Beta-strand mimetics and method relating thereto

Abstract

Conformationally constrained compounds which mimic the secondary structure of β-strand regions of biologically active peptides and proteins are disclosed. Such β-strand mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the β-strand mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members.

Description

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates generally to β-strand mimetic structures, to a chemical library relating thereto, and to uses thereof.

[0004] 2. Description of the Related Art

[0005] Random screening of molecules for possible activity as therapeutic agents has occurred for many years and resulted in a number of important drug discoveries. While advances in molecular biology and computational chemistry have led to increased interest in what has been termed “rational drug design,” such techniques have not proven as fast or reliable as initially predicted. Thus, in recent years there has been a renewed interest and return to random drug screening. To this end, particular strides having been made in new technologies based on the development of combinatorial chemistry libraries, and the screening of such libraries in search for biologically active members.

[0006] In general, combinatorial chemistry libraries are simply a collection of molecules. Such libraries vary by the chemical species within the library, as well as the methods employed to both generate the library members and identify which members interact with biological targets of interest. While this field is still young, methods for generating and screening libraries have already become quite diverse and sophisticated. For example, a recent review of various combinatorial chemical libraries has identified a number of such techniques (Dolle, J. Com. Chem., 2(3): 383-433, 2000), including the use of both tagged and untagged library members (Janda, Proc. Natl. Acad. Sci. USA 91:10779-10785, 1994).

[0007] Initially, combinatorial chemistry libraries were generally limited to members of peptide or nucleotide origin. To this end, the techniques of Houghten et al. illustrate an example of what is termed a “dual-defined iterative” method to assemble soluble combinatorial peptide libraries via split synthesis techniques (Nature (London) 354:84-86,1991; Biotechniques 13:412-421, 1992; Bioorg. Med. Chem. Lett. 3:405-412, 1993). By this technique, soluble peptide libraries containing tens of millions of members have been obtained. Such libraries have been shown to be effective in the identification of opioid peptides, such as methionine- and leucine-enkephalin (Dooley and Houghten, Life Sci. 52, 1509-1517, 1993), and a N-acylated peptide library has been used to identify acetalins, which are potent opioid antagonists (Dooley et al., Proc. Natl. Acad. Sci. USA 90:10811-10815, 1993. More recently, an all D-amino acid opioid peptide library has been constructed and screened for analgesic activity against the mu (“μ”) opioid receptor (Dooley et al, Science 266:2019-2022, 1994).

[0008] While combinatorial libraries containing members of peptide and nucleotide origin are of significant value, there is still a need in the art for libraries containing members of different origin. For example, traditional peptide libraries to a large extent merely vary the amino acid sequence to generate library members. While it is well recognized that the secondary structures of peptides are important to biological activity, such peptide libraries do not impart a constrained secondary structure to its library members.

[0009] To this end, some researchers have cyclized peptides with disulfide bridges in an attempt to provide a more constrained secondary structure (Tumelty et al., J. Chem. Soc. 1067-68, 1994; Eichler et al., Peptide Res. 7:300-306, 1994). However, such cyclized peptides are generally still quite flexible and are poorly bioavailable, and thus have met with only limited success.

[0010] More recently, non-peptide compounds have been developed which more closely mimic the secondary structure of reverse-turns found in biologically active proteins or peptides. For example, U.S. Pat. No. 5,440,013 to Kahn and published PCT WO94/03494 to Kahn both disclose conformationally constrained, non-peptidic compounds, which mimic the three-dimensional structure of reverse-turns.

[0011] While significant advances have been made in the synthesis and identification of conformationally constrained, peptide mimetics, there remains a need in the art for small molecules, which mimic the secondary structure of peptides. There has been also a need in the art for libraries containing such members, as well as techniques for synthesizing and screening the library members against targets of interest, particularly biological targets, to identify bioactive library members. For example U.S. Pat. No. 5,929,237 and its continuation-in-part U.S. Pat. No. 6,013,458 to Kahn also discloses conformationally constrained compounds that mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins.

[0012] The present invention also fulfills these needs, and provides further related advantages by providing confomationally constrained compounds which mimic the secondary structure of the β-strand structures of biologically active peptides and proteins.

BRIEF SUMMARY OF THE INVENTION

[0013] In brief, the present invention is directed to conformationally constrained compounds that mimic the secondary structure of the β-strand structures of biologically active peptides and proteins. This invention also discloses libraries containing such compounds, as well as the synthesis and screening thereof.

[0014] The compounds of the present invention have the following general structure (I): 1

[0015] wherein A is —(CH)—, —N— or —CH2—N—, B is —(C═O)— or —(CH2)m—, W is —(C═O)—, —Y(C═O)—, —NH(C═O)— or nothing, X is —NH—, —NH(C═O)— or nothing, Y is oxygen or sulfur, Z is oxygen or hydrogen, L is hydrogen, R5, —C(O)NHR3 or its equivalents, n=0 or 1 and m=1 or 2; R1, R2, R3, R4 and R5 are the same or different and independently selected from hydrogen, an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers thereof.

[0016] In one embodiment of the invention, X is absent, A is —N—, B is —(C═O)—, L is —C(O)NHR3, and other groups are as defined above in structure (I), so that the compounds of the invention have the following structure (I′): 2

[0017] Optionally, W is absent and Z is oxygen.

[0018] In one embodiment of the invention, X is absent, A is —N—, B is —(CH2)m—, L is —C(O)NHR3, and other groups are as defined above in connection with structure (I), so that the compounds of the invention have the following structure (I″): 3

[0019] Optionally, W is absent and Z is oxygen.

[0020] In one embodiment of the invention, X is —NH—, A is —(CH)—, B is —(CH2)m—, L is —C(O)NHR3, and the other groups are as defined in connection with structure (I), so that the compounds of the invention have the following structure (I′″): 4

[0021] Optionally, when Z is oxygen, then W is absent.

[0022] In one embodiment of the invention, A is —CH2—N—, B is —(CH2)m—, L is —C(O)NHR3, and the other groups are as defined above in connection with structure (I), so that the compounds of the invention have the following structure (I″″): 5

[0023] Optionally, Y is oxygen, and/or W is absent, and/or Z is oxygen.

[0024] The present invention is also directed to libraries containing compounds of structures (I), (I)′), (I″), (I′″), and (I″″) above, as well as methods for synthesizing such libraries and methods for screening the same to identify biologically active compounds. Compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier or diluent are also disclosed.

[0025] These and other aspects of this invention will be apparent upon reference to the following detailed description and the drawings.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0026] FIGS. 1 and 2 illustrate synthetic methodology for preparing libraries of the present invention, and compounds of the present invention.

[0027] FIG. 3 illustrates synthetic methodology for preparing a library of the present invention, and compounds of the present invention, as more thoroughly described in Example 9.

[0028] FIG. 4 illustrates synthetic methodology for preparing a library of the present invention, and compounds of the present invention, as more thoroughly described in Example 10.

DETAILED DESCRIPTION OF THE INVENTION

[0029] Conformationally constrained compounds which mimic the secondary structure of β-strand regions of biologically active peptides and proteins are disclosed. Such β-strand mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the β-strand mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members.

[0030] In one aspect, the present invention is directed to β-strand mimetic structures and chemical libraries containing β-strand mimetic structures. The β-strand mimetic structures of the present invention are useful as bioactive agents, including (but not limited to) use as diagnostic, prophylactic and/or therapeutic agents. The β-strand mimetic structure libraries of this invention are useful in the identification of such bioactive agents. In the practice of the present invention, the libraries may contain from tens to hundreds to thousands (or greater) of individual β-strand mimetic structures (also referred to herein as “members”).

[0031] In one aspect of the present invention, a β-strand mimetic structure is disclosed having the following structure (I): 6

[0032] wherein A is —(CH)—, —N— or —CH2—N—, B is —(C═O)— or —(CH2)m—, W is —(C═O)—, —Y(C═O)—, —NH(C═O)— or nothing, X is —NH—, —NH(C═O)— or nothing, Y is oxygen or sulfur, Z is oxygen or hydrogen (when Z is hydrogen, then C═Z represents CH2), L is hydrogen, R5, —C(O)NHR3 or its equivalents, n=0 or 1 and m=1 or 2; R1, R2, R3, R4 and R5 are the same or different and independently selected from hydrogen, an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers thereof.

[0033] In one aspect of the invention, R1, R2, R3, R4 and R5 are independently selected from the group consisting of aminoC2-5alkyl, guanidineC2-5alkyl, C1-4alkylguanidinoC2-5alkyl, diC1-4alkylguanidino-C2-5alkyl, amidinoC2-5alkyl, C1-4alkylamidinoC2-5alkyl, diC1-4alkylamidinoC2-5alkyl, C1-3alkoxy, phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoroC1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoroC1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), naphthyl, substituted naphthyl (where the substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), pyridyl, substituted pyridyl, (where the substituents are independently selected from one or more of amino amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), pyridylC1-4alkyl, substituted pyridylC1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), pyrimidylC1-4alkyl, substituted pyrimidylC1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoroC1-4alkyl, C1-4alkyl, C1-3alkoxy or nitro, carboxy, cyano, sulfuryl, or hydroxyl), triazin-2-yl-C1-4alkyl, substituted triazin-2-yl-C1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), imidazoC1-4alkyl, substituted imidazol C1-4alkyl (where the imidazole substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), imidazolinylC1-4alkyl, N-amidinopiperazinyl-N—C0-4alkyl, hydroxyC2-5alkyl, C1-5alkylaminoC2-5alkyl, hydroxyC2-5alkyl, C1-5alkylaminoC2-5alkyl, C1-5dialkylaminoC2-5alkyl, N-amidinopiperidinylC1-4alkyl and 4-aminocyclohexylC0-2alkyl.

[0034] In one embodiment, R1, R2 and R3 are the same or different and represent the remainder of the compound, and R4 is selected from an amino acid side chain moiety or derivative thereof. In another embodiment, L represents —C(═O)NHR3, and R1, R2 and R3 are the same or different and represent the remainder of the compound or an amino acid side chain moiety or derivative thereof, and R4 is hydrogen.

[0035] As used herein, the term “amino acid side chain moiety” represents any amino acid side chain moiety present in naturally occurring proteins including (but not limited to) the naturally occurring amino acid side chain moieties identified in Table 1. Other naturally occurring amino acid side chain moieties of this invention include (but are not limited to) the side chain moieties of 3,5-dibromotyrosine, 3,5-diiodotyrosine, hydroxylysine, γ-carboxyglutamate, phosphotyrosine and phosphoserine. In addition, glycosylated amino acid side chains may also be used in the practice of this invention, including (but not limited to) glycosylated threonine, serine and asparagine.

TABLE 1
Amino Acid Side Chain Moieties
Amino Acid Side Chain Moiety Amino Acid
H                            Glycine
CH3                          Alanine
CH(CH3)2                     Valine
CH2 CH(CH3)2                 Leucine
CH(CH3)CH2CH3                Isoleucine
(CH2)4NH3+                   Lysine
(CH2)3NHC(NH2)NH2+           Arginine
7                            Histidine
CH2COO-                      Aspartic acid
CH2CH2COO                    Glutamic acid
CH2CONH2                     Asparagine
CH2CH2CONH2                  Glutamine
8                            Phenylalanine
9                            Tyrosine
10                           Tryptophan
CH2SH                        Cysteine
CH2CH2SCH3                   Methionine
CH2OH                        Serine
CH(OH)CH3                    Threonine
11                           Proline
12                           Hydroxyproline

[0036] In addition to naturally occurring amino acid side chain moieties, the amino acid side chain moieties of the present invention also include various derivatives thereof. As used herein, a “derivative” of an amino acid side chain moiety includes modifications and/or variations to naturally occurring amino acid side chain moieties. For example, the amino acid side chain moieties of alanine, valine, leucine, isoleucine and phenylalanine may generally be classified as lower chain alkyl, aryl, or arylalkyl moieties. Derivatives of amino acid side chain moieties include other straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated lower chain alkyl, aryl or arylalkyl moieties.

[0037] As used herein, the terms “remainder of the compound” and “remainder of the molecule” are used to mean any moiety, agent, compound, support, molecule, linker, amino acid, peptide or protein covalently attached to the β-strand mimetic structure. The attachment is preferably at either the R1 and/or R2 and/or R3 positions. This term also includes amino acid side chain moieties and derivatives thereof.

[0038] As used herein, “lower chain alkyl moieties” contain from 1-12 carbon atoms, “lower chain aryl moieties” contain from 6-12 carbon atoms and “lower chain aralkyl moieties” contain from 7-12 carbon atoms. Thus, in one embodiment, the amino acid side chain derivative is selected from a C1-12 alkyl, a C6-12 aryl and a C7-12 arylalkyl, and in a more preferred embodiment, from a C1-7 alkyl, a C6-10 aryl and a C7-11 arylalkyl.

[0039] Amino side chain derivatives of this invention further include substituted derivatives of lower chain alkyl, aryl, and arylalkyl moieties, wherein the substituent is selected from (but are not limited to) one or more of the following chemical moieties: —OH, —OR, —COOH, —COOR, —CONH2, —NH2, —NHR, —NRR, —SH, —SR, —SO2R, —SO2H, —SOR and halogen (including F, Cl, Br and I), wherein each occurrence of R is independently selected from straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated lower chain alkyl, aryl and aralkyl moieties. In one aspect the substituent has less than 18 carbon atoms. Moreover, cyclic lower chain alkyl, aryl and arylalkyl moieties of this invention include naphthalene, as well as heterocyclic compounds such as thiophene, pyrrole, furan, imidazole, oxazole, thiazole, pyrazole, 3-pyrroline, pyrrolidine, pyridine, pyrimidine, purine, quinoline, isoquinoline and carbazole. Amino acid side chain derivatives further include heteroalkyl derivatives of the alkyl portion of the lower chain alkyl and aralkyl moieties, including (but not limited to) alkyl and aralkyl phosphonates and silanes.

[0040] In one aspect of he invention, R1, R2 and R3 moieties are selected from —OH, —OR, —COR, —COOR, —CONH2, —CONR, —CONRR, —NH2, —NHR, —NRR, —SO2R and —COSR, wherein each occurrence of R is as defined above.

[0041] In a further embodiment, and in addition to being an amino acid side chain moiety or derivative thereof (or the remainder of the compound in the case of R1, R2 and R3), R1, R2 or R3 may be a linker facilitating the linkage of the compound to another moiety or compound. For example, the compounds of this invention may be linked to one or more known compounds, such as biotin, for use in diagnostic or screening assay. Furthermore, R1, R2 or R3 may be a linker joining the compound to a solid support (such as a support used in solid phase peptide synthesis) or alternatively, may be the support itself. In this embodiment, linkage to another moiety or compound, or to a solid support, is preferable at the R1, R2 or R3 position, and more preferably at the R3 position.

[0042] In the embodiment wherein X is absent, A is N, B is —(C═O)— and L is —C(O)NHR3, the β-strand compounds of this invention have the following structure (I′): 13

[0043] wherein R1, R2, R3, R4, W, Y, Z and n are as defined above. In a preferred embodiment, R2 and R3 represent the remainder of the compound, R1 and R4 are selected from amino acid side chain moieties.

[0044] In the embodiment wherein X is absent, A is N, B is —(CH2)m— and L is —C(O)NHR3, the β-strand mimetic structures of this invention include the following structure (I″): 14

[0045] wherein R1, R2, R3, R4, W, Y, Z, m and n are as defined above. In a preferred embodiment, R2 and R3 represent the remainder of the compound, and R1 and R4 are selected from amino acid side chain moieties.

[0046] In a more specific embodiment wherein X is —NH—, A is —(CH)—, and B is —(CH2)m— and L is —C(O)NHR3, the β-strand mimetic structure has the following structure (I′″): 15

[0047] wherein R1, R2, R3, R4, W, Y, Z, m and n are as defined above.

[0048] In a more specific embodiment wherein A is —CH2—N—, B is —(CH2)m— and L is —C(O)NHR3, the compounds of this invention have the following structure (I″″): 16

[0049] Optionally wherein R1, R2, R3, R4, W, X, Y, Z, m and n are as defined above, W is absent, Z is oxygen, and Y is oxygen.

[0050] The β-strand mimetic structures of the present invention may be prepared by utilizing appropriate starting component molecules (hereinafter referred to as “component pieces”). Briefly, in the synthesis of β-strand mimetic structures having structure (I′), first and second component pieces are coupled to form a combined first-second intermediate, and if necessary, third and/or fourth component pieces are coupled to form a combined third-fourth intermediate (or, if commercially available, a single third intermediate may be used), the combined first-second intermediate and third-fourth intermediate (or third intermediate) are then coupled to provide a first-second-third-fourth intermediate (or first-second-third intermediate) which is cyclized to yield the β-strand mimetic structures of this invention. Alternatively, the β-strand mimetic structures of structure (I′) may be prepared by sequential coupling of the individual component pieces either stepwise in solution or by solid phase synthesis as commonly practiced in solid phase peptide synthesis.

[0051] Within the context of the present invention, a “first component piece” has the following structure 1: 17

[0052] wherein R2, A and B are as defined above, and R is a protective group suitable for use in peptide synthesis. Suitable R groups include alkyl groups and, in a preferred embodiment, R is a methyl group. Such first component pieces may be readily synthesized by reductive amination by mating CH(OR)2—(CH2)m—CHO with H2N—R2, or by displacement from CH(OR)2—(CH2)m—Br.

[0053] A “second component piece” of this invention has the following structure 2: 18

[0054] where L and R4 are as defined above, P is an amino protective group suitable for use in peptide synthesis, and X represents the leaving group of the activated carboxylic acid group. Preferred protective groups include t-butyl dimethylsilyl (TBDMS), BOC, FMOC, and Alloc(allyloxycarbonyl). When L is C(O)NHR3, then —NHR3 may be an carboxyl protective group. N-Protected amino acids are commercially available, for example, FMOC amino acids are available from a variety of sources. The conversion of these N-protected amino acids to the second component pieces of this invention may be readily achieved by activation of the carboxylic acid group of the N-protected amino acid. Suitable activated carboxylic acid groups include acid halides where X is a halide such as chloride or bromide, acid anhydrides where X is an acyl group such as acetyl, reactive esters such as an N-hydroxysuccinimide esters and pentafluorophenyl esters, and other activated intermediates such as the active intermediate formed in a coupling reaction using a carbodiimide such as dicyclohexylcarbodiimide (DCC).

[0055] In the case of the azido derivative of an amino acid serving as the second component piece, such compounds may be prepared from the corresponding amino acid by the reaction disclosed by Zaloom et al. (J. Org. Chem. 46:5173-76, 1981).

[0056] A “third component piece” of this invention has the following structure 3:

R1—NH2 or R3—NH2

[0057] where R1 and R3 are as defined above. Suitable third component pieces are commercially available from a variety of sources, or may be readily prepared by standard organic synthetic techniques commonly utilized for the synthesis of primary amines.

[0058] More specifically, the β-strand mimetic structures of this invention of structure (I′) are synthesized by reacting a first component piece with a second component piece to yield a combined first-second intermediate, followed by either reacting the combined first-second intermediate with third component pieces sequentially, or third and fourth component pieces, to provide a combined first-second-third-fourth intermediate, and then cyclizing this intermediate to yield the β-strand mimetic structure.

[0059] The general synthesis of a β-strand mimetic structure having structure I′ may be accomplished by the following technique. A first component piece 1 is coupled with a second component piece 2 by using a coupling reagent such as phosgene to yield, after N-deprotection, a combined first-second intermediate 1-2 as illustrated below: 19

[0060] wherein, A, B, L, R, R2, R4, P, X and n are as defined above. X2C(═S) is an example of a coupling agent, and other type of coupling agents can be employed. The syntheses of representative component pieces of this invention are described in the Examples. The β-strand mimetic compounds of structures (I″) through (I′″) may be made by techniques analogous to the modular component synthesis disclosed above, but with appropriate modifications to the component pieces.

[0061] In another aspect of this invention, libraries containing the β-strand mimetic structures of the present invention are disclosed. Once assembled, the libraries of the present invention may be screened to identify individual members having bioactivity. Such screening of the libraries for bioactive members may involve; for example, evaluating the binding activity of the members of the library or evaluating the effect the library members have on a functional assay. Screening is normally accomplished by contacting the library members (or a subset of library members) with a target of interest, such as, for example, an antibody, enzyme, receptor or cell line. Library members that are capable of interacting with the target of interest are referred to herein as “bioactive library members” or “bioactive mimetics”. For example, a bioactive mimetic may be a library member which is capable of binding to an antibody or receptor, which is capable of inhibiting an enzyme, or which is capable of eliciting or antagonizing a functional response associated, for example, with a cell line. In other words, the screening of the libraries of the present invention determines which library members are capable of interacting with one or more specific biological targets of interest. When interaction does occur, the interacting bioactive mimetic (or mimetics) may be identified from the library members. The identification of a single (or limited number) of bioactive mimetic(s) from the library yields β-strand mimetic structures which are themselves biologically active, and thus useful as diagnostic, prophylactic or therapeutic agents, and may further be used to significantly advance identification of lead compounds in these fields.

[0062] Synthesis of the peptide mimetics of the library of the present invention may be accomplished using known peptide synthesis techniques, in combination with the first, second, third, and optionally fourth component pieces of this invention. More specifically, any amino acid sequence may be added to the N-terminal and/or C-terminal of the conformationally constrained compound. To this end, the mimetics may be synthesized on a solid support (such as PAM resin) by known techniques (see, e.g., John M. Stewart and Janis D. Young, Solid Phase Peptide Synthesis, 1984, Pierce Chemical Comp., Rockford, Ill.) or on a silyl-linked resin by alcohol attachment (see Randolph et al., J. Am Chem. Soc. 117:5712-14, 1995).

[0063] In addition, a combination of both solution and solid phase synthesis techniques may be utilized to synthesize the peptide mimetics of this invention. For example, a solid support may be utilized to synthesize the linear peptide sequence up to the point that the conformationally constrained β-strand is added to the sequence. A suitable conformationally constrained β-strand mimetic structure which has been previously synthesized by solution synthesis techniques may then be added as the next “amino acid” to the solid phase synthesis (i.e., the conformationally constrained β-strand mimetic, which has both an N-terminus and a C-terminus, may be utilized as the next amino acid to be added to the linear peptide). Upon incorporation of the conformationally constrained β-strand mimetic structure into the sequence, additional amino acids may then be added to complete the peptide bound to the solid support. Alternatively, the linear N-terminus and C-terminus protected peptide sequences may be synthesized on a solid support, removed from the support, and then coupled to the conformationally constrained β-strand mimetic structures in solution using known solution coupling techniques.

[0064] In another aspect of this invention, methods for constructing the libraries are disclosed. Traditional combinatorial chemistry techniques (see, e.g., Gallop et al., J. Med. Chem. 37:1233-1251, 1994) permit a vast number of compounds to be rapidly prepared by the sequential combination of reagents to a basic molecular scaffold. Combinatorial techniques have been used to construct peptide libraries derived from the naturally occurring amino acids. For example, by taking 20 mixtures of 20 suitably protected and different amino acids and coupling each with one of the 20 amino acids, a library of 400 (i.e., 202) dipeptides is created. Repeating the procedure seven times results in the preparation of a peptide library comprised of about 26 billion (i.e., 208) octapeptides.

[0065] In a further aspect of this invention, methods for screening the libraries for bioactivity and isolating bioactive library members are disclosed. The libraries of the present invention may be screened for bioactivity by a variety of techniques and methods. Generally, the screening assay may be performed by (1) contacting a library with a biological target of interest, such as a receptor, and allowing binding to occur between the mimetics of the library and the target, and (2) detecting the binding event by an appropriate assay, such as by the calorimetric assay disclosed by Lam et al. (Nature 354:82-84,1991) or Griminski et al. (Biotechnology 12:1008-1011, 1994) (both of which are incorporated herein by reference). In a preferred embodiment, the library members are in solution and the target is immobilized on a solid phase. Alternatively, the library may be immobilized on a solid phase and may be probed by contacting it with the target in solution.

[0066] The synthesis of the peptide mimetics of a library of the present invention may be accomplished using the general scheme for preparing a β-strand mimetics library as shown in FIG. 1. The synthesis of selected peptide mimetics of the bicyclic template libraries of the present invention was accomplished using a FlexChem Reactor Block which has a 96 well plate. In the above scheme ‘Pol’ represents 2-chlorotrityl chloride resin (Novabiochem) and a detailed procedure is provided below.

[0067] Step 1 The 2-chlorotrityl chloride resin (1 mmol/g) and a solution Fmoc-R1-Amino Acid (1.5 equiv.) and DIEA (2 equiv.) in DCE were placed in a 96 well Robinson block (Flexchem). The reaction mixture was shaken for 12 hours at room temperature. The resin washed with DMF, MeOH, and the DCM.

[0068] Step 2 To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and the product mixture was washed with DMF, MeOH, and then DCM. A solution of 4R2-amino-2-Fmoc-aminobutyric acid (1.5 equiv.), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0069] Step 3 To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and the product mixture was washed with DMF, MeOH, and then DCM. A solution of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-5, 5-dimethoxy-pentanoic acid (1.5 equiv.), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. The reaction mixture was shaken for 12 hours at room temperature, and then the resin was washed with DMF, MeOH, and then DCM.

[0070] Step 4 To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and the product mixture was washed with DMF, MeOH, and then DCM. A solution of commercially available R3-acid (1.5 equiv.), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. The reaction mixture was shaken for 12 hours at room temperature, and then the resin was washed with DMF, MeOH, and then DCM.

[0071] Step 5 The resin was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. Thereafter, the resin was removed by filtration, the filtrate was condensed under reduced pressure using SpeedVac (Servant) to give the product as oil. These products were diluted with 50% water/acetonitrile and then lyophilized after freezing.

[0072] Table 2 shows a β-strand mimetics library that may be prepared according to the present invention, of which representative preparation is given in Example 9. Compounds of Table 2 illustrate one aspect of the invention, namely compounds wherein A is —(CH)—, B is —(CH2)m— with m=1, W is —(C═O)—, X is —NH(C═O)—, Y is oxygen, Z is hydrogen so that C═Z represents CH2, L is —C(═O)NHR3, n=0, R4 is hydrogen, and R1, R2, and R3 are the same or different and are independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers thereof. In various embodiments of this aspect of the invention, R1, R2, and R3 are independently selected from relatively low molecular weight moieties, i.e., organic groups having molecular weights of between 15 (methyl) and 1,000 g/mol; and/or at least one of R1, R2, and R3 represents an amino acid side chain or derivative thereof. For example, in the compounds of Table 2, R3 represents aspartic acid derivatives. In one aspect, the compounds of the present invention have a molecular weight within the range of about 440 to 750 g/mol, where the compounds of Table 2 provide numerous illustrations of such compounds.

TABLE 2
THE BETA-STRAND MIMETICS LIBRARY
20
				Mol.
No.	Ra	Rb	Rc	Weight	M + H
1	Methyl	Phenyl	4-Methoxybenzyl	522	522
2	Methyl	Phenyl	3,4-Cl2-benzyl	547	547
3	Methyl	Phenyl	1-Naphthyl	528	528
4	Methyl	Phenyl	Piperonyl	522	522
5	Methyl	Phenyl	2,4,5-Trimethoxyphenyl	568	568
6	Methyl	Phenyl	2-Thienylmethyl	498	498
7	Methyl	Phenyl	1-Naphthylmethyl	542	542
8	Methyl	Phenyl	Phenethyl	506	506
9	Methyl	Phenyl	3-Methoxyphenyl	508	508
10	Methyl	Phenyl	N-Benzoylaminoethyl 535	535
11	Methyl	Phenyl	Benzyl	492	492
12	Methyl	Phenyl	4-Nitrobenzyl	537	537
13	Isopropyl	Phenyl	4-Methoxybenzyl	550	550
14	Isopropyl	Phenyl	3,4-Cl2-benzyl	575
15	Isopropyl	Phenyl	1-Naphthyl	556	556
16	Isopropyl	Phenyl	Piperonyl	550	550
17	Isopropyl	Phenyl	2,4,5-Trimethoxyphenyl	596	596
18	Isopropyl	Phenyl	2-Thienylmethyl	526	526
19	Isopropyl	Phenyl	1-Naphthylmethyl	570	570
20	Isopropyl	Phenyl	Phenethyl	534	534
21	Isopropyl	Phenyl	3-Methoxyphenyl	536	536
22	Isopropyl	Phenyl	N-Benzoylaminoethyl 563	563
23	Isopropyl	Phenyl	Benzyl	520	520
24	Isopropyl	Phenyl	4-Nitrobenzyl	565	565
25	Isobutyl	Phenyl	4-Methoxybenzyl	564	564
26	Isobutyl	Phenyl	3,4-Cl2-benzyl	589	589
27	Isobutyl	Phenyl	1-Naphthyl	570	570
28	Isobutyl	Phenyl	Piperonyl	564	564
29	Isobutyl	Phenyl	2,4,5-Trimethoxyphenyl	610	610
30	Isobutyl	Phenyl	2-Thienylmethyl	540	540
31	Isobutyl	Phenyl	1-Naphthylmethyl 584	584
32	Isobutyl	Phenyl	Phenethyl	548	548
33	Isobutyl	Phenyl	3-Methoxyphenyl	550	550
34	Isobutyl	Phenyl	N-Benzoylaminoethyl 577	577
35	Isobutyl	Phenyl	Benzyl	534	534
36	Isobutyl	Phenyl	4-N itrobenzyl	579	579
37	Benzyl	Phenyl	4-Methoxybenzyl598	598
38	Benzyl	Phenyl	3,4-Cl2-benzyl623	623
39	Benzyl	Phenyl	1-Naphthyl	604	604
40	Benzyl	Phenyl	Piperonyl	598	598
41	Benzyl	Phenyl	2,4,5-Trimethoxyphenyl	644	644
42	Benzyl	Phenyl	2-Thienylmethyl	574	574
43	Benzyl	Phenyl	1-Naphthylmethyl	618	618
44	Benzyl	Phenyl	Phenethyl	582	582
45	Benzyl	Phenyl	3-Methoxyphenyl	584	584
46	Benzyl	Phenyl	N-Benzoylaminoethyl	611	611
47	Benzyl	Phenyl	Benzyl	568	568
48	Benzyl	Phenyl	4-Nitrobenzyl	613	613
49	Methyl	Methoxy	4-Methoxybenzyl	476	476
50	Methyl	Methoxy	3,4-Cl2-benzyl	501	501
51	Methyl	Methoxy	1-Naphthyl	482	482
52	Methyl	Methoxy	Piperonyl	476	476
53	Methyl	Methoxy	2,4,5-Trimethoxyphenyl	522	522
54	Methyl	Methoxy	2-Thienylmethyl452	452
55	Methyl	Methoxy	1-Naphthylmethyl	496	496
56	Methyl	Methoxy	Phenethyl	460	460
57	Methyl	Methoxy	3-Methoxyphenyl	462	462
58	Methyl	Methoxy	N-Benzoylaminoethyl	489	489
59	Methyl	Methoxy	Benzyl	446	446
60	Methyl	Methoxy	4-Nitrobenzyl	491	491
61	Isopropyl	Methoxy	4-Methoxybenzyl	504	504
62	Isopropyl	Methoxy	3,4-Cl2-benzyl	529	529
63	Isopropyl	Methoxy	1-Naphthyl	510	510
64	Isopropyl	Methoxy	Piperonyl	504	504
65	Isopropyl	Methoxy	2,4,5-Trimethoxyphenyl	550	550
66	Isopropyl	Methoxy	2-Thienylmethyl	480	480
67	Isopropyl	Methoxy	1-Naphthylmethyl 524	524
68	Isopropyl	Methoxy	Phenethyl	488	488
69	Isopropyl	Methoxy	3-Methoxyphenyl	490	490
70	Isopropyl	Methoxy	N-Benzoylaminoethyl	517	517
71	Isopropyl	Methoxy	Benzyl	474	474
72	Isopropyl	Methoxy	4-Nitrobenzyl	519	519
73	Isobutyl	Methoxy	4-Methoxybenzyl	518	518
74	Isobutyl	Methoxy	3,4-Cl2-benzyl	543	543
75	Isobutyl	Methoxy	1-Naphthyl	524	524
76	Isobutyl	Methoxy	Piperonyl	518	518
77	Isobutyl	Methoxy	2,4,5-Trimethoxyphenyl	564	564
78	Isobutyl	Methoxy	2-Thienylmethyl	494	494
79	Isobutyl	Methoxy	1 -Naphthylmethyl	538	538
80	Isobutyl	Methoxy	Phenethyl	502	502
81	Isobutyl	Methoxy	3-Methoxyphenyl	504	504
82	Isobutyl	Methoxy	N-Benzoylaminoethyl	531	531
83	Isobutyl	Methoxy	Benzyl	488	488
84	Isobutyl	Methoxy	4-Nitrobenzyl	533	533
85	Benzyl	Methoxy	4-Methoxybenzyl	552	552
86	Benzyl	Methoxy	3,4-Cl2-benzyl	577	577
87	Benzyl	Methoxy	1-Naphthyl	558	558
88	Benzyl	Methoxy	Piperonyl	552	552
89	Benzyl	Methoxy	2,4,5-Trimethoxyphenyl	598	598
90	Benzyl	Methoxy	2-Thienylmethyl	528	528
91	Benzyl	Methoxy	1-Naphthylmethyl	572	572
92	Benzyl	Methoxy	Phenethyl	536	536
93	Benzyl	Methoxy	3-Methoxyphenyl	538	538
94	Benzyl	Methoxy	N-Benzoylaminoethyl	565	565
95	Benzyl	Methoxy	Benzyl	522	522
96	Benzyl	Methoxy	4-Nitrobenzyl	567	567
97	2-Methylpropyl	Phenyl	4-Methoxybenzyl	564	564
98	2-Methylpropyl	Phenyl	3,4-Cl2-benzyl	589	589
99	2-Methylpropyl	Phenyl	1-Naphthyl	570	570
100	2-Methylpropyl	Phenyl	Piperonyl	564	564
101	2-Methylpropyl	Phenyl	2,4,5-Trimethoxyphenyl	610	610
102	2-Methylpropyl	Phenyl	2-Thienylmethyl	550	550
103	2-Methylpropyl	Phenyl	1-Naphthylmethyl	584	584
104	2-Methylpropyl	Phenyl	Phenethyl	548	548
105	2-Methylpropyl	Phenyl	3-Methoxyphenyl	550	550
106	2-Methylpropyl	Phenyl	N-Benzoylaminoethyl	577	577
107	2-Methylpropyl	Phenyl	Benzyl	534	534
108	2-Methylpropyl	Phenyl	4-Nitrobenzyl	579	579
109	Methylthioethyl	Phenyl	4-Methoxybenzyl	582	582
110	Methylthioethyl	Phenyl	3,4-Cl2-benzyl	607	607
111	Methylthioethyl	Phenyl	1-Naphthyl	588	588
112	Methylthioethyl	Phenyl	Piperonyl	582	582
113	Methylthioethyl	Phenyl	2,4,5-Trimethoxyphenyl	628	628
114	Methylthioethyl	Phenyl	2-Thienylmethyl	568	568
115	Methylthioethyl	Phenyl	1-Naphthylmethyl	602	602
116	Methylthioethyl	Phenyl	Phenethyl	566	566
117	Methylthioethyl	Phenyl	3-Methoxyphenyl	568	568
118	Methylthioethyl	Phenyl	N-Benzoylaminoethyl	595	595
119	Methyithioethyl	Phenyl	Benzyl	552	552
120	Methylthioethyl	Phenyl	4-Nitrobenzyl	597	597
121	4-Hydroxybenzyl	Phenyl	4-Methoxybenzyl	614	614
122	4-Hydroxybenzyl	Phenyl	3,4-Cl2-benzyl	639	639
123	4-Hydroxybenzyl	Phenyl	1-Naphthyl	620	620
124	4-Hydroxybenzyl	Phenyl	Piperonyl	614	614
125	4-Hydroxybenzyl	Phenyl	2,4,5-Trimethoxyphenyl	660	660
126	4-Hydroxybenzyl	Phenyl	2-Thienylmethyl	600	600
127	4-Hydroxybenzyl	Phenyl	1-Naphthylmethyl	634	634
128	4-Hydroxybenzyl	Phenyl	Phenethyl	598	598
129	4-Hydroxybenzyl	Phenyl	3-Methoxyphenyl	600	600
130	4-Hydroxybenzyl	Phenyl	N-Benzoylaminoethyl	627	627
131	4-Hydroxybenzyl	Phenyl	Benzyl	584	584
132	4-Hydroxybenzyl	Phenyl	4-Nitrobenzyl	629	629
133	Cyclohexylmethyl	Phenyl	4-Methoxybenzyl	604	604
134	Cyclohexylmethyl	Phenyl	3,4-Cl2-benzyl	629	629
135	Cyclohexylmethyl	Phenyl	1-Naphthyl	610	610
136	Cyclohexylmethyl	Phenyl	Piperonyl	604	604
137	Cyclohexylmethyl	Phenyl	2,4,5-Trimethoxyphenyl	650	650
138	Cyclohexylmethyl	Phenyl	2-Thienylmethyl	590	590
139	Cyclohexylmethyl	Phenyl	1-Naphthylmethyl	624	624
140	Cyclohexylmethyl	Phenyl	Phenethyl	588	588
141	Cyclohexylmethyl	Phenyl	3-Methoxyphenyl	590	590
142	Cyclohexylmethyl	Phenyl	N-Benzoylaminoethyl	617	617
143	Cyclohexylmethyl	Phenyl	Benzyl	574	574
144	Cyclohexylmethyl	Phenyl	4-Nitrobenzyl	619	619
145	2-Methylpropyl	Methoxy	4-Methoxybenzyl	518	518
146	2-Methylpropyl	Methoxy	3,4-Cl2-benzyl	543	543
147	2-Methylpropyl	Methoxy	1-Naphthyl 524	524
148	2-Methylpropyl	Methoxy	Piperonyl 518	518
149	2-Methylpropyl	Methoxy	2,4,5-Trimethoxyphenyl	564	564
150	2-Methylpropyl	Methoxy	2-Tthienylmethyl	504	504
151	2-Methylpropyl	Methoxy	1-Naphthylmethyl	538	538
152	2-Methylpropyl	Methoxy	Phenethyl	502	502
153	2-Methylpropyl	Methoxy	3-Methoxyphenyl	504	504
154	2-Methylpropyl	Methoxy	N-Benzoylaminoethyl	531	531
155	2-Methylpropyl	Methoxy	Benzyl	488	488
156	2-Methylpropyl	Methoxy	4-Nitrobenzyl	533	533
157	Methylthioethyl	Methoxy	4-Methoxybenzyl	536	536
158	Methylthioethyl	Methoxy	3,4-Cl2-benzyl	561	561
159	Methylthioethyl	Methoxy	1-Naphthyl	542	542
160	Methylthioethyl	Methoxy	Piperonyl	536	536
161	Methylthioethyl	Methoxy	2,4,5-Trimethoxyphenyl	582	582
162	Methylthioethyl	Methoxy	2-Tthienylmethyl	522	522
163	Methylthioethyl	Methoxy	1-Naphthylmethyl	556	556
164	Methylthioethyl	Methoxy	Phenethyl	520	520
165	Methylthioethyl	Methoxy	3-Methoxyphenyl	522	522
166	Methylthioethyl	Methoxy	N-Benzoylaminoethyl	549	549
167	Methylthioethyl	Methoxy	BenzyI	506	506
168	Methylthioethyl	Methoxy	4-Nitrobenzyl	551	551
169	4-Hydroxybenzyl	Methoxy	4-Methoxybenzyl	568	568
170	4-Hydroxybenzyl	Methoxy	3,4-Cl2-benzyl	593	593
171	4-Hydroxybenzyl	Methoxy	1-Naphthyl	574	574
172	4-Hydroxybenzyl	Methoxy	Piperonyl	568	568
173	4-Hydroxybenzyl	Methoxy	2,4,5-Trimethoxyphenyl	614	614
174	4-Hydroxybenzyl	Methoxy	2-Tthienylmethyl	554	554
175	4-Hydroxybenzyl	Methoxy	1-Naphthylmethyl	588	588
176	4-Hydroxybenzyl	Methoxy	Phenethyl	552	552
177	4-Hydroxybenzyl	Methoxy	3-Methoxyphenyl	554	554
178	4-Hydroxybenzyl	Methoxy	N-Benzoylaminoethyl	581	581
179	4-Hydroxybenzyl	Methoxy	Benzyl	538	538
180	4-Hydroxybenzyl	Methoxy	4-Nitrobenzyl	583	583
181	Cyclohexylmethyl	Methoxy	4-Methoxybenzyl	558	558
182	Cyclohexylmethyl	Methoxy	3,4-Cl2-benzyl	583	583
183	Cyclohexylmethyl	Methoxy	1-Naphthyl	564	564
184	Cyclohexylmethyl	Methoxy	Piperonyl	558	558
185	Cyclohexylmethyl	Methoxy	2,4,5-Trimethoxyphenyl	604	604
186	Cyclohexylmethyl	Methoxy	2-Thienylmethyl	544	544
187	Cyclohexylmethyl	Methoxy	1-Naphthylmethyl 578	578
188	Cyclohexylmethyl	Methoxy	Phenethyl	542	542
189	Cyclohexylmethyl	Methoxy	3-Methoxyphenyl	544	544
190	Cyclohexylmethyl	Methoxy	N-Benzoylaminoethyl	571	571
191	Cyclohexylmethyl	Methoxy	Benzyl	528	528
192	Cyclohexylmethyl	Methoxy	4-Nitrobenzyl	573	573
193	Methyl	Phenyl	4-Methoxybenzyl	521	521
194	Methyl	Phenyl	3,4-Cl2-benzyl	546	546
195	Methyl	Phenyl	1-Naphthyl	527	527
196	Methyl	Phenyl	Piperonyl	521	521
197	Methyl	Phenyl	2,4,5-Trimethoxyphenyl	567	567
198	Methyl	Phenyl	3-Hydroxybenzyl	507	507
199	Methyl	Phenyl	1-Naphthylmethyl	541	541
200	Methyl	Phenyl	Phenethyl	505	505
201	Methyl	Phenyl	3-Methoxyphenyl	507	507
202	Methyl	Phenyl	N-Benzoylaminoethyl	534	534
203	Methyl	Phenyl	Benzyl	491	491
204	Methyl	Phenyl	4-Nitrobenzyl	536	536
205	Isopropyl	Phenyl	4-Methoxybenzyl	549	549
206	Isopropyl	Phenyl	3,4-Cl2-benzyl	574	574
207	Isopropyl	Phenyl	1-Naphthyl
208	Isopropyl	Phenyl	Piperonyl	549	549
209	Isopropyl	Phenyl	2,4,5-Trimethoxyphenyl	595	595
210	Isopropyl	Phenyl	3-Hydroxybenzyl	535	535
211	Isopropyl	Phenyl	1-Naphthylmethyl	569	569
212	Isopropyl	Phenyl	Phenethyl	533	533
213	Isopropyl	Phenyl	3-Methoxyphenyl	535	535
214	Isopropyl	Phenyl	N-Benzoylaminoethyl	562	562
215	Isopropyl	Phenyl	Benzyl	519	519
216	Isopropyl	Phenyl	4-Nitrobenzyl	564	564
217	Isobutyl	Phenyl	4-Methoxybenzyl	563	563
218	Isobutyl	Phenyl	3,4-Cl2-benzyl	588	588
219	Isobutyl	Phenyl	1-Naphthyl	569	569
220	Isobutyl	Phenyl	Piperonyl	563	563
221	Isobutyl	Phenyl	2,4,5-Trimethoxyphenyl	609	609
222	Isobutyl	Phenyl	3-Hydroxybenzyl	549	549
223	Isobutyl	Phenyl	1-Naphthylmethyl	583	583
224	Isobutyl	Phenyl	Phenethyl	547	547
225	Isobutyl	Phenyl	3-Methoxyphenyl	549	549
226	Isobutyl	Phenyl	N-Benzoylaminoethyl	576	576
227	Isobutyl	Phenyl	Benzyl	533	533
228	Isobutyl	Phenyl	4-Nitrobenzyl	578	578
229	Benzyl	Phenyl	4-Methoxybenzyl	597	597
230	Benzyl	Phenyl	3,4-Cl2-benzyl	622	622
231	Benzyl	Phenyl	1-Naphthyl	603	603
232	Benzyl	Phenyl	Piperonyl	597	597
233	Benzyl	Phenyl	2,4,5-Trimethoxyphenyl	643	643
234	Benzyl	Phenyl	3-Hydroxybenzyl	583	583
235	Benzyl	Phenyl	1-Naphthylmethyl	617	617
236	Benzyl	Phenyl	Phenethyl	581	581
237	Benzyl	Phenyl	3-Methoxyphenyl	583	583
238	Benzyl	Phenyl	N-Benzoylaminoethyl	610	610
239	Benzyl	Phenyl	Benzyl	567	567
240	Benzyl	Phenyl	4-Nitrobenzyl	612	612
241	2-Methylpropyl	Phenyl	4-Methoxybenzyl	563	563
242	2-Methylpropyl	Phenyl	3,4-Cl2-benzyl	588	588
243	2-Methylpropyl	Phenyl	1-Naphthyl	569	569
244	2-Methylpropyl	Phenyl	Piperonyl	563	563
245	2-Methylpropyl	Phenyl	2,4,5-Trimethoxyphenyl	609 609
246	2-Methylpropyl	Phenyl	3-Hydroxybenzyl	549	549
247	2-Methylpropyl	Phenyl	1-Naphthylmethyl	583	583
248	2-Methylpropyl	Phenyl	Phenethyl	547	547
249	2-Methylpropyl	Phenyl	3-Methoxyphenyl	549	549
250	2-Methylpropyl	Phenyl	N-Benzoylaminoethyl	576	576
251	2-Methylpropyl	Phenyl	Benzyl	533	533
252	2-Methylpropyl	Phenyl	4-Nitrobenzyl	578	578
253	Methylthioethyl	Phenyl	4-Methoxybenzyl	581	581
254	Methylthioethyl	Phenyl	3,4-Cl2-benzyl	606	606
255	Methylthioethyl	Phenyl	1-Naphthyl	587	587
256	Methylthioethyl	Phenyl	Piperonyl	581	581
257	Methylthioethyl	Phenyl	2,4,5-Trimethoxyphenyl	627	627
258	Methylthioethyl	Phenyl	3-Hydroxybenzyl	567	567
259	Methylthioethyl	Phenyl	1-Naphthylmethyl	601	601
260	Methylthioethyl	Phenyl	Phenethyl	565	565
261	Methylthioethyl	Phenyl	3-Methoxyphenyl	567	567
262	Methylthioethyl	Phenyl	N-Benzoylaminoethyl	594	594
263	Methylthioethyl	Phenyl	Benzyl	551	551
264	Methylthioethyl	Phenyl	4-Nitrobenzyl	596	596
265	4-Hydroxybenzyl	Phenyl	4-Methoxyberlzyl	613	613
266	4-Hydroxybenzyl	Phenyl	3,4-Cl2benzyl	638	638
267	4-Hydroxybenzyl	Phenyl	1-Naphthyl	619	619
268	4-Hydroxybenzyl	Phenyl	Piperonyl	613	613
269	4-Hydroxybenzyl	Phenyl	2,4,5-Trimethoxyphenyl	659	659
270	4-Hydroxybenzyl	Phenyl	3-Hydroxybenzyl	599	599
271	4-Hydroxybenzyl	Phenyl	1-Naphthylmethyl	633	633
272	4-Hydroxybenzyl	Phenyl	Phenethyl	597	597
273	4-Hydroxybenzyl	Phenyl	3-Methoxyphenyl	599	599
274	4-Hydroxybenzyl	Phenyl	N-Benzoylaminoethyl	626	626
275	4-Hydroxybenzyl	Phenyl	Benzyl	583	583
276	4-Hydroxybenzyl	Phenyl	4-Nitrobenzyl	628	628
277	Cyclohexylmethyl	Phenyl	4-Methoxybenzyl	603	603
278	Cyclohexylmethyl	Phenyl	3,4-Cl2-benzyl	628	628
279	Cyclohexylmethyl	Phenyl	1-Naphthyl	609	609
280	Cyclohexylmethyl	Phenyl	Piperonyl	603	603
281	Cyclohexylmethyl	Phenyl	2,4,5-Trimethoxyphenyl	649	649
282	Cyclohexylmethyl	Phenyl	3-Hydroxybenzyl	589	589
283	Cyclohexylmethyl	Phenyl	1-Naphthylmethyl	623	623
284	Cyclohexylmethyl	Phenyl	Phenethyl	587	587
285	Cyclohexylmethyl	Phenyl	3-Methoxyphenyl	589	589
286	Cyclohexylmethyl	Phenyl	N-Benzoylaminoethyl	616	616
287	Cyclohexylmethyl	Phenyl	Benzyl	573	573
288	Cyclohexylmethyl	Phenyl	4-Nitrobenzyl	618	618
289	Methyl	Benzyloxy	4-Methoxybenzyl	553	553
290	Methyl	Benzyloxy	3,4-Cl2-benzyl	577	577
291	Methyl	Benzyloxy	1-Naphthyl	559	559
292	Methyl	Benzyloxy	Piperonyl	553	553
293	Methyl	Benzyloxy	2,4,5-Trimethoxyphenyl	599	599
294	Methyl	Benzyloxy	2-Thienylmethyl	539	539
295	Methyl	Benzyloxy	1-Naphthylmethyl	573	573
296	Methyl	Benzyloxy	Phenethyl	537	537
297	Methyl	Benzyloxy	3-Methoxyphenyl	539	539
298	Methyl	Benzyloxy	N-Benzoylaminoethyl	566	566
299	Methyl	Benzyloxy	Benzyl	523	523
301	Isopropyl	Benzyloxy	4-Methoxybenzyl	581	581
302	Isopropyl	Benzyloxy	3,4-Cl2-benzyl	605	605
303	Isopropyl	Benzyloxy	1-Naphthyl	587	587
304	Isopropyl	Benzyloxy	Piperonyl	581	581
305	Isopropyl	Benzyloxy	2,4,5-Trimethoxyphenyl	627	627
306	Isopropyl	Benzyloxy	2-Thienylmethyl	567	567
307	Isopropyl	Benzyloxy	1-Naphthylmethyl	601	601
308	Isopropyl	Benzyloxy	Phenethyl	565	565
309	Isopropyl	Benzyloxy	3-Methoxyphenyl 567	567
310	Isopropyl	Benzyloxy	N-Benzoylaminoethyl	594
311	Isopropyl	Benzyloxy	BenzyI	551	551
312	Isopropyl	Benzyloxy	4-Nitrobenzyl	596	596
313	Isobutyl	Benzyloxy	4-Methoxybenzyl	595	595
314	Isobutyl	Benzyloxy	3,4-Cl2-benzyl	620	620
315	Isobutyl	Benzyloxy	1-Naphthyl	601	601
316	Isobutyl	Benzyloxy	Piperonyl	595	595
317	Isobutyl	Benzyloxy	2,4,5-Trimethoxyphenyl	641	641
318	Isobutyl	Benzyloxy	2-Thienylmethyl	581	581
319	Isobutyl	Benzyloxy	1-Naphthylmethyl	615	615
320	Isobutyl	Benzyloxy	Phenethyl	579	579
321	Isobutyl	Benzyloxy	3-Methoxyphenyl	581	581
322	Isobutyl	Benzyloxy	N-Benzoylaminoethyl	608	608
323	Isobutyl	Benzyloxy	Beiizyl	565	565
324	Isobutyl	Benzyloxy	4-Nitrobenzyl	610	610
325	Benzyl	Benzyloxy	4-Methoxybenzyl	629	629
326	Benzyl	Benzyloxy	3,4-Cl2-berizyl	654	654
327	Benzyl	Benzyloxy	1-Naphthyl	635	635
328	Benzyl	Benzyloxy	Piperonyl	629	629
329	Benzyl	Benzyloxy	2,4,5-Trimethoxyphenyl	675	675
330	Benzyl	Benzyloxy	2-Thienylmethyl	615	615
331	Benzyl	Benzyloxy	1-Naphthylrnethyl	649	649
332	Benzyl	Benzyloxy	Phenethyl	613	613
333	Benzyl	Benzyloxy	3-Methoxyphenyl	615	615
334	Benzyl	Benzyloxy	N-Benzoylaminoethyl	642	642
335	Benzyl	Benzyloxy	Benzyl	599	599
336	Benzyl	Benzyloxy	4-Nitrobenzyl	644	644
337	2-Methylpropyl	Benzyloxy	4-Methoxybenzyl	595	595
338	2-Methylpropyl	Benzyloxy	3,4-Cl2-benzyl	620	620
339	2-Methylpropyl	Benzyloxy	1-Naphthyl	601	601
340	2-Methylpropyl	Benzyloxy	Piperonyl	595	595
341	2-Methylpropyl	Benzyloxy	2,4,5-Trimethoxyphenyl	641	641
342	2-Methylpropyl	Benzyloxy	2-Thienylmethyl	581	581
343	2-Methylpropyl	Benzyloxy	1-Naphthylmethyl	615	615
344	2-Methylpropyl	Benzyloxy	Phenethyl 579	579
345	2-Methylpropyl	Benzyloxy	3-Methoxyphenyl	581	581
346	2-Methylpropyl	Benzyloxy	N-Benzoylaminoethyl	608	608
347	2-Methylpropyl	Benzyloxy	Benzyl	565	565
348	2-Methylpropyl	Benzyloxy	4-Nitrobenzyl	610	610
349	Methylthioethyl	Benzyloxy	4-Methoxybenzyl	613	613
350	Methylthioethyl	Benzyloxy	3,4-Cl2-benzyl	638	638
351	Methylthioethyl	Benzyloxy	1-Naphthyl 619	619
352	Methylthioethyl	Benzyloxy	Piperonyl 613	613
353	Methylthioethyl	Benzyloxy	2,4,5-Trimethoxyphenyl	659	659
354	Methylthioethyl	Benzyloxy	2-Tthienylmethyl	599	599
355	Methylthioethyl	Benzyloxy	1-Naphthylmethyl	633	633
356	Methylthioethyl	Benzyloxy	Phenethyl	597	597
357	Methylthioethyl	Benzyloxy	3-Methoxyphenyl	599	599
358	Methylthioethyl	Benzyloxy	N-Benzoylaminoethyl	626	626
359	Methylthioethyl	Benzyloxy	Benzyl	583	583
360	Methylthioethyl	Benzyloxy	4-Nitrobenzyl	628	628
361	4-Hydroxybenzyl	Benzyloxy	4-Methoxybenzyl	645	645
362	4-Hydroxybenzyl	Benzyloxy	3,4-Cl2-benzyl	670	670
363	4-Hydroxybenzyl	Benzyloxy	1-Naphthyl	651	651
364	4-Hydroxybenzyl	Benzyloxy	Piperonyl	645	645
365	4-Hydroxybenzyl	Benzyloxy	2,4,5-Trimethoxyphenyl	691	691
366	4-Hydroxybenzyl	Benzyloxy	2-Thienylmethyl	631	631
367	4-Hydroxybenzyl	Benzyloxy	1-Naphthylmethyl	665	665
368	4-Hydroxybenzyl	Benzyloxy	Phenethyl 629	629
369	4-Hydroxybenzyl	Benzyloxy	3-Methoxyphenyl	631	631
370	4-Hydroxybenzyl	Benzyloxy	N-Benzoylaminoethyl	658	658
371	4-Hydroxybenzyl	Benzyloxy	BenzyI	615	615
372	4-Hydroxybenzyl	Benzyloxy	4-Nitrobenzyl	660	660
373	Cyclohexylmethyl	Benzyloxy	4-Methoxybenzyl	635	635
374	Cyclohexylmethyl	Benzyloxy	3,4-Cl2-benzyl	660	660
375	Cyclohexylmethyl	Benzyloxy	1-Naphthyl	641	641
376	Cyclohexylmethyl	Benzyloxy	Piperonyl	635	635
377	Cyclohexylmethyl	Benzyloxy	2,4,5-Trimethoxyphenyl	681	681
378	Cyclohexylmethyl	Benzyloxy	2-Thienylmethyl	621	621
379	Cyclohexylmethyl	Benzyloxy	1-Naphthylmethyl	655	655
380	Cyclohexylmethyl	Benzyloxy	Phenethyl	619	619
381	Cyclohexylmethyl	Benzyloxy	3-Methoxyphenyl	621	621
382	Cyclohexylmethyl	Benzyloxy	N-Benzoylaminoethyl	648	648
383	Cyclohexylmethyl	Benzyloxy	Benzyl	605	605
384	Cyclohexylmethyl	Benzyloxy	4-Nitrobenzyl	650	650
385	Methyl	Methoxy	Acetoxymethyl	422	422
386	Methyl	Methoxy	4-(2,5-Cl2pyridyl)methyl	502	502
387	Methyl	Methoxy	Chromen-2-one-3-	500	500
			methyl
388	Methyl	Methoxy	Methoxymethyl	400	400
389	Methyl	Methoxy	Pyran-2-one-5-methyl	450	450
390	Methyl	Methoxy	Ethyl	384	384
391	Methyl	Methoxy	2-Ethyldecanyl	510	510
392	Methyl	Methoxy	Pyrazine-2-methyl	434	434
393	Methyl	Methoxy	4-Pyridylmethyl	433	433
394	Methyl	Methoxy	1-Butenyl	410	410
395	Methyl	Methoxy	2-N itro-5-Chlorophenyl	511	511
396	Methyl	Methoxy	Cyanomethyl	395	395
397	Isopropyl	Methoxy	Acetoxymethyl	450	450
398	Isopropyl	Methoxy	4-(2,5-Cl2pyridyl)methyl	530	530
399	Isopropyl	Methoxy	Chromen-2-one-3-	528	528
			methyl
400	Isopropyl	Methoxy	Methoxymethyl	428	428
401	Isopropyl	Methoxy	Pyran-2-one-5-methyl	478	478
402	Isopropyl	Methoxy	Ethyl	412	412
403	Isopropyl	Methoxy	2-Ethyldecanyl	538	538
404	Isopropyl	Methoxy	Pyrazine-2-methyl 462	462
405	Isopropyl	Methoxy	4-Pyridylmethyl	461	461
406	Isopropyl	Methoxy	1-Butenyl	438	438
407	Isopropyl	Methoxy	2-Nitro-5-Chlorophenyl539	539
408	Isopropyl	Methoxy	Cyanomethyl	423	423
409	Isobutyl	Methoxy	Acetoxymethyl	464	464
410	Isobutyl	Methoxy	4-(2,5-Cl2pyridyl)methyl	544	544
411	Isobutyl	Methoxy	Chromen-2-one-3-	542	542
			methyl
412	Isobutyl	Methoxy	Methoxymethyl	442	442
413	Isobutyl	Methoxy	Pyran-2-one-5-methyl	492	492
414	Isobutyl	Methoxy	Ethyl	426	426
415	Isobutyl	Methoxy	2-Ethyldecanyl	552	552
416	Isobutyl	Methoxy	Pyrazine-2-methyl	476	476
417	Isobutyl	Methoxy	4-Pyridylmethyl	475	475
418	Isobutyl	Methoxy	1-Butenyl	452	452
419	Isobutyl	Methoxy	2-Nitro-5-Chlorophenyl	553	553
420	Isobutyl	Methoxy	Cyanomethyl	437	437
421	Benzyl	Methoxy	Acetoxymethyl	498	498
422	Benzyl	Methoxy	4(2,5-Cl2pyridyl)methyl	578	578
423	Benzyl	Methoxy	Chromen-2-one-3- 576	576
			methyl
424	Benzyl	Methoxy	Methoxymethyl	476	476
425	Benzyl	Methoxy	Pyran-2-one-5-methyl	526	526
426	Benzyl	Methoxy	Ethyl	460	460
427	Benzyl	Methoxy	2-Ethyldecanyl	586	586
428	Benzyl	Methoxy	Pyrazine-2-methyl	510	510
429	Benzyl	Methoxy	4-Pyridylmethyl509	509
430	Benzyl	Methoxy	1-Butenyl	486	486
431	Benzyl	Methoxy	2-Nitro-5-Chlorophenyl	587	587
432	Benzyl	Methoxy	Cyanomethyl	471	471
433	2-Methylpropyl	Methoxy	Acetoxymethyl	464	464
434	2-Methylpropyl	Methoxy	4-(2,5-Cl2pyridyl)methyl	544	544
435	2-Methyipropyl	Methoxy	Chromen-2-one-3-	542	542
			methyl
436	2-Methylpropyl	Methoxy	Methoxymethyl	442	442
437	2-Methylpropyl	Methoxy	Pyran-2-one-5-methyl	492	492
438	2-Methylpropyl	Methoxy	Ethyl	426	426
439	2-Methylpropyl	Methoxy	2-Ethyldecanyl	552	552
440	2-Methylpropyl	Methoxy	Pyrazine-2-methyl	476	476
441	2-Methylpropyl	Methoxy	4-Pyridylmethyl	475	475
442	2-Methylpropyl	Methoxy	1-Butenyl	452	452
443	2-Methylpropyl	Methoxy	2-Nitro-5-Chlorophenyl	553	553
444	2-Methylpropyl	Methoxy	Cyanomethyl	437	437
445	Methylthioethyl	Methoxy	Acetoxymethyl	482	482
446	Methylthioethyl	Methoxy	4-(2,5-Cl2pyridyl)methyl	562	562
447	Methylthioethyl	Methoxy	Chromen-2-one-3-	560	560
			methyl
448	Methylthioethyl	Methoxy	Methoxymethyl	460	460
449	Methylthioethyl	Methoxy	Pyran-2-one-5-methyl	510	510
450	Methylthioethyl	Methoxy	Ethyl	444	444
451	Methylthioethyl	Methoxy	2-Ethyldecanyl	570	570
452	Methylthioethyl	Methoxy	Pyrazine-2-methyl	494	494
453	Methylthioethyl	Methoxy	4-Pyridylmethyl	493	493
454	Methylthioethyl	Methoxy	1 -Butenyl	470	470
455	Methylthioethyl	Methoxy	2-Nitro-5-Chlorophenyl	571	571
456	Methylthioethyl	Methoxy	Cyanomethyl	455	455
457	4-Hydroxybenzyl	Methoxy	Acetoxymethyl	514	514
458	4-Hydroxybenzyl	Methoxy	4-(2,5-Cl2pyridyl)methyl	594	594
459	4-Hydroxybenzyl	Methoxy	Chromen-2-one-3-	592	592
			methyl
460	4-Hydroxybenzyl	Methoxy	Methoxymethyl	492	492
461	4-Hydroxybenzyl	Methoxy	Pyran-2-one-5-methyl	542	542
462	4-Hydroxybenzyl	Methoxy	Ethyl	476	476
463	4-Hydroxybenzyl	Methoxy	2-Ethyldecanyl	602	602
464	4-Hydroxybenzyl	Methoxy	Pyrazine-2-methyl	526	526
465	4-Hydroxybenzyl	Methoxy	4-Pyridylmethyl	525	525
466	4-Hydroxybenzyl	Methoxy	1-Butenyl	502	502
467	4-Hydroxybenzyl	Methoxy	2-Nitro-5-Chlorophenyl	603 603
468	4-Hydroxybenzyl	Methoxy	Cyanomethyl	487	487
469	2-Hydroxyethyl	Methoxy	Acetoxymethyl	452	452
470	2-Hydroxyethyl	Methoxy	4-(2,5-Cl2pyridyl)methyl	532	532
471	2-Hydroxyethyl	Methoxy	Chromen-2-one-3-	530	530
			methyl
472	2-Hydroxyethyl	Methoxy	Methoxymethyl	430	430
473	2-Hydroxyethyl	Methoxy	Pyran-2-one-5-methyl	480	480
474	2-Hydroxyethyl	Methoxy	Ethyl	414	414
475	2-Hydroxyethyl	Methoxy	2-Ethyldecanyl	540	540
476	2-Hydroxyethyl	Methoxy	Pyrazine-2-methyl	464	464
477	2-Hydroxyethyl	Methoxy	4-Pyridylmethyl	463	463
478	2-Hydroxyethyl	Methoxy	1-Butenyl	440	440
479	2-Hydroxyethyl	Methoxy	2-Nitro-5-Chlorophenyl	541	541
480	2-Hydroxyethyl	Methoxy	Cyanomethyl	425	425
481	Methyl	Phenyl	2,4-Pentadienyl	469	469
482	Methyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	548	548
483	Methyl	Phenyl	Chromen-2-one-3-	547	547
			methyl
484	Methyl	Phenyl	Methoxymethyl	446	446
485	Methyl	Phenyl	Pyran-2-one-5-methyl	496	496
486	Methyl	Phenyl	Ethyl	430	430
487	Methyl	Phenyl	2-Ethyldecanyl	501	501
488	Methyl	Phenyl	Pyrazine-2-methyl	480	480
489	Methyl	Phenyl	4-Pyridylmethyl	479	479
490	Methyl	Phenyl	1-Butenyl	457	457
491	Methyl	Phenyl	2-Nitro-5-Chlorophenyl	558	558
492	Methyl	Phenyl	Cyanomethyl	441	441
493	Isopropyl	Phenyl	2,4-Pentadienyl	497	497
494	Isopropyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	576	576
495	Isopropyl	Phenyl	Chromen-2-one-3-	575	575
			methyl
496	Isopropyl	Phenyl	Methoxymethyl	475	475
497	Isopropyl	Phenyl	Pyran-2-one-5-methyl	525	525
498	Isopropyl	Phenyl	Ethyl	459	459
499	Isopropyl	Phenyl	2-Ethyldecanyl	529	529
500	Isopropyl	Phenyl	Pyrazine-2-methyl	509	509
501	Isopropyl	Phenyl	4-Pyridylmethyl	508	508
502	Isopropyl	Phenyl	1-Butenyl	485	485
503	Isopropyl	Phenyl	2-Nitro-5-Chlorophenyl	586	586
504	Isopropyl	Phenyl	Cyanomethyl	470	470
505	Isobutyl	Phenyl	2,4-Pentadienyl	511	511
506	Isobutyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	590	590
507	Isobutyl	Phenyl	Chromen-2-one-3-	589	589
			methyl
508	Isobutyl	Phenyl	Methoxymethyl	489	489
509	Isobutyl	Phenyl	Pyran-2-one-5-methyl	539	539
510	Isobutyl	Phenyl	Ethyl	473	473
511	Isobutyl	Phenyl	2-Ethyldecanyl	543	543
512	Isobutyl	Phenyl	Pyrazine-2-methyl 523	523
513	Isobutyl	Phenyl	4-Pyridylmethyl	522	522
514	Isobutyl	Phenyl	1-Butenyl	499	499
515	Isobutyl	Phenyl	2-Nitro-5-Chlorophenyl	600	600
516	Isobutyl	Phenyl	Cyanomethyl	484	484
517	Benzyl	Phenyl	2,4-Pentadienyl	545	545
518	Benzyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	624	624
519	Benzyl	Phenyl	Chromen-2-one-3-	623	623
			methyl
520	Benzyl	Phenyl	Methoxymethyl	523	523
521	Benzyl	Phenyl	Pyran-2-one-5-methyl	573	573
522	Benzyl	Phenyl	Ethyl	507	507
523	Benzyl	Phenyl	2-Ethyldecanyl	577	577
524	Benzyl	Phenyl	Pyrazine-2-methyl	557	557
525	Benzyl	Phenyl	4-Pyridylmethyl	556	556
526	Benzyl	Phenyl	1-Butenyl	533	533
527	Benzyl	Phenyl	2-Nitro-5-Chlorophenyl	634	634
528	Benzyl	Phenyl	Cyanomethyl	518	518
529	2-Methylpropyl	Phenyl	2,4-Pentadienyl	511	511
530	2-Methylpropyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	590	590
531	2-Methylpropyl	Phenyl	Chromen-2-one-3-	589	589
			methyl
532	2-Methylpropyl	Phenyl	Methoxymethyl	489	489
533	2-Methylpropyl	Phenyl	Pyran-2-one-5-methyl	539	539
534	2-Methylpropyl	Phenyl	Ethyl	473	473
535	2-Methylpropyl	Phenyl	2-Ethyldecanyl	543	543
536	2-Methylpropyl	Phenyl	Pyrazine-2-methyl	523	523
537	2-Methylpropyl	Phenyl	4-Pyridylmethyl	522	522
538	2-Methylpropyl	Phenyl	1-Butenyl	499	499
539	2-Methylpropyl	Phenyl	2-Nitro-5-Chlorophenyl	600	600
540	2-Methylpropyl	Phenyl	Cyanomethyl	484	484
541	Methylthioethyl	Phenyl	2,4-Pentadienyl	529	529
542	Methylthioethyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	609	609
543	Methylthioethyl	Phenyl	Chromen-2-one-3-	607	607
			methyl
544	Methylthioethyl	Phenyl	Methoxymethyl	507	507
545	Methylthioethyl	Phenyl	Pyran-2-one-5-methyl	557
546	Methylthioethyl	Phenyl	Ethyl	491	491
547	Methyithioethyl	Phenyl	2-Ethyldecanyl	561	561
548	Methylthioethyl	Phenyl	Pyrazine-2-methyl	541	541
549	Methylthioethyl	Phenyl	4-Pyridylmethyl	540	540
550	Methylthioethyl	Phenyl	1-Butenyl	517	517
551	Methyithioethyl	Phenyl	2-Nitro-5-Chlorophenyl	618	618
552	Methylthioethyl	Phenyl	Cyanomethyl	502	502
553	4-Hydroxybenzyl	Phenyl	2,4-Pentadienyl	561	561
554	4-Hydroxybenzyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	640	640
555	4-Hydroxybenzyl	Phenyl	Chromen-2-one-3-	639	639
			methyl
556	4-Hydroxybenzyl	Phenyl	Methoxymethyl	539	539
557	4-Hydroxybenzyl	Phenyl	Pyran-2-one-5-methyl	589	589
558	4-Hydroxybenzyl	Phenyl	Ethyl	523	523
559	4-Hydroxybenzyl	Phenyl	2-Ethyldecanyl	593	593
560	4-Hydroxybenzyl	Phenyl	Pyrazine-2-methyl	573	573
561	4-Hydroxybenzyl	Phenyl	4-Pyridylmethyl	572	572
562	4-Hydroxybenzyl	Phenyl	1-Butenyl	549	549
563	4-Hydroxybenzyl	Phenyl	2-Nitro-5-Chlorophenyl	650	650
564	4-Hydroxybenzyl	Phenyl	Cyanomethyl	534	534
565	2-Hydroxyethyl	Phenyl	2,4-Pentadienyl	499	499
566	2-Hydroxyethyl	Phenyl	4-(2,5-Cl2pyridyl)methyl	578	578
567	2-Hydroxyethyl	Phenyl	Chromen-2-one-3-	577	577
			methyl
568	2-Hydroxyethyl	Phenyl	Methoxymethyl	476	476
569	2-Hydroxyethyl	Phenyl	Pyran-2-one-5-methyl	527	527
570	2-Hydroxyethyl	Phenyl	Ethyl	460	460
571	2-Hydroxyethyl	Phenyl	2-Ethyldecanyl	531	531
572	2-Hydroxyethyl	Phenyl	Pyrazine-2-methyl	511	511
573	2-Hydroxyethyl	Phenyl	4-Pyridylmethyl	510	510
574	2-Hydroxyethyl	Phenyl	1-Buterlyl	487	487
575	2-Hydroxyethyl	Phenyl	2-Nitro-5-Chlorophenyl	588	588
576	2-Hydroxyethyl	Phenyl	Cyatiomethyl	471	471
577	Methyl	Methyl	2,4-Pentadienyl	406	406
578	Methyl	Methyl	4-(2,5-Cl2pyridyl)methyl	486	486
579	Methyl	Methyl	Chromen-2-one-3-	484	484
			methyl
580	Methyl	Methyl	Methoxymethyl	384	384
581	Methyl	Methyl	Pyran-2-one-5-methyl	434	434
582	Methyl	Methyl	Ethyl	368	368
583	Methyl	Methyl	2-Ethyldecanyl	438	438
584	Methyl	Methyl	Pyrazine-2-methyl	418	418
585	Methyl	Methyl	4-Pyridylmethyl	417	417
586	Methyl	Methyl	1-Butenyl	394	394
587	Methyl	Methyl	2-Nitro-5-Chlorophenyl	495	495
588	Methyl	Methyl	Cyanomethyl	434	434
589	Isopropyl	Methyl	2,4-Pentadienyl	434	434
590	Isopropyl	Methyl	4-(2,5-Cl2pyridyl)methyl	514	514
591	Isopropyl	Methyl	Chromen-2-one-3-	512	512
			methyl
592	Isopropyl	Methyl	Methoxytiiethyl	412	412
593	Isopropyl	Methyl	Pyran-2-one-5-methyl	462	462
594	Isopropyl	Methyl	Ethyl	396	396
595	Isopropyl	Methyl	2-Ethyldecanyl	466	466
596	Isopropyl	Methyl	Pyrazine-2-methyl	446	446
597	Isopropyl	Methyl	4-Pyridylmethyl	445	445
598	Isopropyl	Methyl	1-Butenyl	422	422
599	Isopropyl	Methyl	2-Nitro-5-Chlorophenyl	523	523
600	Isopropyl	Methyl	Cyanomethyl	462	462
601	Isobutyl	Methyl	2,4-Pentadienyl	448	448
602	Isobutyl	Methyl	4-(2,5-Cl2pyridyl)methyl	528	528
603	Isobutyl	Methyl	Chromen-2-one-3-	526	526
			methyl
604	Isobutyl	Methyl	Methoxymethyl	426	426
605	Isobutyl	Methyl	Pyran-2-one-5-methyl	476	476
606	Isobutyl	Methyl	Ethyl	410	410
607	Isobutyl	Methyl	2-Ethyldecanyl	480	480
608	Isobutyl	Methyl	Pyrazine-2-methyl	460	460
609	Isobutyl	Methyl	4-Pyridylmethyl	459	459
610	Isobutyl	Methyl	1-Butenyl	436	436
611	Isobutyl	Methyl	2-Nitro-5-Chlorophenyl	537	537
612	Isobutyl	Methyl	Cyanomethyl	476	476
613	Benzyl	Methyl	2,4-Pentadienyl	482	482
614	Benzyl	Methyl	4-(2,5-Cl2pyridyl)methyl	562	562
615	BenzyI	Methyl	Chromen-2-one-3- 560	560
			methyl
616	Benzyl	Methyl	Methoxyniethyl	460	460
617	Benzyl	Methyl	Pyran-2-one-5-methyl	510	510
618	Benzyl	Methyl	Ethyl	444	444
619	Benzyl	Methyl	2-Ethyldecanyl	514	514
620	Benzyl	Methyl	Pyrazine-2-methyl	494	494
621	Benzyl	Methyl	4-Pyridylmethyl	493	493
622	Benzyl	Methyl	1-Butenyl	470	470
623	Benzyl	Methyl	2-Nitro-5-Chlorophenyl	571	571
624	Benzyl	Methyl	Cyanomethyl	510	510
625	2-Methylpropyl	Methyl	2,4-Pentadienyl	448	448
626	2-Methylpropyl	Methyl	4-(2,5-Cl2pyridyl)methyl	528	528
627	2-Methylpropyl	Methyl	Chromen-2-one-3-	526	526
			methyl
628	2-Methylpropyl	Methyl	Methoxymethyl	426	426
629	2-Methylpropyl	Methyl	Pyran-2-one-5-methyl	476	476
630	2-Methylpropyl	Methyl	Ethyl	410	410
631	2-Methylpropyl	Methyl	2-Ethyldecanyl	480	480
632	2-Methylpropyl	Methyl	Pyrazine-2-methyl460	460
633	2-Methylpropyl	Methyl	4-Pyridylmethyl	459	459
634	2-Methylpropyl	Methyl	1-Butenyl	436	436
635	2-Methylpropyl	Methyl	2-Nitro-5-Chlorophenyl	537	537
636	2-Methylpropyl	Methyl	Cyanomethyl	476	476
637	Methylthioethyl	Methyl	2,4-Pentadienyl	466	466
638	Methylthioethyl	Methyl	4-(2,5-Cl2pyridyl)methyl	546	546
639	Methylthioethyl	Methyl	Chromen-2-one-3-	544	544
			methyl
640	Methylthioethyl	Methyl	Methoxymethyl	444	444
641	Methylthioethyl	Methyl	Pyran-2-one-5-methyl	494	494
642	Methylthioethyl	Methyl	Ethyl	428	428
643	Methylthioethyl	Methyl	2-Ethyldecanyl	498	498
644	Methylthioethyl	Methyl	Pyrazine-2-methyl	478	478
645	Methylthioethyl	Methyl	4-Pyridylmethyl	477	477
646	Methylthioethyl	Methyl	1-Butenyl	454	454
647	Methylthioethyl	Methyl	2-Nitro-5-Chlorophenyl	555	555
648	Methylthioethyl	Methyl	Cyanomethyl	494	494
649	4-Hydroxybenzyl	Methyl	2,4-Pentadienyl	498	498
650	4-Hydroxybenzyl	Methyl	4-(2,5-Cl2pyridyl)methyl	578	578
651	4-Hydroxybenzyl	Methyl	Chromen-2-one-3-	576	576
			methyl
652	4-Hydroxybenzyl	Methyl	Methoxymethyl	476	476
653	4-Hydroxybenzyl	Methyl	Pyran-2-one-5-methyl	526	526
654	4-Hydroxybenzyl	Methyl	Ethyl	460	460
655	4-Hydroxybenzyl	Methyl	2-Ethyldecanyl	530	530
656	4-Hydroxybenzyl	Methyl	Pyrazine-2-methyl	510	510
657	4-Hydroxybenzyl	Methyl	4-Pyridylmethyl	509	509
658	4-Hydroxybenzyl	Methyl	1-Butenyl	486	486
659	4-Hydroxybenzyl	Methyl	2-Nitro-5-Chlorophenyl	587	587
660	4-Hydroxybenzyl	Methyl	Cyanomethyl	526	526
661	2-Hydroxyethyl	Methyl	2,4-Pentadienyl	436	436
662	2-Hydroxyethyl	Methyl	4-(2,5-Cl2pyridyl)methyl	516	516
663	2-Hydroxyethyl	Methyl	Chromen-2-one-3-	514	514
			methyl
664	2-Hydroxyethyl	Methyl	Methoxymethyl	414	414
665	2-Hydroxyethyl	Methyl	Pyran-2-one-5-methyl	464	464
666	2-Hydroxyethyl	Methyl	Ethyl	398	398
667	2-Hydroxyethyl	Methyl	2-Ethyldecanyl	468	468
668	2-Hydroxyethyl	Methyl	Pyrazine-2-methyl	448	448
669	2-Hydroxyethyl	Methyl	4-Pyridylmethyl	447	447
670	2-Hydroxyethyl	Methyl	1-Butenyl	424	424
671	2-Hydroxyethyl	Methyl	2-Nitro-5-Chlorophenyl	525	525
672	2-Hydroxyethyl	Methyl	Cyanomethyl	464	464
673	Cyclohexylmethyl	Methoxy	4-Methoxybenzyl	559	559
674	4-Phenylbenzyl	Methoxy	4-Methoxybenzyl	629	629
675	4-NO2-benzyl	Methoxy	4-Methoxybenzyl	598	598
676	3,4-Cl2-benzyl	Methoxy	4-Methoxybenzyl	621	621
677	Cyclopentyl(spiro)	Methoxy	4-Methoxybenzyl	531	531
678	4-Methylbenzyl	Methoxy	4-Methoxybenzyl	567	567
679	1-Naphthylmethyl	Methoxy	4-Methoxybenzyl	603	603
680	4-F-benzyl	Methoxy	4-Methoxybenzyl	571	571
681	3,4-F2-Benzyl	Methoxy	4-Methoxybenzyl	589	589
682	Cyclohexyl	Methoxy	4-Methoxybenzyl	545	545
683	2-Cl-benzyl	Methoxy	4-Methoxybenzyl	587	587
684	4-Cl-benzyl	Methoxy	4-Methoxybenzyl	587	587
685	Cyclohexylmethyl	Methoxy	3,4-Cl2-phenyl	583	583
686	4-Phenylbenzyl	Methoxy	3,4-Cl2-phenyl	654	654
687	4-NO2-benzyl	Methoxy	3,4-Cl2-phenyl	622	622
688	3,4-Cl2-benzyl	Methoxy	3,4-Cl2-phenyl	646	646
689	Cyclopentyl(spiro)	Methoxy	3,4-Cl2-phenyl	555	555
690	4-Methylbenzyl	Methoxy	3,4-Cl2-phenyl	591	591
691	1-Naphthylmethyl	Methoxy	3,4-Cl2-phenyl	627	627
692	4-F-benzyl	Methoxy	3,4-Cl2-phenyl	595	595
693	3,4-F2-Benzyl	Methoxy	3,4-Cl2-phenyl	613	613
694	Cyclohexyl	Methoxy	3,4-Cl2-phenyl	569	569
695	2-Cl-benzyl	Methoxy	3,4-Cl2-phenyl	612	612
696	4-Cl-benzyl	Methoxy	3,4-Cl2-phenyl	612	612
697	Cyclohexylmethyl	Methoxy	1-Naphthyl	565	565
698	4-Phenylbenzyl	Methoxy	1-Naphthyl	635	635
699	4-NO2-benzyl	Methoxy	1-Naphthyl	604	604
700	3,4-Cl2-benzyl	Methoxy	1-Naphthyl	627	627
701	Cyclopentyl(spiro)	Methoxy	1-Naphthyl	537	537
702	4-Methylbenzyl	Methoxy	1-Naphthyl	573	573
703	1-Naphthylmethyl	Methoxy	1-Naphthyl	609	609
704	4-F-benzyl	Methoxy	1-Naphthyl	577	577
705	3,4-F2-Benzyl	Methoxy	1-Naphthyl	595	595
706	Cyclohexyl	Methoxy	1-Naphthyl	551	551
707	2-Cl-benzyl	Methoxy	1-Naphthyl	593	593
708	4-Cl-benzyl	Methoxy	1-Naphthyl	593	593
709	Cyclohexylmethyl	Methoxy	Piperonyl	559	559
710	4-Phenylbenzyl	Methoxy	Piperonyl	629	629
711	4-NO2-benzyl	Methoxy	Piperonyl	598	598
712	3,4-Cl2-benzyl	Methoxy	Piperonyl	621	621
713	Cyclopentyl(spiro)	Methoxy	Piperonyl	531	531
714	4-Methylbenzyl	Methoxy	Piperonyl	567	567
715	1-Naphthylmethyl	Methoxy	Piperonyl	603	603
716	4-F-benzyl	Methoxy	Piperonyl	571	571
717	3,4-F2-Benzyl	Methoxy	Piperonyl	589	589
718	Cyclohexyl	Methoxy	Piperonyl	545	545
719	2-Cl-benzyl	Methoxy	Piperonyl	587	587
720	4-Cl-benzyl	Methoxy	Piperonyl	587	587
721	Cyclohexylmethyl	Methoxy	2,4,5-Trimethoxyphenyl	605	605
722	4-Phenylbenzyl	Methoxy	2,4,5-Trimethoxyphenyl	675	675
723	4-NO2-benzyl	Methoxy	2,4,5-Trimethoxyphenyl	644	644
724	3,4-Cl2-benzyl	Methoxy	2,4,5-Trimethoxyphenyl	668	668
725	Cyclopentyl(spiro)	Methoxy	2,4,5-Trimethoxyphenyl	577	577
726	4-Methylbenzyl	Methoxy	2,4,5-Trimethoxyphenyl	613	613
727	1-Naphthylmethyl	Methoxy	2,4,5-Trimethoxyphenyl	649	649
728	4-F-benzyl	Methoxy	2,4,5-Trimethoxyphenyl	617	617
729	3,4-F2-Benzyl	Methoxy	2,4,5-Trimethoxyphenyl	635	635
730	Cyclohexyl	Methoxy	2,4,5-Trimethoxyphenyl	591	591
731	2-Cl-benzyl	Methoxy	2,4,5-Trimethoxyphenyl	633	633
732	4-Cl-benzyl	Methoxy	2,4,5-Trimethoxyphenyl	633	633
733	Cyclohexylmethyl	Methoxy	3-Hydroxybenzyl	545	545
734	4-Phenylbenzyl	Methoxy	3-Hydroxybenzyl	615	615
735	4-NO2-benzyl	Methoxy	3-Hydroxybenzyl	584	584
736	3,4-Cl2-benzyl	Methoxy	3-Hydroxybenzyl	607	607
737	Cyclopentyl(spiro)	Methoxy	3-Hydroxybenzyl	517	517
738	4-Methylbenzyl	Methoxy	3-Hydroxybenzyl	553	553
739	1-Naphthylmethyl	Methoxy	3-Hydroxybenzyl	589	589
740	4-F-benzyl	Methoxy	3-Hydroxybenzyl	557	557
741	3,4-F2-Benzyl	Methoxy	3-Hydroxybenzyl	575	575
742	Cyclohexyl	Methoxy	3-Hydroxybenzyl	531	531
743	2-Cl-benzyl	Methoxy	3-Hydroxybenzyl	573	573
744	4-Cl-benzyl	Methoxy	3-Hydroxybenzyl	573	573
745	Cyclohexylmethyl	Methoxy	1-Naphthylmethyl	579	579
746	4-Phenylbenzyl	Methoxy	1-Naphthylmethyl	649	649
747	4-NO2-benzyl	Methoxy	1-Naphthylmethyl	618	618
748	3,4-Cl2-benzyl	Methoxy	1-Naphthylmethyl	642	642
749	Cyclopentyl(spiro)	Methoxy	1-Naphthylmethyl	551	551
750	4-Methylbenzyl	Methoxy	1-Naphthylmethyl	587	587
751	1-Naphthylmethyl	Methoxy	1-Naphthylmethyl	623	623
752	4-F-benzyl	Methoxy	1-Naphthylmethyl	591	591
753	3,4-F2-Benzyl	Methoxy	1-Naphthylmethyl	609	609
754	Cyclohexyl	Methoxy	1-Naphthylmethyl	565	565
755	2-Cl-benzyl	Methoxy	1-Naphthylmethyl	607	607
756	4-Cl-benzyl	Methoxy	1-Naphthylmethyl	607	607
757	Cyclohexylmethyl	Methoxy	Phenethyl	543	543
758	4-Phenylbenzyl	Methoxy	Phenethyl	613	613
759	4-NO2-benzyl	Methoxy	Phenethyl	582	582
760	3,4-Cl2-benzyl	Methoxy	Phenethyl	605	605
761	Cyclopentyl(spiro)	Methoxy	Phenethyl	515	515
762	4-Methylbenzyl	Methoxy	Phenethyl	551	551
763	1-Naphthylmethyl	Methoxy	Phenethyl	587	587
764	4-F-benzyl	Methoxy	Phenethyl	555	555
765	3,4-F2-Benzyl	Methoxy	Phenethyl	573	573
766	Cyclohexyl	Methoxy	Phenethyl	529	529
767	2-Cl-benzyl	Methoxy	Phenethyl	571	571
768	4-Cl-benzyl	Methoxy	Phenethyl	571	571
769	Cyclohexylmethyl	Methoxy	3-Methoxyphenyl	545	545
770	4-Phenylbenzyl	Methoxy	3-Methoxyphenyl	615	615
771	4-NO2-benzyl	Methoxy	3-Methoxyphenyl	584	584
772	3,4-Cl2-benzyl	Methoxy	3-Methoxyphenyl	607	607
773	Cyclopentyl(spiro	Methoxy	3-Methoxyphenyl	517	517
	)
774	4-Methylbenzyl	Methoxy	3-Methoxyphenyl	553	553
775	1-Naphthylmethyl	Methoxy	3-Methoxyphenyl	589	589
776	4-F-benzyl	Methoxy	3-Methoxyphenyl	557	557
777	3,4-F2-Benzyl	Methoxy	3-Methoxyphenyl	575	575
778	Cyclohexyl	Methoxy	3-Methoxyphenyl	531	531
779	2-Cl-benzyl	Methoxy	3-Methoxyphenyl	573	573
780	4-Cl-benzyl	Methoxy	3-Methoxyphenyl	573	573
781	Cyclohexylmethyl	Methoxy	N-Benzoylaminoethyl	572	572
782	4-Phenylbenzyl	Methoxy	N-Benzoylaminoethyl	642	642
783	4-NO2-benzyl	Methoxy	N-Benzoylaminoethyl	611	611
784	3,4-Cl2-benzyl	Methoxy	N-Benzoylaminoethyl	634	634
785	Cyclopentyl(spiro	Methoxy	N-Benzoylaminoethyl	544	544
	)
786	4-Methylbenzyl	Methoxy	N-Benzoylaminoethyl	580	580
787	1-Naphthylmethyl	Methoxy	N-Benzoylaminoethyl	616	616
788	4-F-benzyl	Methoxy	N-Benzoylaminoethyl	584	584
789	3,4-F2-Benzyl	Methoxy	N-Benzoylaminoethyl	602	602
790	Cyclohexyl	Methoxy	N-Benzoylaminoethyl	558	558
791	2-Cl-benzyl	Methoxy	N-Benzoylaminoethyl	600	600
792	4-Cl-benzyl	Methoxy	N-Benzoylaminoethyl	600	600
793	Cyclohexylmethyl	Methoxy	Benzyl	529	529
794	4-Phenylbenzyl	Methoxy	Benzyl	599	599
795	4-NO2-benzyl	Methoxy	Benzyl	568	568
796	3,4-Cl2-benzyl	Methoxy	Benzyl	591	591
797	Cyclopentyl(spiro	Methoxy	Benzyl	501	501
	)
798	4-Methylbenzyl	Methoxy	Benzyl	537	537
799	1-Naphthylmethyl	Methoxy	Benzyl	573	573
800	4-F-benzyl	Methoxy	Benzyl	541	541
801	3,4-F2-Benzyl	Methoxy	Benzyl	559	559
802	Cyclohexyl	Methoxy	Benzyl	515	515
803	2-Cl-benzyl	Methoxy	Benzyl	557	557
804	4-Cl-benzyl	Methoxy	Benzyl	557	557
805	Cyclohexylmethyl	Methoxy	4-NO2-benzyl	574	574
806	4-Phenylbenzyl	Methoxy	4-NO2-benzyl	644	644
807	4-NO2-benzyl	Methoxy	4-NO2-benzyl	613	613
808	3,4-Cl2-benzyl	Methoxy	4-NO2-benzyl	636	636
809	Cyclopentyl(spiro	Methoxy	4-NO2-benzyl	546	546
	)
810	4-Methylbenzyl	Methoxy	4-NO2-benzyl	582	582
811	1-Naphthylmethyl	Methoxy	4-NO2-benzyl	618	618
812	4-F-benzyl	Methoxy	4-NO2-benzyl	586	586
813	3,4-F2-Benzyl	Methoxy	4-NO2-benzyl	604	604
814	Cyclohexyl	Methoxy	4-NO2-benzyl	560	560
815	2-Cl-benzyl	Methoxy	4-NO2-benzyl	602	602
816	4-Cl-benzyl	Methoxy	4-NO2-benzyl	602	602
817	Cyclohexylmethyl	Methoxy	2,4-Pentadienyl	505	505
818	4-Phenylbenzyl	Methoxy	2,4-Pentadienyl	575	575
819	4-NO2-benzyl	Methoxy	2,4-Pentadienyl	544	544
820	3,4-Cl2-benzyl	Methoxy	2,4-Pentadienyl	567	567
821	Cyclopentyl(spiro	Methoxy	2,4-Pentadienyl	477	477
	)
822	4-Methylbenzyl	Methoxy	2,4-Pentadienyl	513	513
823	1-Naphthylmethyl	Methoxy	2,4-Pentadienyl	549	549
824	4-F-benzyl	Methoxy	2,4-Pentadienyl	517	517
825	3,4-F2-Benzyl	Methoxy	2,4-Pentadienyl	535	535
826	Cyclohexyl	Methoxy	2,4-Pentadienyl	491	491
827	2-Cl-benzyl	Methoxy	2,4-Pentadienyl	533	533
828	4-Cl-benzyl	Methoxy	2,4-Pentadienyl	533	533
829	Cyclohexylmethyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	584	584
830	4-Phenylbenzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	655	655
831	4-NO2-benzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	623	623
832	3,4-Cl2-benzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	647	647
833	Cyclopentyl(spiro	Methoxy	3-(2,6-Cl2-pyridyl)methyl	556	556
834	4-Methylbenzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	592	592
835	1-Naphthylmethyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	628	628
836	4-F-benzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	596	596
837	3,4-F2-Benzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	614	614
838	Cyclohexyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	570	570
839	2-Cl-benzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	613	613
840	4-Cl-benzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	613	613
841	Cyclohexylmethyl	Methoxy	Chromen-2-one-3-methyl	583	583
842	4-Phenylbenzyl	Methoxy	Chromen-2-one-3-methyl	653	653
843	4-NO2-benzyl	Methoxy	Chromen-2-one-3-methyl	622	622
844	3,4-Cl2-benzyl	Methoxy	Chromen-2-one-3-methyl	645	645
845	Cyclopentyl(spiro	Methoxy	Chromen-2-one-3-methyl	555	555
	)
846	4-Methylbenzyl	Methoxy	Chromen-2-one-3-methyl	591	591
847	1-Naphthylmethyl	Methoxy	Chromen-2-one-3-methyl	627	627
848	4-F-benzyl	Methoxy	Chromen-2-one-3-methyl	595	595
849	3,4-F2-Benzyl	Methoxy	Chromen-2-one-3-methyl	613	613
850	Cyclohexyl	Methoxy	Chromen-2-one-3-methyl	569	569
851	2-Cl-benzyl	Methoxy	Chromen-2-one-3-methyl	611	611
852	4-Cl-benzyl	Methoxy	Chromen-2-one-3-methyl	611	611
853	Cyclohexylmethyl	Methoxy	Methoxymethyl	483	483
854	4-Phenylbenzyl	Methoxy	Methoxymethyl	553	553
855	4-NO2-benzyl	Methoxy	Methoxymethyl	521	521
856	3,4-Cl2-benzyl	Methoxy	Methoxymethyl	545	545
857	Cyclopentyl(spiro	Methoxy	Methoxymethyl	454	454
	)
858	4-Methylbenzyl	Methoxy	Methoxymethyl	491	491
859	1-Naphthylmethyi	Methoxy	Methoxymethyl	527	527
860	4-F-benzyl	Methoxy	Methoxymethyl	494	494
861	3,4-F2-Benzyl	Methoxy	Methoxymethyl	512	512
862	Cyclohexyl	Methoxy	Methoxymethyl	469	469
863	2-Cl-benzyl	Methoxy	Methoxymethyl	511	511
864	4-Cl-benzyl	Methoxy	Methoxymethyl	511	511

[0073] The synthesis of peptide mimetics in a library of the present invention accomplished using the general scheme of β-strand mimetics library as n FIG. 2. The synthesis of selected peptide mimetics of a bicyclic e library of the present invention was accomplished using a FlexChem Block which has a 96 well plate. In the above scheme ‘Pol’ represents 2tyl chloride resin (Novabiochem) and a detailed procedure is provided Step 1 The 2-chlorotrityl chloride resin (1 mmol/g) and a Fmoc-R1-beta-Amino Acid (1.5 equiv.) and DIEA (2 equiv.) in DCE were in a 96 well Robinson block (Flexchem). The reaction mixture was shaken ours at room temperature. The resin was washed with DMF, MeOH, and M.

[0074] Step2 To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and then the product mixture was washed with DMF, MeOH, and then DCM. A solution of 4R2-amino-2-Fmoc-aminobutyric acid (1.5 equiv.), DIC (1.5 equiv.), HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0075] Step 3 To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and the product mixture was washed with DMF, MeOH, and then DCM. A solution of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-5,5-dimethoxy-pentanoic acid (1.5 equiv.), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0076] Step 4 To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and then the product mixture was washed with DMF, MeOH, and then DCM. A solution of commercially available R3-acid (1.5 equiv.), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0077] Step 5 The resin was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. Thereafter, the resin was removed by filtration, and the filtrate was condensed under reduced pressure using SpeedVac (Servant) to give the product as oil. These products were diluted with 50% water/acetonitrile and then lyophilized after freezing.

[0078] Table 3 shows a β-strand mimetics library which can be prepared according to the present invention, of which representative preparation is given in Example 10. Compounds of Table 3 illustrate one aspect of the invention, namely compounds wherein A is —(CH)—, B is —(CH2)m— with m=1, W is nothing, i.e., it is a direct bond between Rb and N of the heterocyclic ring, X is —NH(C═O)—, Y is oxygen, Z is hydrogen so that C═Z represents CH2, L is —C(═O)NHR3, n=0, R4 is hydrogen, and R1, R2, and R3 are the same or different and are independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers thereof. In various embodiments of this aspect of the invention, R1, R2, and R3 are independently selected from relatively low molecular weight moieties, i.e., organic groups having molecular weights of between 15 (methyl) and 1,000 g/mol; and/or at least one of R1, R2, and R3 represents an amino acid side chain or derivative thereof. For example, in the compounds of Table 3, R3 represents glutaric acid derivatives. In one aspect, the compounds of the present invention have a molecular weight within the range of about 450 to 800 g/mol, where the compounds of Table 3 provide numerous illustrations of such compounds.

TABLE 3
THE BETA-STRAND MIMETICS LIBRARY
21
				Mol.
No.	Ra	Rb	Rc	Weight	M + H
865	Propyl	Phenyl	4-Methoxybenzyl	565	565
866	Propyl	Phenyl	3,4-Cl2-benzyl	585	585
867	Propyl	Phenyl	1-Naphthyl	589	589
868	Propyl	Phenyl	Piperonyl	549	549
869	Propyl	Phenyl	2,4,5-Trimethoxyphenyl	571	571
870	Propyl	Phenyl	3-Hydroxybenzyl	551	551
871	Propyl	Phenyl	1-Naphthylmethyl	565	565
872	Propyl	Phenyl	Phenethyl	578	578
873	Propyl	Phenyl	3-Methoxyphenyl	611	611
874	Propyl	Phenyl	N-Benzoylaminoethyl 535	535
875	Propyl	Phenyl	Benzyl	551	551
876	Propyl	Phenyl	4-NO2-benzyl	580	580
877	Propyl	Methoxy	4-Methoxybenzyl	519	519
878	Propyl	Methoxy	3,4-Cl2-benzyl	539	539
879	Propyl	Methoxy	1-Naphthyl	543	543
880	Propyl	Methoxy	Piperonyl	503	503
881	Propyl	Methoxy	2,4,5-Trimethoxyphenyl	525	525
882	Propyl	Methoxy	3-Hydroxybenzyl	505	505
883	Propyl	Methoxy	1-Naphthylmethyl	519	519
884	Propyl	Methoxy	Phenethyl	532	532
885	Propyl	Methoxy	3-Methoxyphenyl	565	565
886	Propyl	Methoxy	N-Benzoylaminoethyl	489	489
887	Propyl	Methoxy	Renzyl	505	505
888	Propyl	Methoxy	4-NO2-benzyl	534	534
889	Isobutyl	Phenyl	4-Methoxybenzyl	593	593
890	Isobutyl	Phenyl	3,4-Cl2-benzyl	613	613
891	Isobutyl	Phenyl	1-Naphthyl	618	618
892	Isobutyl	Phenyl	Piperonyl	577	577
893	Isobutyl	Phenyl	2,4,5-Trimethoxyphenyl	599	599
894	Isobutyl	Phenyl	3-Hydroxybenzyl	579	579
895	Isobutyl	Phenyl	1-Naphthylmethyl	593	593
896	Isobutyl	Phenyl	Phenethyl	606	606
897	Isobutyl	Phenyl	3-Methoxyphenyl	639	639
898	Isobutyl	Phenyl	N-Benzoylaminoethyl	563	563
899	Isobutyl	Phenyl	Benzyl	579	579
900	Isobutyl	Phenyl	4-NO2-benzyl	608	608
901	Isobutyl	Methoxy	4-Methoxybenzyl	547	547
902	Isobutyl	Methoxy	3,4-Cl2-benzyl	567	567
903	Isobutyl	Methoxy	1-Naphthyl	571	571
904	Isobutyi	Methoxy	Piperonyl	531	531
905	Isobutyl	Methoxy	2,4,5-Trimethoxyphenyl	553	553
906	Isobutyl	Methoxy	3-Hydroxybenzyl	533	533
907	Isobutyl	Methoxy	1-Naphthylmethyl	547	547
908	Isobutyl	Methoxy	Phenethyl	560	560
909	Isobutyl	Methoxy	3-Methoxyphenyl	593	593
910	Isobutyl	Methoxy	N-Benzoylaminoethyl	517	517
911	Isobutyl	Methoxy	Benzyl	533	533
912	Isobutyl	Methoxy	4-NO2-benzyl	562	562
913	4-Br-benzyl	Phenyl	4-Methoxybenzyl	692	692
914	4-Br-benzyl	Phenyl	3,4-Cl2-benzyl	712	712
915	4-Br-benzyl	Phenyl	1-Naphthyl	716	716
916	4-Br-benzyl	Phenyl	Piperonyl	676	676
917	4-Br-benzyl	Phenyl	2,4,5-Trimethoxyphenyl	698	698
918	4-Br-benzyl	Phenyl	3-Hydroxybenzyl	678	678
919	4-Br-benzyl	Phenyl	1-Naphthylmethyl	692	692
920	4-Br-benzyl	Phenyl	Phenethyl	705	705
921	4-Br-benzyl	Phenyl	3-Methoxyphenyl	738	738
922	4-Br-benzyl	Phenyl	N-Benzoylaminoethyl	662	662
923	4-Br-benzyl	Phenyl	Benzyl	678	678
924	4-Br-benzyl	Phenyl	4-NO2-benzyl	707	707
925	4-Br-benzyl	Methoxy	4-Methoxybenzyl	646	646
926	4-Br-benzyl	Methoxy	3,4-Cl2-benzyl	666	666
927	4-Br-benzyl	Methoxy	1-Naphthyl	670	670
928	4-Br-benzyl	Methoxy	Piperonyl	630	630
929	4-Br-benzyl	Methoxy	2,4,5-Trimethoxyphenyl	652	652
930	4-Br-benzyl	Methoxy	3-Hydroxybenzyl	631	631
931	4-Br-benzyl	Methoxy	1-Naphthylmethyl	645	645
932	4-Br-benzyl	Methoxy	Phenethyl	659	659
933	4-Br-benzyl	Methoxy	3-Methoxyphenyl	692	692
934	4-Br-benzyl	Methoxy	N-Benzoylaminoethyl	615	615
935	4-Br-benzyl	Methoxy	Benzyl	631	631
936	4-Br-benzyl	Methoxy	4-NO2-benzyl	660	660
937	Benzyl	Phenyl	4-Methoxybenzyl	613	613
938	Benzyl	Phenyl	3,4-Cl2-benzyl	633	633
939	Benzyl	Phenyl	1-Naphthyl	638	638
940	Benzyl	Phenyl	Piperonyl	597	597
941	Benzyl	Phenyl	2,4,5-Trimethoxyphenyl	619	619
942	Benzyl	Phenyl	3-Hydroxybenzyl	599	599
943	Benzyl	Phenyl	1-Naphthylmethyl	613	613
944	Benzyl	Phenyl	Phenethyl	626	626
945	Benzyl	Phenyl	3-Methoxyphenyl	659	659
946	Benzyl	Phenyl	N-Benzoylaminoethyl	583	583
947	Benzyl	Phenyl	Benzyl	599	599
948	Benzyl	Phenyl	4-NO2-benzyl	628	628
949	Benzyl	Methoxy	4-Methoxybenzyl	567	567
950	Benzyl	Methoxy	3,4-Cl2-benzyl	587	587
951	Benzyl	Methoxy	1-Naphthyl	591	591
952	Benzyl	Methoxy	Piperonyl	551	551
953	Benzyl	Methoxy	2,4,5-Trimethoxyphenyl	573	573
954	Benzyl	Methoxy	3-Hydroxybenzyl	553	553
955	Benzyl	Methoxy	1-Naphthylmethyl	567	567
956	Benzyl	Methoxy	Phenethyl	580	580
957	Benzyl	Methoxy	3-Methoxyphenyl613	613
958	Benzyl	Methoxy	N-Benzoylaminoethyl	537	537
959	Benzyl	Methoxy	Benzyl	553	553
960	Benzyl	Methoxy	4-NO2-benzyl	582	582
961	Propyl	Benzyloxy	2,4-Pentadienyl	541	541
962	Propyl	Benzyloxy	3-(2,6-Cl2-pyridyl)methyl	620	620
963	Propyl	Benzyloxy	Chromen-2-one-3-	619	619
			methyl
964	Propyl	Benzyloxy	Methoxymethyl	519	519
965	Propyl	Benzyloxy	Pyran-2-one-4-methyl	569	569
966	Propyl	Benzyloxy	Ethyl	503	503
967	Propyl	Benzyloxy	2-Ethyldecanyl	629	629
968	Propyl	Benzyloxy	Pyrazin-2-methyl	553	553
969	Propyl	Benzyloxy	4-Pyridylmethyl	552	552
970	Propyl	Benzyloxy	4-Butenyl	529	529
971	Propyl	Benzyloxy	2-NO2-5-CI-phenyl	630	630
972	Propyl	Benzyloxy	Cyanomethyl	514	514
973	Propyl	Methoxy	2,4-Pentadienyl	465	465
974	Propyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	544	544
975	Propyi	Methoxy	Chromen-2-one-3-	543	543
			methyl
976	Propyl	Methoxy	Methoxymethyl	442	442
977	Propyl	Methoxy	Pyran-2-one-4-methyl	492	492
978	Propyl	Methoxy	Ethyl	426	426
979	Propyl	Methoxy	2-Ethyldecanyl	553	553
980	Propyl	Methoxy	Pyrazin-2-methyl	476	476
981	Propyl	Methoxy	4-Pyridylmethyl	476	476
982	Propyl	Methoxy	4-Btiteflyl	453	453
983	Propyl	Methoxy	2-NO2-5-CI-phenyl	554	554
984	Propyl	Methoxy	Cyanomethyl	437	437
985	Isobutyl	Benzyloxy	2,4-Pentadienyl 569	569
986	Isobutyl	Benzyloxy	3-(2,6-Cl2-pyridyl)methyl	649	649
987	Isobutyl	Benzyloxy	Chromen-2-one-3-	647	647
			methyl
988	Isobutyl	Benzyloxy	Methoxymethyl	547	547
989	Isobutyl	Benzyloxy	Pyran-2-one-4-methyl	597	597
990	Isobutyl	Benzyloxy	Ethyl	531	531
991	Isobutyl	Benzyloxy	2-Ethyldecanyl	657	657
992	Isobutyl	Benzyloxy	Pyrazin-2-methyl	581	581
993	Isobutyl	Benzyloxy	4-Pyridylmethyl 580	580
994	Isobutyl	Benzyloxy	4-Butenyl	557	557
995	Isobutyl	Benzyloxy	2-NO2-5-Cl-phenyl	658	658
996	Isobutyl	Benzyloxy	Cyanomethyl	542	542
997	Isobutyl	Methoxy	2,4-Pentadienyl	493	493
998	Isobutyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	572	572
999	Isobutyl	Methoxy	Chromen-2-one-3-	571	571
			methyl
1000	Isobutyl	Methoxy	Methoxymethyl	471	471
1001	Isobutyl	Methoxy	Pyran-2-one-4-methyl	521	521
1002	Isobutyl	Methoxy	Ethyl	455	455
1003	Isobutyl	Methoxy	2-Ethyldecanyl	581	581
1004	Isobutyl	Methoxy	Pyrazin-2-methyl	505	505
1005	Isobutyl	Methoxy	4-Pyridylmethyl	504	504
1006	Isobutyl	Methoxy	4-Biiteriyl	481	481
1007	Isobutyl	Methoxy	2-NO2-5-Cl-phenyl	582	582
1008	Isobutyl	Methoxy	Cyanomethyl	466	466
1009	Benzyl	Benzyloxy	2,4-Pentadienyl	589	589
1010	Benzyl	Benzyloxy	3-(2,6-Cl2-pyridyl)methyl	669	669
1011	Benzyl	Benzyloxy	Chromen-2-one-3-	667	667
			methyl
1012	Benzyl	Benzyloxy	Methoxymethyl	567	567
1013	Benzyl	Benzyloxy	Pyran-2-one-4-methyl	617	617
1014	Benzyl	Benzyloxy	Ethyl	551	551
1015	Benzyl	Benzyloxy	2-Ethyldecanyl	677	677
1016	Benzyl	Benzyloxy	Pyrazin-2-methyl	601	601
1017	Benzyl	Benzyloxy	4-Pyridylmethyl	600	600
1018	Benzyl	Benzyloxy	4-Butenyl	577	577
1019	Benzyl	Benzyloxy	2-NO2-5-CI-phenyl	678	678
1020	Benzyl	Benzyloxy	Cyanomethyl	562	562
1021	Benzyl	Methoxy	2,4-Pentadienyl	513	513
1022	Benzyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	592	592
1023	Benzyl	Methoxy	Chromen-2-one-3- 591	591
			methyl
1024	Benzyl	Methoxy	Methoxymethyl	491	491
1025	Benzyl	Methoxy	Pyran-2-one-4-methyl	541	541
1026	Benzyl	Methoxy	Ethyl	475	475
1027	Benzyl	Methoxy	2-Ethyldecanyl	601	601
1028	Benzyl	Methoxy	Pyrazin-2-methyl	525	525
1029	Benzyl	Methoxy	4-Pyridylmethyl	524	524
1030	Benzyl	Methoxy	4-Butenyl	501	501
1031	Benzyl	Methoxy	2-NO2-5-Cl-phenyl	602	602
1032	Benzyl	Methoxy	Cyanomethyl	486	486
1033	Phenylpropyl	Benzyloxy	2,4-Pentadienyl	617	617
1034	Phenylpropyl	Benzyloxy	3-(2,6-Cl2-pyridyl)methyl	697	697
1035	Phenylpropyl	Benzyloxy	Chromen-2-one-3-	695	695
			methyl
1036	Phenylpropyl	Benzyloxy	Methoxymethyl	595	595
1037	Phenylpropyl	Benzyloxy	Pyran-2-one-4-methyl	645	645
1038	Phenylpropyl	Benzyloxy	Ethyl	579	579
1039	Phenylpropyl	Benzyloxy	2-Ethyldecanyl	705	705
1040	Phenylpropyl	Benzyloxy	Pyrazin-2-methyl	629	629
1041	Phenylpropyl	Benzyloxy	4-Pyridylmethyl	628	628
1042	Phenylpropyl	Benzyloxy	4-Butenyl	605	605
1043	Phenylpropyl	Benzyloxy	2-NO2-5-Cl-phenyl	706	706
1044	Phenylpropyl	Benzyloxy	Cyaflomethyl	590	590
1045	Phenylpropyl	Methoxy	2,4-Pentadienyl	541	541
1046	Phenylpropyl	Methoxy	3-(2,6-Cl2-pyridyl)methyl	620	620
1047	Phenylpropyl	Methoxy	Chromen-2-one-3-	619	619
			methyl
1048	Phenylpropyl	Methoxy	Methoxymethyl 519	519
1049	Phenylpropyl	Methoxy	Pyran-2-one-4-methyl	569	569
1050	Phenylpropyl	Methoxy	Ethyl	503	503
1051	Phenylpropyl	Methoxy	2-Ethyldecanyl	629	629
1052	Phenylpropyl	Methoxy	Pyrazin-2-methyl	553	553
1053	Phenylpropyl	Methoxy	4-Pyridylmethyl	552	552
1054	Phenylpropyl	Methoxy	4-Butenyl	529	529
1055	Phenylpropyl	Methoxy	2-NO2-5-Cl-phenyl	630	630
1056	Phenylpropyl	Methoxy	Cyanomethyl	514	514
1057	Methyl	Methoxy	4-Methoxybenzyl	491	491
1058	Methyl	Methoxy	3,4-Cl2-benzyl	515	515
1059	Methyl	Methoxy	1-Naphthyl	497	497
1060	Methyl	Methoxy	Piperonyl	490	490
1061	Methyl	Methoxy	2,4,5-Trimethoxyphenyl	537	537
1062	Methyl	Methoxy	3-Hydroxybenzyl	476	476
1063	Methyl	Methoxy	1-Naphthylmethyl	511	511
1064	Methyl	Methoxy	Phenethyl	475	475
1065	Methyl	Methoxy	3-Methoxyphenyl	476	476
1066	Methyl	Methoxy	N-Benzoylaminoethyl	504	504
1067	Methyl	Methoxy	Benzyl	460	460
1068	Methyl	Methoxy	4-NO2-benzyl	505	505
1069	Amino	Methoxy	4-Methoxybenzyl	492	492
1070	Amino	Methoxy	3,4-Cl2-benzyl	516	516
1071	Amino	Methoxy	1-Naphthyl	498	498
1072	Amino	Methoxy	Piperonyl	491	491
1073	Amino	Methoxy	2,4,5-Trimethoxyphenyl	538	538
1074	Amino	Methoxy	3-Hydroxybenzyl	477	477
1075	Amino	Methoxy	1-Naphthylmethyl 512	512
1076	Amino	Methoxy	Phenethyl	476	476
1077	Amino	Methoxy	3-Methoxyphenyl	477	477
1078	Amino	Methoxy	N-Benzoylaminoethyl	505
1079	Amino	Methoxy	Benzyl	461	461
1080	Amino	Methoxy	4-NO2-benzyl	506	506
1081	3-Propenyl	Methoxy	4-Methoxybenzyl 517	517
1082	3-Propenyl	Methoxy	3,4-Cl2-benzyl	541	541
1083	3-Propenyl	Methoxy	1-Naphthyl	523	523
1084	3-Propenyl	Methoxy	Piperonyl	517	517
1085	3-Propenyl	Methoxy	2,4,5-Trimethoxyphenyl	563	563
1086	3-Propenyl	Methoxy	3-Hydroxybenzyl 503	503
1087	3-Propenyl	Methoxy	1-Naphthylmethyl 537	537
1088	3-Propenyl	Methoxy	Phenethyl	501	501
1089	3-Propenyl	Methoxy	3-Methoxyphenyl 503	503
1090	3-Propenyl	Methoxy	N-Benzoylaminoethyl	530	530
1091	3-Propenyl	Methoxy	Benzyl	487	487
1092	3-Propenyl	Methoxy	4-NO2-benzyl	532	532
1093	Ethanoic acid	Methoxy	4-Methoxybeflzyl	535	535
1094	Ethanoic acid	Methoxy	3,4-Cl2-benzyl	559	559
1095	Ethanoic acid	Methoxy	1-Naphthyl	541	541
1096	Ethanoic acid	Methoxy	Piperonyl	534	534
1097	Ethanoic acid	Methoxy	2,4,5-Trimethoxyphenyl	581	581
1098	Ethanoic acid	Methoxy	3-Hydroxybenzyl	521	521
1099	Ethanoic acid	Methoxy	1-Naphthylmethyl
1100	Ethanoic acid	Methoxy	Phenethyl	519	519
1101	Ethanoic acid	Methoxy	3-Methoxyphenyl	521	521
1102	Ethanoic acid	Methoxy	N-Benzoylaminoethyl	548	548
1103	Ethanoic acid	Methoxy	Benzyl	505
1104	Ethanoic acid	Methoxy	4-NO2-benzyl	549	549
1105	Propionic acid	Methoxy	4-Methoxybenzyi	549	549
1106	Propionic acid	Methoxy	3,4-Cl2-benzyl	573	573
1107	Propionic acid	Methoxy	1 -Naphthyl	555
1108	Propionic acid	Methoxy	Piperonyl	549	549
1109	Propionic acid	Methoxy	2,4,5-Trimethoxyphenyl	595	595
1110	Propionic acid	Methoxy	3-Hydroxybenzyl	535	535
1111	Propionic acid	Methoxy	1-Naphthylmethyl	569	569
1112	Propionic acid	Methoxy	Phenethyl	533	533
1113	Propionic acid	Methoxy	3-Methoxyphenyl	535	535
1114	Propionic acid	Methoxy	N-Benzoylaminoethyl	562	562
1115	Propionic acid	Methoxy	Benzyl	519	519
1116	Propionic acid	Methoxy	4-NO2-benzyl	564	564
1117	4-Vinylbenzyl	Methoxy	4-Methoxybenzyl	593	593
1118	4-Vinyibenzyl	Methoxy	3,4-Cl2-benzyl	617	617
1119	4-Vinylbenzyl	Methoxy	1 -Naphthyl	599	599
1120	4-Vinylbenzyl	Methoxy	Piperonyl	593	593
1121	4-Vinylbenzyl	Methoxy	2,4,5-Trimethoxyphenyl	639	639
1122	4-Vinylbenzyl	Methoxy	3-Hydroxybenzyl	579	579
1123	4-Vinylbenzyl	Methoxy	1-Naphthylmethyl	613	613
1124	4-Vinylbenzyl	Methoxy	Phenethyl	577	577
1125	4-Vinylbenzyl	Methoxy	3-Methoxyphenyl	579	579
1126	4-Vinylbenzyl	Methoxy	N-Benzoylaminoethyl	606	606
1127	4-Vinylbenzyl	Methoxy	Renzyl	563	563
1128	4-Vinylbenzyl	Methoxy	4-NO2-benzyl	608	608
1129	Piperonylmethyl	Methoxy	4-Methoxybenzyl	611	611
1130	Piperonylmethyl	Methoxy	3,4-Cl2-benzyl	635	635
1131	Piperonylmethyl	Methoxy	1-Naphthyl	617	617
1132	Piperonylmethyl	Methoxy	Piperonyl	611	611
1133	Piperonylmethyl	Methoxy	2,4,5-Trimethoxyphenyl	657 657
1134	Piperonylmethyl	Methoxy	3-Hydroxybenzyl	597	597
1135	Piperonylmethyl	Methoxy	1-Naphthylmethyl	631	631
1136	Piperonylmethyl	Methoxy	Phenethyl	595	595
1137	Piperonylmethyl	Methoxy	3-Methoxyphenyl	597	597
1138	Piperonylmethyl	Methoxy	N-Benzoylaminoethyl	624	624
1139	Piperonylmethyl	Methoxy	Benzyl	581	581
1140	Piperonylmethyl	Methoxy	4-NO2-benzyl	626	626
1141	4-F-benzyl	Methoxy	4-Methoxybenzyl	585	585
1142	4-F-benzyl	Methoxy	3,4-Cl2-benzyl	609	609
1143	4-F-benzyl	Methoxy	1-Naphthyl	591	591
1144	4-F-benzyl	Methoxy	Piperonyl	585	585
1145	4-F-benzyl	Methoxy	2,4,5-Trimethoxyphenyl	631	631
1146	4-F-benzyl	Methoxy	3-Hydroxybenzyl	571	571
1147	4-F-benzyl	Methoxy	1-Naphthylmethyl 605	605
1148	4-F-benzyl	Methoxy	Phenethyl	569	569
1149	4-F-benzyl	Methoxy	3-Methoxyphenyl	571	571
1150	4-F-benzyl	Methoxy	N-Benzoylaminoethyl	598	598
1151	4-F-benzyl	Methoxy	Benzyl
1152	4-F-benzyl	Methoxy	4-NO2-berizyl	600	600
1153	Methyl	Benzyloxy	4-Methoxybenzyl	567	567
1154	Methyl	Benzyloxy	3,4-Cl2-benzyl	591	591
1155	Methyl	Benzyloxy	1-Naphthyl	573	573
1156	Methyl	Benzyloxy	Piperonyl	567	567
1157	Methyl	Benzyloxy	2,4,5-Trimethoxyphenyl	613	613
1158	Methyl	Benzyloxy	3-Hydroxybenzyl	553	553
1159	Methyl	Benzyloxy	1 -Naphthylmethyl	587	587
1160	Methyl	Benzyloxy	Phenethyl	551	551
1161	Methyl	Benzyloxy	3-Methoxyphenyl	553	553
1162	Methyl	Benzyloxy	N-Benzoylaminoethyl	580	580
1163	Methyl	Benzyloxy	Benzyl	537	537
1164	Methyl	Benzyloxy	4-NO2-benzyl	582	582
1165	Amino	Benzyloxy	4-Methoxybenzyl	568	568
1166	Amino	Benzyloxy	3,4-Cl2-benzyl	592	592
1167	Amino	Benzyloxy	1-Naphthyl	574	574
1168	Amino	Benzyloxy	Piperonyl	568	568
1169	Amino	Benzyloxy	2,4,5-Irimethoxyphenyl	614	614
1170	Amino	Benzyloxy	3-Hydroxybenzyl	554	554
1171	Amino	Benzyloxy	1-Naphthylmethyl	588	588
1172	Amino	Benzyloxy	Phenethyl	552	552
1173	Amino	Benzyloxy	3-Methoxyphenyl	554	554
1174	Amino	Benzyloxy	N-Benzoylaminoethyl	581	581
1175	Amino	Benzyloxy	Benzyl	538	538
1176	Amino	Benzyloxy	4-NO2-benzyl	583	583
1177	3-Propenyl	Benzyloxy	4-Methoxybenzyl	593
1178	3-Propenyl	Benzyloxy	3,4-Cl2-benzyl	617	617
1179	3-Propenyl	Benzyloxy	1-Naphthyl	599	599
1180	3-Propenyl	Benzyloxy	Piperonyl	593	593
1181	3-Propenyl	Benzyloxy	2,4,5-Trimethoxyphenyl	639	639
1182	3-Propenyl	Benzyioxy	3-Hydroxybenzyl	579	579
1183	3-Propenyl	Benzyloxy	1-Naphthylmethyl	613	613
1184	3-Propenyl	Benzyloxy	Phenethyl	577
1185	3-Propenyl	Benzyloxy	3-Methoxyphenyl	579	579
1186	3-Propenyl	Benzyloxy	N-Benzoylaminoethyl	606	606
1187	3-Propenyl	Benzyloxy	Benzyl	563	563
1188	3-Propenyl	Benzyloxy	4-NO2-benzyl	608	608
1189	Ethanoic acid	Benzyloxy	4-Methoxybenzyl	611	611
1190	Ethanoic acid	Benzyloxy	3,4-Cl2-benzyl	635	635
1191	Ethanoic acid	Benzyloxy	1-Naphthyl	617	617
1192	Ethanoic acid	Benzyloxy	Piperonyl	611	611
1193	Ethanoic acid	Benzyloxy	2,4,5-Trimethoxyphenyl	657	657
1194	Ethanoic acid	Benzyloxy	3-Hydroxybenzyl	597	597
1195	Ethanoic acid	Benzyloxy	1-Naphthylmethyl 631	631
1196	Ethanoic acid	Benzyloxy	Phenethyl	595	595
1197	Ethanoic acid	Benzyloxy	3-Methoxyphenyl	597	597
1198	Ethanoic acid	Benzyloxy	N-Benzoylaminoethyl	624	624
1199	Ethanoic acid	Benzyloxy	Benzyl	581	581
1200	Ethanoic acid	Benzyloxy	4-NO2-benzyl	626	626
1201	Propionic acid	Benzyloxy	4-Methoxybenzyl	625	625
1202	Propionic acid	Renzyloxy	3,4-Cl2-benzyl	649	649
1203	Propionic acid	Benzyloxy	1-Naphthyi 631	631
1204	Propionic acid	Benzyloxy	Piperonyl 625	625
1205	Propionic acid	Benzyloxy	2,4,5-Trimethoxyphenyl	671	671
1206	Propionic acid	Benzyloxy	3-Hydroxybenzyl	611	611
1207	Propionic acid	Benzyloxy	1-Naphthylmethyl	645	645
1208	Propionic acid	Benzyioxy	Phenethyl	609	609
1209	Propionic acid	Benzyloxy	3-Methoxyphenyl	611	611
1210	Propionic acid	Benzyloxy	N-Benzoylaminoethyl	638	638
1211	Propionic acid	Benzyloxy	Benzyl	595	595
1212	Propionic acid	Benzyloxy	4-NO2-benzyl	640	640
1213	4-Vinylbenzyl	Benzyloxy	4-Methoxybenzyl	669	669
1214	4-Vinylbenzyl	Benzyloxy	3,4-Cl2-benzyl	694	694
1215	4-Vinylbenzyl	Benzyloxy	1-Naphthyl	675	675
1216	4-Vinylbenzyl	Benzyloxy	Piperonyl	669	669
1217	4-Vinylbenzyl	Benzyloxy	2,4,5-Trimethoxyphenyl	715	715
1218	4-Vinylbenzyl	Benzyloxy	3-Hydroxybenzyl	655	655
1219	4-Vinylbenzyl	Benzyloxy	1-Naphthylmethyl	689	689
1220	4-Vinylbenzyl	Benzyloxy	Phenethyl	653	653
1221	4-Vinylbenzyl	Benzyloxy	3-Methoxyphenyl	655	655
1222	4-Vinylbenzyl	Benzyloxy	N-Benzoylaminoethyl	682	682
1223	4-Vinylbenzyl	Benzyloxy	Benzyl	639	639
1224	4-Vinylbenzyl	Benzyloxy	4-NO2-benzyl	684	684
1225	Piperonylmethyl	Benzyloxy	4-Methoxybenzyl	687	687
1226	Piperonylmethyl	Benzyloxy	3,4-Cl2-benzyl	712 712
1227	Piperonylmethyl	Benzyloxy	1-Naphthyl	693	693
1228	Piperonylmethyl	Benzyloxy	Piperonyl	687	687
1229	Piperonylmethyl	Benzyloxy	2,4,5-Trimethoxyphenyl	733	733
1230	Piperonylmethyl	Benzyloxy	3-Hydroxybenzyl	673	673
1231	Piperonyimethyl	Benzyloxy	1-Naphthylmethyl	707	707
1232	Piperonylmethyl	Benzyloxy	Phenethyl	671	671
1233	Piperonylmethyl	Renzyioxy	3-Methoxyphenyl	673 673
1234	Piperonylmethyl	Benzyloxy	N-Benzoylaminoethyl	700	700
1235	Piperonylmethyl	Benzyloxy	Benzyl	657	657
1236	Piperonylmethyl	Benzyloxy	4-NO2-benzyl	702	702
1237	4-F-benzyl	Benzyloxy	4-Methoxybenzyl	661	661
1238	4-F-benzyl	Benzyloxy	3,4-Cl2-benzyl	686	686
1239	4-F-benzyl	Benzyloxy	1-Naphthyl	667	667
1240	4-F-benzyl	Benzyloxy	Piperonyl	661	661
1241	4-F-benzyl	Benzyloxy	2,4,5-Trimethoxyphenyl	707	707

[0079] The β-strand mimetic structures of the present invention may be used as bioactive agents, such as diagnostic, prophylactic, and therapeutic agents. Preferably, the compounds are formulated into a pharmaceutically acceptable form and then administered to a patient in need of treatment by the β-strand mimetic structures of the present invention.

[0080] Thus, the present invention provides a pharmaceutical composition containing a compound of structures (I″) through (I′″). For the preparation of the pharmaceutical composition containing the present compounds, a skilled person in the art can use publicly known knowledge and techniques that are known in the pertinent art. Generally known varieties of carriers and other additives are used for the preparation of the composition of the present invention. The pharmaceutical compositions of this invention may be administered in a standard manner for the disease condition that is desired to be treated, for example by oral, rectal or parenteral administration.

[0081] For these purposes, the compounds of the present invention may be formulated by means known in the art into a form of, for example, tablets, capsules, aqueous or oily solutions or suspension, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

[0082] A suitable pharmaceutical composition of the present invention is one suitable for oral administration in unit dosage form such as, for example a tablet or capsule that contains from about 1 mg to about 1 g of the compound of this invention.

[0083] In another aspect, a pharmaceutical composition of the present invention is one suitable for intravenous, subcutaneous or intramuscular injection. A patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of about 1 μg/kg to about 1 g/kg of the compound of the present invention. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time.

[0084] Alternatively a patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to about 4 times per day.

[0085] The following table illustrates representative pharmaceutical dosage forms containing the compound or pharmaceutically-acceptable salt thereof for therapeutics or prophylactic use in humans:

mg/tablet
Tablet 1
Compound                  100
Lactose Ph. Eur.          179
Croscarmellose sodium     12.0
Polyvinylpyrrolidone      6
Magnesium stearate        3.0
Tablet 2
Compound                  50
Lactose Ph. Eur.          229
Croscarmellose sodium     12.0
Polyvinylpyrrolidone      6
Magnesium stearate        3.0
Tablet 3
Compound                  1.0
Lactose Ph. Fur.          92
Croscarmellose sodium     4.0
Polyvinylpyrrolidone      2.0
Mag nesiumstearate        1.0
Capsule                   mg/capsule
Compound                  10
Lactose Ph. Fur.          389
Croscarmellose sodium     100
Magnesium stearate        1.0
Injection I               (50 mg/ml)
Compound                  0.5% w/v
Isotonic aqueous solution to 100%

[0086] The pharmaceutical composition containing the compound of general formula (I) can be used for a variety of biologically desirable effects, including inhibiting a protease in a warm-blooded animal, modulating a cell signaling transcription factor related peptide in a warm-blooded animal, and for inhibiting a kinase in a warm-blooded animal. These effects may be achieved by a method comprising administering to the animal in need thereof an effective amount of the compound of formula (I).

[0087] Furthermore, and as discussed in detail below, the β-strand mimetic structures of the present invention may also be effective for inhibiting MHC-I and/or MHC-II presentation of peptides to T cell receptors in a warm-blooded animal; for inhibiting peptide binding to SH2 domains in a warm-blooded animal; for inhibiting peptide binding to SH3 domains in a warm-blooded animal; for inhibiting peptide binding to PTB domains in a warm-blooded animal; for modulating G protein coupled receptor (GPCR) and ion channel in a warm-blooded animal; and for modulating cytokines in a warm-blooded animal.

[0088] Kinase Inhibition (Including SH2 and SH3 Domain Inhibition)

[0089] In one aspect, the present invention provides a method for inhibiting a kinase in a warm-blooded animal. The method comprises administering to the animal an amount of a compound of the present invention, where the amount is effective to inhibit a kinase. Kinases (also known as protein kinases) are a class of enzymes that catalyze a reaction whereby a biomolecule (typically another enzyme) is phosphorylated. As many as 1000 kinases are thought to be encoded in the mammalian genome (Hunter, Cell 50:823-829, 1987). The large number of kinases allow for rapid signal amplification and multiple points of regulation.

[0090] Phosophorylation is a very common covalent modification found in signal transduction processes, and causes an alteration in the activity of those proteins which become phosphorylated. Kinases are thus a critical component of signaling pathways. Kinases are typically organized into several modular functional regions, or “domains” (Cohen, G. B., et al. Cell 80:237-248,1995). One domain, known as “SH3,” is a region of 55-70 amino acids that binds to proline-rich peptides, particularly extended strand. Another domain, known as “SH2,” is a phosphotyrosine binding region of about 100 amino acids in length. These two domains are believed to be involved in recognizing and binding to the protein substrates. These, as well as other domains including myristoylation and palmitoylation sites, are responsible for assembling multiprotein complexes which guide the catalytic domain to the correct targets (Mayer et al. Mol. Cell. Biol. 12:609-618,1992; and Mayer and Baltimore, Mol. Cell. Biol. 14:2883-2894,1994). While SH2 and SH3 domains are known to be present in some kinases, these domains are also present in other proteins. The compounds of the present invention may be used to inhibit SH2- or SH3-mediated binding in kinase or other proteins.

[0091] Kinases are used by the body in a vast number of different, but often interrelated, intracellular signal transduction mechanisms. For example, growth factors, transcription factors, hormones, cell cycle regulatory proteins, and many other classes of cellular regulators utilize tyrosine kinases in their signaling cascades (see, e.g., Bolen et al. FASEB J. 6:3403-3409,1992; and Ullrich and Schlessinger, Cell 61:203-212,1990). The serine/threonine kinases make up the majority of the remainder of the kinase family.

[0092] One important approach for determining the role, and understanding the function, of enzymes, both in vitro and in vivo, is the use of specific enzyme inhibitors. If one or more compounds can be found that will inhibit the enzyme, the inhibitor can be used to modulate the enzyme's activity, and the effects of that decrease can be observed. Such approaches have been instrumental in deciphering many of the pathways of intermediary metabolism, and have also been important in learning about enzyme kinetics and determining catalytic mechanisms. The present invention provides such compounds.

[0093] Regulation of many immune responses is mediated through receptors that transmit signals through tyrosine kinases containing SH2 domains. T-cell activation via the antigen specific T-cell receptor (TCR) initiates a signal transduction cascade leading to lymphokine secretion and cell proliferation. One of the earliest biochemical responses following TCR activation is an increase in tyrosine kinase activity. In particular, T-cell activation and proliferation is controlled through T-cell receptor mediated activation of p56lck and p59fyn tyrosine kinases, as well as ZAP-70 and Syk (Weiss and Litman, Cell 76:263-274,1994) which contain SH2 domains. Additional evidence indicates that several src-family kinases (lck, blk, fyn) participate in signal transduction pathways leading from B-cell antigen receptors and hence may serve to integrate stimuli received from several independent receptor structures. Thus, inhibitors that block interactions of these SH2 domain kinases with their cognate receptors could serve as immunosuppressive agents with utility in autoimmune diseases, transplant rejection or as anti-inflammatory agents as well as anticancer drugs in cases of lymphocytic leukemias.

[0094] Additionally, non-transmembrane PTPase containing SH2 domains are known and nomenclature refers to them as SH-PTP1 and SH-PTP2 (Neel, Cell Biology 4:419-432,1993) SH-PTP1 is identical to PTP1 C, HCP or SHP and SH-PTP2 is also known as PTP1 D or PTP2C. SH-PTP1 is expressed at high levels in hematopoietic cells of all lineages and all stages of differentiation. Since the SH-PTP1 gene was identified as responsible for the motheaten (me) mouse phenotype, this provides a basis for predicting the effects of inhibitors that would block its interaction with its cellular substrates. Thus, inhibition of SH-PTP1 function would be expected to result in impaired T-cell responses to mitogenic stimulation, decreased NK cell function, and depletion of B-cell precursors with potential therapeutic applications as described above.

[0095] The ability of a compound of the present invention to bind to the SH2 domain of STAT6, or to bind to the SH2 domain of the protein tyrosine phosphatase SH-PTP1, can be demonstrated by the procedures disclosed by Payne et al., P.N.A.S. USA 90:4902-4906,1993). Libraries of SH2 binding mimetics may be screened by the procedure of Songyang et al., Cell 72:767-778, 1993. See also by the procedure of Songyang et al., Current Biology 4:973-982, 1994), to test for the ability of a compound to act as a substrate or inhibitor of protein kinases.

[0096] Accordingly, in one aspect, the present invention provides a method for inhibiting a phosphatase in a warm-blooded animal, where the method comprises administering to the animal an amount of a compound of the present invention, where the amount is effective to inhibit the phosphatase.

[0097] In Type 2 (non-insulin dependent) diabetes, tyrosine phosphatases (PTP-1 b) counter-balance the effect of activated insulin-receptor kinases and may represent important drug targets. In vitro experiments show that injection of PTPase blocks insulin stimulated-phosphorylation of tyrosyl residues on endogenous proteins. Thus, compounds of the invention may be used to modulate insulin action in diabetes

[0098] In another aspect, the present invention provides a method for inhibiting the binding of a phosphotyrosine residue in a first protein to an SH2 domain of a second protein. The method comprises contacting an amount of a compound of the present invention with a composition comprising the first and second protein. The amount is effective to mitigate the binding between the first and second protein that occurs via the SH2 domain of the second protein and the phosphotyrosine residue of the first protein.

[0099] Protease Inhibition

[0100] In another aspect, the present invention provides a method for inhibiting a protease in a warm-blooded animal. The method comprises administering to the animal an amount of a compound of the present invention as described herein. The amount is effective to inhibit a protease in the animal. In various embodiments: protease is a serine protease; the protease is a serine protease selected from thrombin, Factor X, Factor IX, Factor VII, Factor XI, urokinase, HCV protease, chymase tryptase and kallikrein; the protease is thrombin; the protease is Factor VII; and the protease is selected from an aspartic, cysteine and metallo protease.

[0101] With regard to protease inhibition, Cathepsin B is a lysosomal cysteine protease normally involved in proenzyme processing and protein turnover. Elevated levels of activity have been implicated in tumor metastasis (Sloane, B. F. et al., Cancer Metastasis Rev. 9:333-352, 1990), rheumatoid arthritis (Werb, Z. Textbook of Rheumatology, Keller, W. N.; Harris, W. D.; Ruddy, S.; Sledge, C. S., Eds., 1989, W. B. Saunder Co., Philadelphia, Pa., pp. 300-321), and muscular dystrophy (Katunuma and Kominami, Rev. Physiol. Biochem. Pharmacol. 108:1-20,1987).

[0102] Calpains are cytosolic or membrane bound Ca++-activated proteases which are responsible for degradation of cytoskeletal proteins in response to changing calcium levels within the cell. They contribute to tissue degradation in arthritis and muscular dystrophy (see Wang and Yuen Trends Pharmacol. Sci. 15:412-419,1994).

[0103] Interleukin Converting Enzyme (ICE) cleaves pro-IL-1 beta to IL-1 beta, a key mediator of inflammation, and therefore inhibitors of ICE may prove useful in the treatment of arthritis (see, e.g., Miller B. E. et al., J. Immunol. 154:1331-1338, 1995). ICE or ICE-like proteases may also function in apoptosis (programmed cell death) and therefore play roles in cancer, AIDS, Alzheimer's disease, and other diseases in which disregulated apoptosis is involved (see Barr and Tomei, Biotechnol. 12:487-493,1994).

[0104] HIV protease plays a key role in the life cycle of HIV, the AIDS virus. In the final steps of viral maturation it cleaves polyprotein precursors to the functional enzymes and structural proteins of the virion core. HIV protease inhibitors were quickly identified as an excellent therapeutic target for AIDS (see Huff, J. R., J. Med. Chem. 34:2305-2314) and have already proven useful in its treatment as evidenced by the recent FDA approval of ritonavir, Crixivan, and saquinavir.

[0105] Hepatitis C virus (HCV) is the major cause of non-A and non-B hepatitis in the world today. It is estimated to infect up to 50 million people. Currently there is no satisfactory treatment available to halt the progression of this debilitating disease. During the life cycle of the virus, a polyprotein of about 3000 amino acids is produced and is proteolytically cleaved by host and viral proteases to produce the mature viral gene products. A serine proteinase located within the HCV NS3 protein cleaves at four specific sites to produce non-structural proteins considered essential for viral replication. Hence, inhibitors of HCV protease are attractive targets for drug design, and could be of great therapeutic benefit. (Neddermann et al., Biol. Chem. 378:469-476,1997.)

[0106] Angiotensin converting enzyme (ACE) is part of the renin-angiotensin system which plays a central role in the regulation of blood pressure. ACE cleaves angiotensin I to the octapeptide angiotensin II, a potent pressor agent due to its vasoconstrictor activity. Inhibition of ACE has proved therapeutically useful in the treatment of hypertension (Williams, G. H., N. Engl. J. Med. 319:1517-1525, 1989).

[0107] Collagenases cleave collagen, the major constituent of the extracellular matrix (e.g., connective tissue, skin, blood vessels). Elevated collagenase activity contributes to arthritis (Krane et al., Ann. N.Y. Acad. Sci. 580:340-354,1990.), tumor metastasis (Flug and Kopf-Maier, Acta Anat. Basel 152:69-84,1995), and other diseases involving the degradation of connective tissue.

[0108] Trypsin-like serine proteases form a large and highly selective family of enzymes involved in hemostasis/coagulation (Davie and Fujikawa, Ann. Rev. 799-829,1975) and complement activation (Muller-Eberhard, Ann. Rev. Biochem. 44:697-724,1975). Sequencing of these proteases has shown the presence of a homologous trypsin-like core with amino acid insertions that modify specificity and which are generally responsible for interactions with other macromolecular components (Magnusson et al., Miami Winter Symposia 11:203-239,1976).

[0109] Thrombin, a trypsin-like serine protease, acts to provide limited proteolysis, both in the generation of fibrin from fibrinogen and the activation of the platelet receptor, and thus plays a critical role in thrombosis and hemostasis (Mann, K. G., Trends Biochem. Sci. 12:229-233,1987). Thrombin exhibits remarkable specificity in the removal of fibrinopeptides A and B of fibrinogen through the selective cleavage of only two Arg-Gly bonds of the one-hundred and eighty-one Arg- or Lys-Xaa sequences in fibrinogen (Blomback, Blood Clotting Enzymology, Seeger, W. H. (ed.), Academic Press, New York, 1967, pp.143-215).

[0110] Many significant disease states are related to abnormal hemostasis, including acute coronary syndromes. Aspirin and heparin are widely used in the treatment of patients with acute coronary syndromes. However, these agents have several intrinsic limitations. For example, thrombosis complicating the rupture of atherosclerotic plaque tends to be a thrombin-mediated, platelet-dependent process that is relatively resistant to inhibition by aspirin and heparin (Fuster et al., N. Engl. J. Med. 326:242-50,1992).

[0111] Thrombin inhibitors prevent thrombus formation at sites of vascular injury in vivo. Furthermore, since thrombin is also a potent growth factor which initiates smooth muscle cell proliferation at sites of mechanical injury in the coronary artery, inhibitors block this proliferative smooth muscle cell response and reduce restenosis. Thrombin inhibitors would also reduce the inflammatory response in vascular wall cells (Harker et al., Am. J. Cardiol. 75:122-16B, 1995).

[0112] Furthermore, at least two well-defined transcription factors, nuclear factor (NF) κB and activator protein (AP)-1, are regulated by the intracellular reduction-oxidation (redox) state. The regulation of gene expression by the redox state holds promising therapeutic implications. For example, binding sites of the redox-regulated transcription factors NF-κB and AP-1 are located in the promoter region of a large variety of genes that are directly involved in the pathogenesis of diseases, such as AIDS, cancer, atherosclerosis and diabetic complications (Sen and Packer, FASEB Journal 10:709-720,1996). More specifically, the binding of transcription factors such NF-κB and AP-1 to consensus sites on DNA is driven by oxidant-antioxidant homeostasis, especially by the thiol-disulfide balance.

[0113] In the case of NF-κB, a physiologically relevant thiol that plays a crucial role in the regulation of NF-κB function is reduced thioredoxin or a reduced thioredoxin-like protein. Thioredoxin is an important protein oxidoreductase with antioxidant functions. Thioredoxin has been found to upregulate DNA binding of activated NF-κB and thus augments gene expression (Schenk et al., Proc. Natl. Acad. Sci. USA 91:1672-1676,1994). Thioredoxin has been implicated in reducing activated cytosolic NF-κB (specifically reduction of cys-62), which may thus contribute to its nuclear translocation and DNA binding (Hayashi et at., J. Biol. Chem. 268:11380-11388,1993).

[0114] DNA binding activity of Fos and Jun in the AP-1 complex has also been found to be regulated by the redox state (Abate et al., Science 249:11571162,1990). Each protein contains a single conserved cysteine (flanked by lysine and arginine) in its DNA binding domain. This thiol does not appear to be part of a disulfide bond and may exist as a sulfenic or sulfinic acid in its oxidized form. Ref-1, a bifunctional nuclear protein also possessing endonuclease DNA repair activity, stimulates AP-1 DNA binding by reduction of this regulatory cysteine. A Fos mutant in which the critical cysteine was replaced with serine elicited a threefold increase in AP-1 DNA binding activity and was no longer subject to redox control (Okuno et al., Oncogene 8:695-701,1993). Hence, since at least four members of the fos family, 3 of the jun family, and at least 4 of the ATF/CREB family of transcription factors all contain this conserved cysteine, redox control of transcription factors appears widespread.

[0115] As mentioned above, the regulation of transcription factors such as NF-κB and AP-1 have important therapeutic implications. For example, AP-1 is an important mediator of tumor production (Yoshioka et al., Proc. Natl. Acad. Sci. USA 92:4972-4976, 1995). Thus, compounds that repress AP-1 transcriptional activity have utility in the treatment of cancer. Furthermore, due to its direct role in regulating responses to inflammatory cytokines and endotoxins, the activation of NF-κB plays an important role in the development of chronic diseases such as rheumatoid arthritis and acute conditions such as septic shock. Autoimmune diseases, such as systemic lupus erythromatus (SLE), and Alzheimer's disease are also believed involved in activation of NF-κB. Similarly, NF-κB plays an important role in the activation of HIV gene expression. Further conditions which are believed to involve NF-κB include the flu, atherosclerosis, oncogenesis and ataxia telangiectasia (AT).

[0116] Oxidoreductase Inhibition

[0117] With respect to regulation of transcription factors, the compounds of this invention regulate transcription factors whose ability to bind to DNA is controlled by reduction of a cysteine residue by a cellular oxidoreductase. In one embodiment, the transcription factor is NF-κB. In this embodiment, the compounds of this invention have activity as mediators of immune and/or inflammatory responses, or serve to control cell growth. In another embodiment, the transcription factor is AP-1, and the cellular oxidoreductase is Ref-1. In this embodiment, the compounds of this invention have activity as anti-inflammatory and/or anticancer agents. In yet further embodiments, the transcription factor is selected from Myb and glucocorticoid receptor. Other transcription factors that may be regulated within the context of this invention also include: those of the NF-κB family, such as Rel-A, c-Rel, Rel-B, p50 and p52; those of the AP-1 family, such as Fos, FosB, Fra-1, Fra-2, Jun, JunB and JunD; ATF; CREB; STAT-1, -2, -3, -4, -5 and -6; NFAT-1, -2 and -4; MAF; Thyroid Factor; IRF; Oct-1 and -2; NF-Y; Egr-1; and USF-43.

[0118] Accordingly, in one aspect the present invention provides a method for inhibiting an oxidoreductase in a warm-blooded animal, comprising administering to the animal an amount of a compound of the present invention, where the amount is effective to inhibit the oxidoreductase. Inhibition of oxidoreductase activity can be used as a means to regulate transcription.

[0119] CAAX Inhibition

[0120] In another aspect, the present invention provides a method for CAAX inhibition in a warm-blooded animal. The method comprises administering to the animal an amount of a compound of the present invention as described herein. The amount is effective to provide CAAX inhibition in the animal.

[0121] Ras, the protein product of the ras oncogene, is a membrane bound protein involved in signal transduction regulating cell division and growth. Mutations in the ras gene are among the most common genetic abnormalities associated with human cancers (Barbacid, M. Annu Rev Biochem 56:779-827, 1987). These mutations result in a growth signal that is always “on,” leading to a cancerous cell. In order to localize to the cell membrane, Ras requires prenylation of the cysteine within its C-terminal CAAX sequence by farnesyl transferase (FTase) where, in the sequence CAAX, “a” is defined as an amino acid with a hydrophobic side chain and “X” is another amino acid. This post-translational modification is crucial to its activity. Peptidyl inhibitors of FTase with the sequence CaaX have been shown to block or slow the growth of tumors in cell culture and in whole animals (Kohl et al., Science 260:1934-1937,1993; Buss and Marsters, Chemistry and Biology 2:787-791,1995).

[0122] Methods to screen for the activity of a compound to inhibit CAAX activity are known in the art. See, e.g., U.S. Pat. No. 6,391,574, which describes a method of identifying a compound which inhibits the proteolytic removal of an AAX tripeptide of a CAAX protein in a cell. See also U.S. Pat. No. 5,990,277, which discloses several suitable assays, and references Gibbs et al., Cell 77:175,1994; Gibbs, Cell 65:1,1991; Maltese, FASEB J. 4:3319,1990; Moores et al., J. Biol. Chem. 266:14603,1991; Goldstein et al., J. Biol. Chem. 266:15575,1991; European Patent 0 461 869 A2; Casey, J. Lipid Res. 33:1731-1740, 1992; Cox et al., Curr. Opin. Cell Biol. 4:1008-1016.1992; Garcia et al., J. Biol. Chem. 268:18415-18418,1993; Vogt et al., J. Biol. Chem. 270:660-664, 1995; Kohl et al., Science, 260:1934-1937, 1993; Garcia et al., J. Biol. Chem., 268:18415-18418,1993; and Vogt et al., J. Biol. Chem. 270:660-664,1995).

[0123] MHC Molecules

[0124] In another aspect, the present invention provides a method for inhibiting the binding of an antigenic peptide to either a class one or class two MHC molecule. The method comprises contacting a compound according to the present invention with a composition comprising an antigenic peptide and either a class one or class two MHC molecule. The compound is contacted with the antigen/molecule in an amount effective to reduce the binding affinity between the two species.

[0125] An important aspect of the immune system is the T cell response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens (“HLA”), or major histocompatibility complexes (“MHCs”), and peptides (see, e.g., Male et al., Advanced Immunology (J. P. Lipincott Company, 1987). Antigens mobilize an immune response, at least in part, by being ingested by an antigen-presenting cell (APC) which contains on its surface a Class II glycoprotein encoded by a gene in the major histocompatibility complex (MHC). The antigen is then presented to a specific T helper cell in the context of the surface bound MHC glycoprotein, and by interaction of the antigen specific T cell receptor with the antigen—MHC complex, the T helper cell is stimulated to mediate the antigen-specific immune response, including induction of cytotoxic T cell function, induction of B cell function, and secretion of a number of factors aiding and abetting this response. In one aspect of the invention, the MHC molecule is HLA-A2.1, HLA-A1 or HLA-A3.1, or any other HLA allele that is present in melanoma patients.

[0126] The ability of a compound of the present invention to bind to MHC I molecules can be demonstrated essentially as described by Elliot et al., Nature 351:402-406,1991. Similarly, the ability of a compound of the invention to bind to MHC II molecules can be demonstrated by the procedure of Kwok et al., J. Immunol. 155:2468-2476,1995.

[0127] Protein With 14-3-3 Domain

[0128] In another aspect, the present invention provides a method for inhibiting the binding of a first peptide to a second pepetide that comprises a 14-3-3 domain, where the first peptide has a binding affinity to the 14-3-3 domain of the second peptide. The method comprises contacting a compound of the present invention with a composition comprising a (first) peptide that has a binding affinity to the 14-3-3 domain of the second protein.

[0129] Proteins having the 14-3-3 domain, and binding partners thereof, have been described in the literature. These peptides may be used in the method of the present invention. See, e.g., Dai and Murakami, J Neurochem 2003 January 84(1):23-34; Lim et al., J Biol Chem Oct. 25, 2002, 277(43):40997-1008; Parvaresch et al., FEBS Lett Dec. 18, 2002, 532(3):357-62; Eilers et al., Mol Cell Biol 2002 December ;22(24):8514-26; Liu et al., Cancer Res Nov. 15, 2002, 62(22):6475-80; Truong et al., Proteins Nov. 15, 2002, 49(3):321-5; Birkenfeld et al., Biochem J Jan. 1, 2003, 369(Pt 1):45-54; Espejo et al., Biochem J Nov. 1, 2002, 367(Pt 3):697-702; and Benzing et al., J Biol Chem Sep. 6, 2002, 277(36):32954-62.

[0130] In the practice of the methods of this invention, a therapeutically effective amount of a compound of this invention is administered to a warm-blooded animal in need thereof. For example, the compounds of this invention may be administered to a warm-blooded animal that has been diagnosed with, or is at risk of developing, a condition selected from any one or more of Chrohn's disease, asthma, rheumatoid arthritis, ischemia, reperfusion injury, graft versus host disease (GVHD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, allograft rejection and adult T-cell leukemia.

[0131] Tuberous Sclerosis Complex

[0132] Patients having tuberous sclerosis complex (TSC) typically develop multiple focal lesions in the brain, heart, kidney and other tissues (see, e.g., Gomez, M. R. Brain Dev. 17(suppl):55-57,1995). Studies in mammalian cells have shown that overexpression of TSC1 (which expresses hamartin) and TSC2 (which expresses tuberin) negatively regulates cell proliferation and induces G,/S arrest (see, e.g., Miloloza, A. et al., Hum. Mol. Genet. 9:1721-1727, 2000). Other studies have shown that hamartin and tuberin function at the level of the β-catenin degradation complex, and more specifically that these proteins negatively regulate beta-catenin stability and activity by participating in the beta-catenin degradation complex (see, e.g., Mak, B. C., et al. J. Biol. Chem. 278(8):5947-5951, 2003). Beta-catenin is a 95-kDa protein that participates in cell adhesion through its association with members of the membrane-bound cadherin family, and in cell proliferation and differentiation as a key component of the Wnt/Wingless pathway (see, e.g., Daniels, D. L., et al., Trends Biochem. Sci. 26:672-678, 2001). Disruption of this pathway has been shown to be oncogenic in humans and rodents. The present invention provides compounds that modulate β-catenin activity, and particularly its interactions with other proteins, and accordingly may be used in the treatment of TSC.

[0133] The following examples are provided for purposes of illustration, not limitation.

EXAMPLES

[0134] In the Preparation Examples and Examples, the following abbreviations are used:

[0135] BMS: Boron dimethyl sulfide

[0136] CbzOSu: Benzyloxycarbonyl N-hydroxysuccinimide

[0137] DIC: 1,3-Diisopropylcarbodiimide

[0138] DIEA: N,N-Diisopropylethylamine

[0139] DIPEA: N,N-Diisopropylethylamine

[0140] DMAP: N,N-Dimethylaminopyridine

[0141] DMF: Dimethylformamide

[0142] DMSO: Dimethyl sulfoxide

[0143] EA: Ethyl acetate

[0144] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0145] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0146] FmocOsu: 9-Fluorenyloxycarbonyl N-hydroxysuccinimide

[0147] HATU: [2-(1H-9-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate]

[0148] Hex.: Hexane

[0149] HOBT: N-Hydroxybenzotriazole

[0150] MC: Methylene chloride

[0151] MeOH: Methanol

[0152] -OBn:—O-benzyl

[0153] PPTS: Pyridinium p-toluenesulfonate

[0154] PyBOP: Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate

[0155] p-TsOH: p-Toluenesulfonic acid

[0156] THF: Tetrahydrofuron

[0157] TLC: Thin Layer Chromatography

Preparative Example 1

(1) PREPARATION OF NAPHTHALENE-2-CARBOXYLIC ACID AMIDE

[0158] 22

[0159] To a solution of 2-naphthoic acid (25 g, 0.145 mol) in MC (200 ml), oxalyl chloride (38 ml, 0.4356 mol) and a catalytic amount of DMF were added and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was diluted with MC (200 ml), to which a solution of ammonium hydroxide in water (160 ml) was dropwise added at an ice bath temperature. After stirring for 1 hr, the precipitated product was collected by suction filtration, triturated in hexane and dried to obtain the title compound, which was used next step without further purification.

(2) PREPARATION OF NAPHTHALENE-2-YL-METHYLAMINE

[0160] 23

[0161] To a solution of the crude amide obtained in the above step (1) in THF (100 ml), BMS (27.5 ml, 0.2904 mol) was slowly added at 0° C. The resulted reaction mixture was heated to 60° C. for 3 hrs, quenched with 5% HCl at 0° C., extracted with EA and washed with 5% HCl. The aqueous layers were combined and basified with 1N NaOH, and again extracted with EA. The organic layers were combined and concentrated to give the title compound (13 g) as white solid.

[0162] TLC System 1: MC/MeOH=90:10 v/v; Rf=0.23

[0163] 1 H-NMR (300 MHz, CDCl3) δ ppm: 4.07(s, 2H), 7.48 (m, 3H), 7.79 (m, 4H)

Preparative Example 2

(1) PREPARATION OF 1H—INDOLE-2-CARBOXYLIC ACID AMIDE

[0164] 24

[0165] To a solution of indole-2-carboxylic acid (1 g, 6.21 mmol) in MC (30 ml), oxalyl chloride (1.64 ml, 0.18.62 mmol) and a catalytic amount of DMF were added and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was diluted with MC (20 ml), to which a solution of ammonium hydroxide in water (7 ml) was dropwise added with cooling in an ice bath. After stirring for 1 hr, the precipitated product was collected by suction filtration, triturated in hexane and dried to give the title compound, which was used in the next step without further purification.

(2) PREPARATION OF (1H—INDOL-2-YL)-METHYLAMINE

[0166] 25

[0167] To a solution of the crude amide obtained in the above step (1) in THF (30 ml), BMS (1.18 ml, 12.42 mmol) was slowly added at 0° C. The resulting reaction mixture was heated to 60° C. for 3 hrs, quenched with 5% HCl at 0° C., extracted with EA, and washed with 5% HCl. The aqueous layers were combined and basified with 1N NaOH, and again extracted with EA. The organic layers were combined and concentrated to obtain the title compound (0.28 g) as yellow oil.

[0168] TLC System 1: MC/MeOH=90:10 v/v; Rf=0.15

[0169] 1 H-NMR (300 MHz, CDCl3) δ ppm: 3.98(s, 2H), 7.08 (m, 3H), 7.26 (m, 1H), 7.58(d, 1H), 9.10(brs, 1H)

Preparative Example 3

(1) PREPARATION OF 2-BENZYLOXYCARBONYLAMINO-4-OXO-BUTYRIC ACID BENZYL ESTER

[0170] 26

[0171] To a solution of Z-Asp-OBn (10 g, 0.028 mol) in MC (200 ml), oxalyl chloride (2.93 ml, 0.0336 mol) and a catalytic amount of DMF were added at 0° C. and stirred at room temperature for 2 hrs. After the solvent was evaporated, the crude acyl chloride was dissolved in benzene (400 ml), and tributyltin hydride (15.1 ml, 0.056 mol) and a catalytic amount of Pd(0) were added slowly at 0° C. and stirred at room temperature overnight. After the solvent was evaporated, ether (100 ml)/10% KF in water (100 ml) was added and stirred at room temperature for 2 hrs, followed by filtration to give a biphasic solution. The organic layer was separated and concentrated to give a crude product, which was purified by column chromatography to obtain the title compound, Z-Asp-OBn aldehyde (6 g) as pale-yellow oil.

[0172] Rf: 0.29 in Hexane/EA (2/1)

(2) PREPARATION OF 2-BENZYLOXYCARBONYLAMINO-4,4-DIMETHOXY-BUTYRIC ACID BENZYL ESTER

[0173] 27

[0174] To a solution of Z-Asp-OBn aldehyde (6 g, 17.58 mmol) obtained in the above step (1) in MeOH (100 ml), a catalytic amount of p-TsOH was added and stirred at room temperature for 5 hrs. After the reaction was complete, the solvent was evaporated to give a crude product, which was purified by column chromatography to obtain the title compound, Z-Asp-OBn acetal, (5 g) as pale-yellow oil.

[0175] Rf: 0.32 in Hexane/EA (2/1)

(3) PREPARATION OF 2-BENZYLOXYCARBONYLAMINO-4,4-DIMETHOXY-BUTYRIC ACID

[0176] 28

[0177] The Z-Asp-OBn acetal (0.5 g, 1.29 mmol) obtained in the above step (2) was dissolved in THF (20 ml)/NaOH (0.11 g, 2.1 mmol) in water (20 ml) and stirred at room temperature for 30 min. After the starting material had disappeared completely, the reaction mixture was concentrated by evaporation and then diluted with water/EA. The aqueous layer was separated, acidified very carefully to pH 4-5 with 1N HCl at 0° C., and again extracted with EA. The organic layers were combined and concentrated to obtain the title compound, Z-Asp-OBn acetal, (0.27 g) as pale-yellow oil.

[0178] TLC System 1: Hexane/EA=20:10 v/v; Rf=0.10

[0179] 1 H-NMR (300 MHz, CDCl3) δ ppm: 2.20(s, 2H), 3.35(d, 6H), 4.52 (m, 2H), 5.19(t, 2H), 5.80(d, 1H), 7.37(brs, 5H)

(4) PREPARATION OF 2-AMINO-4,4-DIMETHOXY-BUTYRIC ACID

[0180] 29

[0181] In a reaction vessel equipped with a hydrogen gas balloon, a solution of the Z-Asp-OBn acetal (2.22 g, 5.73 mmol) obtained in the above step (3) in acetic acid (20 ml) and Pearlman's catalyst was added and stirred at room temperature overnight. The resulting reaction mixture was filtered, concentrated and lyophilized to give a crude product, which was used in the next step without further purification.

(5) PREPARATION OF 2-(9H-FLUOREN-9-YLMETHOXYCARBONYLAMINO)-4,4-DIMETHOXY-BUTYRIC ACID

[0182] 30

[0183] To a solution of the crude Asp-OH acetal obtained in the above step (4) in THF (100 ml)/water (100 ml), FmocOsu (2.13 g, 6.3 mmol)/sodium bicarbonate (1.93 g, 22.92 mmol) was added and stirred at room temperature overnight. The resulting reaction mixture was concentrated and diluted with water/EA. The aqueous layer was separated, acidified very carefully to pH 4-5 with 1N HCl at 0° C., and again extracted with EA. The organic layers were combined and concentrated to give a crude product, which was purified by column chromatography to obtain the title compound (1.5 g) as a foamy solid.

[0184] Rf: 0.15 in Hexane/EA (2/1)

Preparative Example 4

(1) PREPARATION OF 2-BENZYLOXYCARBONYLAMINO-PENTADIOIC ACID

[0185] 31

[0186] To a solution of L-glutamic acid (20 g, 136 mmol) in water/THF (1/1, 400 ml), sodium bicarbonate (45.7 g, 544 mmol) was added and cooled to 0° C. in an ice bath. To the reaction mixture, CbzOSu (37.3 g, 150 mmol) was added and stirred overnight at room temperature. After the reaction was completed, the resulting reaction mixture was extracted with EA. The aqueous layer was separated, acidified to pH 2 with conc. HCl at 0° C., and again extracted with EA (4 times). The organic layers were concentrated to give a crude product, which was purified by column chromatography to obtain the title compound (16 g) as colorless oil.

[0187] Rf: 0.2 in MC/MeOH (9/1)

(2) PREPARATION OF 4-(2-CARBOXY-ETHYL)-5-OXO-OXAZOLIDINE-3-CARBOXYLIC ACID BENZYL ESTER

[0188] 32

[0189] In a Dean-Stark apparatus, N-Cbz-L-glutamic acid (4 g, 14.22 mmol) obtained in the above step (1), paraformaldehyde (5 g), a catalytic amount of pTsOH, molecular sieves (5 g), and toluene (100 ml) were placed and refluxed until the starting material disappeared. The resultant reaction mixture was cooled to room temperature, filtered and concentrated to give a crude product, which was purified by column chromatography to obtain the title compound (2 g) as colorless oil.

[0190] Rf: 0.45 in only EA

(3) PREPARATION OF 5-OXO-5-(3-OXO-PROPYL)-OXAZOLIDINE-3-CARBOXYLIC ACID BENZYL ESTER

[0191] 33

[0192] To a solution of the di-protected glutamic acid (2 g, 6.82 mmol) obtained in the above step (2) in MC (200 ml), oxalyl chloride (0.7 ml, 7.5 mmol) and a catalytic amount of DMF were added at 0° C. and stirred at room temperature for 2 hrs. After the solvent was evaporated, the resultant crude acyl chloride was dissolved in THF (400 ml), to which tributyltin hydride (3.86 ml, 14.34 mmol) and a catalytic amount of Pd (0) were slowly added at 0° C. and stirred at room temperature overnight. After the solvent had been evaporated, ether (100 ml)/10% KF in water (100 ml) was added and stirred at room temperature for 2 hrs, followed by filtration to give a biphasic solution. The organic layer was separated and concentrated to give a crude product, which was purified by column chromatography to obtain the title compound (0.7 g) as colorless oil.

[0193] Rf: 0.23 in hexane/EA (4/1)

(4) PREPARATION OF 4-(3,3-DIMETHOXY-PROPYL)5-OXO-OXAZOLIDINE-3-CARBOXYLIC ACID BENZYL ESTER

[0194] 34

[0195] To a solution of di-protected aldehyde (0.7 g, 2.53 mmol) obtained in the above step (3) in MeOH (30 ml), a catalytic amount of pTsOH was added and stirred at room temperature for 7 hrs. After the reaction was complete, the reaction mixture was concentrated by evaporation of solvent to give a crude product, which was purified by column chromatography to obtain the title compound (0.5 g) as colorless oil.

[0196] Rf: 0.33 in Hexane/EA (4/1)

(5) PREPARATION OF 2-BENZYLOXYCARBONYLAMINO-5,5-DIMETHOXY-PENTANOIC ACID

[0197] 35

[0198] The diprotected acetal (0.456 g, 1.411 mmol) obtained in the above step (4) was dissolved in MeOH (20 ml)/1N NaOH (10 ml) and stirred at room temperature overnight. After the starting material had disappeared completely, the reaction mixture was concentrated by evaporation of solvent and diluted with water/EA. The aqueous layer was separated, acidified very carefully to pH 4-5 with 1N HCl at 0° C., and again extracted with EA. The organic layers were combined and concentrated to obtain the title compound (0.35 g) as colorless oil.

[0199] Rf: 0.1 in Hexane/EA (1/1)

(6) PREPARATION OF 2-AMINO-5,5-DIMETHOXY-PENTANOIC ACID

[0200] 36

[0201] In a reaction vessel equipped with a hydrogen gas balloon, a solution of the Cbz-acetal (0.35 g, 1.13 mmol) obtained in the above step (5) in MeOH (10 ml) and a catalytic amount of 10% Pd/C was added and stirred at room temperature overnight. The resultant reaction mixture was filtered and concentrated to give a crude product (0.2 g) as colorless oil, which was used in the next step without further purification.

[0202] Rf: 0.01 in Hexane/EA (1/1)

(7) PREPARATION OF 2-(9H-FLUOREN-9-YLMETHOXYCARBONYLAMINO)-5,5-DIMETHOXY-PENTANOIC ACID

[0203] 37

[0204] To a solution of the crude Glu-OH acetal obtained in the above step (6) in THF (10 ml)/water (10 ml), FmocOsu (0.42 g, 1.24 mmol)/sodium bicarbonate (0.5 g, 5.9 mmol) was added and stirred at room temperature overnight. After solvent was evaporated, the resultant reaction mixture was diluted with water/EA. The aqueous layer was separated and acidified very carefully to pH 4-5 with 1N HCl at 0° C., and again extracted with EA. The organic layers were combined and concentrated to obtain the title compound (0.19 g) as colorless oil.

[0205] TLC System 1: only EA; Rf=0.25

[0206] 1 H-NMR (300 MHz, CDCl3) δ ppm: 1.75(br m, 4H), 3.28(d, 6H), 3.43(q, 1H), 4.20(t, 1H), 4.38 (m, 3H), 5.62(d, 1H), 7.31 (m, 4H), 7.65(d, 2H), 7.75(d, 2H)

Preparative Example 5

(1) PREPARATION OF 2-TERT-BUTOXYCARBONYLAMINO-4-METHOXYCARBONYL-AMINO-BUTYRIC ACID

[0207] 38

[0208] To a solution of Boc-Dab-OH (3 g, 13.75 mmol) in H2O (50 mL), NaOH (2.75 g, 68.75 mmol, 5 equiv.) was slowly added until pH>11, to which methyl chloroformate (2.6 g, 27.5 mmol, 2 equiv.) in toluene (50 mL) was added. The resultant reaction mixture was stirred for 2 hrs. For the TLC checking, a small amount of aqueous phase was taken out and acidified with 1N HCl. After confirming the reaction completion by TLC, the organic phase was separated and the aqueous phase was acidified with 10% HCl solution and extracted by EA (5 mL X 2). The organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give a crude product (3.277 g, 11.86 mmol, 86%) as a colorless oil.

[0209] TLC System: EA only; Rf=0.2

[0210] 1 H-NMR (300 MHz, CDCl3) δ ppm: 1.30˜1.50 (bs, 9H), 2.00˜2.30 (m, 2H), 3.10˜3.30 (m, 2H), 3.70 (bs, 3H), 4.35 (m, 1H), 5.40 (m, 1H), 5.65 (bs, 1H).

(2) PREPARATION OF (1-BENZYLCARBAMOYL-3-METHOXYCARBONYLAMINO-PROPYL)CARBAMIC ACID TERT-BUTYL ESTER

[0211] 39

[0212] To a solution of 2-tert-Butoxycarbonylamino-4-methoxycarbonylamino-butyric acid (1.1 g, 3.98 mmol) obtained in the above step (1) in DMF (20 mL), EDCI (763 mg, 3.98 mmol, 1 equiv.), HOBT (538 mg, 3.98 mmol, 1 equiv.) and DIEA (1.4 mL, 7.96 mmol, 2 equiv.) were added at 5° C. and stirred for 1 day. After the confirming the reaction completion by the TLC checking, the reaction solution was acidified by 10% HCl at 5° C. (until pH ˜4) and extracted by EA (20 mL). The organic phases were combined and washed with sat NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated in vacuum to give a residue, which was solidified by adding EA and n-Hexane and purified by column chromatography to obtain the title compound (620 mg, 1.7 mmol, 43%) as a white solid.

[0213] Rf=0.7 (EA)

[0214] 1 H-NMR (300 MHz, CDCl3) δ ppm: 1.45 (bs, 9H), 1.75˜2.10 (m, 2H), 3.05 (m, 1H), 3.45 (m, 1H), 3.65 (s, 3H), 4.25 (m, 1H), 4.45 (d, 2H, J=5.7 Hz), 5.45 (m, 1H), 7.05 (m, 1H), 7.20˜7.45 (m, 5H).

(3) PREPARATION OF (3-AMINO-3-BENZYLCARBONYL-PROPYL)-CARBAMIC ACID TERT-BUTYL ESTER HYDROCHLORIDE

[0215] 40

[0216] To a solution of (1-Benzylcarbamoyl-3-methoxycarbonylamino-propyl)-carbamic acid tert-butyl ester (1 g, 2.7 mmol) obtained in the above step (2) in 1,4-dioxane (10 mL), 4N HCl in 1,4-dioxane (6.8 mL, 27 mmol) were added and stirred for 2 hours. After the confirming the reaction completion by the TLC checking, the reaction solution was concentrated and dried in vacuum to afford the title compound as a white solid.

Example 1

1-BENZYL-7-METHYL-6-THIOXO-HEXAHYDRO-PYRIMIDO[1,6-A]PYRIMIDIN-2-ONE

[0217] (A) Preparation of N-benzyl-3-[3-(2-[1,3]dioxolan-2-yl-ethyl)-3methyl-thioureido]-propionamide 41

[0218] A suspension of β-alanine benzylamido hydrochloride (1.0 eq) and N-methylmorpholine (2.2 eq) in dichloromethane was treated with thiophosgene (1.2 eq) at 0° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for additional 2 hrs. The clear solution was diluted with ethyl acetate and washed with 10% KHSO4 solution, distilled water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue.

[0219] This product was dissolved in dichloromethane and treated with 2-(N-methyl-2aminoethyl)-1,3-dioxolane (0.9 eq) at 0° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for additional 4 hrs. The reaction was diluted with ethyl acetate and washed with 10% KHSO4 solution, distilled water, sat. NaHCO3 solution, distilled water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue. This crude product was purified by column chromatography (silica gel, ethyl acetate/hexane=5/2) to give the pure product.

[0220] 1 H-NMR (500 MHz, CDCl3) δ ppm; 2.02 (m, 2H), 2.60 (m, 2H), 3.18 (s, 3H), 3.82 (m, 2H), 3.88 (m, 2H), 4.03 (m, 4H), 4.44 (m, 2H), 4.91 (m, 1H), 6.84 (br.s, 1H), 7.25-7.38 (m, 5H);

[0221] MS (m/z, ESI), 352 (MH+)

[0222] (B) Preparation of 1-benzyl-7-methyl-6-thioxo-hexahydro-pyrimido[1,6-a]pyrimidin-2-one 42

[0223] Amide obtained in the above step (A) was treated with formic acid at 60° C. for 4 days. After evaporation of formic acid under reduced pressure, the residue was purified by preparative TLC (silica gel, ethyl acetate/methanol=5/1) to give the pure title product.

[0224] 1 H-NMR (500 MHz, CDCl3) δ ppm: 2.05 (m, 1H), 2.36 (m, 1H), 2.64(d, 1H), 2.96 (m, 1H), 3.30 (m, 3H), 3.44(s, 3H), 4.42(d, 1H), 4.86(br.s, 1H), 5.08(d, 1H), 5.49 (m, 1H) 7.25-7.38 (m, 5H);

[0225] MS (m/z, ESI), 290 (MH+), 311 (M+Na)

Example 2

1,7-DIBENZYL-6-THIOXO-HEXAHYDRO-PYRIMIDO[1,6-A]PYRIMIDIN-2-ONE

[0226] (A) Preparation of N-benzyl-3-[3-benzyl-(3,3-diethoxy-propyl)-thioureido]propionamide 43

[0227] A suspension of α-alanine benzylamido hydrochloride (1.0 eq) and N-methylmorpholine (2.2 eq) in dichloromethane was treated with thiophosgene (1.2 eq) at 0° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for additional 2 hrs. The clear solution was diluted with ethyl acetate and washed with 10% KHSO4 solution, distilled water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue. This product was dissolved in dichloromethane and treated with 2(N-benzyl-1-amino-3,3-diethoxy propane (0.9 eq) at 0° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for additional 6 hrs. The resulting reaction mixture was diluted with ethyl acetate and washed with 10% KHSO4 solution, distilled water, sat. NaHCO3 solution, distilled water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue. This crude product was purified by column chromatography (silica gel, ethyl acetate/hexane=2/1) to give the pure title product.

[0228] 1 H-NMR (400 MHz, CDCl3) δ ppm; 1.22(t, 6H), 1.95 (m, 2H), 2.60 (m, 2H), 3.46 (m, 2H), 3.60(br. t, 2H), 3.63 (m, 2H), 3.97 (m, 2H), 4.38 (m, 2H), 4.52 (m, 1H), 5.07((br.s, 2H), 6.16(br.s, 1H), 6.98(br.s, 1H), 7.25-7.38 (m, 10H); MS (m/z, ESI), 458(MH+)

[0229] (B) Preparation of 1,7-dibenzyl-6-thioxo-hexahydro-pyrimido[1,6-a]pyrimidin-2-one 44

[0230] Amide obtained in the above step (A) was treated with formic acid at 60° C. for 4 days. After evaporation of formic acid under reduced pressure, the residue was purified by preparative TLC (silica gel, ethyl acetate/methanol=5/1) to give the pure product.

[0231] 1 H-NMR (500 MHz, CDCl3) δ ppm: 1.94 (m, 1H), 2.24 (m, 1H), 2.62 (m, 1H), 3.01 (m, 1H), 3.18 (m, 1H), 3.43 (m, 1H), 3.62 (m, 1H), 4.39(d, 1H), 4.51 (m, 1H), 4.91 (m, 1H), 5.02(d, 1H), 5.26(d, 1H), 5.53 (m, 1H), 7.25-7.40 (m, 10H);

[0232] MS (m/z, APCI), 366(MH+)

Example 3

[0233] 1,7-DIBENZYL-HEXAHYDRO-PYRIMIDO[1,6-A]PYRIMIDIN-2,6-DIONE

[0234] (A) Preparation of N-benzyl-3-[3-benzyl-(3,3-diethoxy-propyl)-thioureido]-propionamide 45

[0235] A suspension of β-alanine benzylamido hydrochloride (1.0 eq) and N-methylmorpholine (3.2 eq) in dichloromethane was treated with triphosgene (0.7 eq) at 0° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for additional 2 hrs. The clear solution was diluted with ethyl acetate and washed with 10% KHSO4 solution, distilled water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue. This product was dissolved in dichloromethane and treated with 2-(N-benzyl-1-amino3,3-diethoxy propane (0.9 eq) at 0° C. for 10 min. The reaction mixture was allowed to warm to room temperature and stirred for additional 4 hrs. The resulted reaction mixture was diluted with ethyl acetate and washed with 10% KHSO4 solution, distilled water, sat. NaHCO3 solution, distilled water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue. This crude product was purified by column chromatography (silica gel, ethyl acetate/hexane=2/1) to give the pure title product.

[0236] 1 H-NMR (400 MHz, CDCl3) δ ppm: 1.23(t, 6H), 1.87 (m, 2H), 2.55 (m, 2H), 3.24 (m, 2H), 3.49 (m, 2H), 3.59 (m, 2H), 3.65 (m, 2H), 4.45-4.58 (m, 5H), 5.62(br.s, 1H), 6.57(br.s, 1H), 7.25-7.48 (m, 10H);

[0237] MS (m/z, ESI), 442(MH+)

[0238] (B) Preparation of 1,7-dibenzyl-hexahydro-pyrimido[1,6-a]pyrimidin-2,6-dione 46

[0239] Amide obtained in the above (A) was treated with formic acid at 60° C. for 4 days. After evaporation of formic acid under reduced pressure, the residue was purified by preparative TLC (silica gel, ethyl acetate) to give the titled compound.

[0240] 1 H-NMR (400 MHz, CDCl3) δ ppm; 1.89 (m, 1H), 2.19 (m, 1H), 2.58 (m, 1H), 2.75 (m, 1H), 3.02 (m, 3H), 4.42(d, J=12.4 Hz, 1H), 4.55(d, J=2.4 Hz, 2H), 4.65 (m, 1H), 4.78 (m, 1H), 4.98(d, J=12.4 Hz, 1H), 7.25-7.38 (m, 10H);

[0241] MS (m/z, ESI), 350(MH+)

Example 4

1,7-DIBENZYL-6-OXO-OCTAHYDRO-PYRIMIDO[1,6-A]PYRIMIDIN-2-ONE

[0242] (A) Preparation of (3-Bromo-1-methoxypronpan-1-oxy)-Linked ArgoGel Resin 47

[0243] A suspension of dry ArgoGel resin and pyridinium para-toluensulphonate (240 mg, 0.96 mmol) in 1,2-dichloroethane (15 mL) was heated to reflux while continuously removing the solvent and traces of water. After removing about 5 mL of the distillate, a solution of 3-bromo-1,1-dimethoxypropane (700 mg, 3.84 mmol) in 1,2-dichloroethane (5 mL) was added and the mixture was kept at reflux for 4h with continuous removal of EtOH/EDC, after which the resin was washed with DMF and dioxane followed by lyophilization to give the desired product.

[0244] (B) Preparation of (3-benzylamino-1-methoxypropan-1-oxy)-linked ArgoGel Resin 48

[0245] A solution of benzyl amine (520 mg, 4.85 mmol) in DMSO (4 mL) was added to the bromoacetal resin (1 g, 0.48 mmol) and the suspension was shaken at 60° C. for 15 hrs. The resulted resin was filtered, washed with DMSO, MeOH and MC, and dried in vacuo overnight. The secondary amine was detected by chloranil test.

[0246] (C) Preparation of β-alanine Benzyl Amine Urea 49

[0247] To a solution of β-alanine benzyl amide HCl (80 mg, 0.36 mmol) in N-methyl morpholine (120 μi) and MC (2 mL), triphosgene (0.72 mmol) was added at room temperature. After 10 minutes, the resulted isocyanate solution was added to a suspension of the secondary amine resin obtained in above step (2) (100 mg, 0.048 mmol) and kept shaking for 3 hrs at room temperature. The resin was washed with DMF, MeOH and MC, and the completion of reaction was checked with chloranil test.

[0248] (D) Preparation of 1,7-dibenzyl-6-oxo-octahydro-pyrimido[1,6-a]pyrimidin-2-one 50

[0249] The thiourea group-containing resin of step (C) was treated with formic acid and kept shaking for 15 hrs. The resin was filtered off and the filtrate was concentrated and purified by chromatography (silica gel) to obtain the title compound.

[0250] 1 H-NMR (500 MHz, CDCl3) δ ppm: 1.94 (m, 1H), 2.24 (m, 1H), 2.62 (m, 1H), 3.01 (m, 1H), 3.18 (m, 1H), 3.43 (m, 1H), 3.62 (m, 1H), 4.39(d, 1H), 4.51 (m, 1H), 4.91 (m, 1H), 5.02(d, 1H), 5.26(d, 1H), 5.53 (m, 1H), 7.25-7.40 (m, 1 OH);

[0251] MS (m/z, APCI), 366(MH+)

Example 5

1,7-DIBENZYL-2-OXO-6-THIOXO-OCTAHYDRO-PYRIMIDO[1,6-A]PYRIMIDINE-4-CARBOXYLIC ACID BENZYL ESTER

[0252] (A) Preparation of 2-isothiocyanato-succinic Acid 1-benzyl Ester 4-(9H-fluoren-9-ylmethyl) Ester 51

[0253] To a solution of 2-tert-butoxycarbonylamino-succinic acid 1-benzyl ester (1 g, 3.09 mmol) in MC, DIC (532 μl, 1.1 eq), DMAP (188 mg, 0.5 eq) and fluorenyl methanol (635 mg, 1.05 eq) were added. After the reaction was completed, the resultant reaction mixture was washed with 1N HCl and sat. NaHCO3 solution, and purified by column chromatography (silica gel) to obtain the fluorenyl methyl ester (400 mg).

[0254] This ester was diluted in dioxane (10 ml) and a 4N HCl solution of dioxane was added and kept stirring for 2 hrs to remove the Boc protection group. After completion of the reaction, the solution was evaporated to dryness. The HCl salt of the amine was diluted with MC and N-methyl morpholine, and thiophosgene (1.2 eq) was added at ca. 0° C. After the reaction was complete, the mixture was washed with 10% KHSO4 solution, distilled water, sat. NaHCO3 solution, distilled water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue. This crude product was purified by column chromatography (silica gel, ethyl acetate/hexane=1/1) to give the pure title product.

[0255] (C) Aspartic Acid Benzyl, Fluorenyl Ester Thiourea 52

[0256] A MC solution of the isocyanate (0.5 mmol) obtained in the above step (A) with N-methyl morpholine was added to a suspension of the secondary amine resin (200 mg, 0.04 mmol) as obtained in step (B) of Example 4 and kept shaking for 3 hrs at room temperature. The resultant resin was washed with DMF, MeOH and MC, and the completion of reaction was checked with chloranil test.

[0257] (C) Aspartic Acid Thiourea Benzylamide 53

[0258] The resin obtained in the above step (C) was swelled for 30 min in DMF (4 mL), and a 25% piperidine solution was added to cleave the fluorenyl methyl protection. The resultant resin was washed with DMF, MeOH and MC. The resin was dried under reduced pressure and swelled again, to which DIC (8 μL, 0.05 mmol), HOBt (8 mg, 0.05 mmol) and DIEA (18 μL, 0.1 mmol) were added to activate the acid. After shaking for 30 min, benzyl amine was added and kept shaking overnight to obtain the desired benzyl amide resin.

[0259] (D) Preparation of 1,7-dibenzyl-2-oxo-6-thioxo-octahydro-pyrimido[1,6-a]pyrimidine-4-carboxylic Acid Benzyl Ester 54

[0260] The resin obtained in the above step (C) was swelled in MC (4 mL), to which PPTS (10 mg) was added and heated for 4 hrs at 60° C. to obtain the title compound. MS (m/z, ESI), 500 (MH+).

Example 6

7-BENZYL-6-THIOXO-HEXAHYDRO-PYRIMIDO[1,6-A]PYRIMIDINE-1-CARBOXYLIC ACID BENZYL ESTER

[0261] (A) Preparation of {3-[3-benzyl-3-(3,3-d iethoxy-propyl)-thioureido]-propyl}-carbamic Acid Benzyl Ester 55

[0262] A suspension of Cbz-diamino propane HCl (1.0 eq) and N-methylmorpholine (2.2 eq) in MC was treated with thiophosgene (1.2 eq) at 0° C. for 10 min. The resulting solution was allowed to warm to room temperature and stirred for additional 2 hrs. The resulting clear solution was diluted with ethyl acetate and washed with 10% KHSO4, water, and sat. NaCl. The organic layer was dried over Na2SO4 and concentrated to give an oily residue, which was dissolved in MC and treated with N-benzyl-1-amino-3,3-diethoxy propane (0.9 eq) at 0° C. for 10 min, and then allowed to warm to room temperature and stirred for additional 6 hrs. The resulting reaction mixture was diluted with ethyl acetate and washed with 10% KHSO4 solution, water, sat. NaHCO3, water, and sat. NaCl. The organic layer was dried over Na2SO4 and concentrated to give an oily residue, which was then purified by column chromatography (silica gel, ethyl acetate/hexane, 2/1) to give the title compound.

[0263] 1 H-NMR (400 MHz, CDCl3) δ ppm: 1.17 (t, 6H), 1.5 (bs, 2H), 1.75(t, 2H), 1.92 (m, 2H), 3.20 (q, 2H), 3.45 (m, 2H), 3.60 (m, 4H), 3.75 (q, 2H), 4.51 (t, 1H), 5.06 (s, 4H), 6.75 (br.s, 1H), 7.25-7.38 (m, 10H);

[0264] MS (m/z, ESI), 442 (M-OEt+).

[0265] (B) Preparation of 7-Benzyl-6-thioxo-hexahydro-pyrimido[1,6-a]pyrimidine-1-carboxylic Acid Benzyl Ester 56

[0266] To a solution of the amide obtained in the above step (A) in MC, PPTS was added and stirred at 70° C. overnight. The resulting reaction mixture was concentrated under a reduced pressure to give a residue, which was purified by preparative TLC (ethyl acetate only) to obtain the title compound.

[0267] 1 H-NMR (400 MHz, CDCl3) δ ppm: 1.89 (m, 2H), 1.95 (m, 1H), 2.63 (m, 1H), 2.80 (m, 1H), 3.10 (m, 1H), 3.45 (m, 1H), 3.89 (m, 1H), 4.01 (m, 1H), 4.39(d, 1H), 4.51 (m, 1H), 4.92 (m, 2H), 5.10 (m, 2H), 7.16-7.4 (m, 10H);

[0268] MS (m/z, ESI): 396(MH+)

Example 7

8-ACETYL-6-OXO-HEXAHYDRO-PYRAZINO[1,2-A]PYRIMIDINE-1-CARBOXYLIC ACID BENZYL ESTER

[0269] (A) Preparation of [acetyl-(2,2-dimethoxy-ethyl)-amino]-acetic Acid 57

[0270] To a solution of benzyl glycine HCl salt (1 eq) in MeOH, dimethoxy acetaldehyde (1.05 eq) and then NaCNBH3 (1.2 eq) were added at room temperature and stirred for 5 hrs. The resulting reaction mixture was concentrated under reduced pressure to give an oily residue, which was dissolved in MC and washed with sat. NaHCO3 solution, water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue, which was dissolved in MC and treated with triethyl amine (3eq) and acetyl chloride (1.1eq) at 0° C.

[0271] After the reaction was complete, the resulting reaction mixture was washed with sat. NaHCO3 solution, water, and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated to give an oily residue, which was purified by column chromatography (silica gel, ethyl acetate) to give the pure product. This product was hydrogenolyzed with 10% Pd/C and an H2-containing balloon to obtain the title compound, which was used in the next step without further purification.

[0272] 1 H-NMR (400 MHz, CDCl3) δ ppm: 2.09(s, 1H), 2.20 (s, 2H), 3.40 (d, 6H), 3.48 (d, 2H), 4.16 (s, 2H), 4.44 (m, 1H)

[0273] (B) Preparation of (3-{2-[acetyl-(2,2-dimethoxy-ethyl)-amino]-acetylamino}-propyl)-carbamic Acid Benzyl Ester 58

[0274] To a solution of the acid (1 eq) obtained in the above step (A) in MC, HATU (1 eq), DIPEA (3 eq) and Cbz-diamino propane HCl (1.0 eq) were added and stirred for 3 hrs at room temperature. The reaction mixture was concentrated under a reduced pressure to give an oily residue, which was purified by preparative TLC to obtain the title compound.

[0275] 1 H-NMR (400 MHz, CDCl3) δ ppm: 1.60 (m, 2H), 2.01(s, 1H), 2.20 (s, 2H), 3.20(d, 2H), 3.24 (m, 2H), 3.40 (d, 6H), 3.50(d, 2H), 4.06 (s, 2H), 4.44 (m, 1H), 5.08(s, 2H), 5.18(d, 1H), 6.91(brd, 1H), 7.16(brs, 5H);

[0276] MS (m/z, ESI): 396(MH+)

[0277] (C) Preparation of 8-acetyl-6-oxo-hexahydro-pyrazino[1,2-a]pyrimidine-1-carboxylic Acid Benzyl Ester 59

[0278] To a solution of the Cbz protected amide precursor obtained in the above step (B) in MC, PPTS (1 eq.) was added at room temperature and heated to 70° C. for 5 hrs. The resulting reaction mixture was concentrated to give a residue, which was characterized as follows.

[0279] 1 H-NMR (400 MHz, CDCl3) δ ppm: 1.90 (m, 2H), 2.10(s, 1H), 2.30 (s, 2H), 2.61 (m, 1H), 2.82 (m, 1H), 3.15 (m, 1H) 3.50 (m, 1H), 3.9 (m, 1H), 4.0 (m, 1H), 4.2 (m, 1H), 4.3(s, 1H), 4.47 (m, 1H), 5.08-5.18 (m, 2H), 5.28(br s, 1H), 7.16(br s, 5H);

[0280] MS (m/z, ESI): 332(MH+)

Example 8

7-BENZOYLAMINO-4-BENZYLCARBAMOYL-6-OXO-HEXAHYDRO-PYRROLO[1,2-A]PYRIMIDINE-1-CARBOXYLIC ACID METHYL ESTER

[0281] (A) Preparation of [1-(1-benzylcarbamoyl-3-methoxycarbonylamino-propylcarbamoyl)-3,3-dimethoxy-propyl]-carbamic Acid Benzyl Ester 60

[0282] To a solution of the Cbz protected amino acid acetal (100 mg, 1.3eq) obtained in the Preparative Example 3(3) in MC, PyBOP (1 eq to acid), DIPEA (6 eq to acid) and HOBt (1.3 eq) were added and stirred for 30 min. To the reaction mixture, amino benzyl amide HCl salt (71 mg, 0.27 mmol) was added and stirred for 7 hrs. The resulting reaction mixture was washed with sat. NaHCO3, water, and sat. NaCl. The organic layer was dried over MgSO4 and concentrated to give an oily residue, which was purified by column chromatography (silica gel, ethyl acetate) to obtain the title compound (50 mg, yield: 35%).

[0283] 1 H-NMR (300 MHz, CDCl3) δ ppm: 2.1(t, 2H), 3.05 (m, 1H), 3.50(ss, 6H), 3.45 (m, 1H), 3.75(s, 3H), 4.25(q, 1H), 4.41 (m, 2H), 4.55 (m, 1H), 5.0(q, 2H), 5.3 (m, 1H), 5.95 (m, 1H), 7.2-7.4 (m, 1 OH)

[0284] (B) Preparation of 4-benzylcarbamoyl-7-benzyloxycarbonylamino-6-oxo-hexahydro-pyrrolo[1,2-a]pyrimidine-1-carboxylic Acid Methyl Ester 61

[0285] The acetal amide cyclization precursor (5 mg, 0.009 mmol) obtained in the above step (A) was dissolved in formic acid (1 mL) and stirred overnight. The resulting reaction mixture was concentrated to dryness, which is used in the next step without further purification.

[0286] 1 H-NMR (300 MHz, CDCl3) δ ppm: 2.25 (m, 2H), 2.61(t, 2H), 3.24 (m, 1H), 3.50(s, 3H), 3.55 (m, 1H), 3.95 (m, 1H), 4.45 (m, 2H), 4.65(d, 1H), 4.8 (m, 2H), 5.3 (m, 1H), 5.7(d, 1H), 7.15-7.4 (m, 10H), 7.85 (m, 1H)

[0287] (C) Preparation of 7-benzoylamino-4-benzylcarbamoyl-6-oxo-hexahydro-pyrrolo[1,2-a]pyrimidine-1-carboxylic Acid Methyl Ester 62

[0288] In a reaction vessel equipped with a hydrogen gas balloon, a solution of the Cbz bicyclic ring compound obtained in the above step (B) in MeOH and Pd/C (1 mg) were placed at room temperature and stirred for 2 hrs. After the reaction was complete, the reaction mixture was filtered by celite filter to remove Pd/C and the solvent was evaporated under reduced pressure. The resulting oily residue was dissolved in MC, to which a solution of benzoic acid (1.1 eq) in MC and PyBOP (1.1 eq), HOBt (1.1 eq) and DIPEA (3 eq) were added and stirred for 30 min. To the resulting solution of the activated acid, an amine solution was added and kept stirring for 3 hrs. The resulting reaction mixture was concentrated under reduced pressure to give oily residue, which was purified by preparative TLC to obtain the title compound.

[0289] 1 H-NMR (300 MHz, CDCl3) δ ppm: 2.25 (m, 2H), 2.65 (m, 2H), 3.27 (m, 1H), 3.70(s, 3H), 3.6 (m, 1H), 4.10 (m, 1H), 4.54 (m, 2H), 4.8(t, 1H), 5.45 (m, 1H), 7.15-7.42 (m, 1 OH), 7.9(d, 1H), 8.31 (t, 1H)

Example 9

7-BENZOYLAMINO-4-(1-CARBOXY-ETHYLCARBAMOYL)-6-OXO-HEXAHYDRO-PYRROLO[1,2-A]PYRIMIDINE-1-CARBOXYLIC ACID METHYL ESTER

[0290] A synthetic scheme showing the methodology of Example 9 is presented in FIG. 3.

[0291] 2-Chlorotrityl chloride resin (200 mg, 1 mmol/g) and a solution of Fmoc-Alanine (1.5 equiv. commercially available) and DIEA (2 equiv.) in DCE (2 mL) were placed in vial with screw cap. The reaction mixture was shaken at room temperature for 12 hours. The resin was collected by filtration and washed with DMF, MeOH, and then DCM, to provide a first component piece.

[0292] To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and then the product mixture was washed with DMF, MeOH, and then DCM. A solution of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-4-methoxycarbonylamino-butyric acid (1.5 equiv. 2nd component piece), DIC (1.5 equiv.), HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0293] To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and the product mixture was washed with DMF, MeOH, and then DCM. A solution of 2-(9H-fluoren-9ylmethoxycarbonylamino)-5,5-dimethoxy-pentanoic acid (1.5 equiv.), DIC (1.5 equiv.), HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0294] To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and then the product mixture was washed with DMF, MeOH, and then DCM. A solution of commercially available benzoic acid (1.5 equiv.), DIC (1.5 equiv.), HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0295] The resin was treated with formic acid (1.2 mL each well) for 18 hours at room temperature. Thereafter, the resin was removed by filtration and the filtrate was condensed under reduced pressure to give the product as oil.

[0296] 1 H-NMR (300 MHz, MeOH-d4) δ 1.40 (d, 3H), 1.90 (m, 1H), 2.20 (m, 1H), 2.30˜2.50 (m, 2H), 3.15 (m, 1H), 3.20 (m, 1H), 3.45 (s, 3H), 3.40˜3.60 (m, 1H), 4.20˜4.40 (m, 2H), 4.70 (t, 1H), 5.40 (t, 1H), 7.25˜7.45 (m, 3H), 7.75 (d, 2H);

[0297] MS(m/z, ESI) 433 (MH+), 455 (MNa+)

Example 10

7-BENZOYLAMINO-4-(2-CARBOXY-PROPYLCARBAMOYL)-6-OXO-HEXAHYDRO-PYRROLO[1,2-A]PYRIMIDINE-1-CARBOXYLIC ACID METHYL ESTER

[0298] A synthetic scheme showing the methodology of Example 10 is presented in FIG. 4.

[0299] 2-Chlorotrityl chloride resin (200 mg, 1 mmol/g) and a solution of Fmoc-beta-alanine (1.5 equiv.) and DIEA (2 equiv.) in DCE (2 mL) were placed in a vial with screw cap. The reaction mixture was shaken at room temperature for 12 hours. The resin was collected by filtration and washed with DMF, MeOH, and then DCM, to provide a first component piece.

[0300] To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and the product mixture was washed with DMF, MeOH, and then DCM. A solution of 2-(9H-fluoren-9ylmethoxycarbonylamino)-4-methoxycarbonylamino-butyric acid (1.5 equiv. 2nd component piece), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0301] To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and then the product mixture was washed with DMF, MeOH, and then DCM. A solution of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-5,5-dimethoxy-pentanoic acid (1.5 equiv.), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0302] To the resin swollen by DMF before reaction was added 25% piperidine in DMF. Thereafter, the reaction mixture was shaken for 30 min at room temperature. The deprotection step was repeated and then the product mixture was washed with DMF, MeOH, and then DCM. A solution of commercially available benzoic acid (1.5 equiv.), DIC (1.5 equiv.), and HOBT (1.5 equiv.) in NMP was added to the resin. After the reaction mixture was shaken for 12 hours at room temperature, the resin was washed with DMF, MeOH, and then DCM.

[0303] The resin was treated with formic acid (1.2 mL in each well) for 18 hours at room temperature. After the resin was removed by filtration, the filtrate was condensed under reduced pressure to give the product as oil.

[0304] 1 H-NMR (300 MHz, MeOH-d4) δ 1.40 (d, 3H), 1.90 (m, 1H), 2.20 (m, 1H), 2.30˜2.50 (m, 2H), 3.15 (m, 2H), 3.35 (s, 3H), 3.40˜3.60 (m, 3H), 4.20˜4.40 (m, 2H), 4.70 (t, 1H), 5.40 (t, 1H), 7.25˜7.45 (m, 3H), 7.75 (d, 2H);

[0305] MS(m/z, ESI): 447 (MH+), 469 (MNa+)

[0306] Various references are set forth herein, which describe in detail certain procedures, compounds and/or compositions, and are incorporated by reference in their entirety.

[0307] It will be appreciated that, although specific embodiments of the invention have been described herein for the purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the appended claims.

Claims

1. A compound having the structure:

2. The compound of claim 1, wherein R1, R2, R3, R4 and R5 are independently selected from the group consisting of aminoC2-5alkyl, guanidinoC2-5alkyl, C1-4alkylguanidinoC2-5alkyl, diC1-4alkylguanidino-C2-5alkyl, amidinoC2-5alkyl, C1-4alkylamidinoC2-5alkyl, diC1-4alkylamidinoC2-5alkyl, C1-3alkoxy, phenyl, substituted phenyl (where the substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), benzyl, substituted benzyl (where the substituents on the benzyl are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), naphthyl, substituted naphthyl (where the substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), bis-phenyl methyl, substituted bis-phenyl methyl (where the substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), pyridyl, substituted pyridyl (where the substituents are independently selected from one or more of amino amid ino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), pyridylC1-4alkyl, substituted pyridylC1-4alkyl (where the pyridine substituents are independently selected from one or more of amino, amidino, guanidino, hydrazino, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), pyrimidylC1-4alkyl, substituted pyrimidylC1-4alkyl (where the pyrimidine substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), triazin-2-yl-C1-4alkyl, substituted triazin-2-yl-C1-4alkyl (where the triazine substituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), imidazoC1-4alkyl, substituted imidazol C1-4alkyl (where the imidazole sustituents are independently selected from one or more of amino, amidino, guanidine, hydrazine, amidrazonyl, C1-4alkylamino, C1-4dialkylamino, halogen, perfluoro C1-4alkyl, C1-4alkyl, C1-3alkoxy, nitro, carboxy, cyano, sulfuryl, or hydroxyl), imidazolinylC1-4alkyl, N-amidinopiperazinyl-N—C0-4alkyl, hydroxyC2-5alkyl, C1-5alkylaminoC2-5alkyl, C1-5dialkylaminoC2-5alkyl, N-amidinopiperidinylC1-4alkyl and 4-aminocyclohexylC0-2alkyl.

3. The compound of claim 1 wherein X is absent, A is N, B is —(C═O)— and L is —C(O)NHR3, and the compound has the structure:

4. The compound of claim 3 wherein W is absent and Z is oxygen.

5. The compound of claim 1 wherein X is absent, A is N, B is —(CH2)m— and L is —C(O)NHR3, and the compound has the structure:

6. The compound of claim 5 wherein W is absent and Z is oxygen.

7. The compound of claim 1 wherein X is —NH—, A is —(CH)—, B is —(CH2)m— and L is —C(O)NHR3, and the compound has the structure:

8. The compound of claim 7 wherein Z is oxygen and W is absent.

9. The compound of claim 1 wherein A is —CH2—N—, B is —(CH2)m— and L is —C(O)NHR3, and the compound has the structure:

10. The compound of claim 9 wherein Y is oxygen.

11. The compound of claim 10 wherein W is absent and Z is oxygen.

12. The compound of claim 9 wherein W is absent and Z is oxygen.

13. The compound of claim 1 wherein A is —(CH)—, B is —(CH2)m— with m=1, W is —(C═O)— or nothing, X is-NH(C═O)—, Y is oxygen, Z is hydrogen so that C═Z represents CH2, L is —C(═O)NHR3, n=0, R4 is hydrogen, and R1, R2, and R3 are the same or different and are independently selected from an amino acid side chain moiety or derivative thereof, the remainder of the molecule, a linker and a solid support, and stereoisomers thereof.

14. The compound of claim 13 wherein R1, R2, and R3 are independently selected from organic groups having molecular weights of between 15 and 1,000 g/mol; and at least one of R1, R2, and R3 represents an amino acid side chain or derivative thereof.

15. The compound of any one of claims 1-14 wherein R3 is joined to a solid support or solid support derivatives.

16. A library of compounds, comprising at least one compound of any one of claims 1-14.

17. A pharmaceutical composition comprising a compound of claims 114 and pharmaceutically acceptable carrier.

18. A method of identifying a biologically active compound, comprising contacting the library of claim 17 with a target to detect or screen the biologically active compound.

19. A method for inhibiting a kinase in a warm-blooded animal, comprising administering to the animal an amount of a compound of any of claims 1-14 effective to inhibit the kinase.

20. A method for CAAX inhibition in a warm-blooded animal, comprising administering to the animal an amount of a compound of any of claims 1-14 effective to inhibit CAAX.

21. A method for inhibiting a protease in a warm-blooded animal comprising administering to the animal an amount of a compound of any of claims 1-14 effective to inhibit the protease.

22. A method for inhibiting the binding of an antigenic peptide to either a class one or class two MHC molecule, comprising contacting an amount of a compound of any of claims 1-14 with a composition comprising an antigenic peptide and either a class one or class two MHC molecule, where the amount is effective to inhibit the binding.

23. A method for inhibiting the binding of a phosphotyrosine residue present in a first peptide, to an SH2 domain in a second peptide, comprising contacting an amount of a compound of any of claims 1-14 with a composition comprising the first peptide and the second peptide, where the amount is effective to inhibit the binding.

24. A method for inhibiting the binding of a proline-rich region of a first peptide to a SH3 domain in a second peptide, comprising contacting an amount of a compound of any of claims 1-14 with a composition comprising the first peptide and the second peptide, where the amount is effective to inhibit the binding.

25. A method for inhibiting an oxidoreductase in a warm-blooded animal, comprising administering to the animal an amount of a compound of any of claims 1-14, where the amount is effective to inhibit the oxidoreductase.

26. A method for inhibiting a phosphatase in a warm-blooded animal, comprising administering to the animal an amount of a compound of any of claims 1-14, where the amount is effective to inhibit the phosphatase.

27. A method for inhibiting the binding of a first peptide to a 14-3-3 domain in a second peptide, comprising contacting a compound of any of claims 1-14 with an amount of a composition comprising the first peptide that has a binding affinity to a 14-3-3 domain of a second peptide, and a second peptide having a 14-3-3 domain, where the amount is effective to inhibit the binding.