WO2000025768A1 - Oxadiazole, thiadiazole and triazole derivatives and combinatorial libraries thereof - Google Patents

Oxadiazole, thiadiazole and triazole derivatives and combinatorial libraries thereof Download PDF

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Publication number
WO2000025768A1
WO2000025768A1 PCT/US1999/025331 US9925331W WO0025768A1 WO 2000025768 A1 WO2000025768 A1 WO 2000025768A1 US 9925331 W US9925331 W US 9925331W WO 0025768 A1 WO0025768 A1 WO 0025768A1
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Prior art keywords
thiocarbamyl
carbamyl
substituted
chloro
benzene
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PCT/US1999/025331
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French (fr)
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WO2000025768A8 (en
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R. Normand Hebert
Amy L. Hannah
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Trega Biosciences, Inc.
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Priority to AU14555/00A priority Critical patent/AU1455500A/en
Priority to EP99971314A priority patent/EP1126833A4/en
Publication of WO2000025768A1 publication Critical patent/WO2000025768A1/en
Publication of WO2000025768A8 publication Critical patent/WO2000025768A8/en

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    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
    • 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

Definitions

  • the present invention relates generally to the synthesis of compounds comprising heterocyclic rings.
  • the invention provides novel oxadiazoles 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.
  • Oxadiazoles for example, have been the subject of investigation in a number of different biological areas.
  • a number of patents cite oxadiazole derivatives as pesticides and acaricides. 1, 2, 4-Oxadiazoles have been proposed as: (a) muscarinic receptor agonists (as described by esser W. S. Jr., et al . , J " . Med. Chem.
  • Oxadiazoles with a 5-chloromethyl substituent have been described as plant growth regulators (Jpn. Kokai Tokkyo Koho, 4 pp. CODEN: JKXXAF, JP 57188503 A2 821119; Showa, Application Ser. No.:
  • Liang and Feng used the symmetrical anhydrides generated from 2-hydroxy carboxylic acids in the presence of a carbodiimide as the acylating species to give 5-hydroxymethyl substituted oxadiazoles (Liang, G. B., et al . Tetrahedron Lett . , 37:
  • the present invention satisfies these needs and provides related advantages as well.
  • the present invention overcomes the known limitations to classical organic synthesis of oxadiazoles, 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 molecules bound to a resin.
  • the present invention can utilize a readily available pool of building blocks 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 functionality. Therefore, building blocks, such as those described above, 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 oxadiazole, thiadiazole and triazole compounds .
  • the present invention relates to novel oxadiazole, thiadiazole and triazole compounds of the following formula:
  • 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 2 provides Reaction Scheme 2 showing the attachment of cyanophenols to solid support .
  • Figure 3 provides Reaction Scheme 3 showing linking nitriles to solid support.
  • Figure 4 provides Reaction Scheme 4 showing the conversion of resin-bound nitriles into oxadiazoles.
  • Figure 5 provides Reaction Scheme 5 showing the derivatization of oxadiazoles.
  • the present invention provides novel compounds and libraries of novel compounds of Formula (I) :
  • T, U and V are independently selected from an oxygen, sulfur or nitrogen atom, provided that at least two of T, U and V are a nitrogen atom;
  • X is H, -NHC(0)NR 1 R 2 , -C0 2 R 1# -OR lf -NR ⁇ , -C(0)NR x R 2 , or wherein R ⁇ is a hydrogen atom or a functionalized resin; and R 2 is a hydrogen atom, ⁇ to C 6 alkyl, C : to C 6 substituted alkyl, C 2 to C 7 alkenyl, C 2 to cy substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, heteroaryl or substituted heteroaryl, heterocycle or substituted heterocycle; or - RiR 2 together is of the formula :
  • Q is a hydrogen atom or functionalized resin
  • X 2 is Ci to C 12 alkylene, Cj to C 12 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 cycloalkylene, C 3 to C substituted cycloalkylene, C 5 to C 7 cycloalkenylene, C 5 to C 7 substituted cycloalkenylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C 7 to C 12 phenylalkylene, or C 7 to C 12 substituted phenylalkylene C 7 to C 12 phenylalkox, or C 7 to C 12 substituted phenylalkoxy; or
  • X 2 is of the formula:
  • n and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and G is phenylene or substituted phenylene; or
  • X 2 is of the formula:
  • R 3 is a hydrogen atom, C ⁇ to C 6 alkyl, C x to C 6 substituted alkyl, C ⁇ to C 7 acyl, C ⁇ to C 7 substituted acyl, Ci to C 4 alkyl sulfonyl, C 1 to C 4 substituted alkyl sulfonyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 6 alkylaminocarbonyl, C ⁇ to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C ⁇ to C 6 alkylaminothiocarbonyl, C ⁇ to C 6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl; substituted phenylaminothiocarbony
  • X 7 is of the formula (II) :
  • n is an integer selected from 0 to 6;
  • R 4 and R 5 are together or independently a hydrogen atom, Cj to C 6 alkyl, C : 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 ⁇ to C 7 acyl, C x 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, heteroaryl, substituted heteroaryl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C 7 to C 12 phenylalkoxy, C 7 to C 12 substituted phenylalkoxy,
  • J is phenylene or substituted phenylene
  • K is phenylene or substituted phenylene
  • m and n are independently selected from O and I;
  • X is of the formula (IV) or (V) :
  • X is absent or of the formula:
  • R 4 and R 5 are together or independently a hydrogen atom, Ci to C 6 alkyl, C 2 to C 7 alkenyl, C 2 to C 7 alkynyl, C ⁇ to C 6 substituted alkyl, C 2 to C 7 substituted alkenyl, C 2 to C 7 substituted alkynyl, ⁇ to C 7 acyl, C ⁇ 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, heteroaryl, substituted heteroaryl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C to C 12 phenylalkoxy, C 7 to C 12 substituted phenylalkoxy, phenyl, substituted phenyl, naphthyl,
  • X 3 is of the formula (Via) or (VIb) :
  • m and n are independently selected from O, 1, 2, 3 and 4 and, preferably, are 1; and wherein in formula (VIb) m is O, 1, 2, 3 or 4 and, preferably, is O; or
  • X 3 is of the formula:
  • R 6 is a hydrogen atom, amino, amino-protecting group, -NRR 8 , carboxy, carboxy-protecting group, C(0)NR 7 R 8 wherein R 7 and R 8 are independently selected from a hydrogen atom, C : to C 6 alkyl, C 2 to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C 2 to C 7 acyl, C : to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C ⁇ to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C : to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C : to C 6 alkylaminothiocarbon
  • R 7 and R 8 are independently selected from a hydrogen atom, Ci to C 6 alkyl, C x to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C x to C 7 acyl, Ci to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C x to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylaminothiocarbonyl, C x to C 6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbon
  • R 9 is a hydrogen atom, -OH, hydroxy-protecting group, C x to C 6 alkyl, C x to C 6 substituted alkyl, C x to C 7 alkoxy, C x to C 7 phenylalkoxy, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl; and
  • R 7 and R 8 are independently selected from a functionalized resin, a hydrogen atom, C x to C 6 alkyl, C x to C 6 substituted alkyl, C 7 to C 12 phenylalkyl, C 7 to C 12 substituted phenylalkyl, C x to C 7 acyl, C x to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C x to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylaminocarbonyl, C phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylamino
  • R 9 and R x0 are independently selected from a hydrogen atom, C x to C 6 alkyl, C x to C 6 substituted alkyl, C 7 to C x2 phenylalkyl, C 7 to C X2 substituted phenylalkyl, C 7 to C X2 phenylalkoxy, C 7 to C 12 substituted phenylalkoxy C x to C 7 acyl, C x to C 7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylsulfonyl, C x to C 6 alkylaminocarbonyl, C x to C 6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C x to C 6 alkylaminothiocarbonyl, C x
  • T is N, U is O and V is N;
  • X x is -C0 2 R x , -OR x , -NR X R 2 or -C (0) NR x R 2 ; or -NR X R 2 together is of the formula:
  • X 2 is C x to C x2 alkylene, C x to C x2 substituted alkylene, C 3 to C 7 cycloalkylene, C 3 to C 7 substituted cycloalkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C 7 to C x2 phenylalkylene, or C 7 to C X2 substituted phenylalkylene; or
  • X 2 is of the formula:
  • n 1 to 4;
  • X 2 is of the formula (II)
  • X 2 is of the formula (III) :
  • n and n are integers independently selected from 0 and 1;
  • X 3 is absent or of the formula:
  • R 4 and R 5 are together or independently a hydrogen atom, C x to C 6 alkyl, C 7 to C x2 substituted phenylalkyl, substituted phenyl, hydroxymethyl, protected hydroxymethyl, C 3 to C 7 cycloalkyl or C 3 to C 7 substituted cycloalkyl; or
  • X 3 is of the formula (VIb) :
  • X 3 is of the formula
  • X 4 is of the formula (VII) , (X) , (XI) , (XII) or (XIII) :
  • R 9 is a hydrogen atom or -OH, and R 7 , R 8 , q, r, s and t are as described above .
  • the compounds and libraries are of Formula (I) wherein:
  • X x is -C0 2 R x , -OR x , -NR X R 2 or -C(0)NR x R 2 ; or -NR X R 2 together is of the formula:
  • X x is OH or C0NH 2 ;
  • X 2 is methylene, 1, 1-cyclopropyl, 1, 3 -phenylene, 1, 4 -phenylene, 1-methyl-l- (4-oxyphenylene) ethane; 3 -methoxy-1, 4 -phenylene, 2-fluoro-1, 4 -phenylene, 4 , 4 ' -biphenylene, 1, 2 -phenylene,
  • X 3 is 1-aminomethylene, 1- (1-aminoethyl) , 1- (2-aminoethyl) , 1- (l-amino-2- (3-pyridyl) ethyl) , 1- (l-amino-2- (2-thienyl) ethyl) , 1- (1-aminopropyl) , 1- (3-aminopropyl) , 1- (5-aminopentyl) ,
  • X 4 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, eyelobutanecarbonyl , 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 , triphenylace
  • the present invention also provides a method of preparing libraries wherein compounds of Formula (I) , in particular, oxadiazoles, are made by reacting a resin- bound amine with a nitrile-containing carboxylic acid, nitrile-containing isocyanate or nitrile-containing radical with a leaving group to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing an amino-protected group; deprotecting the amino-protected group to obtain an oxadiazole amine; and reacting the oxadiazole amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadiazole library.
  • compounds of Formula (I) in particular, oxadiazoles
  • Another method of preparing oxadiazole libraries comprises reacting a resin-bound amine with a nitrile-containing carboxylic acid, isocyanate or leaving group to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing a leaving group; and reacting the leaving group with a primary amine or secondary amine to obtain a oxadiazole secondary amine or oxadiazole tertiary amine; and optionally reacting the secondary amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadizaole library.
  • the resin-bound amine can be prepared by displacing a resin-b ⁇ und leaving group with a primary amine.
  • the resin-bound amine can be prepared by reducing a resin-bound imine formed from either a resin-bound aldehyde with a primary amine or a resin-bound primary amine with an aldehyde.
  • Yet another method comprises reacting a resin- bound leaving group with a nitrile-containing phenoxide ion or amine to obtain a resin-bound nitrile; cyclizing the nitrile to obtain to an oxadiazole containing an amino-protected group; deprotecting the amino-protected group to obtain an amine; and reacting the amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadiazole library.
  • Still another method comprises reacting a resin-bound leaving group with a nitrile-containing phenoxide ion to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing a leaving group; and reacting the leaving group with a primary or secondary amine to obtain a secondary or a tertiary amine of the oxadiazole library; and optionally reacting the secondary amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadizaole library.
  • the present invention also provides a method of preparing oxadiazole libraries wherein oxadiazole compounds of Formula (I) are made by reducing an imine formed between a resin-bound aldehyde and an amine containing a protected carboxylic acid to give a protected carboxylic acid bound to resin; deprotecting the protected carboxylic acid to give a resin bound carboxylic acid and reacting the carboxylic acid with an amidoxime to give an oxadiazole library.
  • Another method of preparing oxadiazole libraries comprises reacting a resin-bound alcohol with an amine containing a protected carboxylic acid to give a protected carboxylic acid bound to resin through a carbamate linkage; deprotecting the protected carboxylic acid to give a carboxylic acid and reacting the carboxylic acid with an amidoxime to give an oxadiazole library.
  • the methods described above further comprise the step of cleaving the library from the resin.
  • 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 x 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 "C x 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- pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2 -heptynyl, 3-heptynyl, 4- heptynyl, 5-heptynyl as well as di- and tri-ynes of straight and branched chains.
  • C x to C 6 substituted alkyl denotes that the above C x to C 6 alkyl groups and C 2 to C 7 alkenyl and C 2 to C 7 alkynyl groups and C x to C X2 alkylene 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 x to C 7 alkoxy
  • Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3-oxo-but-l-yl, cyanomethyl, nitromethyl , chloromethyl , hydroxymethyl, tetrahydropyranyloxymethyl , trityloxymethyl, propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl , chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexy1 , 2,4- dichloro (n-butyl) , 2-aminopropyl 1-chloroethyl, 2- chloroethyl, 1- bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl,
  • 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 denotes an alkene 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 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide
  • 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.
  • C x to C 7 substituted alkoxy means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to C x to C 6 substituted alkyl.
  • C x to C 7 phenylalkoxy as used herein means "C x to C 7 alkoxy" bonded to a phenyl raidcal .
  • C x to C 7 acyloxy denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.
  • C x 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 x to C 7 alkoxy, C x to C 7 acyl, C x to C 7 acyloxy, nitro, C x to C 6 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, protected N-
  • C x 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.
  • the substituent term “C 3 to C, substituted cycloalkyl” indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 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)
  • 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 substituent.
  • 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 (monosubstituted) amino, (disubstituted) amino, phenyl, substituted phenyl, amino, or protected amino.
  • 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 x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 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, (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 morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen-yl .
  • substituted heterocyce 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 are the same or different which 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 x to C 7 acyl, C x to C 7 acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl , hydroxymethyl, protected hydroxymethyl, amino, protected amino,
  • 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 are the same or different which 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 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,
  • C 7 to C x2 phenylalkyl denotes a C x to C 6 alkyl group substituted at any position by a phenyl, substituted phenyl, heteroaryl or substituted heteroaryl. Examples of such a group include benzyl, 2-phenylethyl,
  • C 7 to C X2 phenylalkyl groups are the benzyl and the phenylethyl groups .
  • C 7 to C X2 substituted phenylalkyl denotes a C 7 to C x2 phenylalkyl group substituted on the C x 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 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, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected
  • C 7 to C 12 substituted phenylalkyl examples include groups such as 2-phenyl-l- 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 x2 phenylalkylene specifies a C 7 to C X2 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.
  • C 7 to C X2 substituted phenylalkylene means a C 7 to C X2 phenylalkylene as defined above 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 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 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, phenyl, substituted phenyl, phenylthio,
  • 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, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alky
  • 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
  • 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,
  • 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, C x 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, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, N, N-di (C x to C 6 alkyl) carboxamide, trifluoromethyl, N- ( (C x to C 6 al
  • substituted phenoxy examples include 2-methylphenoxy, 2-ethylphenoxy, 2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy, 2-tert-butylphenoxy, 2-allylphenoxy, 2-propenylphenoxy, -cyclopentylphenoxy, 2-fluorophenoxy, - (trifluoromethyl) phenoxy, 2-chlorophenoxy, -bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy, -isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy, -isopropylphenoxy, 3-tert-butylphenoxy, -pentadecylphenoxy, 3- (trifluoromethyl) phenoxy, -fluorophenoxy, 3-chlorophenoxy, 3-bromophenoxy, -iodophenoxy, 3-methoxyphenoxy, - (trifluoromethoxy) phenoxy, 4-methylphenoxy, -e
  • 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-d
  • C 7 to C x2 substituted phenylalkoxy denotes a C 7 to C X2 phenylalkoxy group wherein the C x to C 6 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
  • 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.
  • C 7 to C X2 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, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 7 substituted alkoxy, CI 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, N- (C x to C 6 alkyl) carboxamide, protected N- (C x to C 6 alkyl) carboxamide, protected
  • substituted phthalimides examples include
  • 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, C x to C 6 alkyl, C x to C 7 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,
  • 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 nitronaphthyl
  • 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-yl, 4-ethyl-2-hydroxynaphth-l-yl, 3-hydroxy-4-nitronaphth-2- yl, 2-hydroxy-4-chloronaphth-l-yl, 2-methoxy-7- bromonaphth-1-yl, 4-ethyl-5-hydroxynaphth-2-yl , 3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-l- yl and the like.
  • 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 4 alkylsulfonyl, C x to C 4 substituted alkylthio, C x to C 4 substituted alkylsulfoxide, C x to C 4 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, 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 "protected (monosubstituted) amino.
  • (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, C x 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.
  • protected N- (C x to C 6 alkyl) 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 , cyclopentanyloxycarbonyl ,
  • 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.
  • 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, - (trimethylsilyl) ethyl,
  • 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
  • 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,
  • 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, "Protective Groups in Organic Chemistry," J.G.W.
  • 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 4 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 means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl.”
  • C x to C 6 alkylaminocarbonyl means a C x to C 6 alkyl attached to a nitrogen of the aminocarbonyl group.
  • Examples of C x to C 6 alkylaminocarbonyl include methylaminocarbonyl (from methylisocyanate) , ethylaminocarbonyl (from ethylisocyanate) , propylaminocarbonyl (from propylisocyanate) , butylaminocarbonyl (from butylisocyatate) .
  • C x to C 6 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 6 substituted alkyl.
  • C x to C 6 substituted alkylaminocarbonyl examples include, for example, methoxymethylammocarbonyl (from methoxymethylisocyanate) , 2-chloroethylaminocarbonyl (from 2-chloroethylisocyanate) , 2-oxopropylaminocarbonyl (from 2-oxopropylisocyanate) , and 4-phenylbutylaminocarbonyl (from phenylbutylisocyanate) .
  • C x to C 7 alkoxycarbonyl means a
  • C x to C 7 alkoxy group attached to a carobonyl 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. Examples of substituted phenylaminocarbonyl include
  • C x to C 6 alkylaminothiocarbonyl means a C x 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 ethylisothiocyanate) , 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 6 substituted alkylaminothiocarbonyl examples include, for example, methoxymethylaminothiocarbonyl (from methoxymethylisothiocyanate) , 2-chloroethylaminothiocarbonyl (from 2-chloroethylisothiocyanate) , 2-oxopropylaminothiocarbonyl (from 2-oxopropylisothiocyanate) , and 4-phenylbutylaminothiocarbonyl (from phenylbutylisothiocyanate) .
  • 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
  • C x to C 12 alkylene means a C x to C X2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups.
  • Examples of “C x to C X2 alkylene” include methylene, 1,2-ethyl, 1,1-ethyl, 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 C x to C x2 alkylene means a C x to C X2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent.
  • substituted C x to C 12 alkylene includes 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 .
  • substituted phenylene means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, 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-l, 2-phenylene from 3,4-dihydroxybenzonitrile, 2,3,5, 6-tetrafluoro-1, 4-phen
  • substituted 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, C x to C 4 acyloxy, formyl, C x to C 7 acyl, C x to C 6 alkyl, C x to C 7 alkoxy, C x to C 4 alkylthio, C x to C 4 alkylsulfoxide, C x to C 4 alkylsulfonyl, halo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, hydroxymethyl or a protected hydroxymethyl.
  • the cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members.
  • saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro- indanyl and a tetralin ring.
  • 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.
  • 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, sulf ric, 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, cyclohexylamine; 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 can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form.
  • 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, pivaloyloxyethyl
  • 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 peptide 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,
  • 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 Oxadiazole.
  • 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 the Reaction Schemes provided in the Reaction Schemes 2 through 5 and described below.
  • cyano carboxylic acids were coupled to resin-bound primary or secondary amines which become incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • resin-bound primary or secondary amines which become incorporated into the product as secondary or tertiary amides after cleavage from the resin.
  • These could be prepared by reductive amination of a primary amine to an aldehyde resin or vice-versa, or to any other resin-bound primary or secondary amine prepared by methods known to those skilled in the art.
  • Cyanophenols were coupled to solid support via an ether linkage as shown in Scheme 2 : Attachment of cyanophenols to solid support which releases the free phenol after cleavage, by. alkylation of a benzyl halide resin such as Merrifield resin or alkoxybenzyl bromide resin (Wang bromide resin) .
  • the cyanophenols were coupled to an alkyl halide moiety which remains covalently attached to the oxadiazole product after cleavage from the resin.
  • a primary or secondary amine bound to the resin through a cleavable linker is acylated with chloroacetic anhydride or 3- or 4 -chloromethyl benzoic acid.
  • a cyanophenol was then introduced by nucleophilic displacement of the alkyl halide. In this way, a wide range of cyanophenyl compounds was made, and converted to oxadiazole compounds by the methods described below.
  • nitrile containing compounds can be similarly linked to common resins as shown in Scheme 3: Linking nitriles to solid support. For example, 3- cyanophenyl isocyanate and 4 -cyanophenyl isocyanate were linked to the resin by forming a urea linkage and the nitrile function elaborated into an oxadiazole. Additionally, cyanohydrins may be formed on the resin by the action of Trimethylsilyl cyanide on resin-bound aldehydes and ketones . Alkyl nitriles may be formed by displacement of leaving groups with cyanide anion.
  • N-Boc 2-cyanoethyl glycine was also found to be a useful precursor to a large number of oxadiazole derivatives.
  • the cyanoethyl group was first converted to the oxadiazole followed by conversion of the Boc-protected amine to a variety of derivatives.
  • amidoximes were treated with chloroacetic anhydride to give the 5- chloromethyl oxadiazoles.
  • This primary chloride could be displaced with diverse primary or secondary amines to give substituted 2% or 3% amines. These could be derivatized further to introduce an additional variable substituent.
  • This strategy was particularly useful for the preparation of compounds attached to the resin by TFA labile bonds which preclude the use of N-Boc-protected amino acids (vide infra) . This was also the method of choice with cyanoethyl glycine derivatives.
  • amidoximes were converted to oxadiazoles by reaction with BOC amino acid anhydrides or FMOC amino acid anhydrides to give the substituted oxadiazole derivatives.
  • Natural L-amino acid derivatives e.g. Gly, Phe, Leu
  • D- or L-amino acids e.g. D- or L-amino acids
  • cyclic amino acids e.g. Pro, Nipecotic acid, Isonipecotic acid, tetrahydroisoquinoline carboxylic acid
  • unnatural amino acids or other aliphatic carboxylic acids and anhydrides. In all cases, the carboxylic acid moiety becomes incorporated into the oxadiazole ring.
  • N-BOC or N-FMOC protecting group could be removed under standard conditions and the resulting amine derivatized with an additional diverse set of reagents (Scheme 5: Derivatization of Oxadiazoles) .
  • Scheme 5 Derivatization of Oxadiazoles
  • amide, sulfonamide, urea and thiourea derivatives were obtained by reaction with acid anhydride, sulfonyl chloride, isocyanates and isothiocyanates respectively.
  • the amidoximes can be reacted with activated carboxylic acid derivatives other than anhydrides.
  • acylating reagent known in the art could be used in the synthesis of oxadiazoles, including but not limited to acid chlorides, and fluorides, mixed anhydrides, active esters such as pentafluorophenyl, 4-nitrophenyl, hydroxybenzotriazole, N-hydroxysuccinimide and the like.
  • the libraries are described as having three variable positions, or three diversity sites.
  • the first diversity site is defined by the nitrile containing moiety, or its precursor, attached to the resin. This includes, but is not limited to, cyanocarboxylic acids, cyanobenzyl halides and cyanophenols, and the coupling of these through appropriate chemistry to diverse compounds on solid support. Additionally, these methods are meant to include as starting materials other products synthesized on solid phase whereby an aliphatic, aromatic or heteroaromatic nitrile compound is obtained.
  • the second diversity site is introduced in the oxadiazole formation and is defined by the appropriately functionalized carboxylic acid anhydride used in the cyclization step.
  • the third diversity site is created by the derivatization of a reactive site introduced by the carboxylic acid moiety in the previous step. More specifically, the use of protected amino acid derivatives is particularly useful in the present invention.
  • the amino acid side chain provides the second diversity site as defined above. Derivatization of the amino group with carboxylic acids, sulfonyl chlorides, isocyanates, isothiocyanates, alkyl halides or aldehydes provides the third diversity site. Other reactive functional groups incorporated in protected or unprotected form can also serve to introduce the third diversity element.
  • bifunctional carboxylic acid derivatives are used to form the oxadiazole ring and an attachment point for a third diversity site.
  • This attachment point can be a nucleophilic site (e.g. alcohol, thiol, carbon nucleophile, etc.) or an electrophilic site (halide, tosylate, triflate, activated carboxylate, etc) .
  • cyclic anhydrides such as succinic anhydride, diglycolic anhydride, 1, 2-cyclopropane dicarboxylic anhydride are preferred embodiments.
  • the oxadiazole cyclization produces a pendant carboxylic acid which can be further activated with standard coupling reagents and coupled to diverse amines .
  • Another preferred embodiment of the invention is the use of chloroacetic anhydride or other halocarboxylic acid anhydrides in the oxadiazole cyclization creating a chloromethyl group which is readily displaced with diverse nucleophiles such as amines, thiols, alcohols, phenols or carbon nucleophiles.
  • nucleophiles such as amines, thiols, alcohols, phenols or carbon nucleophiles.
  • primary amines or secondary diamines are used which are derivatized further with carboxylic acids, sulfonyl chlorides, isocyanates, isothiocyanates or alkyl halides.
  • a carboxylic acid moiety could be attached to the solid support in a variety of different ways, for example, an amino acid ester is attached to a resin by reductive amination, or by reaction with a chloroformate resin derivative, followed by hydrolysis of the ester.
  • a resin bound amine can be reacted with a cyclic anhydride such as succinic anhydride.
  • a cyclic anhydride such as succinic anhydride.
  • Other methods of providing a free carboxylic acid on solid support are known in the art.
  • the carboxylic acid is then converted to an activated derivative such as the mixed anhydride with isobutyl chloroformate, or an active ester with pentafluorophenol, 4-nitrophenol, N- hydroxysuccinimide, HOBT or other activated derivatives such as those used routinely in the formation of amide or ester bonds.
  • This activated resin bound carboxylate is then treated immediately with a solution of amidoxime, prepared by the reaction of a nitrile compound with hydroxylamine under standard conditions.
  • the nonsupport-bound combinatorial libraries can be screened as mixtures 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 oxadiazole derivatives, can be used as pesticides, acaricides, receptor agonisits 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 36 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 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 K, 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 . Natl .
  • 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 . , Mol . 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.
  • 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.
  • standard curves in which 3 H-DAMG0 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) .
  • IC 50 values (the concentration necessary to inhibit 50% of 3 H-DAMGO binding) are then calculated. IC 50 values of less than 1000 nM are indicative of highly active opioid compounds which bind to the ⁇ receptor, with particularly active compounds having IC 50 values of 100 nM or less and the most active compounds with values of less than 10 nM.
  • 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 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 example of an assay that identifies CaM antagonists is a CaMPDE assay. In brief, 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) and 10 ⁇ l of CaCl 2 (4.5 mM) to a final volume of 251 ⁇ l .
  • calmodulin stock solution (Boehringer Mannheim; 0.01 ⁇ g/ ⁇ l) is then added and the samples then sit at room temperature for 10 minutes. 14 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of PDE (Sigma; 2 Units dissolved in 4 ml of water; stock concentration: 0.0005 Units/ ⁇ l) is then added, followed by 50 ⁇ l of P
  • 5 ' -nucleotidase (Sigma; 100 Units dissolved in 10 ml of 10 mM Tris-HCl containing 0.5 mM Mg(CH 3 COO) 2 , pH 7.0; stock concentration: 10 Units/ml) .
  • the samples are then incubated for 10 minutes at 30°C.
  • 50 ⁇ l of adenosine 3 ',5 '-cyclic monophosphate (cAMP) (20 mM in water at pH 7.0) is added, the samples incubated for 1 hour at 30°C and then vortexed.
  • cAMP adenosine 3 ',5 '-cyclic monophosphate
  • trichloroacetic acid 55% in water
  • 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. IN H 2 S0 4 ) 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 ⁇ l 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 ⁇ l 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.
  • 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- (1H- 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- (1H- benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate
  • TRT trityl
  • ACM acetamidomethyl
  • MTR 2,3, 6-trimethyl-4-methoxybenzenesulfonyl
  • MBH 4,4 '
  • a teabag containing 100 g of resin bound piperazine from Examples 5 (120 mmol) was swollen in DCM and a solution of chloroacetic anhydride (41 g, 240 mmol) in 500 ml DCM was added, followed by DIEA (42 ml, 240 mmol) .
  • the solution was shaken at RT overnight, and washed with DCM, DMF, IPA and MeOH and dried to yield 4- chloroacetyl piperazine bound resin.
  • Other primary and secondary amines of Example 4 and 5 are also used.
  • halo carboxylic acids shown below can be substituted for chloroacetic anhydride and used in a similar manner, such as, preparing the anhydride of the carboxylic acid with dusopropyl carbodiimide in DCM for 30 minutes before addition of the amine resin.
  • a teabag containing 300 g of resin bound amine from Examples 4 and 5 (360 mmol) was swollen in DMF (1.51) and 4-cyanobenzyl bromide (200g, 1.02 mmol) was added, followed by DIEA (177 ml, 1.02 mol).
  • the solution was shaken at RT overnight and then washed with DCM, IPA and MeOH.
  • the resin was dried under high vacuum to provide N- (4-cyano) benzyiamine bound resin.
  • MBHA-HC1 resin (5.0g, 4.05 mmol) was neutralized with 10% DIEA in DMF, then washed with DCM.
  • Resin bound nitrile compounds prepared in examples 6,7,8,9,10, and 11 above were placed in teabags. Hydroxylamine-HCl (4-10 eq. based on loading of resin) and DIEA (4-10 eq) were placed in sufficient 2- methoxyethanol to give a 0.2 M solution. The resin was added and the solution heated to 80-85-C overnight. The solution was cooled to RT and the resin washed 4X with MeOH and dried to yield in each case the desired amidoxime bound to resin.
  • Each of the nitrile resins from Example 3 was distributed to 36 bags with 400 mg of resin each according to Table 1: Distribution of Nitrile Resins and a number of control bags were made. To each of 36 tubes was added 55 ml of anhydrous 2 -methoxyethanol, 0.83 g (12mmol) of Hydroxylamine Hydrochloride and 2.08 ml (12 mmol) DIEA. Once all the solids were dissolved the bags containing nitrile resins A-E were added (see table below) and the reaction tubes were heated to 85-C overnight . The tubes were cooled and the bags washed with MeOH (4X) and dried to yield the corresponding amidoxime .
  • Resin B 1-Cyano-1-cyclopropane carboxylic acid: 18.1 g, 162.5 mmol
  • a resin bound amidoxime of Example 12 was swollen in 2-methoxyethyl ether.
  • a solution of the appropriate carboxylic acid anhydride (7 eq) in 2- methoxyethyl ether (0.2M) was added to the amidoxime.
  • the anhydride was not commercially available it was prepared from a solution of carboxylic acid (14 eq, 0.4M) in 2-methoxyethyl ether to which was added DIC (7 eq, 0.2M) and shaken for 30 minutes before addition of the resin bags.
  • the solution of anhydride and the resin bound amidoxime were heated to 60-C for 16 hours. The solution was cooled and the resin washed twice with fresh 2-methoxyethyl ether.
  • Boc-protected amino acid derivatives according to Table 2: Distribution of Amino Acids. Each amino acid (28 mmol) was dissolved in 55 ml of 2-methoxyethyl ether. To each tube was then added DIC (14 mmol) and the solution stirred at RT for 1 hr at which time a white precipitate had formed. The appropriate bags containing amidoxime from the previous step were then added and the reaction tubes were placed in a heating block at 60-C for 16 hr. The supernatant was removed and the resins washed twice with fresh 2- methoxyethyl ether. The bags were placed in 50 ml 2- methoxyethyl ether and heated to 85-C for 6 hr. The tubes were cooled, and the bags washed 3X DMF, 3X DCM, 3X MeOH and dried to give 5- (N-Boc-amino) substituted oxadiazoles bound to resin.
  • the bags were placed in 10 ml 2-methoxyethyl ether and heated to 85-C for 6 hr. The tubes were cooled, and the bags washed 3X DMF, 3X DCM, 3X MeOH and dried to give 5- ( (N-FMOC- amino) substituted oxadiazoles bound to resin.
  • the resins from Example 17 were placed in a solution of amine according to Table 3 : Primary and secondary amines (0.2 M, 10 eq) in anhydrous DMF and shaken at RT for 2 hrs . The bags were then washed with DMF 4X, DCM 2X and MeOH to give 5-substituted aminomethyl oxadiazoles bound to resin.
  • the Boc-protected Oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected Oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate.
  • the supernatant solvent was removed and the following solutions were added: a carboxylic acid solution, a solution of DMAP, HOBT and DIEA, a solution of DIC in DMF or DCM.
  • Other coupling agents such as BOP, PyBOP, HATU, HBTU and others known in the art were also used in separate experiments.
  • the quantities of each solution were adjusted according to the amount of resin per well in the plate, in order to have a five to tenfold excess of reagents.
  • the 96 well plates were capped and shaken overnight at RT. The resins were then washed with DMF (8X) , MeOH (4X) and the resin allowed to dry resulting in the N-acylated-5- (substituted aminomethyl) oxadiazoles bound to resin.
  • the Boc-protected oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate. The supernatant solvent was removed, and the resin washed with acetonitrile.
  • the Boc-protected oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate.
  • the resin was then washed and neutralized with 5% DIEA in 1, 2-dichloroethane (DCE) /THF (2:1) and washed with DCE/THF (2:1) to remove excess base.
  • DCE 1, 2-dichloroethane
  • the following Isocyanates were dissolved to a concentration of 0.2 M in DCE/THF (2:1) and added to the plates. The solutions were shaken at RT overnight and then the plates were washed with DCE/THF (2:1), DMF, MeOH and dried to give N-substituted ureido oxadiazole resins.
  • Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried.
  • the FMOC-protected Oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried.
  • the aminomethyl oxadiazoles of Example 18 were used without further precautions.
  • the resins were suspended in DMF and distributed into a 96 well microtiter plate. The resin was then washed and neutralized with 5% DIEA in 1, 2-dichloroethane (DCE) /THF (2:1) and washed with DCE/THF (2:1) to remove excess base.
  • DCE 2-dichloroethane
  • Boc 2-cyanoethyl glycine was loaded onto MBHA resin and converted to the Amidoxime as described in the general procedures of Example 13.
  • This amidoxime resin was treated with a BOC amino acid anhydride as described in Example 15.
  • the bis BOC protected oxadiazole derivative was then treated with 50 % TFA in DCM (2 X 15 min) and washed with DCM and MeOH.
  • the diamines were then treated with 0.2 M benzoic acid, DIC, HOBT and DIEA in DCM or with acetic anhydride in DCM at RT overnight.
  • the resin was washed with DMF 4X, DCM 2X and MeOH and dried to give the di-acylated oxadiazole resins.
  • the amidoxime is treated with an FMOC amino acid anhydride as in the procedure of Example 16 to give mono-acylated- (FMOC amino) oxadiazole resins.
  • Boc 2-cyanoethyl glycine is loaded onto MBHA resin and converted to the oxadiazole as described in Example 17. Individual tea bags containing portions of the resulting 5-chloromethyl oxadiazole derivative are then treated with diverse amines in DMF as in Example 18.
  • the 5-aminomethyl oxadiazole derivatives are then acylated to give the N-acylated-5- (substituted aminomethyl) oxadiazole resins, sulfonylated to give N- sulfonyl-5- (substituted aminomethyl) oxadiazole resins, alkylated to give N- alkylated-5- (substituted aminomethyl) oxadiazole resins, treated with isocyanates to give N-substituted ureidooxadiazole resins or isothiocyanates to give N- substituted thioureidooxadiazole resins as described in Example 19, Example 20, Example 21, and Example 22.
  • the products are then treated with 50% TFA in DCM to remove the remaining BOC group.
  • the amino group from the groups defined above are further converted to either an amide, sulfonamide, urea or thiourea derivative following the general procedures of Example 19, Example 20, Example 21, and Example 22 to give a diverse library of oxadiazole resins.

Abstract

The present invention relates to novel compounds of formula (I) wherein X1, X2, X3, X4, T, U and V have the meanings provided. 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

OXADIAZOLE, THIADIAZOLE AND TRIAZOLE 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 oxadiazoles 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 oxadiazoles. 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 a-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 rarely been applied to the .syntheses of complex heterocyclic structures. Therefore a need exists to develop more complex "organic" libraries based on heterocyclic medicinal compounds which would need less time and effort in the synthesis and testing required to bring an organic pharmaceutical product to fruition. In short, improved methods for generating therapeutically useful heterocyclic compounds, such as oxadiazole and thiadiazole derivatives, are desired.
Oxadiazoles, for example, have been the subject of investigation in a number of different biological areas. A number of patents cite oxadiazole derivatives as pesticides and acaricides. 1, 2, 4-Oxadiazoles have been proposed as: (a) muscarinic receptor agonists (as described by esser W. S. Jr., et al . , J". Med. Chem.
40:1230 (1997); Showell, G. A., et al . , J. Med. Chem. , 34:1086 (1991); Orlek, B. S., et al . , J. Med. Chem. , 34:
2726 (1991) ) , (b) benzodiazepine receptor agonists (as described by Watjen, F., et al . J. Med. Chem. , 32:2282
(1989) ) , (c) histamine H3 receptor antagonists (as described by Clitherow, J. W. ; et al . Bioorg. Med. Chem. Lett., 6: 833 (1996)), and (d) antiviral compounds (as described by Diana, G. D., et al . J". Med. Chem. , 37:2421
(1994)). In general, the oxadiazole ring system has been used as a replacement for ester or amide functionalities and has been primarily limited to simpler alkyl and aryl derivatives (Andersen, K. E., et al . Eur. J. Med. Chem. ,
31:417 (1996)). A series of dipeptidomimetic oxadiazoles have been made and incorporated into peptide sequences as replacements for dipeptides (Borg, S., et al . , Proc. Am.
Pept . Symp. , 14 th, 689-690, (Mayflower Scientific, Kingswinford, UK 1996); Borg, S., et al . J. Org. Chem. ,
60:3112 (1996); Borg, S., et al . Eur. J. Med. Chem. 28:
801 (1993) ) . Oxadiazoles with a 5-chloromethyl substituent have been described as plant growth regulators (Jpn. Kokai Tokkyo Koho, 4 pp. CODEN: JKXXAF, JP 57188503 A2 821119; Showa, Application Ser. No.:
JP 81-74643 810518) . Other chloromethyl oxadiazoles have been made and used to alkylate amines and other nucleophiles (Crovetti, A. J. , et al . , J. Heterocycl . Chem . , 9:435 (1972)). However, a systematic exploration of oxadiazoles has not been performed.
The general methods for the synthesis of 1,2,4- oxadiazoles fall into two categories: acylation and cyclization of amidoximes, or dipolar cycloaddition of nitrile oxides to nitriles (Lianis, P.S., et al . , J".
Heterocyclic Chem. , 26:1683 (1989)). The latter is possible only with highly activated nitriles and thus has limited utility. The most general method of synthesis relies on the acylation and cyclization of amidoximes. Amidoximes are prepared from aliphatic or aromatic nitriles by addition of hydroxylamine . Conversion to the oxadiazoles is realized by treatment with acid chlorides (Chiou, S., et al . , Chem. Ber. 17:1685 (1984)) or anhydrides in refluxing pyridine (Claisse, J. A., et al . J. Chem. Soc. Perkin I, 2241 (1973)). Liang and Feng used the symmetrical anhydrides generated from 2-hydroxy carboxylic acids in the presence of a carbodiimide as the acylating species to give 5-hydroxymethyl substituted oxadiazoles (Liang, G. B., et al . Tetrahedron Lett . , 37:
6627 (1996)). However, in the majority of examples, only simple aliphatic or aromatic carboxylic acid derivatives have been used.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of oxadiazoles, 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 molecules bound to a resin. The present invention can utilize a readily available pool of building blocks 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 functionality. Therefore, building blocks, such as those described above, 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 oxadiazole, thiadiazole and triazole compounds .
SUMMARY OF THE INVENTION
The present invention relates to novel oxadiazole, thiadiazole and triazole compounds of the following formula:
Figure imgf000008_0001
Formula (I)
wherein Xx, X2, X3, X4, T, U and V 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 attachment of cyanocarboxylic acids to solid support.
Figure 2 provides Reaction Scheme 2 showing the attachment of cyanophenols to solid support .
Figure 3 provides Reaction Scheme 3 showing linking nitriles to solid support.
Figure 4 provides Reaction Scheme 4 showing the conversion of resin-bound nitriles into oxadiazoles.
Figure 5 provides Reaction Scheme 5 showing the derivatization of oxadiazoles.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel compounds and libraries of novel compounds of Formula (I) :
Figure imgf000009_0001
Formula (I)
wherein:
T, U and V are independently selected from an oxygen, sulfur or nitrogen atom, provided that at least two of T, U and V are a nitrogen atom;
X: is H, -NHC(0)NR1R2, -C02R1# -ORlf -NR^, -C(0)NRxR2, or
Figure imgf000009_0002
wherein Rλ is a hydrogen atom or a functionalized resin; and R2 is a hydrogen atom, λ to C6 alkyl, C: to C6 substituted alkyl, C2 to C7 alkenyl, C2 to cy substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, heteroaryl or substituted heteroaryl, heterocycle or substituted heterocycle; or - RiR2 together is of the formula :
Figure imgf000010_0001
Figure imgf000010_0002
wherein Q is a hydrogen atom or functionalized resin; and
X2 is Ci to C12 alkylene, Cj to C12 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 cycloalkylene, C3 to C substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C7 to C12 phenylalkylene, or C7 to C12 substituted phenylalkylene C7 to C12 phenylalkox, or C7 to C12 substituted phenylalkoxy; or
X2 is of the formula:
-(CH2)m-G-(CH2)n-
wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and G is phenylene or substituted phenylene; or
X2 is of the formula:
-(CH2)m-NR3-(CH2)n-
wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and R3 is a hydrogen atom, Cα to C6 alkyl, Cx to C6 substituted alkyl, Cτ to C7 acyl, Cα to C7 substituted acyl, Ci to C4 alkyl sulfonyl, C1 to C4 substituted alkyl sulfonyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C6 alkylaminocarbonyl, Cλ to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cα to C6 alkylaminothiocarbonyl, Cλ to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl; substituted phenylaminothiocarbonyl, Cλ to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, phenoxycarbonyl or substituted phenoxycarbonyl ; or
X7 is of the formula (II) :
Figure imgf000012_0001
wherein n is an integer selected from 0 to 6; R4 and R5 are together or independently a hydrogen atom, Cj 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, Cλ 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, a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy, 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, carboxy, protected carboxy, hydroxymethyl or protected hydroxymethyl ; and G is phenylene or substituted phenylene; or X2 is of the formula (III)
Figure imgf000013_0001
(III)
wherein J is phenylene or substituted phenylene, K is phenylene or substituted phenylene, and m and n are independently selected from O and I; or
X, is of the formula (IV) or (V) :
Figure imgf000013_0002
(IV) (V) and
X, is absent or of the formula:
Figure imgf000013_0003
wherein;
R4 and R5 are together or independently a hydrogen atom, Ci to C6 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, Cλ to C6 substituted alkyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, λ to C7 acyl, Cα 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, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy, 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, carboxy, protected carboxy, hydroxymethyl or protected hydroxymethyl; or
X3 is of the formula (Via) or (VIb) :
Figure imgf000014_0001
(Vla) (Vlb)
wherein in formula (Via) m and n are independently selected from O, 1, 2, 3 and 4 and, preferably, are 1; and wherein in formula (VIb) m is O, 1, 2, 3 or 4 and, preferably, is O; or
X3 is of the formula:
Figure imgf000014_0002
wherein R6 is a hydrogen atom, amino, amino-protecting group, -NRR8, carboxy, carboxy-protecting group, C(0)NR7R8 wherein R7 and R8 are independently selected from a hydrogen atom, C: to C6 alkyl, C2 to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C2 to C7 acyl, C: to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cλ to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, C: to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C: to C6 alkylaminothiocarbonyl, C1 to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and m and n are independently selected from 0, 1, 2, 3 and 4; or
is of the formula (VII) to (XIII)
Figure imgf000015_0001
(VII ) (VIII)
Figure imgf000015_0002
wherein q is 1 or 2; r is 0 or 1; s and t are independently selected from 0, 1 or 2; and
R7 and R8 are independently selected from a hydrogen atom, Ci to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, Ci to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and
R9 is a hydrogen atom, -OH, hydroxy-protecting group, Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 alkoxy, Cx to C7 phenylalkoxy, phenyl, substituted phenyl, heteroaryl or substituted heteroaryl; and
is absent or a hydrogen atom, -OH, -C02H, -C(0)NR7R8 or - NR7R8, wherein R7 and R8 are independently selected from a functionalized resin, a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; or -NR7R8 together is of the formula:
Figure imgf000017_0001
wherein R9 and Rx0 are independently selected from a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to Cx2 phenylalkyl, C7 to CX2 substituted phenylalkyl, C7 to CX2 phenylalkoxy, C7 to C12 substituted phenylalkoxy Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and s is an integer selected from 1 to 5; or
a pharmaceutically acceptable salt of a compound of the formula (I) .
In a preferred embodiment of this invention, the oxadiazole compounds and libraries containing Formula (I) :
Figure imgf000017_0002
Formula (I)
wherein T is N, U is O and V is N; and
Xx is -C02Rx , -ORx , -NRXR2 or -C (0) NRxR2 ; or -NRXR2 together is of the formula:
Figure imgf000018_0001
where Q is defined above; and
X2 is Cx to Cx2 alkylene, Cx to Cx2 substituted alkylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C7 to Cx2 phenylalkylene, or C7 to CX2 substituted phenylalkylene; or
X2 is of the formula:
-(CH2)m-NR3-(CH2)n-
wherein m is 1 to 3 and n is 1 to 4; or
X2 is of the formula (II)
Figure imgf000019_0001
wherein n is 0 or 1; R4 and R5 are together or independently a hydrogen atom, Cx to C6 alkyl or Cx to C10 substituted alkyl; or
X2 is of the formula (III) :
Figure imgf000019_0002
(Ill)
wherein m and n are integers independently selected from 0 and 1; or
X3 is absent or of the formula:
Figure imgf000019_0003
wherein:
R4 and R5 are together or independently a hydrogen atom, Cx to C6 alkyl, C7 to Cx2 substituted phenylalkyl, substituted phenyl, hydroxymethyl, protected hydroxymethyl, C3 to C7 cycloalkyl or C3 to C7 substituted cycloalkyl; or
X3 is of the formula (VIb) :
Figure imgf000020_0001
(Vlb)
wherein m is 0; or
X3 is of the formula;
Figure imgf000020_0002
wherein m is 0 to 2 and n is 1 to 4, and R6 is as described above; and
where X3 is absent, X4 is of the formula (VII) , (X) , (XI) , (XII) or (XIII) :
Figure imgf000021_0001
wherein R9 is a hydrogen atom or -OH, and R7, R8, q, r, s and t are as described above .
In another preferred embodiment of this invention, the compounds and libraries are of Formula (I) wherein:
Xx is -C02Rx, -ORx, -NRXR2 or -C(0)NRxR2; or -NRXR2 together is of the formula:
/ \
N-Q r N-
\ /
where Q is defined above. In another preferred embodiment of this invention, the compounds and libraries are of Formula (I) wherein:
U is oxygen, T is nitrogen and V is nitrogen;
Xx is OH or C0NH2; or
Xx is
2- (1-pyrrolidino) ethylamine,
2-pyridinemethylamine, 2- (4-imidazole) ethylamine, cyclopentylamine, allylamine, 2-methoxyethylamine, (+/-) -tetrahydrofurylamine, benzyiamine,
2-methylbenzylamine, 3-methylbenzylamine,
4-methylbenzylamine, 2-fluorobenzylamine,
3-fluorobenzylamine, 4-fluorobenzylamine,
3- (1-imidazole) ropylamine, 4 -aminomethylbenzylamine, 4-methoxybenzylamine, 3-chlorobenzylamine,
3-bromobenzylamine, 4-bromobenzylamine, eyelopropylamine, cyclopropanemethylamine,
4-pyridinemethylamine, 3-pyridinemethylamine,
2-thiophenemethylamine, phenethylamine, 2- (morpholine) ethylamine, 3- methoxybenzylamine, piperonylamine, 4-methoxyphenethylamine,
2-fluorophenethylamine, 2- (4-chlorophenyl) ethylamine,
2- (3-chlorophenyl) ethylamine,
2- (2-chlorophenyl) ethylamine, 2 , 3-dimethoxy- benzyiamine, 3,4-dimethoxyphenethylamine, 2,4- dichlorophenethylamine, 2- (diethylamino) ethylamine,
2- (1-methylpyrrolidin-2-yl) ethylamine,
3- (diethylamino) propylamine,
2- (5-nitro-2-pyridyl) ethylamine, 3- (dimethylamino) -2 , 2-dimethylpropylamine,
3- (dimethylamino) propylamine, 2-aminoethylamine,
2- (piperidino) ethylamine, isoamylamine,
3-ethoxypropylamine, 3- (2-pipecolinyl) propylamine,
3-butoxypropylamine, 3 - (pyrrolidin-2-one-l-yl) propylamine, 3- (morpholino) propylamine,
2- (N-ethyl-3-methylanilino) ethylamine, 3-phenyl-l- propylamine, 2 -methyl-2 -phenylethylamine , 4 -phenylbutylamine , 3,3 -diphenylpropylamine , isobutylamine, 2- (2 -pyridyl) ethylamine, cyclohexanemethylamine , 3 -methoxyphenethylamine, 3-phenylbenzylamine, piperazine; and
X2 is methylene, 1, 1-cyclopropyl, 1, 3 -phenylene, 1, 4 -phenylene, 1-methyl-l- (4-oxyphenylene) ethane; 3 -methoxy-1, 4 -phenylene, 2-fluoro-1, 4 -phenylene, 4 , 4 ' -biphenylene, 1, 2 -phenylene,
3 , 5-dibromo-l, 4 -phenylene, 4-phenyl-l- (methylene-1-yl) , 3 , 5-diiodo-l, 4-phenylene, 3-hydroxy-l, 4-phenylene, 2,3,5, 6-tetrafluoro-1, 4-phenylene,
3 -bromo-1, 4-phenylene, 3,5-di-tert- butyl-1, 4-phenylene, 3 , 5-di-tert-butyl-4-phenyl-l- (methylene-1-yl) , 3 -methoxy-4 -phenyl- 1- (methylene-1-yl) , 3-nitro-l, 4-phenylene, 5-hydroxy-l, 3-phenylene, 4-phenyl-l- (-2-ethyl) ,
3 -ethoxy-4-phenyl-l- (methylene-1-yl) ,
2-chloro-l, 4-phenylene, 2-fluoro-1, 4-phenylene,
3 , 5-dimethyl-l, 4-phenylene, 2 , 6-dimethyl-1 , 4-phenylene,
3 , 5-dichloro-l, 4-phenylene, 3 -methoxy-2 -phenyl-1- (methylene-1-yl) , 8-quinoline-2-yl, 5-indole-3- (methylene-1-yl) , 3, hydroxy-4-phenyl-l- (methylene-1-yl) , 4-chloro-l, 2-phenylene, 6-nitro-1, 2-phenylene, 5-nitro-1, 2-phenylene, 2 -amino-1, 4-phenylene, 2-carboxymethyl-l , 4-phenylene, 3-bromo-5-methoxy-4-phenyl-l- (methylene-1-yl) , 3, 5-dimethoxy-4-phenyl-l- (methylene-1-yl) , 2-iodo-6-nitro-l, 4-phenylene;
X3 is 1-aminomethylene, 1- (1-aminoethyl) , 1- (2-aminoethyl) , 1- (l-amino-2- (3-pyridyl) ethyl) , 1- (l-amino-2- (2-thienyl) ethyl) , 1- (1-aminopropyl) , 1- (3-aminopropyl) , 1- (5-aminopentyl) ,
1- (1-methyl-l-aminoethyl) , 1- (4-aminomethylcyclohexyl) , 1- (l-amino-3-guanidinopropyl) , 3- (3-aminopropionic acid), 3- (2-aminopropionic acid),
3-methylene-l-phenyl-l, 3, 8-triazaspiro [4.5] decane-4-one, 1- (l-amino-2- (4-chlorophenyl) ethyl) , 1- (l-amino-2- (cyclohexyl) ethyl) , 4- (4-aminobutyric acid) , -4- (2-aminobutyric acid) ,
-1- (l-amino-2- (4-imidazolyl) ethyl) , -1- (l-amino-2-methylbutyl) , -4-piperidinyl , 1- (l-amino-3-methylbutyl) , 3-piperidinyl, 1- (1-aminobutyl) , 1- (l-amino-2-phenylethyl) , 2-piperidinyl, 2-pyrrolidinyl,
1- (l-amino-2-hydroxyethyl) , 4-thiazolidinyl,
1- (l-amino-2-hydroxypropyl) , 3-tetrahydroisoquinolinyl,
1- (l-amino-2- (3 -indolyl) ethyl) ,
1- (l-amino-2- (4-hydroxyphenyl) ethyl) , 1- (l-amino-2- (4-ethoxyphenyl) ethyl) , 1- (1-amino -2-methylpropyl) , 1- (1, 5-diaminopentyl) ; or
3 is 2- (1-pyrrolidino) ethylaminomethylene,
2-pyridinemethylaminomethylene,
2- (4 -imidazole) ethylaminomethylene, cyclopentylaminomethylene, allylaminomethylene,
2-methoxyethylaminomethylene,
(+/-) -tetrahydrofurylaminomethylene, benzylaminomethylene, 2-methylbenzylaminomethylene,-
3-methylbenzylaminomethylene, 4-methylbenzylaminomethylene,
2-fluorobenzylaminomethylene,
3-fluorobenzylaminomethylene,
4-fluorobenzylaminomethylene,
3- (1-imidazole) propylaminomethylene, -aminomethylbenzylaminomethylene, -methoxybenzylaminomethylene, 3 -chlorobenzylaminomethylene, 3-bromobenzylaminomethylene ,
4-bromobenzylaminomethylene, cyclopropylaminomethylene, cyclopropanemethylaminomethylene, 4-pyridinemethylaminomethylene, 3-pyridinemethylaminomethylene, 2-thiophenemethylaminomethylene, phenethylaminomethylene, 2- (morpholine) ethylaminomethylene, 3- methoxybenzylaminomethylene, piperonylaminomethylene, 4-methoxyphenethylaminomethylene,
2-fluorophenethylaminomethylene ,
2- (4-chlorophenyl) ethylaminomethylene,
2- (3 -chlorophenyl) ethylaminomethylene, 2- (2-chlorophenyl) ethylaminomethylene, 2 , 3-dimethoxy- benzylaminomethylene,
3 , 4-dimethoxyphenethylaminomethylene , 2,4- dichlorophenethylaminomethylene,
2- (diethylamino) ethylaminomethylene, 2- (l-methylpyrrolidin-2-yl) ethylaminomethylene,
3- (diethylamino) propylaminomethylene,
2- (5-nitro-2-pyridyl) ethylaminomethylene,
3- (dimethylamino) -2 , 2-dimethylpropylaminomethylene,
3- (dimethylamino) propylaminomethylene, 2-aminoethylaminomethylene,
2- (piperidino) ethylaminomethylene, isoamylaminomethylene, 3-ethoxypropylaminomethylene,
3- (2-pipecolinyl) propylaminomethylene,
3-butoxypropylaminomethylene, 3- (pyrrolidin-2-one-l-yl) propylaminomethylene,
3- (morpholino) propylaminomethylene,
2- (N-ethyl-3-methylanilino) ethylaminomethylene,
3-phenyl-1- propylaminomethylene,
2-methyl-2-phenylethylaminomethylene, 4-phenylbutylaminomethylene,
3 , 3 -diphenylpropylaminomethylene, isobutylaminomethylene, 2 - (2 -pyridyl) ethylaminomethylene, cyclohexanemethylaminomethylene, 3 -methoxyphenethylaminomethylene, 3-phenylbenzylaminomethylene, piperazinomethylene; and
X4 is acetyl, alpha-methylcinnamyl, benzoyl, crotonyl, eyelobutanecarbonyl , 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-eyelohexanecarbonyl , 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; or
4 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, -trifluoromethylbenzenesulfonyl, -ethylbenzenesulfonyl , pentamethylbenzenesulfonyl, ,3, 4 -trifluorobenzenesulfonyl, , 4-dichlorobenzenesulfonyl, ,5-dichlorothiophene-3-sulfonyl , , 6-dichlorobenzenesulfonyl, , 6-difluorobenzenesulfonyl, -chloro-4- (trifluoromethyl) benzenesulfonyl, -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- sulfonyl, 2- (benzoylaminomethyl) thiophene-5-sulfonyl, 3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulfonyl,
5- (isoxazol-3-yl) thiophene-2-sulfonyl, 4-cyanobenzene sulfonyl, 3-chloro- -methylbenzenesulfonyl,
2 , 4-difluorobenzenesulfonyl , 2-fluorobenzenesulfonyl,
4-isopropylbenzene sulfonyl, 2 , 5-dimethoxybenzenesulfonyl ,
3 , 4-dichlorobenzenesulfonyl; or
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) -(-) -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, - (carbamyl) -2,4, 5-trichlorobenzene, - (carbamyl) -2,4,5-trimethylbenzene, 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, 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, - (carbamyl) -2, 6-difluorobenzene, - (carbamyl) -2, 6-diisopropylbenzene, - (carbamyl) -2, 6-dimethylbenzene, - (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, - (carbamyl) -2-chloro-5-nitrobenzene, - (carbamyl) -2-chloro-6-methylbenzene, - (carbamyl) -2-chlorobenzyl, - (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, 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-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, - (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, 4 ' - (carbamyl) -5 ' -nitrobenzo-15-crown-5, 4 ' - (carbamyl) benzo-15-crown-5, ' - (carbamyl) benzo-18-crown-6, 1- (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, 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, 4- (carbamyl) benzoyl chloride, 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
is 1- (thiocarbamyl) - (2-methoxy-5-phenyl) benzene,
1- (thiocarbamyl) adamantane,
1- (thiocarbamyl) naphthalenemethane ,
(thiocarbamyl) naphthalene, 1- (thiocarbamyl) 2, 2-diphenylethane, - (thiocarbamyl) -2,3,4, 5-tetrachlorobenzene, - (thiocarbamyl) -2, 3,4-trichlorobenzene, - (thiocarbamyl) - (2 , 3 , 4 -1rimethoxyphenyl) methane, - (thiocarbamyl) -2,3,5,6-tetrachlorobenzene , - (thiocarbamyl) -2,3,5, 6-tetrafluorobenzene, - (thiocarbamyl) -2, 3-dibromopropane, - (thiocarbamyl) -2, 3-dichlorobenzene, - (thiocarbamyl) - (2, 3 -dimethoxyphenyl) methane, - (thiocarbamyl) -2, 3 -dimethylbenzene, - (thiocarbamyl) -2,4, 5-trichlorobenzene, - (thiocarbamyl) -2,4, 6-tribromobenzene, 1- (thiocarbamyl) -2,4, 6-trichlorobenzene,
1- (thiocarbamyl) -2,4, 6-trifluorobenzene,
1- (thiocarbamyl) -2, 4 , 6-trimethylbenzene,
1- (thiocarbamyl) -2 , 4-dichlorobenzene, 1- (thiocarbamyl) -2, 4-difluorobenzene, - (thiocarbamyl) -2 , 4-dimethoxybenzene, - (thiocarbamyl) -2, 4-dimethylbenzene, - (thiocarbamyl) -2, 5-dibromobenzene, - (thiocarbamyl) -2 , 5-dichlorobenzene, - (thiocarbamyl) -2, 5-difluorobenzene, - (thiocarbamyl) -2 , 5-dimethoxybenzene, - (thiocarbamyl) -2, 5-dimethylbenzene, - (thiocarbamyl) -2 , 6-dichlorobenzene, - (thiocarbamyl) -2, 6-diethylbenzene, - (thiocarbamyl) -2 , 6-difluorobenzene, - (thiocarbamyl) -2, 6-diisopropylbenzene, - (thiocarbamyl) -2, 6-dimethylbenzene, - (thiocarbamyl) -2- (3 , 4-dimethoxyphenyl) ethane, - (thiocarbamyl) -2- (4-chlorophenyl) ethane, - (thiocarbamyl) -2- (methylthio) benzene, - (thiocarbamyl) -2- (trifluoromethoxy) benzene, - (thiocarbamyl) -2- (trifluoromethyl) benzene, - (thiocarbamyl) -2 -bromo-4-methylbenzene, - (thiocarbamyl) -2-bromoethane, - (thiocarbamyl) -2-bromobenzene, - (thiocarbamyl) -2-chloro-4-methylbenzene, - (thiocarbamyl) -2-chloro-4-nitrobenzene, - (thiocarbamyl) -2-chloro-5- (trifluoromethyl) benzene, - (thiocarbamyl) -2-chloro-5-nitrobenzene, - (thiocarbamyl) -2 -chloro-6-methylbenzene, - (thiocarbamyl) - (2-chlorophenyl) methane, - (thiocarbamyl) -2-chloroethane, - (thiocarbamyl) -2-chlorobenzene, - (thiocarbamyl) -2-cyanobenzene, - (thiocarbamyl) -2-ethoxycarbonylbenzene, - (thiocarbamyl) -2-ethoxybenzene, - (thiocarbamyl) -2-ethyl-6- (1-methylpropyl) benzene, 1- (thiocarbamyl) -2-ethyl-6-isopropylbenzene, 1- (thiocarbamyl) -2-ethyl-6-methylbenzene, 1- (thiocarbamyl) -2-ethylbenzene, 1- (thiocarbamyl) - (2-fluorophenyl) methane, - (thiocarbamyl) -2-fluoroethane, - (thiocarbamyl) -2-fluorobenzene, 2- (thiocarbamyl) furan, - (thiocarbamyl) hexane, 1- (thiocarbamyl) -2-iodobenzene, - (thiocarbamyl) -2-isopropyl-6-methylbenzene, - (thiocarbamyl) -2-isopropylbenzene, - (thiocarbamyl) -2-methoxy-4-nitrobenzene, - (thiocarbamyl) -2-methoxy-5-methylbenzene, - (thiocarbamyl) -2-methoxy-5-nitrobenzene, - (thiocarbamyl) - (2-methoxyphenyl) methane, - (thiocarbamyl) -2-methoxyethane, - (thiocarbamyl) -2-methoxybenzene, - (thiocarbamyl) -2-methyl-4-nitrobenzene, - (thiocarbamyl) -2-methyl-5-nitrobenzene, - (thiocarbamyl) - (2-methylphenyl) methane, - (thiocarbamyl) -2-methylbutane, - (thiocarbamyl) -2- (morpholino) ethane, - (thiocarbamyl) -naphthalene, 2- (thiocarbamyl) pentane, - (thiocarbamyl) -2-phenylethane, - (thiocarbamyl) -2-piperidinoethane, - (thiocarbamylmethyl) -tetrahydrofuran, - (thiocarbamyl) -3 , 4 , 5-trimethoxybenzene, - (thiocarbamyl) -3,4- (ethylenedioxy) benzene, - (thiocarbamyl) -3,4-dichlorophenyl)me hane, - (thiocarbamyl) -3, 4-dichlorobenzene, - (thiocarbamyl) - (3 , 4-dimethoxyphenyl) methane, - (thiocarbamyl) -3, 4-dimethoxybenzene, - (thiocarbamyl) -3, 4-dimethylbenzene, - (thiocarbamyl) - (3, 4-methylenedioxyphenyl) methane, - (thiocarbamyl) -3, 4-methylenedioxybenzene, - (thiocarbamyl) -3 , 5-bis (trifluoromethyl) benzene, - (thiocarbamyl) -3, 5-dichlorobenzene, - (thiocarbamyl) -3 , 5-dimethoxybenzene, - (thiocarbamyl) -3, 5-dimethylbenzene, 1- (thiocarbamyl) -3- (diethylamino) propane, 1- (thiocarbamyl) -3- (methylthio) benzene, 1- (thiocarbamyl) -3- (trifluoromethyl) benzene, 1- (thiocarbamyl) -3-acetylbenzene, 1- (thiocarbamyl) -3-benzyloxybenzene, 1- (thiocarbamyl) -3-bromobenzene, 1- (thiocarbamyl) -3-bromopropane, 1- (thiocarbamyl) -3-carboxybenzene, - (thiocarbamyl) -3-chloro-2-methylbenzene, - (thiocarbamyl) -3-chloro-4-fluorobenzene, - (thiocarbamyl) - (3-chloro-4-methylphenyl) methane, - (thiocarbamyl) -3-chloro-4-methylbenzene, - (thiocarbamyl) - (3-chlorophenyl) methane, - (thiocarbamyl) -3-chlorobenzene, - (thiocarbamyl) -3-chloropropane, - (thiocarbamyl) -3-cyanobenzene, - (thiocarbamyl) -3-dimethylaminopropane, - (thiocarbamyl) -3-ethoxycarbonylbenzene, - (thiocarbamyl) -3-ethylbenzene, - (thiocarbamyl) - (3-fluorophenyl) methane, - (thiocarbamyl) -3-fluorobenzene, - (thiocarbamyl) -3-iodobenzene, - (thiocarbamyl) - (3-methoxyphenyl) methane, - (thiocarbamyl) -3-methoxycarbonylbenzene, - (thiocarbamyl) -3-methoxybenzene, - (thiocarbamyl) -3-methoxypropane, - (thiocarbamyl) -3-methyl-2-butane, - (thiocarbamyl) - (3-methylphenyl) methane, - (thiocarbamyl) -3-methylbutane, - (thiocarbamyl) -3-morpholinopropane, - (thiocarbamyl) -3-nitrobenzene, - (thiocarbamyl) -3-pentane, - (thiocarbamyl) -3-phenylpropane, - (thiocarbamyl) pyridine, - (thiocarbamyl) -4- (benzyloxy) benzene, - (thiocarbamyl) -4- (dimethylamino) benzene, - (thiocarbamyl) -4- (methylthio) benzene, 1- (thiocarbamyl) -4- (trifluoromethoxy) benzene, 1- (thiocarbamyl) -4- (trifluoromethyl) benzene, 1- (thiocarbamyl) -4-acetylbenzene, 1- (thiocarbamyl) -4-bromo-2, 6-dimethylbenzene, - (thiocarbamyl) -4-bromo-2-chlorobenzene, - (thiocarbamyl) -4 -bromo-2-methylbenzene, - (thiocarbamyl) -4-bromo-2-trifluoromethylbenzene, - (thiocarbamyl) -4-bromobenzene, - (thiocarbamyl) -4-carboxybenzene, - (thiocarbamyl) -4-chloro-2- (trifluoromethyl) benzene, - (thiocarbamyl) -4-chloro-2 -methylbenzene, - (thiocarbamyl) -4 -chloro-3 -nitrobenzene, - (thiocarbamyl) -4 -chloro-3 -trifluoromethylbenzene, - (thiocarbamyl) - (4-chlorophenyl) methane, - (thiocarbamyl) -4-chlorobenzene, - (thiocarbamyl) -4-cyanobenzene, - (thiocarbamyl) -4-diethylaminobenzene, - (thiocarbamyl) -4-ethoxycarbonylbenzene, - (thiocarbamyl) -4-ethoxybenzene, - (thiocarbamyl) -4-ethylbenzene, - (thiocarbamyl) -4-fluoro-2-methylbenzene, - (thiocarbamyl) - (4-fluorophenyl) ethane, - (thiocarbamyl) - (4-fluorophenyl) methane, - (thiocarbamyl) -4-fluorobenzene, - (thiocarbamyl) -4-iodobenzene, - (thiocarbamyl) -4-isopropylbenzene, - (thiocarbamyl) -4-methoxy-2-methylbenzene, - (thiocarbamyl) -4-methoxy-2-nitrobenzene, - (thiocarbamyl) - (4-methoxyphenyl) methane, - (thiocarbamyl) -4-methoxycarbonylbenzene, - (thiocarbamyl) -4-methoxybenzene, - (thiocarbamyl) -4 -methyl-2-nitrobenzene, - (thiocarbamyl) - (4 -methylphenyl) methane, - (thiocarbamyl) -4-n-butyl-2-methylbenzene, - (thiocarbamyl) -4-n-butylbenzene, - (thiocarbamyl) -4-nitrobenzene, - (thiocarbamyl) -4-phenoxybenzene, 1- (thiocarbamyl) -4-phenylazobenzene,
1- (thiocarbamyl) -4-phenylbutane,
1- (thiocarbamyl) -4-sulfamoylbenzene,
1- (thiocarbamyl) -4-tert-butylbenzene, 1- (thiocarbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (thiocarbamyl) -5-chloro-2-methoxybenzene,
1- (thiocarbamyl) -5-chloro-2-methylbenzene,
1- (thiocarbamyl) -5-fluoro-2-methylbenzene,
1- (thiocarbamyl) -5-indane, 2- (thiocarbamyl) -5-norbornene,
2- (thiocarbamyl) -6-methylheptane,
9- (thiocarbamyl) acridine, 1- (thiocarbamyl) -2-propene,
1- (thiocarbamyl) - (1-phenyl) ethane,
1- (thiocarbamyl) -phenylmethane, 1- (thiocarbamyl) -cycloheptane,
1- (thiocarbamyl) -cyclohexylmethane, 1- (thiocarbamyl) -cyclohexane, 1- (thiocarbamyl) -cyclooctane, 1- (thiocarbamyl) -eye1opentane, 1- (thiocarbamyl) -cyclopropane, diethyl L-2-thiocarbamyl-glutarate, dimethyl L-thiocarbamyl-succinate, ethyl
2-thiocarbamylpropionate, ethyl 3-thiocarbamylbutyrate, ethyl 3-thiocarbamylpropionate, ethyl 4-thiocarbamylbutyrate, 1- (thiocarbamyl) -ethane, ethyl thiocarbamylacetate, 1- (thiocarbamyl) -2-methylpropane, 1- (thiocarbamyl) -1-methylethane, thiocarbamylacetaldehyde dimethyl acetal, thiocarbamylphenyl sulfone, 1- (thiocarbamyl) -2-butene, 1- (thiocarbamyl) -methoxymethane, methyl
2-thiocarbamylacetate, methyl 2-thiocarbamylbenzoate, methyl 3-thiocarbamylpropionate, methyl 2-thiocarbamylbutyrate, methyl, methyl L-2-thiocarbamyl-3-methyl-butyrate, methyl L-2-thiocarbamyl-3 -phenyl-propionate, methyl
L-2-thiocarbamyl-4- (methylthio) butyrate, methyl L-2-thiocarbamyl-4 -methylvalerate, 1- (thiocarbamyl) -pentane, 1- (thiocarbamyl) -butane, 1- (thiocarbamyl) -hexane, 1- (thiocarbamyl) -propane, 2- (thiocarbamyl) -norbornane, 1- (thiocarbamyl) -4-vinylbenzene, 1- (thiocarbamyl) -pentafluorobenzene,
1- (thiocarbamyl) -benzene, 1- (thiocarbamyl) -propyne, 2- (thiocarbamyl) -butane.
The present invention also provides a method of preparing libraries wherein compounds of Formula (I) , in particular, oxadiazoles, are made by reacting a resin- bound amine with a nitrile-containing carboxylic acid, nitrile-containing isocyanate or nitrile-containing radical with a leaving group to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing an amino-protected group; deprotecting the amino-protected group to obtain an oxadiazole amine; and reacting the oxadiazole amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadiazole library. Another method of preparing oxadiazole libraries comprises reacting a resin-bound amine with a nitrile-containing carboxylic acid, isocyanate or leaving group to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing a leaving group; and reacting the leaving group with a primary amine or secondary amine to obtain a oxadiazole secondary amine or oxadiazole tertiary amine; and optionally reacting the secondary amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadizaole library. In a preferred embodiment the resin-bound amine can be prepared by displacing a resin-bόund leaving group with a primary amine. In another embodiment, the resin-bound amine can be prepared by reducing a resin-bound imine formed from either a resin-bound aldehyde with a primary amine or a resin-bound primary amine with an aldehyde. Yet another method comprises reacting a resin- bound leaving group with a nitrile-containing phenoxide ion or amine to obtain a resin-bound nitrile; cyclizing the nitrile to obtain to an oxadiazole containing an amino-protected group; deprotecting the amino-protected group to obtain an amine; and reacting the amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadiazole library. Still another method comprises reacting a resin-bound leaving group with a nitrile-containing phenoxide ion to obtain a resin-bound nitrile; cyclizing the nitrile to obtain an oxadiazole containing a leaving group; and reacting the leaving group with a primary or secondary amine to obtain a secondary or a tertiary amine of the oxadiazole library; and optionally reacting the secondary amine with a carboxylic acid or a sulfonyl chloride or an isocyanate or an isothiocyanate to obtain the oxadizaole library.
Alternatively, the present invention also provides a method of preparing oxadiazole libraries wherein oxadiazole compounds of Formula (I) are made by reducing an imine formed between a resin-bound aldehyde and an amine containing a protected carboxylic acid to give a protected carboxylic acid bound to resin; deprotecting the protected carboxylic acid to give a resin bound carboxylic acid and reacting the carboxylic acid with an amidoxime to give an oxadiazole library.
Another method of preparing oxadiazole libraries comprises reacting a resin-bound alcohol with an amine containing a protected carboxylic acid to give a protected carboxylic acid bound to resin through a carbamate linkage; deprotecting the protected carboxylic acid to give a carboxylic acid and reacting the carboxylic acid with an amidoxime to give an oxadiazole library. In a preferred embodiment, the methods described above further comprise the step of cleaving the library from the resin.
In the above Formula (I) , the stereochemistry of chiral centers associated with R2 and R3 when X3 is:
Figure imgf000041_0001
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 "Cx 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 "Cx 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- pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2 -heptynyl, 3-heptynyl, 4- heptynyl, 5-heptynyl as well as di- and tri-ynes of straight and branched chains. The terms "Cx to C6 substituted alkyl," "C2 to C7 substituted alkenyl," "C2 to C7 substituted alkynyl," and "Cx to C12 substituted alkylene" denote that the above Cx to C6 alkyl groups and C2 to C7 alkenyl and C2 to C7 alkynyl groups and Cx to CX2 alkylene 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, Cx to C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N,N-di(Cx to C6 alkyl) carboxamide, cyano, methylsulfonylamino, thiol, Cx to C4 alkylthio or Cx to C4 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-l-yl, cyanomethyl, nitromethyl , chloromethyl , hydroxymethyl, tetrahydropyranyloxymethyl , trityloxymethyl, propionyloxymethyl, amino, methylamino, aminomethyl, dimethylamino, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl , chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexy1 , 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-1-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 term "C2 to C7 substituted alkenylene" as used herein denotes an alkene 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 C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N,N-di(Cx to C6 alkyl) carboxamide, cyano, methylsulfonylamino, thiol, Cx to C4 alkylthio or Cx to C 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 "Cx to C7 substituted alkoxy" means the alkyl portion of the alkoxy can be substituted in the same manner as in relation to Cx to C6 substituted alkyl. Similalry, the term "Cx to C7 phenylalkoxy" as used herein means "Cx to C7 alkoxy" bonded to a phenyl raidcal .
The term "Cx to C7 acyloxy" denotes herein groups such as formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.
Similarly, the term "Cx 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, Cx to C7 alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, nitro, Cx to C6 alkyl ester, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N,N-di(Cx to C6 alkyl) carboxamide, cyano, methylsulfonylamino, thiol, Cx to C4 alkylthio or Cx to C4 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 Cx to C7 substituted acyl groups include 4-phenylbutyroyl, 3-phenylbutyroyl, 3-phenylpropanoyl, 2- cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and 3 -dimethylaminobenzoyl .
The substituent term "C3 to C7 cycloalkyl" includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. The substituent term "C3 to C, substituted cycloalkyl" indicates the above cycloalkyl rings substituted by one or two halogen, hydroxy, protected hydroxy, Cx to C4 alkylthio, Cx to C4 alkylsulfoxide, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cx to C4 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 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 substituent.
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, Cx to C4 alkylthio, Cx to C4 alkylsulfoxide, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cx to C4 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 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 morpholino, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen-yl .
The term "substituted heterocyce" 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 are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 alkyl, Cx 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, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N-di (Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino or N- (phenylsulfonyl) amino 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 are the same or different which substituents can be halogen, hydroxy, protected hydroxy, cyano, nitro, Cx to C6 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, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N-di (Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino or N- (phenylsulfonyl) amino groups .
The term "C7 to Cx2 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 CX2 phenylalkyl groups are the benzyl and the phenylethyl groups .
The term "C7 to CX2 substituted phenylalkyl" denotes a C7 to Cx2 phenylalkyl group substituted on the Cx 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, 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, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (C to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N- (Cx to C6 dialkyl) carboxamide, cyano, N- (Cx to C6 alkylsulfonyl) amino, thiol, Cx to C4 alkylthio, Cx to C4 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, 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, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N-di (Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino, cyclic C2 to C7 alkylene 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 C12 substituted phenylalkyl" include groups such as 2-phenyl-l- 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 Cx2 phenylalkylene" specifies a C7 to CX2 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 CX2 substituted phenylalkylene" means a C7 to CX2 phenylalkylene as defined above that is further substituted by halogen, hydroxy, protected hydroxy, Cx to C4 alkylthio, Cx to C4 alkylsulfoxide, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cx to C4 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 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, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N-di (Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino or phenyl, wherein the 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 -carboxypheny1 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) phenyl 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, Cx 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, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N-di (Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino and N- (phenylsulfonyl) amino.
Examples of substituted phenoxy include 2-methylphenoxy, 2-ethylphenoxy, 2-propylphenoxy, 2-isopropylphenoxy, 2-sec-butylphenoxy, 2-tert-butylphenoxy, 2-allylphenoxy, 2-propenylphenoxy, -cyclopentylphenoxy, 2-fluorophenoxy, - (trifluoromethyl) phenoxy, 2-chlorophenoxy, -bromophenoxy, 2-methoxyphenoxy, 2-ethoxyphenoxy, -isopropoxyphenoxy, 3-methylphenoxy, 3-ethylphenoxy, -isopropylphenoxy, 3-tert-butylphenoxy, -pentadecylphenoxy, 3- (trifluoromethyl) phenoxy, -fluorophenoxy, 3-chlorophenoxy, 3-bromophenoxy, -iodophenoxy, 3-methoxyphenoxy, - (trifluoromethoxy) phenoxy, 4-methylphenoxy, -ethylphenoxy, 4-propylphenoxy, 4-isopropylphenoxy, -sec-butylphenoxy, 4-tert-butylphenoxy, -tert-amylphenoxy, 4-nonylphenoxy, 4-dodecylphenoxy, -cyclopenylphenoxy, 4- (trifluoromethyl) phenoxy, -fluorophenoxy, 4-chlorophenoxy, 4-bromophenoxy, -iodophenoxy, 4-methoxyphenoxy, - (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-tert-butyl-4-methylphenoxy,
2 , 4-di-tert-butylphenoxy, 2 , 4-di-tert-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 Cx2 substituted phenylalkoxy" denotes a C7 to CX2 phenylalkoxy group wherein the Cx to C6 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 C alkoxy, Cx to C7 acyl, Cx to C7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carboxamide, protected carboxamide, N- (Cx to C6 alkyl) carboxamide, protected N-(CX to C6 alkyl) carboxamide, N, -N- (Cx to C6 dialkyl) carboxamide, cyano, N- (Cx to C6 alkylsulfonyl) amino, thiol, Cx to C4 alkylthio, Cx to C4 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, Cx to C7 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, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N-di(Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino, N- (phenylsulfonyl) amino 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 CX2 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, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C7 substituted 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, N, N-di(Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino and N- (phenylsulfonyl) amino.
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, Cx to C6 alkyl, Cx to C7 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, N- (Cx to C6 alkyl) carboxamide, protected N- (Cx to C6 alkyl) carboxamide, N, N-di (Cx to C6 alkyl) carboxamide, trifluoromethyl, N- ( (Cx to C6 alkyl) sulfonyl) amino or N- (phenylsulfonyl) amino.
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 1, 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 1, 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 1, 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-yl, 4-ethyl-2-hydroxynaphth-l-yl, 3-hydroxy-4-nitronaphth-2- yl, 2-hydroxy-4-chloronaphth-l-yl, 2-methoxy-7- bromonaphth-1-yl, 4-ethyl-5-hydroxynaphth-2-yl , 3-hydroxy-8-nitronaphth-2-yl, 2-hydroxy-5-chloronaphth-l- 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 C4 alkylsulfonyl, Cx to C4 substituted alkylthio, Cx to C4 substituted alkylsulfoxide, Cx to C4 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, 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, Cx 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. Similarly, the term "protected N- (Cx to C6 alkyl) 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 , l-methylcyclohexanyloxycarbonyl , 2-methylcyclohexanyloxycarbonyl, 2- (4-toluylsulfonyl) - ethoxycarbonyl , 2- (methylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino) -ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("Fmoc") , 2- (trimethylsilyl) ethoxycarbonyl, allyloxycarbonyl, 1- (trimethylsilylmethyl)prop-l-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. 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 C4 alkylsulfonyl" encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like. The terms "Cx to C4 substituted alkylthio, " "Cx to C4 substituted alkylsulfoxide, " and "Cx to C4 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 "Cx to C6 alkylaminocarbonyl" means a Cx to C6 alkyl attached to a nitrogen of the aminocarbonyl group. Examples of Cx to C6 alkylaminocarbonyl include methylaminocarbonyl (from methylisocyanate) , ethylaminocarbonyl (from ethylisocyanate) , propylaminocarbonyl (from propylisocyanate) , butylaminocarbonyl (from butylisocyatate) . The term "Cx to C6 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 C6 substituted alkyl. Examples of Cx to C6 substituted alkylaminocarbonyl include, for example, methoxymethylammocarbonyl (from methoxymethylisocyanate) , 2-chloroethylaminocarbonyl (from 2-chloroethylisocyanate) , 2-oxopropylaminocarbonyl (from 2-oxopropylisocyanate) , and 4-phenylbutylaminocarbonyl (from phenylbutylisocyanate) .
The term "Cx to C7 alkoxycarbonyl" means a
"Cx to C7 alkoxy" group attached to a carobonyl 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 Cx 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 ethylisothiocyanate) , 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 C6 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 C12 alkylene" means a Cx to CX2 alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups. Examples of "Cx to CX2 alkylene" include methylene, 1,2-ethyl, 1,1-ethyl, 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 Cx to Cx2 alkylene" means a Cx to CX2 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 "substituted Cx to C12 alkylene" includes 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 "substituted phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, 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-l, 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-hydroxybenzonitrile, 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-l, 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-l, 4-phenylene from
3 , 5-dimethyl-4-hydroxybenzonitrile, 2 , 6-dimethyl-l, 4- phenylene from 2, 6-dimethyl-4-hydroxybenzonitrile, 2,6 dichloro-1, 4-phenylene from 2 , 6-dichloro-4- hydroxybenzonitrile, 4-chloro-1, 2- phenylene from 4-chloro-2-hydroxybenzonitrile, 6-nitro-1, 2-phenylene from 2-cyano-6-nitro-phenol, 5-nitro-l, 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, Cx to C4 acyloxy, formyl, Cx to C7 acyl, Cx to C6 alkyl, Cx to C7 alkoxy, Cx to C4 alkylthio, Cx to C4 alkylsulfoxide, Cx to C4 alkylsulfonyl, halo, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, hydroxymethyl or a protected hydroxymethyl.
The cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it 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 "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, sulf ric, 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, cyclohexylamine; 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, phenylglycine, 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 peptide 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.
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 Gbh, 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 a mixture 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 Oxadiazole. 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 the Reaction Schemes provided in the Reaction Schemes 2 through 5 and described below.
Several variant oxadiazole combinatorial libraries have been prepared in order to achieve a high level of diversity. Different types of nitrile containing substrates were attached to solid support. Among the available nitriles, those containing a carboxylic acid moiety were coupled to a resin-bound amine via an amide bond (Scheme 1: Attachment of Cyanocarboxylic acids to solid support) . The carboxylic acid was coupled directly to a resin bound primary amine such as methyl benzhydrylamine (MBHA) , or RINK amide linker or other resins known in the art which afford a primary amide functional group after cleavage. Alternatively the cyano carboxylic acids were coupled to resin-bound primary or secondary amines which become incorporated into the product as secondary or tertiary amides after cleavage from the resin. These could be prepared by reductive amination of a primary amine to an aldehyde resin or vice-versa, or to any other resin-bound primary or secondary amine prepared by methods known to those skilled in the art.
Cyanophenols were coupled to solid support via an ether linkage as shown in Scheme 2 : Attachment of cyanophenols to solid support which releases the free phenol after cleavage, by. alkylation of a benzyl halide resin such as Merrifield resin or alkoxybenzyl bromide resin (Wang bromide resin) . Alternatively, the cyanophenols were coupled to an alkyl halide moiety which remains covalently attached to the oxadiazole product after cleavage from the resin. For example, a primary or secondary amine bound to the resin through a cleavable linker is acylated with chloroacetic anhydride or 3- or 4 -chloromethyl benzoic acid. A cyanophenol was then introduced by nucleophilic displacement of the alkyl halide. In this way, a wide range of cyanophenyl compounds was made, and converted to oxadiazole compounds by the methods described below.
Other types of nitrile containing compounds can be similarly linked to common resins as shown in Scheme 3: Linking nitriles to solid support. For example, 3- cyanophenyl isocyanate and 4 -cyanophenyl isocyanate were linked to the resin by forming a urea linkage and the nitrile function elaborated into an oxadiazole. Additionally, cyanohydrins may be formed on the resin by the action of Trimethylsilyl cyanide on resin-bound aldehydes and ketones . Alkyl nitriles may be formed by displacement of leaving groups with cyanide anion.
Primary and secondary amines attached to the resin were alkylated with 3- and 4-cyanobenzylbromide, and the cyanobenzylamines converted to oxadiaxoles. Because of the relatively low number of suitable commercially available nitriles, N-Boc 2-cyanoethyl glycine was also found to be a useful precursor to a large number of oxadiazole derivatives. The cyanoethyl group was first converted to the oxadiazole followed by conversion of the Boc-protected amine to a variety of derivatives.
In order to provide further diversity, conversion of the nitrile function into the oxadiazole ring was done following a number of methods (Scheme 4 : Conversion of Nitriles into Oxadiazoles) . Treatment of the nitriles with hydroxylamine in alcohol solvent provided the amidoximes in quantitative yield. The amidoximes were then treated with different types of acylating agents to give 3, 5-substituted oxadiazoles. In a first embodiment, the amidoximes were treated with trichloroacetic anhydride to give the 5-trichloromethyl derivatives which were further reacted with secondary amines to give 5-amino oxadiazoles by displacement of the trichloromethyl group. Alternatively, the amidoximes were treated with chloroacetic anhydride to give the 5- chloromethyl oxadiazoles. This primary chloride could be displaced with diverse primary or secondary amines to give substituted 2% or 3% amines. These could be derivatized further to introduce an additional variable substituent. This strategy was particularly useful for the preparation of compounds attached to the resin by TFA labile bonds which preclude the use of N-Boc-protected amino acids (vide infra) . This was also the method of choice with cyanoethyl glycine derivatives. Third, the amidoximes were converted to oxadiazoles by reaction with BOC amino acid anhydrides or FMOC amino acid anhydrides to give the substituted oxadiazole derivatives. Natural L-amino acid derivatives (e.g. Gly, Phe, Leu) were used as well as D- or L-amino acids, cyclic amino acids (e.g. Pro, Nipecotic acid, Isonipecotic acid, tetrahydroisoquinoline carboxylic acid) , unnatural amino acids, or other aliphatic carboxylic acids and anhydrides. In all cases, the carboxylic acid moiety becomes incorporated into the oxadiazole ring.
Furthermore, the N-BOC or N-FMOC protecting group could be removed under standard conditions and the resulting amine derivatized with an additional diverse set of reagents (Scheme 5: Derivatization of Oxadiazoles) . For example amide, sulfonamide, urea and thiourea derivatives were obtained by reaction with acid anhydride, sulfonyl chloride, isocyanates and isothiocyanates respectively. Fourth, the amidoximes can be reacted with activated carboxylic acid derivatives other than anhydrides. Any acylating reagent known in the art could be used in the synthesis of oxadiazoles, including but not limited to acid chlorides, and fluorides, mixed anhydrides, active esters such as pentafluorophenyl, 4-nitrophenyl, hydroxybenzotriazole, N-hydroxysuccinimide and the like.
In general, large diverse combinatorial libraries of oxadiazole compounds were prepared by assembling the three sets of building blocks in all possible permutations. Thus the libraries are described as having three variable positions, or three diversity sites. In one embodiment of these methods, the first diversity site is defined by the nitrile containing moiety, or its precursor, attached to the resin. This includes, but is not limited to, cyanocarboxylic acids, cyanobenzyl halides and cyanophenols, and the coupling of these through appropriate chemistry to diverse compounds on solid support. Additionally, these methods are meant to include as starting materials other products synthesized on solid phase whereby an aliphatic, aromatic or heteroaromatic nitrile compound is obtained. The second diversity site is introduced in the oxadiazole formation and is defined by the appropriately functionalized carboxylic acid anhydride used in the cyclization step. The third diversity site is created by the derivatization of a reactive site introduced by the carboxylic acid moiety in the previous step. More specifically, the use of protected amino acid derivatives is particularly useful in the present invention. The amino acid side chain provides the second diversity site as defined above. Derivatization of the amino group with carboxylic acids, sulfonyl chlorides, isocyanates, isothiocyanates, alkyl halides or aldehydes provides the third diversity site. Other reactive functional groups incorporated in protected or unprotected form can also serve to introduce the third diversity element. In another embodiment of the invention, bifunctional carboxylic acid derivatives are used to form the oxadiazole ring and an attachment point for a third diversity site. This attachment point can be a nucleophilic site (e.g. alcohol, thiol, carbon nucleophile, etc.) or an electrophilic site (halide, tosylate, triflate, activated carboxylate, etc) . In particular, cyclic anhydrides such as succinic anhydride, diglycolic anhydride, 1, 2-cyclopropane dicarboxylic anhydride are preferred embodiments. The oxadiazole cyclization produces a pendant carboxylic acid which can be further activated with standard coupling reagents and coupled to diverse amines . Another preferred embodiment of the invention is the use of chloroacetic anhydride or other halocarboxylic acid anhydrides in the oxadiazole cyclization creating a chloromethyl group which is readily displaced with diverse nucleophiles such as amines, thiols, alcohols, phenols or carbon nucleophiles. In a most preferred embodiment primary amines or secondary diamines are used which are derivatized further with carboxylic acids, sulfonyl chlorides, isocyanates, isothiocyanates or alkyl halides.
The synthesis of oxadiazoles on solid support could also be performed in the opposite orientation. A carboxylic acid moiety could be attached to the solid support in a variety of different ways, for example, an amino acid ester is attached to a resin by reductive amination, or by reaction with a chloroformate resin derivative, followed by hydrolysis of the ester.
Alternatively, a resin bound amine can be reacted with a cyclic anhydride such as succinic anhydride. Other methods of providing a free carboxylic acid on solid support are known in the art. The carboxylic acid is then converted to an activated derivative such as the mixed anhydride with isobutyl chloroformate, or an active ester with pentafluorophenol, 4-nitrophenol, N- hydroxysuccinimide, HOBT or other activated derivatives such as those used routinely in the formation of amide or ester bonds. This activated resin bound carboxylate is then treated immediately with a solution of amidoxime, prepared by the reaction of a nitrile compound with hydroxylamine under standard conditions.
The nonsupport-bound combinatorial libraries can be screened as mixtures 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 . , Na ture, 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 oxadiazole derivatives, can be used as pesticides, acaricides, receptor agonisits 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 36 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 K, 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 . Natl .
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 . , Mol . 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-DAMG0 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-DAMGO 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 (cAMP) (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 : DMA, dimethyl acetamide; RT, room temperature; DMF, dimethylforamide; IPA, isopropyl alcohol; Wang resin, p-benzyloxybenzylalcohol-polystyrene; DCM, dichloromethane; MTBE, methyl-tert-butyl ether; MBHA-HC1 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-pentamethylchroman-6-sulfonyl; TBU, 2- (1H- 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, methanoi; 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 Synthesis of 4-alkoxy-2-methoxybenzaldehyde resin (DAB resin)
Chloromethyl polystyrene (500 g, 1.48 mmol/g, 740 mmol) was swollen in Dimethyl acetamide . 4-hydroxy- 2-methoxybenzaldehyde (250g, 1645 mmol) was dissolved in 400 ml DMA and potassium t-butoxide was added (185 g,
1645 mmol) in portions. The green solution was added to the loose resin and the suspension was shaken overnight at 50 %C. The solution was cooled to RT, and the resin transfered to teabags washed with 2 1 portions of DMF (IX), and 5%, 10% and 20% H20 in DMF (4X each), IPA and MeOH (3X) . The resin was dried, to give 4-alkoxy-2- methoxybenzaldehyde polystyrene resin.
EXAMPLE 2 Preparation of Wang bromide resin
Wang resin (20 g, 24 mmol) was swollen in DCM.
A solution of triphenylphosphine dibromide (30.4g, 72 mmol) in 500 ml DCM was added and the solution shaken for 3 hours or overnight. The resin was washed with DCM and MTBE and dried under vacuum, to give 4-alkoxybenzyl bromide polystyrene resin.
EXAMPLE 3 Coupling of Nitrile Carboxylic acids to MBHA Resin
MBHA-HCl resin (Methylbenzhydrylamine
Hydrochloride) (125 g, 162.5 mmol NH2) was dispensed into 15 10X15 cm PP mesh bags (8.33 g/bag) . The resin was washed 3X with 5% DIEA/ DCM then 2X with DCM. The carboxylic acids below were dissolved in 500 ml DCM in separate Nalgene bottles, . DIEA (28.3 ml, 162.5 mmol) and HOBT (24.9 g, 162.5 mmol) added to each. Once dissolved, A and B were cooled to -10-C, C, D, and E were left at RT. DIC (25.4 ml, 162.5 mmol) was added in 5 ml portions over 1 hr to each bottle. Once the addition of DIC was complete, 3 bags were added to each bottle, and the solutions shaken overnight at RT. The bags were then removed from the anhydride solutions and washed 3X with DCM, 3X with MeOH and dried to yield the carboxynitrile attached to the resin through a carboxamide linkage. Kaiser test of the resins was negative.
List of Cyano Carboxylic Acids.
Resin A Cyanoacetic acid: 13.8 g, 162.5 mmol
Resin B 1-Cyano-1-cyclopropane carboxylic acid: 18.1 g, 162.5 mmol Resin C 3-Cyanobenzoic acid: 23.9 g, 162.5 mmol
Resin D 4-Cyanobenzoic acid: 23.9 g, 162.5 mmol
Resin E 2- (4-Cyanophenoxy) -2-methyl propionic acid: 33.3 g, 162.5 mmol
EXAMPLE 4 Preparation of DAB resin bound amines by reductive amination (Type 1 amines)
A 200 mg portion of DAB resin in a teabag was swollen in DMF + 1% AcOH. The amine or amine salt was added (0.25M amine) and the solutions shaken at RT for 1 hour. Sodium cyanoborohydride was then added (0.25 M) and the solution shaken at RT overnight . The supernatant was poured off and the resin washed with DMF (4X) , MeOH (4X) and DCM (2X) to yield secondary amines on resin.
List of amines:
Isobutylamine Benzyiamine
Glycine t-butyl ester hydrochloride 1- (3-aminopropyl) imidazole
EXAMPLE 5
Preparation of Wang resin bound diamines (Type 2 amines)
Wang resin (100 g, 120 mmol) was swollen in DCM for 15 min and the excess poured off. A solution of carbonyl diimidazole (100 g, 0.5 mol) in 800 ml DCM was added and shaken for 3 hours . The solvent was poured off and the resin washed with DCM (2X) then a solution of anhydrous piperazine (43 g, 0.5 mol) in 800 ml DCM was added, and the solution shaken overnight. The supernatant was removed, and the resin washed with DCM, IPA, DMF, IPA and MeOH to yield piperazine linked to resin. The same procedure is followed with the following diamines:
1, 10-diaminodecane 1, ll-diaminoundecane 1 , 12-diaminododecane
1 , 2-diaminocyclohexane
1, 3-bis (aminomethyl) cyclohexane
1, 3-diamino-2-propanol 1, 3-diaminopropane
1, 4-diaminobutane
1, 5-diamino-3-oxapentane
1, 5-diaminopentane
1, 6-hexanediamine 1, 7-diaminoheptane
1, 8-diaminooctane
1, 9-diaminononane
2 , 2-dimethyl-1, 3-propanediamine
2 , 2-dimethyl-l, 5-diaminopentane 2-methyl-1, 5-diaminopentane
2.4/2.6-diamino-l-methylcyclohexane mixture
3 , 3-oxetanebis (methylamine) dihydrobromide
4,4' -diaminodicyclohexylmethane
5-amino-2 ,2,4-trimethyl-1-cyclopentanemethylamine 9, 9-bis (3-aminopropyl) fluorene
Trans-1, 2-diaminocyclohexane
Trans-1, 4-diaminocyclohexane
EXAMPLE 6 Acylation of resin bound amines with Cyanocarboxylic acids
To a solution of 4-cyanobenzoic acid (27 mmol, 4.0g) in 45 ml DCM/DMF (2:1) was added DIC (2.11 ml, 13.5 mmol) . The solution was shaken 10 min, then DIEA (2.34 ml, 13.5 mmol) and DMAP (1.0 mmol, 120 mg) were added. The teabags containing resin-bound amines from Examples 4 and 5 were then added and the solution shaken overnight. The bags were washed with DCM, DMF, DCM and MeOH, then dried to yield 4-cyanobenzamide resin. Other acids used: Cyanoacetic acid
1-Cyano-1-cyclopropane carboxylic acid
3-Cyanobenzoic acid
2- (4 -Cyanophenoxy) -2-methyl propionic acid
EXAMPLE 7
Acylation of resin bound amines with halocarboxylic acids
A teabag containing 100 g of resin bound piperazine from Examples 5 (120 mmol) was swollen in DCM and a solution of chloroacetic anhydride (41 g, 240 mmol) in 500 ml DCM was added, followed by DIEA (42 ml, 240 mmol) . The solution was shaken at RT overnight, and washed with DCM, DMF, IPA and MeOH and dried to yield 4- chloroacetyl piperazine bound resin. Other primary and secondary amines of Example 4 and 5 are also used.
The halo carboxylic acids shown below can be substituted for chloroacetic anhydride and used in a similar manner, such as, preparing the anhydride of the carboxylic acid with dusopropyl carbodiimide in DCM for 30 minutes before addition of the amine resin.
4- (bromomethyl) benzoic acid
4- (chloromethyl) benzoic acid
Bromopyruvic acid
11-bromoundecanoic acid 12-bromododecanoic acid
3-bromopropionic acid
3-chloropropionic acid
3-iodopropionic acid
4-bromobutyric acid -chlorobutyric acid
3-chloropivalic acid - (bromomethyl) acrylic acid -bromovaleric acid 5-chlorovaleric acid 6-bromohexanoic acid 8-bromooctanoic acid 4- (bromomethyl) phenylacetic acid 4- (2-chloroethyl) benzoic acid 4-iodobutyric acid 6-iodohexanoic acid 4- (2-bromoethyl) -benzoic acid 7-bromoheptanoic acid Bromopivalic acid
3- (chloromethyl) benzoic acid
4- (bromomethyl) -3-nitrobenzoic acid
4- (2-chloroacetamido) benzoic acid
2- (2-chloroacetamido) -4-thiazoleacetic acid
EXAMPLE 8
Alkylation of resin bound amines with cyanobenzyl bromides
A teabag containing 300 g of resin bound amine from Examples 4 and 5 (360 mmol) was swollen in DMF (1.51) and 4-cyanobenzyl bromide (200g, 1.02 mmol) was added, followed by DIEA (177 ml, 1.02 mol). The solution was shaken at RT overnight and then washed with DCM, IPA and MeOH. The resin was dried under high vacuum to provide N- (4-cyano) benzyiamine bound resin.
3 -Cyanobenzyl bromide was used under the same conditions.
EXAMPLE 9 Coupling of Cyanophenols to Wang bromide resin
Wang bromide resin (70 g, 70 mmol) was washed with Dimethylacetamide (DMA) . 4-cyanophenol (25g, 210 mmol) was dissolved in 500 ml DMA, and KOtBu (23.5 g, 210 mmol) was added in portions. The solution of phenolate was added in one portion to the swollen resin and heated to 50-C overnight. The mixture was cooled and the resin was washed with DMF/H20 (4:1), DMF and MeOH 4 times each. The resin was then dried under vacuum to give 4- cyanophenol bound to resin via an ether linkage.
The following phenols were used in the same conditions:
4-hydroxy-3-methoxybenzonitrile
4-cyanophenol 2-fluoro-4 -hydroxybenzonitrile
3 -cyanophenol
4-cyano-4 ' -hydroxybiphenyl
2-cyanophenol
3 , 5-dibromo-4-hydroxybenzonitrile 4-hydroxybenzyl cyanide
3, 5-diiodo-4-hydroxybenzonitrile
3 , 4-dihydroxybenzonitrile
4-hydroxytetrafluorobenzonitrile
3-bromo-4 -hydroxybenzonitrile 3, 5-di-tert-butyl-4 -hydroxybenzonitrile
3 , 5-di-tert-butyl-4-hydroxyphenylacetonitrile 4-hydroxy-3-methoxyphenylacetonitrile 4-hydroxy-3-nitrobenzonitrile 3,5-dihydroxybenzonitrile 3- (4 -hydroxyphenyl) propionitrile
3-ethoxy-4-hydroxyphenylacetonitrile
2-chloro-4-hydroxybenzonitrile
4-cyano-2-fluorophenol
3 , 5-dimethyl-4-hydroxybenzonitrile 2, 6-dimethyl-4-hydroxybenzonitrile
2, 6-dichloro-4-hydroxybenzonitrile 2-hydroxy-3-methoxyphenylacetonitrile 8-hydroxyquinoline-2-carbonitrile
3-hydroxy-naphthalene-2-carboxylic acid (3 -cyano-phenyl) - amide 2-hydroxy-3-naphthoic acid-4-cyanoanilide 5-hydroxyindole-3 -acetonitrile 3 , 4-dihydroxyphenylacetonitrile
Benzo (beta) -thiophene, 2-cyanomethyl-5-hydroxy- 3 -chloro-4 -hydroxybenzyl cyanide 4 -chloro-2 -hydroxybenzonitrile 2 -cyano-6 -nitro-phenol 2-hydroxy-5-nitrobenzonitrile 2 -amino-4 -cyanopheno1 Methyl-2 -hydroxy-5-cyano-benzoate
3 -bromo-4 -hydroxy-5-methoxy-phenylacetonitrile 3 , 5-dimethoxy-4-hydroxyphenyl-acetonitrile 4 -cyano-2 -iodo-6 -nitrophenol
EXAMPLE 10 Coupling of Cyanophenols to Alkyl halides on resin
The chloroacetyl piperazine carbamate resin from Example 7 (330 g, 360 mmol) was swollen in DMA. To a solution of 4 -cyanophenol (128.6 g, 1.08 mol) in 2 1 DMA was added potassium t-butoxide (121.2 g, 1.08 mol) in portions. The solution was added to the resin bound alkyl halide, and the solution shaken at RT overnight. The resin was washed 3 times each with DMF, 5% H20/DMF, 10% H20/DMF, 20% H20/DMF, IPA, and MeOH. The resin was then vacuum dried overnight to yield 4- cyanophenoxyacetylpiperazine carbamate resin.
The cyanophenols of Example 9 are also used in this step by substituting for 4 -cyanophenol in the above procedure . EXAMPLE 11 Coupling of BOC-cyanoethylglycine to MBHA
MBHA-HC1 resin (5.0g, 4.05 mmol) was neutralized with 10% DIEA in DMF, then washed with DCM. N-BOC-N-cyanoethylglycine (2.05g, 9 mmol) and DIEA
(1.56ml) were dissolved in 35 ml DCM, to which was added DIC (4.5 mmol, 0.71 ml). After 10 minutes HOBT (2.0 mmol, 0.3g) was added and the solution added to the resin. The solution was shaken overnight and then the resin was washed with DCM, DMF, MeOH, and dried in vacuo to give N-Boc cyanoethyl glycinamide linked to resin.
EXAMPLE 12 Synthesis of Amidoximes from Nitriles
General procedure :
Resin bound nitrile compounds prepared in examples 6,7,8,9,10, and 11 above were placed in teabags. Hydroxylamine-HCl (4-10 eq. based on loading of resin) and DIEA (4-10 eq) were placed in sufficient 2- methoxyethanol to give a 0.2 M solution. The resin was added and the solution heated to 80-85-C overnight. The solution was cooled to RT and the resin washed 4X with MeOH and dried to yield in each case the desired amidoxime bound to resin.
EXAMPLE 13 Synthesis of Library TRG 3600
Each of the nitrile resins from Example 3 was distributed to 36 bags with 400 mg of resin each according to Table 1: Distribution of Nitrile Resins and a number of control bags were made. To each of 36 tubes was added 55 ml of anhydrous 2 -methoxyethanol, 0.83 g (12mmol) of Hydroxylamine Hydrochloride and 2.08 ml (12 mmol) DIEA. Once all the solids were dissolved the bags containing nitrile resins A-E were added (see table below) and the reaction tubes were heated to 85-C overnight . The tubes were cooled and the bags washed with MeOH (4X) and dried to yield the corresponding amidoxime .
List of Cyano Carboxylic Acids.
Resin A Cyanoacetic acid: 13.8 g, 162.5 mmol
Resin B 1-Cyano-1-cyclopropane carboxylic acid: 18.1 g, 162.5 mmol
Resin C 3-Cyanobenzoic acid: 23.9 g, 162.5 mmol
Resin D 4-Cyanobenzoic acid: 23.9 g, 162.5 mmol
Resin E 2- (4-Cyanophenoxy) -2-methyl propionic acid: 33.3 g, 162.5 mmol
Table 1: Distribution of Nitrile Resins
Figure imgf000099_0001
A23, B23, C23, D23, E23 1.75 6.1
A25, B25, C25, D25, E25 1.75 6.1
A27, B27, C27, D27, E27 1.75 6.1
A29, B29, C29, D29, E29 1.75 6.1
A31, B31, C31, D31, E31 1.75 6.1
A33, B33, C33, D33, E33 1.75 6.1
A35, B35, C35, D35, E35 1.75 6.1
A37, B37, C37, D37, E37 1.75 6.1
A39, B39, C39, D39, E39 1.75 6.1
A41, B41, C41, D41, E41 1.75 6.1
A43, B43, C43, D43, E43 1.75 6.1
A45, B45, C45, D45, E45 1.75 6.1
A47, B47, C47, D47, E47 1.75 6.1
A49, B49, C49, D49, E49 1.75 6.1
A51, B51, C51, D51, E51 1.75 6.1
A53, B53, C53, D53, E53 1.75 6.1
A55, B55, C55, D55, E55 1.75 6.1
A57, B57, C57, D57, E57 1.75 6.1
A59, B59, C59, D59, E59 1.75 6.1
A61, B61, C61, D61, E61 1.75 6.1
A63, B63, C63, D63, E63 1.75 6.1
A65, B65, C65, D65, E65 1.75 6.1
A67, B67, C67, D67, E67 1.75 6.1
A69, B69, C69, D69, E69 1.75 6.1
A71, B71, C71, D71, E71 1.75 6.1 EXAMPLE 14 Synthesis of Oxadiazoles from Amidoximes
General Procedure
A resin bound amidoxime of Example 12 was swollen in 2-methoxyethyl ether. A solution of the appropriate carboxylic acid anhydride (7 eq) in 2- methoxyethyl ether (0.2M) was added to the amidoxime. When the anhydride was not commercially available it was prepared from a solution of carboxylic acid (14 eq, 0.4M) in 2-methoxyethyl ether to which was added DIC (7 eq, 0.2M) and shaken for 30 minutes before addition of the resin bags. The solution of anhydride and the resin bound amidoxime were heated to 60-C for 16 hours. The solution was cooled and the resin washed twice with fresh 2-methoxyethyl ether. Sufficient 2-methoxyethyl ether was added to cover the resin and the solution heated to 85-C for 6 hours. The solvent was removed and the resin washed with DMF, DCM, MeOH and dried to give the anticipated oxadiazole bound resin.
EXAMPLE 15
Oxadiazoles from Amidoximes and BOC-Amino Acid Anhydrides TRG3600
To each of 36 tubes was added Boc-protected amino acid derivatives according to Table 2: Distribution of Amino Acids. Each amino acid (28 mmol) was dissolved in 55 ml of 2-methoxyethyl ether. To each tube was then added DIC (14 mmol) and the solution stirred at RT for 1 hr at which time a white precipitate had formed. The appropriate bags containing amidoxime from the previous step were then added and the reaction tubes were placed in a heating block at 60-C for 16 hr. The supernatant was removed and the resins washed twice with fresh 2- methoxyethyl ether. The bags were placed in 50 ml 2- methoxyethyl ether and heated to 85-C for 6 hr. The tubes were cooled, and the bags washed 3X DMF, 3X DCM, 3X MeOH and dried to give 5- (N-Boc-amino) substituted oxadiazoles bound to resin.
Table 2: Distribution of Amino Acids
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
EXAMPLE 16
Oxadiazoles from Amidoximes and
FMOC-Amino Acid Anhydrides
The resin bound amidoximes from Example 12 were swollen in 2-methoxyethyl ether (0.1 mmol). The appropriate FMOC amino acids, Table 3: FMOC-amino acids, (3 mmol) were dissolved in 8 ml of 2-methoxyethyl ether. To each tube was then added DIC (1.5 mmol) and the solution stirred at RT for 1 hr at which time a white precipitate had formed. The appropriate bags containing amidoxime were then added and the reaction tubes were placed in a heating block at 60-C for 16 hr. The supernatant was removed and the resins washed twice with fresh 2-methoxyethyl ether. The bags were placed in 10 ml 2-methoxyethyl ether and heated to 85-C for 6 hr. The tubes were cooled, and the bags washed 3X DMF, 3X DCM, 3X MeOH and dried to give 5- ( (N-FMOC- amino) substituted oxadiazoles bound to resin. Table 3 FMOC-amino acids FMOC-Amino Acid FMOC-phenylalanine FMOC-b-alanine FMOC-arginine- (PMC) -OH FMOC-arginine- (TOS) -OH FMOC-isonipecotic acid FMOC-L-proline FMOC-L-valine FMOC-L-isoleucine FMOC-L-tryptophan FMOC-ser (TBU) -OH FMOC-L-phenylalanine FMOC-tyr(TBU) -OH FMOC-cys(TBU) -OH FMOC-asp (OTBU) -OH FMOC-L-asparagine FMOC-L-leucine FMOC-L-methionine FMOC-glu (OTBU) -OH N-ALPHA-FMOC-L-glutamine FMOC-lys (BOC) -OH FMOC-L-alanine FMOC-gly-OH FMOC-nle-OH FMOC-cys (TRT) -OH FMOC-cys (ACM) -OH FMOC-cys (STBU) -OH FMOC-arg(MTR) -OH FMOC-his (TRT) -OH FMOC-p-nitro-phe-OH BOC-lys (FMOC) -OH FMOC-D-val-OH FMOC-D-trp-OH FMOC-D-phe-OH FMOC-D-asn-OH FMOC-D-leu-OH FMOC-D-met-OH FMOC-D-gln-OH FMOC-D-ala-OH FMOC-BETA-ala-OH N-FMOC-3, 5-diiodo-L-tyrosine FMOC-arg(TOS) -OH FMOC-cha-OH FMOC-D-arg(MTR) -OH FMOC-arg(N02) -OH FMOC-arg(PMC) -OH FMOC-D-arg (PMC) -OH FMOC-D-arg (TOS) -OH FMOC-asn(MBH) -OH FMOC-D-asn(MBH) -OH FMOC-asp (0-2-ADA) -OH FMOC-asp (OBzl) -OH FMOC-asp-OTBU FMOC-cys (BZL) -OH FMOC-cys (PMEOBZL) -OH FMOC-glu(OBzl) -OH FMOC-gln(MBH) -OH FMOC-D-gln(MBH) -OH FMOC-glu-OTBU FMOC-L-ALPHA-T-butylglycine FMOC-TBU-D-gly-OH FMOC-hyp-OH FMOC-hyp(TBU) -OH FMOC-D-lys (BOC) -OH FMOC-lys (Z) -OH FMOC-D-lys(Z)-OH FMOC-lys (2-CL-Z) -OH FMOC-orn(BOC) -OH FMOC-ser (BZL) -OH FMOC-sta-OH FMOC-thi-OH FMOC-D-thi-OH FMOC-tyr (2-BR-Z) -OH FMOC-D-tyr(TBU) -OH FMOC-tyr (2,6-dichloro-BZL) -OH FMOC-EPSILON-acp-OH FMOC-asn(TRT) -OH FMOC-D-asp(OTBU) -OH FMOC-D-cys (ACM) -OH FMOC-D-glu(OTBU) -OH FMOC-gln(TRT) -OH N-ALPHA-FMOC-pI-benzyloxymethyl-L-histidine FMOC-D-his(TRT) -OH FMOC-met (O) -OH FMOC-D-orn (BOC) -OH FMOC-D-phe (4-cl) -OH FMOC-D-pro-OH FMOC-D-ser-OH FMOC-D-ser(TBU) -OH FMOC-thr-OH FMOC-thr(BZL) -OH FMOC-thr(TBU) -OH FMOC-asp (O-l-ADA) -OH FMOC-lys (AC) -OH FMOC-abu-OH 95 FMOC-lys (FMOC) -OH
96 N-FMOC-4-chloro-L-phenylalanine
97 FMOC-D-thr (TBU) -OH
98 FMOC-tyr-OH
99 FMOC-D-tic-OH
100 FMOC-tic-OH
101 FMOC-GAMMA-ab -OH
102 FMOC-D-cha-OH
103 FMOC-aib-OH
104 FMOC-D-asn(TRT) -OH
105 FMOC-D-cys (TRT) -OH
106 FMOC-N-ME-gly-OH
107 FMOC-ME-leu-OH
108 FMOC-D-pen (ACM) -OH
109 FMOC-pen (ACM) -OH
110 FMOC-ME-phe-OH
111 FMOC-DELTA-pro-OH
112 FMOC-cit-OH
113 FMOC-arg(MTS) -OH
114 FMOC-L-asn (TMOB) -OH
115 FMOC-L-gln (TMOB) -OH
116 FMOC-D-gln(TRT) -OH
117 FMOC-his (BOC) -OH
118 FMOC-his (MTT) -OH
119 FMOC-lys (TFA) -OH
120 FMOC-met (02) -OH
121 FMOC-orn (FMOC) -OH
122 FMOC-ser (TRT) -OH
123 FMOC-D-thr
124 FMOC-trp (BOC) -OH
125 FMOC-D-trp (BOC) -OH
126 FMOC-ME-ala-OH 127 FMOC-D-ME-ala-OH
128 FMOC-ME-ile-OH
129 FMOC-D-ME-phe-OH
130 FMOC-ME-val-OH 131 FMOC-D-ME-val-OH
132 FMOC-AHPPA
133 FMOC-nva-OH
134 FMOC-phg-OH
135 FMOC-D-nle-OH 136 FMOC-D-nva-OH
137 FMOC-D-phg-OH
138 FMOC-L-arg- (PBF) -OH
139 FMOC-D-arg (PBF) -OH 140 FMOC-D-asp-OTBU 141 FMOC-thr(TRT) -OH
142 FMOC-lys (MTT) -OH
143 FMOC-cys (MMT) -OH
144 FMOC-hse (TRT) -OH
145 FMOC-L-pentafluorophenylalanme 146 FMOC-lys (DDE) -OH
147 DDE-lys(FMOC) -OH
148 FMOC-asp-OAII
149 FMOC-D-dpr (DDE) -OH
150 FMOC-L-dpr (DDE) -OH 151 FMOC-glu-OALL
152 FMOC-ser [PO (OH) -OBzl] -OH
153 FMOC-his (TOS)
154 FMOC-tyr (ME) -OH
155 FMOC-ACHPA 156 FMOC-orn (MTT) -OH
157 FMOC-asu-OME
158 FMOC-glu(ODMAB) -OH 159 FMOC-D-his (BOC) -OH
160 FMOC-glu-ODMAB
161 FMOC-APNS
162 FMOC-asp (ODMAB) -OH 163 FMOC- (FMOCHMB) asp (OTBU) -OH
164 FMOC-D-orn(MTT) -OH
165 FMOC- (FMOCHMB) lys (BOC) -OH
166 FMOC-thr(PO(OBzl)OH) -OH
167 FMOC-tyr (PO (OBzl) OH) -OH
EXAMPLE 17
5-Chloromethyl Oxadiazoles from Amidoximes
To a solution of chloroacetic anhydride (0.2M) in 2 -Methoxyethyl ether (8 eq.) was added teabags containing Amidoximes from Example 12 . The reaction tubes were placed in a heating block at 60-C for 16 hrs, the supernatant removed and the resins washed twice with fresh 2-methoxyethyl ether. The bags were covered in 2- methoxyethyl ether and heated to 85-C for 6 hr. The tubes were cooled, and the bags washed 3X times each with DMF, DCM, MeOH and dried to give 5-chloromethyl oxadiazoles bound to resin.
EXAMPLE 18 5-Aminomethyl oxadiazoles from 5-Chloromethyl Oxadiazoles
The resins from Example 17 were placed in a solution of amine according to Table 3 : Primary and secondary amines (0.2 M, 10 eq) in anhydrous DMF and shaken at RT for 2 hrs . The bags were then washed with DMF 4X, DCM 2X and MeOH to give 5-substituted aminomethyl oxadiazoles bound to resin.
Table 4: Primary and secondary amines 1 1- (2 -Aminoethyl) pyrrolidine
2 2- (Aminomethyl) pyridine
3 Histamine
4 Cyclopentylamine
5 Allylamine
6 2 -Methoxyethylamine
7 (+/-) -Tetrahydrofurylamine
8 Benzyiamine
9 2-Methylbenzylamine
10 3-Methylbenzylamine
11 4-Methylbenzylamine
12 2-Fluorobenzylamine
13 3-Fluorobenzylamine
14 4-Fluorobenzylamine
15 1- (3-Aminopropyl) imidazole
16 p-Xylylenediamine ,
17 4 -Methoxybenzylamine
18 3 -Chlorobenzylamine
19 3-Bromobenzylamine HCl
20 4-Bromobenzylamine HCl
21 Cyclopropylamine
22 (Aminomethyl) cyclopropane
23 4- (Aminomethyl) pyridine
24 3- (Aminomethyl) pyridine
25 2-Thiophenemethylamine
26 Phenethylamine
27 4- (2-Aminoethyl)morpholine
28 3 -Methoxybenzylamine
29 Piperonylamine
30 4 -Methoxyphenethylamine
31 2 -Fluorophenethylamine
32 2- (4 -Chlorophenyl) ethylamine 33 2- (3 -Chlorophenyl) ethylamine
34 2- (2-Chlorophenyl) ethylamine
35 2 , 3 -Dimethoxybenzylamine
36 3 , 4-Dimethoxyphenethylamine
37 2 , 4 -Dichlorophenethylamine
38 N,N-Diethylethylenediamine
39 2- (2-Aminoethyl) -1-methylpyrrolidine
40 3 -Diethylaminopropylamine
41 2- (2-Aminoethylamino) -5-nitropyridine
10 42 N,N, 2, 2-Tetramethyl-l, 3-propanediamine
43 3 -Dimethylaminopropylamine
44 Ethylenediamine
45 1- (2-Aminoethyl)piperidine
46 isoamylamine
15 47 3-Ethoxypropylamine
48 1- (3-Aminopropyl) -2-pipecoline
49 3 -Butoxypropylamine
50 N- (3 ' -Aminopropyl) -2 -pyrrolidinone, tech
51 4- (3-Aminopropyl) morpholine
20 52 N- (2-Aminoethyl) -N-ethyl-m-toluidine
53 3 -Phenyl-1-propylamine
54 b-Methylphenethylamine
55 4-Phenylbutylamine
56 3 , 3 -Diphenylpropylamine
25 57 Isobutylamine
58 2- (2-Aminoethyl) pyridine
59 Cyclohexanemethylamine
60 3 -Methoxyphenethylamine
61 | 3 -Phenylbenzylamine
30 62 Piperazine EXAMPLE 19 Acylation of Oxadiazole Amines - General procedure
The Boc-protected Oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried. The FMOC-protected Oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried. The aminomethyl oxadiazoles of Example 18 were used without further precautions. The resins were suspended in DMF and distributed into a 96 well microtiter plate. The supernatant solvent was removed and the following solutions were added: a carboxylic acid solution, a solution of DMAP, HOBT and DIEA, a solution of DIC in DMF or DCM. Other coupling agents such as BOP, PyBOP, HATU, HBTU and others known in the art were also used in separate experiments. The quantities of each solution were adjusted according to the amount of resin per well in the plate, in order to have a five to tenfold excess of reagents. The 96 well plates were capped and shaken overnight at RT. The resins were then washed with DMF (8X) , MeOH (4X) and the resin allowed to dry resulting in the N-acylated-5- (substituted aminomethyl) oxadiazoles bound to resin.
List of Carboxylic acids
o. Carboxylic Acid Group
1 (3, 4-Dimethoxyphenyl)Acetic acid 1
2 (a,a,a-Trifluoro-m-Tolyl) acetic acid 1 (Methylthio) acetic acid 1 1- (4-Chlorophenyl) -1-Cyclopentanecarboxylic acid 1 1-Adamantaneacetic acid 1 1-cyano-1-cyclopropane carboxylic acid 1 l-Naphthylacetic acid 1 1-Phenyl-l-Cyclopropanecarboxylic acid 1 2 , 4-Dichlorobenzoic acid 1 2- (2 -cyanophenylthio) benzoic acid 1 2- (methylthio) nicotinic acid 1 2-chloro-5- (methylthio) benzoic acid 1 2-Fluorobenzoic acid 1 2-Methylcyclopropanecarboxylic acid 1 2-Norbornaneacetic acid 1 2-Pyrazinecarboxylic acid 1 2-Thiopheneacetic acid 1 3 , 4, 5-Trimethoxyphenylacetic acid 1 3 , 4-Dichlorobenzoic acid 1 3 ,4-Dichlorophenylacetic acid 1 3 , 5, 5-Trimethylhexanoic acid 1 3 , 5-Di-tert-butyl-4-hydroxybenzoic acid 1 3 , 5-Dichloro-4-hydroxybenzoic acid 1 3-Benzoylpropionic acid 1 3 -Bromo-4 -Methylbenzoic acid 1 3-Cyanobenzoic acid 1 3 -Fluoro-4 -Methylbenzoic acid 1 3-lndolepropionic acid 1 3-Methyl-2-thiophenecarboxaldehyde 1 3-Phenoxybenzoic acid 1 4- (dimethylamino) butyric acid hydrochloride 1 4- (methylthio) benzoic acid 1 4-Biphenylacetic acid 1 4-Bromophenylacetic acid 1 4-carboxybenzenesulfonamide 1 4-Cyanobenzoic acid 1 4-Dimethylaminobenzoic acid 1 4-Ethoxyphenylacetic acid 1 4-Fluorophenylacetic acid 1 4-Iodobenzoic acid 1 4-Isopropoxybenzoic acid 1 4-Isopropylbenzoic acid 1 4-Methyl-l-Cyclohexanecarboxylic acid 1 4-Methylvaleric acid 1 4-nitrophenylacetic acid 1 4-Phenoxybenzoic acid 1 4-tert-Butyl-cyclohexanecarboxylic acid 1 5-Bromo-2-chlorobenzoic acid 1 5-Bromonicotinic acid 1 5-Methoxyindole-2-carboxylic acid 1 5-Methylsalicylic acid 1 6-Chloronicotinic acid 1 Acetic acid 1 alpha-Methylcinnamic acid 1 Benzoic acid 1 coumarin-3-carboxylic acid 1 Crotonic acid 1 Cyclohexanepropionic acid 1 diphenylacetic acid 1 DL-2- (3 -Chlorophenoxy) -propionic acid 1 Hydrocinnamic acid 1 Isobutyric acid 1 Isonicotinic acid 1 Isovaleric acid 1 Levulinic acid 1 m-Anisic acid 1 m-Toluic acid 1 Methoxyacetic acid 1 Nicotinic acid 1 p-Tolylacetic acid 1 Picolinic acid 1 Piperonylic acid 1 R (-) -2-oxothiazolidine-4-carboxylic acid 1 S- (+) -Mandelic acid 1 succinamic acid 1 Tetrahydro-3-furoic acid 1 theophylline-7-acetic acid 1 trans-3- (3-Pyridyl) acrylic acid 1 Trimethylacetic acid 1 Triphenylacetic acid 1 (+/-) -camphorcarboxylic acid 2 82 1- (4-chlorophenyl) -1-cyclohexanecarboxylic acid 2
83 l-acetylpiperidine-4-carboxylic acid 2
84 1-methyl-l-cyclohexanecarboxylic acid 2 85 l-Phenyl-5- (trifluoromethyl)pyrazole-4- carboxylic acid 2
86 2,2,3, 3-tetramethylcyclopropanecarboxylic acid 2
87 2,4-dibromophenoxyacetic acid 2 88 2, 5-dimethyl-3-furoic acid 2
89 2, 6-dichlorocinnamic acid 2
90 2- (2, 6-Dimethylmorpholino) -5-Nitrobenzoic acid 2
91 2- (2- (2-methoxyethoxy) ethoxy) acetic acid 2 92 2- (allylthio) nicotinic acid 2
93 2- (carboxymethylthio)pyrimidine 2
94 2- (pentamethylbenzoyl) benzoic acid 2
95 2-bromo-5-methoxybenzoic acid 2
96 2-chloro-n-butyric acid 2 97 2-cyano-3- (4-methoxy-phenyl) -acrylic acid 2
98 2-furoic acid 2
99 2-hydroxyisobutyric acid 2
100 2-methyl-3-butenoic acid 2
101 2-methylvaleric acid 2 102 2-phenoxynicotinic acid 2
103 2-phenyl-4-quinolinecarboxylic acid 2
104 3, 3 ' -dichloropivalic acid 2
105 3,3-diphenylpropionic acid 2
106 3 , 4-difluorobenzoic acid 2 107 3,4-dihydro-2, 2-dimethyl-4-oxo-2h-pyran-6- carboxylic acid 2
108 3 ,4-dimethoxybenzoic acid 2
109 3 , 5-dibenzyloxybenzoic acid 2
110 3 , 5-dimethylisoxazole-4-carboxylic acid 2 111 3- (3-thienyl) acrylic acid 2
112 3-Ethoxythiophene-2-carboxylic acid 2
113 3-methoxycyclohexanecarboxylic acid 2 114 3-methoxypropionic acid 2
115 3-methyl-4-nitrobenzoic acid 2
116 3-pyridinepropionic acid 2
117 3- [4- (3 , 4 -Dichlorobenzyloxy) phenyl] acrylic acid 2
118 4 ' - (trifluoromethyl) -2-biphenylcarboxylic acid 2
119 4- (lh-pyrrol-1-yl) benzoic acid 2
120 4- (3-methyl-5-oxo-2-pyrazolin-l-yl) benzoic acid 2
121 4-acetoxycinnamic acid 2
122 4 -acetyl-3 , 5-dimethyl-2 -pyrrolecarboxylic acid 2
123 4-acetylphenoxyacetic acid 2 124 4-azidobenzoic acid 2
125 4-benzyloxyphenoxyacetic acid 2
126 4-butoxyphenylacetic acid 2
127 4-Carboxy-1- (4-Chlorobenzyl) pyrrolidin-2- one 2 128 4-Carboxy-l- (furfuryl) pyrrolidin-2-one 2
129 4-Carboxy-l- (then-2-yl) pyrrolidin-2-one 2
130 4-cyclohexylbenzoic acid 2
131 4-guanidinobutyric acid 2
132 4-hydroxy-3- (morpholinomethyl) benzoic acid 2 133 4-iodophenoxyacetic acid 2
134 4-isopropylcinnamic acid 2
135 4-methoxy-2-quinolinecarboxylic acid 2
136 4-methoxycyclohexanecarboxylic acid 2
137 4-Methyl-l, 2, 3-thiadiazole-5-carboxylic acid 2 138 4-N-propylbenzoic acid 2
139 4-nitrobenzoic acid 2
140 4-pentylbenzoic acid 2
141 4-phenoxybutyric acid 2
142 4-thioureido-benzoic acid 2 143 5- (4-chlorophenyl) -2-furoic acid 2
144 5-methyl-3-phenylisoxazole-4-carboxylic acid 2
145 6 -bromocoumarin-3 -carboxylic acid 2 146 6-hydroxypicolinic acid 2
147 6 -methylchromone-2-carboxylic acid 2
148 7-methoxy-2-benzofurancarboxylic acid 2
149 alpha-bromophenylacetic acid 2 150 alpha-cyanocinnamic acid 2
151 alpha-phenyl-o-toluic acid 2
152 alpha-phenylcinnamic acid 2
153 benzofuran-2 -carboxylic acid 2
154 benzyloxyacetic acid 2 155 bicyclo (2.2.1) hept-5-ene-2-carboxylic acid 2
156 citrazinic acid 2
157 coumalic acid 2
158 cyclohexylidenecyanoacetic acid 2
159 cyclopentylacetic acid 2 160 cyclopropanecarboxylic acid 2
161 diethyl 1, 3 , 5-benzenetricarboxylate 2
162 diethylphosphonoacetic acid 2
163 3- (2-chloro-6- fluorophenyl) -5- methylisoxazole-4 -carboxylic acid 2 164 flurbiprofen 2
165 hydantoic acid 2
166 ibuprofen 2
167 itaconic acid monomethyl ester 2
168 L-pyroglutamic acid 2 169 Phenylmalonic acid monobenzyl ester 2
170 mesitylglyoxylic acid 2
171 monoethyl fumarate 2
172 N,N-dimethylglycine 2
173 N- (2, 4-difluorophenyl)maleamic acid 2 174 N- (3-methoxyphenyl)maleamic acid 2
175 N- (4-carboxyphenyl) succinimide 2
176 N- (4-nitrobenzoyl) -beta-alanine 2
177 N-carbamoylmaleamic acid 2
178 N-carboxyethylrhodanine 2 179 N-phthaloylglycine 2
180 p-toluic acid 2
181 phthalide-3-acetic acid 2 182 pinonic acid 2
183 probenecid 2
184 quinaldic acid 2
185 thiazolidine-2-carboxylic acid 2 186 thymine-1-acetic acid 2
187 trans-2- (2-methoxyphenyl) -5- oxotetrahydrofuran-3 -carboxylic acid 2
188 trans-2-phenyl-l-cyclopropanecarboxylic acid 2
189 uracil-5-carboxylic acid monohydrate 2 190 (4 -Pyridylthio) acetic acid 3
191 1, 3 -phenylene diacetic acid 3
192 1-Adamantanecarboxylic acid 3
193 2-Acetylbenzoic acid 3
194 2-Benzimidazolepropionic acid 3 195 2-Imino-l-imidazolidineacetic acid 3
196 2-Methoxy-4- (methylthio) -benzoic acid 3
197 2-Naphthylacetic acid 3
198 2-Napthoic acid 3
199 3 , 4-Dimethoxycinnamic acid 3 200 3, 5-bis (Trifluoromethyl) benzoic acid 3
201 3, 5-Dichlorobenzoic acid 3
202 3-Acetamidobenzoic acid 3
203 3-Carboxy-l, 4-dimethyl-2-pyrroleacetic acid 3
204 3 -Chloro-4-hydroxybenzoic acid hemihydrate 3 205 3-Hydroxyphenylacetic acid 3
206 3-Indoleglyoxylic acid 3
207 4 ' -Ethyl-4-biphenylcarboxylic acid 3
208 4-Fluoro-alpha-methylphenylacetic acid 3
209 4 -Hydroxyquinoline-2-carboxylic acid hydrate 3
210 4-Nitrophenyl guanidinobenzoate hydrochloride 3
211 4-Pyridylacetic acid hydrochloride 3
212 4-Sulfobenzoic acid, potassium salt 3 213 5-Benzimidiazolecarboxylic acid 3
214 Benzotriazole-5-carboxylic acid 3
215 Benzoylformic acid 3 216 Furylacrylic acid 3
217 Indole-6-carboxylic acid 3
218 N-Acetylanthranilic acid 3
219 Nalidixic acid 3 220 Niflumic acid 3
221 Oxolinic acid 3
222 Pyrrole-2-carboxylic acid 3
223 trans-3-Furanacrylic acid 3
224 Xanthene-9-carboxylic acid 3 225 (Phenylthio) acetic acid 4
226 1-Isoquinolinecarboxylic acid 4
227 2-Pyridylacetic acid hydrochloride 4
228 3 , 4, 5-Triethoxybenzoic acid 4
229 3 , 4- (Methylenedioxy) -Phenylacetic acid 4 230 3, 5-Bis (Trifluoromethyl) -Benzoic acid 4
231 3 , 5-Dimethyl-p-anisic acid 4
232 3-Thiopheneacetic acid 4
233 4-Ethoxybenzoic acid 4
234 4 -Hydroxybenzoic acid 4 235 Boc-isonipecotic acid 4
236 Cyclobutanecarboxylic acid 4
EXAMPLE 20 Sulfonylation of Oxadiazole Amines
The Boc-protected oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried. The FMOC-protected oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried. The aminomethyl oxadiazoles of Example 18 were used without further precautions. The resins were suspended in DMF and distributed into a 96 well microtiter plate. The supernatant solvent was removed, and the resin washed with acetonitrile. A solution of N- methylimidazole (5.5 to 11 eq/mmol resin) in acetonitrile was added followed by a solution of sulfonyl chloride in ACN ( 5 to 10 eq/mmol resin) . The plates were capped and vortexed and shaken overnight . The plates were then washed with ACN (8X) and MeOH (8X) , and dried to give substituted 5- (N-sulfonyl) -oxadiazoles bound to resin.
List of Sulfonyl chlorides.
(lr) - (-) -10-camphorsulfonyl chloride
1, 2-naphthoquinone-2-diazido-4 -sulfonyl chloride
1, 2-naphthoquinone-2-diazido-4-sulfonyl chloride 1-butanesulfonyl chloride
1-naphthalenesulfonyl chloride
1-propanesulfonyl chloride
10-camphorsulfonyl chloride ,2, 2-trifluoroethanesulfonyl chloride , 3, 4-trichlorobenzenesulfonyl chloride ,3, 4-trifluorobenzenesulphonyl chloride ,3,5, 6-tetramethylbenzenesulfonyl chloride , 3-dichlorobenzenesulfonyl chloride , 3-dichlorothiophene-5-sulphonyl chloride , 4 , 5-trichlorobenzenesulfonyl chloride ,4 , 5-trifluorobenzenesulfonyl chloride ,4, 6-trichlorobenzenesulfonyl chloride ,4, 6-triisopropylbenzenesulfonyl chloride , 4-dichlorobenzenesulfonyl chloride , 4-difluorobenzenesulfonyl chloride , 4-dinitrobenzenesulfonyl chloride , 5-di (2,2,2-trifluoroethoxy)benzenesulphonyl chloride , 5-dibromo-3, 6-difluorobenzenesulfonyl chloride , 5-dibromobenzenesulfonyl chloride , 5-dichlorobenzenesulfonyl chloride , 5-dichlorothiophene-3-sulphonyl chloride , 5-dimethoxybenzenesulfonyl chloride , 6-dichloro-4- (trifluoromethyl) benzenesulfonyl chloride , 6-dichlorobenzenesulfonyl chloride , 6-difluorobenzenesulfonyl chloride 2- (1-naphthyl) ethanesulfonyl chloride
2- (trifluoromethoxy) benzenesulfonyl chloride
2- (trifluoromethyl) benzenesulfonyl chloride
2-acetamido-4-methyl-5-thiazolesulfonyl chloride 2-bromobenzenesulfonyl chloride
2-chloro-4- (trifluoromethylbenzene) sulfonyl chloride
2-chloro-4-fluorobenzenesulfonyl chloride
2-chloro-5- (trifluoromethyl) enzenesulfonyl chloride
2-chloro-6-methylbenzenesulfonyl chloride 2-chlorobenzenesulfonyl chloride
2-chloroethanesulfonyl chloride
2-cyanobenzenesulfonyl chloride
2-fluorobenzenesulfonyl chloride
2-mesitylenesulfonyl chloride 2-methyl-5-nitrobenzenesulfonyl chloride
2-methylsulfonylbenzenesulfonyl chloride
2-naphthalenesulfonyl chloride
2-nitro-4- (trifluoromethyl) benzenesulfonyl chloride
2-nitro-alpha-toluenesulfonyl chloride 2-nitrobenzenesulfonyl chloride
2-thiophenesulfonyl chloride
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] -thiophene-5- sulfonyl chloride
2- [3- (trifluoromethyl) pyrid-2-ylsulfonyl] -thiophene-5- sulfonyl chloride
2- [5- (trifluoromethyl) pyrid-2-ylsulfonyl] -thiophene-5- sulfonyl chloride
3 , 4-dibromobenzenesulfonyl chloride
3 , 4-dichlorobenzenesulfonyl chloride 3, 4-difluorobenzenesulphonyl chloride
3 , 4-dimethoxybenzenesulfonyl chloride
3, 5-bis (trifluoromethyl) benzenesulfonyl chloride
3, 5-dibromothiophene-2-sulfonyl chloride , 5-dichloro-2-hydroxybenzenesulfonyl chloride , 5-dichloro-4-hydroxybenzenesulphonyl chloride , 5-dichlorobenzenesulfonyl chloride , 5-dimethylisoxazole-4-sulfonyl chloride 3 , 5-dinitro-4-methoxybenzenesulfonyl chloride 3- (chlorosulfonyl) benzoic acid - (trifluoromethyl) benzenesulfonyl chloride -bromobenzenesulfonyl chloride -chloro-2-methylbenzenesulfonyl chloride -chloro-4-fluorobenzenesulfonyl chloride -chlorobenzenesulfonyl chloride -chloropropanesulfonyl chloride -fluorobenzenesulfonyl chloride -nitrobenzenesulfonyl chloride , 5-dibromothiophene-2-sulfonyl chloride - (bromomethyl) benzenesulphonyl chloride - (chlorosulfonyl) benzoic acid - (chlorosulfonyl) phenyl isocyanate - (N-butoxy)benzenesulfonyl chloride - (trifluoromethoxy) benzenesulfonyl chloride - (trifluoromethyl) benzenesulfonyl chloride -acetamido-3-chlorobenzenesulfonyl chloride -acetamidobenzenesulfonyl chloride -benzenesulphonylthiophene-2-sulphonyl chloride -biphenylsulfonyl chloride -bromo-2, 5-dichlorothiophene-3 -sulfonyl chloride -bromo-2, 5-difluorobenzenesulphonyl chloride -bromo-2- (trifluoromethoxy) benzene sulphonyl chloride -bromobenzenesulfonyl chloride -chloro-3-nitrobenzenesulfonyl chloride -chloro-7-chlorosulfonyl-2, 1, 3-benzoxadiazole -chlorobenzenesulfonyl chloride -cyanobenzenesulfonyl chloride -dimethylaminoazobenzene-4 ' -sulfonyl chloride -ethylbenzenesulfonyl chloride -fluorobenzenesulfonyl chloride -isopropylbenzenesulfonyl chloride -methoxy-2, 3, 6-trimethyl benzenesulfonyl chloride -methoxy-2, 3, 6-trimethylbenzoylsulfonyl chloride -methoxy-2, 6-dimethylbenzenesulfonyl chloride -methoxy-2-nitrobenzenesulfonyl chloride 4 -methoxybenzenesulfonyl chloride 4 -methyl-3 -nitrobenzenesulfonyl chloride 4 -methylsulfonylbenzenesulfonyl chloride 4-N-amylbenzenesulfonyl chloride 4-N-amylbenzenesulfonyl chloride 4 -N-butylbenzenesulfonyl chloride 4 -N-propylbenzenesulfonyl chloride 4 -N-propylbenzenesulfonyl chloride 4 -nitrobenzenesulfonyl chloride 4-phenylazobenzenesulfonyl chloride 4-tert-butylbenzenesulfonyl chloride 5-bromo-2 -methoxybenzenesulfonyl chloride 5-bromothiophene-2-sulfonyl chloride 5-chloro-2-methoxybenzenesulfonyl chloride 5-chloro-4-nitrothiophene-2-sulfonyl chloride 5-chloronaphthalene-1-sulfonyl chloride 5-chloronaphthalene-2-sulfonyl chloride 5-chlorothiophene-2-sulfonyl chloride 5-diethylamino-1-naphthalenesulfonyl chloride 5-fluoro-2 -methylbenzenesulfonyl chloride 5- [3-chloro-5- (trifluoromethyl) pyrid-2-yl- sulfonyl] thiophene-2-sulfonyl chloride 6-methoxy-m-toluenesulfonyl chloride 8-quinolinesulfonyl chloride 9, 10-dibromoanthracene-2-sulfonyl chloride alpha-toluenesulfonyl chloride bansyl chloride benzenesulfonyl chloride beta-styrene sulfonyl chloride beta-styrene sulfonyl chloride d-camphor-10-sulfonyl chloride d-camphor-10-sulfonyl chloride dansyl chloride ethanesulfonyl chloride isopropylsulfonyl chloride isoquinoline-5-sulfonyl chloride m-toluenesulfonyl chloride methanesulfonyl chloride methyl 2- (chlorosulfonyl) benzoate O-toluenesulfonyl chloride p-styrenesulfonyl chloride p-toluenesulfonyl chloride p-xylene-2-sulfonyl chloride pentafluorobenzenesulfonyl chloride pentamethylbenzenesulfonyl chloride pipsyl chloride pmc-cl
EXAMPLE 21 Synthesis of Oxadiazole Ureas
The Boc-protected oxadiazole resins of Example 15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried. The FMOC-protected oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried. The aminomethyl oxadiazoles of Example 18 were used without further precautions. The resins were suspended in DMF and distributed into a 96 well microtiter plate. The resin was then washed and neutralized with 5% DIEA in 1, 2-dichloroethane (DCE) /THF (2:1) and washed with DCE/THF (2:1) to remove excess base. The following Isocyanates were dissolved to a concentration of 0.2 M in DCE/THF (2:1) and added to the plates. The solutions were shaken at RT overnight and then the plates were washed with DCE/THF (2:1), DMF, MeOH and dried to give N-substituted ureido oxadiazole resins.
List of Isocyanates
(2S,3S) -2-isocyanato-3 -methylvaleric acid methyl ester (R) - (+) -alpha-methylbenzyl isocyanate (R) - (-) -1- (1-naphthyl) ethyl isocyanate (S) - (+) -1- (1-naphthyl) ethyl isocyanate
(S) - (+) -2-isocyanato-3-tert-butoxypropionic acid methyl ester
(S) - (-) -2-isocyanato-3-methylbutyric acid methyl ester (S) - (-) -2-isocyanato-4- (methylthio) butyric acid methyl ester
(S) -(-) -2-isocyanato-4 -methylvaleric acid methyl ester
(S) - (-) -2-isocyanatoglutaric acid diethyl ester
(S) - (-) -2-isocyanatopropionic acid methyl ester (S) -(-) -alpha-methylbenzyl isocyanate
(S) -2-isocyanato-3-phenylpropionic acid methyl ester
(Tridecafluoro-1-hexyl) isocyanate 1,1,3, 3 -tetramethylbutyl isocyanate - (1-naphthyl) ethyl isocyanate - (4-bromophenyl) ethyl isocyanate -adamantyl isocyanate -naphthyl isocyanate , 3, 4-trifluorophenyl isocyanate , 3-dichlorophenyl isocyanate , 3-dimethylphenyl isocyanate , 4, 5-trichlorophenyl isocyanate ,4, 5-trimethylphenylisocyanate , 4, 6-trichlorophenyl isocyanate , 4-dichlorophenyl isocyanate , 4-difluorophenyl isocyanate , 4-dimethoxyphenyl isocyanate , 4-dimethylphenyl isocyanate , 5-dichlorophenyl isocyanate , 5-difluorophenyl isocyanate , 5-dimethoxyphenyl isocyanate , 5-dimethylphenyl isocyanate , 6-dibromo-4-fluorophenyl isocyanate , 6-dibromo-4 -isopropylphenyl isocyanate , 6-dichlorophenyl isocyanate , 6-diethylphenyl isocyanate , 6-difluorobenzoyl isocyanate , 6-difluorophenyl isocyanate 2, 6-diisopropylphenyl isocyanate
2, 6-dimethylphenyl isocyanate
2- (chloromethyl) phenyl isocyanate
2- (difluoromethoxy) phenyl isocyanate 2- (methylthio)phenyl isocyanate - (trifluoromethoxy) phenyl isocyanate - (trifluoromethyl) phenyl isocyanate -biphenylyl isocyanate -bromo-4, 6-difluorophenyl isocyanate -bromoethyl isocyanate -bromophenyl isocyanate -chloro-4-nitrophenyl isocyanate -chloro-5- (trifluoromethyl) phenyl isocyanate -chloro-5-nitrophenyl isocyanate -chloro-6-methylphenyl isocyanate -chlorobenzyl isocyanate -chloroethyl isocyanate -chlorophenyl isocyanate -cyanophenyl • isocyanate -ethoxyphenyl isocyanate -ethyl-6-methylphenyl isocyanate -ethylphenyl isocyanate -fluoro-3- (trifluoromethyl) phenyl isocyanate -fluoro-5- (trifluoromethyl)phenyl isocyanate -fluoro-5-methylphenyl isocyanate -fluoro-5-nitrophenyl isocyanate -fluoro-6- (trifluoromethyl) phenyl isocyanate -fluorophenyl isocyanate -iodophenyl isocyanate -isopropyl-6-methylphenyl isocyanate -isopropylphenyl isocyanate -methoxy-5-chloro phenyl isocyanate -methoxy-5-methylphenyl isocyanate -methoxy-5-nitrophenyl isocyanate -methoxyphenyl isocyanate -methyl-3-nitrophenyl isocyanate -methyl-5-nitrophenyl isocyanate -methyl-6-t-butylphenyl isocyanate -methylbenzyl isocyanate -n-propylphenyl isocyanate -naphthyl isocyanate -nitrophenyl isocyanate -phenoxyphenyl isocyanate -tert-butylphenyl isocyanate ,3' -dimethoxy-4 , 4 ' -biphenylene diisocyanate ,4, 5-trimethoxyphenyl isocyanate , 4-dichlorobenzyl isocyanate , 4-dichlorophenyl isocyanate , 4-difluorophenyl isocyanate , 4 -dimethylphenyl isocyanate , 5-bis (trifluoromethyl) phenyl isocyanate , 5-dichlorophenyl isocyanate , 5-dimethoxyphenyl isocyanate , 5-dimethylphenyl isocyanate , 5-dinitrophenyl isocyanate - (methylthio) phenyl isocyanate - (trifluoromethyl) phenyl isocyanate - (trifluoromethylthio) phenyl isocyanate -acetylphenyl isocyanate -bromophenyl isocyanate -bromopropyl isocyanate -bromopropyl isocyanate -carbomethoxyphenyl isocyanate -chloro-2-methoxyphenyl isocyanate -chloro-2-methylphenyl isocyanate -chloro-4-fluorophenyl isocyanate -chloro-4-methylphenyl isocyanate -chlorophenyl isocyanate -chloropropyl isocyanate -cyanophenyl isocyanate -cyclopentoxy-4-methoxyphenyl isocyanate -ethylphenyl isocyanate -fluoro-4-methylphenyl isocyanate -fluorophenyl isocyanate -iodopropyl isocyanate -isocyanatobenzoyl chloride -isopropenyl-alpha, alpha-dimethylbenzyl isocyanate -methoxyphenyl isocyanate -methylbenzyl isocyanate -nitrophenyl isocyanate -pyridyl isocyanate ' -isocyanato-5 ' -nitrobenzo-15-crown-5 ' -isocyanatobenzo-15-crown-5 ' -isocyanatobenzo-18-crown-6 , 5-dimethyl-2-nitrophenyl isocyanate - (6 -methyl-2 -benzothiazolyl) phenyl isocyanate - (chloromethyl) phenyl isocyanate - (chlorosulfonyl) phenyl isocyanate - (difluoromethoxy) phenyl isocyanate - (methylthio) phenyl isocyanate - (tert-butyl) phenylisocyanate - (trifluoromethoxy) phenyl isocyanate - (trifluoromethyl) phenyl isocyanate - (trifluoromethylthio) phenyl isocyanate -acetylphenyl isocyanate -benzyloxyphenyl isocyanate -bromo-2, 6-dimethylphenyl isocyanate -bromo-2- (trifluoromethyl) phenyl isocyanate -bromo-2-chlorophenyl isocyanate -bromo-2 -fluorophenyl isocyanate -bromo-2-methylphenyl isocyanate -bromophenyl isocyanate -chloro-2- (trifluoromethyl) phenyl isocyanate -chloro-2-methoxyphenyl isocyanate -chloro-2-methylphenyl isocyanate -chloro-2-nitrophenyl isocyanate -chloro-3- (trifluoromethyl) phenyl isocyanate -chloro-3 -nitrophenyl isocyanate -chlorophenyl isocyanate -dimethylaminophenyl isocyanate -ethoxyphenyl isocyanate 4-ethylphenyl isocyanate
4-fluoro-2- (trifluoromethyl) phenyl isocyanate
4-fluoro-2-nitrophenyl isocyanate
4-fluoro-3- (trifluoromethyl) phenyl isocyanate 4-fluoro-3-nitrophenyl isocyanate
4-fluorobenzoyl isocyanate
4-fluorobenzyl isocyanate
4-fluorophenyl isocyanate
4-heptyloxyphenyl isocyanate 4-iodophenyl isocyanate
4-isocyanatobenzoyl chloride
4-isopropylphenyl isocyanate
4-methoxy-2-methylphenyl isocyanate
4-methoxybenzyl isocyanate 4-methoxyphenyl isocyanate
4-methyl-2-nitrophenyl isocyanate
4-methyl-3-nitrophenyl isocyanate
4-methylbenzyl isocyanate
4-N-butoxycarbonylphenyl isocyanate 4-N-butoxyphenyl isocyanate
4-N-butyl-2-methylphenyl isocyanate 4-N-butylphenyl isocyanate 4-nitrophenyl isocyanate 4-phenoxyphenyl isocyanate 5-bromopentyl isocyanate
5-chloro-2, 4-dimethoxyphenyl isocyanate 5-chloro-2, 4-toluene diisocyanate 5-chloro-o-tolyl isocyanate 5-fluoro-2-methylphenyl isocyanate 5-iodopentyl isocyanate
6, 7-methylenedioxy-4-isocyanate-methylcoumarin allyl isocyanate benzoyl isocyanate benzyl isocyanate chloroacetyl isocyanate cyclohexyl isocyanate Ethoxycarbonyl isocyanate Ethyl 2-isocyanato-3 -methylbutyrate
Ethyl 2-isocyanato-3-phenylpropionate
Ethyl 2-isocyanato-4- (methylthio) butyrate
Ethyl 2-isocyanato-4-methylvalerate Ethyl 2-isocyanatobenzoate
Ethyl 2-isocyanatopropionate
Ethyl 3-isocyanatobenzoate
Ethyl 3-isocyanatopropionate
Ethyl 4-isocyanatobenzoate Ethyl 6-isocyanatohexanoate
Ethyl isocyanate
Ethyl isocyanatoacetate
Heptyl isocyanate
Hexyl isocyanate Isobutylisocyanate
Isocyanatoethyl methacrylate
Isocyanic acid chloromethyl ester
Isopropyl isocyanate m-tolyl isocyanate m-xylylene diisocyanate Mesityl isocyanate Methyl 2-isocyanatobenzoate Methyl isocyanate Methylisocyanatopropionate N- (chlorocarbonyl) isocyanate N-butyl isocyanate N-butyl isocyanatoacetate N-propyl isocyanate O-tolyl isocyanate p-tolyl isocyanate Pentyl isocyanate Phenethyl isocyanate Phenyl isocyanate
Tert-butyl 3 -isothiocyanatopropionate Tert-butyl isocyanate
Tetrahydro-2-pyranyl isocyanate Trans-2-phenyleyelopropyl isocyanate Trichloroacetyl isocyanate Trichloromethyl isocyanate
EXAMPLE 22 Synthesis of Oxadiazole Thioureas
The Boc-protected Oxadiazole resins of Example
15 were treated with two portions of 50% TFA/DCM (5 min. then 30 min.), washed 3 times each with DCM, MeOH, MTBE and dried. The FMOC-protected Oxadiazole resins of Example 16 were treated with two portions of 20% piperidine in DMF, then washed with DMF, MeOH, MTBE and dried. The aminomethyl oxadiazoles of Example 18 were used without further precautions. The resins were suspended in DMF and distributed into a 96 well microtiter plate. The resin was then washed and neutralized with 5% DIEA in 1, 2-dichloroethane (DCE) /THF (2:1) and washed with DCE/THF (2:1) to remove excess base. The following Isothiocyanates were dissolved to a concentration of 0.2 M in DCE/THF (2:1) and added to the plates. The solutions were shaken at RT overnight and then the plates were washed with DCE/THF (2:1), DMF, MeOH and dried to give N-substituted thioureido oxadiazole resins.
List of Isothiocyanates
(2-methoxy-5-phenyl) phenyl isothiocyanate 1-adamantyl isothiocyanate
1-naphthalenemethyl isothiocyanate
1-naphthyl isothiocyanate
2 , 2-diphenylethyl isothiocyanate
2,3,4, 5-tetrachlorophenyl isothiocyanate , 3 , 4-trichlorophenyl isothiocyanate ,3, 4-trimethoxybenzyl isothiocyanate ,3,5, 6-tetrachlorophenyl isothiocyanate ,3,5, 6-tetrafluorophenyl isothiocyanate , 3-dibromopropyl isothiocyanate , 3 -dichlorophenyl isothiocyanate , 3 -dimethoxybenzyl isothiocyanate , 3 -dimethylphenyl isothiocyanate , 4 , 5-trichlorophenyl isothiocyanate ,4, 6-tribromophenyl isothiocyanate ,4, 6-trichlorophenyl isothiocyanate ,4, 6-trifluorophenyl isothiocyanate ,4,6-trimethylphenyl isothiocyanate , 4 -dichlorophenyl isothiocyanate , 4-difluorophenyl isothiocyanate , 4-dimethoxyphenyl isothiocyanate , 4 -dimethylphenyl isothiocyanate , 5-dibromophenyl isothiocyanate , 5-dichlorophenyl isothiocyanate , 5-difluorophenyl isothiocyanate , 5-dimethoxyphenyl isothiocyanate , 5-dimethylphenyl isothiocyanate , 6-dichlorophenyl isothiocyanate , 6-diethylphenyl isothiocyanate , 6-difluorophenyl isothiocyanate , 6-diisopropylphenyl isothiocyanate , 6-dimethylphenyl isothiocyanate - (3 , 4-dimethoxyphenyl) ethyl isothiocyanate - (4-chlorophenyl) ethyl isothiocyanate - (methylthio) phenyl isothiocyanate - (trifluoromethoxy) phenyl isothiocyanate - (trifluoromethyl) phenyl isothiocyanate -bromo-4-methylphenyl isothiocyanate -bromoethyl isothiocyanate -bromophenyl isothiocyanate -chloro-4 -methylphenyl isothiocyanate -chloro-4-nitrophenyl isothiocyanate -chloro-5- (trifluoromethyl) phenyl isothiocyanate -chloro-5-nitrophenyl isothiocyanate -chloro-6-methylphenyl isothiocyanate -chlorobenzyl isothiocyanate -chloroethyl isothiocyanate -chlorophenyl isothiocyanate -cyanophenyl isothiocyanate -ethoxycarbonylphenyl isothiocyanate -ethoxyphenyl isothiocyanate -ethyl-6- (1-methylpropyl) phenyl isothiocyanate -ethyl-6-isopropylphenyl isothiocyanate -ethyl-6-methylphenyl isothiocyanate -ethylphenyl isothiocyanate -fluorobenzyl isothiocyanate -fluoroethyl isothiocyanate -fluorophenyl isothiocyanate -furfuryl isothiocyanate -hexyl isothiocyanate -iodophenyl isothiocyanate -isopropyl-6-methylphenyl isothiocyanate -isopropylphenyl isothiocyanate -methoxy-4-nitrophenyl isothiocyanate -methoxy-5-methylphenyl isothiocyanate -methoxy-5-nitrophenyl isothiocyanate -methoxybenzyl isothiocyanate -methoxyethyl isothiocyanate -methoxyphenyl isothiocyanate -methyl-4-nitrophenyl isothiocyanate -methyl-5-nitrophenyl isothiocyanate -methylbenzyl isothiocyanate -methylbutyl isothiocyanate -morpholinoethyl isothiocyanate -naphthyl isothiocyanate -pentyl isothiocyanate -phenylethyl isothiocyanate -piperidinoethyl isothiocyanate -tetrahydrofurfuryl isothiocyanate , 4, 5-trimethoxyphenyl isothiocyanate ,4- (ethylenedioxy)phenyl isothiocyanate , 4-dichlorobenzyl isothiocyanate , 4-dichlorophenyl isothiocyanate 3 , 4 -dimethoxybenzyl isothiocyanate
3 , 4-dimethoxyphenyl isothiocyanate
3 , 4 -dimethylphenyl isothiocyanate
3 , 4 -methylenedioxybenzyl isothiocyanate 3 , 4-methylenedioxyphenyl isothiocyanate , 5-bis (trifluoromethyl) phenyl isothiocyanate , 5-dichlorophenyl isothiocyanate , 5-dimethoxyphenyl isothiocyanate , 5-dimethylphenyl isothiocyanate - (diethylamino) propyl isothiocyanate - (methylthio) phenyl isothiocyanate - (trifluoromethyl) phenyl isothiocyanate -acetylphenyl isothiocyanate -benzyloxyphenyl isothiocyanate -bromophenyl isothiocyanate -bromopropyl isothiocyanate -carboxyphenyl isothiocyanate -chloro-2-methylphenyl isothiocyanate -chloro-4-fluorophenyl isothiocyanate -chloro-4-methylbenzyl isothiocyanate -chloro-4-methylphenyl isothiocyanate -chlorobenzyl isothiocyanate -chlorophenyl isothiocyanate -chloropropyl isothiocyanate -cyanophenyl isothiocyanate -dimethylaminopropylisothiocyanate -ethoxycarbonylphenyl isothiocyanate -ethylphenyl isothiocyanate -fluorobenzyl isothiocyanate -fluorophenyl isothiocyanate -iodophenyl isothiocyanate -methoxybenzyl isothiocyanate -methoxycarbonylphenyl isothiocyanate -methoxyphenyl isothiocyanate -methoxypropyl isothiocyanate -methyl-2-butyl isothiocyanate -methylbenzyl isothiocyanate 3 -methylbutyl isothiocyanate
3-morpholinopropyl isothiocyanate
3-nitrophenyl isothiocyanate
3-pentyl isothiocyanate 3-phenylpropyl isothiocyanate -picolyl isothiocyanate hydrobromide - (benzyloxy) phenyl isothiocyanate - (dimethylamino) phenyl isothiocyanate - (methylthio) phenyl isothiocyanate - (trifluoromethoxy) phenyl isothiocyanate - (trifluoromethyl) phenyl isothiocyanate -acetylphenyl isothiocyanate -bromo-2, 6-dimethylphenyl isothiocyanate -bromo-2-chlorophenyl isothiocyanate -bromo-2-methylphenyl isothiocyanate -bromo-2-trifluoromethylphenyl isothiocyanate -bromophenyl isothiocyanate -carboxyphenyl isothiocyanate -chloro-2- (trifluoromethyl) phenyl isothiocyanate -chloro-2-methylphenyl isothiocyanate -chloro-3 -nitrophenyl isothiocyanate -chloro-3 -trifluoromethylphenyl isothiocyanate -chlorobenzyl isothiocyanate -chlorophenyl isothiocyanate -cyanophenyl isothiocyanate -diethylaminophenyl isothiocyanate -ethoxycarbonylphenyl isothiocyanate -ethoxyphenyl isothiocyanate -ethylphenyl .isothiocyanate -fluoro-2-methylphenyl isothiocyanate -fluoro-alpha-methylbenzyl isothiocyanate -fluorobenzyl isothiocyanate -fluorophenyl isothiocyanate -iodophenyl isothiocyanate -isopropylphenyl isothiocyanate -isothiocyanato-4 ' -nitrodiphenyl sulfide -methoxy-2-methylphenyl isothiocyanate 4-methoxy-2-nitrophenyl isothiocyanate
4-methoxybenzyl isothiocyanate
4-methoxycarbonylphenyl isothiocyanate
4-methoxyphenyl isothiocyanate 4-methyl-2-nitrophenyl isothiocyanate
4-methylbenzyl isothiocyanate
4-N-butyl-2-methylphenyl isothiocyanate
4-N-butylphenyl isothiocyanate
4-nitrophenyl isothiocyanate 4-phenoxyphenyl isothiocyanate
4-phenylazophenyl isothiocyanate
4-phenylbutyl isothiocyanate
4-sulfamoylphenyl isothiocyanate
4-tert-butylphenyl isothiocyanate 5-chloro-2, 4-dimethoxyphenyl isothiocyanate
5-chloro-2-methoxyphenyl isothiocyanate
5-chloro-2-methylphenyl isothiocyanate
5-fluoro-2-methylphenyl isothiocyanate
5-indanyl isothiocyanate 5-norbornene-2-isothiocyanate
6-methyl-2-heptyl isothiocyanate
9-isothiocyanatoacridine Allyl isothiocyanate Allyl isothiocyanate Alpha-methylbenzyl isothiocyanate Alpha-methylbenzyl isothiocyanate Benzyl isothiocyanate Crotonyl isothiocyanate Cycloheptyl isothiocyanate Cyclohexanemethyl isothiocyanate Cyclohexyl isothiocyanate Cyclooctyl isothiocyanate Cyclopentyl isothiocyanate Cyclopropyl isothiocyanate D-alpha-methylbenzyl isothiocyanate Diethyl 1-2-isothiocyanatoglutarate Dimethyl 1-isothiocyanatosuccinate Ethyl 2-isothiocyanatopropionate Ethyl 3-isothiocyanatobutyrate Ethyl 3 -isothiocyanatopropionate Ethyl 4-isothiocyanatobutyrate Ethyl isothiocyanate
Ethyl isothiocyanatoacetate Isobutyl isothiocyanate Isopropyl isothiocyanate
Isothiocyanatoacetaldehyde dimethyl acetal Isothiocyanatophenyl sulfone m-tolyl isothiocyanate Methallyl isothiocyanate Methoxymethyl isothiocyanate Methyl 2-isothiocyanatoacetate Methyl 2-isothiocyanatobenzoate Methyl 3-isothiocyanatopropionate Methyl dl-2-isothiocyanatobutyrate Methyl isothiocyanate
Methyl 1-2-isothiocyanato-3-methyl-butyrate Methyl l-2-isothiocyanato-3-phenyl-propionate
Methyl l-2-isothiocyanato-4- (methylthio) butyrate Methyl 1-2-isothiocyanato-4-methyl-valerate N-amyl isothiocyanate N-butyl isothiocyanate N-hexyl isothiocyanate N-propyl isothiocyanate Nitroscanate
Norbornyl-2-isothiocyanate O-tolyl isothiocyanate p-tolyl isothiocyanate p-vinylphenyl isothiocyanate Pentafluorophenyl isothiocyanate" Phenyl isothiocyanate Propargyl isothiocyanate Sec-butyl isothiocyanate Tert-amyl isothiocyanate Tert-butyl isothiocyanate Tert-octyl isothiocyanate
EXAMPLE 23 Oxadiazoles derived from 2-Cyanoethylglycine
(Part 1)
Boc 2-cyanoethyl glycine was loaded onto MBHA resin and converted to the Amidoxime as described in the general procedures of Example 13. This amidoxime resin was treated with a BOC amino acid anhydride as described in Example 15. The bis BOC protected oxadiazole derivative was then treated with 50 % TFA in DCM (2 X 15 min) and washed with DCM and MeOH. The diamines were then treated with 0.2 M benzoic acid, DIC, HOBT and DIEA in DCM or with acetic anhydride in DCM at RT overnight. The resin was washed with DMF 4X, DCM 2X and MeOH and dried to give the di-acylated oxadiazole resins.
Alternatively, the amidoxime is treated with an FMOC amino acid anhydride as in the procedure of Example 16 to give mono-acylated- (FMOC amino) oxadiazole resins.
EXAMPLE 24 Aminomethyl Oxadiazoles derived from 2-Cyanoethylglycine (Part 2)
Boc 2-cyanoethyl glycine is loaded onto MBHA resin and converted to the oxadiazole as described in Example 17. Individual tea bags containing portions of the resulting 5-chloromethyl oxadiazole derivative are then treated with diverse amines in DMF as in Example 18. The 5-aminomethyl oxadiazole derivatives are then acylated to give the N-acylated-5- (substituted aminomethyl) oxadiazole resins, sulfonylated to give N- sulfonyl-5- (substituted aminomethyl) oxadiazole resins, alkylated to give N- alkylated-5- (substituted aminomethyl) oxadiazole resins, treated with isocyanates to give N-substituted ureidooxadiazole resins or isothiocyanates to give N- substituted thioureidooxadiazole resins as described in Example 19, Example 20, Example 21, and Example 22. The products are then treated with 50% TFA in DCM to remove the remaining BOC group. The amino group from the groups defined above are further converted to either an amide, sulfonamide, urea or thiourea derivative following the general procedures of Example 19, Example 20, Example 21, and Example 22 to give a diverse library of oxadiazole resins.
EXAMPLE 25 Cleavage and Extraction of Products Synthesized on
MBHA resin
To the dry microtiter plates containing the oxadiazole resin products was added 25 ul anisole in each well. The plates were then exposed to HF gas in an HF apparatus at RT for 1 hr. Some HF condensed in each well thus nitrogen was blown through the apparatus to remove the excess HF. The plates were then transferred to a polypropylene vacuum dessicator and evacuated overnight. The plates were then extracted into tared plates with either 1:1 Acetonitrile/water, Acetic acid or DMF. The plates containing product were lyophilized and the average yield measured. The products were analyzed by mass spectrometry and HPLC/MS.
EXAMPLE 26 Cleavage and Extraction of Products Synthesized on Wang or DAB resin
To the dry microtiter plates containing the oxadiazole resin products was added 1 ml of a solution of TFA/DCM (25 TO 50% TFA) in each well. The plates were then transferred to a vacuum centrifuge and evacuated overnight. The plates were then extracted into tared plates with either 1:1 Acetonitrile/water, Acetic acid or DMF. The plates containing product were lyophilized and the yield measured. The products were analyzed by mass spectrometry and HPLC/MS.
EXAMPLE 27 Analysis of the products
The products were analyzed by HPLC-MS using a
Hewlett-Packard HPLC system hooked up to Finnigan-Mat LCQ spectrometer. FIA-MS was performed on a Sciex instrument, and HPLC was performed on a Waters HPLC system equipped with a UV detector and an evaporative light scattering detector (ELSD) .
EXAMPLE 28 Preparation of carboxylic acids on solid support.
(Part 1)
A resin bound amine of Example 4 and Example 5 (l.Og, 1 mmol) was treated with succinic anhydride (5 mmol) in 10 ml DCM at RT overnight. The resin teabag was washed with DCM and MTBE and dried to give the resin bound succinylated amine . EXAMPLE 29 Preparation of carboxylic acids on solid support.
(Part 2)
Wang resin (10 g, 12 mmol) was swollen in DCM for 15 min and the excess solvent poured off. A solution of carbonyl diimidazole (10 g, 50 mmol) in DCM was added and shaken for 3 hours. The solvent was poured off and the resin washed with DCM (2X) then a solution of an amino acid ester (50 mmol) and DIEA (50 mmol) in DCM was added, and the solution shaken overnight. The supernatant was removed, and the resin washed with DCM, IPA, DMF, IPA and MeOH. The resulting amino acid ester, linked to the resin through a carbamate linkage, was then treated with a solution of tetramethylammonium hydroxide (50 mmol) in DCM at RT overnight. The supernatant was removed, and the resin washed with DCM, IPA, DMF, IPA and MeOH to give the resin-bound carboxylic acid.
EXAMPLE 30 Synthesis of Amidoximes from nitriles in solution
To a solution of benzonitrile (10 mmol) in 100 ml absolute ethanol was added hydroxylamine hydrochloride (12 mmol) and K2C03 (12 mmol) . The solution was heated to reflux and monitored by thin layer chromatography for the disappearance of nitrile. The solution was then cooled and filtered and the solvent evaporated to give the crude benzamidoxime which was used in the next step directly. Other aliphatic, benzylic and aromatic nitriles were treated similarly to give the corresponding amidoximes . EXAMPLE 31 Preparation of oxadiazoles from resin bound carboxylic acids
The resin bound carboxylic acids of Example 28 and Example 29, (1 g, 10 mmol) were placed in DCM and treated with 10 equivalents each of pentafluorophenol, DIEA and dusopropyl carbodiimide. After shaking for 3 hours, the solvent was poured off and the pentafluorophenyl esters were washed with 2-methoxyethyl ether and treated with a solution of 10 equivalents amidoxime from Example 30 in 2-methoxyethyl ether. The solution was heated to 60° C overnight. The solvent was then removed and the resin washed twice with 2- methoxyethyl ether and then heated to 85 %C in fresh with 2-methoxyethyl ether. The solvent was removed and the resin washed with MeOH and dried to give oxadiazole resins.
EXAMPLE 32 Preparation of Oxadiazole combinatorial libraries: Synthesis of TRG 3600
Five carboxylic acid nitriles were coupled to 15 g of MBHA resin each as described in Example 3. Each nitrile resin was then distributed to 36 teabags and sets of 5 teabags were converted to oxadiazole derivatives by conversion to the amidoxime as in Example 13, and each amidoxime was reacted with 36 different Boc amino acids to give 180 different oxadiazole intermediates as described in Example 15. Each of the 180 intermediates was deprotected by treatment with 50% TFA/DCM, and each resin was transferred to a 96 well reaction block. Each intermediate in the reaction block was then treated with 96 carboxylic acids from Example 19. The final products were then cleaved from the resin with HF, extracted from the resin using acetic acid and lyophilized as described in Example 25. An aliquot of each product was taken and analyzed by mass spectrometry and HPLC with UV and ELSD detection. This created 17280 oxadiazole amide products which correspond to all permutations of the reagents listed below.
Carboxylic acid nitriles:
Cyanoacetic acid
1-Cyano-1-cyclopropane carboxylic acid 3-Cyanobenzoic acid 4-Cyanobenzoic acid
2- (4 -Cyanophenoxy) -2-methyl propionic acid
Boc amino acids :
Boc-Alanine-OH
Boc-b-Alanine-OH Boc-3- (Pyridyl) -Alanine-OH
Boc-2- (Thienyl) -Alanine-OH
Boc-a-Aminobutyric Acid-OH
Boc-g-Aminobutyric Acid-OH
Boc-e-Aminocaproic Acid-OH Boc-a-Aminoisobutyric Acid-OH
Boc-trans-4- (Aminomethyl) -Cylohexane Carboxylic Acid-OH
Boc-Arginine (Tos) -OH
Boc-Aspartic Acid-OBzl
Boc-Aspartic Acid (OcHex) -OH Boc-3 -Carboxymethyl-1-Phenyl-1,3, 8- triazaspiro [4.5] decane-4-one-OH
Boc-4-Chlorophenylalanine-OH
Boc-Cyclohexylalanine-OH
Boc-Glutamic Acid-OBzl Boc-Glutamic Acid (OcHex) -OH
Boc-Glycine-OH
Boc-Histidine (Tos) -OH
Boc-Isoleucine-OH Hemihydrate
Boc-Isonipecotic Acid-OH Boc-Leucine-OH Hydrate
Boc-Nipecotic Acid-OH
Boc-Norleucine-OH
Boc-Phenylalanine-OH Boc-D, L-Pipecolinic Acid-OH
Boc-Proline-OH
Boc-Serine (Bzl) -OH
Boc-Thioproline-OH
Boc-Threonine (Bzl) -OH Boc-TIC-OH
Boc-Tryptophan(For) -OH
Boc-Tyrosine (Bzl) -OH
Boc-OEt-Tyrosine-OH
Boc-Valine-OH N-Fmoc-Lysine (Boc) -OH
Carboxylic acids :
Acetic acid alpha-Methylcinnamic acid
Benzoic acid Crotonic acid
Cyclobutanecarboxylic acid
Cyclohexanepropionic acid
4-Cyanobenzoic acid
Hydrocinnamic acid 4-Dimethylaminobenzoic acid
4-Ethoxybenzoic acid
Isobutyric acid
4-Ethoxyphenylacetic acid
Isovaleric acid Levulinic acid m-Anisic acid m-Toluic acid
Methoxyacetic acid
Isonicotinic acid p-Tolylacetic acid Picolinic acid
Piperonylic acid
4-Fluoro-alpha-methylphenylacetic acid
4-Fluorophenylacetic acid Tetrahydro-3-furoic acid trans-3- (3 -Pyridyl) acrylic acid
Trimethylacetic acid
Triphenylacetic acid
Nicotinic acid (3, 4 -Dimethoxyphenyl) Acetic acid
Boc-isonipecotic acid
(alpha-alpha-alpha-Trifluoro-m-Tolyl) acetic acid
(Methylthio) acetic acid
(Phenylthio) acetic acid 1- (4 -Chlorophenyl) -1-Cyclopentanecarboxylic acid
1-Adamantaneacetic acid
1-Naphthylacetic acid
1-Phenyl- 1-Cyclopropanecarboxylic acid -Iodobenzoic acid -Isopropoxybenzoic acid , 4-Dichlorobenzoic acid -Methyl-l-Cyclohexanecarboxylic acid
Pyrrole-2 -carboxylic acid -Methylvaleric acid -Naphthylacetic acid -Fluorobenzoic acid , 3 -phenylene diacetic acid -Norbornaneacetic acid -Pyrazinecarboxylic acid -Pyridylacetic acid hydrochloride -Thiopheneacetic acid ,4, 5-Triethoxybenzoic acid ,4- (Methylenedioxy) -Phenylacetic acid , 4-Dichlorobenzoic acid -Isopropylbenzoic acid ,4-Dichlorophenylacetic acid -tert-Butyl-cyclohexanecarboxylic acid 4-carboxybenzenesulfonamide
3 , 5, 5-Trimethylhexanoic acid
3 , 5-Bis (Trifluoromethyl) -Benzoic acid
5-Bromo-2-chlorobenzoic acid 5-Bromonicotinic acid
6-Chloronicotinic acid
3, 5-Dimethyl-p-anisic acid
3 -Bromo-4 -Methylbenzoic acid
3, 4, 5-Trimethoxyphenylacetic acid 3-Benzoylpropionic acid
3 , 5-Dichlorobenzoic acid
3-Cyanobenzoic acid
3 -Fluoro-4 -Methylbenzoic acid
1-Isoquinolinecarboxylic acid 3-Methyl-2-thiophenecarboxaldehyde
3-Phenoxybenzoic acid
3-Thiopheneacetic acid
4-Biphenylacetic acid
4-Bromophenylacetic acid S- (+) -Mandelic acid
3 , 5-Di-tert-butyl-4-hydroxybenzoic acid
3, 5-Dichloro-4 -hydroxybenzoic acid
4 -Hydroxybenzoic acid
5-Methylsalicylic acid 2-Methylcyclopropanecarboxylic acid
3-lndolepropionic acid diphenylacetic acid
5-Methoxyindole-2 -carboxylic acid succinamic acid 4- (dimethylamino) butyric acid hydrochloride
4- (methylthio) benzoic acid
2- (methylthio) nicotinic acid
R(-) -2-oxothiazolidine-4 -carboxylic acid
4-nitrophenylacetic acid coumarin-3 -carboxylic acid
1-cyano-1-cyclopropane carboxylic acid
2-chloro-5- (methylthio) benzoic acid theophylline-7-acetic acid
2- (2 -cyanophenylthio) benzoic acid
EXAMPLE 33 Preparation of Oxadiazole combinatorial libraries: Synthesis of TRG 3900
Five carboxylic acid nitriles were coupled to 15 g of MBHA resin each as described in Example 3. Each nitrile resin was then distributed to 36 teabags and sets of 5 teabags were converted to oxadiazole derivatives by conversion to the amidoxime as in Example 13, and each amidoxime was reacted with 36 different Boc amino acids to give 180 different oxadiazole intermediates as described in Example 15. Each of the 180 intermediates was deprotected by treatment with 50% TFA/DCM, and each resin was transferred to one half of a 96 well reaction block. Each of the 180 intermediates was then reacted with 48 sulfonyl chlorides following Example 20. The final products were then cleaved from the resin with HF, extracted from the resin using acetic acid and lyophilized as described in Example 25. An aliquot of each product was taken and analyzed by mass spectrometry and HPLC with UV and ELSD detection. This created 8640 oxadiazole sulfonamide products corresponding to all permutations of the reagents listed below.
Carboxylic acid nitriles:
Cyanoacetic acid
1-Cyano-1-cyclopropane carboxylic acid 3-Cyanobenzoic acid 4-Cyanobenzoic acid 2- (4-Cyanophenoxy) -2-methyl propionic acid
oc amino acids: Boc-Alanine-OH
Boc-b-Alanine-OH
Boc-3- (Pyridyl) -Alanine-OH
Boc-2- (Thienyl) -Alanine-OH Boc-a-Aminobutyric Acid-OH
Boc-g-Aminobutyric Acid-OH
Boc-e-Aminocaproic Acid-OH
Boc-a-Aminoisobutyric Acid-OH
Boc-trans-4- (Aminomethyl) -Cylohexane Carboxylic Acid-OH Boc-Arginine (Tos) -OH
Boc-Aspartic Acid-OBzl
Boc-Aspartic Acid (OcHex) -OH
Boc-3 -Carboxymethyl-1-Phenyl-1,3,8- triazaspiro [4.5] decane-4-one-OH Boc-4-Chlorophenylalanine-OH
Boc-Cyclohexylalanine-OH
Boc-Glutamic Acid-OBzl Boc-Glutamic Acid (OcHex) -OH Boc-Glycine-OH Boc-Histidine (Tos) -OH
Boc-Isoleucine-OH Hemihydrate Boc-Isonipecotic Acid-OH Boc-Leucine-OH Hydrate Boc-Nipecotic Acid-OH Boc-Norleucine-OH
Boc-Phenylalanine-OH Boc-D, L-Pipecolinic Acid-OH Boc-Proline-OH Boc-Serine (Bzl) -OH Boc-Thioproline-OH
Boc-Threonine (Bzl) -OH Boc-TIC-OH
Boc-Tryptophan(For) -OH Boc-Tyrosine (Bzl) -OH Boc-OEt-Tyrosine-OH Boc-Valine-OH N-Fmoc-Lysine (Boc) -OH List of Sulfonyl chlorides:
2-mesitylenesulfonyl chloride
2-naphthalenesulfonyl chloride
2-thiophenesulfonyl chloride 4-chlorobenzenesulfonyl chloride
4-fluorobenzenesulfonyl chloride
4-methoxybenzenesulfonyl chloride
4-methylsulfonylbenzenesulfonyl chloride
Benzenesulfonyl chloride Dansyl chloride
N-acetylsulfanilyl chloride
2-acetamido-4-methyl-5-thiazolesulfonyl chloride
4- (trifluoromethoxy) benzenesulphonyl chloride
4-tert-butylbenzenesulfonyl chloride 8-quinolinesulfonyl chloride
2, 3-dichlorothiophene-5-sulphonyl chloride
3 , 4-dimethoxybenzenesulfonyl chloride
3,5-di (trifluoromethyl) benzenesulphonyl chloride
3-chloro-4-fluorobenzenesulphonyl chloride 3-trifluoromethylbenzenesulphonyl chloride
4-ethylbenzenesulfonyl chloride
Pentamethylbenzenesulfonyl chloride
2,3, 4-trifluorobenzenesulphonyl chloride
2 , 4 -dichlorobenzenesulfonyl chloride 2, 5-dichlorothiophene-3-sulphonyl chloride
2, 6-dichlorobenzenesulfonyl chloride
2, 6-difluorobenzenesulphonyl chloride -chloro-4- (trifluoromethyl) benzenesulphonyl chloride -chloro-5- (trifluoromethyl) benzenesulphonyl chloride -chloro-6-methylbenzenesulphonyl chloride , 4-difluorobenzenesulphonyl chloride , 5-dichlorobenzenesulfonyl chloride -chlorobenzenesulfonyl chloride - (N-butoxy) benzenesulphonyl chloride -trifluoromethylbenzene sulphonyl chloride , 5-dimethylisoxazole-4-sulfonyl chloride 2- (methoxycarbonyl) thiophene-3 -sulfonyl chloride
4-acetamido-3-chlorobenzene sulfonyl chloride
2- [l-methyl-5- (trifluoromethyl) pyrazol-3-yl] thiophene-5- sulfonyl chloride 2- (benzoylammomethyl) thiophene-5-sulfonyl chloride
3-methoxy-4- (methoxycarbonyl) -thiophene-2-sulphonyl chloride
5- (isoxazol-3-yl) thiophene-2-sulphonyl chloride
4-cyanobenzene sulfonyl chloride 3-chloro-4 -methylbenzenesulfonyl chloride
2 , 4 -difluorobenzenesulfonyl chloride -fluorobenzenesulphonyl chloride -isopropylbenzene sulphonyl chloride , 5-dimethoxybenzenesulfonyl chloride , 4-dichlorobenzenesulfonyl chloride
EXAMPLE 34 Preparation of Oxadiazole combinatorial libraries: Synthesis of TRG 4000
Four carboxylic acid nitriles were coupled to lOOg of MBHA resin each as described in Example 3. Each nitrile resin was then distributed to 24 teabags and sets of 4 teabags were converted to oxadiazole derivatives by conversion to the amidoxime as in Example 13, and each amidoxime was reacted with 24 different Boc amino acids to give 96 different oxadiazole intermediates as described in Example 15. Each of the 96 intermediates was deprotected by treatment with 50% TFA/DCM, and each resin was transferred to a 96 well reaction block. Each intermediate in the reaction block was then treated with 80 carboxylic acids from Example 19, and 16 isocyanates from the list below as described in Example 21. The final products were then cleaved from the resin with HF, extracted from the resin using acetic acid and lyophilized as described in Example 25. An aliquot of each product was taken and analyzed by mass spectrometry and HPLC with UV and ELSD detection. This created 9216 oxadiazole amide and urea products which correspond to all permutations of the reagents listed below.
List of Carboxylic acid nitriles:
1-Cyano-1-cyclopropane carboxylic acid 3-Cyanobenzoic acid 4-Cyanobenzoic acid 2- (4 -Cyanophenoxy) -2-methyl propionic acid List of Amino Acids
Boc-Alanine-OH
Boc-3- (Pyridyl) -Alanine-OH
Boc-a-Aminobutyric Acid-OH Boc-g-Aminobutyric Acid-OH
Boc-a-Aminoisobutyric Acid-OH
Boc-Arginine (Tos) -OH
Boc-Aspartic Acid (OcHex) -OH
Boc-3 -Carboxymethyl-l-Phenyl-1, 3,8- triazaspiro [4.5] decane-4-one-OH
Boc-4 -Chlorophenylalanine-OH
Boc-Cyclohexylalanine-OH
Boc-Glutamic Acid-OBzl
Boc-Histidine (Tos) -OH Boc-Isoleucine-OH
Boc-Isonipecotic Acid-OH
Boc-Leucine-OH
Boc-Nipecotic Acid-OH
Boc-Norleucine-OH Boc-Phenylalanine-OH
Boc-D, L-Pipecolinic Acid-OH
Boc-Proline-OH
Boc-Serine (Bzl) -OH
Boc-Threonine (Bzl) -OH Boc-OEt-Tyrosine-OH
Boc-Valine-OH
List of Carboxylic acids
Acetic acid alpha-Methylcinnamic acid Benzoic acid Crotonic acid Cyclohexanepropionic acid 4-Cyanobenzoic acid Hydrocinnamic acid 4-Dimethylaminobenzoic acid
Isobutyric acid
Isonicotinic acid
4-Ethoxyphenylacetic acid Isovaleric acid
Levulinic acid m-Anisic acid m-Toluic acid
Methoxyacetic acid Nicotinic acid p-Tolylacetic acid
Picolinic acid
Piperonylic acid
4-Fluorophenylacetic acid Tetrahydro-3-furoic acid trans-3- (3 -Pyridyl) acrylic acid
Trimethylacetic acid
Triphenylacetic acid
(3 , 4 -Dimethoxyphenyl) Acetic acid (alpha-alpha-alpha-Trifluoro-m-Tolyl) cetic acid
(Methylthio) acetic acid
1- (4 -Chlorophenyl) -1-Cyclopentanecarboxylic acid 1-Adamantaneacetic acid 1-Naphthylacetic acid 1-Phenyl-l-Cyclopropanecarboxylic acid -Iodobenzoic acid -Isopropoxybenzoic acid -Isopropylbenzoic acid , 4-Dichlorobenzoic acid -Methyl-l-Cyclohexanecarboxylic acid -Methylvaleric acid -Fluorobenzoic acid -Methylcyclopropanecarboxylic acid -Norbornaneacetic acid -Pyrazinecarboxylic acid -Thiopheneacetic acid , 4-Dichlorobenzoic acid 3 , 4-Dichlorophenylacetic acid
4-tert-Butyl-cyclohexanecarboxylic acid
3 , 5, 5-Trimethylhexanoic acid 5-Bromo-2-chlorobenzoic acid 5-Bromonicotinic acid
6-Chloronicotinic acid
3 , 4 , 5-Trimethoxyphenylacetic acid
3-Benzoylpropionic acid
3 -Bromo- -Methylbenzoic acid 3-Cyanobenzoic acid
3 -Fluoro-4 -Methylbenzoic acid
3-Methyl-2-thiophenecarboxaldehyde
3-Phenoxybenzoic acid
4-Biphenylacetic acid 4-Bromophenylacetic acid
S- (+) -Mandelic acid
3 , 5 -Di-tert-butyl-4 -hydroxybenzoic acid
3 , 5-Dichloro-4 -hydroxybenzoic acid
5-Methylsalicylic acid 3-lndolepropionic acid
5 -Methoxyindole-2 -carboxylic acid
1-cyano-l-cyclopropane carboxylic acid succinamic acid
4- (dimethylamino) butyric acid hydrochloride 4- (methylthio) benzoic acid
2- (methylthio) nicotinic acid
4-nitrophenylacetic acid coumarin-3 -carboxylic acid
4 -carboxybenzenesulfonamide 2-chloro-5- (methylthio) benzoic acid theophylline-7-acetic acid
2- (2 -cyanophenylthio) benzoic acid
R(-) -2-oxothiazolidine-4 -carboxylic acid diphenylacetic acid DL-2- (3 -Chlorophenoxy) -propionic acid 4-Phenoxybenzoic acid List of isocyanates
1-adamantyl isocyanate 1-naphthyl isocyanate 2, 4 -difluorophenyl isocyanate 2, 4-dimethoxyphenyl isocyanate 2,4-dimethylphenyl isocyanate 2 , 6-diisopropylphenyl isocyanate 2-ethyl-6 -isopropylphenyl isocyanate 2-methoxy-5-nitrophenyl isocyanate 2 -methyl-4 -nitrophenyl isocyanate 2 -phenylphenyl isocyanate 3, 5-dicarbomethoxyphenyl isocyanate 3 , 5-dichlorophenyl isocyanate 3-acetylphenyl isocyanate 3 -chlorophenyl isocyanate 3-fluorophenyl isocyanate 3 -trifluoromethylphenyl isocyanate 4- (trifluoromethoxy) phenyl isocyanate 4-chlorophenyl isocyanate 4 -cyanophenyl isocyanate
4 -fluoro-3 -nitrophenyl isocyanate 4-fluorophenyl isocyanate 4-methoxyphenyl isocyanate 4-N-carbobutoxyphenyl isocyanate 4-nitrophenyl isocyanate 4 -phenoxyphenyl isocyanate 5-chloro-2 , 4-dimethoxyphenyl isocyanate 5-chloro-2-methoxyphenyl isocyanate Ethyl 4 -isocyanato benzoate Isopropyl isocyanate m-tolyl isocyanate N- (methoxycarbonyl) isocyanate N-amyl isocyanate Phenethyl isocyanate Phenyl isocyanate EXAMPLE 35 Preparation of Oxadiazole combinatorial libraries: Synthesis of TRG 5500
The cyanophenols listed below were coupled to 300 g each of Wang bromide resin to give the corresponding cyanophenyl ethers, following the procedure of Example 9. 600g of resin bound piperazine prepared in Example 5 was converted to 300 g of resin bound 4- cyanobenzyl piperazine following Example 8, and 300 g of resin bound 4-cyanophenoxyacetyl piperazine according to the procedures of Example 7 and Example 10. The seven resulting resin bound nitriles were converted to the amidoxime as described in the general procedure of Example 12. The amidoximes were converted to the 5- chloromethyl oxadiazoles as described in Example 17.
Each chloromethyl oxadiazole resin was reacted with the 60 primary amines listed below following the procedure of Example 18 to give 420 aminomethyl oxadiazole intermediates. Each of the 420 intermediates was reacted with 80 carboxylic acids to give the amide derivatives and 48 sulfonyl chlorides to give sulfonamides according to the procedures of Example 19 and Example 20 respectively. The final products were cleaved from the resin with 50% TFA/DCM, and evaporated. The products were extracted from the resin using acetic acid and lyophilized as described in Example 25. An aliquot of each product was taken and analyzed by mass spectrometry and HPLC with UV and ELSD detection.
List of Cyanophenols :
1 4 -hydroxy-3 -methoxybenzonitrile
2 4 -cyanophenol
3 2-fluoro-4 -hydroxybenzonitrile
4 3 -cyanophenol
5 4-cyano-4 ' -hydroxybiphenyl List of amines:
1 1- (2-Aminoethyl) pyrrolidine
2 2- (Aminomethyl) pyridine
3 Histamine 4 Cyclopentylamine
5 Allylamine
6 2-Methoxyethylamine
7 (A) -Tetrahydrofurylamine
8 Benzyiamine 9 2-Methylbenzylamine
10 3-Methylbenzylamine 1 4-Methylbenzylamine 2 2-Fluorobenzylamine 3 3-Fluorobenzylamine 4 4 -Fluorobenzylamine 5 1- (3-Aminopropyl) imidazole 6 p-Xylylenediamine, 7 4-Methoxybenzylamine 8 3-Chlorobenzylamine 9 3-Bromobenzylamine HCl 0 4-Bromobenzylamine HCl 1 Cyclopropylamine 2 (Aminomethyl) cyclopropane 3 4- (Aminomethyl) pyridine 4 3- (Aminomethyl) pyridine 5 2-Thiophenemethylamine 6 Phenethylamine 7 4- (2-Aminoethyl) morpholine 8 3-Methoxybenzylamine 9 Piperonylamine 0 4 -Methoxyphenethylamine 1 2-Fluorophenethylamine 2 2- (4 -Chlorophenyl) ethylamine 3 2- (3 -Chlorophenyl) ethylamine 4 2- (2-Chlorophenyl) ethylamine 5 2, 3-Dimethoxybenzylamine 36 3 , 4-Dimethoxyphenethylamine
37 2, 4-Dichlorophenethylamine
38 N,N-Diethylethylenediamine
39 2- (2 -Aminoethyl) -1-methylpyrrolidine 40 3-Diethylaminopropylamine
41 2- (2-Aminoethylamino) -5-nitropyridine
42 N,N, 2, 2-Tetramethyl-l, 3-propanediamine
43 3-Dimethylammopropylamine
44 Ethylenediamine 45 1- (2 -Aminoethyl) piperidine
46 isoamylamine
47 3-Ethoxypropylamine
48 1- (3-Aminopropyl) -2-pipecoline
49 3-Butoxypropylamine 50 N- (3 ' -Aminopropyl) -2-pyrrolidinone, tech
51 4- (3-Aminopropyl) morpholine
52 N- (2 -Aminoethyl) -N-ethyl-m-toluidine
53 3-Phenyl-1-propylamine
54 b-Methylphenethylamine 55 4-Phenylbutylamine
56 3 , 3 -Diphenylpropylamine
57 Isobutylamine
58 2- (2 -Aminoethyl) pyridine
59 Cyclohexanemethylamine 60 3-Methoxyphenethylamine
61 3-Phenylbenzylamine
EXAMPLE 36 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 screening, 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.
Compounds listed in the table below are described in reference to Formula (I) , wherein the ring structure is a 1, 2, 4 oxadiazole (where U is an oxygen), Rj corresponds to the starting material of Xx and X2, R2 corresponds to the starting material of X3 and R3 corresponds to the starting material of X4. The compounds were assayed at a concentration of 170 μg/ml . Percent inhibition for each compound was calculated using the following formulae:
Color correct =
(O.D. 0 hr - Blank 0 hr) - (Solvent Control 0 hr - Blank 0 hr)
% Inhibition = 100 - (O.D. test compound 4 hr - Blank 4 hr - color correct) divided by (O.D. growth/solvent control 4 hr - Blank 4 hr)
Figure imgf000161_0001
Figure imgf000161_0002
o
Figure imgf000162_0001
σ
Figure imgf000163_0001
S3
Figure imgf000164_0002
Figure imgf000164_0001
σ
Figure imgf000165_0001
4S»
Figure imgf000166_0001
Figure imgf000167_0002
Figure imgf000167_0001
4389 2- (4-Cyanophenoxy) -2- Boc-Histidine (Tos) 4 -Methyl-1-Cyclohexanec Methyl-propionic acid arboxylic acid
598 4-Cyanobenzoic acid Boc-3 -Carboxymethyl-1-Pheny 4-Methylvaleric acid
Figure imgf000168_0001
1-1, 3 , 8-triazaspiro [4.5] dec ane-4-one
4941 4-Cyanobenzoic acid Boc-Leucine 4-n-carbobutoxyphenyl Isocyanate
2447 1-Cyano-1-Cyclopropane-C Boc-Cyclohexylalanine 4 -nit Rophenyl OOH isocyanate
4103 1-Cyano-1-Cyclopropane-C Boc-Proline 4-nitrophenylac OOH etic acid σ
ON
3552 4-Cyanobenzoic acid Boc-Leucine 4-Phenoxybenzoic acid 4-Phenoxybenzoic acid
4814 3-Cyanobenzoic acid Boc-Aspartic Acid (OcHex) Acid (ochex) 4-phenoxyphe nyl isocyanate
4478 2- (4-Cyanophenoxy) -2- Boc-Isonipecotic Acid 4-tert-Butyl-cyclohexan Methyl-propionic acid ecarboxylic acid
3521 4-Cyanobenzoic acid Boc-Leucine 5-Bromonicotinic acid
2300 4-Cyanobenzoic acid Boc-Isonipecotic Acid 5 -chloro-2 , 4 -dimethoxyp henyl isocyanate
Figure imgf000169_0001
Figure imgf000169_0002
Figure imgf000170_0001
EXAMPLE 37 Preparation of 1, 3 , 4-Oxadiazoles
The resin bound carboxylic acids of examples 28 and 29 are placed in a solution of 4-nitrophenyl trifluoroacetate (10 equivalents) in DCM and shaken at RT for 6 hours to give the corresponding 4-nitrophenyl esters. The resins are washed 5 times with DCM and a solution of an acyl hydrazide in DMF is added. to the 4- nitrophenyl esters. After shaking overnight, the resulting resin bound diacyl hydrazides are washed with DMF, DCM and Methanoi (4 times each) and dried. The resin bound diacyl hydrazides are then suspended in a solution of triethylamine (10 eq) and triphenylphosphine (10 eq) in DCM. To the solutions is added carbon tetrachloride (9 eq) dropwise over 15 minutes. The cyclization reaction is allowed to proceed overnight at 45°C. The resins are then washed with DCM and Methanoi and dried to provide the resin bound 1 , 3 , 4-oxadiazole compounds .
EXAMPLE 38
Preparation of 1, 3 , 4-Thiadiazoles
The resin bound carboxylic acids of examples 28 and 29 are placed in a solution of 4-nitrophenyl trifluoroacetate (10 equivalents) in DCM and shaken at RT for 6 hours to give the corresponding 4-nitrophenyl esters. The resins are washed 5 times with DCM and a solution of an acyl hydrazide in DMF is added to the 4- nitrophenyl esters. After shaking overnight, the resulting resin bound diacyl hydrazides are washed with DMF, DCM and Methanoi (4 times each) and dried. The diacylhydrazides are suspended in a solution of Lawesson's reagent (10 eq) in toluene, and the solutions heated to 110°C overnight. The resins are then washed with DCM, DMF, DCM and Methanoi (4X each) and dried to provide the resin bound 1, 3 , 4-thiadiazole compounds.
EXAMPLE 39 Preparation of 1, 2, 4-Triazoles
The resin bound carboxylic acids of examples 28 and 29 are placed in a solution of 4-nitrophenyl trifluoroacetate (10 equivalents) in DCM and shaken at RT for 6 hours to give the corresponding 4-nitrophenyl esters . The resins are washed 5 times with DCM and a solution of hydrazide in DMF is added to the 4- nitrophenyl esters. After shaking overnight, the resulting resin bound acyl hydrazides are washed with DMF, DCM and Methanoi (4 times each) and dried. The resins are treated with a solution of an amidine (5 eq) and potassium carbonate (10 eq) in 2-methoxyethanol . The mixtures are heated at 100°C for 3 days, then the resins are washed with DMF and Methanoi and dried to provide the corresponding resin bound 1, 2 , 4-triazole compounds.
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

WE CLAIM :
1. A single compound of the structure :
Figure imgf000173_0001
.Formula (I)
wherein:
T, U and V are independently selected from an oxygen, sulfur or nitrogen atom, provided that at least two of T, U and V are a nitrogen atom;
X: is selected from the group consisting of H,
-NHC(0)NR1R2 -C02R1, -ORly -NR1R2, -C ONR^, and -C^NRxR;,, wherein Rα is a hydrogen atom or a functionalized resin, and R2 is a hydrogen atom, C: to C6 alkyl, C: 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, substituted heterocycle, the formulae:
Figure imgf000174_0001
Figure imgf000174_0002
Figure imgf000174_0003
wh erein Q is a hydrogen atom or functionalized resin;
X2 is selected from the group consisting of C2 to C12 alkylene, Cα to C12 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C7 to C12 phenylalkylene, C7 to C12 substituted phenylalkylene, C7 to C12 phenylalkoxy, C to C12 substituted phenylalkoxy, the formula:
-(CH2)m-G-(CH2)n-
wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and G is selected from phenylene and substituted phenylene,
the formula :
-(CH2)ra-NR3-(CH2)n-
wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and R3 is selected from the group consisting of a hydrogen atom, Cj to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 acyl, C: to C7 substituted acyl, Cx to C4 alkyl sulfonyl, C2 to C4 substituted alkyl sulfonyl, phenylsulfonyl, substituted phenylsulfonyl, C: to C6 alkylaminocarbonyl, Cτ to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, d to C6 alkylaminothiocarbonyl, C: to C6 substituted alkylaminothiocarbonyl , phenylaminothiocarbonyl , substituted phenylaminothiocarbonyl, Cλ to C7 alkoxycarbonyl, Cj to C7 substituted alkoxycarbonyl, phenoxycarbonyl and substituted phenoxycarbonyl, the formula :
Figure imgf000176_0001
wherein n is an integer selected from 0 to 6; R4 and R5 are together or independently a hydrogen atom, Cx to C6 alkyl, Cj to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, Cλ 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, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, cyclic C2 to C7 alkylene, substituted cyclic C to C7 alkylene, cyclic C2 to C7 heteroalkylene, substituted cyclic C2 to C7 heteroalkylene, carboxy, protected carboxy, hydroxymethyl and protected hydroxymethyl; and G is selected from phenylene and substituted phenylene, and the formula :
Figure imgf000177_0001
(III)
wherein J and K are each selected from the group consisting of phenylene and substituted phenylene, and m and n are independently selected from 0 and 1, and
the formulae (IV) and (V) :
Figure imgf000177_0002
(IV) (V) and
absent or is selected from the group consisting of the formula :
Figure imgf000177_0003
wherein:
R4 and R5 are together or independently selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C: to C6 substituted alkyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, x to C7 acyl, C: 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, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy, 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, carboxy, protected carboxy, hydroxymethyl and protected hydroxymethyl,
the formulae (Via) and (VIb) :
Figure imgf000178_0001
(Nla) (VIb)
wherein in formula (Via) m and n are independently selected from O, 1, 2, 3 and 4; and wherein in formula (VIb) m is selected from O, 1, 2, 3 and 4; the formula :
Figure imgf000179_0001
wherein R6 is selected from the group consisitng of a hydrogen atom, amino, amino- protecting group, -NR7R8, carboxy, carboxy- protecting group, -C(0)NR7R8, wherein R7 and R8 are independently selected from a hydrogen atom, C2 to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, C-, to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cλ to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cj to C6 alkylaminocarbonyl, C to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl , phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and m and n are independently selected from 0, 1, 2, 3 and 4; and the formulae (VII) to (XIII)
Figure imgf000180_0001
(XIII)
wherein q is 1 or 2; r is 0 or 1; s and t are independently selected from 0, 1 or 2; and R7 and R8 are independently selected from a hydrogen atom, Cj to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, Cα to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Ci to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cλ to C6 alkylaminothiocarbonyl, Cτ to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and R9 is selected from a hydrogen atom, -OH, hydroxy-protecting group, Cx to C6 alkyl, Cτ to C6 substituted alkyl, Cτ to C7 alkoxy, Cx to C7 phenylalkoxy, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl ; and
absent or is selected from the group consisting of a hydrogen atom, -OH, -C02H, -C(0)NR7R8 and -NR7R8, wherein R7 and R8 are independently selected from a functionalized resin, a hydrogen atom, Cx to C6 alkyl, C! to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, C to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C2 to C6 alkylaminothiocarbonyl, x to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl, and the formulae :
Figure imgf000182_0001
wherein R9 and R10 are independently selected from a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy Cx to C7 acyl, Cα to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cj to
C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and s is an integer selected from 1 to 5;
a pharmaceutically acceptable salt of a compound thereof; or
a biologically active ester form of a compound thereof.
2. The single compound of claim 1, wherein one of T, U and V is oxygen and the other two positions are each nitrogen.
3. The single compound of claim 2, wherein U is oxygen, T is nitrogen and V is nitrogen.
4. The single compound of claim 1, wherein
X: is selected from the group consisitng of -C02Ri, -ORi, NR^, -C(0)NR!R2
and the formulae :
Figure imgf000183_0001
Figure imgf000183_0002
X2 is selected from the group consisting of Cx to C12 alkylene, Cx to C12 substituted alkylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C7 to C12 phenylalkylene, C7 to C12 substituted phenylalkylene,
the formula:
(CH2)m-NR3-(CH2)n- wherein m is 1 to 3 and n is 1 to 4,
and the formula:
Figure imgf000184_0001
wherein n is 0 or 1; R4 and R5 are together or independently a hydrogen atom, Cx to C6 alkyl or Cx to C10 substituted alkyl,
and the formula :
Figure imgf000184_0002
(Ill)
wherein m and n are integers independently selected from 0 and 1;
bsent or the formula:
Figure imgf000184_0003
wherein :
R4 and R5 are together or independently selected from the group consisting of a hydrogen atom, C: to C6 alkyl, C7 to C12 substituted phenylalkyl, substituted phenyl, hydroxymethyl, protected hydroxymethyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl,
the formula :
Figure imgf000185_0001
(Vlb)
wherein m is 0,
and the formula :
Figure imgf000185_0002
wherein m is 0 to 2 and n is 1 to 4; and
where X3 is absent, X4 is selected from the group consisting of the formulae:
Figure imgf000186_0001
(VII ) (XI )
Figure imgf000186_0002
wherein R9 is selected from a hydrogen atom and -OH.
5. The single compound of claim 1, wherein:
Xx is selected from the group consisting of -CO^, -OR, - NRXR2, -C(0)NR!R2,
and the formula:
Figure imgf000186_0003
The single compound of claim 3, wherein:
Xx is selected from the group consisting of OH, CONH2,
2- (1-pyrrolidino) ethylamine, 2-pyridinemethylamine, 2- (4-imidazole) ethylamine, cyclopentylamine, allylamine, 2-methoxyethylamine, (+/-) -tetrahydrofurylamine, benzyiamine, 2-methylbenzylamine, 3-methylbenzylamine , 4-methylbenzylamine, 2-fluorobenzylamine, 3 -fluorobenzylamine, 4-fluorobenzylamine, 3 - (1-imidazole) propylamine,
4-aminomethylbenzylamine, 4-methoxybenzylamine, 3-chlorobenzylamine, 3-bromobenzylamine, 4-bromobenzylamine, cyclopropylamine, cyclopropanemethylamine, 4-pyridinemethylamine, 3 -pyridinemethylamine, 2-thiophenemethylamine, phenethylamine, 2- (morpholine) ethylamine, 3- methoxybenzylamine, piperonylamine, 4-methoxyphenethylamine, 2-fluorophenethylamine, 2- (4-chlorophenyl) ethylamine, 2- (3-chlorophenyl) ethylamine,
2- (2-chlorophenyl) ethylamine, 2 , 3-dimethoxy- benzylamine, 3 , 4-dimethoxyphenethylamine, 2,4- dichlorophenethylamine, 2- (diethylamino) ethylamine, 2- (l-methylpyrrolidin-2-yl) ethylamine, 3- (diethylamino) propylamine,
2- (5-nitro-2-pyridyl) ethylamine, 3- (dimethylamino) -2, 2-dimethylpropylamine, 3- (dimethylamino) propylamine, 2-aminoethylamine, 2- (piperidino) ethylamine, isoamylamine, 3-ethoxypropylamine, 3- (2-pipecolinyl) propylamine, 3 -butoxypropylamine,
3- (pyrrolidin-2-one-l-yl) propylamine, 3- (morpholino) propylamine,
2- (N-ethyl-3-methylanilino) ethylamine, 3-phenyl-l- propylamine, 2-methyl-2-phenylethylamine,
4-phenylbutylamine, 3 , 3-diphenylpropylamine, isobutylamine , 2- (2-pyridyl) ethylamine, cyclohexanemethylamine, 3-methoxyphenethylamine, 3-phenylbenzylamine, and piperazine;
selected from the group consisting of methylene, 1, 1-cyclopropyl, 1, 3 -phenylene, 1 , 4-phenylene,
1-methyl-l- (4-oxyphenylene) ethane,
3 -methoxy-1 , 4 -phenylene , 2-fluoro-1 , 4 -phenylene,
4, 4 ■ -biphenylene, 1, 2-phenylene, 3 , 5-dibromo-l, 4-phenylene,
4-phenyl-l- (methylene-1-yl) ,
3 , 5-diiodo-l, 4-phenylene, 3 -hydroxy-1, 4-phenylene,
2,3,5, 6 -tetrafluoro-1, 4-phenylene,
3 -bromo-1, 4-phenylene, 3 , 5-di-tert- butyl-1, 4-phenylene,
3 , 5-di-tert-butyl-4-phenyl-l- (methylene-1-yl) ,
3 -methoxy-4-phenyl-1- (methylene-1-yl) ,
3 -nitro- 1, 4-phenylene, 5-hydroxy-1, 3 -phenylene,
4-phenyl-l- (-2-ethyl) , 3-ethoxy-4-phenyl-l- (methylene-1-yl) ,
2-chloro-1, 4-phenylene, 2-fluoro-1, 4-phenylene,
3, 5-dimethyl-l, 4-phenylene, , 6-dimethyl-l, 4-phenylene, , 5-dichloro-l, 4-phenylene, -methoxy-2-phenyl-l- (methylene-1-yl) , -quinoline-2-yl, 5-indole-3- (methylene-1-yl) , , hydroxy-4 -phenyl-1- (methylene-1-yl) , -chloro-l, 2-phenylene, 6-nitro-l, 2-phenylene, -nitro-1 , 2-phenylene , -amino-l, 4-phenylene, 2-carboxymethyl-l, 4-phenylene, -bromo-5-methoxy-4-phenyl-l- (methylene-1-yl) , , 5-dimethoxy-4-phenyl-l- (methylene-1-yl) , -iodo-6-nitro-l, 4-phenylene;
selected from the group consisting of -aminomethylene, - (1-aminoethyl) , 1- (2-aminoethyl) , - (l-amino-2- (3 -pyridyl) ethyl) , - (l-amino-2- (2-thienyl) ethyl) , 1- (1-aminopropyl) , - (3-aminopropyl) , 1- (5-aminopentyl) , - (1-methyl-l-aminoethyl) , - (4-aminomethylcyclohexyl) , 1- (l-amino-3 -guanidinopropyl) , 3- (3-aminopropionic acid) , 3- (2-aminopropionic acid) ,
3-methylene-l-phenyl-l, 3, 8-triazaspiro [4.5] decane-4 - one, 1- (l-amino-2- (4-chlorophenyl) ethyl) , 1- (l-amino-2- (cyclohexyl) ethyl) , 4- (4-aminobutyric acid) , 4- (2-aminobutyric acid) , 1- (l-amino-2- (4 -imidazolyl) ethyl) , 1- (l-amino-2-methylbutyl) , 4-piperidinyl, 1- (l-amino-3-methylbutyl) , 3-piperidinyl, 1- (1-aminobutyl) , 1- ( l-amino-2 -phenylethyl) , 2-piperidinyl, 2 -pyrrolidinyl, 1- (l-amino-2-hydroxyethyl) , 4-thiazolidinyl, 1- (l-amino-2-hydroxypropyl) , 3-tetrahydroisoquinolinyl, 1- (l-amino-2- (3 -indolyl) ethyl) ,
1- (l-amino-2- (4-hydroxyphenyl) ethyl) , 1- (l-amino-2- (4-ethoxyphenyl) ethyl) , 1- (l-amino -2-methylpropyl) , 1- (1, 5-diaminopentyl) , 2- (1-pyrrolidino) ethylaminomethylene, 2 -pyridinemethylaminomethylene,
2- (4 -imidazole) ethylaminomethylene, cyclopentylaminomethylene , allylaminomethylene , 2 -methoxyethylaminomethylene , (+/- ) -tetrahydrofurylaminomethylene, benzylammomethylene, 2 -methylbenzylaminomethylene, 3 -methylbenzylaminomethylene , 4 -methylbenzylaminomethylene , 2-fluorobenzylaminomethylene , 3 -fluorobenzylaminomethylene , 4-fluorobenzylaminomethylene,
3- (1-imidazole) propylaminomethylene , 4 -aminomethylbenzylaminomethylene , 4-methoxybenzylaminomethylene, 3 -chlorobenzylaminomethylene , 3-bromobenzylaminomethylene, -bromobenzylaminomethylene , cyclopropylaminomethylene , cyclopropanemethylaminomethylene, 4 -pyridinemethylaminomethylene, 3-pyridinemethylaminomethylene, 2-thiophenemethylaminomethylene, phenethylaminomethylene,
2- (morpholine) ethylaminomethylene, 3- methoxybenzylaminomethylene, piperonylaminomethylene, 4 -methoxyphenethylaminomethylene, 2-fluorophenethylaminomethylene,
2- (4-chlorophenyl) ethylaminomethylene, 2- (3-chlorophenyl) ethylaminomethylene,
2- (2-chlorophenyl) ethylaminomethylene, 2 , 3-dimethoxy- benzylammomethylene, 3 , 4-dimethoxyphenethylaminomethylene, 2,4- dichlorophenethylaminomethylene, 2- (diethylamino) ethylaminomethylene, 2- (l-methylpyrrolidin-2-yl) ethylaminomethylene,
3 - (diethylamino) propylaminomethylene , 2- (5-nitro-2-pyridyl) ethylaminomethylene,
3- (dimethylamino) -2 , 2-dimethylpropylaminomethylene, 3- (dimethylamino) propylaminomethylene,
2-aminoethylaminomethylene,
2- (piperidino) ethylaminomethylene, isoamylammomethylene, 3-ethoxypropylaminomethylene,
3 - (2-pipecolinyl) propylaminomethylene , 3-butoxypropylaminomethylene,
3 - (pyrrolidin-2-one-1-yl) propylaminomethylene,
3- (morpholino)propylaminomethylene, 2- (N-ethyl-3-methylanilino) ethylaminomethylene,
3-phenyl-1- propylaminomethylene,
2-methyl-2-phenylethylaminomethylene,
4-phenylbutylaminomethylene,
3 , 3-diphenylpropylaminomethylene, isobutylaminomethylene,
2- (2-pyridyl) ethylaminomethylene, cyclohexanemethylaminomethylene, 3 -methoxyphenethylaminomethylene , 3 -phenylbenzylaminomethylene, and piperazinomethylene; and
selected from the group consisting of 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-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-hydroxybenzoy1 , 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- -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- is (trifluoromethyl) benzenesulfonyl ,
3-chloro-4 -fluorobenzenesulfonyl, -trifluoromethylbenzenesulfonyl, -ethylbenzenesulfonyl , pentamethylbenzenesulfonyl , ,3, 4-trifluorobenzenesulfonyl, , 4-dichlorobenzenesulfonyl, ,5-dichlorothiophene-3-sulfonyl , , 6-dichlorobenzenesulfonyl, , 6-difluorobenzenesulfonyl , -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] thiophen e-5-sulfonyl,
2- (benzoylammomethyl) 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-di isopropylbenzene, 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,
1- (carbamyl) -2- (trifluoromethyl) benzene, - (carbamyl) -2-biphenyl, - (carbamyl) -2-bromo-4 , 6-difluorobenzene, - (carbamyl) -2-bromoethane, - (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, - (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-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,
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,
4 ' - (carbamyl) -5 ' -nitrobenzo-15-crown-5,
4 ' - (carbamyl) benzo- 15 -crown- 5,
4 ' - (carbamyl) benzo-18-crown-6 ,
1- carbamyl) -4 , 5-dimethyl-2-nitrobenzene , 1- carbamyl) -4- (6 -methyl -2 -benzothiazolyl) benzene, 1- 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 , 1- (carbamyl) -4-bromo-2-methylbenzene,
1- (carbamyl) -4-bromobenzene,
1- (carbamyl) -4-chloro-2- (trifluoromethyl) benzene,
1- (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, 4- (carbamyl) benzoyl chloride, 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, - (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, 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 ,
1- (thiocarbamyl) - (2 -methoxy-5 -phenyl) benzene, 1- (thiocarbamyl) adamantane, 1- (thiocarbamyl) naphthalenemethane, (thiocarbamyl) naphthalene,
1- (thiocarbamyl) 2, 2-diphenylethane, 1- (thiocarbamyl) -2,3,4, 5-tetrachlorobenzene, - (thiocarbamyl) -2,3, 4-trichlorobenzene, - (thiocarbamyl ) - (2 , 3 , 4 -1rimethoxyphenyl) methane , - (thiocarbamyl) -2,3,5, 6-tetrachlorobenzene, - (thiocarbamyl) -2,3,5, 6-tetrafluorobenzene, - (thiocarbamyl) -2 , 3-dibromopropane, 1- (thiocarbamyl) -2 , 3-dichlorobenzene,
1- (thiocarbamyl) - (2 , 3-dimethoxyphenyl) methane,
1- (thiocarbamyl) -2, 3 -dimethylbenzene,
1- (thiocarbamyl) -2,4,5-trichlorobenzene, 1- (thiocarbamyl) -2,4, 6-tribromobenzene,
1- (thiocarbamyl) -2,4, 6-trichlorobenzene,
1- (thiocarbamyl) -2,4, 6-trifluorobenzene,
1- (thiocarbamyl) -2,4, 6-trimethylbenzene,
1- (thiocarbamyl) -2 , 4-dichlorobenzene, 1- (thiocarbamyl) -2, 4-difluorobenzene,
1- (thiocarbamyl) -2 , 4-dimethoxybenzene,
1- (thiocarbamyl) -2 , 4-dimethylbenzene,
1- (thiocarbamyl) -2 , 5-dibromobenzene,
1- (thiocarbamyl) -2 , 5-dichlorobenzene, 1- (thiocarbamyl) -2 , 5-difluorobenzene,
1- (thiocarbamyl) -2, 5-dimethoxybenzene, 1- (thiocarbamyl) -2 , 5-dimethylbenzene, 1- (thiocarbamyl) -2 , 6-dichlorobenzene, 1- (thiocarbamyl) -2 , 6-diethylbenzene, 1- (thiocarbamyl) -2 , 6-difluorobenzene,
1- (thiocarbamyl) -2 , 6-diisopropylbenzene, 1- (thiocarbamyl) -2 , 6-dimethylbenzene, 1- (thiocarbamyl) -2- (3 , 4-dimethoxyphenyl) ethane, 1- (thiocarbamyl) -2- (4-chlorophenyl) ethane, 1- (thiocarbamyl) -2- (methylthio) benzene,
1- (thiocarbamyl) -2- (trifluoromethoxy) benzene, 1- (thiocarbamyl) -2- (trifluoromethyl) benzene, 1- (thiocarbamyl) -2-bromo-4-methylbenzene, 1- (thiocarbamyl) -2-bromoethane, 1- (thiocarbamyl) -2-bromobenzene,
1- (thiocarbamyl) -2-chloro-4-methylbenzene, 1- (thiocarbamyl) -2-chloro-4-nitrobenzene, 1- (thiocarbamyl) -2-chloro-5- (trifluoromethyl) benzene , 1- (thiocarbamyl) -2-chloro-5-nitrobenzene, - (thiocarbamyl) -2-chloro-6-methylbenzene, - (thiocarbamyl) - (2-chlorophenyl) methane, - (thiocarbamyl) -2-chloroethane, - (thiocarbamyl) -2-chlorobenzene, - (thiocarbamyl) -2-cyanobenzene, - (thiocarbamyl) -2-ethoxycarbonylbenzene, - (thiocarbamyl) -2-ethoxybenzene, - (thiocarbamyl) -2-ethyl-6- (1-methylpropyl) benzene, - (thiocarbamyl) -2-ethyl-6-isopropylbenzene, - (thiocarbamyl) -2-ethyl-6-methylbenzene, - (thiocarbamyl) -2-ethylbenzene, - (thiocarbamyl) - (2-fluorophenyl) methane, - (thiocarbamyl) -2-fluoroethane, - (thiocarbamyl) -2-fluorobenzene, - (thiocarbamyl) furan, 2- (thiocarbamyl) hexane, - (thiocarbamyl) -2 -iodobenzene, - (thiocarbamyl) -2-isopropyl-6-methylbenzene, - (thiocarbamyl) -2-isopropylbenzene, - (thiocarbamyl) -2-methoxy-4-nitrobenzene, - (thiocarbamyl) -2-methoxy-5-methylbenzene, - (thiocarbamyl) -2-methoxy-5-nitrobenzene, - (thiocarbamyl) - (2-methoxyphenyl) methane, - (thiocarbamyl) -2-methoxyethane, - (thiocarbamyl) -2-methoxybenzene, - (thiocarbamyl) -2-methyl-4-nitrobenzene, - (thiocarbamyl) -2-methyl-5-nitrobenzene, - (thiocarbamyl) - (2-methylphenyl) methane, - (thiocarbamyl) -2-methylbutane, - (thiocarbamyl) -2- (morpholino) ethane, - (thiocarbamyl) -naphthalene, - (thiocarbamyl) pentane, - (thiocarbamyl) -2-phenylethane, - (thiocarbamyl) -2-piperidinoethane, - (thiocarbamylmethyl) -tetrahydrofuran, - (thiocarbamyl) -3,4, 5-trimethoxybenzene, - (thiocarbamyl) -3,4- (ethylenedioxy) benzene, - (thiocarbamyl) -3 , 4-dichlorophenyl) methane, - (thiocarbamyl) -3 , 4-dichlorobenzene, - (thiocarbamyl) - (3 , 4-dimethoxyphenyl) methane, - (thiocarbamyl) -3 , 4-dimethoxybenzene, - (thiocarbamyl) -3 , 4 -dimethylbenzene, - (thiocarbamyl) - (3 , 4-methylenedioxyphenyl) methane, - (thiocarbamyl) -3, 4-methylenedioxybenzene, - (thiocarbamyl) -3 , 5-bis (trifluoromethyl) benzene, - (thiocarbamyl) -3 , 5-dichlorobenzene, - (thiocarbamyl) -3, 5-dimethoxybenzene, - (thiocarbamyl) -3 , 5-dimethylbenzene, - (thiocarbamyl) -3- (diethylamino) propane, - (thiocarbamyl) -3- (methylthio) benzene, - (thiocarbamyl) -3- (trifluoromethyl) benzene, - (thiocarbamyl) -3-acetylbenzene, - (thiocarbamyl) -3-benzyloxybenzene, - (thiocarbamyl) -3-bromobenzene, - (thiocarbamyl) -3-bromopropane, - (thiocarbamyl) -3-carboxybenzene, - (thiocarbamyl) -3-chloro-2-methylbenzene, - (thiocarbamyl) -3 -chloro-4 -fluorobenzene, - (thiocarbamyl) - (3 -chloro-4 -methylphenyl) methane, - (thiocarbamyl) -3 -chloro-4 -methylbenzene, - (thiocarbamyl) - (3 -chlorophenyl ) methane , - (thiocarbamyl) -3-chlorobenzene, - (thiocarbamyl) -3-chloropropane, - (thiocarbamyl) -3-cyanobenzene, - (thiocarbamyl) -3-dimethylaminopropane, - (thiocarbamyl) -3-ethoxycarbonylbenzene, - (thiocarbamyl) -3-ethylbenzene, - (thiocarbamyl) - (3-fluorophenyl) methane, - (thiocarbamyl) -3-fluorobenzene, - (thiocarbamyl) -3 -iodobenzene, - (thiocarbamyl) - (3-methoxyphenyl) methane, - (thiocarbamyl) -3-methoxycarbonylbenzene, - (thiocarbamyl) -3 -methoxybenzene, - (thiocarbamyl) -3-methoxypropane, - (thiocarbamyl) -3 -methyl-2 -butane, - (thiocarbamyl) - (3 -methylphenyl) methane, - (thiocarbamyl) -3-methylbutane, - (thiocarbamyl) -3-morpholinopropane, 1- (thiocarbamyl) -3 -nitrobenzene, 1- (thiocarbamyl) -3 -pentane, 1- (thiocarbamyl) -3-phenylpropane, 3- (thiocarbamyl) pyridine, 1- (thiocarbamyl) -4- (benzyloxy) benzene,
1- (thiocarbamyl) -4- (dimethylamino) benzene, 1- (thiocarbamyl) -4- (methylthio) benzene, 1- (thiocarbamyl) -4- (trifluoromethoxy) benzene, 1- (thiocarbamyl) -4- (trifluoromethyl) benzene, 1- (thiocarbamyl) -4-acetylbenzene,
1- (thiocarbamyl) -4-bromo-2 ,
6-dimethylbenzene,
1- (thiocarbamyl) -4-bromo-2-chlorobenzene,
1- (thiocarbamyl) -4 -bromo-2 -methylbenzene,
1- (thiocarbamyl) -4 -bromo-2 -trifluoromethylbenzene, 1- (thiocarbamyl) -4-bromobenzene,
1- (thiocarbamyl) -4-carboxybenzene,
1- (thiocarbamyl) -4-chloro-2- (trifluoromethyl) benzene
, 1- (thiocarbamyl) -4-chloro-2-methylbenzene, - (thiocarbamyl) -4 -chloro-3 -nitrobenzene, - (thiocarbamyl) -4 -chloro-3 -trifluoromethylbenzene, - (thiocarbamyl) - (4-chlorophenyl) methane, - (thiocarbamyl) -4-chlorobenzene, - (thiocarbamyl) -4-cyanobenzene, - (thiocarbamyl) -4-diethylaminobenzene, - (thiocarbamyl) -4-ethoxycarbonylbenzene, - (thiocarbamyl) -4-ethoxybenzene, - (thiocarbamyl) -4-ethylbenzene, - (thiocarbamyl) -4-fluoro-2-methylbenzene, - (thiocarbamyl) - (4-fluorophenyl) ethane , - (thiocarbamyl) - (4-fluorophenyl) methane, - (thiocarbamyl) -4-fluorobenzene, - (thiocarbamyl) -4 -iodobenzene, - (thiocarbamyl) -4 -isopropylbenzene, - (thiocarbamyl) -4 -methoxy-2 -methylbenzene, - (thiocarbamyl) -4 -methoxy-2 -nitrobenzene, - (thiocarbamyl) - (4-methoxyphenyl) methane, - (thiocarbamyl) -4-methoxycarbonylbenzene, 1- (thiocarbamyl) -4 -methoxybenzene,
1- (thiocarbamyl) -4-methyl-2-nitrobenzene,
1- (thiocarbamyl) - (4 -methylphenyl) methane,
1- (thiocarbamyl) -4-n-butyl-2-methylbenzene, 1- (thiocarbamyl) -4-n-butylbenzene,
1- (thiocarbamyl) -4 -nitrobenzene,
1- (thiocarbamyl) -4-phenoxybenzene,
1- (thiocarbamyl) -4-phenylazobenzene,
1- (thiocarbamyl) -4-phenylbutane, 1- (thiocarbamyl) -4-sulfamoylbenzene,
1- (thiocarbamyl) -4-tert-butylbenzene,
1- (thiocarbamyl) -5-chloro-2 , 4-dimethoxybenzene,
1- (thiocarbamyl) -5-chloro-2 -methoxybenzene,
1- (thiocarbamyl) -5-chloro-2-methylbenzene, 1- (thiocarbamyl) -5-fluoro-2 -methylbenzene,
1- (thiocarbamyl) -5-indane,
2- (thiocarbamyl) -5-norbornene,
2- (thiocarbamyl) -6-methylheptane,
9- (thiocarbamyl) acridine, 1- (thiocarbamyl) -2 -propene,
1- (thiocarbamyl) - (1-phenyl) ethane,
1- (thiocarbamyl) -phenylmethane,
1- (thiocarbamyl) -cycloheptane,
1- (thiocarbamyl) -cyclohexylmethane, 1- (thiocarbamyl) -cyclohexane,
1- (thiocarbamyl) -cyclooctane, 1- (thiocarbamyl) -cyclopentane, 1- (thiocarbamyl) -cyclopropane, diethyl L-2-thiocarbamyl-glutarate, dimethyl L-thiocarbamyl-succinate, ethyl 2-thiocarbamylpropionate, ethyl 3-thiocarbamylbutyrate, ethyl 3-thiocarbamylpropionate, ethyl
4-thiocarbamylbutyrate, 1- (thiocarbamyl) -ethane, ethyl thiocarbamylacetate,
1- (thiocarbamyl) -2-methylpropane, 1- (thiocarbamyl) -l-methylethane, thiocarbamylacetaldehyde dimethyl acetal, thiocarbamylphenyl sulfone,
1- (thiocarbamyl) -2-butene,
1- (thiocarbamyl) -methoxymethane, methyl 2 -thiocarbamylacetate, methyl
2-thiocarbamylbenzoate, methyl
3 -thiocarbamylpropionate, methyl
2-thiocarbamylbutyrate, methyl, methyl
L-2-thiocarbamyl-3 -methyl-butyrate , methyl L-2-thiocarbamyl-3-phenyl-propionate, methyl
L-2-thiocarbamyl-4- (methylthio) butyrate, methyl
L-2-thiocarbamyl-4-methylvalerate,
1- (thiocarbamyl) -pentane, 1- (thiocarbamyl) -butane,
1- (thiocarbamyl) -hexane, 1- (thiocarbamyl) -propane, 2- (thiocarbamyl) -norbornane,
1- (thiocarbamyl) -4-vinylbenzene,
1- (thiocarbamyl) -pentafluorobenzene,
1- (thiocarbamyl) -benzene, 1- (thiocarbamyl) -propyne and 2- (thiocarbamyl) -butane.
7. A combinatorial library of two or more compounds of the structure:
Figure imgf000204_0001
Formula (I)
wherein:
T, U and V are independently selected from an oxygen, sulfur or nitrogen atom, provided that at least two of T, U and V are a nitrogen atom; selected from the group consisting of H,
-NHC(0)NR!R2, -C02R1# -ORlf -NR:R2, -C^NR^, and -CH2NR1R2, wherein R: is a hydrogen atom or a functionalized resin, and R2 is 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, substituted heterocycle, the formulae:
Figure imgf000205_0001
Figure imgf000205_0002
Figure imgf000205_0003
wherein Q is a hydrogen atom or functionalized resin;
selected from the group consisting of C to C12 alkylene, Cx to C12 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C cycloalkenylene, C5 to C7 substituted cycloalkenylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C7 to C12 phenylalkylene, C7 to C12 substituted phenylalkylene, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy,
the formula :
-(CH2)m-G-(CH2)n-
wherein m and n are integers independently selected from 0 to 6 , provided that m and n are not together 0; and G is selected from phenylene and substituted phenylene,
the formula :
- (CH2)m-NR3- (CH2)n-
wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and R3 is selected from the group consisting of a hydrogen atom, C to C6 alkyl, C: to C6 substituted alkyl, Cx to C7 acyl,
Cx to C7 substituted acyl, C2 to C4 alkyl sulfonyl, Cx to C4 substituted alkyl sulfonyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl , phenylaminothiocarbonyl , substituted phenylaminothiocarbonyl, Cx to C7 alkoxycarbonyl, Cx to C7 substituted alkoxycarbonyl, phenoxycarbonyl and substituted phenoxycarbonyl ,
the formula :
Figure imgf000207_0001
wherein n is an integer selected from 0 to 6; R4 and R5 are together or independently 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 C 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, a heterocyclic ring, substituted heterocyclic ring, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to CI2 phenylalkoxy, C7 to C12 substituted phenylalkoxy, 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, carboxy, protected carboxy, hydroxymethyl and protected hydroxymethyl; and G is selected from phenylene and substituted phenylene, and
the formula:
Figure imgf000208_0001
(Ill)
wherein J and K are each selected from the group consisting of phenylene and substituted phenylene, and m and n are independently selected from 0 and 1, and
the formulae (IV) and (V) :
Figure imgf000208_0002
(IV) (V) and
absent or is selected from the group consisting of the formula:
Figure imgf000209_0001
wherein:
R4 and R5 are together or independently selected from the group consisting of a hydrogen atom, C: to C6 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C to C6 substituted alkyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, C: to C7 acyl, Cx 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, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy, 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, carboxy, protected carboxy, hydroxymethyl and protected hydroxymethyl, the formulae (Via) and (Vib)
Figure imgf000210_0001
(Vla) (vib)
wherein in formula (Via) m and n are independently selected from O, 1, 2, 3 and 4; and wherein in formula (VIb) m is selected from O, 1, 2, 3 and 4;
the formula:
Figure imgf000210_0002
wherein R6 is selected from the group consisitng of a hydrogen atom, amino, amino-protecting group, -NR7R8, carboxy, carboxy-protecting group, -C(0)NR7R8, wherein R7 and R8 are independently selected from a hydrogen atom, Cx to C6 alkyl, Cα to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl , phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and m and n are independently selected from 0, 1, 2, 3 and 4 ,- and
the formulae (VII) to (XIII) :
Figure imgf000211_0001
(XIII) wherein q is 1 or 2; r is 0 or 1; s and t are independently selected from 0, 1 or 2; and R7 and R8 are independently selected from a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to
C12 substituted phenylalkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and
R9 is selected from a hydrogen atom, -OH, hydroxy-protecting group, Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 alkoxy, Ci to C7 phenylalkoxy, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; and
absent or is selected from the group consisting of a hydrogen atom, -OH, -C02H, -C(0)NR7R8 and -NR7R8, wherein R7 and R8 are independently selected from a functionalized resin, a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, C to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cj to C4 alkylsulfonyl, C: to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl, and the formulae :
Figure imgf000213_0001
wherein R9 and R10 are independently selected from a hydrogen atom, Cx to C6 alkyl, C: to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to
C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Ci to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, C: to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl , phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and s is an integer selected from 1 to 5 ;
a pharmaceutically acceptable salt of a compound thereof; or
a biologically active ester form of a compound thereof.
8. The combinatorial library of claim 7, wherein one of T, U and V is oxygen and the other two positions are each nitrogen.
9. The combinatorial library of claim 8, wherein U is oxygen, T is nitrogen and V is nitrogen.
10. The combinatorial library of claim 7, wherein
Xx is selected from the group consisitng of -C02Rι, -ORx,
Figure imgf000214_0001
and the formulae :
Figure imgf000214_0002
Figure imgf000214_0003
X2 is selected from the group consisting of C to C12 alkylene, Cx to C12 substituted alkylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C7 to C12 phenylalkylene, C7 to C12 substituted phenylalkylene,
the formula :
-(CH2)m-NR3-(CH2)n-
wherein m is 1 to 3 and n is 1 to 4, and the formula :
Figure imgf000215_0001
wherein n is 0 or 1; R4 and R5 are together or independently a hydrogen atom, Cx to C6 alkyl or Cj to C10 substituted alkyl,
and the formula:
Figure imgf000215_0002
(III)
wherein m and n are integers independently selected from 0 and 1;
absent or the formula:
Figure imgf000216_0001
wherein:
R4 and R5 are together or independently selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C7 to C12 substituted phenylalkyl, substituted phenyl, hydroxymethyl, protected hydroxymethyl, C3 to C7 cycloalkyl, C3 to C7 substituted cycloalkyl,
the formula :
Figure imgf000216_0002
(Vlb)
wherein m is 0,
and the formula:
Figure imgf000216_0003
wherein m is 0 to 2 and n is 1 to 4; and where X3 is absent, X4 is selected from the group consisting of the formulae:
Figure imgf000217_0001
(VII) (XI)
Figure imgf000217_0002
wherein R9 is selected from a hydrogen atom and -OH.
11. The combinatorial library of claim 7, wherein;
X is selected from the group consisting of -CO^, -0Rα,
Figure imgf000217_0003
and the formula :
Figure imgf000218_0001
12. The combinatorial library of claim 9, wherein:
Xx is selected from the group consisting of OH, CONH2,
2- (1-pyrrolidino) ethylamine, 2-pyridinemethylamine,
2- (4-imidazole) ethylamine, cyclopentylamine, allylamine, 2-methoxyethylamine, (+/-) -tetrahydrofurylamine, benzyiamine, 2-methylbenzylamine, 3-methylbenzylamine,
4-methylbenzylamine, 2-fluorobenzylamine,
3-fluorobenzylamine, 4-fluorobenzylamine,
3- (1-imidazole) propylamine,
4-aminomethylbenzylamine, 4 -methoxybenzylamine, 3-chlorobenzylamine, 3-bromobenzylamine,
4-bromobenzylamine, cyclopropylamine , cyclopropanemethylamine, 4-pyridinemethylamine,
3-pyridinemethylamine, 2-thiophenemethylamine, phenethylamine, 2- (morpholine) ethylamine, 3- methoxybenzylamine, piperonylamine,
4-methoxyphenethylamine, 2-fluorophenethylamine,
2- (4-chlorophenyl) ethylamine,
2- (3 -chlorophenyl) ethylamine,
2- (2-chlorophenyl) ethylamine, 2,3-dimethoxy- benzyiamine, 3 , 4-dimethoxyphenethylamine, 2,4- dichlorophenethylamine, 2- (diethylamino) ethylamine,
2- (l-methylpyrrolidin-2-yl) ethylamine,
3- (diethylamino) propylamine,
2- (5-nitro-2-pyridyl) ethylamine, 3- (dimethylamino) -2 , 2-dimethylpropylamine,
3- (dimethylamino) propylamine, 2-aminoethylamine,
2- (piperidino) ethylamine, isoamylamine, 3 -ethoxypropylamine, 3 - (2 -pipecolinyl ) propylamine, 3 -butoxypropylamine ,
3- (pyrrolidin-2-one-l-yl) propylamine, 3- (morpholino) propylamine, 2- (N-ethyl-3-methylanilino) ethylamine, 3-phenyl-l- propylamine, 2 -methyl-2 -phenylethylamine , 4 -phenylbutylamine , 3 , 3 -diphenylpropylamine , isobutylamine, 2- (2 -pyridyl) ethylamine, cyclohexanemethylamine , 3 -methoxyphenethylamine , 3-phenylbenzylamine, and piperazine;
selected from the group consisting of methylene, 1, 1-cyclopropyl, 1, 3 -phenylene, 1, 4-phenylene, 1-methyl-l- (4-oxyphenylene) ethane, 3-methoxy-1, 4-phenylene, 2-fluoro-1, -phenylene, 4 , 4 ' -biphenylene, 1, 2-phenylene, 3 , 5-dibromo-l, 4-phenylene, 4-phenyl-l- (methylene-1-yl) ,
3 , 5-diiodo-l, 4-phenylene, 3-hydroxy-1 , 4-phenylene, 2,3,5, 6 -tetrafluoro-1, 4-phenylene, 3 -bromo-1, 4 -phenylene, 3,5-di-tert- butyl-1,4 -phenylene,
3, 5-di-tert-butyl-4-phenyl-l- (methylene-1-yl) , 3 -methoxy-4-phenyl-l- (methylene-1-yl) , 3 -nitro-1, 4-phenylene, 5-hydroxy-1, 3 -phenylene, 4-phenyl-l- (-2-ethyl) ,
3-ethoxy-4-phenyl-l- (methylene-1-yl) ,
2-chloro-1, 4-phenylene, 2-fluoro-1, 4-phenylene,
3, 5-dimethyl-l, 4-phenylene,
2, 6-dimethyl-1, 4-phenylene, , 5-dichloro-1,4 -phenylene, -methoxy-2-phenyl-1- (methylene-1-yl) , -quinoline-2-yl, 5-indole-3- (methylene-1-yl) , , hydroxy-4-phenyl-l- (methylene-1-yl) , -chloro- 1, 2-phenylene, 6-nitro-l, 2-phenylene, -nitro-1, 2-phenylene, -amino-l, 4-phenylene, 2-carboxymethyl-l, 4-phenylene, 3 -bromo-5-methoxy-4-phenyl-l- (methylene-1-yl) , 3 , 5-dimethoxy-4-phenyl-1- (methylene-1-yl) , 2-iodo-6-nitro-l, 4-phenylene;
selected from the group consisting of 1-aminomethylene,
1- (1-aminoethyl) ,1- (2-aminoethyl) ,
1- (l-amino-2- (3 -pyridyl) ethyl) ,
1- (l-amino-2- (2-thienyl) ethyl) , 1- (1-aminopropyl) ,
1- (3-aminopropyl) , 1- (5-aminopentyl) , 1- (1-methyl-l-aminoethyl) ,
1- (4-aminomethylcyclohexyl) ,
1- (l-amino-3-guanidinopropyl) , 3- (3-aminopropionic acid) , 3- (2-aminopropionic acid) ,
3-methylene-l-phenyl-l, 3 , 8-triazaspiro [4.5] decane-4- one, 1- (l-amino-2- (4-chlorophenyl) ethyl) ,
1- (l-amino-2- (cyclohexyl) ethyl) , 4- (4-aminobutyric acid), 4- (2-aminobutyric acid),
1- (l-amino-2- (4-imidazolyl) ethyl) ,
1- (l-amino-2-methylbutyl) , 4-piperidinyl , 1- (l-amino-3-methylbutyl) , 3-piperidinyl,
1- (1-aminobutyl) , 1- (l-amino-2-phenylethyl) ,
2-piperidinyl, 2-pyrrolidinyl,
1- (l-amino-2-hydroxyethy1) , 4-thiazolidinyl,
1- (l-amino-2-hydroxypropyl) , 3-tetrahydroisoquinolinyl,
1- (l-amino-2- (3-indolyl) ethyl) ,
1- (l-amino-2- (4-hydroxyphenyl) ethyl) ,
1- (l-amino-2- (4-ethoxyphenyl) ethyl) , 1- (l-amino
-2-methylpropyl) , 1- (1, 5-diaminopentyl) , 2- (1-pyrrolidino) ethylaminomethylene,
2-pyridinemethylaminomethylene,
2- (4-imidazole) ethylaminomethylene, cyclopentylaminomethylene, allylaminomethylene, 2-methoxyethylaminomethylene, (+/-) -tetrahydrofurylaminomethylene, benzylaminomethylene, 2-methylbenzylaminomethylene, 3-methylbenzylaminomethylene, 4-methylbenzylaminomethylene,
2-fluorobenzylaminomethylene,
3-fluorobenzylaminomethylene, 4-fluorobenzylaminomethylene,
3- (1-imidazole) propylaminomethylene ,
4-aminomethylbenzylaminomethylene, 4-methoxybenzylaminomethylene,
3 -chlorobenzylaminomethylene, 3-bromobenzylaminomethylene,
4-bromobenzylaminomethylene, cyclopropylaminomethylene, cyclopropanemethylaminomethylene,
4-pyridinemethylaminomethylene, 3-pyridinemethylaminomethylene,
2-thiophenemethylaminomethylene, phenethylaminomethylene,
2- (morpholine) ethylaminomethylene, 3- methoxybenzylaminomethylene, piperonylaminomethylene,
4-methoxyphenethylaminomethylene,
2-fluorophenethylaminomethylene,
2- (4-chlorophenyl) ethylaminomethylene, 2- (3-chlorophenyl) ethylaminomethylene, 2- (2-chlorophenyl) ethylaminomethylene, 2 , 3-dimethoxy- benzylaminomethylene, 3 , 4-dimethoxyphenethylaminomethylene, 2,4- dichlorophenethylaminomethylene, 2- (diethylamino) ethylaminomethylene, 2- (1-methylpyrrolidin-2-yl) ethylaminomethylene,
3- (diethylamino) propylaminomethylene,
2- (5-nitro-2-pyridyl) ethylaminomethylene,
3- (dimethylamino) -2, 2-dimethylpropylaminomethylene, 3- (dimethylamino) propylaminomethylene, 2-aminoethylaminomethylene,
2- (piperidino) ethylaminomethylene, isoamylammomethylene, 3-ethoxypropylaminomethylene, 3 - (2-pipecolinyl)propylaminomethylene,
3 -butoxypropylaminomethylene,
3- (pyrrolidin-2-one-1-yl) propylaminomethylene,
3 - (morpholino) propylaminomethylene, 2- (N-ethyl-3-methylanilino) ethylaminomethylene,
3-phenyl-1- propylaminomethylene ,
2-methyl-2-phenylethylaminomethylene,
4-phenylbutylaminomethylene,
3 , 3-diphenylpropylaminomethylene, isobutylaminomethylene,
2- (2-pyridyl) ethylaminomethylene, cyclohexanemethylaminomethylene,
3 -methoxyphenethylaminomethylene,
3-phenylbenzylaminomethylene, and piperazinomethylene; and
selected from the group consisting of 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) aerylyl, 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-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-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] thiophen e-5-sulfonyl,
2- (benzoylammomethyl) 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-di isopropylbenzene, 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, 1- (carbamyl) -2- (trifluoromethyl) benzene, - (carbamyl) -2-biphenyl, - (carbamyl) -2-bromo-4 , 6-difluorobenzene, - (carbamyl) -2-bromoethane, - (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, - (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, - (carbamyl) -2-fluorobenzene, - (carbamyl) -2-iodobenzene, - (carbamyl) -2-isopropyl-6-methylbenzene, - (carbamyl) -2-isopropylbenzene, - (carbamyl) -2-methoxy-5-chloro benzene, - (carbamyl) -2-methoxy-5-methylbenzene, - (carbamyl) -2-methoxy-5-nitrobenzene, - (carbamyl) -2-methoxybenzene, - (carbamyl) -2-methyl-3-nitrobenzene, - (carbamyl) -2-methyl-5-nitrobenzene, - (carbamyl) -2-methyl-6-t-butylbenzene, - (carbamyl) -1- (2-methylphenyl) methane, - (carbamyl) -2-n-propylbenzene, - (carbamyl) -2-naphthalene, - (carbamyl) -2-nitrobenzene, - (carbamyl) -2-phenoxybenzene, - (carbamyl) -2-tert-butylbenzene, - (carbamyl) -3,4, 5-trimethoxybenzene, - (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, 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,
4 ' - (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, 1- (carbamyl) -4- (difluoromethoxy) benzene,
1- (carbamyl) -4- (methylthio) benzene,
1- (carbamyl) -4- (tert-butyl) benzene,
1- (carbamyl) -4- (trifluoromethoxy) benzene, 1- (carbamyl) -4- (trifluoromethyl) benzene,
1- (carbamyl) -4- (trifluoromethylthio) benzene,
1- (carbamyl) -4-acetylbenzene,
1- (carbamyl) -4-benzyloxybenzene,
1- (carbamyl) -4-bromo-2, 6-dimethylbenzene, 1- (carbamyl) -4-bromo-2- (trifluoromethyl) benzene,
1- (carbamyl) -4-bromo-2-chlorobenzene,
1- (carbamyl) -4-bromo-2-fluorobenzene,
1- (carbamyl) -4-bromo-2-methylbenzene,
1- (carbamyl) -4-bromobenzene, 1- (carbamyl) -4-chloro-2- (trifluoromethyl) benzene,
1- (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, 4- (carbamyl) benzoyl chloride, 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,
1- (thiocarbamyl) - (2-methoxy-5-phenyl) benzene, 1- (thiocarbamyl) adamantane, 1- (thiocarbamyl) naphthalenemethane , (thiocarbamyl) naphthalene,
1- (thiocarbamyl) 2 , 2-diphenylethane, 1- (thiocarbamyl) -2,3,4,5-tetrachlorobenzene, 1- (thiocarbamyl) -2,3, 4-trichlorobenzene, 1- (thiocarbamyl)- (2, 3 , 4-trimethoxyphenyl) methane, - (thiocarbamyl) -2,3,5, 6-tetrachlorobenzene, - (thiocarbamyl) -2,3,5, 6-tetrafluorobenzene, - (thiocarbamyl) -2 , 3-dibromopropane, - (thiocarbamyl) -2, 3-dichlorobenzene, - (thiocarbamyl) - (2 , 3-dimethoxyphenyl) methane, - (thiocarbamyl) -2 , 3 -dimethylbenzene, - (thiocarbamyl) -2,4, 5-trichlorobenzene, - (thiocarbamyl) -2,4, 6-tribromobenzene, - (thiocarbamyl) -2,4, 6-trichlorobenzene, - (thiocarbamyl) -2,4, 6-trifluorobenzene, - (thiocarbamyl) -2,4, 6-trimethylbenzene, - (thiocarbamyl) -2 , 4-dichlorobenzene, - (thiocarbamyl) -2 , 4-difluorobenzene, - (thiocarbamyl) -2 , 4-dimethoxybenzene, - (thiocarbamyl) -2 , 4-dimethylbenzene, - (thiocarbamyl) -2 , 5-dibromobenzene, - (thiocarbamyl) -2, 5-dichlorobenzene, - (thiocarbamyl) -2, 5-difluorobenzene, - (thiocarbamyl) -2 , 5-dimethoxybenzene, - (thiocarbamyl) -2 , 5-dimethylbenzene, - (thiocarbamyl) -2 , 6-dichlorobenzene, - (thiocarbamyl) -2, 6-diethylbenzene, - (thiocarbamyl) -2, 6-difluorobenzene, - (thiocarbamyl) -2, 6-diisopropylbenzene, - (thiocarbamyl) -2, 6-dimethylbenzene, - (thiocarbamyl) -2- (3,4-dimethoxyphenyl) ethane, - (thiocarbamyl) -2- (4-chlorophenyl) ethane, - (thiocarbamyl) -2- (methylthio) benzene, 1- (thiocarbamyl) -2- (trifluoromethoxy) benzene, 1- (thiocarbamyl) -2- (trifluoromethyl) benzene, 1- (thiocarbamyl) -2-bromo-4-methylbenzene, 1- (thiocarbamyl) -2-bromoethane, 1- (thiocarbamyl) -2-bromobenzene,
1- (thiocarbamyl) -2-chloro-4 -methylbenzene, 1- (thiocarbamyl) -2-chloro-4-nitrobenzene, 1- (thiocarbamyl) -2-chloro-5- (trifluoromethyl) benzene , 1- (thiocarbamyl) -2-chloro-5-nitrobenzene, - (thiocarbamyl) -2-chloro-6-methylbenzene, - (thiocarbamyl) - (2-chlorophenyl) methane, - (thiocarbamyl) -2-chloroethane, - (thiocarbamyl) -2-chlorobenzene, - (thiocarbamyl) -2-cyanobenzene, - (thiocarbamyl) -2-ethoxycarbonylbenzene, - (thiocarbamyl) -2-ethoxybenzene, - (thiocarbamyl) -2-ethyl-6- (1-methylpropyl) benzene, - (thiocarbamyl) -2-ethyl-6-isopropylbenzene, - (thiocarbamyl) -2-ethyl-6-methylbenzene, - (thiocarbamyl) -2-ethylbenzene, - (thiocarbamyl) - (2-fluorophenyl) methane, - (thiocarbamyl) -2-fluoroethane, - (thiocarbamyl) -2-fluorobenzene, - (thiocarbamyl) furan, 2- (thiocarbamyl) hexane, - (thiocarbamyl) -2-iodobenzene, - (thiocarbamyl) -2-isopropyl-6-methylbenzene, - (thiocarbamyl) -2-isopropylbenzene, - (thiocarbamyl) -2-methoxy-4-nitrobenzene, - (thiocarbamyl) -2-methoxy-5-methylbenzene, - (thiocarbamyl) -2-methoxy-5-nitrobenzene, - (thiocarbamyl) - (2-methoxyphenyl) methane, - (thiocarbamyl) -2-methoxyethane, - (thiocarbamyl) -2-methoxybenzene, - (thiocarbamyl) -2-methyl-4-nitrobenzene, - (thiocarbamyl) -2-methyl-5-nitrobenzene, - (thiocarbamyl) - (2-methylphenyl) methane, - (thiocarbamyl) -2-methylbutane, 1- (thiocarbamyl) -2- (morpholino) ethane, 2- (thiocarbamyl) -naphthalene, - (thiocarbamyl) pentane, 1- (thiocarbamyl) -2-phenylethane, - (thiocarbamyl) -2-piperidinoethane, - (thiocarbamylmethyl) -tetrahydrofuran, - (thiocarbamyl) -3,4, 5-trimethoxybenzene, - (thiocarbamyl) -3,4- (ethylenedioxy) benzene, - (thiocarbamyl) -3, 4 -dichlorophenyl) methane, - (thiocarbamyl) -3 , 4-dichlorobenzene, - (thiocarbamyl) - (3, 4-dimethoxyphenyl) methane, - (thiocarbamyl) -3 , 4-dimethoxybenzene, - (thiocarbamyl) -3 , 4 -dimethylbenzene, - (thiocarbamyl) - (3 , 4-methylenedioxyphenyl) methane, - (thiocarbamyl) -3 , 4-methylenedioxybenzene, - (thiocarbamyl) -3 , 5-bis (trifluoromethyl) benzene, - (thiocarbamyl) -3 , 5-dichlorobenzene, - (thiocarbamyl) -3 , 5-dimethoxybenzene, - (thiocarbamyl) -3 , 5-dimethylbenzene, - (thiocarbamyl) -3- (diethylamino) propane, - (thiocarbamyl) -3- (methylthio) benzene, - (thiocarbamyl) -3- (trifluoromethyl) benzene, - (thiocarbamyl) -3-acetylbenzene, - (thiocarbamyl) -3-benzyloxybenzene, - (thiocarbamyl) -3-bromobenzene, - (thiocarbamyl) -3-bromopropane, - (thiocarbamyl) -3-carboxybenzene, - (thiocarbamyl) -3 -chloro-2 -methylbenzene, - (thiocarbamyl) -3-chloro-4-fluorobenzene, - (thiocarbamyl) - (3 -chloro-4 -methylphenyl) methane, - (thiocarbamyl) -3 -chloro-4 -methylbenzene, - (thiocarbamyl) - (3 -chlorophenyl) methane, - (thiocarbamyl) -3-chlorobenzene, - (thiocarbamyl) -3-chloropropane, - (thiocarbamyl) -3-cyanobenzene, - (thiocarbamyl) -3-dimethylaminopropane, - (thiocarbamyl) -3-ethoxycarbonylbenzene, 1- (thiocarbamyl) -3-ethylbenzene,
1- (thiocarbamyl) - (3-fluorophenyl) methane,
1- (thiocarbamyl) -3-fluorobenzene,
1- (thiocarbamyl) -3 -iodobenzene, 1- (thiocarbamyl ) - (3 -methoxyphenyl) methane ,
1- (thiocarbamyl) -3-methoxycarbonylbenzene,
1- (thiocarbamyl) -3 -methoxybenzene,
1- (thiocarbamyl) -3-methoxypropane,
1- (thiocarbamyl) -3 -methyl-2-butane, 1- (thiocarbamyl ) - (3 -methylphenyl ) methane ,
1- (thiocarbamyl) -3-methylbutane,
1- (thiocarbamyl) -3-morpholinopropane,
1- (thiocarbamyl) -3 -nitrobenzene,
1- (thiocarbamyl) -3 -pentane, 1- (thiocarbamyl) -3-phenylpropane,
3- (thiocarbamyl) pyridine,
1- (thiocarbamyl) -4- (benzyloxy) benzene,
1- (thiocarbamyl) -4- (dimethylamino) benzene,
1- (thiocarbamyl) -4- (methylthio) benzene, 1- (thiocarbamyl) -4- (trifluoromethoxy) benzene,
1- (thiocarbamyl) -4- (trifluoromethyl) benzene,
1- (thiocarbamyl) -4-acetylbenzene,
1- (thiocarbamyl) -4 -bromo-2 , 6-dimethylbenzene,
1- (thiocarbamyl) -4-bromo-2-chlorobenzene, 1- (thiocarbamyl) -4 -bromo-2 -methylbenzene,
1- (thiocarbamyl) -4-bromo-2-trifluoromethylbenzene,
1- (thiocarbamyl) -4-bromobenzene,
1- (thiocarbamyl) -4-carboxybenzene,
1- (thiocarbamyl) -4-chloro-2- (trifluoromethyl) benzene , 1- (thiocarbamyl) -4 -chloro-2 -methylbenzene, - (thiocarbamyl) -4-chloro-3-nitrobenzene, - (thiocarbamyl) -4-chloro-3-trifluoromethylbenzene, - (thiocarbamyl) - (4 -chlorophenyl) methane, - (thiocarbamyl) -4-chlorobenzene, - (thiocarbamyl) -4 -cyanobenzene, - (thiocarbamyl) -4-diethylaminobenzene, - (thiocarbamyl) -4-ethoxycarbonylbenzene, 1- (thiocarbamyl) -4-ethoxybenzene,
1- (thiocarbamyl) -4-ethylbenzene,
1- (thiocarbamyl) -4-fluoro-2-methylbenzene,
1- (thiocarbamyl) - (4-fluorophenyl) ethane , 1- (thiocarbamyl) - (4-fluorophenyl) methane,
1- (thiocarbamyl) -4-fluorobenzene,
1- (thiocarbamyl) -4-iodobenzene, - (thiocarbamyl) -4-isopropylbenzene, - (thiocarbamyl) -4 -methoxy-2-methylbenzene, - (thiocarbamyl) -4 -methoxy-2-nitrobenzene, - (thiocarbamyl) - (4-methoxyphenyl) methane, - (thiocarbamyl) -4-methoxycarbonylbenzene, - (thiocarbamyl) -4 -methoxybenzene, - (thiocarbamyl) -4-methyl-2-nitrobenzene, - (thiocarbamyl) - (4-methylphenyl) methane, - (thiocarbamyl) -4 -n-butyl-2-methylbenzene, - (thiocarbamyl) -4-n-butylbenzene, - (thiocarbamyl) -4 -nitrobenzene, - (thiocarbamyl) -4-phenoxybenzene, - (thiocarbamyl) -4-phenylazobenzene, - (thiocarbamyl) -4-phenylbutane, - (thiocarbamyl) -4-sulfamoylbenzene, - (thiocarbamyl) -4-tert-butylbenzene, - (thiocarbamyl) -5-chloro-2 , 4-dimethoxybenzene, - (thiocarbamyl) -5-chloro-2-methoxybenzene, - (thiocarbamyl) -5-chloro-2-methylbenzene, - (thiocarbamyl) -5-fluoro-2-methylbenzene, - (thiocarbamyl) -5-indane, - (thiocarbamyl) -5-norbornene, - (thiocarbamyl) -6-methylheptane, - (thiocarbamyl) acridine, - (thiocarbamyl) -2-propene, - (thiocarbamyl) - (1-phenyl) ethane, - (thiocarbamyl) -phenylmethane, - (thiocarbamyl) -cycloheptane, - (thiocarbamyl) -cyclohexylmethane, - (thiocarbamyl) -cyclohexane, 1- (thiocarbamyl) -cyclooctane,
1- (thiocarbamyl) -cyclopentane,
1- (thiocarbamyl) -cyclopropane, diethyl
L-2 -thiocarbamyl-glutarate , dimethyl L-thiocarbamyl-succinate, ethyl
2-thiocarbamylpropionate, ethyl
3-thiocarbamylbutyrate, ethyl
3-thiocarbamylpropionate, ethyl
4-thiocarbamylbutyrate, 1- (thiocarbamyl) -ethane, ethyl thiocarbamylacetate,
1- (thiocarbamyl) -2-methylpropane,
1- (thiocarbamyl) -1-methylethane, thiocarbamylacetaldehyde dimethyl acetal, thiocarbamylphenyl sulfone, 1- (thiocarbamyl) -2 -butene,
1- (thiocarbamyl) -methoxymethane, methyl
2 -thiocarbamylacetate, methyl
2-thiocarbamylbenzoate, methyl
3-thiocarbamylpropionate , methyl 2-thiocarbamylbutyrate, methyl, methyl
L-2 -thiocarbamyl-3 -methyl-butyrate, methyl
L-2 -thiocarbamyl-3 -phenyl-propionate , methyl
L-2-thiocarbamyl-4- (methylthio) butyrate, methyl
L-2 -thiocarbamyl-4-methylvalerate, 1- (thiocarbamyl) -pentane, 1- (thiocarbamyl) -butane,
1- (thiocarbamyl) -hexane, 1- (thiocarbamyl) -propane, 2- (thiocarbamyl) -norbornane,
1- (thiocarbamyl) -4-vinylbenzene, 1- (thiocarbamyl) -pentafluorobenzene, 1- (thiocarbamyl) -benzene, 1- (thiocarbamyl) -propyne and 2- (thiocarbamyl) -butane.
13. A method for preparing the combinatorial library of claim 9, comprising: (a) reacting one or more resin-bound amines with one or more nitrile-containing carboxylic acids, nitrile-containing isocyanates or nitrile-containing radicals with a leaving group to obtain two or more resin-bound nitriles;
(b) cyclizing the resin-bound nitriles to obtain oxadiazoles containing an amino- protected group; and
(c) deprotecting the amino-protected group to obtain oxadiazole a combinatorial library of two or more oxadiazole amine compounds .
14. The method of claim 13, further comprising step (d) , reacting the oxadiazole amine compounds with one or more carboxylic acid, sulfonyl chloride, isocyanate or isothiocyanate containing compounds to obtain a combinatorial library of two or more oxadiazole compounds .
15. A method for preparing the combinatorial library of claim 9, comprising:
(a) reacting one or more resin-bound amines with one or more nitrile-containing carboxylic acids, nitrile-containing isocyanates or nitrile-containing radicals with a leaving group to obtain two or more resin-bound nitriles;
(b) cyclizing the nitriles to obtain oxadiazoles containing a leaving group; and
(c) reacting the leaving group with a primary amine or secondary amine to obtain a combinatorial library of two or more oxadiazole secondary amine or oxadiazole tertiary amine compounds.
16. The method of claim 15, further comprising step (d) , reacting the secondary oxadiazole amine compounds with one or more carboxylic acid, sulfonyl chloride, isocyanate or isothiocyanate containing compounds to obtain a combinatorial library of two or more oxadiazole compounds .
17. The method of claim 15, wherein the resin- bound amine is prepared by displacing a resin-bound leaving group with a primary amine .
18. The method of claim 15, wherein the resin- bound amine is prepared by reducing a resin-bound imine formed from either a resin-bound aldehyde with a primary amine or a resin-bound primary amine with an aldehyde.
19. A method for preparing the combinatorial library of claim 9, comprising:
(a) reacting one or more resin-bound leaving groups with one or more nitrile-containing phenoxide ions or amines to obtain two or more resin-bound nitriles;
(b) cyclizing the nitriles to obtain oxadiazoles containing an amino-protected group; and
(c) deprotecting the amino-protected group to obtain a combinatorial library of two or more oxadiazole compounds .
20. The method of claim 19, further comprising step (d) , reacting the oxadiazole amine compounds with one or more carboxylic acid, sulfonyl chloride, isocyanate or isothiocyanate containing compounds to obtain a combinatorial library of two or more oxadiazole compounds .
21. A method for preparing the combinatorial • library of claim 9, comprising:
(a) reacting one or more resin-bound leaving groups with one or more nitrile-containing phenoxide ions or amines to obtain two or more resin-bound nitriles;
(b) cyclizing the nitriles to obtain oxadiazoles containing a leaving group; and
(c) reacting the leaving group with a primary amine or secondary amine to obtain a combinatorial library of two or more oxadiazole secondary amines or oxadiazole tertiary amines.
22. The method of claim 21, further comprising step (d) , reacting the secondary oxadiazole amine compounds with one or more carboxylic acid, sulfonyl chloride, isocyanate or an isothiocyanate containing compounds to obtain a combinatorial library of two or more oxadiazole compounds.
23. A method for preparing the combinatorial library of claim 9, comprising:
(a) reducing an imine formed between one or more resin-bound aldehydes and one or more amines containing a protected carboxylic acid to obtain two or more protected carboxylic acids bound to resin;
(b) deprotecting the protected carboxylic acids to obtain resin bound carboxylic acids; and
(c) reacting the resin bound carboxylic acids with one or more amidoxime containing compounds to obtain a combinatorial library of two or more oxadiazole compounds .
24. A method for preparing the combinatorial library of claim 9, comprising:
(a) reacting one or more resin-bound alcohols with one or more amines containing a protected carboxylic acid to obtain two or more protected carboxylic acids bound to resin through a carbamate linkage ,-
(b) deprotecting the resin-bound protected carboxylic acids to obtain resin bound carboxylic acids; and
(c) reacting the resin-bound carboxylic acids with one or more amidoxime containing compounds to obtain a combinatorial library of two or more oxadiazole compounds . AMENDED CLAIMS
[received by the International Bureau on 31 March 2000 (31.03.00); original claim 1 amended; new claims 25-27 added; remaining claims unchanged (11 pages)]
1. A single compound of the structure:
Figure imgf000240_0001
Formula (I)
wherein :
5 T, U and V are independently selected from an oxygen, sulfur or nitrogen atom, provided that at least two of T, U and V are a nitrogen atom;
X: is selected from the group consisting of
-NHC(0)NRιR2,-C02Rα, -OR!, -NRαR2, -C(0)NRαR2, and 0 -CH2NR1R2, wherein Rx is a hydrogen atom or a functionalized resin, and R2 is a hydrogen atom, C: to C€ alkyl, Cx to C6 substituted alkyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, 5 C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, the formulae:
--.39
25. A single compound of the structure:
Figure imgf000241_0001
Formula (I)
wherein:
T, U and V are independently selected from an oxygen, sulfur or nitrogen atom, provided that at least two of T, U and V are a nitrogen atom;
Xx is selected from the group consisting of H,
-NHC(0)NR1R2,-C02R1, -ORlf -NR^, -C(0)NR:R2, and -CH^RxR;,, wherein Rx is a hydrogen atom or a functionalized resin, and R2 is a hydrogen atom, Cx to C6 alkyl, C: 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, substituted heterocycle, the formulae:
Figure imgf000242_0001
Figure imgf000242_0002
Figure imgf000242_0003
wherein Q is a hydrogen atom or functionalized resin;
X2 is selected from the group consisting of Cx to C12 alkylene, Cx to C12 substituted alkylene, C2 to C7 alkenylene, C2 to C7 substituted alkenylene, C2 to C7 alkynylene, C3 to C7 cycloalkylene, C3 to C7 substituted cycloalkylene, C5 to C7 cycloalkenylene, C5 to C7 substituted cycloalkenylene, phenylene, substituted phenylene, naphthylene, substituted naphthylene, C7 to C12 phenylalkylene, C7 to C12 substituted phenylalkylene,
the formula: - ( CH2 ) m-G- ( CH2 ) n-
wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and G is selected from phenylene and substituted phenylene,
the formula:
-(CH2)m-NR3-(CH2)n-
wherein m and n are integers independently selected from 0 to 6, provided that m and n are not together 0; and R3 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, C: to C4 alkyl sulfonyl, C: to C, substituted alkyl sulfonyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C6 alkylaminocarbonyl, Cj to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl, substituted phenylaminothiocarbonyl, Cx to C7 alkoxycarbonyl, C: to C7 substituted alkoxycarbonyl, phenoxycarbonyl and substituted phenoxycarbonyl, the formula:
Figure imgf000244_0001
wherein n is an integer selected from 0 to 6; R4 and R5 are together or independently 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, C: 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, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy, 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, carboxy, protected carboxy, hydroxymethyl and protected hydroxymethyl; and G is selected from phenylene and substituted phenylene, and the formula:
Figure imgf000245_0001
(III)
wherein J and K are each selected from the group consisting of phenylene and substituted phenylene, and m and n are independently selected from 0 and 1, and
the formulae (IV) and (V) :
Figure imgf000245_0002
(IV) (V) and
absent or is selected from the group consisting of the formula:
Figure imgf000245_0003
wherein:
R„ and R5 are together or independently selected from the group consisting of a hydrogen atom, Cx to C6 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, Cx to C6 substituted alkyl, C2 to C7 substituted alkenyl, C2 to C7 substituted alkynyl, Cx to C7 acyl, Cx 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, heteroaryl, substituted heteroaryl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy, 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, carboxy, protected carboxy, hydroxymethyl and protected hydroxymethyl,
the formulae (Via) and (VIb) :
-(CH2)m-0-(CH2)n-C- -(CH2 C(0)-
(Nla) (VIb)
wherein in formula (Via) m and n are independently selected from 0, 1, 2, 3 and 4; and wherein in formula (VIb) m is selected from 0, 1, 2, 3 and 4; the formula:
Figure imgf000247_0001
wherein R6 is selected from the group consisitng of a hydrogen atom, amino, amino- protecting group, -NR7R8, carboxy, carboxy- protecting group, -C(0)NR7R8, wherein R7 and R8 are independently selected from a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and m and n are independently selected from 0, 1, 2, 3 and 4; and the formulae (VII ) to (XI I i ;
Figure imgf000248_0001
wherein q is 1 or 2; r is 0 or 1; s and t are independently selected from 0, 1 or 2; and R7 and R8 are independently selected from a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C:2 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, C to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and R9 is selected from a hydrogen atom, -OH, hydroxy-protecting group, Cx to C6 alkyl, Cx to C6 substituted alkyl, Cx to C7 alkoxy, Cx to C7 phenylalkoxy, phenyl, substituted phenyl, heteroaryl and substituted heteroaryl; and
absent or is selected from the group consisting of a hydrogen atom, -OH, -C02H, -C(0)NR7R8 and -NR7R8, wherein R7 and R8 are independently selected from a functionalized resin, a hydrogen atom, Cx to C6 alkyl, Cx to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, Cx to C7 acyl, Cx to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl,
and the formulae: 4o
Figure imgf000250_0001
wherein R9 and R10 are independently selected from a hydrogen atom, Cx to C6 alkyl, C: to C6 substituted alkyl, C7 to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, C7 to C12 phenylalkoxy, C7 to C12 substituted phenylalkoxy Cx to C7 acyl, C: to C7 substituted acyl, phenylsulfonyl, substituted phenylsulfonyl, Cx to C4 alkylsulfonyl, Cx to C4 substituted alkylsulfonyl, Cx to C6 alkylaminocarbonyl, Cx to C6 substituted alkylaminocarbonyl, phenylaminocarbonyl, substituted phenylaminocarbonyl, Cx to C6 alkylaminothiocarbonyl, Cx to C6 substituted alkylaminothiocarbonyl, phenylaminothiocarbonyl and substituted phenylaminothiocarbonyl; and s is an integer selected from 1 to 5;
a pharmaceutically acceptable salt of a compound thereof; or
a biologically active ester form of a compound thereof.
26. The single compound of claim 25, wherein one of T, U and V is oxygen and the other two positions are each nitrogen.
27. The single compound of claim 26, wherein U is oxygen, T is nitrogen and V is nitrogen.
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