CA2286862A1 - Combinatorial libraries of peptidomimetic aminothioether acids - Google Patents

Abstract

The present invention relates to a novel diverse library of aminothioether compounds and derivatives thereof, processes for the preparation thereof, and to an apparatus providing a readily accessible source of individual members of the library. The apparatus can be used in assay kits and as a replaceable element in automated assay machines.

Description

COMBINATORIAL LIBRARIES OP' PEPTIDOMIMETIC
AMINOTHIOETHER ACIDS
Field of the Invention This Application claims the benefit of U.S. Provisional Application No. 60/043,496, filed April 11, 1997.
The present invention relates to diverse libraries of peptidomimetic aminothioether acid compounds and derivatives thereof, methods of making such libraries, and an apparatus for storing and providing a readily accessible source of diverse peptidomimetic compounds.
The apparatus harboring the present combinatorial libraries is a useful component of assay systems for identifying compounds for drug development.
Background of the Invention Research and development expenses account for a large outlay of capital in the pharmaceutical industry.
Synthesis of compounds is an expensive and time consuming phase of research and development. Historically, research chemists individually synthesized and analyzed high purity compounds for biological screening to develop pharmaceutical leads. Although such methods were successful in bringing new drugs to the market, the limitations of individual synthesis and complete compound characterization considerably slowed the discovery of new pharmaceutically active compounds. The need for more rapid and less expensive drug discovery methodology is increasingly important in today's competitive pharmaceutical industry.

-2 -Recently, modern drug discovery has utilized combinatorial chemistry to generate large numbers (102 -106) of compounds generically referred to as "libraries". _ An important objective of combinatory chemistry is to generate a large number of novel compounds that can be _ screened to identify lead compounds for pharmaceutical research.
Theoretically the total number of compounds which may be produced for a given library is limited only by the number of reagents available to form substituents on the variable positions-on the library's molecular scaffold. The combinatorial process lends itself to automation, both in the generation of compounds and in their biological screening, thereby greatly enhancing the opportunity and efficiency of drug discovery.
Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures with complete identification of the individual compounds postponed until after positive screening results are obtained. However, a preferred form of combinatorial chemistry is "parallel array synthesis", where individual reaction products are simultaneously synthesized, but are retained in separate vessels. For example, the individual library compounds can be prepared, stored, and assayed in separate wells of a microtiter plate, each well containing one member of the parallel array. The use of standardized mi.crotiter plates or equivalent apparatus, is advantageous because such an apparatus is readily accessed by programmed robotic machinery, both during library synthesis and during library sampling or assaying.
Combinatorial chemistry can be carried out in solution phase where both reactants are dissolved in solution or in solid phase where one of the reactants is covalently bound to a solid support. Typically, completion of the solution phase reactions in

-3-combinatorial chemistry schemes are ensured by selecting high yielding chemical reactions and/or by using one reagent in considerable excess. When one reagent is used in excess, completion of the reaction produces a mixture of a soluble product with at least one soluble unreacted reagent. Solid phase synthesis offers the advantage that the solid support bound-products are easily washed free of excess reagent. Solution phase synthesis typically requires use of one or more reaction mixture work up procedures to separate reaction product from unreacted excess reagent.
Combinatorial chemistry may be used at two distinct phases of drug development. In the discovery phase diverse libraries are created to find lead compounds. In a second optimization phase, strong lead compounds are more narrowly modified to find optimal molecular configurations.
Summary of the Invention The present invention is directed to the use of a combinatorial chemistry approach to prepare novel peptidomimetics, and the use of those compounds to identify lead compounds. Small peptides as a class of compounds possess rich diversity and potent bioactivity and thus remain a vital starting point for drug discovery. However, due to a litany of undesirable pharmacokinetic properties of peptides, peptidomimetics are frequently used to redeploy important peptide mainchain and sidechain pharmacophores onto less peptide-like scaffolds. Peptidomimetics vary greatly in their resemblance to peptides. Success has been achieved with peptides containing hydrolytically stable amide surrogates, mixed organo-peptide frameworks, and with non-peptide scaffolds alike. For example, benzodiazepines, penicillins and cephalosporins are well-established peptidomimetic drugs and it is easy to see

-4-that organo-peptide chimeras are essential to both rational design and combinatorial chemistry approaches to drug discovery.
In one embodiment of the present invention there is -provided a series of novel amino thioether acid compounds and their corresponding sulfoxides and sulfones (collectively hereinafter "ATAs") that unite key elements of organic and peptide chemistry to generate novel, diverse structures. In their simplest form, ATAs are dipeptides where a thioether bridge (or oxidized derivatives thereof) replaces the central amide linkage.
Several of such structures have been previously described by Spatola, A.F., in Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B: Weinstein, Ed.; Marcel Dekker: New York, 1983; Vol. 7; pages 267-357. The diverse library of ATAs in accordance with one embodiment of this invention generally represent a continuum of related structures ranging from analogs of known dipeptides, through organo-peptide hybrids, to bona fide organic compounds. The present ATA libraries can be prepared using combinatorial chemistry protocols and tested for biological activity. Alternatively, the ATAs can be prepared in quantity using classical organic synthesis techniques and used as starting materials for preparation of diverse ATA derivative libraries, or they can be used as building blocks to construct ATA polymer libraries for biological testing. The ATAs can be used alone or in combination with amino acids encoded by the genetic code, or with other amino acids, to prepare predetermined peptide mixtures analogous to those described in, for example, U.S. Patent No 5,266,684, the disclosure of which is incorporated herein by reference.
The general method used to prepare the diverse libraries of ATA library compounds in accordance with _ this invention utilizes commercially available or readily synthesized amino acids or amino alcohols and mercapto acids. One embodiment of the method is illustrated using

-5-a subset of available amino acids/amino alcohols in the reaction scheme (Scheme I) shown below:
Scheme I
R O R OH R OMs OH

SH
COOH
R S- W~-COOH
NHP
An amino-protected amino alcohol (optionally derived by reduction of an amino acid) is converted to its corresponding mesylate and reacted with a dibasic salt of a mercapto acid (or a mercaptide salt of an ester or amide derivative thereof) to form ATA and ATA derivative library compounds of the present invention. In general, R and W are selected from non-interfering substituents and P is an amino-protecting group stable under conditions of thioether formation, e.g., t-butyloxycarbonyl (Boc) or allyloxycarbonyl (Alloc).
Thioether formation is preferably conducted in solution phase. However, the reaction can be carried out using solid phase synthesis techniques wherein the mercapto acid is bound through its acid moiety to a solid support having acid reactive groups, and the covalently bound mercapto compound is reacted as its mercaptide salt with the amino alcohol derived mesylates to provide

6 PCT/US98/07151 support bound amino thioether library compounds of. this invention which can optionally be further reacted and either cleaved from the solid support or retained as a solid phase source of library compounds.
The resulting diverse library is useful in the identification of new lead compounds. Alternatively ATA _ library compounds can be selected for preparation of diverse ATA libraries derived, for example, by oxidation to the corresponding sulfoxide and/or sulfone, by removal of the amino protecting group and reacting the resulting amine functionality with electrophilic reagents, and/or by reacting the ATA acid functionality, either with bases to prepare the corresponding salts, or in activated form, with ester forming alcohols or amide-forming amines. The libraries are created, stored, and used as an apparatus comprising a two-dimensional array of reservoirs, each reservoir containing a predetermined library reaction product differing from those in adjacent reservoirs. The diverse ATA library also serves as a convenient source of ATAs useful for the preparation of protein/peptide mimetic polymers useful for identifying lead compounds.
Another embodiment of the present invention provides an assay kit for the identification of pharmaceutical lead ATA and ATA derivative compounds, said kit comprising assay materials and a well plate apparatus or equivalent apparatus providing a two-dimensional array of defined reservoirs. The well plate apparatus provides a diverse combinatorial library, wherein each well (reservoir) contains a unique library compound. The well plate apparatus is used to provide multiple reaction zones for making the library, to store the library and to provide a readily accessible source of library compounds.
Brief Description of the Drawings Fig. 1 is a top view of a well plate in accordance with this invention.

WO 98/46786 PC'T/US98/07151 Fig. 2 is a side view of a well plate apparatus for use in the process of this invention.
Detailed Description of the Invention - The term "assay kit" as used in accordance with the present invention refers to an assemblage of two cooperative elements, namely (1) a well plate apparatus and (2) biological assay materials.
"Biological assay materials" are materials necessary to conduct a biological evaluation of the efficacy of any library compound in a screen relevant to a selected disease state.
A "library" is a collection of compounds created by a combinatorial chemical process, said compounds having a common scaffold with one or more variable substituents.
The scaffold of the present invention comprises peptidomimetic aminothioether acids and derivatives thereof.
A "library compound" is an individual reaction product, a single compound or a mixture of isomers, in a combinatorial library.
A "Lead compound" is a library compound in a selected combinatorial library for which the assay kit has revealed significant activity relevant to a selected disease state.
A "diverse library" means a library where the substituents on the combinatorial library scaffold or core structure, are highly variable in constituent atoms, molecular weight, and structure, and the library, considered in its entirety, is not a collection of closely related homologues or analogues (compare to "directed library").
A "directed library" is a collection of compounds created by a combinatorial chemical process, for the purpose of optimization of the activity of a lead compound, wherein each library compound has a common _g_ scaffold, and the library, considered in its entirety, is a collection of closely related homologues or analogues to the lead compound (compare with "diverse library").
The term "scaffold" as used in accordance with the -present invention refers to the invariable region (a thioether core in the present invention) of the compounds which are members of the combinatorial library.
"Substituents" are chemical radicals which are bonded to or incorporated onto or into the thioether scaffold through the combinatorial synthesis process.
The different functional groups account for the diversity of the molecules throughout the library and are selected to impart diversity of biological activity to the scaffold in the case of diverse libraries, and optimization of a particular biological activity in the case of directed libraries.
"Reagent" means a reactant, any chemical compound used in the combinatorial synthesis to place substituents on the scaffold of a library.
"Parallel array synthesis" refers to the method of conducting combinatorial chemical synthesis of libraries wherein the individual combinatorial library compounds are separately prepared and stored without prior and subsequent intentional mixing.
"Simultaneous synthesis" means making of library compounds within one production cycle of a combinatorial method (not making all library compounds at the same instant in time).
The "reaction zone" refers to the individual vessel location where the combinatorial chemical library compound preparation process of the invention is carried out and where the individual library compounds are synthesized. Suitable reaction zones include, but are not intended to be limited to, the individual wells of a _ well plate apparatus.
"Well plate apparatus" refers to a structure comprising a plurality of reservoirs capable of holding a _g_ library of compounds in dimensionally fixed and defined positions.
"Non-interfering substituents" are those groups that do not significantly impede the process of the invention and yield stable aminothioether acid library compounds.
"Aryl" means one or more aromatic rings, each of 5 or 6 ring carbon atoms and includes substituted aryl having one or more non-interfering substituents.
Multiple aryl rings may be fused, as in naphthyl, or unfused, as in biphenyl.
"Alkyl" means straight or branched chain or cyclic hydrocarbon having 1 to 20 carbon atoms.
"Substituted alkyl" is alkyl having one or more non-interfering substituents.
"Halo" means chloro, fluoro, iodo or bromo.
"Heterocycle" or "heterocyclic radical" means one or more rings of 5, 6 or 7 atoms with or without unsaturation or aromatic character, optionally substituted with one or more non-interfering substituents, and at least one ring atom which is not carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused, as in quinoline or benzofuran, or unfused as in 4-phenylpyridine. Suitable substituents on the heterocyclic ring structure include, but are not limited to halo, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 alkoxy, C~-C12 aralkyl, C~-C12 alkaryl, C1-C10 alkylthio, arylthio, aryloxy, arylamino, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, di(C1-C10)-alkylamino, C2-C12 alkoxyalkyl, C1-C6 alkylsulfinyl, C1-C10 alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy(C1-. C10)alkyl, aryloxy(C1-C10)alkyl, C1-C10 alkoxycarbonyl, aryloxycarbonyl, C1-C10 alkanoyloxy, aryloyloxy, substituted alkoxy, fluoroalkyl, nitro, cyano, cyano(C1-Clp)alkyl, C1-C10 alkanamido, aryloylamido, arylaminosulfonyl, sulfonamido, amidino, carbamido, protected amino, protected carboxy, protected hydroxy, carboxy, amino, heterocyclic radical, nitroalkyl, and -(CH2)m-Z-(Cl-C1p alkyl), where m is 1 to 8 and Z is oxygen or sulfur.
"Heteroaryl" is heterocycle or heterocyclic radical having aromatic character.
"Organic moiety" means a substituent comprising a non-interfering substituent covalently bonded through at least one carbon atom. Suitable radicals for substitution onto a connecting carbon atom include, but are not limited to hydrogen, halo, optionally substituted Cl-Clp alkyl, C2-Clp alkenyl, C2-Clp alkynyl, Cl-C10 alkoxy, C~-C12 aralkyl, C~-C12 alkaryl, C1-Clp alkylthio, arylthio, aryloxy, arylamino, C3-Clp cycloalkyl, C3-C10 cycloalkenyl, di(C1-Clp)-alkylamino, C2-C12 alkoxyalkyl, Cl-C6 alkylsulfinyl, Cl-Clp alkylsulfonyl, arylsulfonyl, aryl, hydroxy, hydroxy(Cl-Clp)alkyl, aryloxy(Cl-Clp)alkyl, Cl-Clp alkoxycarbonyl, aryloxycarbonyl, Cl-C10 alkanoyloxy, aryloyloxy, substituted alkoxy, fluoroalkyl, nitro, cyano, cyano(Cl-C1p)alkyl, C1-Clp alkanamido, aryloylamido, arylaminosulfonyl, sulfonamido, carbamido, amidino, protected amino, protected carboxy, protected hydroxy, carboxy, amino, heterocyclic radical, nitroalkyl, and -(CH2)m-Z-(C1-Clp alkyl), where m is 1 to 8 and Z is oxygen or sulfur.
The term "amino acid" as used in accordance with the present invention includes the 20 proteiogenic amino acids encoded by the genetic code, as well as hydroxyproline, alpha-aminaisobutyric acid, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, beta-alanine, 4-aminobutyric acid and other compounds of the general formula:
HN Q COOH
Rn wherein Rn is hydrogen or an organic moiety, and Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N and S; or Rn taken together with Q and the nitrogen atom to which they are bound form a 5 or 6-membered ring.
"Proteiogenic amino acids" are those amino acids of the formula H ~ CHR1COOH
Rn wherein R1 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, sulfhydrylmethyl, 2(methylthio)ethyl, benzyl, 4-hydroxybenzyl, 3-indolylmethyl, carboxymethyl, 2-carboxyethyl, carbamidomethyl, 2-carbamidoethyl, 4-aminobutyl, 3-guanadinylpropyl and 4-imidazolylmethyl, and Rn is hydrogen, or Rn and R1 taken together with the common bonded nitrogen atom form a pyrrolidine ring.
"Activated acid" or "activated acid group" refers to a carboxylic acid that has been reacted to form a group -C(O)X wherein X is a leaving group subject to nucleophilic displacement by nucleophiles. Exemplary of the group X are acid halides, such as acid chlorides, acid fluorides, and the like, acid anhydrides, active esters, and the like. Preparation of such activated acid derivatives and their use in preparation of other acid derivatives are well known in the art "Acid reactive groups" refer to those nucleophilic groups capable of reacting with activated acids to form a covalent bond. Exemplary of acid reactive groups are -OH, -SH or -NHRr, where Rr is hydrogen or an organic moiety and stabilized carbon anions.
"Solid support" refers to a solvent insoluble substrate having acid reactive groups for forming cleavable covalent bonds with acid reagents, such as S-protected mercapto acids for use in preparing the present library compounds in accordance with one embodiment of this invention.
The present invention provides a diverse combinatorial library of peptidomimetic aminothioether acids and derivatives thereof of the general formula:
~~)m P ~ Q- IH-S W-C A I

Rn Rg wherein is hydrogen, a substituent derived from an P

electrophilic reagent, or an amino-protecting group;

Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N

and S;

Rs is hydrogen or an organic moiety; and Rn is hydrogen or an organic moiety, or P in combination with Rn is an amino-protecting group; or Rn and Rs taken together with -Q- and the atoms to which they are bonded form a 4- to

7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms; or Rn or RS

taken together with -Q- and the atoms to which they are commonly bonded form a 4- to 7-membered ring;

m is 0, 1 or 2;

W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N and S; and A is OH, NH2, an ester-forming substituent derived from an alcohol, or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally covalently bound to a solid support, and when A is OH, salts of the acid represented thereby.
The library compounds of this invention have a molecular weight of about'150 to about 800, more typically about 200 to about 600. They include thioethers (m = 0), and the corresponding sulfoxides (m =
1) and sulfones (m = 2).
In one embodiment there is provided a diverse library of ATA compounds of Formula I wherein A is OH and P is hydrogen. The library can be prepared using combinatorial synthesis protocols or the individual ATA
library compounds and their amino-protected derivatives can be prepared by standard chemical synthesis techniques and used as core structures for preparation of directed libraries; or they can be used in preparation of peptidomimetic polymers of ATAs and other amino acid compounds using conventional peptide coupling protocols.
Thus amino-protected ATAs are converted to an activated acid form and reacted with either an amino acid or another ATA, optionally covalently bound to a solid support, to provide peptide-linked oligomers or polymers.
Such procedures can be used to prepare combinatorial libraries of peptidomimetic compounds, such as those described and claimed in US Patent No. 5,266,684, wherein ATAs are substituted for one or more conventional amino acid compounds in preparation of the described combinatorial libraries.
Amino-protected ATAs and amino-protected ATA
derivative compounds in accordance with this invention are those compounds of Formula I above wherein Rn is hydrogen or a substituent derived from an electrophilc - agent and P is an amino-protecting group or wherein P and Rn taken together form a divalent amino-protecting group, such as phthaloyl or diphenylmethylene. Exemplary of monovalent amino-protecting groups include, but are not intended to be limited to, 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), 2-trimethylsilylethoxycarbonyl (Teoc), biphenylisopropyloxycarbonyl (Bpoc), nitroveratryloxycarbonyl (Nvoc), -(4-methoxyphenyl)diphenylmethyl (MMTr), (4,4'-dimethoxyphenyl)phenylmethyl (DMT), benzyloxycarbonyl (Cbz or Z), and the like. Reaction conditions for the preparation of protected-amines utilizing such protecting groups and conditions for the selective removal of such groups to provide the corresponding amines are well-known in the art. See for example, "Protective Groups in Organic Synthesis" 2nd ed., by Theodora W. Greene and Peter G.M. Wuts (1991), John Wiley and Sons (New York).
In accordance with another embodiment of this invention, there is provided a diverse library of ATA
compounds of Formula I wherein A is an ester-forming substituent derived from an alcohol or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally being covalently bound to a solid support. Such library compounds are typically prepared from the corresponding ATAs (A=OH), or precursors thereof, by reacting an activated form of the acid with alcohols or amines, or solid supports bearing acid reactive hydroxy or amino groups. The nature/structure of the amine or alcohol is not critical;
primary or secondary alcohols and primary or secondary amines having a molecular weight of about 30 to about 500 are preferred.
Optionally, the amine or alcohol functionality can be covalently bound to a solid support. A general compilation of solid supports (resins) can be found in "Supports for Solid Phase Organic Synthesis," Martin Winter, pp 465-510, in Combinatorial Pe tide and Non- _ peptide Libraries, edited by Giinther Jung (1996), VCH
Publishers (Weinheim, Germany). Many solid supports having acid reactive groups, such as hydroxy and primary or secondary amino groups (or precursors thereto) are commercially available. The acid reactive groups covalently bound to solid supports are typically designed to have selectively cleavable covalent bonds linking it to the solid support. Illustrative of commercially available solid supports include, but are not intended to be limited to, the following resins:
Wang resin (where the sphere represents commercial divinylbenzene-crosslinked polystyrene):
~e~"~.
Wang resin functionalized with various amino acids (many varieties are commercially available):
~R

NHfmoc Wang p-nitrophenylcarbonate resin:
NOZ
O
O"O"u ~O
Rink Amide AM resin:
FmocHN OMB
ado i _a ro Rink Amide MBHA resin:

FnoeHN
\ / "
~o oM.

Knorr Resin:
FmoeHN OMe \ H p\~
H ~-z ~O ~ OMe and the like.
In another embodiment of this invention, there is provided a diverse library of compounds of Formula I
wherein W is a divalent organic moiety selected from the group consisting of a divalent organic group comprising a 5- or 6-membered aromatic ring containing 0 to 4 heteroatoms selected from O, N and S, -CHRg- , and -CR4R5CR6R~- , wherein Rg is hydrogen or a noninterfering substituent; R4~ RS~ and R6 are independently hydrogen or alkyl; and R~ is hydrogen, hydroxy, protected hydroxy, amino or protected amino or substituted amino wherein the substituent is derived from an electrophilic reagent.
Such groups are derived generally from mercapto acids of the formula HS-W-COOH
having a molecular weight of about 90 to about 400.
In one particular embodiment of this invention there is provided a diverse library of compounds of Formula I
wherein W is a divalent moiety selected from the group consisting of N N N
S ~S~
and N/N~ N
N
In still another embodiment of this invention there is provided a diverse library of compounds of Formula I
wherein Q is a group of the formula R~C~R I
1 2 or 1 wherein R1 is hydrogen or a non-interfering substituent;
R2 is hydrogen or a non-interfering substituent; or R1 taken together with Rn forms a 5- or 6-membered ring; or R1 taken together with Rs forms a 5- or 6-membered ring; or R1 taken together with R2 forms a 3- to 6-membered ring. Other embodiments of this invention within that embodiment, but having more restricted diversity in the group Q, are libraries wherein:
R1 taken together with Rn forms a 5- or 6-membered ring; or wherein R1 taken together with Rs forms a 5- or 6-membered _ ring; or wherein R1 taken together with R2 forms a 3- to 6-membered ring.

In still another embodiment of this invention.
wherein Q is -CR1R2- or -CH2CHR1-, R1 is selected from the group consisting of hydrogen, phenyl, substituted phenyl, C1-C4 alkyl, substituted C1-C4 alkyl, C5-C6 cycloalkyl, C1-C4 alkoxyl, substituted C1-C4 alkoxyl, hydroxy, protected hydroxy, carboxy, protected carboxy, alkylthio, protected alkylthio, carbamido, amidino; and R2 is hydrogen, C1-C4 alkyl, or substituted C1-C4 alkyl.
Such library compounds are derived from amino alcohols of the formula H Ro R' P I I I IH ~H
Rn H H Rs P I I IH OH or Rn R2 Rs wherein P, Rn, R1, R2 and Rs are as defined above, said amino alcohols having a molecular weight of about 60 to about 400.

Further in accordance with this invention there is provided a process for preparing a combinatorial library of compounds of the formula -P ~ Q-CIH-S W C A I
Rn Rs having diversity in P, Rn, Rs~ Q, W, m and A, each as defined above. The process comprises the step of reacting a compound of the formula P N Q-CH-X
R" Rs II

wherein P is an amino-protecting group, X is an electrophilic group subject to nucleophilic displacement from its bonded carbon atom, and Rn, Q,~Rs are as defined above with a salt of a mercapto compound of the formula O
HS W C A
where W and A are as defined above; and when A is OH in Formula I, optionally reacting the aminothioether acid represented thereby with an ester-forming alcohol or an amide-forming primary or secondary amine;
optionally oxidizing the aminothioether to provide a library compound wherein m is 1 or 2;
removing the protecting group P to provide a library compound of the formula;
~ ~ )m H ~ O- IH-S-W C A
R" RS ; and optionally reacting the deprotected amine with an amine reactive electrophilic reagent.
Each of the reaction steps, whether conducted on solid phase (A is covalently bound to a solid support) or in solution phase, is typically carried out using a dry, inert, polar, aprotic solvent at a temperature of about 0° to about 30°C, using stoichiometrically equivalent amounts or near stoichiometrically equivalent amounts of reactants, and standard work up procedures. Suitable solvents include dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, ethyl acetate, diethyl ether and the like. The reaction steps can be carried out using standard combinatorial chemistry protocols to produce arrays of library compounds, or they can be carried out on a larger scale using standard chemical synthesis, work-up, and product isolation and purification procedures.
In the first step in preparation of the present library compounds, a library compound of Formula I above wherein m = O, an aminothioether, is prepared by reacting a compound of the formula P N Q-CH-X
II
Rn Rs with about 1 to about 1.2 stoichiometric equivalents of a mercaptide salt of a mercapto compound of the formula O
HS W C A
wherein in the above formulas P, Rn, Rs, X, W and A are defined above. In one preferred embodiment the reaction is carried out in solution phase, and a solution of the compound of Formula II is added slowly to a solution of the mercaptide salt. In another embodiment the reaction is carried out on solid phase (wherein A is a covalently bound solid support). The mercaptide salt is most typically generated by reacting the corresponding mercaptan in solution with about one stoichiometric equivalent amount of an alkali metal alkoxide base, for example sodium methoxide. Other mercaptide forming bases can be used (e. g. alkali metal dimsylates or hydrides), but without advantage. When A in the above formula is OH
(representative of a mercapto acid), about 2 stoichiometric equivalents of base are used to generate the di-alkali metal mercaptide carboxylate salt of the mercapto acid. Examples of suitable mercapto acids for WO 98/46786 PCTliTS98/0715i use in preparing the library compounds of this invention include, but are not intended to be limited to:
THIOSALICYLIC ACID
' N-ACETYL-DL-PENICILLAMINE
DL-PENICILLAMINE
2,3-DIMERCAPTOSUCCINIC ACID
MERCAPTOSUCCINIC ACID
N-(2-MERCAPTOPROPIONYL)GLYCINE
N-ACETYL-L-CYSTEINE
DL-CYSTEINE

DL-HOMOCYSTEINE

D-CYSTEINE HYDROCHLORIDE

GUANIDINOETHYLTHIOPROPANOIC ACID

L-THIOHISTIDINE

CYS-GLY
DL-THIORPHAN

D-PENICILLAMINE
L-PENICILLAMINE
L-CYSTEINE
DL-CYSTEINE HYDROCHLORIDE
BOC-CYS-OH
GLUTATHIONE
D-CYSTEINE
MESO-ALPHA, ALPHA'-DIMERCAPTOADIPIC ACID
N-ACETYL-D-PENICILLAMINE
MERCAPTOTETRAZOLYLACETIC ACID
ALPHA-MERCAPTO-P-TOLUIC ACID

2-THIOACETIC ACID-5-MERCAPTO-1,3,4-THIADIAZOLE
N-ISOBUTYRYL-L-CYSTEINE
N-ISOBUTYRYL-D-CYSTEINE
CAPTOPRIL

SALOR 598,217-2 2,6-CSBA (2-C1-6-mercaptobenzoic acid) MAYBRIDGE RJC 01025, and the like.

In the preparation of aminothioether compounds of this invention the mercaptide salt is reacted with a compound of the Formula II. The substituent X is a suitable leaving group subject to nucleophilic displacement by the mercaptide salt. Exemplary of .
suitable X groups are mesylate, tosylate, and halo. Such compounds are typically derived from an amino alcohol or protected-amino alcohol of the formula N ~2 CHOH
Rn Rs wherein P, Rn, Q and Rs are as defined above. The amino alcohol is selected to have a molecular weight of about 60 to about 450, most typically about 60 to about 300.
In one preferred embodiment the amino alcohol starting material is reacted with methane sulfonyl chloride to provide the corresponding mesylate in high yield using the mesylation protocol of Crossland and Servis [JOC 35, 31952-6 (1970)]. Suitable amino alcohols for use in preparing the present library compounds include, but are not intended to be limited to:

3-AMINOMETHYL-3,5,5-TRIMETHYLCYCLOHEXANOL
(1R,2R)-(-)-PSEUDOEPHEDRINE
L-ADRENALINE
DL-HOMOSERINE
Z-L-SERINE

N-ACETYLETHANOLAMINE
2-(METHYLAMINO)ETHANOL
N-BENZYLETHANOLAMINE
2-(ETHYLAMINO)ETHANOL
DIETHANOLAMINE
2-(PROPYLAMINO)ETHANOL
D-SERINE -(1S,2S)-(+)-2-AMINO-1-PHENYL-1,3-PROPANEDIOL
D-ALLO-THREONINE

DIISOPROPANOLAMINE
2-AMINO-2-METHYL-1,3-PROPANEDIOL
TRIS(HYDROXYMETHYL)AMINOMETHANE
N-METHYL-D-GLUCAMINE

L-ISOLEUCINOL
L-PHENYLALANINOL

L-METHIONINOL

L-PROLINOL

D-(-)-ALPHA-PHENYLGLYCINOL
(-)-NOREPHEDRINE

(+/-)-2-AMINO-1-BUTANOL

DL-ISOSERINE

3-AMINO-1,2-PROPANEDIOL

1,3-DIAMINO-2-PROPANOL
2-(2-AMINOETHYLAMINO)ETHANOL
ETHANOLAMINE

(1S,2S)-(+)-2-AMINO-3-METHOXY-1-PHENYL-DL-PROPRANOLOL HYDROCHLORIDE

TRIS(HYDROXYMETHYL)AMINOMETHANE
HYDROCHLORIDE
DL-SERINE METHYL ESTER HYDROCHLORIDE
L-SERINE ETHYL ESTER HYDROCHLORIDE
L-PHENYLEPHRINE HYDROCHLORIDE

DL-OCTOPAMINE HYDROCHLORIDE
DL-NORMETANEPHRINE HYDROCHLORIDE
ETHANOLAMINE HYDROCHLORIDE

N-CYCLOHEXYLETHANOLAMINE
L-NORADRENALINE

L-ADRENALINE BITARTRATE
D-SPHINGOSINE
N-(TERT-BUTOXYCARBONYL)-L-SERINE
N-ACETYL-DL-SERINE
L-THREONINE METHYL ESTER HYDROCHLORIDE
L-ARGININIC ACID
D-GLUCOSAMINIC ACID
L-TYROSINOL HYDROCHLORIDE
L-SERINE BENZYL ESTER HYDROCHLORIDE

HYDROCHLORIDE
2-AMINO-1,3-PROPANEDIOL OXALATE

GLUCOPYRANOSIDE
2-AMINO-1,3-PROPANEDIOL
DL-SERINE HYDROXAMATE
L-SERINE BETA-NAPHTHYLAMIDE
N-CBZ-D-GLUCOSAMINE
N-(TERT-BUTOXYCARBONYL)ETHANOLAMINE
DL-THREONINE HYDROXAMATE
SER-BETA-ALA
N-T-BOC-L-HOMOSERINE

MANNOPYRANOSIDE HYDROCHLORIDE
L-THREONINAMIDE HYDROCHLORIDE
3-AMINO-2,2-DIMETHYL-1-PROPANOL
L-HOMOSERINE
N-T-BOC-D-SERINE
N-CARBOBENZOXY-DL-SERINE
L-LEUCINOL
L-SERINE METHYL ESTER HYDROCHLORIDE
DL-THREONINE
DL-SERINE
L-SERINE
(+)-PSEUDOEPHEDRINE
(-)-EPHEDRINE
L-ALLO-THREONINE
D-THREONINE
L-THREONINE
L-VALINOL
D-VALINOL
D-PHENYLALANINOL

L-HYDROXYPROLINE
D-PROLINOL
L-(+)-ALPHA-PHENYLGLYCINOL
(1S,2R)-(+)-PHENYL-PROPANOLAMINE
(S)-(+)-2-AMINO-1-PROPANOL
D-ALANINOL
(S)-(+)-2-AMINO-1-BUTANOL
(R)-(-)-2-AMINO-1-BUTANOL
(R)-(-)-1-AMINO-2-PROPANOL

WO '98/46786 PCT/US98/07151 (S)-(+)-1-AMINO-2-PROPANOL
(+)-EPHEDRINE HYDROCHLORIDE
D-MANNOSAMINE HYDROCHLORIDE
D(+)-NOREPHEDRINE HYDROCHLORIDE
NOREPHEDRINE HYDROCHLORIDE
BOC-L-THREONINE
N-CBZ-L-THREONINE
DL-ALLOTHREONINE
L-SERINAMIDE HYDROCHLORIDE
ALPHA-D-GLUCOSAMINE HYDROCHLORIDE
DL-METHIONINOL
(1S,2R)-(+)-2-AMINO-1,2-DIPHENYLETHANOL
{1R,2S)-(-)-2-AMINO-1,2-DIPHENYLETHANOL
S-BENZYL-L-CYSTEINOL
BOC-L-PHENYLALANINOL
L-HISTIDINOL DIHYDROCHLORIDE
D-(-)-THREO-2-AMINO-1-(4-NITROPHENYL)-1,3-PROPANEDIOL
ETHAMBUTOL DIHYDROCHLORIDE
(+/-)-ARTERENOL BITARTRATE SALT
S-ALPHA-HYDROXYMETHYL TYROSINE
(1S,2S)-{+)-THIOMICAMINE

HYDROCHLORIDE

HYDROCHLORIDE

HYDROCHLORIDE

N-(2-HYDROXYETHYL)CARBAMIC ACID BENZYL
ESTER
N-(TERT-BUTOXYCARBONYL)-L-SERINE METHYL
ESTER
(R)-(+)-3-HYDROXYPIPERIDINE
HYDROCHLORIDE
(S)-TERT-LEUCINOL
N-TRITYL-L-SERINE METHYL ESTER

(+/-)-NOREPINEPHRINE L-BITARTRATE
HYDRATE
(15,2R)-{-)-CI5-1-AMINO-2-INDANOL

2-[2-(AMINOPHENYLTHIO]BENZYL ALCOHOL, and the like.
Amino alcohol starting materials can also be prepared in high yield from available amino acids and protected amino acids of the formula N Q COON
Rn III
wherein P, Rn and Q are as defined above. Thus available amino acid compounds can be protected with an amino-protecting group and converted in good yields to the corresponding protected-amino alcohols of the formula N Q CHOH
Rn Rs For example, when Rs is hydrogen, these compounds can be obtained from sodium borohydride reduction of the mixed carbonate formed, for example, between the starting acid and isobutyryl chloroformate. Amino acids available for conversion to the corresponding amino alcohols for use in preparing library compounds of this invention include, but are not intended to be limited to, the following listed amino acids:

N-ALPHA-CBZ-L-ARGININE
N-ALPHA-BENZOYL-L-ARGININE
CHLOROACETYL-L-TYROSINE
DL-M-TYROSINE
L-DOPA

O-METHYL-L-TYROSINE
O-BENZYL-L-TYROSINE
L-TYROSINE

S-(TERT-BUTYLTHIO)-L-CYSTEINE HYDRATE
D-CYSTINE -S-TRITYL-L-CYSTEINE
S-METHYL-L-CYSTEINE
S-BENZYL-L-CYSTEINE
S-CARBOXYMETHYL-L-CYSTEINE

LANTHIONINE
L-ASPARTIC ACID
L-LEUCINE
DL-HOMOSERINE
L-HOMOPHENYLALANINE
DL-METHIONINE SULFOXIDE
L-METHIONINE SULFOXIMINE
D-METHI ONINE
L-ETHIONINE
L-C-ALLYLGLYCINE
GAMMA-L-GLUTAMYL-L-GLUTAMIC ACID

L-GLUTAMIC ACID GAMMA-BENZYL ESTER
L-GLUTAMIC ACID
L-ARGININE
L-ALPHA-AMINOADIPIC ACID
2,6-DIAMINOPIMELIC ACID
N-EPSILON-CBZ-L-LYSINE
N-EPSILON-ACETYL-L-LYSINE
N-CBZ-L-ALANINE
Z-L-SERINE
N-(TERT-BUTOXYCARBONYL)-L-PHENYLALANINE
5-BROMO-N-(CARBOXYMETHYL)ANTHRANILIC ACID
N-(4-HYDROXYPHENYL)GLYCINE
N-(TERT-BUTOXYCARBONYL)GLYCINE
N-CBZ-GLYCINE
HIPPURIC ACID

Z-L-ASPARTIC ACID
L-ASPARTYL-L-PHENYLALANINE METHYL ESTER
N-CBZ-L-GLUTAMIC ACID
N-ACETYL-L-GLUTAMIC ACID
DL-ALPHA-METHYLTYROSINE

2-(METHYLAMINO)ISOBUTYRIC ACID
ALPHA-HYDROXYHIPPURIC ACID
ETHYLENEDIAMINE-DI(0-HYDROXYPHENYLACETIC ACID) D-(-)-P-HYDROXYPHENYLGLYCINE
D-PENICILLAMINE DISULFIDE
D-TERT-LEUCINE
DL-DOPS
DL-VALINE
DL-ISOLEUCINE
D-SERINE
D-PHENYLALANINE

N-ACETYLGLYCINE
N-TRITYLGLYCINE
TRICINE
GUANIDOACETIC ACID
SARCOSINE
IMINODIACETIC ACID
ETHYLENEDIAMINE-N, N'-DIACETIC ACID
D-ALLO-THREONINE
N-CBZ-S-BENZYL-L-CYSTEINE
N-ACETYL-DL-PENICILLAMINE
DL-PENICILLAMINE
DL-CYSTEINE

DL-HOMOCYSTEINE

L-CARNOSINE
DL-HISTIDINE
L-THIAZOLIDINE-4-CARBOXYLIC ACID _ 3,4-DEHYDRO-DL-PROLINE

DL-PROLINE

DL-ALPHA-(2-THIENYL)GLYCINE

L-ABRINE
D-TRYPTOPHAN

L-PIPECOLINIC ACID
NIPECOTIC ACID
ISONIPECOTIC ACID
NITRO-L-ARGININE

DL-HOMOCYSTEIC ACID
P-AMINOOXANILIC ACID

ALBIZZIIN
DL-CITRULLINE
S-CARBAMYL-L-CYSTEINE
N-ALPHA-CBZ-L-ASPARAGINE
D-ASPARAGINE
N-CBZ-L-GLUTAMINE
L-GLUTAMINE
2,2-DIPHENYLGLYCINE

D-(-)-ALPHA-PHENYLGLYCINE

D-ALANINE

D-NORVALINE
D-NORLEUCINE

GLYCINE
DL-ISOSERINE

BETA-ALANINE

N-ALPHA-ACETYL-L-LYSINE
Z-L-VALINE
N-(4-NITROBENZOYL)-BETA-ALANINE
N-(4-AMINOBENZOYL)-BETA-ALANINE

(R)-(-)-N-(3,5-DINITROBENZOYL)-ALPHA-PHENYLGLYCINE
N-(3,5-DINITROBENZOYL)-DL-LEUCINE

(+/-)-3-AMINOADIPIC ACID
ALPHA-METHYL-DL-PHENYLALANINE

(+/-)-INDOLINE-2-CARBOXYLIC ACID
BETA-(2-THIAZOLYL)-DL-ALANINE
L-GAMMA-CARBOXYGLUTAMIC ACID
L-2-(BENZYLOXYCARBONYLAMINO)-4-SULFAMOYLBUTYRIC ACID

SARCOSINE HYDROCHLORIDE
4-(METHYLAMINO)BUTYRIC ACID HYDROCHLORIDE
L-TYROSINE HYDROCHLORIDE
L-GLUTAMIC ACID HYDROCHLORIDE
D-ARGININE MONOHYDROCHLORIDE
N-EPSILON-METHYL-L-LYSINE HYDROCHLORIDE
L-HOMOARGININE HYDROCHLORIDE

(+/-)-1,2,3,4-TETRAHYDRO-3-ISOQUINOLINEC
HYDROCHLORIDE
DL-PIPECOLINIC ACID HYDROCHLORIDE

GLYCINE HYDROCHLORIDE

DL-2,3-DIAMINOPROPIONIC ACID HYDROBROMIDE
DL-2,3-DIAMINOPROPIONIC ACID MONOHYDROCHLORIDE
DL-2,4-DIAMINOBUTYRIC ACID DIHYDROCHLORIDE
D-ORNITHINE HYDROCHLORIDE
D-ORNITHINE HYDROCHLORIDE

D-LYSINE MONOHYDROCHLORIDE

N-PHENYLGLYCINE

N-CBZ-L-PHENYLALANINE
N-(CARBOXYMETHYL)ANTHRANILIC ACID
N-(P-TOLUOYL)-GLYCINE
L-ASPARTIC ACID MONOPOTASSIUM SALT
L-ASPARTIC ACID MONOPOTASSIUM SALT
N-CARBOBENZYLOXY-L-LEUCINE
N-CARBOBENZYLOXY-L-ISOLEUCINE
3-AMINO-2,3-DIHYDROBENZOIC ACID HYDROCHLORIDE
FMOC-L-VALINE
N-ALPHA-FMOC-L-ISOLEUCINE
FMOC-L-TRYPTOPHAN
N-ALPHA-FMOC-L-PHENYLALANINE
N-ALPHA-FMOC-L-ASPARAGINE
FMOC-L-LEUCINE
FMOC-L-METHIONINE
N-ALPHA-FMOC-L-GLUTAMINE
FMOC-GLYCINE
N-(TERT-BUTOXYCARBONYL)-L-TYROSINE
N-EPSILON-BOC-L-LYSINE
N-(TERT-BUTOXYCARBONYL)-L-ALANINE
N-(TERT-BUTOXYCARBONYL)-L-SERINE
N-(P-TOLUENESULFONYL)-L-PHENYLALANINE
STATINE
BOC-L-ASPARTIC ACID
N-ALPHA-BOC-L-ASPARAGINE
N-ALPHA-BOC-L-LYSINE

N-ALPHA-CBZ-L-LYSINE
N-(TERT-BUTOXYCARBONYL)-L-ISOLEUCINE
N-(TERT-BUTOXYCARBONYL)-D-METHIONINE, DI
BOC-L-ARGININE
DL-(2-FLUOROPHENYL)-GLYCINE
L-ALPHA-(2-AMINOETHOXYVINYL)GLYCINE HYDROCHLORIDE
N-P-TOSYLGLYCINE
BETA-GUANIDINOPROPIONIC ACID
N-(PHOSPHONOMETHYL)-GLYCINE
N-ALPHA-FMOC-D-TRYPTOPHAN
DL-3-(3,4-DIHYDROXYPHENYL)ALANINE

P-IODO-D-PHENYLALANINE

D-TYROSINE
DL-TYROSINE

D-ASPARTIC ACID
DL-ASPARTIC ACID
DL-LEUCINE
D-LEUCINE
L-HOMOSERINE
D-HOMOPHENYLALANINE
DL-HOMOPHENYLALANINE
DL-METHIONINE
L-METHIONINE
D-ETHIONINE
DL-ETHIONINE

D-GLUTAMIC ACID
D-ARGININE
D-ALPHA-AMINOADIPIC ACID
DL-ALPHA-AMINOADIPIC ACID
N-CBZ-DL-ALANINE
N-CARBOBENZOXY-DL-SERINE
DL-THREONINE
L-ALPHA-METHYLTYROSINE
L-TERT-LEUCINE
D-VALINE
L-VALINE
D-ISOLEUCINE -L-ISOLEUCINE
DL-SERINE
L-SERINE
DL-PHENYLALANINE
L-PHENYLALANINE
L-CYSTINE
L-ALLO-THREONINE
D-THREONINE
L-THREONINE
D-PENICILLAMINE
L-PENICILLAMINE
L-CYSTEINE
L-HISTIDINE
D-PROLINE
L-PROLINE

L-HYDROXYPROLINE
BETA-(2-THIENYL}-L-ALANINE
DL-TRYPTOPHAN
L-TRYPTOPHAN

D-PIPECOLINIC ACID
DL-PIPECOLINIC ACID
L-CITRULLINE
L-ASPARAGINE
DL-ALPHA-PHENYLGLYCINE
L(+)-ALPHA-PHENYLGLYCINE
DL-ALANINE
L-ALANIME
(R)-(-)-2-AMINOBUTYRIC ACID
(S)-(+)-2-AMINOBUTYRIC ACID
DL-NORVALINE
L-NORVALINE ' DL-NORLEUCINE
L-NORLEUCINE
DL-LYSINE
L-LYSINE
N-ACETYL-L-METHIONINE
N-(3,5-DINITROBENZOYL)-DL-ALPHA-PHENYLGLYCINE
(S)-(+)-N-(3,5-DINITROBENZOYL)-ALPHA-PHENYLGLYCINE
N-(3,5-DINITROBENZOYL)-L-LEUCINE
L-ARGININE MONOHYDROCHLORIDE
L-2,4-DIAMINOBUTYRIC ACID DIHYDROCHLORIDE
L-ORNITHINE MONOHYDROCHLORIDE
DL-LYSINE MONOHYDROCHLORIDE
L-LYSINE MONOHYDROCHLORIDE
N-(TERT-BUTOXYCARBONYL)-L-ASPARTIC ACID
N-ALPHA-(TERT-BUTOXYCARBONYL)-L-GLUTAMINE
N-ALPHA-(TERT-BUTOXYCARBONYL)-L-HISTIDINE

BOC-L-METHIONINE
N-(TERT-BUTOXYCARBONYL)-L-TRYPTOPHAN
N-(TERT-BUTOXYCARBONYL)-L-VALINE
L-CYSTEINE HYDROCHLORIDE MONOHYDRATE
Z-L-TRYPTOPHAN
DL-TERT-LEUCINE
BOC-L-THREONINE
N-CBZ-L-THREONINE
N-CBZ-L-HISTIDINE
3,4-DEHYDRO-L-PROLINE
N-ALPHA-ACETYL-L-ASPARAGINE
L-LYSINE DIHYDROCHLORIDE
L-BUTHIONINE-(S, R)-SULFOXIMINE
P-AMINO-D-PHENYLALANINE
DL-BUTHIONINE (S, R)-SULFOXIMINE

(S)-(-)-INDOLINE-2-CARBOXYLIC ACID
N-(PHOSPHONOMETHYL)GLYCINE, MONOISOPROPYLAMINE SALT
MIMOSINE
D-HOMOSERINE
(+)-OCTOPINE

DL-CYSTINE
3-(CARBOXYMETHYLAMINOMETHYL)-4-HYDROXYBENZOIC ACID

(S)-(-)-1,2,3,4-TETRAHYDRO-3-ISOQUINOLII~
N-(GAMMA-L-GLUTAMYL)-1-NAPHTHYLAMIDE MONOHYDRATE
3-(3,4-DIHYDROXYPHENYL)-2-METHYL-L-ALANI

N-METHYL-D-ASPARTIC ACID MONOHYDRATE

N-(4-NITROBENZOYL)-L-GLUTAMIC ACID HEMIHYDRATE

L-CYSTEIC ACID MONOHYDRATE

D-ASPARAGINE MONOHYDRATE
D-LYSINE HYDRATE
L-(+)-CANAVANINE SULFATE MONOHYDRATE -D-CYSTEINE HYDROCHLORIDE MONOHYDRATE
D-HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE .
DL-PENICILLAMINE ACETONE ADDUCT HYDROCHL

L-GLUTAMIC ACID, MONOSODIUM SALT, MONOHYDRATE
3,5-DIIODO-L-TYROSINE DIHYDRATE
N-(9-FLUORENYLMETHOXYCARBONYL)-L-ALANINE MONOHYDRATE
3,5-DINITRO-L-TYROSINE MONOHYDRATE

DL-GLUTAMIC ACID MONOHYDRATE
L-CYSTEINESULFINIC ACID MONOHYDRATE
KAINIC ACID MONOHYDRATE

IBOTENIC ACID MONOHYDRATE
L-HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE
DL-HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE
DL-CYSTEINE HYDROCHLORIDE MONOHYDRATE
DL-ARGININE HYDROCHLORIDE MONOHYDRATE
L-LYSINE MONOHYDRATE
L-ASPARAGINE MONOHYDRATE
DL-ASPARAGINE MONOHYDRATE
(S)-(-)-ALPHA-AMINOCYCLOHEXANEPROPIONIC ACID HYDRATE
N-BENZYLGLYCINE HYDROCHLORIDE

(+/-)-TRANS-3-AZABICYCLO(3.1.0)HEXANE-2-N-CARBOBENZYLOXY-L-TYROSINE HYDRATE
4-HYDROXY-2,2,6,6-TETRA METHYL-4-PIPERIDI
and the like.
Where the thioether-forming reaction is carried out using a dialkali metal of a mercaptoacid in excess of a stoichiometric amount relative to the amino alcohol derived compound of Formula II above, the excess reagent frequently migrates with the thioether acid product on a flash silica column and cannot be removed by simple extraction. The excess acid can be separated from the product by dissolving the reaction mixture in ethyl acetate and adding a 2-fold molar excess of solid mercuric acetate to the solution. After 3-20 hours the resulting slurry is filtered through a celite pad, the WO 98/46786 PC1'1US98/07151 filtrate containing the desired thioether product is subjected to flash chromatography on silica, and the filtrate is evaporated to provide the purified reaction product. Reaction Scheme II below (bold-face numerals correspond to compound numerals in Scheme II) is illustrative of the preparation of ATA library compounds in accordance with this invention using amino acid starting materials, such as, for example, amino acid 1 [Formula III, where P = Rn = hydrogen and Q =
'- C

wherein R1 is hydrogen and R2 = CHzR). Amino acid 1 is protected, reduced to the corresponding alcohol, and then converted to mesylate 2. The ATA is formed by condensing the disodium salt of a mercapto acid with mesylate 2 to form 3a. The next step of the process involves exchanging protecting groups to yield a N-Fmoc-protected ATA 3b. Each of the reaction steps proceed smoothly and can be carried out on multigram scale.
HS W COOH
R 0 R OMs R S-O--COOH
a,b,c d OH

3b 3a P=Fmoc P=Alloc P=AlloC
or Boc or Boc Scheme II
- 25 a) Allyl chloroformate or di-t-butyl dicarbonate, Na2C03, 1:1 H20:dioxane, 4°C, 90-95~, P=Alloc or Boc, respectively; b) isobutyryl chloroformate, N-methyl morpholine (NMM) in ethylene glycol dimethyl ether (DME), -15°C, then aq NaBH4, -15°C, 65-90~; c) CH3S02C1, TEA in THF, 4°C, 90-95~; d) mercapto acid (1eq) , NaOMe WO 98/46786 PCTlUS98/07151 (2eq) in DMF, r.t., 65-95~; e) P= Alloc~EFmoc, PPh3 (0.25eq), Pd(PPh3)4 (0.03eq), HOAc (2eq) in THF, then Fmoc-OSu, Na2C03 in 1:1 H20:dioxane, 4°C to r.t., 50~;
P= BoclEFmoc, 4N HC1 in dioxane or EtOAc, 1.5h, then Na2C03 and Fmoc-OSu in 1:1 H20:dioxane, 90-95~.
VAhen the substituent group A in Formula I is OH, the defined acid can optionally be converted into its corresponding carboxylate salt by addition of a suitable salt-forming base, such as ammonium or alkali metal hydroxides or primary or secondary amines.
Alternatively the acid group can be converted to an activated acid group and reacted with an ester-forming alcohol or an amide-forming primary or secondary amine to form the corresponding ester or amide derivatives respectively. Suitable amines and alcohols have a molecular weight of about 30 to about 500. Exemplary of primary and secondary amines for use in preparing library compounds of this invention include, but are not intended to be limited to, the following:
Primary Amine Reagents:
aniline cyclopropylamine cyclobutylamine (-)-cis-myrtanylamine cyclopentylamine cyclohexylamine 2-methylcyclohexylamine 2,3-dimethylcyclohexylamine 4-methylcyclohexylamine (aminomethyl)cyclohexane 3-aminomethyl-3,5,5-trimethylcyclohexanol 1,2,3,4-tetrahydro-1-naphthylamine cyclooctylamine 1-tyrosine methyl ester 2-(2-aminoethyl)-1-methylpyrrolidine n-(2-aminoethyl)pyrrolidine n-(3'-aminopropyl)-2-pyrrolidinone furfurylamine cyclododecylamine 1-aminoindan WO 98/46786 PCT/tTS98/07151 dl-1-(1-naphthyl)ethylamine 1-naphthalenemethylamine cycloheptylamine (ls,2s)-(+)-2-amino-1-phenyl-1,3-propanediol dl-2-amino-3-methyl-1-butanol 1-isoleucinol 1-phenylalaninol dl-4-chlorophenylalaninol d-(-)-leucinol 1-methioninol histamine tetrahydrofurfurylamine dl-alpha-methyltryptamine tryptamine 5-methoxytryptamine 6-methoxytryptamine piperonylamine n-(2-aminoethyl)morpholine n-(3-aminopropyl)morpholine 2-(2-aminoethylamino)-5-nitropyridine 2-(aminomethyl)pyridine 2-(2-aminoethyl)pyridine 3-(aminomethyl)pyridine 4-(aminomethyl)pyridine ethyl 4-amino-1-piperidinecarboxylate 4-amino-1-benzylpiperidine 1-(2-aminoethyl)piperidine 2-(3-aminopropyl)-2-pipecoline 1,2-diamino-2-methylpropane benzhydrylamine d-(-)-alpha-phenylglycinol 1,2-diphenylethylamine dl-1-phenylethylarnine (-)-norephedrine 1,2-dimethylpropylamine isopropylamine 2-methoxyisopropylamine dl-2-amino-1-propanol ethyl-3-aminobutyrate 1,3-dimethylbutylamine 3-amino-1-phenylbutane 2-amino-5-diethylaminopentane 1,5-dimethylhexylamine sec-butylamine (+/-)-2-amino-1-butanol 3-aminopentane 2-aminopentane 3-aminoheptane 2-aminoheptane 2-aminooctane benzylamine 2-fluorobenzylamine 2-chlorobenzylamine 2,4-dichlorobenzylamine 2-methoxybenzylamine 2-ethoxybenzylamine 2-methylbenzylamine 3-fluorobenzylamine 3,4-dichlorobenzylamine 3,4-dimethoxybenzylamine 3-(trifluoromethyl)benzylamine 3-methylbenzylamine 4-fluorobenzylamine 4-chlorobenzylamine 4-methoxybenzylamine 4-methylbenzylamine 2,2,2-trifluoroethylamine 2-amino-1-phenylethanol 1-amino-2-propanol 3-amino-1,2-propanediol 2,2-diphenylethylamine beta-methylphenethylamine isobutylamine 2-methylbutylamine 2-ethylhexylamine n-decylamine n-undecylamine dodecylamine tridecylamine 1-tetradecylamine hexadecylamine octadecylamine ethylamine 2-(2-aminoethylamino)ethanol 2-methoxyethylamine 2-(2-aminoethoxy)ethanol ethanolamine phenethylamine 2-(2-chlorophenyl)ethylamine 2-(2-methoxyphenyl)ethylamine 3-methoxyphenethylamine 2-(3,4-dimethoxyphenyl)ethylamine 4-bromophenethylamine 2-(4-chlorophenyl)ethylamine 2-(4-methoxyphenyl)ethylamine tyramine 2-(4-aminophenyl)ethylamine 2-(p-tolyl)ethylamine taurine propargylamine allylamine 3,3-dimethylbutylamine 3,3-diphenylpropylamine isoamylamine propylamine 3-dimethylaminopropylamine 3-diethylaminopropylamine 3-(di-n-butylamino)propylamine 3-isopropoxypropylamine 3-ethoxypropylamine 3-amino-1-propanol 3-phenylpropylamine 4-amino-1-butanol 4-phenylbutylamine n-amylamine 5-amino-1-pentanol hexylamine 6-amino-1-hexanol n-heptylamine n-octylamine n-nonylamine dl-2-amino-1-pentanol dl-2-amino-1-hexanol 1-(3-aminopropyl)imidazole 3,5-bis(trifluoromethyl)benzylamine 2,4-difluorobenzylamine 2,5-difluorobenzylamine 2,6-difluorobenzylamine 3,4-difluorobenzylamine 4-(trifluoromethyl)benzylamine 2-(trifluoromethyl)benzylamine 4-(2-aminoethyl)benzenesulfonamide n-(4-aminobutyl)-n-ethylisoluminol n-butylamine 2-(1-cyclohexenyl)ethylamine 3-methoxypropylamine 3,4,5-trimethoxybenzylamine 3-butoxypropylamine aminomethylcyclopropane pentadecylamine 4-(2,4-di-tert-amylphenoxy)butylamine 3-chlorobenzylamine 4-fluoro-alpha-methylbenzylamine (r)-(+)-bornylamine n,n-di-n-butylethylenediamine (r)-(-)-1-cyclohexylethylamine n,n,2,2-tetramethyl-1,3-propanediamine 1-phenylalanine beta-naphthyl-amide 2-(3-chlorophenyl)ethylamine 2-amino-1,3-propanediol 2-(2-thienyl)ethylamine 2,3-dimethoxybenzylamine 3,5-dimethoxybenzylamine 2,4-dichlorophenethylamine 2,5-dimethoxyphenethylamine 3-fluoro-5-(trifluoromethyl)benzylamine 4-(trifluoromethoxy)benzylamine 1-leucinol 1-leucine-4-nitroanilide (r)-(+)-1-(1-naphthyl)ethylamine (s)-(-)-1-(1-naphthyl)ethylamine 1-valinol d-valinol d-phenylalaninol 1-(+)-alpha-phenylglycinol 20 d-(+)-alpha-methylbenzylamine 1(-)-alpha-methylbenzylamine (ls,2r)-(+)-phenyl-propanolamine (s)-(+)-2-amino-1-propanol d-alaninol (r)-(-)-sec-butylamine (s)-(+)-sec-butylamine (s)-(+)-2-amino-1-butanol (r)-(-)-2-amino-1-butanol (r)-(-)-1-amino-2-propanol (s)-(+)-1-amino-2-propanol (s)-(-)-2-methylbutylamine (s)-(+)-1-cyclohexylethylamine oleylamine 1-adamantanemethylamine (ls,2r)-(+)-2-amino-1,2-diphenylethanol (lr,2s)-(-)-2-amino-2,2-diphenylethanol s-benzyl-1-cysteinol 2-(2-(aminomethyl)phenylthio)benzyl alcohol 3-fluorophenethylamine 2-aminobenzylamine 2-fluorophenethylamine 4-aminobenzylamine d-glucamine (+/-)-2,5-dihydro-2,5-dimethoxyfurfurylamine (s)-(+)-tetrahydrofurfurylamine 4-fluorophenethylamine (ls,2s)-(+)-thiomicamine (-)-3,4-dihydroxynorephedrine (r)-(+)-1-(p-tolyl)ethylamine (s)-(-)-1-(p-tolyl)ethylamine (s)-(-)-2-amino-1,1-diphenyl-1-propanol (+/-)-exo-2-aminonorbornane (s)-(+)-2-(aminomethyl)pyrrolidine 3-amino-1-propanol vinyl ether geranylamine 4-(hexadecylamino)benzylamine (lr,2r,3r,5s)-(-)-isopinocampheylamine (ls,2s,3s,5r)-(+)-isopinocampheylamine n1-isopropyldiethylenetriamine (s)-tert-leucinol (r)-(-)-tetrahydrofurfurylamine dehydroabietylamine 2-bromo-4,5-dimethoxyphenethylamine (is,2r)-(-)-cis-1-amino-2-indanol (lr,2s)-(+)-cis-1-amino-2-indanol, and the like.
Secondary Amine Reagents:
n-propylcyclopropanemethylamine (n-butylamino)acetonitrile n-methyl-beta-alaninenitrile 3-(benzylamino)propionitrile 3,3'-iminodipropionitrile (r)-(-)-isoproterenol (lr,2r)-(-)-pseudoephedrine 1-adrenaline synephrine 2-(methylamino)ethanol n-benzylethanolamine 2-(ethylamino)ethanol diethanolamine 2-(propylamino)ethanol heptamethyleneimine n,n',n " -methylidynetrisformamide n-isopropylcyclohexylamine n-methylcyclohexylamine n-ethylcyclohexylamine allylcyclohexylamine diisopropanolamine n-methyl-d-glucamine dibenzylamine noreleagnine propyleneimine azetidine n-omega-acetylhistamine thiazolidine 3-pyrroline 2,5-dimethyl-3-pyrroline pyrrolidine 1-prolinamide 1-prolinol 3-pyrrolidinol n-omega-methyltryptamine 1-piperonylpiperazine 1,2,3,6-tetrahydropyridine 1-phenylpiperazine 1-(2-methoxyphenyl)piperazine n-(3-trifluoromethylphenyl)piperazine 1-(4-fluorophenyl)piperazine 1-(4-nitrophenyl)piperazine WO 98/46786 PC'T/US98/07151 4-piperazinoacetophenone 1-ethoxycarbonylpiperazine 1-(4-chlorobenzhydryl)piperazine n-methylpiperazine 1-benzylpiperazine 1-(pyrrolidinocarbonylmethyl)piperazine n-isopropyl-1-piperazineacetamide n-beta-hydroxyethylpiperazine morpholine 2,6-dimethylmorpholine thiomorpholine 1,4-dioxa-8-azaspiro[4.5]decane piperidine ethyl pipecolinate 2-methylpiperidine 2-piperidinemethanol 2-ethylpiperidine 2-piperidineethanol n,n-diethylnipecotamide ethyl nipecotate nipecotamide 3-methylpiperidine 3,3-dimethylpiperidine .

3,5-dimethylpiperidine 3-piperidinemethanol 4-hydroxypiperidine 4-hydroxy-4-phenylpiperidine 4-(4-chlorophenyl)-4-hydroxypiperidine 4-phenylpiperidine ethyl isonipecotate 4-methylpiperidine 4-benzylpiperidine 1-(2-pyridyl)piperazine 2-(2-methylaminoethyl)pyridine 4-piperidinopiperidine 1-methyl-4-(methylamino)piperidine decahydroquinoline 1,2,3,4-tetrahydroisoquinoline hexamethyleneimine dimethylamine n-methylbenzylamine n-methylphenethylamine n'-benzyl-n,n-dimethylethylenediamine methylaminoacetaldehyde dimethylacetal n-methylpropargylamine dipropargylamine n-methylallylamine diallylamine diisopropylamine n-isopropylbenzylamine diisobutylamine n-methyloctadecylamine n-ethylmethylamine n-ethylbenzylamine diethylamine n,n-dimethyl-n'-ethylethylenediamine n,n-diethyl-n'-methylethylenediamine n,n,n'-triethylethylenediamine n-benzylglycine ethyl ester di-sec-butylamine methyl-n-propylamine dipropylamine n-methylbutylamine n-butylbenzylamine n-ethyl-n-butylamine dibutylamine di(2-ethylhexyl)amine dipentylamine di-n-hexylamine di-n-octylamine n-benzyl-2-phenylethylamine 9-(methylaminomethyl)anthracene (s)-(+)-2-(methoxymethyl)pyrrolidine 2-methylaminomethyl-1,3-dioxolane pindolol n-ethylmethallylamine dicyclohexylamine 1,4,5,6-tetrahydropyrimidine n-(trimethylsilylmethyl)benzylamine 4,4-dimethyl-2-imidazoline (s)-(+)-1-(2-pyrrolidinylmethyl}pyrrolidine n,n,n'-trimethylethylenediamine n,n,n'-trimethyl-1,3-propanediamine tetramethylimino-bis-propylamine (r)-(+)-n-benzyl-1-phenylethylamine n-ethylisopropylamine (s)-(+)-2-(anilinomethyl)pyrrolidine (+/-)-nornicotine 2-(butylamino)ethanol 4-(ethylaminomethyl)pyridine bis(2-methoxyethyl)amine 4-(1-pyrrolidinyl)piperidine isonipecotamide methylisopropylamine n-methylhexylamine (r)-(+}-n-methyl-1-phenylethylamine 3-(3-pyridylmethylamino)propionitrile di-n-decylamine 1-acetylpiperazine n-methylhomopiperazine 1-ethylpiperazine dl-adrenaline trans-1-cinnamylpiperazine (+)-pseudoephedrine (-)-ephedrine d-prolinol 2,6-dimethylpiperidine (s)-(-)-n-benzyl-1-phenylethylamine 1,3,3-trimethyl-6-azabicyclo(3.2.1)octane 4-(4-bromophenyl)-4-piperidinol (s)-(-)-n-methyl-1-phenylethylamine n-methylhomoveratrylamine (r)-(+)-atenolol (s)-(-)-atenolol 1-hydroxyethylethoxypiperazine demecolcine n-allylcyclopentylamine mitomycin c di-beta-d-xylopyranosylamine cytisine, and the like.
Optionally the aminothioether library compounds of this invention can be further diversified by oxidizing the library compounds of Formula I where m - O to provide the corresponding sulfoxides (m _ 1) and/or sulfones (m - 2). The oxidation can be accomplished in high yields using stoichiometric amounts of any one of several oxidizing agents including m-chloroperbenzoic acid, periodate, and oxone (a mixture of potassium hydrogen persulfate, potassium bisulfate and potassium sulfate). The oxidation reaction is carried out in any one of a wide variety of solvents at a temperature of about -10 C to about 30 C. The preparation of sulfoxides and sulfones by oxidation of thioethers are well known in the art.
Oxidation of a sulfide to its corresponding sulfoxide~
1). P. G. Hunt, J. I. Grayson, S. Warren and J. Durman J. Chem. Soc. Perkin Trans 1 (1986), p. 1939.
[Uses m-CPBA (meta-chloro-peroxybenzoic acid) or sodium periodate.to give desired products in 92-100 yield].
2). D. M. Hedstrand, S. R. Byrn, A. T. McKenzie and P.
L. Fuchs J. Org. Chem. 52 (1987), pp. 592-598.
3). C. Jouen, M. C. Lasne and J. C. Pommelet Tet. Lett.
37 (1996), pp. 2413-2416.

Oxidation of a sulfide to its corresponding sulfone~
4). B. M. Trost and R. Braslau J. Org. Chem. 53 (1988), pp. 532-537. [Uses Oxone from DuPont which is "...a mixture of potassium hydrogen persulfate, potassium bisulfate and potassium sulfate...."].

The next step in the process of the present invention includes removing the protecting group P to produce compounds of the formula ~~)m HN Q-CH-S-W C A
R" Rg IV
The reaction conditions used to accomplish removal of the amino-protecting group are dependent on the nature of the protecting group and are well known to skilled practitioners in the art. Thus, for example, the tert-butyloxycarbonyl groups can be removed with trifluoracetic acid while the allyloxycarbonyl group is removed by reaction with triphenylphosphine and tetrakis (triphenylphosphine) palladium.
The resulting library compounds of Formula IV
(having a free amino group) are optionally reacted with an electrophilic agent having a molecular weight of about 30 to about 600. Suitable electrophilic agents include organic halides, aryl halides, sulfonic acid esters, organohaloformates, organosulfonyl halides, organic isocyanates, organic isothiocyanates, aldehydes and ketones. Examples of such electrophilic agents include, but are not intended to be limited to:

3,5-bis(trifluoromethyl)benzoyl chloride benzoyl chloride 2-bromobenzoyl chloride 2-fluorobenzoyl chloride pentafluorobenzoyl chloride 2,4-difluorobenzoyl chloride 2,6-difluorobenzoyl chloride 2-chlorobenzoyl chloride 2,4-dichlorobenzoyl chloride 2,6-dichlorobenzoyl chloride o-acetylsalicyloyl chloride 2-methoxybenzoyl chloride 2,6-dimethoxybenzoyl chloride 2-(trifluoromethyl)benzoyl chloride o-toluoyl chloride 3-bromobenzoyl chloride 3-fluorobenzoyl chloride 3-chlorobenzoyl chloride 3,4-dichlorobenzoyl chloride m-anisoyl chloride 3,4-dimethoxybenzoyl chloride 3,4,5-trimethoxybenzoyl chloride 3,5-dimethoxybenzoyl chloride 3-ethoxybenzoyl chloride isophthaloyl chloride trimesoyl chloride 3-(trifluoromethyl)benzoyl chloride m-toluoyl chloride 3-(chloromethyl) benzoyl chloride 4-bromobenzoyl chloride 4-fluorobenzoyl chloride 4-chlorobenzoyl chloride p-anisoyl-chloride 4-ethoxybenzoyl chloride 4-n-butoxybenzoyl chloride 4-n-hexyloxybenzoyl chloride 4-heptyloxybenzoyl chloride 4-biphenylcarbonyl chloride terephthaloyl chloride 4-(trifluoromethyl)benzoyl chloride 4-tert-butylbenzoyl chloride p-toluoyl chloride 4-ethylbenzoyl chloride 4-n-propylbenzoyl chloride 4-butylbenzoyl chloride 4-pentylbenzoyl chloride 4-hexylbenzoyl chloride 4-n-heptylbenzoyl chloride methyl oxalyl chloride ethyl oxalyl chloride heptafluorobutyryl chloride 2-acetoxyisobutyryl chloride pivaloyl chloride 3-chloropivaloyl chloride 2-bromopropionyl chloride 2,3-dibromopropionyl chloride 2,3-dichloropropionyl chloride o-acetylmandelic acid chloride itaconyl chloride methacryloyl chloride isobutyryl chloride 2-ethylhexanoyl chloride acetyl chloride bromoacetyl chloride chloroacetyl chloride phenoxyacetyl chloride 4-chlorophenoxyacetyl chloride methoxyacetyl chloride phenylacetyl chloride 3,3-dimethylacryloyl chloride cinnamoyl chloride fumaryl chloride ethyl malonyl chloride tert-butylacetyl chloride isovalezyl chloride undecanoyl chloride lauroyl chloride myristoyl chloride palmitoyl chloride heptadecanoyl chloride stearoyl chloride propionyi chloride 3-bromopropionyl chloride 3-chloropropionyl chloride hydrocinnamoyl chloride succinyl chloride 3-carbomethoxypropionyl chloride ethyl succinyl chloride butyryl chloride 4-bromobutyryl chloride 4-chlorobutyrylchloride valeryl chloride 5-chlorovaleryl chloride adipoyl chloride hexanoyl chloride 6-bromohexanoyl chloride pimeloyl chloride heptanoyl chloride suberoyl chloride octanoyl chloride 10-undecenoyl chloride 2-chloro-2,2-diphenylacetyl chloride dichloroacetyl chloride alpha-chlorophenylacetyl chloride 2-chloropropionyl chloride 2-iodobenzoyl chloride 4-iodobenzoyl chloride cyclopropanecarbonyl chloride trans-2-phenyl-1-cyclopropanecarbonyl chloride cyclobutanecarbonyl chloride cyclopentanecarbonyl chloride 3-cyclopentylpropionyl chloride cyclohexanecarbonyl chloride 4-cyanobenzoyl chloride 2-furoyl chloride 1-naphthoyl chloride 2-naphthoyl chloride thiophene-2-carbonyl chloride 2-thiopheneacetyl chloride trimellitic anhydride chloride 2,6-pyridinedicarboxylic acid chloride 2-quinoxaloyl chloride 2-nitrobenzoyl chloride 3-nitrobenzoyl chloride 3,5-dinitrobenzoyl chloride 4-nitrobenzoyl chloride 3,4-dimethoxyphenylacetyl chloride 3-methyladipoyl chloride 3,5-dichlorobenzoyl chloride 2,5-difluorobenzoyl chloride 3,4-difluorobenzoyl chloride 9-fluorenone-4-carbonyl chloride 3,5-difluorobenzoyl chloride (s)-(-)-n-(trifluoroacetyl)prolyl chloride benzyloxyacetyl chloride acetoxy acetyl chloride 3-cyanobenzoyl chloride 2,5-dimethoxyphenylacetyl chloride 3-methoxyphenylacetyl chloride iminodibenzyl-5-carbonyl chloride 2,4,6-trimethylbenzoyl chloride tetrafluorosuccinyl chloride perfluorooctanoyl chloride diphenylacetyl chloride alpha-methyl valeroyl chloride methyl malonyl chloride ethyl glutaryl chloride 5-bromovaleryl chloride methyl adipyl chloride 3-cyclohexenecarbonyl chloride 3-isocyanato benzoyl chloride 2,4,6-triisopropylbenzoyl chloride fluoroacetyl chloride 2-ethoxybenzoyl chloride piperonyloyl chloride 2,4-dimethoxybenzoyl chloride 2,3,5,6-tetrachloroterephthaloyl chloride 5-(dimethylsulfamoyl)-2-methoxybenzoyl chloride 2-(4-chlorobenzoyl)benzoyl chloride 2,2-bis(chloromethyl)propionyl chloride cinnamylidenemalonyl chloride 2-phenoxypropionyl chloride 2-phenylbutyryl chloride 2-ethylbutyryl chloride p-tolylacetyl chloride gamma-methylvaleroyl chloride 3,3-dichloropivaloyl chloride 1-methyl-1-cyclohexanecarboxylic acid chloride 2-(2,4,5-trichlorophenoxy)acetyl chloride 4-chloro-3-nitrobenzoyl chloride 4-methyl-3-nitrobenzoyl chloride 2,3-dichlorobenzoyl chloride morpholine-4-carbonyl chloride p-chlorophenylacetyl chloride bicyclo[2.2.1]heptane-2-carbonyl chloride d(-)-alpha-formyloxy-alpha-phenylacetyl chloride d(-)-alpha-phenylglycine chloride hydrochloride trifluoroacetyl chloride pentafluoropropionyl chloride hexafluoroglutaryl chloride 2-chlorocinnamoyl chloride o-methoxycinnamyl chloride 5-nitro-2-furoyl chloride 2-chlorobutyryl chloride 4-phenylazobenzoyl chloride 4-n-amyloxybenzoyl chloride 4-decylbenzoyl chloride 4-octylbenzoyl chloride dl-2-methylbutyryl chloride linolenoyl chloride linolelaidoyl chloride llh-eicosafluoroundecanoyl chloride 9h-hexadecafluorononanoyl chloride 2,3-difluorobenzoyl chloride 2-(benzoyloxymethyl)benzoyl chloride 2,2-dimethylvaleroyl chloride 3,5,5-trimethylhexanoyl chloride phenothiazine-10-carbonyl chloride 3,4-dimethyl benzoyl chloride (+)-p-(2-methylbutyl)benzoyl chloride 2,4-dichlorophenoxyacetic chloride pentadecanoyl chloride nonadecanoyl chloride neoheptanoyl chloride 9-anthracenecarbonyl chloride 2-ethoxy-1-naphthoyl chloride pyrrolidine carbonyl chloride m-(chlorosulfonyl)benzoyl chloride 2-n-propyl-n-valeroyl chloride 2-chloro-4-nitrobenzoyl chloride 2-phenoxybutyryl chloride 2-chloronicotinyl chloride 6-chloronicotinyl chloride 4-(trifluoromethoxy)benzoyl chloride 2-(trifluoromethoxy)benzoyl chloride 2,6-dichloropyridine-4-carbonyl chloride 3-chlorobenzo[blthiophene-2-carbonyl chloride 4-chloromethylbenzoyl chloride neodecanoyl chloride (phenylthio)acetyl chloride 4-carbethoxyhexafluorobutyryl chloride octafluoroadipoyl chloride 2-diazo-3,3,3-trifluoropropionylchloride 2-bromobutyryl chloride arachidoyl chloride cis-vaccenoyl chloride 11-eicosenoyl chloride behenoyl chloride petroselinoyl chloride palmitoleoyl chloride tridecanoyl chloride 2-chloro-5-nitrobenzoyl chloride 3-methylthiopropionyl chloride methyl 4-chlorocarbonylbenzoate anthraquinone-2-carbonyl chloride carbazole-n-carbonyl chloride 2-nitrophenoxyacetyl chloride 2-bromo-2-methylpropionyl chloride 2-fluoro-3-(trifluoromethyl)benzoyl chloride 2-fluoro-4-(trifluoromethyl)benzoyl chloride 2-fluoro-5-(trifluoromethyl)benzoyl chloride 3-fluoro-5-(trifluoromethyl)benzoyl chloride 4-fluoro-2-(trifluoromethyl)benzoyl chloride 4-fluoro-3-(trifluoromethyl)benzoyl chloride 2-fluoro-6-(trifluoromethyl)benzoyl chloride 2,3,6-trifluorobenzoyl chloride 2,4,5-trifluorobenzoyl chloride 2,4-di(trifluoromethyl)benzoyl chloride 2,6-di(trifluoromethyl)benzoyl chloride 3-(trifluoromethoxy)benzoyl chloride m-(fluorosulfonyl)benzoyl chloride trans-1,2-cyclobutanedicarboxylic acid chloride 3-cyclohexylpropionyl chloride 4-ethyl-2,3-dioxo-1-piperazinecarbonylchloride isoxazole-5-carbonyl chloride bromodifluoroacetyl chloride erucoyl chloride 2,4,6-trifluorobenzoyl chloride dichlorochzysanthemic acid chloride isononanoyl chloride 1-adamantanecarbonyl chloride 2,5-bis(trifluoromethyl)benzoyl chloride 2,3,4-trifluorobenzoyl chloride 2,3,4,5-tetrafluorobenzoyl chloride 2,4,6-trichlorobenzoyl chloride 2,4-dichloro-5-fluorobenzoyl chloride 4-methoxyphenylacetyl chloride trans-3-(trifluoromethyl)cinnamoyl chloride 3-(dichloromethyl) benzoyl chloride 4-isocyanato benzoyl chloride heneicosanoyl chloride 2-chloroisobutyryl chloride trans-4-nitrocinnamoyl chloride 3,4,5-trifluorobenzoyl chloride 5-fluoro-2-(trifluoromethyl)benzoyl chloride 2,3,5-trifluorobenzoyl chloride 2-chloro-4-fluorobenzoyl chloride (-)-alpha-chlorophenylacetyl chloride 2-(para-tolylsulfonyl)acetyl chloride 4-methyl-4-nitrohexanoyl chloride 1-chloro-4-fluorosulfonyl-2-naphthoyl chloride 2,3-dibromo-3-phenylpropionyl chloride 2-menthoxyacetyl chloride 2-phenyl-2-(phenylsulfonyl)acetyl chloride 4,4,4-trifluorocrotonyl chloride 4,4,4-trifluorobutyryl chloride 3,4-dichloro-2,5-thiophenedicarbonyl chloride pentachlorobenzoyl chloride 4,4,7,7-tetranitrosebacoyl chloride alpha,alphal-dimethylsuccinyl chloride alpha-bromoisovaleryl chloride benzoyl chloride oleoyl chloride methyl suberyl chloride gamma-linolenoyl chloride (-)-camphanic acid chloride 4,4'-stilbenedicarbonyl chloride chlorinated benzoyl chloride (lr)-(+)-camphanic chloride 2-(4-nitrophenoxy)tetradecanoyl chloride 7-[(chlorocarbonyl)methoxy]-4-methylcoumarin n,n-bis(2-chloroethyl)carbamoyl chloride (s)-(-)-2-acetoxypropionyl chloride linoleoyl chloride 3-chlorotetrafluoropropionyl chloride 3,4-dichloropentafluorobutyryl chloride 7h-dodecafluoroheptanoyl chloride 5h-octafluoropentanoyl chloride perfluorononanoyl chloride 3h-tetrafluoropropionyl chloride 2-bromo-2,3,3,3-tetrafluoropropanoyl chloride arachidonoyl chloride pentachloropropionyl chloride 4-decenoyl chloride tridecafluoroheptanoyl chloride undecafluorocyclohexanecarbonyl chloride 4-n-nonylbenzoyl chloride 3-(trichlorogermyl)propionylchloride 3,4,5-triiodobenzoyl chloride 2-(phenylthio)propionyl chloride 2,2,2-triphenylacetyl chloride d(-)-alpha-azido-phenyl acetyl chloride 4-azido-benzoyl chloride difluoroacetyl chloride 5-chloropyrazine-2-carbonyl chloride n-(1-naphthalenesulfonyl)-1-phenylalanyl chloride n-(4-nitrophenylsulfonyl)-1-phenylalanyl chloride n-(p-toluenesulfonyl)-1-phenylalanyl chloride dimethylmalonyl chloride methyl sebacoyl chloride 2,5-:dichloropyridine-3-carbonyl chloride 3-(2,5 xylyloxy) propionyl chloride, and the like.
Organic Halides:
benzyl bromide alpha-bromo-o-xylene alpha-bromo-m-xylene 4-(tert-butyl)benzyl bromide alpha-bromo-p-xylene tert-butyl bromoacetate methyl bromoacetate benzyl bromoacetate ethyl bromoacetate 2-bromoacetophenone 2-bromo-2'-methoxyacetophenone 2-bromo-2',4'-dimethoxyacetophenone 2-bromo-2',5'-dimethoxyacetophenone 3-methoxyphenacyl bromide 2-bromo-4'-methoxyacetophenone 2-bromo-4'-phenylacetophenone 2-bromo-4'-methylacetophenone ethyl bromopyruvate 1-bromopinacolone 1-bromo-2-butanone 1-bromo-2,2-dimethoxypropane 1-bromo-2,2-dimethylpropane bromoacetaldehyde dimethyl acetal bromoacetaldehyde diethyl acetal 1-bromo-2-methylpropane 1-bromo-2-ethylbutane 2-ethylhexyl bromide-I-bromodecane 1-bromoundecane 2-bromoacetamide iodoacetamide 4-(bromomethyl)phenylacetic acid phenacyl ester isopropyl bromoacetate 5-bromo-2-methyl-2-pentene 3,4-difluorobenzyl bromide 2,5-difluorobenzyl bromide 3,5-bis(trifluoromethyl)benzyl bromide 2-bromo-2'-nitroacetophenone 3,5-difluorobenzyl bromide 2,4-bis(trifluoromethyl)benzyl bromide

8-bromo-1-octanol 4-(bromomethyl)phenylacetic acid methyl (r)-(+)-3-bromo-2-methylpropionate 4-iodobutyl acetate 7-acetoxy-4-bromomethylcoumarin 4-bromomethyl-6,7-dimethoxycoumarin 2,4-difluorobenzyl bromide methyl 2-(bromomethyl)acrylate 3-bromopropionaldehyde dimethyl acetal.
(r)-(-)-3-bromo-2-methyl-1-propanol, and the like.
Sulfonic Acid Esters:
ethyl trifluoromethanesulfonate 2,2,2-trifluoroethyl p-toluenesulfonate 2-chloroethyl-p-toluenesulfonate 1,3-propane sultone 5'-tosyladenosine 1,4-butane sultone cyanomethyl benzenesulfonate hexadecyl methanesulfonate ethyl methanesulfonate 2-chloroethyl methanesulfonate ethyl p-toluenesulfonate trans-2-hydroxycyclohexyl p-toluenesulfonate (2r)-(-)-glycidyl tosylate (s)-(+)-2-methylbutyl methanesulfonate (s)-(+)-2-methylbutyl p-toluenesulfonate (s)-(+)-1-phenyl-1,2-ethanediol 2-tosylate (2r)-(-)-glycidyl 3-nitrobenzenesulfonate propargyl benzenesulfonate 2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (r)-(-)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate (s)-(+)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate 1,2:5,6-di-o-isopropylidene-3-o-(methylsulfonyl)-alpha-d-glucofuranose ethyl 1-2-((methylsulfonyl)oxy)propionate (2s)-(+)-glycidyl tosylate (2s)-(+)-glycidyl 3-nitrobenzenesulfonate 3-o-acetyl-6-o-benzoyl-5-o-(methylsulfonyl)-1,2-0-isopropylidene-alpha-d-glucofu (r)-(-)-1-benzyloxy-3-(p-tosyloxy)-2-propanol (s)-(+)-1-benzyloxy-3-(p-tosyloxy)-2-propanol ethyl 1-2-((trifluoromethylsulfonyl)oxy)propionate 2-(2-chloroethoxy)ethyl methanesulfonate 1-cyanoethyl p-toluenesulfonate, and the like.
Organohaloformates:

9-fluorenylmethyl chloroformate phenyl chloroformate 4-chlorophenyl chloroformate methyl chloroformate benzyl chloroformate vinyl chloroformate isobutyl chloroformate 2-ethylhexyl chloroformate ethyl chloroformate 2-bromoethyl chloroformate 2-chloroethyl chloroformate 1-chloroethyl chloroformate allyl chloroformate n-propyl chloroformate butyl chloroformate n-hexyl chloroformate octyl chloroformate 2,2,2-trichloro-1,1-dimethylethyl chloroformate 2,2,2-trichloroethyl chloroformate cholesteryl chloroformate 4-nitrophenyl chloroformate 4-nitrobenzyl chloroformate (-)-menthyl chloroformate 4-t-butylcyclohexyl chloroformate cetyl chloroformate (+)-1-(9-fluorenyl)ethyl chloroformate isopropyl chloroformate 3-chlorocyclohexyl chloroformate decyl chloroformate oleyl chloroformate octadecyl chloroformate butenediol bischloroformate 2-chlorobenzyl chloroformate 4-chlorobutyl chloroformate (+)-menthyl chloroformate 4,5-dimethoxy-2-nitrobenzyl chloroformate cyclopentyl chloroformate t-butylcyclohexyl chloroformate menthylchloroformate p-tolyl chloroformate 4-bromophenyl chloroformate 4-fluorophenyl chloroformate 4-methoxyphenyl chloroformate 2-nitrophenyl chloroformate 4-methoxycarbonylphenyl chloroformate 1-chloro-2-methylpropyl chloroformate (+/-)-1,2,2,2-tetrachloroethyl chloroformate 2,2-dichloroethyl chloroformate rnyristyl chloroformate cyclohexyl chloroformate chloromethyl chloroformate, and the like.
Organosulfonylhalides:
1-naphthalenesulfonyl chloride dansyl chloride 2-naphthalenesulfonyl chloride 2-acetamido-4-methyl-5-thiazolesulfonyl chloride 2-thiophenesulfonyl chloride B-quinolinesulfonyl chloride benzenesulfonyl chloride pentafluorobenzenesulfonyl chloride 2,5-dichlorobenzenesulfonyl chloride 2-nitroberizenesulfonyl chloride 2,4-dinitiobenzenesulfonyl chloride 3,5-dichloro-2-hydroxybenzenesulfonyl chloride 2,4 6-triisopropylbenzenesulfonyl chloride 2-mesitylenesulfonyl chloride 3-nitrobenzenesulfonyl chloride p-bromobenzenesulfonyl chloride 4-fluorobenzenesulfonyl chloride 4-chlorobenzenesulfonyl chloride 4-chloro-3-nitrobenzenesulfonyl chloride pipsyl chloride 4-nitrobenzenesulfonyl chloride 4-methoxybenzenesulfonyl chloride 4-tert-butylbenzenesulfonyl chloride p-toluenesulfonyl chloride trifluoromethanesulfonyl chloride trichloromethanesulfonyl chloride isopropylsulfonyl chloride methanesulfonyl chloride alpha-toluenesulfonyl chloride trans-beta-styrenesulfonyl chloride 2,2,2-trifluoroethanesulfonyl chloride 1-hexadecanesulfonyl chloride ethanesulfonyl chloride 2-chloroethanesulfonyl chloride WO 98/46786 PCTNS98/0?151 1-propanesulfonyl chloride 3-chloropropanesulfonyl chloride 1-butanesulfonyl chloride methyl 2-(chlorosulfonyl)benzoate 2-nitro-4-(trifluoromethyl)benzenesulfonyl chloride 3-(trifluoromethyl)benzenesulfonyl chloride 1-octanesulfonyl chloride 4-(trifluoromethoxy)benzenesulphonyl chloride (1r)-(-)-10-camphorsulfonyl chloride d-(+)-10-camphorsulfonyl chloride (+/-)-10-camphorsulfonyl chloride 2-nitro-alpha-toluenesulfonyl chloride, and the like.
Isocyanate Reagents:
trans-2-phenylcyclopropyl isocyanate phenyl isocyanate 2-bromophenyl isocyanate 2-fluorophenyl isocyanate 2,4-difluorophenyl isocyanate 2,6-difluorophenyl isocyanate 2-chlorophenyl isocyanate 2,3-dichlorophenyl isocyanate 2,4-dichlorophenyl isocyanate 2,5-dichlorophenyl isocyanate 2,6-dichlorophenyl isocyanate 2-methoxyphenyl isocyanate 2,4-dimethoxyphenyl isocyanate 2,5-dimethoxyphenyl isocyanate 2-ethoxyphenyl isocyanate 2-(trifluoromethyl)phenyl isocyanate o-tolyl isocyanate 2,6-dimethylphenyl isocyanate 2-ethylphenyl isocyanate 3-bromophenyl isocyanate 3-fluorophenyl isocyanate 3-chlorophenyl isocyanate 3,4-dichlorophenyl isocyanate 3-methoxyphenyl isocyanate 3-(trifluoromethyl)phenyl isocyanate m-tolyl isocyanate 4-bromophenyl isocyanate 4-fluorophenyl isocyanate 4-chlorophenyl isocyanate 4-methoxyphenyl isocyanate ethyl 4-isocyanatobenzoate 4-(trifluoromethyl)phenyl isocyanate p-tolyl isocyanate n-(chlorocarbonyl) isocyanate benzoyl isocyanate tert-butyl isocyanate (s)-(-)-alpha-methylbenzyl isocyanate isopropyl isocyanate methyl isocyanate ethyl isocyanatoacetate octadecyl isocyanate ethyl isocyanate 2-chloroethyl isocyanate allyl isocyanate n-propyl isocyanate butyl isocyanate cyclohexyl isocyanate 1-naphthyl isocyanate (r)-(-)-1-(1-naphthyl)ethyl isocyanate 4-fluoro-3-nitrophenyl isocyanate 2-nitrophenyl isocyanate 3-nitrophenyl isocyanate 4-nitrophenyl isocyanate 2,6-diisopropylphenyl isocyanate benzyl isocyanate 3-chloropropyl isocyanate ethoxycarbonyl isocyanate 3,5-bis(trifluoromethyl)phenyl isocyanate 2,4,6-tribromophenyl isocyanate 2,5-difluorophenyl isocyanate 2,4,5-trichlorophenyl isocyanate 2,4,6-trichlorophenyl isocyanate 2-methoxycarbonylphenyl isocyanate 2-ethoxycarbonylphenyl isocyanate 2-isopropylphenyl isocyanate 2,3-dimethylphenyl isocyanate 4-methoxy-2-methylphenyl isocyanate 2,4-dimethylphenyl isocyanate 2,5-dimethylphenyl isocyanate 2-ethyl-6-methylphenyl isocyanate 3-cyanophenyl isocyanate 5-chloro-2,4-dimethoxyphenyl isocyanate 3-chloro-4-methylphenyl isocyanate 3,5-dichlorophenyl isocyanate 5-chloro-2-methoxyphenyl isocyanate 3,4,5-trimethoxyphenyl isocyanate 3,5-dimethoxyphenyl isocyanate 3-(methylthio)phenyl isocyanate 3-ethoxycarbonylphenyl isocyanate 3-acetylphenyl isocyanate 3,4-dimethylphenyl isocyanate 3,5-dimethylphenyl isocyanate 2-methoxy-5-methylphenyl.isocyanate 3-ethylphenyl isocyanate 4-chloro-2-methoxyphenyl isocyanate 4-chloro-2-trifluoromethylphenyl isocyanate 4-chloro-3-trifluoromethylphenyl isocyanate 4-iodophenyl isocyanate WO 98/46786 PCTlUS98/07151 4-phenoxyphenyl isocyanate 4-ethoxyphenyl isocyanate 4-(methylthio)phenyl isocyanate 4-acetylphenyl isocyanate 4-isopropylphenyl isocyanate _ 4-ethylphenyl isocyanate 4-n-butylphenyl isocyanate 3-(dichloromethylsilyl)propyl isocyanate octyl isocyanate 4-methyl-3-nitrophenyl isocyanate 4-chloro-2-nitrophenyl isocyanate 2-methyl-4-nitrophenyl isocyanate 4-methyl-2-nitrophenyl isocyanate 2-fluoro-5-nitrophenyl isocyanate 2-methyl-5-nitrophenyl isocyanate 3-bromopropyl isocyanate 2,4,6-trimethylphenyl isocyanate 2-isopropyl-6-methylphenyl isocyanate 2,6-diethylphenyl isocyanate 5-chloro-2-methylphenyl isocyanate 4-chloro-2-methylphenyl isocyanate 4-(trifluoromethoxy)phenyl isocyanate 4-trifluoromethylthiophenylisocyanate 2,4-dibromophenyl isocyanate 2,6-dibromo-4-ethylphenyl isocyanate 2,3,4,5-tetrachlorophenyl isocyanate 2-chloro-5-trifluoromethylphenyl isocyanate 2-chloro-6-methylphenyl isocyanate 2-n-carbobutoxyphenyl isocyanate 2,4,5-trimethylphenyl isocyanate 2-methyl-6-(t-butyl)phenyl isocyanate 2-ethyl-6-isopropylphenyl isocyanate 3-chloro-2-methoxyphenyl isocyanate 3-chloro-2-methylphenyl isocyanate 3-chloro-4-fluorophenyl isocyanate 4-cyanophenyl isocyanate 4-bromo-2-methylphenyl isocyanate 4-bromo-2,6-dimethylphenyl isocyanate 2,6-dibromo-4-fluorophenyl isocyanate 4-n-butoxyphenyl isocyanate 4-butoxycarbonylphenyl isocyanate phenethyl isocyanate 2-methyl-3-nitrophenyl isocyanate hexyl isocyanate hexadecyl isocyanate _ methylene bis(o-chlorophenyl isocyanate) 4-chloro-3-nitrophenyl isocyanate 2-chloro-4-nitrophenyl isocyanate , 4,5-dimethyl-2-nitrophenyl isocyanate 2-chloro-5-nitrophenyl isocyanate 2-methoxy-4-nitrophenyl isocyanate 3-fluoro-4-methylphenyl isocyanate 5-fluoro-2-methylphenyl isocyanate 3,5-dicarbomethoxyphenyl isocyanate 2,4-dichlorobenzyl isocyanate 2-(methylthio)phenyl isocyanate n-(methoxycarbonyl)isocyanate n-(phenoxycarbonyl)isocyanate 2-biphenylyl isocyanate 3-iodophenyl isocyanate 4-phenylphenyl isocyanate tetrahydro-2-pyranyl isocyanate 4-(tert-butyl)phenylisocyanate 1-(4-bromophenyl)ethyl isocyanate isocyanatoacetic acid n-butyl ester dodecyl iqocyanate 6,7-methylenedioxy-4-isocyanate-methylcoumarin (r)-(+)-alpha-methylbenzyl isocyanate (+/-)-I-(1-naphthyl)ethyl isocyanate (s)-(+)-1-(1-naphthyl)ethyl isocyanate 3,4-difluoropher,yl isocyanate 2-methoxy-5-nitrophenyl isocyanate undecyl isocyanate ethyl 2-isocyanato-4-methyl valerate ethyl 6-isocyanatohexanoate ethyl 2-isocyanato-4-methylthiobutyrate ethyl 2-isocyanatopropionate ethyl 3-isocyanatopropionate ethyl 2-isocyanato-3-methylbutyrate tert-butyl 3-isothiocyanatopropionate ethyl 2-isocyanato-3-phenylpropionate 1,3-bis(isocyanatom ethyl)cyclohexane 2-(trifluoromethoxy)phenyl isocyanate 4-(chloromethyl) phenyl isocyanate 1-adamantyl isocyanate 1,3-bis(2-isocyanato-2-propyl)benzene n-amyl isocyanate n-heptyl isocyanate 2-chloroethyl isocyanate, [ethyl-1,2-14c]
1,1,3,3-tetramethylbutyl isocyanate 3,5-dinitrophenyl isocyanate, and the like.
Aldehydes:
Ethyl 2-formyl-1-cyclopropanecarboxylate Cyclohexanecarboxaldehyde 1,2,3,6-Tetrahydrobenzaldehyde Diphenylacetaldehyde 2-Phenylpropionaldehyde 2,3-Dimethylvaleraldehyde Isobutyraldehyde 2,6-Dimethyl-5-hepten-1-al 2-Methylbutyraldehyde 2-Ethylbutyraldehyde 2-Methylpentanal 2-Ethylhexanal 2-Methylundecanal Phenylacetaldehyde Isovaleraldehyde 7-Methoxy-3,7-dimethyloctanal Undecanal Dodecanal Tridecanal Tetradecyl aldehyde Propionaldehyde 3-Phenylpropionaldehyde 3-(Methylthio)propionaldehyde Butyraldehyde Cis-4-decen-1-al N-valeraldehyde Hexanal Heptaldehyde Octanal Nonanal Decanal Undecylenic aldehyde Cis-11-hexadecenal Cis-13-octadecenal Cis-9-hexadecenal 2,5-Dimethoxy-3-tetrahydrofurancarboxaldehyde 3,5,5-Trimethylhexanal Succinic semialdehyde (+/-)-3-Phenylbutyraldehyde 2,6,6-Trimethyl-1-cyclohexene-1-acetaldehyde Cyclopropanecarboxaldehyde 3-Cyclohexylpropionaldehyde Hydroxycitronellal Cis-4-heptenal Cis-6-nonen-1-al Tetrahydrocitral Cis-7-decen-1-al Cis-8-undecen-1-al 3,5,6-Trimethyl-3-cyclohexene-1-carboxaldehyde Lyral (r) Bis(2-chlorophenyl)acetaldehyde 2-Thioglyceraldehyde 3-(4-Isopropylphenyl)isobutyraldehyde 2-Ethyl-3-methylbutanal .
2-Ethylcaprylaldehyde 3-Methylvaleraldehyde 3-Phenyl-3-(p-tosyl)propionaldehyde 3-Hexenal 3-(Methylthio)butanal Veltonal Citronellal 2-(Trifluoromethyl)propionaldehyde 3,3-Dimethylbutyraldehyde Campholene aldehyde 2-Formylpropionic acid methyl ester 5-Hydroxypentanal p-Methylphenylacetaldehyde Omega-ketoheptanoic acid 4-Chlorophenylcyanoacetaldehyde Hexadecanal Methyl 7-oxoheptanoate Diethyl formyl succinate 4-Pregnene-20-beta-carboxaldehyde-3-one Cis-7-tetradecenal Cyclopentylmethanal 3,4-Dimethyl-3-cyclohexenylmethanal 2,4,6-Trimethyl-3-cyclohexen-1-carboxaldehyde Adipic semialdehyde methyl ester Cis-14-methyl-8-hexadecenal Cis-3-hexen-1-al Trans-4-decen-1-al 2,2-Dichlorooctadecanal 2,2-Dichlorotetradecanal 2,2-Dichlorooctanal 2,2-Dichlorohexanal (r)-(+)-Citronellal 8-Methyl-7-nonenal 2-(p-Tolyl)propionaldehyde Aldehyde C-11 MOA (2-methyldecanal) Alpha-rnethylhydrocinnamaldehyde (s)-(-)-Citronellal 4-Hydroxybutanal 4-Oxobutyric acid methyl ester 3,3,4,4,5,5,5-Heptafluoropentanal 3-Methylbutanal-1-13c 6-Methyl-3-cyclohexene-1-carboxaldehyde 4-(4-Methyl-2-pentenyl)-3-cyclohexene-1-carboxaldehyde 3-Pentyn-1-al 3-Pyridylacetaldehyde n-oxide 2,3-Dihydro-5-methoxy-3-phenyl-2-indolecarboxaldehyde 2,4-biphenyl-3-oxobutyraldehyde 3,3,3-Triphenylpropionaldehyde 2-Bromo-n-(3-formyl-1-methylpropyl)benzamide 3-(Phenylthio)butyraldehyde Diethyl 2-(diethoxymethyl)-3-formylsuccinate 2-Chloro-3-(4-nitrophenyl)-propionaldehyde 2-Acetoxypropionaldehyde 2-Methyl-4-phenylpentanal (lr,2s,3r,4s)-(+)-2-Benzyloxy-3-formyl-oxybornane 5-(4'-Chlorophenoxy)-1-pentanal Boc-ala-CHO
Boc-leu-CHO
Boc-phe-CHO _ Boc-tyr(OBzl)-CHO
Boc-tyr(OMe)-CHO
Boc-val-CHO
4-Pentenal 1-Formyl-6-(dimethylamino)fulvene 1,4-Dioxaspiro(4.5)decane-7-acetaldehyde Alpha-citronellal Diethyl 2-Acetamido-2-(2-formylethyl)malonate 3,4,4,5,5,5-Hexafluoro-3-(trifluoromethyl)pentanal 3,4,4,4-Tetrafluoro-3-(heptafluoropropoxy)butanal 3,4,4,4-Tetrafluoro-3-(trifluoromethoxy)butanal 3,4,4,4-Tetrafluoro-3-(trifluoromethyl)butanal 3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctanal 3,3,3-Trifluoropropanal Beta,beta-dimethylhydrocinnamaldehyde 5-Norbornene-2-carboxaldehyde Chrysanthal 9-Decenal Decyl aldehyde, [1-14c]
4,4,4-Trifluorobutyraldehyde 3-Methyl-3-butenal 3-(5-Methyl-2-furyl)butanal 3-Phenyl-4-pentenal Tert-butyl (s)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate Trans-2-dodecenal 9,10-Dihydro-9,10-ethanoanthracene-11-carboxaldehyde Methyl hexyl acetaldehyde 2,3-Dihydro-2-oxo-1H-imidazol-4-carboxaldehyde N-Acetylmuramic acid, and the like.
Other suitable aldehydes useful in preparation of the present libraries are further illustrated by the following formulas, wherein L is -CHO:

L L L I
L
O / 1 L i L
/ \ ~ p / \ ~ I o L L L

\ \

/O ~ /

~ N O

~~ \
O- CH
O

L L

O
a \ \
NCO

/ CHI /
\
/

O /

OH

OH

L L
~C/~ ~ ~ \ ~ \
~3 ~ / ~CH3 ~O
H3C ~ O O~ CH3 O H

L L
OH ~i a i w I w r OH
r L L
I_ O O
I' rNw L
Br O~ \OH
L
i i I ~ \

HN
HN _ 'CH3 II~IIO
L
r ( r w ~c. w I ( cH

O O

L L
~O
N;
Ci I - Br F
L L
of °~
/ /
H3C~0 L L L
O
HsC~ ~
O ~ N. ~ O ~ CHs II &
O

L O L
w w ~ OV
i ~ ~ CH
Br L L L

O

WO 98/46786 PCT/US98/0?ISI

L L
/
-Br CI
F CI
_ L L L
O'' \ /
O
O O
C H, L L
/ F /
\ \
/ /

O
L L L
\ \ F
/ /
I-~C~ N~ CHb F
L L L
CI
I
\ ~ i L
~3 OH
L
F
L L
\ \
O~CH3 CH3 u C L ,3Cv\/'v\/'L

~./~ L ~'~
o ~~ ( w O~CH3 L
i \ L L
HaC / ~ i L O L L
HsC
'~/ ~. O
HaC ~ H3C
CEb ~ ~- o HOC ' L L
1~ ~ /
0 o Fi~C!~ O

I
\ \ L O L \ L
/ ~C ~ ~ HOC /
\ .O v / CHa L L
L
C
\ C~' H3C ~ ~ W /\/\i \
H3 C O ' L
/ ~ CI
w i C H3 ,c L
. 1 w w ° ~ ° H' O ~ ~ ~ o /
Br L
H3C \ \
O
O
H3C ~
Ketones:

1,1,1-TRIFLUORO-2,4-PENTANEDIONE
FLUOROACETONE

4'-CHLOROACETOACETANILIDE

CHLOROACETONE
1,3-DICHLOROACETONE

CYCLOTRIDECANONE
CYCLOPENTADECANONE
DICYCLOPROPYL KETONE
CYCLOPROPYL METHYL KETONE
(-)-THUJONE
CYCLOBUTANONE

4-CYCLOPENTENE-1,3-DIONE
1,3-CYCLOPENTANEDIONE
2-METHYL-1,3-CYCLOPENTANEDIONE
CYCLOPENTANONE

2,4-DIMETHYLCYCLOPENTANONE

BETA-IONONE
BETA-IONONE
ALPHA-IONONE

3,5-DIMETHYL-2-CYCLOHEXEN-1-ONE
ISOPHORONE
1,3-CYCLOHEXANEDIONE
2-ACETYL-1,3-CYCLOHEXANEDIONE
2-METHYL-1,3-CYCLOHEXANEDIONE
DIMEDONE
1,4-CYCLOHEXANEDIONE
DIMETHYL 1,4-CYCLOHEXANEDIONE-2,5-DICARBOXYLATE
DIETHYL 1,4-CYCLOHEXANEDIONE-2,5-DICARBOXYLATE
CYCLOHEXANONE

2-(3-METHOXYPHENYL)CYCLOHEXANONE

L-MENTHONE

(+)-DIHYDROCARVONE
2,6-DIMETHYLCYCLOHEXANONE

3,3,5,5-TETRAMETHYLCYCLOHEXANONE

3,4,8,8A-TETRAHYDRO-8A-METHYL-1,6(2H,7H)-NAPHTHALENEDIONE

BETA-TETRALONE

CYCLOOCTANONE
CYCLONONANONE
ALPHA-ACETYL-PHENYLACETONITRILE

4-(4-HYDROXYPHENYL)-2-BUTANONE
1,3-ACETONEDICARBOXYLIC ACID
LEVULINIC ACID
4,6-DIOXOHEPTANOIC ACID

4-ANDROSTENE-3,17-DIONE
CYCLODECANONE
CYCLOUNDECANONE
CYCLODODECANONE
CIS-BICYCLO(3.3.0)OCTANE-3,7-DIONE
CIS-1,5-DIMETHYLBICYCLO(3.3.0)OCTANE-3,7-DIONE

CYCLOHEPTANONE

HYDROXYACETONE

TROPINONE

1-(BETA-PHENYLETHYL)-4-PIPERIDONE

1,4-CYCLOHEXANEDIONE MONO-2,2-DIMETHYLTRIMETHYLENE KETAL

METHYLGLYOXAL
DIMETHYL ACETYLSUCCINATE
DIMETHYL 1,3-ACETONEDICARBOXYLATE

4-(4-ACETOXYPHENYL)-2-BUTANONE

METHYLGLYOXAL DIMETHYL ACETAL
1,1-DIPHENYLACETONE
1,1-DIPHENYLACETONE

3-METHYL-2,4-PENTANEDIONE
3-ETHYL-2,4-PENTANEDIONE
ACETONE
(DIMETHYLAMINO)ACETONE
PHENOXYACETONE
METHOXYACETONE
DIMETHYL (2-OXOPROPYL)PHOSPHONATE

3,4-DIMETHOXYPHENYLACETONE

METHYL VINYL KETONE

BENZYLIDENEACETONE
BENZYLIDENEACETONE
ACETOACETANILIDE
O-ACETOACETANISIDIDE
O-ACETOACETOTOLUIDIDE
P-ACETOACETANISIDIDE
METHYL ACETOACETATE
BENZYL ACETOACETATE
BENZOYLACETONE
ACETYLACETONE
DIACETONE ACRYLAMIDE
ACETYLACETALDEHYDE DIMETHYL ACETAL
BENZYLACETONE
4-(4-METHOXYPHENYL)-2-BUTANONE
ACETONYLACETONE

N-TERT-BUTYLACETOACETAMIDE
TERT-BUTYL ACETOACETATE
4,4-DIMETHYL-2-PENTANONE
MESITYL OXIDE
PHORONE

GERANYLACETONE
GERANYLACETONE
DIISOPROPYL KETONE

METHYL ISOBUTYL KETONE
6-METHYL-2,4-HEPTANEDIONE
2,6-DIMETHYL-4-HEPTANONE

DIETHYLAMINOACETONE

ETHYL 2,4-DIOXOVALERATE

DIETHYL ACETYLSUCCINATE

ETHYL ISOBUTYRYLACETATE
ETHYL ACETOACETATE
DIETHYL 1,3-ACETONEDICARBOXYLATE
ETHYL LEVULINATE

ETHYL VINYL KETONE
ETHYL PROPIONYLACETATE
2,4-HEXANEDIONE

ETHYL BUTYRYLACETATE

BUTYL LEVULINATE

DIMETHYL (2-OXOHEPTYL)PHOSPHONATE

10-NONADECANONE

1,1-DICHLOROACETONE
6,7-DIMETHOXY-2-TETRALONE
4,4-DIMETHYL-2-CYCLOHEXEN-1-ONE

N-(ACETOACETYL)GLYCINE
3,5-DIACETYLTETRAHYDROPYRAN-2,4,6-TRIONE
ALLYL ACETOACETATE
4-(TRIMETHYLSILYLOXY)-3-PENTEN-2-ONE
ETHYL DIACETOACETATE
(R)-(-)-4,4A,5,6,7,8-HEXAHYDRO-4A-METHYL-2(3H)NAPHTHALENONE
4,4-DIMETHOXY-2,5-CYCLOHEXADIEN-1-ONE

TETRONIC ACID

DI-TERT-BUTYL 1,3-ACETONEDICARBOXYLATE
1,4-CYCLOHEXANEDIONE MONOETHYLENEKETAL
DIMETHYL (3-PHENOXYACETONYL)PHOSPHONATE

5-METHYL-1,3-CYCLOHEXANEDIONE

2-CHLORO-5,5-DIMETHYL-1,3-CYCLOHEXANEDIONE

4-(TERT-BUTYLDIMETHYLSILYLOXY)-3-PENTEN-2-ONE

ETHYL 2-(TRIMETHYLSILYLMETHYL)ACETOACETATE

CARBOXYLATE
METHYL 4-ALLYL-3,5-DIOXO-1-CYCLOHEXANECARBOXYLATE

METHYL ETHYL KETONE

4-(4-HYDROXY-3-METHOXYPHENYL)-3-BUTEN-2-ONE
(S)-(+)-2,3,7,7A-TETRAHYDRO-7A-METHYL-1H-INDENE-1,5(6H)-DIONE
2-HYDROXYMETHYL-6-METHOXY-1,4-BENZOQUINONE

2,2,6,6-TETRAMETHYL-4-PIPERIDONE HYDROCHLORIDE

HYDROCHLORIDE

HYDROCHLORIDE

HYDROCHLORIDE

DELTA-AMINOLEVL1LINIC ACID, METHYL ESTER
HYDROCHLORIDE

1,4-DIAMINO-2-BUTANONE DIHYDROCHLORIDE
DIACETONAMINE HYDROGEN OXALATE
ACETOACETIC ACID LITHIUM SALT
S-TERT-BUTYL ACETOTHIOACETATE

N-HYDROXYSUCCINIMIDYL ACETOACETATE

1,3-DIBROMOACETONE
(4-CHLOROPHENYLTHIO)PROPAN-2-ONE

2-(1-CYCLOHEXENYL)CYCLOHEXANONE
2-(BETA-CYANOETHYL)CYCLOHEXANONE

TRO PONE
METHYLSULFONYLACETONE
BIS(4-METHOXYBENZYLIDENE)ACETONE
BIS(4-METHOXYBENZYLIDENE)ACETONE
3,4-DIMETHOXYBENZYLIDENEACETONE

2,6-DIMETHYL-3,5-HEPTANEDIONE

3,5-HEPTANEDIONE

2,4-OCTANEDIONE
2,4-NONANEDIONE

(METHYLTHIO)ACETONE
(+/-)-2-ETHOXYCYCLOHEXANONE

2,6-DIMETHOXY-P-BENZOQUINONE
4-(P-HYDROXYPHENYL)-3-BUTEN-2-ONE
3,4-METHYLENEDIOXYBENZYLIDENE ACETONE
3,4-METHYLENEDIOXYBENZYLACETONE
PHENYLACETONE
2',5'-DICHLOROACETOACETANILIDE

2,4,4-TRIMETHYLCYCLOPENTANONE
CYCLOHEXYLACETONE
3,3,5-TRIMETHYLCYCLOHEXANONE

ACETOACETAMIDE

3-N-BUTYL-2,4-PENTANEDIONE

SALOR S17,446-7 (BENZYLTHIO)ACETONE
6-PHENYLHEXA-3,5-DIEN-2-ONE

N,N-DIETHYLACETOACETAMIDE
ETHYL 2-(PHENYLAZO)ACETOACETATE
DIETHYL ACETOMALONATE

(ETHYLTHIO)ACETONE

N-AMYL ISOPROPYL KETONE

NOOTKATONE
CYCLOBUTYL METHYL KETONE

N,N-DIMETHYLACETOACETAMIDE

FURFURALACETONE
ACETOACET-M-XYLIDIDE

DICYCLOHEXYL KETONE
CYCLOHEXYL METHYL KETONE
1,2:5,6-DI-0-ISOPROPYLIDENE-ALPHA-D-RIBO-3-HEXOFURANOSULOSE

BENZYL ISOPROPYL KETONE
1,1,3-TRICHLOROACETONE
METHYL BUTYRYLACETATE
CHLORODIFLUOROACETYLACETONE
1-(2-FURYL)-1,3-BUTANEDIONE
4,6-NONANEDIONE

N,N-DIMETHYL-2-CHLOROACETOACETAMIDE

2,6,6-TRIMETHYL-2-CYCLOHEXENE-1,4-DIONE

CYCLOPENTYLACETONE

(+/-)-2-ALLYLCYCLOHEXANONE
6-METHYL-3,5-HEPTADIEN-2-ONE
FLUORAL-P
FLUORAL-P
ISOPROPYL ACETOACETATE
N-METHYLACETOACETAMIDE
2-ETHYL-1,3-CYCLOPENTANEDIONE
3,5-DIMETHYL-4-HEPTANONE
EXO-2-CHLORO-5-OXO-BICYCLO[2.2.1]HEPTANE-SYN-7-CARBOXYLIC ACID

ETHYL-6-(2-OXOCYCLOPENTYL)-HEXANOATE
DIETHYL (2-OXOPROPYL)PHOSPHONATE

1,1,1-TRIFLUORO-5-METHYL-2,4-HEXANEDIONE
O-(CHLOROPHENYL)ACETONE
3-AMINO-5,5-DIMETHYL-2-CYCLOHEXEN-1-ONE
PHENYL SULFONYL ACETONE
1,3-DIPHENYL-2,4-PENTANEDIONE

1-PHENYL-2,4-PENTANEDIONE

1,1,1-TRIFLUORO-2,4-HEXANEDIONE

~O 98/46786 PCT/US98/07151 3-CHLORO-5,5-DIMETHYL-2-CYCLOHEXEN-1-ONE

5-PHENYLCYCLOHEXANE-1,3-DIONE
TERT.-BUTYL-4-CHLOROACETOACETATE

3-METHYLENE-2,5-HEPTANEDIONE
(4-METHYLPHENYLTHIO)ACETONE
1-(THIEN-2-YL)BUT-1-EN-3-ONE

ACETOACETOXYETHYL METHACRYLATE

ISOBUTYL ACETOACETATE

BENZYL LEVULINATE
(R)-(+)-3-METHYLCYCLOHEXANONE
(R)-(+)-3-METHYLCYCLOPENTANONE

(S)-(+)-10-METHYL-1(9)-OCTAL-2-ONE
(1S)-(-)-VERBENONE
DEHYDROACETIC ACID
PINONIC ACID
PINONIC ACID
1,3-DIAMINOACETONE DIHYDROCHLORIDE MONOHYDRATE
(5S)-5,6-ISOPROPYLIDENEDIOXY-6-METHYL-HEPTAN-2-ONE

BICYCLO[3.2.1]OCTAN-2-ONE

BICYCLO(3.3.1)NONAN-9-ONE
BICYCLO(3.3.1)NONANE-3,7-DIONE
(1R)-(+)-NOPINONE
NORCAMPHOR
NORCAMPHOR
NERYLACETONE
4,4-DIMETHYL-2-CYCLOPENTEN-1-ONE

4,4-DIPHENYL-2-CYCLOHEXEN-1-ONE
THIOTETRONIC ACID
4,4-DIMETHYL-1,3-CYCLOHEXANEDIONE
2-CHLORO-1,4-BENZOQUINONE

5,5-DIMETHYL-2-PHENACYL-1,3-CYCLOHEXANEDIONE

3-(2-HYDROXYETHYLAMINO)-5,5-DIMETHYL-2-ABSCISIC ACID
ABSCISIC ACID

CYCLOHEXIMIDE
PSEUDOPELLETIERINE HYDROCHLORIDE
DEHYDROCARNITINE HYDROCHLORIDE
3-(PHENYLAMINO)-CYCLOHEX-2-ENE-1-ONE

EXO-2-BROMO-5-OXO-BICYCLO[2.2.1]HEPTANE-SYN-7-CARBOXYLIC ACID
ANTI-3-OXOTRICYCLO(2.2.1.02,6)HEPTANE-7-CARBOXYLIC ACID
(+/-)-ISOPHORONE OXIDE
PHTHALIMIDOACETONE
1-PHENYL-1,4-PENTANEDIONE
(+/-}-2-PHENYLCYCLOHEPTANONE
ACETYLMALONONITRILE

5,7-DIMETHYL-3,5,9-DECATRIEN-2-ONE

2,4-DIHYDRO-5-METHYL-2-PHENYL-4-PROPIONYL-3H-D-(-)-TAGATOSE
3-(DIMETHYLAMINO)-5,5-DIMETHYL-2-CYCLOHEXEN-1-ONE
(3AS,7AS)-(+)-HEXAHYDRO-3A-HYDROXY-7A-METHYL-1,5-INDANDIONE
(+/-)-EXO-6-HYDROXYTROPINONE
(1R-(1ALPHA,2BETA,3ALPHA))-(+)-3-METHYL-2-(NITROMETHYL)-5-OXOCYCLOPENTANEACETIC
MENTHONE

1,5-DIAMINO-3-OXAPENTANE

(1R,3S)-2,2-DIMETHYL-3-(2-OXOPROPYL)-CYCLOPROPANEACETONITRILE
(1S,3S)-3-ACETYL-2,2-DIMETHYLCYCLOBUTANE
ACETONITRILE
5,5-DIMETHYLHEXANE-2,4-DIONE

HYDROCHLORIDE

HYDROCHLORIDE
DL-3-(1-ACETOXY-1-METHYLETHYL)-6-OXOHEPTANENITRILE
DL-3-(1-METHYL-1-ETHENYL)-6-OXOHEPTANENITRILE

METHYL (1R,3S)-2,2-DIMETHYL-3-(2-OXOPROPYL)-CYCLOPROPANEACETATE
N-BENZYLPSEUDOPELLETIERINE
D-(-)-FRUCTOSE
(S)-(+)-ERYTHRULOSE HYDRATE
2,2,6,6-TETRAMETHYL-4-PIPERIDONE MONOHYDRATE

5-ISOPROPYL-1,3-CYCLOHEXANEDIONE HYDRATE
D-(+)-SORBOSE
L-(-)-SORBOSE
METHYL JASMONATE
N-BENZYLTROPINONE

(+/-}-BICYCLO(3.3.1)NONANE-2,6-DIONE
ANTI-5-CARBOXYTRICYCLO[2.2.1.0(2,6)]HEPTAN-3-ONE

BICYCLO[2.2.1]HEPTANE
L-RIBULOSE HYDRATE
4-ACETYL-2,4-DIHYDRO-5-METHYL-2-PHENYL-3H-TRICYCLO[5.2.1.02,6]DECAN-8-ONE

CARBOXYLATE
5,5-DIMETHYL-3-(METHYLAMINO)-2-CYCLOHEXEN-1-ONE
2-ACETYL-1,3-CYCLOPENTANEDIONE
2,4-DIMETHOXYPHENYLACETONE
2,6-DIPHENYLCYCLOHEXANONE

2,2'-METHYLENEBIS(1,3-CYCLOHEXANEDIONE) (+/-)-7-OXABICYCLO(4.1.0)HEPTAN-2-ONE

2-(METHYLTHIO)CYCLOHEXANONE
(S)-(+)-3,4,$,8A-TETRAHYDRO-8A-METHYL-1,6(2H,7H)-NAPHTHALENEDIONE, and the like.

_78_ Where aldehydes and ketones are utilized to functionalize the library compounds of Formula IV (Rn =
hydrogen) in accordance with this invention, the resulting imine compounds can be reduced using sodium borohydride or other borohydride reducing agents to provide the corresponding secondary amine (Formula I; Rn - hydrogen and P is a substituent derived from an electrophilic agent). Still further diversity can be introduced into the present library by reacting the secondary amine library compounds with an electrophilic reagent as described above to provide compounds of Formula I wherein Rn is an organic substituent and P is a substituent derived from an electrophilic reagent.
The process of the present -invention utilized in preparation of a library of the ATAs and ATA derivatives of Formula I above may be carried out in any vessel capable of holding the liquid reaction medium. In one embodiment, the process of the invention can be carried out in containers adaptable to parallel array synthesis.
In particular, the ATA library of this invention can be formed in a well plate apparatus 1 or 3 as illustrated in Figures 1 and 2, respectively, and as described in greater detail below. Such apparatus provide multiple reaction zones most typically in a two-dimensional array of defined reservoirs, wherein one member of the library of this invention is prepared in each reservoir. Thus the diverse ATA and ATA derivative library of the present invention comprises a plurality of reservoir arrays (e. g.
well plates), each reservoir or well containing a library compound of the ATA library. Accordingly the library compounds are typically identified by reference to their well plate number and their X column and Y row well plate _ coordinates.
Following simultaneous preparation of the library member compounds in the reservoir array, the compounds can be transferred in whole or in part to other reservoir arrays (e.g. well plates), to prepare multiple copies of _79_ the library apparatus or to subject the library to additional reaction conditions. Copies of the library apparatus (daughter well plates, each comprising a 2-dimensional array of defined reservoirs with each reservoir containing a predetermined member of the library) are useful as replaceable elements in automated assay machines. The apparatus of this invention allows convenient access to a wide variety of structurally related ATA compounds and derivatives thereof. One preferred reservoir array for use in making and using this invention is a multi-well titer plate, typically a 96-well microtiter plate.

Figure 1 illustrates the top surface of a well plate apparatus (1) of the present invention. The well plate (1) is a plastic plate with 96-wells (depressions) capable of holding liquids for parallel array synthesis.

Individual reaction products are prepared in each well and are labeled by the well plate coordinates. For example, the library compound at location (2), is identified by the alpha numeric coordinate, "A6".

Figure 2 illustrates a side view of a modified well plate apparatus (3) for use in preparation of the library of the present invention. Well plate (3) contains wells (4) with a filter (5), and a retaining frit (6), and a liquid reaction medium used in carrying out the process (7). The wells have an outlet at the bottom which is sealed by gasket (8) held in place by a top cover (9) and bottom cover (10) maintained in position by clamps (11).

Such well plates are typically prepared using conventional 96-well plates. A hole is drilled in the bottom of each well in the plates and a porous frit is placed in the bottom of each well. The plate is then placed in the clamp assembly to seal the bottom of the wells.

Synthesis is initiated by adding reagents to their individual wells according to their assigned plate coordinates. The plate is then capped and tumbled to mix the reagents. Following completion of the reaction., the solvent and residual volatile reagents may be evaporated with a Speed-vac. The residual products are typically redissolved in appropriate solvent and partially purified (e.g., separated from unreacted starting materials) by using one or more standard work up protocols, such as washing, flash chromatography, or treatment with solid scavenger reagents. The reaction products are then analyzed, for example, by thin layer chromatography, mass spectrometry and/or nuclear magnetic resonance spectrometry.
One embodiment of the present invention is an assay kit for the identification of pharmaceutical lead compounds. The assay kit comprises as essential parts, (1) a well plate apparatus (containing one of the ATA or ATA derivative compounds in each of its individual wells), and (2) biological assay materials. The biological assay materials are generally known to be predictive of success for an associated disease state.
Illustrative of biological assay materials useful in the kit of this invention include, but are not intended to be limited to, those for conducting various assays such as:
In vitro assays:
Enzymatic inhibition, Receptor-ligand binding, Protein-Protein interaction, Protein-DNA interaction, and the like;
Cell based, functional assays:
Transcriptional regulation, Signal transduction/Second messenger, Viral Infectivity, Bacteriocidal/Bacteriostatic, Fungicidal/fungistatic, and the like; and Add, Incubate, & Read assays:
Scintillation Proximity Assays, . Glucan Synthase (GS) inhibition assays, Angiotensin II IPA receptor binding assay, Endothelia converting enzyme [125I] SPA assay, HIV proteinase (125I] SPA enzyme assay, Cholesteryl ester transfer (CETP) [3H] SPA assay, Fluorescence Polarization Assays, Fluorescence Correlation Spectroscopy, Calorimetric biosensors, Ca2+ -EGTA Dyes for Cell-based assays, Receptor Gene Constructs for cell based assays, Luciferase, green fluorescent protein, beta-lactamase, Electrical cell impedance sensor assays, and the like, and the like assays.

Example 1 The following ATA compounds have been prepared in accordance with the general methods of Scheme II above:-O OHO N I
~ ~ OH \ \
S~~~OH ~
NHFmoc O I / NHFmoc NHFmoc O OH
4 5 g FmocHN
/ I N\ N~ N O
/S OH \ ~-- ' ~
S I S \~~S~ v 'OH
NHFmoc O / O OH I 'NHFmoc O \ O
~~~ ~ 'OH C ~
~S~OH S ~~~OH
NHFmoc O ~ NHFmoc NHAlloc NHFmoc

11 12 O / I
~ ~ OH
S' Y 'OH S \ C\/ J O
\~oc INHBoc NHFmoc N
O OH Fmoc 13 14 15 N~
o I
BocHN OH ~ ~ S \
S Y 'S OH
NHFmoc NHFmoc O NHFmoc NHBoc ~ O OH

NHBoc / I NHFmoc S' ~ 'OH
BnO~S OH I \ S \\
/ S \ O
NHFmoc O ~ NHFmoc \ I ( /
O OH

Referring now to Compounds 4-21 above, couplings prepared in accordance with Scheme II typically proceeded 10 in 65-95~ yield except for the weak nucleophile 5-mercapto-1-tetrazoleacet.ic acid (e. g., compound 9) where coupling yields dropped to 25-35~. When cysteine or penicillamine free base was used in the coupling step as in compounds 12, 13, 17 and 21, DMSO was used as solvent and the free amine was capped with either Boc-anhydride or allyl chloroformate to simplify recovery of the lanthionine product. Commercially available Boc-amino acids obviate the amine protection step and can be easily converted into ATAs. For example, N-Boc-O-benzyl-L-serine provides diastereomers 19 when reduced and coupled with DL-thiolactic acid. The method utilized in the present invention thus exploits side chain protecting groups as another source of molecular diversity. Amino alcohols facilitate even more direct ATA synthesis since amine protection followed by mesylation affords compounds analogous to compound 2 shown in Scheme II, ready for coupling. ATAs synthesized using this abbreviated route include 5 from L-alaninol, 8 from 2-amino-1-phenylethanol, 13 from L-leucinol, 15 from ~3-piperidinemethanol and 21 from 2-[2-(aminomethyl)phenylthio]benzyl alcohol.
ATAs 4, 5, 7 and 16 are the most dipeptide-like library compounds shown. Deviating more from traditional dipeptides, 10, 11 and 19 contain beta-alanine, alpha-aminoisobutyric and extended phenylalanine analogues, respectively. Lanthionine ATAs 12, 13, 17 and 21 each provide an acid and a pair of differentially protected amines that can easily be converted into cyclic and/or branched structures. This is of great value for building structurally and functionally diverse libraries. Organo-peptide hybrids 14 and 20 fuse leucine and phenylalanine side chains, respectively, with o-thiosalicylic acid to provide conformational constraint. An important feature of heterocyclic library compounds 6, 9 and 18. not seen in 14, 15 and 20~ is the potential to accept hydrogen bonds and so mimic peptide and protein amides.
Library compounds 8. 15 and 21 further dilute peptide character and should be thought of as traditional organic compounds that bear amine and acid functions.
Beyond the obvious structural elements described above, increased lipophilicity, proteolytic stability and the novel geometry inherent to the thioether linkage make ATAs attractive for lead discovery. Also important for lead discovery; ATA flexibility can be tuned (cf. 10 and 14) to balance the need to search large areas of sequence space against the need for conformational restriction.
Methods For Constructing Additional ATA Library Compounds.
Mo ~ l-, n.-7 T
O O
BocHN BocHN
OH -'-' OH
NH2 NHAlloc BocHN
OMs ~-~-- BocHN
OH
NHAlioc NHAlloc BocHN ~ 'OH BocHN
S ~ S~ /OH
NHAIIoc O NHFmoc ~O

N-a-Fmoc-N-e-Boc-L-Lys-[yCH2S]-Gly (27) Referring to the Method A scheme shown above (bold-face compound numerals correspond to bold-face compound 15 numerals referred to below), in a one liter 3-necked flask fitted with a magnetic stir bar, 22.65 grams (92mmo1) of commercially available N-e-tert-butoxycarbonyl-L-lysine 22 and 11.66 grams of sodium carbonate (110mmo1) were added to 400m1 of water and 20 stirred to give a suspension. Addition of 400m1 dioxane to the suspension produced a clear pale yellow solution on stirring. This solution was chilled on an ice-water bath with stirring, then 13.32 grams (11.72m1, 110mmo1) of allyl chloroformate was added over several hours via a 25 dropping funnel. Stirring was continued overnight without replenishing the ice bath to yield a light slurry.

The reaction mixture was basified with a few rnl of 1N NaOH, then washed twice with 800m1 portions of ethyl acetate (EtOAc). The aqueous layer was acidified to pH ~3 with 1N sodium bisulfate (NaHS04) whereupon a heavy slurry formed. The slurry was extracted twice into 800m1 portions of EtOAc, then the organic layers were combined, washed with saturated brine solution, dried over sodium sulfate (Na2S04) and concentrated in vacuo to produce 35 grams (>100~) of 23, a viscous pale yellow oil. TLC
analysis (50:50:1 hexanes:EtOAc:Acetic acid) showed clean product and this was carried to the next step assuming quantitative yield. The crude mass of 23 was dissolved in 150 ml ethylene glycol dimethyl ether (DME), chilled to -15°C (ice/water/NaCl slurry) with stirring, then 9.3 grams (10.11 ml) of N-methylmorpholine (NMM) was added and the solution re-chilled. Isobutyryl chloroformate (12.56 grams, 11.93 ml) was then added in one portion to produce a heavy white precipitate and the resulting slurry was stirred vigorously for 10 minutes on the brine/ice bath. The slurry was filtered through a fritted funnel into a two liter Erlenmeyer flask, retentate washed 5 times with 25 ml portions of DME and the combined filtrate and rinses were re-chilled to -15°C
prior to portionwise addition of a solution 5.22 grams (138 mmol, l.5eq) sodium borohydride (NaBH4) in 150 ml water. Vigorous evolution of gas was observed after each portion of NaBH4 was added and the mixture was stirred for an additional 10 minutes on the ice/brine bath to produce a colorless emulsion. TLC (3:1 CH2C12:EtOAc) revealed good conversion to the alcohol. The emulsion was made basic with a few ml 1N NaOH, then extracted three times with 600 ml portions of EtOAc. The organic layers were combined, washed with saturated brine, then dried over Na2S04 and concentrated in vacuo to yield 25 grams (860) of crude product 24 as a pale yellow oil.
The product was purified on a 500 ml silica column packed and eluted with 7:3 CH2C12:EtOAc to afford 17.5 grams of a nearly colorless oil 24, 60~ overall isolated yield for alloc protection and acid reduction steps. In a 250 ml roundbottom flask; a portion of pure 24 (7.65 grams, 24 mmol) was dissolved in 100 ml dry THF under a nitrogen atmosphere, chilled on an ice bath then 5.06 ml triethylamine (3.67 grams, 36 mmol) was added via syringe. The solution was stirred for a few minutes on ice, then 2.06 ml (3.05 grams, 26 mmol) of methanesulfonyl chloride (MsCl) was added over a 10 minute period. The clear solution immediately turned cloudy on addition of the MsCl and became a heavy white suspension after all of the MsCl had been added. Stirring was continued for 10-15 minutes following MsCl addition when TLC (3:1 CH2C12:EtOAc) indicated complete consumption of starting alcohol. The slurry was filtered, retentate washed 3 times with 100 ml portions of EtOAc, then the combined filtrate and washes were washed once with cold water, once with cold dilute hydrochloric acid, once with saturated sodium bicarbonate (NaHC03) and once with saturated brine before drying over Na2S04 and concentration in vacuo. High vacuum drying of the residue produced 9.22 grams (96°s) of 25 as a colorless oil.
In a 250 ml flame-dried flask fitted with a magnetic stir bar, 1.28 grams (0.97 ml) of mercaptoacetic acid was dissolved in 30 ml of dry dimethylformamide (DMF) under nitrogen atmosphere and to the mercapto acid was added via syringe 6.4 ml (1.5 grams, 2eq) of a 25 weight percent solution of sodium methoxide in methanol (NaOMe/MeOH). The clear acid solution turned cloudy white during NaOMe/MeOH addition then returned to its clear and colorless appearance within 30 seconds after the addition was complete. 5 grams of mesylate 25 dissolved in 15 ml dry DMF was then added by pipette in one portion to the stirring dibasic acid and the resulting mixture stirred 35. overnight at room temperature under a blanket of nitrogen. After ~15 hours of stirring, the mixture turned to a heavy slurry with a gray-pinkish color. TLC (50:50:1 _ CA 02286862 1999-10-12 -87_ hexanes:EtOAc:acetic acid) showed good conversion, so most DMF was removed with a rotovap at 45°C bath temperature to yield a grayish-white paste. The paste was . dissolved in 200 ml water with a few ml of 1N NaOH, and the resulting turbid solution was washed 3 times with 150 ml portions of ethyl ether. The partially clarified aqueous layer was then acidified to pH ~3 with NaHSOq to yield a heavy white slurry that was extracted 3 times with 200 ml portions of EtOAc. The combined EtOAc extracts were washed with saturated brine, dried over Na2S04, then concentrated to afford 4.9 grams of 26 (980) as an oil. The crude product looked relatively clean via TLC (50:50:1 hexanes:EtOAc:acetic acid) and was carried on without purification.
To 5.1 grams of 26 under nitrogen in a 250 ml flame-dried flask fitted with stir bar was added 60 ml dry THF
via cannula and the mixture stirred to give a clear and colorless solution. The septum was then removed and in succession were added 3.36 grams solid 5,5-dimethyl-1,3-cyclohexanedione (dimedone), 787 milligrams (0.25eq)of solid triphenylphosphine (PPh3) and 693 milligrams (0.05eq) of solid tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) to produce a clear orange solution. The flask was recapped, covered with aluminum foil and flushed with nitrogen while stirring at room temperature. TLC in 50:50:1 hexanes:EtOAc:acetic acid showed complete conversion of starting material to a baseline spot after about 1 hour of stirring. Solvent was removed with a rotovap to give an orange oil that was then redissolved in 50 ml EtOAc and extracted 4 times with 25 ml portions of water. To the combined aqueous layers was then added 2 grams solid sodium carbonate and 100 ml of dioxane.
The resulting light emulsion was chilled on an ice bath and when the temperature of the solution was below 10°C, 4.46 grams of solid fluorenylmethyloxycarbonyl _88_ chloride (Fmoc-C1) was added portionwise over a one hour period with stirring. The reaction mixture was then stirred overnight without replenishing the ice bath and TLC indicated good conversion of starting baseline material. Next a few drops of 1N NaOH were added to the mixture and washed 3 times with 200 ml portions of ethyl ether. The aqueous layer was then acidified to pH ~2 with 1N NaHS04 and the off-white slurry was extracted 3 times with 150 ml portions of EtOAc. The EtOAc layers were combined, washed with saturated brine, dried over Na2S04, then concentrated in vacuo to provide a yellow oil contaminated with dimedone. The oil was applied to a 500 ml silica gel column packed with 50:50:1 hexanes:EtOAc:acetic acid and then eluted with the same solvent. Appropriate fractions were pooled, concentrated, then co-evaporated 3 times with toluene/EtOAc to azeotropically remove excess acetic acid. The resulting colorless oil was extensively dried under high vacuum to yield 2.2 grams (35~) of pure 27.
t~to ~- t-,.. ~ n OH OH ~ OMs N ~ N
H Boc Boc ~I ~I

Fmoc O OH Boc O OH
Referring to the Method B scheme shown above (bold-face compound numerals correspond to bold-face compound numerals referred to below), in a one liter 3-necked flask, 11.51 grams (100 mmol) of ~3-piperidinemethanol (28) and 10.6 grams (100 mmol) sodium carbonate were dissolved in 200 ml of water, then 200 ml of dioxane was added and the mixture stirred to produce a pale yellow light emulsion. To the stirring emulsion was next added 24 grams (110mmo1) of di-tert-butyl-dicarbonate and stirring continued overnight. TLC (75:25 CH2C12:EtOAc) . revealed complete conversion, so the light yellow slurry was stripped of dioxane, then extracted twice with 300 ml portions of EtOAc. The organic layers were combined, washed with saturated brine, dried over Na2S04, then concentrated in vacuo to yield 20.6 grams (95~) of clean 29 as an off-white solid.
To 20 grams (93 mmol) of 29 under nitrogen in a flame-dried one liter flask equipped with a stir bar was added 400m1 dry THF via cannula. The resulting pale yellow-tan solution was chilled on an ice-water bath, then 14.12 grams (19.44 ml, 139 mmol) of triethylamine was added by pipette and the solution stirred for a few minutes under nitrogen. Next, 11.72 grams (7.92 ml, 102 mmol) of methanesulfonyl chloride was added by syringe over a 10 minute period with vigorous stirring. The clear solution turned to a cloudy whitish-tan suspension immediately upon mesylate addition and became a heavy slurry within a few minutes after all methanesulfonyl chloride had been added. TLC (3:1 CH2C12:EtOAc) revealed complete conversion of the product within 10 minutes of final sulfonyl chloride addition. The slurry was filtered through a fritted funnel and the retentate rinsed 4 times with 100 ml portions of EtOAc. The combined filtrate and rinses were then washed once each with cold water, cold dilute hydrochloric acid, saturated NaHC03, and saturated brine. The organic layer was dried over Na2S04 and concentrated in vacuo to provide 26.94 grams (9$~) of 30 as a pale yellow crystalline solid.
2-Mercaptonicotinic acid (11 grams, 71 mmol) was dissolved under nitrogen in 400m1 dry DMF under nitrogen in a one liter 3-necked flask fitted with a large egg-shaped stir bar to give a bright yellow solution. Next, 7.67 grams (32.5 ml, 142 mmol) of a 25 weight per cent solution of NaOMe in MeOH was added to the stirring mercaptonicotinic acid/DMF solution, then 20.8 grams (71 mmol) of 30 dissolved in DMF (52 ml final volume) was added by syringe pump over a two day period. The resulting deep yellow viscous slurry was stripped of DMF, then redissolved in 400m1 of water. The turbid yellow aqueous solution was partially clarified by 3 washes with 300 ml portions of ethyl ether. The partially clarified aqueous layer was acidified to pH ~2 with 1N NaHS04 to produce a heavy yellow slurry that was then extracted 3 times with 300 ml portions of EtOAc. The organic layers were combined, washed with saturated brine, dried over Na2S04, and concentrated in vacuo to provide 24.6 grams (98%) of crude 31 as a canary yellow solid.
The crude product was recrystallized from neat EtOAc to provide two crops of pale yellow crystals weighing.
20.95 grams (83% isolated yield). Purified acid 31 (19 grams, 54 mmol) was combined with 108 ml of a 4N
hydrochloric acid solution in dioxane and stirred in a one liter flask to produce a heavy white-caked precipitate. 100 ml of dioxane was added to loosen the slurry and after one hour of stirring, TLC (50:50:1 hexanes:EtOAc:acetic acid) indicated complete conversion of starting material to a baseline product. A large part of the HC1 was removed under light vacuum on a rotovap, then the remains were neutralized with 1N NaOH solution.
To the neutralized solution was then added with stirring 250 ml of water, 5.72 grams (54 mmol) of solid sodium carbonate and another 100 ml of dioxane. The resulting emulsion was chilled on an ice-water bath, then 19.12 grams (56.7 mmol) of fluorenylmethyloxycarbonyl N-hydroxysuccinimide (Fmoc-OSu) was added portionwise over a 10 minute period. Stirring was continued for 36 hours to produce an ivory slurry. Dioxane was removed _in vacuo, then the mixture was washed 3 times with 300 ml portions of ethyl ether. The aqueous layer was then acidified to pH ~2 with 1N NaHS04 and the resulting heavy slurry extracted 3 times with 300 ml portions of EtOAc. The combined EtOAc layers were washed with saturated brine, dried over Na2S04, then concentrated and dried under high vacuum to yield 23.54 grams (92~) of 32 as pale yellow solid that was judged clean by TLC in 50:50:1 hexanes:EtOAc:acetic acid.

Method C
O
Bn0 OH ~ BnO~OH --- BnO~OMs NHBoc NHBoc NHBoc Me Me BnO~S OH---- BnO~S OH
NHFmoc O NHBoc O

N-a-Fmoc-O-benzyl-L-Ser-[y-CH2S]-DL-Alanine (37) In a 500 ml round-bottomed flask fitted with a magnetic stir bar, 25 grams (84.6 mmol) of N-a-Boc-O-benzyl-L-Serine (33) (Novabiochem, San Diego, CA, USA) was dissolved in 150 ml DME and chilled to -15°C with an ice/water/brine bath. 10.23 ml N-methylmorpholine (93 mmol, 1.1 eq) was added to the chilled solution, stirred a few minutes, then 12 ml of isobutyl chloroformate (93 mmol, 1.1 eq) was added in one portion at which time the solution quickly turned to a heavy white slurry. The slurry was stirred vigorously for 10 minutes on the brine/ice bath, then filtered through a fritted funnel into a two liter Erlenmeyer flask. The-retentate was washed 5 times with 15 ml portions of DME and the combined filtrate and rinses were re-chilled to -15°C
prior to portionwise addition of a solution 5.3 grams (140 mmol, 1.66eq) sodium borohydride (NaBH4) in 100 ml water. Vigorous evolution of gas was observed after each portion of NaBH4 was added. The mixture was stirred for an additional 10 minutes on the ice/brine bath to produce a colorless emulsion. TLC (3:1 CH2C12:EtOAc) revealed good conversion to the alcohol. Reaction was quenched with 1000 ml of water and the resulting emulsion was made basic with a few ml 1N NaOH, then extracted three times with 300 ml portions of EtOAc. The organic layers were WO 98/4b78b PCT/US98/07151 combined, washed with saturated brine, then dried over Na2S04 and concentrated in vacuo to yield a pale yellow oil. Product recrystallized from 400 ml of 7:1 petroleum ether: diethyl ether to give 20.28 grams (85%) of alcohol 34 as white needles after washing with hexanes and drying under high vacuum.
In a 1000 ml round-bottomed flask, a portion of pure 34 (9.0 grams, 32 mmol) was dissolved in 125 ml dry THF
under a nitrogen atmosphere, chilled on an ice bath, then 6.69 ml triethylamine (4.86 grams, 48 mmol) was added via syringe. The solution was stirred for a few minutes on ice, then 2.73 ml (4.03 grams, 35.2 mmol) of methanesulfonyl chloride (MsCl) was added over a 10 minute period. The clear solution immediately turned cloudy on addition of the MsCl and became a heavy white suspension after all of the MsCl had been added. Stirring was continued for 10-15 minutes following MsCl addition when TLC (3:1 CH2C12:EtOAc) indicated complete consumption of starting alcohol. The slurry was filtered, retentate washed 3 times with 100 ml portions of EtOAc, then the combined filtrate and washes were washed once with cold water, once with cold dilute hydrochloric acid, once with saturated sodium bicarbonate (NaHC03) and once with saturated brine before drying over Na2S04 and concentration in vacuo. High vacuum drying of the residue produced 12.7 grams (>100%) of 35 as a colorless oil.
In a 250 ml flame-dried flask fitted with a magnetic stir bar, 1.91 grams (1.6 ml) of DL-thiolactic acid was dissolved in 40 ml of dry dimethylformamide (DMF) under nitrogen atmosphere and to the mercapto acid was added via syringe 8.24 ml (1.94 grams, 2eq) of a 25 weight percent solution of sodium methoxide in methanol (NaOMe/MeOH). About 5.4 grams of mesylate 35 (~15 mmol) dissolved in 35 ml dry DMF was then added by pipette in one portion to the stirring dibasic acid and the resulting mixture stirred overnight at room temperature under a blanket of nitrogen. After ~15 hours of stirring, the mixture turned to a heavy slurry with a grayish color. TLC (50:50:1 hexanes:EtOAc:acetic acid) showed good conversion, so most DMF was removed with a rotovap at 45°C bath temperature to yield a grayish-white paste.
The paste was dissolved in 200 ml water with a few ml of 1N NaOH, and the resulting turbid solution was washed3 times with 150 ml portions of ethyl ether. The partially clarified aqueous layer was then acidified to pH ~3 with NaHS04 to yield a heavy white slurry that was extracted 3 times with 200 ml portions of EtOAc. The combined EtOAc extracts were washed with saturated brine, dried over Na2S04, then concentrated to afford 5.6 grams of 36 (101%) as an oil. The crude product looked relatively clean via TLC (50:50:1 hexanes:EtOAc:acetic acid) and was carried on without purification. 3.8 grams of 36 (10.4 mmol) in a 1000 ml round bottomed-flask was chilled on an ice-water bath and combined with 100 ml of a 4N hydrochloric acid solution in ethyl acetate. TLC (50:50:1 hexanes:EtOAc:acetic acid) indicated complete conversion of starting material to a baseline product within one hour of HC1 addition. Most of the HC1 was removed under vacuum on a rotovap, then the remains were dissolved in 100 ml of water. To this solution was then added with stirring 4.4 grams (42 mmol, 4 eq) of solid sodium carbonate and then 75 ml of dioxane. The resulting emulsion was chilled on an ice-water bath, then 3.86 grams (11.4 mmol) of fluorenylmethyloxycarbonyl N-hydroxysuccinimide (Fmoc-OSu) was added portionwise over a 10 minute period. Stirring was continued overnight and TLC (50:50:1 hexanes:EtOAc:acetic acid) of the resulting ivory slurry showed complete consumption of starting 36.
Dioxane was removed in vacuo, the mixture was diluted with 200 ml of water and then washed 3 times with 200 ml portions of ethyl ether. The aqueous layer was then acidified to pH ~2 with 1N NaHS04 and the resulting slurry extracted 3 times with 100 ml portions of EtOAc.
The combined EtOAc layers were washed with saturated WO 9$/46786 PCT/US98707151 brine, dried over Na2S04, then concentrated and dried under high vacuum to yield 5.6 grams (1100 of 37 as a colorless oil. Recrystallization from acetone-hexanes failed, but TLC (50:50:1 hexanes:EtOAc:acetic acid) indicated ~80~ purity.
. The following additional ATA compounds have been prepared in accordance with Methods A, B or C described above:
OH OH
S ~ ~S
, NHFmoc O ~ NHFmoc O
BocH OH
S
NHFmoc O
OH
~S
NHFmoc BocHN OH
S
NHFmoc O
O OH
'S
O NHFmoc O

O
OH
CbzH \ OH
S
NHBoc O
H
OH
S
O NHFmoc O
O S/\/OH 0 S OH
NHFmoc ~O~ , NHFmoc 0 , OH
~S _ OH
S
\ NHFmoc O
NHFmoc O
O
~OH
OH
~S OH
S
Fmoc O
NHFmoc O , O
/S OH OH
S
NHFmoc O
O
OH
Fmoc O
OH
'S OH ~ 'S
NHFmoc , NHFmoc O
O
'S ~ 'OH
NHFmoc NHBoc O
'S ~ 'OH
NHFmoc NHBoc _ _ OH
S ~ S
NHFmoc O
OH
'S
NH Fmoc O

_98_ OH
~S ~ ~S ~ OH
NHFmoc O S
NHFmoc O , O
S OH S/~OH OH
S
NHFmoc ~ NHFmoc NHFmac O , S OH S~ /OH
NHFmoc O , NHFmoc ~O
O~S~OH
NHFmoc 'OI
O~S OH S \
NHFmoc O NHFmoc O O
\~~S OH S OH
NHFmoc NHBoc , NHFmoc NHBoc O
S OH
NHFmoc NHBoc , _99_ p /
S' ~ \
'OH S
' FmocN~ NHFmoc O OH
N~ O
\ S
\ ~ \S OH
/ NHFmoc FmocN
O OH
/
\ OH
S
NHFmoc O
'OH
'S
O
N
Fmoc /
S \
NHFmoc O OH
N~
'S
. NH Fmoc O OH , f Fmoc , \ OH
'S
N O
Fmoc \
/ N~N~N O
S \ OH \\
I 'S OH
NHFmoc O
NHFmoc O O
S' v 'OH
'S = OH
NJ ~ Fmoc NHAlloc Fmoc N~N~N O
N' ~
S~ v 'OH
NHFmoc FmocH~
FmocH~
, O
FmocHN S
OH
S
and

Claims (53)

I Claim:

1. A library of peptidomimetic aminothioether acid compounds and derivatives thereof wherein said library includes a plurality of library compounds of the general formula wherein P is hydrogen, a substituent derived from an electrophilic reagent, or an amino-protecting group;
Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N and S;
R s is hydrogen or an organic moiety; and R n is hydrogen or an organic moiety, or P in combination with R n is an amino-protecting group; or R n and R s taken together with -Q- and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms; or R n or R s taken together with -Q- and the atoms to which they are commonly bonded form a 4- to 7-membered ring;
m is 0, 1 or 2;
W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N
and S; and A is OH, NH2, an ester-forming substituent derived from an alcohol, or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally covalently bound to a solid support, and when A is OH, salts of the acid represented thereby.

2. The library of claim 1 wherein W is a divalent organic moiety selected from the group consisting of a divalent organic group comprising a 5- or 6-membered aromatic ring containing 0 to 4 heteroatoms selected from O, N and S, -CHR8- , -CR4R5CR6R7- , wherein R8 is hydrogen or a noninterfering substituent;
R4, R5, and R6 are independently hydrogen or alkyl; and R7 is hydrogen, hydroxy, protected hydroxy, amino, protected amino or substituted amino wherein the substituent is derived from an electrophilic reagent.

3. The library of claim 1 wherein W is a divalent moiety selected from the group consisting of and

4. The library of claim 1 wherein Q is a group of the formula wherein R1 is hydrogen or a non-interfering substituent;
R2 is hydrogen or a non-interfering substituent; or R1 taken together with R n forms a 5- or 6-membered ring, or R1 taken together with R s forms a 5- or 6-membered ring; or R1 taken together with R2 forms a 3- to 6-membered ring.

5. The library of claim 4 wherein R1 taken together with R n forms a 5- or 6-membered ring.

6. The library of claim 4 wherein R1 taken together with R s forms a 5- or 6-membered ring.

7. The library of claim 4 wherein R1 taken together with R2 forms a 3- to 6-membered ring.

8. The library of claim 1 wherein A is OH.

9. The library of claim 8 wherein P is fluorenylmethyloxycarbonyl.

20. The library of claim 1 wherein the library compounds have a molecular weight range of about 150 to about 800.

11. A compound selected from the group consisting of the library compounds of the library of claim 1.

12. A compound selected from the group consisting of the library compounds of the library of claim 2.

13. A compound selected from the group consisting of the library compounds of the library of claim 6.

14. A compound selected from the group consisting of the library compounds of the library of claim 8.

15. A compound selected from the group consisting of the library compounds of claim 9.

16. A compound selected from the group consisting of the library compounds of claim 10.

17. A compound of the formula wherein P is hydrogen, a substituent derived from an electrophilic reagent, or an amino-protecting group;
Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms,selected from O, N and S;
R s is hydrogen or an organic moiety; and Rn is hydrogen or an organic moiety, or P in combination with Rn is an amino-protecting group; or Rn and Rs taken together with -Q- and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms; or Rn or Rs taken together with -Q- and the atoms to which they are commonly bonded form a 4- to 7-membered ring;
m is 0, 1 or 2;
W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N
and S; and A is OH, NH2, an ester-forming substituent derived from an alcohol, or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally covalently bound to a solid support, and when A is OH, salts of the acid represented thereby.

18. The compound of claim 17 wherein W is a divalent organic moiety selected from the group consisting of a divalent organic group comprising a 5- or 6-membered aromatic ring containing 0 to 4 heteroatoms selected from O, N and S, -CHR8-, -CR4R5CR6R7-, wherein R8 is hydrogen or a noninterfering substituent;

R4, R5, and R6 are independently hydrogen or alkyl; and R7 is hydrogen, hydroxy, protected hydroxy, amino, protected amino or substituted amino wherein the substituent is derived from an electrophilic reagent.

19. The compound of claim 17 wherein W is a divalent moiety selected from the group consisting of

20. The compound of claim 17 wherein Q is a group of the formula wherein R1 is hydrogen or a non-interfering substituent;
R2 is hydrogen or a non-interfering substituent; or R1 taken together with R n forms a 5- or 6-membered ring, or R1 taken together with R n forms a 5- or 6-membered ring; or R1 taken together with R2 forms a 3- to 6-membered ring.

22. The compound of claim 20 wherein R1 taken together with Rn forms a 5- or 6-membered ring.

22. The compound of claim 20 wherein R1 taken together with Rs forms a 5- or 6-membered ring.

23. The compound of claim 20 wherein R1 taken together with R2 forms a 3- to 6-membered ring.

24. The compound of claim 17 wherein A is OH.

25. The compound of claim 24 wherein P is 9-fluorenylmethyloxycarbonyl.

26. A process for preparing a combinatorial library comprising aminothioether compounds and derivatives thereof of the formula having diversity in P, Rn, Rs, Q, W, m and A, wherein P is hydrogen, a substituent derived from an electrophilic reagent, or an amino-protecting group;
Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N and S;
RS is hydrogen or an organic moiety; and Rn is hydrogen or an organic moiety, or P in combination with Rn is an amino-protecting group; or Rn and RS taken together with -Q- and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 9 to 12 carbon atoms; or Rn or Rs taken together with -Q- and the atoms to which they are commonly bonded form a 4- to 7-membered ring;
m is 0, 1 or 2;
W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N
and S; and A is OH, NH2, an ester-forming substituent derived from an alcohol, or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally covalently bound to a solid support, and when A is OH, salts of the acid represented thereby;
said process comprising the steps of reacting a compound of the formula wherein P is an amino-protecting group, X is an electrophilic group subject to nucleophilic displacement from its bonded carbon atom, and Rn, Q, Rs are as defined above, with a salt of a mercapto compound of the formula where W and A are as defined above; and when A is OH in Formula I, optionally reacting the aminothioether acid represented thereby with an ester-forming alcohol or an amide-forming primary or secondary amine;
optionally oxidizing the aminothioether to provide a library compound wherein m is 1 or 2;
removing the protecting group P to provide a library compound of the formula;
optionally reacting the deprotected amine with an amine reactive electrophilic reagent.

27. The process of claim 26 wherein the electrophilic agent has a molecular weight from about 30 to 600 and is selected from organic halides, acyl halides, sulfonic acid esters, organohaloformates, organosulfonyl halides, organic isocyanates, organic isothiocyanates, aldehydes and ketones.

28. The process of claim 26 wherein the electrophilic agent is an aldehyde or ketone and the process further comprises the step of reducing the product imine to form a secondary amine and optionally reacting that product with a second electrophilic agent.

29. The process of claim 26 wherein the amide-forming primary or secondary amine has a molecular weight of about 30 to about 500.

30. The process of claim 26 wherein each library compound is made in a separate reaction zone.

31. The process of claim 26 wherein A is a substituent covalently bound to a solid support.

32. The process of claim 26 wherein the reaction of the salt of the mercapto compound is conducted in solution phase.

33. A process for preparing a compound of the formula wherein P is hydrogen, an organic moiety, or an amino-protecting group;
Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N and S;
Rs is hydrogen or an organic moiety; and Rn is hydrogen or an organic moiety, or P in combination with Rn is an amino-protecting group; or R n and R s taken together with -Q- and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 9 to 12 carbon atoms; or R n or R s taken together with -Q- and the atoms to which they are commonly bonded form a 4- to 7-membered ring;
m is 0, 1 or 2;
W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N
and S; and A is OH, NH2, an ester-forming substituent derived from an alcohol, or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally covalently bound to a solid support, and when A is OH, salts of the acid represented thereby;
said process comprising the steps of reacting a compound of the formula wherein P is an amino-protecting group, X is an electrophilic group subject to nucleophilic displacement from its bonded carbon atom, and R n, Q, R s are as defined above, with a salt of a mercapto compound of the formula where W and A are as defined above; and-when A is OH in Formula I, optionally reacting the aminothioether acid represented thereby with an ester-forming alcohol or an amide-forming primary or secondary amine;
optionally oxidizing the aminothioether to provide a compound wherein m is 1 or 2;
removing the protecting group P to provide a compound of the formula;
optionally reacting the deprotected amine with an amine reactive electrophilic reagent.

34. The process of claim 33 wherein the electrophilic agent has a molecular weight from about 30 to 600 and is selected from organic halides, acyl halides, sulfonic acid esters, aldehydes, organohaloformates, organosulfonyl halides, organic isocyanates organic isothiocyanates, aldehydes and ketones.

35. The process of claim 33 wherein the electrophilic agent is an aldehyde or ketone and the process further comprises the step of reducing the product imine to form a secondary amine and optionally reacting that product with a second electrophilic agent.

36. The process of claim 33 wherein the amide-forming primary or secondary amine has a molecular weight of about 30 to about 500.

37. The process of claim 33 wherein each compound is made in a separate reaction zone.

38. The process of claim 33 wherein A is a substituent covalently bound to a solid support.

39. The process of claim 33 wherein the reaction of the salt of the mercapto compound is conducted in solution phase.

40. An assay kit for identification of pharmaceutical lead compounds, said kit comprising biological assay materials and a well plate apparatus wherein each well in said apparatus contains a library compound of the library of claim 1.

41. The assay kit of claim 40 wherein the biological materials are selected for performing at least one assay test selected from the group consisting of in vitro assays,cell based functional assays, and add, incubate, &
read assays.

42. An apparatus suitable as a replacement element in an automated machine as a source of individual members of a library of structurally related compounds, said apparatus comprising a 2-dimensional array of defined reservoirs, each reservoir comprising a library compound of said library, wherein said structurally related compounds are of the formula wherein P is hydrogen, a substituent derived from an electrophilic reagent or an amino-protecting group;
Q is an organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N and S;
Rs is hydrogen or an organic moiety; and Rn is hydrogen or an organic moiety, or P in combination with Rn is an amino-protecting group; or Rn and Rs taken together with -Q- and the atoms to which they are bonded form a 4- to 7-membered ring or a bicyclic or tricyclic ring comprising 6 to 12 carbon atoms; or Rn or RS taken together with -Q- and the atoms to which they are commonly bonded form a 4- to 7-membered ring;
m is 0, 1 or 2;
W is a divalent organic group comprising 1 to 12 carbon atoms and 0 to 4 heteroatoms selected from O, N
and S; and A is OH, NH2, an ester-forming substituent derived from an alcohol, or an amide-forming substituent derived from a primary or secondary amine, said substituents optionally covalently bound to a solid support, and when A is OH, salts of the acid represented thereby.

43. The apparatus of claim 42 wherein W is a divalent organic moiety selected from the group consisting of a divalent organic group comprising a 5- or 6-membered aromatic ring containing 0 to 4 heteroatoms selected from O, N and S, -CHR8-, -CR4R5CR6R7-, wherein R8 is hydrogen or a noninterfering substituent;
R4, R5, and R6 are independently hydrogen or alkyl; and R7 is hydrogen, hydroxy, protected hydroxy, amino, protected amino or substituted amino wherein the substituent is derived from an electrophilic reagent.

44. The apparatus of claim 42 wherein W is a divalent moiety selected from the group consisting of and

45. The apparatus of claim 42 wherein Q is a group of the formula wherein R1 is hydrogen or a non-interfering substituent;
R2 is hydrogen or a non-interfering substituent; or R1 taken together with Rn forms a 5- or 6-membered ring, or R1 taken together with Rs forms a 5- or 6-membered ring; or R1 taken together with R2 forms a 3-to 6-membered ring.

46. The apparatus of claim 45 wherein R1 taken together with Rn forms a 5- or 6-membered ring.

47. The apparatus of claim 45 wherein R1 taken together with Rs forms a 5- or 6-membered ring.

48. The apparatus of claim 45 wherein R1 taken together with R2 forms a 3- to 6-membered ring.

49. The apparatus of claim 42 wherein A is OH.

50. The apparatus of claim 42 wherein A is an amide-forming substituent derived from a primary or secondary amine.

51. The apparatus of claim 42 wherein each of the structurally related compounds have a molecular weight range of about 150 to about 800.

52. The apparatus of claim 42 wherein each of the structurally related compounds is prepared in accordance with the process of claim 26 and wherein each reservoir provides one reaction zone.

53. The apparatus of claim 42 wherein the 2-dimensional array of defined reservoirs is a multi-well microtiter plate.