryl 4-methylbenzhydryl ;
R2 is selected from the group consisting of a hydrogen atom, 2- (1-pyrrolidino) ethyl, 2-pyridinemethyl, 2- (4-imidazole) ethyl, cyclopentyl, allyl, 2-methoxyethyl, (+/- ) -tetrahydrofuryl , benzyl, 2 -methylbenzyl , 3 -methylbenzyl, 4 -methylbenzyl, 2-fluorobenzyl , 3 -fluorobenzyl, 4-fluorobenzyl, 3- (1-imidazole) propyl , 4-aminomethylbenzyl, 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl , 3- methoxybenzyl, piperonyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4-chlorophenyl) ethyl,
2 - (3 -chlorophenyl) ethyl , 2- (2 -chlorophenyl) ethyl ,
2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl,
2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl,
2- (5-nitro-2-pyridyl) ethyl,
3- (dimethylamino) -2 , 2-dimethylpropyl,
3- (dimethylamino) propyl, 2-aminoethyl,
2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl,
3- (2 -pipecolinyl) propyl, 3 -butoxypropyl,
3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl ,
2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl,
2-methyl-2-phenylethyl , 4 -phenylbutyl ,
3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl and piperazine;
R, is of the formula (II), (III), (IV) or (V)
R 1
Figure imgf000285_0001
R
Λ^m^ CH,
•6H^ Jm
Figure imgf000285_0002
R13
: ιv) :v) wherein n is 1; m is 3 or 4 ;
R12 is selected from the group consisting of a hydrogen atom, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, iso-butyl, pentane, methoxy, ethoxy, propoxy and iso-proproxy;
Ri3 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl , 3 -methylbenzyl, 4 -methylbenzyl , 2-fluorobenzyl , 3-fluorobenzyl , 4-fluorobenzyl , 3- (1-imidazole) propyl, 4-aminomethylbenzyl,
4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl , 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl) propyl , 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl -1-propyl , 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl, 3-methoxyphenethyl and 3-phenylbenzyl; and R14 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl, 4 -methylbenzyl , 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3- (1-imidazole) propyl, 4-aminomethylbenzyl,
4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl , 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2 - (4 -chlorophenyl) ethyl , 2 - (3 -chlorophenyl) ethyl , 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) propyl, 3-butoxypropyl, 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl , 3 -phenyl -1-propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl , isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl , benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl , hydrocinnamyl, 4-dimethylaminobenzoyl , 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl,
4 -fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl , nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl , 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbσnyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl, 4 -methyl-1-cyclohexanecarbonyl , pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3-phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert-butyl-cyclohexanecarbonyl, 4-sulfonamidobenzoyl, 3,5,5 -1rimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl , 5-bromo-2 -chlorobenzoyl , 5-bromonicotinyl , 6-chloronicotinyl , 3 , 5-dimethyl-p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl , 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl, 3 - fluoro-4 -methylbenzoyl , 1- isoquinolinecarbonyl , 3 -methyl-2 -1hiophenecarbonyl , 3 -phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl, 3 , 5-dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl ,
3 - lndolepropionyl , 2 , 2 -diphenylacetyl , 5 -methoxyindole-2 -carbonyl , succinamyl , 4-dimethylaminobutyryl, 4- methylthiobenzoyl,
2-methylthionicotinyl, r (-) -2 -oxothiazolidine-4 -carbonyl,
4 -nitrophenylacetyl , coumarin-3 -carbonyl ,
1-cyano-l-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl , 2- (2-cyanophenylthio) benzoyl, 2-mesitylenesulfonyl,
2-naphthalenesulfonyl, 2-thiophenesulfonyl ,
4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl , 4 -methoxybenzenesulfonyl ,
4-methylsulfonylbenzenesulfonyl , benzenesulfonyl , dansyl, n-acetylsulfanilyl,
2-acetamido-4-methyl-5-thiazolesulfonyl, 4- (trifluoromethoxy) benzenesulfonyl, 4 -tert -butylbenzenesulfonyl , 8 -quinolinesulfonyl , 2 , 3 -dichlorothiophene-5 -sulfonyl , 3 , 4 -dimethoxybenzenesulfonyl , 3 , 5-bis (trifluoromethyl) benzenesulfonyl, 3 -chloro-4 -fluorobenzenesulfonyl,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4 -trifluorobenzenesulfonyl , 2 , 4 -dichlorobenzenesulfonyl,
2 , 5-dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl , 2 , 6 -difluorobenzenesulfonyl ,
2 -chloro-4- (trifluoromethyl) benzenesulfonyl,
2 -chloro-5- (trifluoromethyl) benzenesulfonyl, 2 -chloro-6-methylbenzenesulfonyl, 3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl, 4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4 -sulfonyl, 2- (methoxycarbonyl) thiophene-3 -sulfonyl, 4 -acetamido-3 -chlorobenzene sulfonyl,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5 -sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl, 5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl , 2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl, 4 -isopropylbenzene sulfonyl, 2 , 5 -dimethoxybenzenesulfonyl, 3 , 4 -dichlorobenzenesulfonyl,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester,
(r) - (-) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester,
(s -(-) -2- (carbamyl) propionate methyl ester, (s -2- (carbamyl) -3 - phenylpropionate methyl ester, 1- carbamyl tridecafluoro- 1-hexane, 1- carbamyl 1,1,3,3 -1etramethylbutane , 1- carbamyl ( 1-naphthyl ) ethane , 1- carbamyl (4 -bromophenyl ) ethane , 1- carbamyl adamantane, 1- (carbamyl) naphthalene, 1- carbamyl -2,3, 4-trifluorobenzene, 1- carbamyl 2 , 3 -dichlorobenzene , 1- carbamyl -2 , 3 -dimethylbenzene, 1- carbamyl -2,4, 5-trichlorobenzene, 1- carbamyl 2,4, 5-trimethylbenzene, 1- carbamyl -2,4, 6-trichlorobenzene, 1- carbamyl 2 , 4-dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene,
1- carbamyl -2,4-dimethylbenzene , 1- carbamyl 2 , 5 -dichlorobenzene , 1- carbamyl -2 , 5-difluorobenzene, 1- carbamyl -2 , 5-dimethoxybenzene, 1- carbamyl -2,5- dimethylbenzene , 1- carbamyl -2 , 6 -dibromo-4-fluorobenzene, 1- carbamyl 2 , 6 -dibromo-4- isopropylbenzene, 1- carbamyl 2 , 6 -dichlorobenzene , 1- carbamyl 2 , 6 -diethylbenzene , 1- carbamyl 2 , 6 -difluorobenzoyl , 1- carbamyl 2 , 6-difluorobenzene, 1- carbamyl 2 , 6 -diisopropylbenzene , 1- carbamyl 2,6-dimethylbenzene , 1- carbamyl -2- (chloromethyl) benzene, 1- carbamyl -2- (difluoromethoxy) benzene, 1- carbamyl -2- (methylthio) benzene, 1- carbamyl -2- (trifluoromethoxy) benzene, - carbamyl -2- (trifluoromethyl) benzene, - carbamyl -2-biphenyl, - carbamyl -2 -bromo-4 , 6-difluorobenzene, - carbamyl -2-bromoethane, 1- (carbamyl) -2-bromobenzene, - 2 - chloro-4 -nitrobenzene ,
-2-chloro-5- (trifluoromethyl) benzene,
- 2 -chloro- 5 -nitrobenzene ,
-2 -chloro-6 -methylbenzene ,
-2 -chlorobenzyl , 1 - (carbamyl ) -2 - chloroethane ,
-2 -chlorobenzene ,
-2 -cyanobenzene ,
-2 -ethoxybenzene ,
-2-ethyl - 6 -methylbenzene ,
-2 -ethylbenzene ,
-2-fluoro-3- (trifluoromethyl) benzene,
-2-fluoro-5- (trifluoromethyl) benzene,
-2 - fluoro- 5 -methylbenzene ,
- 2 - fluoro- 5 -nitrobenzene ,
-2-fluoro-6- (trifluoromethyl) benzene,
-2-fluorobenzene, 1- (carbamyl) -2-iodobenzene,
-2 - isopropyl - 6 -methylbenzene ,
-2 - isopropylbenzene ,
-2 -methoxy- 5 -chloro benzene,
-2 -methoxy- 5 -methylbenzene ,
- 2 -methoxy- 5 -nitrobenzene ,
-2 -methoxybenzene ,
-2 -methyl-3 -nitrobenzene ,
-2 -methyl -5 -nitrobenzene,
-2-methyl-6-t-butylbenzene,
-1- (2 -methylphenyl) methane,
- 2 -n-propylbenzene ,
-2-naphthalene, 1- (carbamyl) -2-nitrobenzene,
-2 -phenoxybenzene ,
- 2 -tert -butylbenzene ,
-3,4, 5-trimethoxybenzene,
-1- (3 , 4-dichlorophenyl) methane, 3 , 4-dichlorobenzene, 3 , 4-difluorobenzene, 3 , 4 -dimethylbenzene, 3 , 5-bis (trifluoromethyl) benzene,
Figure imgf000291_0001
3,5- dichlorobenzene, 1- (carbamyl 3 , 5-dimethoxybenzene, 1- (carbamyl 3 , 5 -dimethylbenzene, 1- (carbamyl) -3 , 5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
1- carbamyl -3- (trifluoromethyl) benzene,
1- carbamyl -3- (trifluoromethylthio) benzene,
1- carbamyl -3-acetylbenzene,
1- carbamyl -3 -bromobenzene, 1- (carbamyl) -3-bromopropane,
1- carbamyl -3 -carbomethoxybenzene ,
1- carbamyl -3 -chloro-2 -methoxybenzene ,
1- carbamyl -3 -chloro-2 -methylbenzene ,
1- carbamyl -3 -chloro-4 -fluorobenzene,
1- carbamyl -3 -chloro-4 -methylbenzene,
1- carbamyl -3 -chlorobenzene ,
1- carbamyl - 3 -chloropropane ,
1- carbamyl -3 -cyanobenzene ,
1- carbamyl -3 -cyclopentoxy-4 -methoxybenzene,
1- carbamyl -3-ethylbenzene,
1- carbamyl -3 -fluoro-4 -methylbenzene,
1- carbamyl -3 - fluorobenzene , 1- (carbamyl) -3 -iodopropane ,
3- carbamyl benzoyl chloride,
1- carbamyl -3 -methoxybenzene ,
1- carbamyl - (3 -methylphenyl) methane,
1- carbamyl -3-nitrobenzene, 1- (carbamyl) -3-pyridine, ' (carbamyl ) -5 ' -nitrobenzo-15-crown-5 , ' (carbamyl) benzo-15-crown-5 , ' (carbamyl) benzo-18-crown-6 , - (carbamyl -4 , 5-dimethyl-2-nitrobenzene, - (carbamyl -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert-butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) benzene, - (carbamyl -4- (trifluoromethylthio) benzene, - (carbamyl -4 -acetylbenzene , -4 -benzyloxybenzene ,
-4 -bromo-2 , 6 -dimethylbenzene,
-4 -bromo-2- (trifluoromethyl) benzene,
-4 -bromo-2 -chlorobenzene,
-4 -bromo-2 -fluorobenzene ,
-4 -bromo-2 -methylbenzene ,
-4 -bromobenzene ,
-4-chloro-2- (trifluoromethyl) benzene,
-4 -chloro-2 -methoxybenzene ,
-4 -chloro-2 -methylbenzene ,
-4 -chloro-2 -nitrobenzene,
-4-chloro-3- (trifluoromethyl) benzene,
-4 -chloro-3 -nitrobenzene ,
-4 -chlorobenzene,
-4 -dimethylaminobenzene ,
-4-ethoxybenzene,
-4 -ethylbenzene ,
-4-fluoro-2- (trifluoromethyl) benzene,
-4 -fluoro-2 -nitrobenzene ,
-4-fluoro-3- (trifluoromethyl) benzene,
-4-fluoro-3 -nitrobenzene,
-4 - fluorobenzoyl ,
-4 - fluorobenzyl ,
-4 - fluorobenzene ,
-4-heptyloxybenzene,
-4 - iodobenzene ,
-4 -isopropylbenzene,
-4 -methoxy-2 -methylbenzene ,
- (4-methoxyphenyl) methane,
-4 -methoxybenzene ,
-4 -methyl-2 -nitrobenzene,
-4 -methyl -3 -nitrobenzene ,
- (4 -methylphenyl) methane,
-4 -n-butoxycarbonylbenzene ,
-4-n-butoxybenzene,
-4 -n-butyl-2 -methylbenzene ,
Figure imgf000293_0001
4-n-butylbenzene, 1- (carbamyl) -4 -nitrobenzene,
1- (carbamyl) -4-phenoxybenzene,
1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene, 1- (carbamyl) -5-chloro-2-methylbenzene,
1- (carbamyl) -5 -fluoro-2 -methylbenzene,
1- (carbamyl) -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl 2- (carbamyl) -3 -methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio) butyrate, ethyl
2- (carbamyl) -4-methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl 3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate,
1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane,
1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl
2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl
(carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane,
1- (carbamyl) -tetrahydro-2-pyran,
1- (carbamyl) -trans-2-benzenecyclopropane,
1- (carbamyl) -trichloroacetate and carbamyltrichloromethane; or
R14 is of the formula
Figure imgf000294_0001
wherein R15 is selected from the group consisting of a hydrogen atom, methyl, t-butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4 -methylphenyl, 4-fluorophenyl, 3- fluorophenyl, 4-cyanophenyl, 2 -methoxyphenyl, 3- methoxyphenyl , 4-methoxyphenyl, 4-chlorophenyl, 3,4- difluorophenyl, 4-nitrophenyl, 3 , 4-dihydroxyphenyl, 3- nitrophenyl, 3-methyl-4-chlorophenyl, adamantyl, 2,5- dimethoxyphenyl, 3-chloro-4-methylphenyl, 5- (3- carboethoxy) isoxazole, 4 -phenylphenyl, 3,4- dichlorophenyl, 6- (2-oxo) -1, 2 , 3 , 4-tetrahydroquinoline, 4- (5 -methyl-3 -phenyl) isoxazole, 4 -bromophenyl, 2-(5-chloro- 3 -methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) - 1, 2, 3 , 4-tetrahydronaphthalene, 4 -chlorophenyl , 1-pyrene, 5- [3- (3 ' ,4 ' -dichlorophenyl) ] isoxazole, 5- [3- (2 ',4'- dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole; and Ri6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or R14, Rι5 and Ri6 together form a ring structure selected from the group consisting of the structure
Figure imgf000295_0001
and the structure
Figure imgf000295_0002
R4 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl, 4 -methylbenzyl , 2-fluorobenzyl, 3 -fluorobenzyl , 4-fluorobenzyl, 3 - ( 1- imidazole) propyl , 4 -aminomethylbenzyl , 4 -methoxybenzyl, 3 -chlorobenzyl , 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl,
4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2 - (4 -chlorophenyl) ethyl , 2 - (3 -chlorophenyl) ethyl , 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl,
2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl,
3- (2 -pipecolinyl) propyl, 3-butoxypropyl,
3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl,
2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2-methyl-2-phenylethyl, 4-phenylbutyl,
3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl , cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl , benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl , trimethylacetyl, triphenylacetyl , nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl , (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl ,
1-adamantaneacetyl, 1-naphthylacetyl, 1 -phenyl- 1- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl , 4 -methyl-1-cyclohexanecarbonyl , pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3-phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl,
3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3,4 -dichlorophenylacetyl , 4 -tert-butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5, 5-trimethylhexanoyl, 3 , 5-bis (trifluoromethyl) -benzoyl,
5-bromo-2-chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl , 3-cyanobenzoyl, 3 -fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl, 3 -methyl-2 -thiophenecarbonyl , 3 -phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4-hydroxybenzoyl , 3 , 5-dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5-methylsalicylyl, 2-methylcyclopropanecarbonyl, 3-lndolepropionyl, 2 , 2-diphenylacetyl, 5-methoxyindole-2 -carbonyl , succinamyl, 4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r (-) -2-oxothiazolidine-4-carbonyl, 4-nitrophenylacetyl, coumarin-3 -carbonyl, 1-cyano-1-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl , theophylline-7-acetyl, 2- (2 -cyanophenylthio) benzoyl , 2-mesitylenesulfonyl, 2 -naphthalenesulfonyl , 2 -thiophenesulfonyl , 4 -chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl , 4 -methoxybenzenesulfonyl ,
4-methylsulfonylbenzenesulfonyl, benzenesulfonyl , dansyl, n-acetylsulfanilyl, 2-acetamido-4-methyl-5-thiazolesulfonyl, 4- (trifluoromethoxy) benzenesulfonyl,
4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl, 2 , 3 -dichlorothiophene-5 -sulfonyl ,
3 , 4 -dimethoxybenzenesulfonyl,
3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl, 3-trifluoromethylbenzenesulfonyl, 4-ethylbenzenesulfonyl, pentamethylbenzenesulfonyl ,
2,3, 4-trifluorobenzenesulfonyl,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5 -dichlorothiophene-3 -sulfonyl, 2 , 6-dichlorobenzenesulfonyl, 2 , 6-difluorobenzenesulfonyl,
2 -chloro-4- (trifluoromethyl) benzenesulfonyl,
2-chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro-6 -methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl , 3 , 5-dichlorobenzenesulfonyl , 3 -chlorobenzenesulfonyl,
4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl,
2 - (methoxycarbonyl) thiophene-3 -sulfonyl ,
4 -acetamido-3 -chlorobenzene sulfonyl , 2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene- 5-sulfonyl,
3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl,
5- (isoxazol-3-yl) thiophene-2-sulfonyl, 4-cyanobenzene sulfonyl, 3 -chloro-4 -methylbenzenesulfonyl, 2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl,
4 -isopropylbenzene sulfonyl,
2 , 5-dimethoxybenzenesulfonyl ,
3 , 4 -dichlorobenzenesulfonyl ,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -1- (carbamyl) - (1-naphthyl) ethane,
(s) - (+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4-methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester,
(s) -(-) -2- (carbamyl) propionate methyl ester, (s -2- (carbamyl) -3- phenylpropionate methyl ester,
1- carbamyl -tridecafluoro-1 -hexane ,
1- carbamyl -1,1,3, 3-tetramethylbutane,
1- carbamyl - (1-naphthyl) ethane ,
1- carbamyl - (4 -bromophenyl) ethane,
1- carbamyl -adamantane, 1- (carbamyl) naphthalene,
1- carbamyl -2,3, 4-trifluorobenzene,
1- carbamyl -2 , 3 -dichlorobenzene,
1- carbamyl 2 , 3 -dimethylbenzene ,
1- carbamyl 2,4, 5-trichlorobenzene,
1- carbamyl 2,4, 5-trimethylbenzene,
1- carbamyl 2,4,6- trichlorobenzene ,
1- carbamyl 2, 4-dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene,
1- carbamyl -2 4 -dimethylbenzene ,
1- carbamyl -2 5 -dichlorobenzene,
1- carbamyl -2 5-difluorobenzene,
1- carbamyl -2 5 -dimethoxybenzene ,
1- carbamyl -2 5- dimethylbenzene,
1- carbamyl -2 6 - ibromo-4 - fluorobenzene ,
1- carbamyl -2 6 -dibromo-4 -isopropylbenzene ,
1- carbamyl -2 6 -dichlorobenzene ,
1- carbamyl -2 6 -diethylbenzene ,
1- carbamyl -2 6 -difluorobenzoyl ,
1- carbamyl -2 6 -difluorobenzene ,
1- carbamyl -2 6 -diisopropylbenzene ,
1- carbamyl -2 6 -dimethylbenzene ,
1- carbamyl -2 (chloromethyl ) benzene , - carbamyl -2 (difluoromethoxy) benzene , - carbamyl -2 (methylthio) benzene, - carbamyl -2- (trifluoromethoxy) benzene, - carbamyl -2- (trifluoromethyl) benzene, - carbamyl -2-biphenyl, - carbamyl -2-bromo-4 , 6-difluorobenzene, - carbamyl -2-bromoethane, 1- (carbamyl) -2-bromobenzene, - carbamyl ■2 -chloro-4 -nitrobenzene, - carbamyl ■2 -chloro- 5- (trifluoromethyl) benzene, -2 -chloro-5-nitrobenzene,
-2 -chloro- 6 -methylbenzene ,
-2 -chlorobenzyl , 1- (carbamyl) -2 -chloroethane ,
-2 -chlorobenzene ,
-2 -cyanobenzene ,
-2-ethoxybenzene,
-2 -ethyl-6-methylbenzene ,
-2-ethylbenzene,
-2-fluoro-3- (trifluoromethyl) benzene,
-2-fluoro-5- (trifluoromethyl) benzene,
-2 -fluoro-5-methylbenzene ,
-2-fluoro-5-nitrobenzene ,
-2-fluoro-6- (trifluoromethyl) benzene,
-2-fluorobenzene, 1- (carbamyl) -2-iodobenzene,
-2- isopropyl-6-methylbenzene ,
-2 -isopropylbenzene ,
-2-methoxy-5-chloro benzene,
-2-methoxy-5-methylbenzene ,
-2 -methoxy-5 -nitrobenzene ,
-2 -methoxybenzene ,
-2-methyl-3 -nitrobenzene,
-2 -methyl-5 -nitrobenzene,
-2 -methyl-6 -1-butylbenzene ,
-1- (2 -methylphenyl) methane,
-2-n-propylbenzene,
-2-naphthalene, 1- (carbamyl) -2-nitrobenzene,
-2 -phenoxybenzene ,
-2 -tert-butylbenzene,
-3,4,5-trimethoxybenzene ,
-1- (3 , 4-dichlorophenyl) methane,
-3 , 4-dichlorobenzene,
-3 , 4 -difluorobenzene ,
-3,4 -dimethylbenzene,
-3,5 -bis (trifluoromethyl) benzene,
-3,5- dichlorobenzene,
-3 , 5-dimethoxybenzene,
Figure imgf000300_0001
-3 , 5 -dimethylbenzene, 1- (carbamyl) -3,5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
1- (carbamyl -3- (trifluoromethyl) benzene,
1- (carbamyl -3 - (trifluoromethylthio) benzene,
1- (carbamyl -3 -acetylbenzene ,
1- (carbamyl -3 -bromobenzene, 1- (carbamyl) -3-bromopropane,
1- (carbamyl -3 -carbomethoxybenzene ,
1- (carbamyl -3 -chloro-2 -methoxybenzene,
1- (carbamyl -3 -chloro-2 -methylbenzene ,
1- (carbamyl -3 -chloro-4 -fluorobenzene ,
1- (carbamyl -3 -chloro-4 -methylbenzene ,
1- (carbamyl -3 -chlorobenzene ,
1- (carbamyl -3 -chloropropane ,
1- (carbamyl -3 -cyanobenzene ,
1- (carbamyl -3 -cyclopentoxy-4 -methoxybenzene,
1- (carbamyl -3-ethylbenzene,
1- (carbamyl -3 -fluoro- -methylbenzene ,
1- (carbamyl -3-fluorobenzene, 1- (carbamyl) -3-iodopropane,
3- (carbamyl benzoyl chloride,
1- (carbamyl -3 -methoxybenzene ,
1- (carbamyl - (3 -methylphenyl) methane,
1- (carbamyl -3-nitrobenzene, 1- (carbamyl) -3-pyridine, ' - (carbamyl ) -5 ' -nitrobenzo-15-crown-5 , ' (carbamyl) benzo-15-crown-5, ' (carbamyl) benzo-18-crown-6 , - (carbamyl -4 , 5-dimethyl-2 -nitrobenzene, - (carbamyl -4- (6-methyl-2-benzothiazolyl) benzene, - (carbamyl -4- (chloromethyl) benzene, - (carbamyl -4- (chlorosulfonyl) benzene, - (carbamyl -4- (difluoromethoxy) benzene, - (carbamyl -4- (methylthio) benzene, - (carbamyl -4- (tert -butyl) benzene, - (carbamyl -4- (trifluoromethoxy) benzene, - (carbamyl -4- (trifluoromethyl) benzene, - (carbamyl -4- (trifluoromethylthio) benzene, - (carbamyl -4 -acetylbenzene, - (carbamyl -4-benzyloxybenzene, - (carbamyl -4 -bromo-2, 6 -dimethylbenzene, -4 -bromo-2- (trifluoromethyl) benzene,
-4 -bromo-2 -chlorobenzene ,
-4 -bromo-2 -fluorobenzene ,
-4 -bromo-2 -methylbenzene ,
- -bromobenzene ,
-4-chloro-2- (trifluoromethyl) benzene,
-4 -chloro-2 -methoxybenzene,
-4 -chloro-2 -methylbenzene,
-4 -chloro-2 -nitrobenzene,
-4-chloro-3- (trifluoromethyl) benzene,
-4 -chloro-3 -nitrobenzene ,
-4-chlorobenzene,
-4 -dimethylaminobenzene ,
-4 -ethoxybenzene ,
-4 -ethylbenzene ,
-4-fluoro-2- (trifluoromethyl) benzene,
-4 - fluoro-2 -nitrobenzene ,
-4-fluoro-3- (trifluoromethyl) benzene,
-4 - fluoro-3 -nitrobenzene ,
-4-fluorobenzoyl,
-4-fluorobenzyl ,
-4-fluorobenzene,
-4-heptyloxybenzene,
-4 - iodobenzene ,
-4 -isopropylbenzene ,
-4 -methoxy-2 -methylbenzene ,
- (4-methoxyphenyl) methane,
-4 -methoxybenzene ,
-4 -methyl-2 -nitrobenzene ,
-4 -methyl-3 -nitrobenzene ,
- (4 -methylphenyl) methane,
-4 -n-butoxycarbonylbenzene ,
-4 -n-butoxybenzene ,
-4 -n-butyl-2 -methylbenzene, 4 -n-butylbenzene , 4 -nitrobenzene ,
Figure imgf000302_0001
4 -phenoxybenzene , 1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (carbamyl) -5-chloro-2-methylbenzene,
1- (carbamyl) -5-fluoro-2 -methylbenzene, 1- (carbamyl) -5-iodopentane , 1 - (carbamyl) -2 -propene , benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl
2- (carbamyl) -3 -methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4- (methylthio) butyrate, ethyl
2- (carbamyl) -4-methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate, 1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane,
1 - (carbamyl) -2 -methylpropane , 1- (carbamyl ) ethyl methacrylate, 1- (carbamyl) -2 -methylethane, methyl
2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl
(carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane,
1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane,
1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane,
1- (carbamyl) -trichloroacetate and carbamyltrichloromethane; or
R3, R4 together with the nitrogen atom of Formula (I) form a ring selected from the group consisting of pyrrolidine, 4- (R) -hydroxy-2- (S) -pyrrolidine, 4-(R)- hydroxy-2- (R) -pyrrolidine, 4- (S) -hydroxy-2- (S) - pyrrolidine, 4- (S) -hydroxy-2- (S) -pyrrolidine, 4-(R)- benzyloxy-2- (S) -pyrrolidine, 4- (R) -benzyloxy-2- (R) - pyrrolidine, 4- (S) -benzyloxy-2- (S) -pyrrolidine, 4- (S) - benzyloxy-2- (S) -pyrrolidine, 4-piperidino, 3-(R)- piperidino, 3- (S) -piperidino, 2- (R) -piperidino, 2-(S)- piperidino, octahydroisoquinoline and dihydroindoyl ;
R5 is selected from the group consisting of methyl, t- butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4- methylphenyl , 4-fluorophenyl, 3-fluorophenyl, 4- cyanophenyl, 2 -methoxyphenyl, 3 -methoxyphenyl , 4- methoxyphenyl , 4 -chlorophenyl, 3 , 4-difluorophenyl , 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl, 3- methyl-4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, 3- chloro-4 -methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4-dichlorophenyl, 6- (2-oxo) -1 , 2 , 3 , 4- tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4- bromophenyl, 2- (5-chloro-3-methyl) benzo [2] thiophene, 6- (1, 1,4, 4-tetramethyl) -1, 2, 3, 4-tetrahydronaphthalene, 4- chlorophenyl, 1-pyrene, 5-[3-(3',4'- dichlorophenyl) ] isoxazole, 5-[3-(2',4'- dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole;
R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl ; or
R5 and R6 together with the triazole ring of Formula (I) form a ring structure selected from the group consisting of the structure
Figure imgf000304_0001
and the structure
Figure imgf000305_0001
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1, 4-phenylene, 2-methoxy-l, 4- phenylene, 2-chloro-l, 4-phenylene, 1, 4-phenylene, 2- methoxy-4 -chloro-1, 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l, 3-phenylene, 2-chloro- 1, 3-phenylene, 4-chloro-l , 3-phenylene, 6-chloro-l, 3- phenylene, 5 -carboxy-1, 3-phenylene, 5 -methoxycarbonyl - 1, 3-phenylene, 2 , 6-dimethoxy-l, 3 -phenylene, 2 , 5-dichloro- 1, 3-phenylene, 2 -bromo-1 , 3 -phenylene, 6 -bromo-1,3- phenylene and 2 , 6-dimethoxy-5-chloro-1, 3 -phenylene; and
R8 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl , 4 -methylbenzyl , 2-fluorobenzyl, 3 -fluorobenzyl, 4-fluorobenzyl, 3 - ( 1-imidazole) propyl , 4 -aminomethylbenzyl , 4 -methoxybenzyl, 3 -chlorobenzyl, 3-bromobenzyl , 4-bromobenzyl, cyclopropyl, cyclopropanemethyl,
4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2 - ( -chlorophenyl ) ethyl , 2 - (3 -chlorophenyl ) ethyl , 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5 -nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl , 2-aminoethyl,
2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl, 3- (2 -pipecolinyl) ropyl, 3-butoxypropyl , 3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl , 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl, tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl , trimethylacetyl, triphenylacetyl, nicotinyl, (3 , 4 -dimethoxyphenyl) acetyl , boc-isonipecotyl , (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl, 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl , 4-methyl-l-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3 -phenylene diacetyl, 2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl,
3, 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert-butyl-cyclohexanecarbonyl , 4-sulfonamidobenzoyl , 3,5,5 -1rimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl ,
5-bromo-2-chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl , 3-cyanobenzoyl, 3 -fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl, 3-methyl-2-thiophenecarbonyl , 3-phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl-4 -hydroxybenzoyl,
3 , 5 -dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl,
5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl ,
3-lndolepropionyl, 2, 2-diphenylacetyl, 5 -methoxyindole-2 -carbonyl, succinamyl,
4-dimethylaminobutyryl, 4- methylthiobenzoyl,
2-methylthionicotinyl, r(-) -2 -oxothiazolidine-4 -carbonyl,
4 -nitrophenylacetyl , coumarin-3 -carbonyl ,
1-cyano-1-cyclopropane carbonyl, 2-chloro-5- (methylthio) benzoyl , theophylline-7-acetyl,
2- (2-cyanophenylthio) benzoyl, 2-mesitylenesulfonyl,
2 -naphthalenesulfonyl , 2 -thiophenesulfonyl ,
4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl ,
4 -methoxybenzenesulfonyl , 4 -methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl ,
2 -acetamido-4 -methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4 -tert -butylbenzenesulfonyl , 8 -quinolinesulfonyl , 2 , 3 -dichlorothiophene-5-sulfonyl ,
3 , 4 -dimethoxybenzenesulfonyl ,
3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl,
2,3, 4-trifluorobenzenesulfonyl,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5 -dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl, 2 , 6-difluorobenzenesulfonyl, 2-chloro-4- (trifluoromethyl) benzenesulfonyl,
2-chloro-5- (trifluoromethyl) benzenesulfonyl ,
2 -chloro-6 -methylbenzenesulfonyl,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl, 4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4 -sulfonyl, 2- (methoxycarbonyl) thiophene-3 -sulfonyl ,
4 -acetamido-3 -chlorobenzene sulfonyl,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl,
5- (isoxazol-3-yl) thiophene-2-sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4 -difluorobenzenesulfonyl , 2 -fluorobenzenesulfonyl ,
4 -isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl,
3 , 4 -dichlorobenzenesulfonyl ,
(2s, 3s) -2- (carbamyl) -3-methylvalerate methyl ester, (r) - (-) -1- (carbamyl) - (1-naphthyl) ethane, (s) - (+) -1- (carbamyl) - (1-naphthyl) ethane, (s) -(+) -2- (carbamyl) -3 -tert-butoxypropionate methyl ester, (s) -(-) -2- (carbamyl) -3 -methylbutyrate methyl ester, (s) -(-) -2- (carbamyl) -4- (methylthio) butyrate methyl ester, (s) -(-) -2- (carbamyl) -4 -methylvalerate methyl ester, (s) -(-) -2- (carbamyl) glutarate diethyl ester, (s) -(-) -2- (carbamyl) propionate methyl ester,
(s) -2- (carbamyl) -3 - phenylpropionate methyl ester,
1- (carbamyl) -tridecafluoro- 1-hexane,
1- (carbamyl) -1,1,3, 3 -tetramethylbutane,
1- (carbamyl) - (1-naphthyl) ethane, 1- (carbamyl) - (4 -bromophenyl) ethane,
1- (carbamyl) -adamantane , 1- (carbamyl) naphthalene ,
1- (carbamyl) -2,3, 4-trifluorobenzene,
1- (carbamyl) -2,3 -dichlorobenzene,
1- (carbamyl) -2 , 3 -dimethylbenzene, 1- (carbamyl) -2,4, 5-trichlorobenzene,
1- (carbamyl) -2,4,5-1rimethylbenzene ,
1- (carbamyl) -2,4,6 -1richlorobenzene ,
1- (carbamyl) -2 , 4-dichlorobenzene, 1- (carbamyl) -2,4- difluorobenzene, 1- (carbamyl) -2 , 4-dimethoxybenzene, 1- (carbamyl) -2 , -dimethylbenzene,
1- (carbamyl) -2 , 5-dichlorobenzene, -2 , 5-difluorobenzene,
-2,5-dimethoxybenzene ,
-2,5- dimethylbenzene,
-2 , 6 -dibromo-4-fluorobenzene,
-2,6-dibromo-4 - isopropylbenzene ,
-2 , 6 -dichlorobenzene,
-2 , 6-diethylbenzene,
-2 , 6-difluorobenzoyl,
-2 , 6-difluorobenzene,
-2 , 6-diisopropylbenzene,
-2 , 6 -dimethylbenzene,
-2- (chloromethyl) benzene,
-2- (difluoromethoxy) benzene,
-2- (methylthio) benzene,
-2- (trifluoromethoxy) benzene,
-2- (trifluoromethyl) benzene,
-2-biphenyl,
-2 -bromo-4 , 6-difluorobenzene,
-2-bromoethane, 1- (carbamyl) -2-bromobenzene,
-2 -chloro-4 -nitrobenzene ,
-2 -chloro-5- (trifluoromethyl) benzene,
-2 -chloro-5 -nitrobenzene ,
-2 -chloro- 6-methylbenzene ,
-2 -chlorobenzyl , 1 - (carbamyl ) -2 -chloroethane ,
-2 -chlorobenzene,
-2 -cyanobenzene ,
-2 -ethoxybenzene ,
-2 -ethyl -6 -methylbenzene ,
-2 -ethylbenzene ,
-2-fluoro-3 - (trifluoromethyl) benzene,
-2-fluoro-5- (trifluoromethyl) benzene,
-2 -fluoro-5-methylbenzene ,
-2 - fluoro-5-nitrobenzene ,
-2-fluoro- 6- (trifluoromethyl) benzene,
-2-fluorobenzene, 1- (carbamyl) -2-iodobenzene,
-2 - isopropyl-6 -methylbenzene ,
Figure imgf000309_0001
-2 - isopropylbenzene , 1- (carbamyl) -2 -methoxy-5-chloro benzene,
1- (carbamyl) -2 -methoxy-5 -methylbenzene,
1- (carbamyl) -2 -methoxy-5 -nitrobenzene,
1- (carbamyl) -2-methoxybenzene,
1- (carbamyl) -2 -methyl-3 -nitrobenzene,
1- (carbamyl) -2 -methyl-5 -nitrobenzene,
1- (carbamyl) -2-methyl-6-t-butylbenzene,
1- (carbamyl) -1- (2 -methylphenyl) methane,
1- (carbamyl) -2-n-propylbenzene,
1- (carbamyl) -2-naphthalene, 1- (carbamyl) -2-nitrobenzene,
1- (carbamyl) -2-phenoxybenzene,
1- (carbamyl) -2-tert-butylbenzene,
1- (carbamyl) -3,4, 5-trimethoxybenzene,
1- (carbamyl) -1- (3 , 4-dichlorophenyl) methane,
1- (carbamyl) -3 , 4-dichlorobenzene,
1- (carbamyl) -3 , 4-difluorobenzene,
1- (carbamyl) -3 , 4 -dimethylbenzene,
1- (carbamyl) -3 , 5-bis (trifluoromethyl) benzene,
1- (carbamyl) -3,5- dichlorobenzene,
1- (carbamyl) -3 , 5 -dimethoxybenzene,
1- (carbamyl) -3,5-dimethylbenzene, 1- (carbamyl) -3,5- dinitrobenzene, 1- (carbamyl) -3- (methylthio) benzene,
1- (carbamyl) -3- (trifluoromethyl) benzene,
1- (carbamyl) -3- (trifluoromethylthio) benzene,
1- (carbamyl) -3-acetylbenzene,
1- (carbamyl) -3 -bromobenzene, 1- (carbamyl) -3-bromopropane,
1- (carbamyl) -3-carbomethoxybenzene,
1- (carbamyl) -3-chloro-2-methoxybenzene,
1- (carbamyl) -3-chloro-2-methylbenzene,
1- (carbamyl) -3 -chloro-4 -fluorobenzene,
1- (carbamyl) -3-chloro-4-methylbenzene,
1- (carbamyl) -3 -chlorobenzene,
1- (carbamyl) -3 -chloropropane,
1- (carbamyl) -3-cyanobenzene,
1- (carbamyl) -3 -cyclopentoxy-4 -methoxybenzene,
1- (carbamyl) -3-ethylbenzene,
1- (carbamyl) -3-fluoro-4 -methylbenzene, - (carbamyl) -3 -fluorobenzene, 1- (carbamyl) -3-iodopropane,
- (carbamyl) benzoyl chloride,
- (carbamyl) -3 -methoxybenzene,
- (carbamyl) - (3 -methylphenyl) methane,
- (carbamyl) -3-nitrobenzene, 1- (carbamyl) -3-pyridine,
1 - (carbamyl) -5 ' -nitrobenzo-15-crown-5,
1 - (carbamyl) benzo-15-crown-5,
' - (carbamyl) benzo-18-crown-6,
• (carbamyl -4 , 5 -dimethyl-2 -nitrobenzene, (carbamyl -4- (6-methyl-2-benzothiazolyl) benzene,
■ (carbamyl -4- (chloromethyl) benzene, (carbamyl -4- (chlorosulfonyl) benzene, (carbamyl -4- (difluoromethoxy) benzene, (carbamyl -4- (methylthio) benzene, (carbamyl -4- (tert -butyl) benzene, (carbamyl -4- (trifluoromethoxy) benzene, (carbamyl -4- (trifluoromethyl) benzene, (carbamyl -4- (trifluoromethylthio) benzene, (carbamyl -4 -acetylbenzene, (carbamyl -4 -benzyloxybenzene , (carbamyl -4 -bromo-2 , 6 -dimethylbenzene, (carbamyl -4 -bromo-2- (trifluoromethyl) benzene, (carbamyl -4 -bromo-2 -chlorobenzene , (carbamyl -4 -bromo-2 - fluorobenzene , (carbamyl -4 -bromo-2 -methylbenzene , (carbamyl -4 -bromobenzene , (carbamyl -4 -chloro-2- (trifluoromethyl) benzene, (carbamyl -4 -chloro-2 -methoxybenzene , (carbamyl -4 -chloro-2 -methylbenzene, (carbamyl -4 -chloro-2 -nitrobenzene, (carbamyl -4 -chloro-3 - (trifluoromethyl) benzene , (carbamyl -4 -chloro-3 -nitrobenzene , (carbamyl -4 -chlorobenzene , (carbamyl -4 -dimethylaminobenzene , (carbamyl -4 -ethoxybenzene , (carbamyl -4-ethylbenzene, (carbamyl -4-fluoro-2- (trifluoromethyl) benzene, 1- (carbamyl) -4-fluoro-2 -nitrobenzene,
1- (carbamyl) -4-fluoro-3- (trifluoromethyl) benzene,
1- (carbamyl) -4-fluoro-3 -nitrobenzene,
1- (carbamyl) -4-fluorobenzoyl,
1- (carbamyl) -4-fluorobenzyl,
1- (carbamyl) -4-fluorobenzene,
1- (carbamyl) -4-heptyloxybenzene,
1- (carbamyl) -4-iodobenzene,
1- (carbamyl) -4 -isopropylbenzene,
1- (carbamyl) -4 -methoxy-2 -methylbenzene,
1- (carbamyl) - (4-methoxyphenyl) methane,
1- (carbamyl) -4 -methoxybenzene,
1- (carbamyl) -4-methyl-2-nitrobenzene,
1- (carbamyl) -4 -methyl-3 -nitrobenzene,
1- (carbamyl) - (4 -methylphenyl) methane,
1- (carbamyl) -4-n-butoxycarbonylbenzene,
1- (carbamyl) -4-n-butoxybenzene,
1- (carbamyl) -4-n-butyl-2-methylbenzene,
1- (carbamyl) -4-n-butylbenzene,
1- (carbamyl) -4 -nitrobenzene,
1- (carbamyl) -4-phenoxybenzene,
1- (carbamyl) -5-bromopenane,
1- (carbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (carbamyl) -5-chloro-2-methylbenzene,
1- (carbamyl) -5-fluoro-2 -methylbenzene,
1- (carbamyl) -5-iodopentane, 1- (carbamyl) -2-propene, benzoyl carbamyl, 1- (carbamyl) -1-phenylmethane,
1- (carbamyl) -cyclohexane, carboxyethylcarbamyl, ethyl
2- (carbamyl) -3-methylbutyrate, ethyl
2- (carbamyl) -3 -phenylpropionate, ethyl 2- (carbamyl) -4-
(methylthio) butyrate, ethyl
2- (carbamyl) -4 -methylvalerate, ethyl
2- (carbamyl) benzoate, ethyl 2- (carbamyl) propionate, ethyl
3- (carbamyl) benzoate, ethyl 3- (carbamyl) propionate, ethyl
4- (carbamyl) -benzoate, ethyl 6- (carbamyl) hexanoate,
1- (carbamyl) -ethyl, ethyl (carbamyl) acetate,
1- (carbamyl) -heptane, 1- (carbamyl) -hexane, 1- (carbamyl) -2-methylpropane, 1- (carbamyl) ethyl methacrylate, 1- (carbamyl) -2-methylethane, methyl 2- (carbamyl) benzoate, carbamylmethane, methyl (carbamyl) propionate, 1- (carbamyl) butane, n-butyl (carbamyl) acetate, 1- (carbamyl) -propane,
1- (carbamyl) -pentane, 1- (carbamyl) -phenylthane, 1- (carbamyl) -benzene, 1- (carbamyl) -2 , 2 -dimethylpropane, 1- (carbamyl) -tetrahydro-2-pyran, 1- (carbamyl) -trans-2-benzenecyclopropane, 1- (carbamyl) -trichloroacetate and carbamyltrichloromethane .
35. The single compound of claim 19, wherein q is 0 or 1;
Rx is a hydrogen atom;
R2 is a hydrogen atom;
R3 is selected from the group consisting of 1,2-ethylene, 1, 3-propylene, 1, 4-butylene, 1, 5-pentylene, 1 , 6-hexylene, 1, 7-heptanylene, 1, 8-octanylene, cyclohexyl-4 -methylene, 1-methyl-l, 1-ethylene, D-1, 1-butylene, D-1, 1-ethylene, D- 1 , 1-pentylene, D-1, 1-propylene, D-5-amino-l , 1-pentylene, D-l-amino-1, 5-pentylene, D-2- (2-napthyl) -1, 1-ethylene, D- 2- (2-thienyl) -1, 1-ethylene, D-2- (4-ethoxyphenyl) -1, 1- ethylene, D-2- (4-fluoropehnyl) -1, 1-ethylene, D-2- (4- hydroxyphenyl) -1, 1-ethylene, D-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, D-2-carboxamide-1, 1-ethylene, D-2- carboxamide-1, 2 -ethylene, D-2-carboxy-l , 2-ethylene, D-2- cyclohexyl-1, 1-ethylene, D-2 -hydroxy-1 , 1-ethylene, D-2- hydroxy-1, 1-ethylene, D-2 -hydroxy-1 , 1-propylene, D-2- mercapto-1, 1-ethylene, D-2-methyl-l , 1-butylene, D-2- methyl-1, 1-propylene, D-2-phenyl-l , 1-ethylene, D-3- carboxamido-1 , 1-propylene, D-3 -carboxamido-1, 3-propylene, D-3 -carboxy- 1 , 1-propylene, D-3 -carboxyl-1 , 3-propylene, D- 3 -methyl-1, 1-butylene, D-4 -ureido-1 , 1-butylene, D-5- (9- fluorenylmethoxycarboxamido) -1, 1-pentylene, D-5- acetamiode-1, 1-pentylene, D-5-amino-l, 1-pentylene, D- methylthio-1, 1-propylene, phenylmethylene, D- t- butylmethylene, 1,2-ethylene, 1, 3-propylene, 1,4- butylene, 1, 5-pentylene, 1 , 6-hexylene, 1-methyl-l, 1- ethylene, L-l, 1-butylene, L-l, 1-ethylene, L-1,1- pentylene, 1, 1-propylene, L-5 -amino-1, 1-pentylene, L-l- amino-1, 5-pentylene, L-2- (2-napthyl) -1, 1-ethylene, L-2- (2-thienyl) -1, 1-ethylene, L-2- (4-ethoxyphenyl) -1,1- ethylene, L-2- (4-fluoropehnyl) -1, 1-ethylene, L-2- (4- hydroxyphenyl ) -1, 1-ethylene, L-2- (N-formyl-indol-3-yl) - 1, 1-ethylene, L-2 -carboxamide-1 , 1-ethylene, L-2- carboxamide-1, 2-ethylene, L-2 -carboxy-1, 2 -ethylene, L-2- cyclohexyl-1, 1-ethylene, L-2 -hydroxy-1 , 1-ethylene, L-2- hydroxy-1, 1-ethylene, L-2 -hydroxy-1, 1-propylene, L-2- mercapto-1, 1-ethylene, L-2-methyl-l , 1-butylene, L-2- methyl-1, 1-propylene, L-2 -phenyl-1, 1-ethylene, L-3- carboxamido-1, 1-propylene, L-3 -carboxamido-1 , 3-propylene, L-3 -carboxy-1, 1-propylene, L-3 -carboxyl-1 , 3-propylene, L- 3 -methyl-1, 1-butylene, L-4-ureido-l, 1-butylene, L-5- (9- fluorenylmethoxycarboxamido) -1, 1-pentylene, L-5- acetamiode-1, 1-pentylene, L-5-amino-l, 1-pentylene, methylthio- 1, 1-propylene, L-phenylmethylene, L-t- butylmethylene, 3 -methoxy-1 , 4-phenylene, 2-methoxy-l, 4- phenylene, 2-chloro-l, 4-phenylene, 1, 4-phenylene, 2- methoxy-4 -chloro-1 , 4-phenylene, 4-methoxy-l , 3-phenylene,
2-chloro-l, 3-phenylene, 4-chloro-l, 3-phenylene, 6-chloro-
1, 3-phenylene, 5-carboxy-1, 3-phenylene, 5- methoxycarbonyl-1, 3-phenylene, 2 , 6-dimethoxy-l, 3- phenylene, 2 , 5-dichloro-l, 3 -phenylene, 2-bromo-l,3- phenylene, 6 -bromo- 1, 3-phenylene and 2 , 6-dimethoxy-5- chloro-1 , 3-phenylene; or R3 is of the formula (II) , (III) , (IV) or (V)
Figure imgf000315_0001
N
R 13 \
Figure imgf000315_0002
Figure imgf000315_0003
(IV) (V) wherein n is 1; m is 3 or 4;
R12 is a hydrogen atom;
R13 is a hydrogen atom; and
R14 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2 -methylbenzyl, 3 -methylbenzyl , 4 -methylbenzyl , 2-fluorobenzyl, 3-fluorobenzyl , 4-fluorobenzyl, 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4 -methoxybenzyl , 3 -chlorobenzyl , 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4 -chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5 -nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3 - (dimethylamino) propyl, 2-aminoethyl,
2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl,
3 - (2 -pipecolinyl) propyl , 3 -butoxypropyl ,
3- (pyrrolidin-2-one-l-yl) propyl, 3- (morpholino) propyl,
2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1-propyl, 2-methyl-2-phenylethyl, 4-phenylbutyl,
3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl , tetrahydro-3-furoyl, trans-3 - (3-pyridyl) acrylyl, trimethylacetyl, triphenylacetyl , nicotinyl, (3 , 4 -dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl,
1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 - isopropoxybenzoyl , 2 , 4-dichlorobenzoyl, 4 -methyl-1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3-phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl, 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl , 3 , 4 -dichlorophenylacetyl , 4 -tert-butyl-cyclohexanecarbonyl , 4 -sulfonamidobenzoyl , 3,5, 5-trimethylhexanoyl, 3 , 5-bis (trifluoromethyl) -benzoyl,
5 -bromo-2 -chlorobenzoyl, 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl -p-anisyl, 3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl, 3-fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl, 3 -methyl-2 -thiophenecarbonyl , 3 -phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) - andelyl, 3 , 5-di-tert-butyl-4 -hydroxybenzoyl, 3 , 5 -dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5-methylsalicylyl, 2 -methylcyclopropanecarbonyl , 3 - lndolepropionyl , 2 , 2 -diphenylacetyl , 5 -methoxyindole-2 -carbonyl , succinamyl , 4-dimethylaminobutyryl, 4- methylthiobenzoyl, 2-methylthionicotinyl, r(-) -2 -oxothiazolidine-4 -carbonyl , 4-nitrophenylacetyl , coumarin-3 -carbonyl, 1-cyano-1-cyclopropane carbonyl,
2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl , 2- (2-cyanophenylthio) benzoyl, 2-mesitylenesulfonyl, 2 -naphthalenesulfonyl , 2 -thiophenesulfonyl , 4 -chlorobenzenesulfonyl, 4-fluorobenzenesulfonyl, 4 -methoxybenzenesulfonyl ,
4-methylsulfonylbenzenesulfonyl, benzenesulfonyl , dansyl, n-acetylsulfanilyl , 2 -acetamido-4 -methyl-5-thiazolesulfonyl , 4- (trifluoromethoxy) benzenesulfonyl,
4-tert-butylbenzenesulfonyl, 8-quinolinesulfonyl,
2 , 3 -dichlorothiophene- 5-sulfonyl,
3 , 4 -dimethoxybenzenesulfonyl,
3 , 5-bis (trifluoromethyl) benzenesulfonyl , 3-chloro-4 -fluorobenzenesulfonyl,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2, 5-dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl, 2, 6-difluorobenzenesulfonyl, 2-chloro-4- (trifluoromethyl) benzenesulfonyl,
2 -chloro-5- (trifluoromethyl) benzenesulfonyl,
2 -chloro-6 -methylbenzenesulfonyl ,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5 -dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl, 4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4 -sulfonyl,
2- (methoxycarbonyl) thiophene-3 -sulfonyl,
4 -acetamido-3 -chlorobenzene sulfonyl ,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3 -yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl,
3-methoxy-4- (methoxycarbonyl) -thiophene-2 -sulfonyl,
5- (isoxazol-3-yl) thiophene-2-sulfonyl, 4-cyanobenzene sulfonyl, 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4-difluorobenzenesulfonyl, 2-fluorobenzenesulfonyl, -isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl and 3 , 4 -dichlorobenzenesulfonyl ; or
Ri4 is of the formula:
Figure imgf000318_0001
wherein R15 is selected from the group consisting of a hydrogen atom, methyl, t-butyl, carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4 -methylphenyl , 4-fluorophenyl, 3 fluorophenyl, 4-cyanophenyl, 2 -methoxyphenyl , 3- methoxyphenyl , 4-methoxyphenyl, 4 -chlorophenyl, 3,4- difluorophenyl, 4-nitrophenyl, 3 , 4-dihydroxyphenyl, 3- nitrophenyl, 3 -methyl -4 -chlorophenyl, adamantyl, 2,5- dimethoxyphenyl , 3 -chloro-4 -methylphenyl , 5- (3- carboethoxy) isoxazole, 4 -phenylphenyl , 3,4- dichlorophenyl, 6- (2-oxo) -1, 2 , 3 , 4-tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4 -bromophenyl, 2- (5-chloro- 3 -methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) - 1, 2, 3 , 4-tetrahydronaphthalene, 4 -chlorophenyl , 1-pyrene, 5- [3- (3 ' ,4 ' -dichlorophenyl) ] isoxazole, 5- [3- (2 ' ,4 ' - dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole; and Ri6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N,N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or R14, R15 and Ri6 together form a ring structure selected from the group consisting of the structure
Figure imgf000319_0001
and the structure
Figure imgf000319_0002
R4 is selected from the group consisting of a hydrogen atom and acetyl; or
R3, R4 together with the nitrogen atom of Formula (I) form a pyrrolidine ring;
R5 is selected from the group consisting of methyl, t- butyl, carbomethoxymethyl , ethyl, carboethoxymethyl, carboxy, trifluormethyl , carboethoxy, phenyl, 4- methylphenyl, 4-fluorophenyl , 3-fluorophenyl, 4- cyanophenyl, 2 -methoxyphenyl , 3 -methoxyphenyl , 4- methoxyphenyl, 4 -chlorophenyl, 3 , 4-difluorophenyl, 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl , 3- methyl-4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, 3- chloro-4 -methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4-dichlorophenyl , 6- (2-oxo) -1, 2 , 3 , - tetrahydroquinoline , 4 - (5 -methyl-3 -phenyl ) isoxazole , 4 - bromophenyl, 2- (5-chloro-3-methyl) benzo [2] thiophene, 6- (1,1,4, 4-tetramethyl) -1,2,3, 4-tetrahydronaphthalene, 4- chlorophenyl , 1-pyrene, 5-[3-(3',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ' , 4 ' - dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole;
R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N, N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or
R5 and R5 together with the triazole ring of Formula (I) form a ring structure selected from the group consisting of the structure
Figure imgf000320_0001
and the structure
Figure imgf000320_0002
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1, 4-phenylene, 2-methoxy-l, 4- phenylene, 2-chloro-l , 4-phenylene, 1 , 4-phenylene, 2- methoxy-4 -chloro-1, 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l, 3-phenylene, 2-chloro- 1, 3-phenylene, 4-chloro-l, 3-phenylene, 6 -chloro-1, 3- phenylene, 5 -carboxy-1 , 3-phenylene, 5-methoxycarbonyl - 1, 3-phenylene, 2, 6-dimethoxy-l, 3-phenylene, 2 , 5-dichloro- 1, 3-phenylene, 2 -bromo-1, 3-phenylene, 6 -bromo- 1,3- phenylene and 2 , 6-dimethoxy-5-chloro-l, 3-phenylene; and
R8 is selected from the group consisting of a hydrogen atom and acetyl .
36. The single compound of claim 9, wherein q is 0 or 1;
Ri is a hydrogen atom;
R2 is a hydrogen atom;
R3 is of the formula (II) , (III) , (IV) or (V) :
Figure imgf000322_0001
Figure imgf000322_0002
CH.
Jm N — R14
N R 14 R13
R 13
(IV) (V)
wherein n is 1; m is 3 or 4 ;
R12 is a hydrogen atom;
R13 is a hydrogen atom; and
R14 is selected from the group consisting of a hydrogen atom, 2-pyridinemethyl, allyl, 2-methoxyethyl, benzyl, 2-methylbenzyl, 3 -methylbenzyl, 4 -methylbenzyl, 2-fluorobenzyl, 3 -fluorobenzyl , 4-fluorobenzyl, 3- (1-imidazole) propyl, 4-aminomethylbenzyl, 4-methoxybenzyl, 3 -chlorobenzyl , 3-bromobenzyl, 4-bromobenzyl, cyclopropyl, cyclopropanemethyl, 4-pyridinemethyl, 3-pyridinemethyl, 2-thiophenemethyl, phenethyl, 2- (morpholine) ethyl, 3- methoxybenzyl, piperonylmethyl, 4-methoxyphenethyl, 2-fluorophenethyl, 2- (4-chlorophenyl) ethyl, 2- (3 -chlorophenyl) ethyl, 2- (2 -chlorophenyl) ethyl, 2 , 3-dimethoxy-benzyl, 3 , 4-dimethoxyphenethyl, 2,4- dichlorophenethyl, 2- (diethylamino) ethyl, 2- (l-methylpyrrolidin-2-yl) ethyl, 3- (diethylamino) propyl, 2- (5-nitro-2-pyridyl) ethyl, 3- (dimethylamino) -2 , 2-dimethylpropyl, 3- (dimethylamino) propyl, 2-aminoethyl, 2- (piperidino) ethyl, isoamyl, 3 -ethoxypropyl , 3- (2 -pipecolinyl) propyl, 3-butoxypropyl,
3- (pyrrolidin-2-one-l-yl)propyl, 3- (morpholino) propyl, 2- (N-ethyl-3-methylanilino) ethyl, 3 -phenyl-1 -propyl, 2 -methyl-2 -phenylethyl , 4 -phenylbutyl , 3 , 3-diphenylpropyl, isobutyl, 2- (2-pyridyl) ethyl, cyclohexanemethyl, 3-methoxyphenethyl, 3-phenylbenzyl, acetyl, alpha-methylcinnamyl , benzoyl, crotonyl, cyclobutanecarbonyl , cyclohexanepropionyl , 4-cyanobenzoyl, hydrocinnamyl, 4-dimethylaminobenzoyl, 4-ethoxybenzoyl, isobutyryl, 4-ethoxyphenylacetyl, isovaleryl, levulinyl, m-anisyl, m-toluyl, methoxyacetyl, isonicotinyl, p-tolylacetyl, picolinyl, piperonylyl, 4-fluoro-alpha- methylphenylacetyl, 4-fluorophenylacetyl , tetrahydro-3-furoyl, trans-3- (3-pyridyl) acrylyl, trimethylacetyl , triphenylacetyl , nicotinyl, (3 , 4-dimethoxyphenyl) acetyl, boc-isonipecotyl, (alpha-alpha-alpha-trifluoro-m-tolyl) acetyl, (methylthio) acetyl , (phenylthio) acetyl , 1- (4 -chlorophenyl) -1- cyclopentanecarbonyl , 1-adamantaneacetyl, 1-naphthylacetyl, 1-phenyl-l- cyclopropanecarbonyl, 4-iodobenzoyl, 4 -isopropoxybenzoyl, 2 , 4-dichlorobenzoyl , 4 -methyl -1-cyclohexanecarbonyl, pyrrole-2- carbonyl, 4-methylvaleryl, 1-naphthylacetyl, 2-fluorobenzoyl, 1, 3-phenylene diacetyl,
2-norbornaneacetyl, 2-pyrazinecarbonyl, 2-pyridylacetyl, 2-thiopheneacetyl, 3,4,5- triethoxybenzoyl, 3 , 4-methylenedioxyphenylacetyl , 3 , 4-dichlorobenzoyl, 4- isopropylbenzoyl, 3 , 4-dichlorophenylacetyl,
4 -tert-butyl-cyclohexanecarbonyl, 4-sulfonamidobenzoyl, 3,5,5 -1rimethylhexanoyl , 3 , 5-bis (trifluoromethyl) -benzoyl, 5-bromo-2-chlorobenzoyl , 5-bromonicotinyl, 6-chloronicotinyl, 3 , 5-dimethyl-p-anisyl,
3 -bromo-4 -methylbenzoyl, 3,4,5- trimethoxyphenylacetyl, 3 -benzoylpropionyl, 3 , 5-dichlorobenzoyl, 3-cyanobenzoyl, 3-fluoro-4 -methylbenzoyl, 1-isoquinolinecarbonyl , 3 -methyl-2 -thiophenecarbonyl , 3 -phenoxybenzoyl , 3-thiopheneacetyl, 4-biphenylacetyl, 4-bromophenylacetyl, s- (+) -mandelyl, 3 , 5-di-tert-butyl -4 -hydroxybenzoyl, 3 , 5 -dichloro-4 -hydroxybenzoyl, 4- hydroxybenzoyl, 5 -methylsalicylyl , 2 -methylcyclopropanecarbonyl ,
3 - lndolepropionyl , 2 , 2 -diphenylacetyl , 5 -methoxyindole-2 -carbonyl, succinamyl,
4-dimethylaminobutyryl, 4- methylthiobenzoyl,
2-methylthionicotinyl, r(-) -2 -oxothiazolidine-4 -carbonyl,
4-nitrophenylacetyl , coumarin-3 -carbonyl,
1-cyano-l-cyclopropane carbonyl, 2-chloro-5- (methylthio) benzoyl, theophylline-7-acetyl,
2- (2 -cyanophenylthio) benzoyl, 2-mesitylenesulfonyl,
2-naphthalenesulfonyl , 2-thiophenesulfonyl,
4 -chlorobenzenesulfonyl , 4 -fluorobenzenesulfonyl ,
4 -methoxybenzenesulfonyl , 4-methylsulfonylbenzenesulfonyl, benzenesulfonyl, dansyl, n-acetylsulfanilyl ,
2-acetamido-4-methyl-5-thiazolesulfonyl,
4- (trifluoromethoxy) benzenesulfonyl,
4 -tert -butylbenzenesulfonyl , 8 -quinolinesulfonyl , 2 , 3 -dichlorothiophene-5-sulfonyl ,
3 , 4 -dimethoxybenzenesulfonyl , 3 , 5-bis (trifluoromethyl) benzenesulfonyl,
3 -chloro-4 -fluorobenzenesulfonyl ,
3 -trifluoromethylbenzenesulfonyl , 4-ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , 2,3, 4 -trifluorobenzenesulfonyl ,
2 , 4 -dichlorobenzenesulfonyl ,
2 , 5-dichlorothiophene-3 -sulfonyl,
2 , 6-dichlorobenzenesulfonyl , 2 , 6 -difluorobenzenesulfonyl ,
2 -chloro-4- (trifluoromethyl) benzenesulfonyl, 2-chloro-5- (trifluoromethyl) benzenesulfonyl ,
2 -chloro-6 -methylbenzenesulfonyl,
3 , 4 -difluorobenzenesulphonyl ,
3 , 5-dichlorobenzenesulfonyl, 3 -chlorobenzenesulfonyl ,
4- (n-butoxy) benzenesulfonyl, 4-trifluoromethylbenzene sulfonyl, 3,5- dimethylisoxazole-4-sulfonyl,
2- (methoxycarbonyl) thiophene-3 -sulfonyl,
4 -acetamido-3 -chlorobenzene sulfonyl ,
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5-s ulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl,
5- (isoxazol-3-yl) thiophene-2 -sulfonyl, 4-cyanobenzene sulfonyl , 3 -chloro-4 -methylbenzenesulfonyl ,
2 , 4 -difluorobenzenesulfonyl , 2 -fluorobenzenesulfonyl ,
4 -isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl and 3 , 4 -dichlorobenzenesulfonyl ;
R4 is selected from the group consisting of a hydrogen atom and acetyl; or
R3, R4 together with the nitrogen atom of Formula (I) form a pyrrolidine ring;
R5 is selected from the group consisting of methyl, t- butyl , carbomethoxymethyl, ethyl, carboethoxymethyl, carboxy, trifluormethyl, carboethoxy, phenyl, 4- methylphenyl , 4 -fluorophenyl, 3 -fluorophenyl, 4- cyanophenyl, 2 -methoxyphenyl, 3 -methoxyphenyl , 4- methoxyphenyl, 4 -chlorophenyl, 3 , 4-difluorophenyl, 4- nitrophenyl, 3 , 4-dihydroxyphenyl, 3-nitrophenyl, 3- methyl -4 -chlorophenyl, adamantyl, 2 , 5-dimethoxyphenyl, chloro-4 -methylphenyl, 5- (3 -carboethoxy) isoxazole, 4- phenylphenyl , 3 , 4-dichlorophenyl, 6- (2-oxo) -1, 2 , 3 , 4- tetrahydroquinoline, 4- (5-methyl-3 -phenyl) isoxazole, 4- bromophenyl, 2- (5-chloro-3-methyl)benzo [2] thiophene, 6- (1,1,4,4 -1etramethyl ) -1,2,3,4-1etrahydronaphthalene , 4 - chlorophenyl, 1-pyrene, 5-[3-(3',4'- dichlorophenyl) ] isoxazole, 5- [3- (2 ' , 4 ' - dichlorophenyl) ] isoxazole and 5- (3-phenyl) isoxazole;
R6 is selected from the group consisting of a hydrogen atom, methyl, acetyl, N-methylcarboxamide, carbomethoxy, N,N-dimethylcarboxamide, carboethoxy, phenyl and 4- methylphenyl; or
R5 and R6 together with the triazole ring of Formula (I) form a ring structure selected from the group consisting of the structure
Figure imgf000326_0001
and the structure
Figure imgf000326_0002
R7 is selected from the group consisting of 1,3- phenylene, 3 -methoxy-1 , 4-phenylene, 2-methoxy-l , 4- phenylene, 2-chloro-l, 4-phenylene, 1, 4-phenylene, 2- methoxy-4-chloro-l, 4-phenylene, (need fragment name for 4-aminohippric acid), 4-methoxy-l, 3-phenylene, 2-chloro- 1, 3-phenylene, 4-chloro-l, 3-phenylene, 6-chloro-l, 3- phenylene, 5-carboxy-1, 3-phenylene, 5-methoxycarbonyl- 1, 3-phenylene, 2 , 6-dimethoxy-l, 3 -phenylene, 2 , 5-dichloro- 1 , 3-phenylene, 2-bromo-1, 3-phenylene, 6-bromo-1,3- phenylene and 2 , 6-dimethoxy-5-chloro-1 , 3-phenylene; and
R8 is selected from the group consisting of a hydrogen atom and acetyl .
PCT/US2000/003475 1999-02-08 2000-02-08 Thiazole derivatives and combinatorial libraries thereof WO2000045635A1 (en)

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US7141564B2 (en) 2001-05-25 2006-11-28 Smithkline Beecham P.L.C. Nitrogen-containing bicyclic heterocycles for use as antibacterials
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US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
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JP2016528180A (en) * 2013-06-11 2016-09-15 レセプトス， インコーポレイテッド Novel GLP-1 receptor modulator
US10259823B2 (en) 2013-06-11 2019-04-16 Celgene International Ii Sàrl GLP-1 receptor modulators
US10329265B2 (en) 2014-08-22 2019-06-25 Duke University TRPA1 and TRPV4 inhibitors and methods of using the same for organ-specific inflammation and itch
US11014896B2 (en) 2014-08-22 2021-05-25 Duke University TRPA1 and TRPV4 inhibitors and methods of using the same for organ-specific inflammation and itch
JP2017538711A (en) * 2014-12-10 2017-12-28 セルジーン インターナショナル ツー エスエーアールエル GLP-1 receptor modulator
US11229628B2 (en) 2015-01-09 2022-01-25 Duke University TRPA1 and TRPV4 inhibitors and methods of using the same for organ-specific inflammation and itch
US11564911B2 (en) 2016-04-07 2023-01-31 Duke University Small molecule dual-inhibitors of TRPV4 and TRPA1 for sanitizing and anesthetizing

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