# Patent

## Title
Macrocyclic compounds for inhibition of tumor necrosis factor alpha

## Abstract

Disclosed herein are macrocyclic compounds and methods for their synthesis and use. In particular, macrocyclic compounds are disclosed that modulate the activity of tumor necrosis factor alpha and/or are useful in the treatment of medical conditions, such as, rheumatoid arthritis, psoriasis, and asthma.

## Background
RELATED APPLICATIONS
This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 61/090,410, filed Aug. 20, 2008; U.S. Provisional Patent Application Sero. 61/098,865, filed Sep. 22, 2008; and U.S. Provisional Patent Application Ser. No. 61/151,245, filed Feb. 10, 2009; the contents of each of which are hereby incorporated by reference.


FIELD OF THE INVENTION
The invention relates generally to macrocyclic compounds and their therapeutic use. More particularly, the invention relates to macrocyclic compounds that modulate the activity of tumor necrosis factor alpha and/or are useful in the treatment of medical conditions, such as rheumatoid arthritis, psoriasis, and asthma.
BACKGROUND OF THE INVENTION
Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic inflammatory cytokine having a molecular weight of 17-26 kDa. This cytokine exists in a soluble form and a membrane-bound form, the active form usually being a homotrimer. TNF-alpha is produced in vivo by a variety of cell types. The primary producers of TNF-alpha are stimulated monocytes, fibroblasts, and endothelial cells. However, macrophages, T-cells, B-lymphocytes, granulocytes, smooth muscle cells, eosinophils, chondrocytes, osteoblasts, mast cells, glial cells, and keratinocytes also produce TNF-alpha after stimulation. Physiological stimuli for the synthesis of TNF-alpha include interleukin-1, bacterial endotoxins, platelet-derived growth factor (PDGF), and Oncostatin M. In fibroblasts, the synthesis of TNF-alpha is stimulated by beta-interferon, PDGF, and viral infections. In thymic stromal cells, the synthesis of TNF-alpha can be induced by nerve growth factor. TNF-alpha can also stimulate or inhibits its own synthesis, depending upon the cell type.
TNF-alpha affects many organs in the body and serves a variety of biological functions. For example, this cytokine possesses both growth stimulating properties and growth inhibiting properties. It also appears to have self regulatory properties. The varied biological impact of this cytokine makes it an attractive target for the development of compounds capable of modulating the activity of this physiologically important protein.
Thus, the need exists for new compounds that can modulate the activity of tumor necrosis factor alpha. The present invention fulfills this need and has other related advantages.
SUMMARY
The present invention provides macrocyclic compounds, methods of modulating the activity of tumor necrosis factor alpha, and methods for treating various medical conditions using such compounds. In one aspect, the invention provides a compound represented by formula I:




including pharmaceutically acceptable salts thereof, wherein the variables are as defined in the detailed description.

In another aspect, the invention provides a method of treating a patient suffering from or susceptible to a medical condition. The method comprises administering to the patient a therapeutically effective amount of a composition comprising a macrocyclic compound described herein. A number of medical conditions can be treated using the macrocyclic compounds described herein. For example, the compounds described herein may be used to treat rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic lupus erythematosus, systemic sclerosis, insulin-dependent diabetes mellitus, cancer, multiple sclerosis, septic shock syndrome, asthma, Alzheimer's disease, an inflammatory eye disease, uveitis, and inflammation. The therapeutic methods embrace combination therapies, such as co-administration of a macrocyclic compound together with a therapeutically effective amount of an anti-inflammatory agent or a therapeutic agent for the treatment of any of the aforementioned diseases, including multiple sclerosis.
In another aspect, the invention provides a method of modulating the activity of tumor necrosis factor alpha on a cell comprising a receptor for tumor necrosis factor alpha on its surface. The method comprises exposing the cell to a compound described herein. In an embodiment, the receptor is on the surface of a mammalian cell.
The foregoing and other aspects and embodiments of the invention may be more fully understood by reference to the following detailed description and claims.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts the effect of various doses of a compound of this invention on paw volume in a rat paw edema model.



DETAILED DESCRIPTION OF THE INVENTION
The present invention provides macrocyclic compounds, methods of modulating the activity of tumor necrosis factor alpha, and methods for treating various medical conditions using such compounds. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, and biochemistry. For example, procedures for synthesizing organic compounds are described in the literature, such as “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992). Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls.
I. Macrocyclic Compounds
In one aspect, the invention provides a compound represented by formula I:




including pharmaceutically acceptable salts thereof, wherein

X1, X2, and X3 are each independently —C(R1)(R2)— or —C(R1)(R2)—C(R3)(R4)—;
R1, R2, R3, and R4 each represent independently for each occurrence hydrogen, deuterium, —(C1-C6)-alkyl, —(C2-C6)-alkenyl, —(C2-C6)-alkynyl, —(C1-C6)-alkyl-heterocyclyl, —(C2-C6)-alkenyl-heterocyclyl, —(C2-C6)-alkynyl-heterocyclyl, —(C1-C6)-alkyl-biphenyl, —(C1-C6)-alkyl-carbocyclyl, —(C2-C6)-alkenyl-carbocyclyl, —(C2-C6)-alkynyl-carbocyclyl, —O—(C1-C6)-alkyl, —O—(C2-C6)-alkenyl, —O—(C2-C6)-alkynyl, —O—(C1-C6)-alkyl-heterocyclyl, —O—(C2-C6)-alkenyl-heterocyclyl, —O—(C1-C6)-alkynyl-heterocyclyl, —O—(C1-C6)-alkyl-carbocyclyl, —O—(C2-C6)-alkenyl-carbocyclyl, —O—(C2-C6)-alkynyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, and, when R1 is bound to the same carbon atom as R10, R1 is additionally selected from —CO2—(C1-C6)-alkyl, wherein

    
    
        R1, R2, R3, and R4 are optionally substituted with up to three substituents independently selected from the group consisting of halogen, —NO2, —NHC(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —CN, —OR5, —C(O)N(R5)(R6), —N(R5)(R6), —SR5, —NHC(O)OR5, —NHC(O)R5, —NHC(O)N(R5)(R6), —NHS(O)2R5, —OC(O)R5, —OC(O)N(R5)(R6), —S(O)2N(R5)(R6), and —SO2—(C1-C6)-alkyl;
    
    


R5 and R6 each represent independently for each occurrence deuterium, hydrogen, heterocyclyl, carbocyclyl, —(C1-C4)-alkyl, —(C2-C4)-alkenyl, —(C2-C4)-alkynyl, —(C1-C4)-alkyl-heterocyclyl, —(C2-C4)-alkynyl-heterocyclyl, —(C2-C4)-alkynyl-heterocyclyl, —(C2-C4)-alkenyl-carbocyclyl, —(C2-C4)-alkynyl-carbocyclyl, or —(C1-C4)-alkyl-carbocyclyl; or
R5 and R6, are taken together with the nitrogen atom to which they are both attached to form a heterocyclic ring; and any ring in R5 or R6, or formed by R5 and R6, is optionally substituted with up to two substituents independently selected from the group consisting of halogen, —(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —C(O)aryl, —C(O)(C1-C4)alkyl, —S(O)2aryl, —S(O)2(C1-C4)alkyl, —CO2H, —C(O)N(H)aryl, —C(O)N(H)(C1-C4)alkyl, —OH, ═O, —N3, —NH2, —N(H)((C1-C4)-alkyl), and —N((C1-C4)-alkyl)2;
RA and RB each represent independently hydrogen, deuterium, —(C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, —(C1-C4)-alkyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, wherein RA and RB are optionally substituted with up to three substituents independently selected from the group consisting of deuterium, halogen, —NO2, —N(H)C(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —OC(O)(R5), —OC(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5, and —S(O)2N(R5)(R6); or
RA or RB and an occurrence of R1, R2, R3, or R4; when said R1, R2, R3, or R4 is attached to a carbon atom adjacent a nitrogen atom to which said RA or RB is attached; are taken together with the carbon atom and the nitrogen atom to form a heterocyclic ring optionally substituted with up to three substituents independently selected from group consisting of deuterium, halogen, —NO2, —NHC(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —OC(O)(R5), —OC(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5 and —S(O)2N(R5)(R6);
A1 is —(NR7)—(CH2)n-† or —(NR7)—(CH2)n—(Y)p—(CH2)n†, wherein

    
    
        R7 is hydrogen, deuterium, —(C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, —(C1-C4)-alkyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, wherein R7 is optionally substituted with up to three substituents independently selected from the group consisting of deuterium, halogen, —NO2, —N(H)C(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —OC(O)(R5), —OC(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5, and —S(O)2N(R5)(R6);
        Y represents independently for each occurrence carbocyclyl or heterocyclyl;
        n represents independently for each occurrence 0, 1, 2, 3, 4, or 5;
        p is 1 or 2;
        “†” represents the portion of A1 attached to A2; and one —CH2— unit in A1 is replaced with
    
    






    
    
        the —NR7 unit in A1 is replaced with
    
    






    
    
        R8 is hydrogen, deuterium, —(C1-C6)-alkyl, —(C1-C6)-alkyl-carbocyclyl or —(C1-C6)-alkyl-heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl portion of R8 is optionally substituted;
        R9 is hydrogen, deuterium, —(C1-C6)-alkyl, —(C1-C6)-alkyl-O—(C1-C6)-alkyl, —(C1-C6)-alkyl-OH, —(CH2)t—C(R1)(R10)—(CH2)t—COOH, —(CH2)t—C(R1)(R10)—(CH2)t—SO3H, —(CH2)t—C(R1)(R10)—(CH2)t—C(O)—NH—(CH2)t—C(R1)(R10)—SO3H, —(CH2)t—C(R1)(R10)—(CH2)t—C(O)—NH—(CH2)t—C(R1)(R10)—COOH, —S(O)2R5, —(C1-C6)-alkyl-N(H)S(O)2-carbocyclyl, a carbocyclyl or a heterocyclyl, wherein the —(C1-C6)-alkyl-N(H)S(O)2-carbocyclyl, carbocyclyl or heterocyclyl is optionally substituted with up to three substituents independently selected from the group consisting of deuterium, halogen, —(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —OH, ═O, —CO2H, —NH2, —NH((C1-C4)-alkyl), and —N((C1-C4)-alkyl)2; or
        R8 and R9, taken together with the nitrogen atom to which they are attached to form a heterocyclic ring optionally substituted with up to three substituents independently selected from the group consisting of halogen, —NO2, —NHC(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5 and —S(O)2N(R5)(R6);
        t represents independently for each occurrence 0, 1, or 2;
        each R10 represents independently for each occurrence hydrogen, deuterium, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, —CO2—(C1-C6)-alkyl, -heterocyclyl, or -carbocyclyl; wherein R10 is optionally substituted with —(C1-C4)-alkyl, fluorine-substituted-(C1-C4)-alkyl, —C(O)—(C1-C4)-alkyl, —CN, —C(O)OH, —C(O)—O—(C1-C4)-alkyl, —C(O)(C1-C4)alkyl, —OH, —C(O)NH2, —NO2, —NH2, —N(H)((C1-C4)-alkyl), —N((C1-C4)-alkyl)2, —N(H)C(═NH)NH2, —SCH3, —SH, —N(H)C(O)—(C1-C4)-alkyl, —N(H)C(O)—(C1-C4)-alkyl-C(O)NH2, or —N(H)C(O)O—(C1-C4)-alkyl; or
        
            R1 and R10 bound to a common carbon atom are taken together with the carbon atom to form a 3-7 membered cycloalkane ring;
        
        
    
    


A2 is a bond, —O—, —NH—, —C(O)—, —NHC(O)-‡, —NHC(O)(CH2)—O-‡, —C(O)NH-‡, —C(O)O-‡, or —OC(O)-‡, wherein “‡” represents the portion of A2 attached to A3;
A3 is —(CR11R12)m— or —(CR11R12)m—C(O)-*, wherein

    
    
        “*” represents the portion of A3 attached to A4;
        m is 1, 2, 3, 4, 5, or 6; and
        R11 and R12 each represent independently for each occurrence hydrogen, deuterium, R13, —OH, —OR13, —OC(O)R13, —NH2, —(C1-C6)-alkyl-NH2, —NH(C1-C6)-alkyl, —N((C1-C6)-alkyl)2, —N(H)S(O)2—R13, —N(H)C(O)—R13, —N(H)C(O)—OR13, or —N(H)C(O)—N(H)R13; or R11 and R12 are taken together with the carbon atom or carbon atoms to which they are attached to form a carbocyclyl or a heterocyclyl;
        R13 is —(C1-C6)-alkyl, —(C1-C6)-alkyl-CO2H, aryl, or —(C1-C6)-alkyl-aryl; and A4 is a bond, —O—, —S—, or —N(R14)—, wherein
        R14 is hydrogen, deuterium, —(C1-C4-alkyl, —(C1-C4)-alkyl-heterocyclyl, —(C1-C4)-alkyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, wherein R14 is optionally substituted with up to three substituents independently selected from the group consisting of deuterium, halogen, —NO2, —N(H)C(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —OC(O)(R5), —OC(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5, and —S(O)2N(R5)(R6); and
        R15 and R16 each represent independently hydrogen, C1-C4 alkyl, or —C(O)—O—C1-C4 alkyl.
    
    


In certain embodiments, the compound is not




In certain other embodiments, Y is carbocyclyl. In certain other embodiments, A2 is —O—, —NH—, —C(O)—, —NHC(O)-‡, —NHC(O)(CH2)—O-‡, —C(O)NH-‡, —C(O)O-‡, or —OC(O)-‡. In certain other embodiments, Y is aryl, and A2 is —O—, —NH—, —C(O)—, —NHC(O)-‡, —NHC(O)(CH2)—O-‡, —C(O)NH-‡, —C(O)O-‡, or —OC(O)-‡.

In another aspect, the invention provides a compound represented by formula Ia:




including pharmaceutically acceptable salts thereof, wherein

X1, X2, and X3 are each independently —C(R1)(R2)— or —C(R1)(R2)—C(R3)(R4)—;
R1, R2, R3, and R4 each represent independently for each occurrence hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C2-C6)-alkenyl-heterocyclyl, —(C1-C6)-alkyl-biphenyl, —(C1-C6)-alkyl-carbocyclyl, —(C2-C6)-alkenyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, and, when R1 is bound to the same carbon atom as R10, R1 is additionally selected from —CO2—(C1-C6)-alkyl, wherein

    
    
        R1, R2, R3, and R4 are optionally substituted with up to three substituents independently selected from the group consisting of halogen, —NO2, —CN, —N(H)C(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5, —OC(O)R5, —OC(O)N(R5)(R6) and —S(O)2N(R5)(R6);
        R5 and R6 each represent independently for each occurrence hydrogen, heterocyclyl, carbocyclyl, —(C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, or —(C1-C4)-alkyl-carbocyclyl, or
        R5 and R6 are taken together with the nitrogen atom to which they are both attached to form a heterocyclic ring; and
        any ring in R5 or R6, or formed by R5 and R6, is optionally substituted with up to two substituents independently selected from the group consisting of halogen, —(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —C(O)aryl, —C(O)(C1-C4)alkyl, —S(O)2aryl, —S(O)2(C1-C4)alkyl, —CO2H, —C(O)N(H)aryl, —C(O)N(H)(C1-C4)alkyl, —OH, ═O, —N3, —NH2, —N(H)((C1-C4)-alkyl), and —N((C1-C4)-alkyl)2;
    
    


RA and RB each represent independently hydrogen, —(C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, —(C1-C4)-alkyl-carbocyclyl, -heterocyclyl, or -carbocyclyl; wherein RA and RB are optionally substituted with up to three substituents independently selected from the group consisting of halogen, R5, halo-substituted R5, —OR5, —C(O)N(R5)(R6), —OC(O)(R5), —OC(O)N(R5)(R6), —N(R5)(R6), —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5 and —S(O)2N(R5)(R6); or
RA or RB and an occurrence of R1, R2, R3, or R4; when said R1, R2, R3, or R4 is attached to a carbon atom adjacent a nitrogen atom to which said RA or RB is attached; are taken together with the carbon atom and the nitrogen atom to form a heterocyclic ring optionally substituted with up to three substituents independently selected from the group consisting of halogen, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —OC(O)(R5), —OC(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5 and —S(O)2N(R5)(R6);
A1 is —(NR7)—(CH2)n-† or —(NR7)—(CH2)n—(Y)p—(CH2)n-†, wherein

    
    
        Y represents independently for each occurrence carbocyclyl or heterocyclyl;
        n represents independently for each occurrence 0, 1, 2, 3, or 4;
        p is 1 or 2;
        “†” represents the portion of A1 attached to A2; and
        one —CH2— unit in A1 is replaced with
    
    






    
    
        the —NR7 unit in A1 is replaced with
    
    






    
    
        R8 is hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-carbocyclyl or —(C1-C6)-alkyl-heterocyclyl, wherein the alkyl, carbocyclyl, or heterocyclyl portion of R8 is optionally substituted;
        R9 is hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-O—(C1-C6)-alkyl, —(C1-C6)-alkyl-OH, —(CH2)t—C(R1)(R10)—(CH2)t—COOH, —(CH2)t—C(R1)(R10)—(CH2)t—SO3H, —(CH2)t—C(R1)(R10)—(CH2)t—C(O)—NH—(CH2)t—C(R1)(R10)—SO3H, —S(O)2R5, a carbocyclyl or a heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, —(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —C(O)OH, —C(O)(C1-C4)alkyl, —OH, ═O, —NH2, —NH((C1-C4)-alkyl), and —N((C1-C4)-alkyl)2; or R8 and R9, when taken together with the nitrogen atom to which they are attached, form a heterocyclic ring optionally substituted with up to three substituents independently selected from the group consisting of halogen, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —N(R5)(R6), —SR5, —NHC(O)R5, and —NHC(O)N(R5)(R6);
        t represents independently for each occurrence 0, 1, or 2; and
        R10 represents independently for each occurrence hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, —CO2—(C1-C6)-alkyl, -heterocyclyl, or -carbocyclyl, wherein R10 is optionally substituted with —(C1-C4)-alkyl, fluorine-substituted-(C1-C4)-alkyl, —C(O)—(C1-C4)-alkyl, —CN, —C(O)OH, —OH, —C(O)NH2, —NH2, —NH((C1-C4)-alkyl), —N((C1-C4)-alkyl)2, or —NH—C(O)—(C1-C4)-alkyl,
        or R1 and R10 bound to a common carbon atom are taken together with the carbon atom to form a 3-7 membered cycloalkane ring;
    
    


A2 is a bond, —O—, —NH—, —C(O)—, —NHC(O)-‡, —C(O)NH-‡, —C(O)O-‡, or —OC(O)-‡, wherein “‡” represents the portion of A2 bound to A3;
A3 is —(CR11R12)m—C(O)-*, wherein

    
    
        “*” represents the portion of A3 bound to A4;
        m is 1, 2, 3, 4, 5, or 6; and
        R11 and R12 each represent independently for each occurrence hydrogen, deuterium, R13, —OH, —OR13, —OC(O)R13, —NH2, —(C1-C6)-alkyl-NH2, —NH(C1-C6)-alkyl, —N((C1-C6)-alkyl)2, —N(H)S(O)2—R13, —N(H)C(O)—R13, —N(H)C(O)—OR13, and —N(H)C(O)—N(H)R13; or R11 and R12, when taken together with the carbon atom or carbon atoms to which they are attached, form a carbocyclyl or a heterocyclyl;
        R13 is —(C1-C6)-alkyl, aryl or —(C1-C6)-alkyl-aryl; and
    
    


A4 is a bond, —O—, —S—, or —N(R14)—, wherein

    
    
        R14 is hydrogen, deuterium, —(C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, —(C1-C4)-alkyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, wherein R14 is optionally substituted with up to three substituents independently selected from the group consisting of deuterium, halogen, —NO2, —N(H)C(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —C(O)N(R5)(R6), —OC(O)(R5), —OC(O)N(R5)(R6), —N(R5)(R6), —SR5, —N(H)C(O)OR5, —N(H)C(O)R5, —N(H)C(O)N(R5)(R6), —N(H)S(O)2R5, and —S(O)2N(R5)(R6).
    
    


In certain embodiments, the compound is not




In certain other embodiments, Y is carbocyclyl. In certain other embodiments, A2 is —O—, —NH—, —C(O)—, —NHC(O)-‡, —NHC(O)(CH2)—O-‡, —C(O)NH-‡, —C(O)O-‡, or —OC(O)-‡. In certain other embodiments, Y is aryl, and A2 is —O—, —NH—, —C(O)—, —NHC(O)-‡, —NHC(O)(CH2)—O-‡, —C(O)NH-‡, —C(O)O-‡, or —OC(O)-‡.

In certain instances, R1, R2, R3, and R4 each represent independently for each occurrence hydrogen, —(C1-C4)-alkyl, —(C1-C2)-alkyl-heterocyclyl, —(C1-C3)-alkyl-biphenyl, —(C1-C3)-alkyl-carbocyclyl, or -carbocyclyl, and, when R1 is bound to the same carbon atom as R10, R1 is additionally selected from —CO2—(C1-C6)-alkyl, wherein each of R1, R2, R3, and R4 are independently substituted with up to three substituents selected from the group consisting of halogen, —NO2, —NHC(═NH)NH2, R5, halo-substituted R5, —C(O)—R5, —C(O)OR5, —OR5, —N(R5)(R6), —N(H)C(O)R5, —N(H)C(O)OR5, —N(H)C(O)N(R5)(R6), and —N(H)S(O)2R5; wherein R5 and R6 each represent independently for each occurrence hydrogen, heterocyclyl, carbocyclyl, —(C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, carbocyclyl, or —(C1-C4)-alkyl-carbocyclyl;
RA and RB each represent independently hydrogen, (C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, —(C1-C4)-alkyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, wherein RA and RB are optionally substituted with up to three substituents independently selected from the group consisting of halogen, R5, halo-substituted R5, and —OR5; or RA or RB and an occurrence of R1, R2, R3, or R4; when said R1, R2, R3, or R4 is attached to a carbon atom adjacent a nitrogen atom to which said RA or RB is attached; are taken together with the carbon atom and the nitrogen atom to form a heterocyclic ring optionally substituted with up to three substituents independently selected from the group consisting of halogen, R5, and halo-substituted R5;
A1 is —(NR7)—(CH2)n—(Y)p—(CH2)n-†, wherein

    
    
        Y represents independently for each occurrence carbocyclyl or heterocyclyl;
        n represents independently for each occurrence 0, 1, 2, 3, or 4;
        p is 1 or 2;
        “†” represents the portion of A1 attached to A2; and
        one —CH2— unit in A1 is replaced with
    
    






    
    
        the —NR7 unit in A1 is replaced with
    
    






    
    
        R8 is hydrogen, —(C1-C6)-alkyl, or —(C1-C6)-alkyl-carbocyclyl;
        R9 is hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-OH, —(CH2)t—C(R1)(R10)—(CH2)t—COOH, —(CH2)t—C(R1)(R10)—(CH2)t—SO3H, —(CH2)t—C(R1)(R10)—(CH2)t—C(O)—NH—(CH2)t—C(R1)(R10)—SO3H, —S(O)2R5, a carbocyclyl or a heterocyclyl; wherein the carbocyclyl or heterocyclyl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, —(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —C(O)OH, —C(O)(C1-C4)alkyl, —OH, ═O, —NH2, —NH((C1-C4)-alkyl), or —N((C1-C4)-alkyl)2; or R8 and R9, when taken together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring;
        t represents independently for each occurrence 0, 1, or 2; and
        R10 represents independently for each occurrence hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-carbocyclyl, —(C1-C6)-alkyl-heterocyclyl, or —CO2—(C1-C6)-alkyl, or
        R1 and R10 bound to a common carbon atom are taken together with the carbon atom to form a 3-7 membered cycloalkane ring;
    
    


A2 is a bond, —O—, —NH—, —C(O)—, —NHC(O)-‡, —C(O)NH-‡, —C(O)O-‡, or —OC(O)-‡, wherein “‡” represents the portion of A2 bound to A3;
A3 is —(CR11R12)m— or —(CR11R12)m—C(O)-*, wherein

    
    
        “*” represents the portion of A3 bound to A4;
        m is 1, 2, 3, 4, 5, or 6;
        R11 and R12 each represent independently for each occurrence hydrogen, —OH, —OC(O)R13, —NH2, —(C1-C6)-alkyl-NH2, —N(H)(C1-C6)-alkyl, —N((C1-C6)-alkyl)2, —N(H)S(O)2—R13, —N(H)C(O)—R13, —N(H)C(O)—N(H)R13, or —N(H)C(O)—OR13, or R11 and R12, when taken together with the carbon atom or carbon atoms to which they are attached, form a carbocyclyl or a heterocyclyl;
        R13 is —(C1-C6)-alkyl, aryl or —(C1-C6)-alkyl-aryl; and
    
    


A4 is a bond, —O—, —S—, or —N(R14)—, wherein

    
    
        R14 is hydrogen, (C1-C4)-alkyl, —(C1-C4)-alkyl-heterocyclyl, —(C1-C4)-alkyl-carbocyclyl, -heterocyclyl, or -carbocyclyl, wherein RA and RB are optionally substituted with up to three substituents independently selected from the group consisting of halogen, R5, halo-substituted R5, and —OR5.
    
    


In certain instances, A3 is —(C1-C4)-alkyl-C(O)-*, —(C3-C7-cycloalkyl)-C(O)-*, —CH2CH(NH2)—C(O)-*, —CH(OH)—CH(OH)—C(O)-*, or —CH(OAc)—CH(OAc)—C(O)-*. In certain other instances, A3 is —CH2—CH2—C(O)-* or —CH(OH)—CH(OH)—C(O)-*.
In certain instances, A2 is —NH—, —O—, —C(O)NH-‡, —NH—C(O)-‡, or a bond. In certain other instances, A2 is —NH—C(O)-‡.
In certain instances, RA and RB each represent independently hydrogen, —CH3 or benzyl. In certain other instances, X1, X2, and X3 are each independently —CHR1— or —CHR1—CH2—, and each R1 is independently aryl, heteroaryl, benzofused-cycloalkyl, —(C1-C3)-alkyl-biphenyl, —(C1-C3)-alkyl-aryl, —(C1-C3)-alkyl-heteroaryl, —(C1-C3)-alkyl-O-aryl, —(C1-C3)-alkyl-O—(C1-C3)-alkyl-aryl, —(C1-C3)-alkyl-O—(C1-C3)-alkyl-heteroaryl, or —CH(aryl)(aryl), wherein each aryl or heteroaryl is optionally substituted with an additional aryl or heteroaryl, and any aryl or heteroaryl in R1 is optionally substituted with up to three substituents independently selected from the group consisting of halogen, —(C1-C4)-alkyl, —O—(C1-C4)-alkyl, —C(O)OH, —C(O)(C1-C4)alkyl, —OH, —NH2, —NH((C1-C4)-alkyl), and —N((C1-C4)-alkyl)2, —N(H)C(O)OR5, —N(H)C(O)N(R5)(R6), and —N(H)S(O)2R5. In certain other instances, the R1 substituent of X1 is in an (R) orientation; the R1 substituent of X2 is in an (S) orientation; and the R1 substituent of X3 is in an (R) orientation. In still other instances, the chiral center to which the R1 substituent of X1 is attached is in an (S) orientation; the chiral center to which the R1 substituent of X2 is attached is in an (R) orientation; and the chiral center to which the R1 substituent of X3 is attached is in an (S) orientation.
In certain instances, A1 is —NR7—(CH2)n—Y—(CH2)n-†; Y represents independently for each occurrence phenyl or triazolyl; n represents independently for each occurrence 0, 1, or 2; and one —CH2— unit in A1 is replaced with




or the —NR7 unit in A1 is replaced with





In certain other instances, A1 is —NH—CH2—CH2—C6H5-†, —NH—CH2—C6H5—CH2-†, —NH—CH2—CH2-triazolyl-†, or —NH—C6H5—CH2—CH2-†, wherein one —CH2— unit in A1 is replaced with





the —NH— unit in A1 is replaced with




In certain other instances, A1 is †-C6H5—CH2—CH(COOR4)—NH— or †-C6H5—CH2—CH(C(O)NHR5)—NH—. In certain instances, R4 is OH; and R5 is 1-carboxy-2-phenylethyl or 1-carboxycyclopropyl. In certain other instances, A4 is NR14. In certain other instances, A4 is NH.

In another aspect, the invention provides a compound represented by formula II:




including pharmaceutically acceptable salts thereof, wherein

X is —OH, —O-alkyl, —NH2, —N(H), —N(H)alkyl, —N(H)(substituted alkyl), —N(alkyl)2, —N(substituted alkyl)2, —N(H)—(C1-C6)-alkyl-O—(C1-C6)-alkyl, —N(H)—(CH2)t—C(RV)2—(CH2)t—COOH, —N(H)—(CH2)t—C(RV)2—(CH2)t—SO3H, —NH—(CH2)t—C(RV)2—(CH2)t—C(O)—NH—(CH2)t—C(RV)2—SO3H, —N(alkyl)-(C1-C6)-alkyl-O—(C1-C6)-alkyl, —N(alkyl)-(CH2)t—C(RV)2—(CH2)t—COOH, —N(alkyl)-(CH2)t—C(RV)2—(CH2)t—SO3H, —N(alkyl)-(CH2)t—C(RV)2—(CH2)t—C(O)—NH—(CH2)t—C(RV)2—SO3H, carboxypiperidin-1-yl, carboxypyrrolidin-1-yl, or N-carboxymethyl-N-benzylamino;
Z is alkylene or arylene;
RI is (C1-C4)-alkyl or aryl;
RII is aryl optionally substituted with up to two substituents independently selected from the group consisting of alkyl, haloalkyl, and aryl;
RIII is heteroaryl;
RIV represents independently for each occurrence H or OH;
RV represents independently for each occurrence hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, or —CO2—(C1-C6)-alkyl, wherein each RV is optionally substituted with a substituent selected independently from the group consisting of —NH2, —NH—C(O)—(C1-C4)-alkyl and —OH;
or two RV are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring;
n represents independently for each occurrence 0, 1, 2, 3, or 4; and
t represents independently for each occurrence 0, 1, or 2.
In certain instances, RI is phenyl, RII is biphenyl, and RIII is thiophenyl. In certain instances, n is 1.
In another aspect, the invention provides a compound represented by formula III:




including pharmaceutically acceptable salts thereof, wherein

X is —OH, —N(H)—(CH2)t—C(RV)2—(CH2)t—SO3H, —NH—(CH2)t—C(RV)2—(CH2)t—C(O)—NH—(CH2)t—C(RV)2—SO3H, —N(H)—(CH2)t—C(RV)2—(CH2)t—COOH, carboxypiperidin-1-yl, carboxypyrrolidin-1-yl, or N-carboxymethyl-N-benzylamino;
RI is aryl, —CH2-aryl, or —CH2-heteroaryl;
RII is aryl optionally substituted with up to two substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, aryl and heteroaryl;
RIII is aryl or heteroaryl;
RIV represents independently for each occurrence H or OH;
RV represents independently for each occurrence hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, or —CO2—(C1-C6)-alkyl, wherein each RV is optionally and independently substituted with a substituent selected independently from the group consisting of —NH2, —NH—C(O)—(C1-C4)-alkyl and —OH; or two RV are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring; and
t represents independently for each occurrence 0, 1, or 2.
In certain instances, RI is benzyl, RII is biphenyl, RIII is thiophenyl. In certain instances, the compound is represented by formula III-A:




including pharmaceutically acceptable salts thereof, wherein

X is —OH, —N(H)—(CH2)t—C(RV)2—(CH2)t—SO3H, —NH—(CH2)t—C(RV)2—(CH2)t—C(O)—NH—(CH2)t—C(RV)2—SO3H, —N(H)—(CH2)t—C(RV)2—(CH2)t—COOH, carboxypiperidin-1-yl, carboxypyrrolidin-1-yl, or N-carboxymethyl-N-benzylamino;
RI is aryl, —CH2-aryl, or —CH2-heteroaryl;
RII is aryl optionally substituted with up to two substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, aryl and heteroaryl;
RIII is aryl or heteroaryl;
RIV represents independently for each occurrence H or OH;
RV represents independently for each occurrence hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, or —CO2—(C1-C6)-alkyl, wherein each RV is optionally and independently substituted with a substituent selected independently from the group consisting of —NH2, —NH—C(O)—(C1-C4)-alkyl and —OH; or two RV are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring; and
t represents independently for each occurrence 0, 1, or 2.
In another aspect, the invention provides a compound represented by formula IV:




including pharmaceutically acceptable salts thereof, wherein

RI is —CH2-aryl, —CH2CH2-aryl, —CH2-heteroaryl, or —CH2CH2-heteroaryl;
RII is aryl optionally substituted with up to two substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, aryl, and heteroaryl;
RIII is aryl or heteroaryl; and
q is 1, 2, or 3.
In certain instances, RI is —CH2CH2-aryl or —CH2CH2-heteroaryl.
In another aspect, the invention provides a compound represented by formula V:




including pharmaceutically acceptable salts thereof, wherein

R20 is phenyl, monocyclic heteroaryl, —C1-C3-alkyl-NH—C(O)—C1-C4-alkyl, or —C1-C3-alkyl-C(O)O—C1-C4-alkyl, wherein the phenyl is optionally substituted at the 2-position and the 4-position with a substituent independently selected from the group consisting of chloro, —CN, —OH and —O—C1-C4-alkyl;
R21 is naphthyl, 2,4-dichlorophenyl,




    
    
        R23 is hydrogen, CF3, or phenyl;
        R24 is hydrogen, chloro, fluoro, bromo, CF3, methoxy, phenoxy, benzyloxy, or 4-pyridyl; and
        R25 is hydrogen, chloro, fluoro, methoxy, —C(O)O—CH2—R27, —NH—C(O)O—CH2—R27, or —O—CH2—R27, wherein R27 is selected from hydrogen, C1-C3-alkyl, or phenyl; and
        R26 is hydrogen, fluoro, or methoxy;
    
    


R22 is phenyl, monocyclic heteroaryl, or —C1-C3-alkyl-NH—C(O)—C1-C4-alkyl, wherein the phenyl is (i) optionally monosubstituted at 2-, 3- or 4-position with a substituent selected from the group consisting of bromo, chloro, fluoro, —CN, NO2, CF3, —O—C1-C4-alkyl, and t-butyl; (ii) additionally optionally substituted at the 4-position with 4-pyridyl, phenylethyl, benzyl, or phenyl; and (iii) optionally disubstituted at the 3- and 4-positions with fluoro:
Sp is




and when a and b are simultaneously 0, Sp is additionally selected from





wherein:

 represents the portion of Sp bound to the (NH)b portion of the compound; and

    
    
        “*” represents the portion of Sp bound to the NH—CH((CH2)p—R22) portion of the compound;
    
    


X is —OH, —NH—(CH2)t—C(RV)2—(CH2)t—COOH, —NH—(CH2)t—C(RV)2—SO3H, —NH—(CH2)t—C(RV)2—(CH2)t—C(O)—NH—(CH2)t—C(RV)2—SO3H, carboxypiperidin-1-yl, carboxypyrrolidin-1-yl, or N-carboxymethyl-N-benzylamino, and when Sp is




X is additionally selected from —NH—(C1-C6)-alkyl-OH, wherein:

    
    
        each t independently represents 0, 1 or 2; and
        each RV independently represents hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, or —CO2—(C1-C6)-alkyl, wherein each RV is optionally and independently substituted with a substituent selected independently from the group consisting of —NH2, —NH—C(O)—(C1-C4)-alkyl and —OH; or
        two RV are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring,
    
    


a is 0 or 1;
b is 0 or 1;
each p is independently selected from 1 or 2;
the stereochemistry at (1) and (3) are the same; and
the stereochemistry at (1) and (2) are different.
In another aspect, the invention provides a compound represented by formula VI:




including pharmaceutically acceptable salts thereof, wherein:

R30 is an unsubstituted aryl, 4-t-butoxyphenyl, 4-hydroxyphenyl, or an unsubstituted heteroaryl;
R31 is




    
    
        R40 is hydrogen, halogen, —CF3, methoxy, —NH—C(O)O—CH2-phenyl, or —O—CH2-phenyl;
        R41 is hydrogen or —CF3;
        R42 is hydrogen, 4-pyridyl, or halogen; and
    
    


X is —OH, —NH—(CH2)t—C(RV)2—(CH2)t—COOH, —NH—(CH2)t—C(RV)2—SO3H, —NH—(CH2)t—C(RV)2—(CH2)t—C(O)—NH—(CH2)t—C(RV)2—SO3H, carboxypiperidin-1-yl, carboxypyrrolidin-1-yl, N-carboxymethyl-N-benzylamino, or —NH—(C1-C6)-alkyl-OH, wherein:

    
    
        each t independently represents 0, 1 or 2; and
        each RV independently represents hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, or —CO2-alkyl, wherein each RV is optionally substituted with a substituent selected independently from the group consisting of —NH2, —NH—C(O)—(C1-C4)-alkyl and —OH; or
        two RV are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring,
    
    


p is 1 or 2;
the stereochemistry at (1) is (S);
the stereochemistry at (2) is (S); and
the stereochemistry at (3) is (S).
In yet another aspect, the invention provides a compound represented by formula VII:




including pharmaceutically acceptable salts thereof, wherein:

R50 is benzyl, phenylethyl, indol-3-ylmethyl, thien-2-ylmethyl, biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, or 4-(pyridin-2-yl)benzyl, wherein the benzyl, biphenyl-4-yl or phenylethyl group in R50 is optionally substituted on a terminal phenyl ring with a single substituent selected from the group consisting of halo, methoxy, CF3, hydroxy, cyano, and C1-C4 alkyl; or is optionally substituted with chloro at each of the 2 and 4 positions of the terminal phenyl ring;
R51 is biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, or 4-(pyridin-3-yl)benzyl, wherein the biphenyl group in R51 is optionally monosubstituted at the 4-position of the terminal phenyl ring with amino, halo or hydroxy;
R52 is phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl, heteroarylmethyl, 4-(heteroaryl)benzyl, or biphenyl-4-ylmethyl, wherein the phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl or biphenyl-4-ylmethyl group in R52 is optionally on a terminal phenyl ring with 1 to 2 substituents independently selected from the group consisting of halo, methoxy, hydroxy, C1-C4 alkyl, and C1-C4 haloalkyl;
R53 is hydrogen or methyl;
X is —OH, —N(RW)—[C(RV)2]1-4—COOH, —N(RW)—[C(RV)2]1-3—SO3H, —N(RW)—[C(RV)2]0-4—S(O)2CH3, or —N(RW)—[C(RV)2]1-3-1H-tetrazol-5-yl, wherein:
RW represents hydrogen, methyl or benzyl; and
each RV independently represents hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, or —CO2-alkyl, wherein each RV is optionally substituted with a substituent selected independently from the group consisting of —NH2, —NH—C(O)—(C1-C4)-alkyl and —OH; or
two RV are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring,
the stereochemistry at (1) is the same as the stereochemistry at (3); and
the stereochemistry at (1) is opposite the stereochemistry at (2).
In a more specific aspect of a compound of Formula VII, R50 is selected from benzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2,4-dichlorobenzyl, 3-methoxybenzyl, 4-hydroxybenzyl, 4-cyanobenzyl, 4-methoxybenzyl, 4-t-butylbenzyl, phenylethyl, 2-fluorophenylethyl, indol-3-ylmethyl, thien-2-ylmethyl, biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, or 4-(pyridin-2-yl)benzyl;
R51 is biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, 4-(4-aminophenyl)benzyl, 4-(4-bromophenyl)benzyl, 4-(4-fluorophenyl)benzyl, or 4-(4-hydroxyphenyl)benzyl;
R52 is 2,4-dichlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methylbenzyl, biphenyl-4-ylmethyl, indol-3-ylmethyl, thien-2-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, 4-(pyridin-2-yl)benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, naphthyl, naphthylmethyl, phenylethyl, thiazol-3ylmethyl, 4-(thien-2-yl)benzyl, furan-2ylmethyl, N-phenyl-1H-triazol-4ylmethyl, 4-(4-fluorophenyl)benzyl, or 4-(4-chlorophenyl)benzyl; and
X is —N(CH3)CH2SO3H, —N(CH3)CH(benzyl)COOH, —N(CH3)CH(CH3)COOH, —NHCH2COOH, —NHCH2SO3H, —NHCH2-1H-tetrazol-5-yl, —NH(CH2)2COOH, —NH(CH2)2SO3H, —NH(CH2)3COOH, —NH(CH2)3SO3H, —NH(CH2)2-1H-tetrazol-5-yl, —NHCH(4-hydroxybenzyl)COOH, —NHCH(benzyl)COOH, —NHCH(benzyl)-1H-tetrazol-5-yl, —NHCH(CH2OH)COOH, —NHCH(phenylethyl)COOH, or —NHS(O)2CH3.
In another aspect, the invention provides the compounds listed in Table 1.










TABLE 1





Com-





pound

MS
MS


No.
Structure
Calcd
Observed


















1




786.2961
786.2882


 


2




786.3109
786.3170


 


3




786.3109
786.3104


 


4




818.2855
818.2896


 


5




772.2800
772.2828


 


6




758.3007
758.2973


 


7




800.3113
800.3155


 


8




745.2691
745.2740


 


9




840.3426
840.3406


 


10




933.3640
933.3749


 


11




933.3794
933.3770


 


12




933.3794
933.3788


 


13




933.3794
933.3763


 


14




871.3637
871.3625


 


15




857.3481
857.3528


 


16




965.3539
965.3506


 


17




869.3481
869.3429


 


18




869.3481
869.3526


 


19




843.3171
843.3121


 


20




857.3327
857.3318


 


21




857.3327
857.3372


 


22




873.3276
873.3365


 


23




897.3640
897.3596


 


24




857.3327
857.3305


 


25




871.3484
871.3495


 


26




885.3640
885.3698


 


27




901.3231
901.3143


 


28




914.3911
914.3812


 


29




915.3387
915.3327


 


30




871.3484
871.3432


 


31




883.3484
883.3467


 


32




883.3484
883.3474


 


33




933.3640
933.3663


 


34




871.3406
871.3464


 


35




1014.4435
1014.4315


 


36




931.3489
931.3433


 


37




897.3640
897.3610


 


38




897.3640
897.3634


 


39




869.3327
869.3422


 


42




752.3113
752.3077


 


43




786.2956
786.2896


 


44




710.2643
710.2554


 


45




634.2330
634.2209


 


46




704.3079
704.2955


 


47




800.3113
800.3095


 


48




774.2603
774.2522


 


49




785.2763
785.2687


 


50




787.2909
787.2942


 


51




785.2763
785.2692


 


52




785.2763
785.2809


 


53




785.2763
785.2703


 


54




750.2967
750.2972


 


55




786.2956
786.3016


 


56




798.2967
798.2900


 


57




798.2967
798.2913


 


58




800.2759
800.2723


 


59




800.2759
800.2648


 


60




726.2592
726.2609


 


61




724.2446
724.2427


 


62




808.3022
808.2966


 


63




808.3022
808.2992


 


64




754.2542
754.2531


 


65




752.2396
752.2330


 


66




822.3178
822.3117


 


67




824.3324
824.3272


 


68




768.2698
768.2757


 


69




768.2698
768.2698


 


72




793.3137
793.3073


 


73




793.3137
793.3129


 


74




792.2520
792.2447


 


75




792.2520
792.2620


 


76




772.2800
772.2802


 


77




854.2830
854.2804


 


78




854.2830
854.2861


 


79




854.2830
854.2835


 


80




800.3113
800.3138


 


81




820.2567
820.2551


 


82




778.1869
778.1863


 


83




710.2643
710.2559


 


84




716.3113
716.3038


 


85




788.1748
788.1722


 


86




782.3218
782.3104


 


87




726.2592
726.2487


 


88




740.2749
740.2802


 


89




778.2517
778.2587


 


90




766.3269
766.3218


 


91




724.2800
724.2870


 


92




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816.3036


 


93




770.2854
770.2805


 


94




735.2596
735.2504


 


95




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800.3062


 


96




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796.3118


 


97




716.2207
716.2266


 


98




726.2262
726.2288


 


99




736.2800
736.2870


 


100




714.2705
714.2690


 


101




710.2643
710.2703


 


102




726.2597
726.2664


 


103




724.2805
724.2864


 


104




740.2754
740.2775


 


105




744.2258
744.2218


 


106




755.2499
755.2486


 


107




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788.1765


 


108




768.3397
768.3386


 


109




768.3397
768.3410


 


110




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824.3666


 


111




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796.2358


 


112




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113




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794.3627


 


114




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796.3522


 


115




784.3458
784.3484


 


116




828.3159
828.3107


 


117




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792.341


 


118




846.3115
846.3118


 


119




780.3397
780.3353


 


120




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766.3179


 


121




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796.3316


 


122




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784.2748


 


123




768.3033
768.3011


 


124




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125




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819.3434


 


126




781.335
781.3309


 


127




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779.3175


 


128




780.3397
780.3350


 


129




795.2754
795.2748


 


130




795.2754
795.2807


 


131




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132




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804.2449


 


133




806.2568
806.2598


 


134




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135




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808.2766


 


136




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800.3324


 


137




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802.3115


 


138




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139




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140




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846.3099


 


141




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781.3350


 


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822.3170


 


143




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144




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767.3433


 


145




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759.2859


 


146




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147




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751.1730


 


148




813.2070
813.2111


 


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759.2335


 


150




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821.3181


 


151




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759.2996


 


152




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757.2880


 


153




772.1982
772.1990


 


154




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155




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810.1420


 


156




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906.3494


 


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960.3359


 


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888.2062


 


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802.3086


 


163




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840.2830


 


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798.3129


 


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810.3486


 


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812.3497


 


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800.4058


 


192




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800.3146


 


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935.236*


 


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745.2604


 


216




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918.2019
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222




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896.3550


 


223




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902.3079


 


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226




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820.2759


 


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231




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888.2430


 


234




894.1978
894.1982


 


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237




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824.1951


 


241




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804.2228


 


244




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810.1761


 


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247




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780.3430


 


248




794.3548
794.3606


 


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783.3069


 


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830.3194


 


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263




880.3169
880.3190


 


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809.3674


 


266




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851.3777


 


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270




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273




818.2855
818.2860


 


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818.2875


 


281




818.2855
818.2849


 


282




995.3791
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824.2457


 


284




808.2652
808.2674


 


285




843.2812
843.2819


 


286




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886.2091


 


288




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836.2786


 


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832.3040


 


291




731.2539
731.2563


 


292




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810.1782


 


293




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820.1610


 


294




806.1495
806.1500


 


295




922.4498
922.4511


 


296




946.3809
946.3768


 


297




842.3224
842.3187


 


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842.3213


 


299




840.3067
840.3047


 


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920.3302


 


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830.430*


 


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828.3050


 


306




868.3380
868.3387


 


307




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870.3533


 


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886.3110


 


309




832.3011
832.3054


 


310




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802.2928


 


311




813.3248
813.3250


 


312




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798.3173


 


313




812.3296
812.3334


 


314




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837.3281


 


315




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846.3013


 


316




837.3248
837.3282


 


317




842.3401
842.3423


 


318




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818.2899


 


319




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816.3090


 


320




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920.3743


 


321




816.3067
816.3123


 


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906.3605


 


324




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906.3553


 


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888.3301


 


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327




874.3122
874.3143


 


328




906.3537
906.3549


 


329




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802.2952


 


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332




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876.2925


 


333




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952.3285


 


336




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967.3333


 


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802.2952


 


339




816.3067
816.3093


 


340




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830.3226


 


343




908.3329
908.3321


 


344




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346




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817.3229


 


347




817.3271
817.3220


 


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783.3016


 


350




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351




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353




891.4081
891.4115


 


354




879.4081
879.4113


 


355




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703.1981


 


357




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719.2543


 


358




714.2228
714.2231


 


359




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360




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361




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789.2590


 


362




894.3167
894.3183


 


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775.2836


 


365




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779.2308


 


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746.413*


 


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737.191*


 


368




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731.2487


 


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372




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375




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843.3111


 


376




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843.3151


 


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843.3142


 


379




886.3592
886.3623


 


380




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382




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383




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384




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386




830.3224
830.3173


 


387




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908.3256


 


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389




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916.3495


 


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788.3083


 


391




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906.3481


 


394




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1049.3748


 


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737.463*


 


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903.3421


 


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942.4213


 


404




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699.404*


 


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1051.2570


 


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1063.3899


 


412




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413




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1049.3765


 


414




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1049.3789


 


415




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1065.2717


 


416




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1065.2860


 


417




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1051.2556


 


418




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1051.2538


 


419




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795.3530


 


420




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865.3970


 


421




879.4076
879.4080


 


422




941.4232
941.4266


 


423




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941.4277


 


424




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794.3604


 


425




808.3705
808.3701


 


426




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942.4214


 


427




761.2645
761.2670


 


428




761.2645
761.2606


 


429




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979.3712


 


430




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965.3544


 


431




967.2336
967.2368


 


432




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979.3717


 


433




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434




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965.3569


 


435




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965.3563


 


436




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981.2509


 


437




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981.2558


 


438




967.2336
967.2320


 


439




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967.2325


 


440




943.3030
943.3055


 


441




933.3145
933.3160


 


442




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966.3507


 


443




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999.3163


 


444




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947.3796


 


445




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947.3798


 


446




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871.3491


 


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871.3489


 


449




885.3645
885.374*


 


450




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883.3516


 


452




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885.3699


 


453




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857.3340


 


454




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794.415*


 


455




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941.4252


 


456




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941.4239


 


457




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865.3929


 


458




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865.3914


 


459




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865.3919


 


460




879.4081
879.4088


 


461




893.4238
893.4277


 


462




851.3768
851.3773


 


463




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794.3611


 


464




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466




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794.3560


 


467




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468




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794.3554


 


469




794.3548
794.3530


 


470




955.4394
955.4442


 


471




957.4187
957.4205


 


472




816.3067
816.3090


 


473




830.3224
830.3261


 


475




830.3224
830.3271


 


477




844.3380
844.3428


 


478




842.3224
842.3268


 


479




873.3282
873.3335


 


480




906.3537
906.3583


 


481




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906.3583


 


482




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852.2747


 


483




898.2944
898.2974


 


484




955.3523
955.3572


 


485




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920.3749


 


486




846.3173
846.3233


 


487




858.3537
858.3578


 


488




706.2877
706.2907


 


489




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811.3758


 


490




762.3503
762.3538


 


491




845.3550
845.3603


 


493




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786.2971


 


494




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786.2965


 


495




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786.2995


 


496




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786.2957


 


497




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786.2967


 


498




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786.2978


 


499




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786.2975


 


500




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786.2979


 


501




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786.2973


 


502




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786.2986


 


503




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786.2996


 


504




941.4238
941.4249


 


505




956.4347
956.4343


 


506




754.3235
754.3247


 


507




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739.3108


 


508




776.3654
776.3674


 


509




781.3596
781.3625


 


510




829.3596
829.3623


 


511




753.3283
753.3282


 


512




798.3134
798.3156


 


513




767.3440
767.3470


 


514




825.3858
825.3881


 


515




809.3909
809.3929


 


516




986.4117
986.4133


 


517




817.2232
817.2252


 


518




830.3548
830.3561


 


519




771.3189
771.3201


 


520




821.3157
821.3164


 


521




769.3232
769.3238


 


522




783.3389
783.3395


 


523




754.3235
754.3235


 


524




789.3095
789.3135


 


525




747.1483
747.1501


 


526




893.3215
893.3243


 


527




701.2440
701.2451


 


528




998.4453
998.4461


 


529




1033.4277
1033.4279


 


530




821.3004
821.3016


 


531




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813.2584


 


532




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763.2616


 


533




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813.2593


 


534




761.2640
761.2665


 


535




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775.2825


 


536




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746.2640


 


537




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771.2863


 


538




751.2255
751.2278


 


539




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761.1649


 


540




743.2746
743.2780


 


541




728.2385
728.2375


 


542




1034.4122
1034.4131


 


543




748.31
748.31


 


544




776.32
776.16


 


545




787.29
787.11


 


546




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795.32


 


547




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801.16


 


548




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787.33


 


549




786.30
786.44


 


550




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794.50


 


551




800.31
800.35


 


552




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786.37


 


553




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901.31


 


554




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901.31


 


555




841.36
841.18


 


556




841.36
841.25


 


557




825.36
825.13


 


558




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811.37


 


559




825.36
825.44


 


560




839.38
839.26


 


561




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906.35


 


562




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906.35


 


563




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848.13


 


564




832.30
832.15


 


565




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908.27


 


566




854.25
854.12


 


567




992.42
992.36


 


568




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914.41


 


569




900.40



 


570




886.38
886.14


 


571




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916.44


 


572




900.40
900.35


 


573




976.43
976.47


 


574




976.43
976.47


 


575




844.34
844.23


 


576




844.34
844.09


 


577




900.40
900.28


 


578




797.37
797.24


 


579




901.39
901.68


 


580




915.41
915.52


 


581




977.42
977.35


 


582




977.42
977.43


 


583




917.39
917.44


 


584




917.39
917.37


 


585




993.42
993.40


 


586




993.42
993.48


 


587




910.33
910.71


 


588




898.29
898.62


 


590




930.38
930.38


 


591




916.36
916.77


 


592




826.31
826.53


 


593




925.41
925.72


 


594




925.29
925.45


 


595




838.26
838.21


 


596




852.27
852.22


 


597




866.29
866.29


 


598




847.31
847.25


 


599




861.33
861.19


 


600




875.34
875.40


 


601




831.32
831.35


 


602




836.28
836.26


 


603




866.29
866.11


 


604




880.31
880.23


 


605




852.27
852.27


 


606




880.31
880.31


 


607




965.38
965.15


 


608




922.35
922.39


 


609




936.36
936.31


 


610




950.38
950.38


 


611




910.40
910.28


 


612




924.42
924.35


 


613




856.25
856.04


 


614




844.21
844.06


 


615




915.28
915.15


 


616




773.30
773.42


 


617




911.40
911.52


 


618




923.34
923.43


 


619




835.37
835.33


 


620




915.41
915.22


 


621




990.44
990.30


 


622




920.37
920.22


 


623




990.44
990.45


 


624




991.44
991.33


 


625




991.44
991.33


 


626




763.26
763.22


 


627




763.26
763.07


 


628




763.26
763.14


 


629




759.29
759.07


 


630




775.28
775.27


 


631




775.28
775.12


 


632




751.23
751.23


 


633




822.30
822.24


 


634




822.30
822.24


 


635




822.30
822.24


 


636




801.33
801.16


 


637




758.30
758.11


 


638




758.30
758.11


 


639




770.32
770.17


 


640




770.32
770.17


 


641




784.28
784.07


 


642




784.28
784.07


 


643




813.26
813.07


 


644




817.33
817.21


 


645




817.33
817.21


 


646




817.33
817.36


 


647




740.31
740.21


 


648




808.30
808.26


 


649




808.30
808.26


 


650




808.30
808.19


 


651




808.23
808.11


 


652




774.27
774.16


 


653




746.26
746.13


 


654




779.32
779.19


 


655




756.30
756.19


 


656




777.28
777.35


 


657




775.28
775.32


 


658




760.28
760.27


 


659




760.28
760.29


 


660




697.27
697.27


 


661




754.32
754.20


 


662




755.32
755.22


 


663




754.32
754.20


 


664




755.32
755.29


 


665




755.32
755.15


 


666




755.32
755.15


 


667




755.32
755.22


 


668




755.32
755.29


 


669




755.32
755.22


 


670




761.16
761.00


 


672




717.21
717.21


 


673




663.29
663.29


 


674




769.33
769.21


 


675




759.29
759.15


 


676




759.29
759.15


 


677




745.27
745.09


 


678




745.27
745.09


 


679




771.32
771.35


 


680




771.32
783.1866771.1297


 


681




771.32
771.20


 


682




783.34
783.19


 


683




783.34
783.19


 


684




830.36
830.30


 


685




830.36
830.30


 


686




830.36
830.30


 


687




859.37
859.30


 


688




769.32
769.13


 


689




743.31
743.10


 


690




787.29
787.18


 


691




821.32
821.21


 


692




821.32
821.21


 


693




821.32
821.28


 


694




767.34
767.14


 


695




820.35
820.17


 


696




803.34
803.16


 


697




803.34
803.16


 


698




760.28
760.11


 


699




821.25
821.21


 


700




847.35
847.24


 


701




767.34
767.14


 


702




865.34
865.14


 


703




705.33
705.15


 


704




863.32
863.07


 


705




769.29
769.06


 


706




835.32
835.11


 


707




792.34
792.14


 


708




757.33
757.08


 


709




787.29
787.11


 


710




945.36
945.25


 


711




973.40
973.43


 


712




1001.43
1001.39


 


713




969.46
969.44


 


713




843.35
843.37


 


714




881.37
881.38


 


715




877.39
877.42


 


715




839.38
839.39


 


716




902.39
902.40


 


717




864.37
864.38


 


718




881.37
881.36


 


719




843.35
843.37


 


720




877.39
877.41


 


721




902.39
902.39


 


722




864.37
864.39


 


723




758.30
758.30


 


724




705.33
705.33


 


725




829.36
829.40


 


726




821.30
821.31


 


727




779.32
779.31


 


728




796.31
796.33


 


729




758.30
758.29


 


730




792.34
792.35


 


731




817.33
817.35


 


732




779.32
779.33


 


733




796.31
796.32


 


734




792.34
792.35


 


735




957.40
957.38


 


736




919.38
919.40


 


737




953.42
953.45


 


738




915.41
915.45


 


739




978.42
978.70


 


740




940.40
940.41


 


741




957.40
957.41


 


742




919.38
919.40


 


743




953.42
953.45


 


744




978.42
978.45


 


745




940.40
940.43


 


746




873.38
873.39


 


747




992.43
992.45









In the above table, calculated (MS Calcd) and observed (MS Observed) mass spectrometry values were determined for most compounds using high-resolution mass spectrometry. An “*” after the observed value indicates that the mass spectrometry value for that compound was determined using low-resolution mass spectrometry. Mass spectrometry measurements were performed using electrospray ionization (ESI).
The macrocyclic compounds described herein can be prepared using an iterative peptide coupling procedure as illustrated in following synthetic schemes. An exemplary retrosynthetic analysis is presented in Scheme 1, and exemplary general synthetic protocol is presented in Scheme 2. The schemes and accompanying description of synthetic procedures are given for the purpose of illustrating the invention, and should not be construed as limiting the scope or spirit of the invention.







Scheme 1 shows an exemplary retrosynthetic analysis of a macrocyclic compound. The amide side chain of the macrocyclic compound may be installed last by functionalization of an carboxylic ester macrocyclic precursor. This late-stage functionalization of the carboxylic ester allows for easy introduction of a variety of amide side chain groups, or variously functionalized carboxylic esters by transesterifcation. The macrocyclic ring is formed by an amide bond forming reaction, after removing the amino protecting group from the acyclic precursor. The acyclic precursor compound can be constructed by performing an iterative peptide coupling reaction; the reaction may be performed on a substrate bound to a solid support to simplify purification. The iterative peptide coupling reaction allows for easy installation of a variety of amino acid components into the macrocyclic backbone.







Scheme 2 shows an exemplary synthetic protocol for preparing a macrocyclic compound. The synthesis may be performed on solid support in order to simplify purification of synthetic intermediates. For example, hydroxyl-bearing resin 2A can be reacted with a suitably protected amino acid. Side chain (Ra) of the amino acid may be varied in order to prepare macrocyclic compounds having different substituents at this position. Dipeptide 2C may be prepared by removing the protecting group (Pg) from 2B and then performing a peptide coupling reaction with amino acid HO2CC(H)(R2)N(H)Pg. The third amino acid making up the core of the macrocycle is installed by repeating the deprotection/peptide coupling process using the same or different protected amino acid to provide tripeptide 2D. The remaining portion of the macrocycle backbone is installed in step four, again using a peptide coupling reaction to splice the substituted succinic acid with the resin-bound tripeptide 2D following removal of the protecting group from tripeptide 2D. In the fifth step, the amino protecting group is removed and the substrate is cleaved from the solid support to provide acyclic intermediate 2F. The macrocyclic core is constructed by subjecting 2F to conditions suitable for amide bond formation. The carboxylic ester side chain on macrocycle 2G can be converted to various esters by transesterication, the acid by simply hydrolysis, or to various amide compounds, e.g., 2I, using standard synthetic procedures. See, for example, J. March “Advanced Organic Chemistry Reactions, Mechanisms, and Structure” 4th Edition, John Wiley & Sons, 1992.
Additional synthetic procedures are provided in examples 1-4 below.
Combinations of substituents and variables are only those that result in the formation of compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
II. Therapeutic Applications of Macrocyclic Compounds
It is contemplated that the compounds of formula I and related macrocyclic compounds, for example, those embraced by formula II, provide therapeutic benefits to patients suffering from or susceptible to any one of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic lupus erythematosus, systemic sclerosis, insulin-dependent diabetes mellitus, cancer, multiple sclerosis, septic shock syndrome, asthma, Alzheimer's disease, an inflammatory eye disease, uveitis, and inflammation. Accordingly, one aspect of the invention provides a method of treating a patient suffering from or susceptible to a disorder selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic lupus erythematosus, systemic sclerosis, insulin-dependent diabetes mellitus, cancer, multiple sclerosis, septic shock syndrome, asthma, Alzheimer's disease, an inflammatory eye disease, uveitis, and inflammation, comprising administering a therapeutically effective amount of a composition comprising a compound described herein to the patient in need thereof.
In certain instances, the disorder is rheumatoid arthritis, psoriasis, Crohn's disease, cancer, multiple sclerosis, asthma, Alzheimer's disease, or ulcerative colitis. In certain other instances, the disorder is rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, ulcerative colitis, Wegener's granulomatosis, or sarcoidosis. In certain other instances, the disorder is rheumatois arthritis.
In certain instances, compound is a compound of formula III, III-A, IV, V, VI, or VII.
The invention also provides for combination therapy of a macrocyclic compound described herein and a second therapeutic agent. “Combination therapy” (or “co-therapy”) includes the administration of a macrocyclic compound described herein and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment.) Where the combination therapy further comprises a non-drug treatment, the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
Accordingly, in certain instances, the method further comprises administering a therapeutically effective amount of an anti-inflammatory agent. In certain instances, the anti-inflammatory agent is a salicylate, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, ibuprofen, alminoprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, phenylbutazone, sulfinpyrazone, celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, prednisone, methylprednisolone, hydrocortisone, or budesonide.
In certain instances, the method further comprises administering a therapeutically effective amount of an agent for treating multiple sclerosis. In certain instances, the agent for treating multiple sclerosis is interferon beta-2, interferon beta-1, glatiramer, natalizumab, or mitoxantrone.
In certain instances, the method further comprises administering infliximab, etanercept, adalimumab, or certolizumab pegol.
In certain instances, the method is designed to treat rheumatoid arthritis and further comprises the step of administering to the patient in need thereof a therapeutically effective amount of an agent selected from the group consisting of a salicylate, diclofenac, aceclofenac, acemetacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, ibuprofen, alminoprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, phenazone, sulfinpyrazone, celecoxib, etoricoxib, lumiracoxib, parecoxib, prednisone, methylprednisolone, hydrocortisone, and budesonide.
Another aspect of the invention provides a method of modulating the activity of tumor necrosis factor alpha on a cell, comprising exposing a cell comprising on its surface a receptor for tumor necrosis factor alpha to a compound described herein. In certain instances, the compound reduces or inhibits the activity of tumor necrosis factor alpha on the cell.
IV. Pharmaceutical Compositions and Dosing Considerations
The invention also provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term “pharmaceutically-acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19)
The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically-acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, e.g., Berge et al., supra)
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.
Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection or infusion, by inhalation, topically by lotion or ointment, or by suppositories. Oral administrations are preferred.
The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
The compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or (8) nasally.
In some embodiments, in vivo administration is effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations are carried out with the dose level and pattern being selected by the treating physician.
Suitable dosage formulations and methods of administering the agents are readily determined by those of skill in the art. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.
The pharmaceutical compositions can be administered orally, intranasally, parenterally or by inhalation therapy, and may take the form of tablets, lozenges, granules, capsules, pills, ampoules, suppositories or aerosol form. They may also take the form of suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents, syrups, granulates or powders. In addition to an agent of the present invention, the pharmaceutical compositions can also contain other pharmaceutically active compounds or a plurality of compounds of the invention.
In yet another embodiment, the invention provides any of the pharmaceutical compositions set forth above for use in the treatment of a disease or condition selected from rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic lupus erythematosus, systemic sclerosis, insulin-dependent diabetes mellitus, cancer, multiple sclerosis, septic shock syndrome, asthma, Alzheimer's disease, an inflammatory eye disease, uveitis, and inflammation. In a more specific embodiment, the invention provides a pharmaceutical composition comprising a compound of any one of Formulae I-VII, or any of Compounds 1-747 for use in the treatment of rheumatoid arthritis.
V. Pharamceutical Kits
The invention also provides kits for use to treat rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease, Behcet's disease, ulcerative colitis, Wegener's granulomatosis, sarcoidosis, systemic lupus erythematosus, systemic sclerosis, insulin-dependent diabetes mellitus, cancer, multiple sclerosis, septic shock syndrome, asthma, Alzheimer's disease, an inflammatory eye disease, uveitis, or inflammation. The kits comprise (a) a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat the specific disease.
The container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn contained within a box. In one embodiment, the container is a blister pack.
The kits may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition. Such device may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.
In certain instances, the kits may comprise in a separate vessel or container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a macrocyclic compound described herein.
VI. Definitions
To facilitate an understanding of the present invention, a number of terms and phrases are defined below.
The term “alkyl” is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
The term “substituted” refers to the replacement of a hydrogen atom in a moiety with a functional group. The term “moiety” refers to a portion of a compound of this invention comprising at least one hydrogen atom and at least one carbon atom.
The term “substituted alkyl” refers to an alkyl group that is substituted by at least one functional group. Representative functional groups include halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, —CF3, —CN, or the like. In certain instanes, the substituted alkyl group contains 1 or 2 of the foregoing substituents.
The term “alkylene” refers to the diradical of an alkyl group.
The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. For example, —CH2F, —CHF2, —CF3, —CH2CF3, —CF2CF3, and the like.
The term “aralkyl” refers to an alkyl group substituted with an aryl group.
The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl group.
The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
The term “aryl” is art-recognized and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. The term “aryl” also includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. If specified that the aryl group may be substituted, then the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, —CF3, —CN, or the like.
The term “arylene” refers to the diradical of an aryl group.
The “heteroaryl” is art-recognized and refers to aromatic groups that include at least one ring heteroatom. In certain instances, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representative examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like. If specified that the heteroaryl group may be substituted, then the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, —CF3, —CN, or the like. The term “heteroaryl” also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
The term “carbocyclyl” refers to a saturated or unsaturated carbocyclic group. Representative carbocyclyl groups include cycloalkyl groups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like), and aryl groups (e.g., phenyl, naphthyl, anthracenyl, and the like). The term “carbocyclyl” also includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”).
The term “alkyl-carbocyclyl” refers to an alkyl group that is substituted by a carbocyclyl group. For example, the term “alkyl-carbocyclyl” incompasses benzyl, —CH2CH2-phenyl, —CH2CH2-cyclopropyl, and the like.
As used herein, the terms “heterocyclic” and “heterocyclyl” are used interchangeably and represent a saturated or unsaturated cyclic group that includes at least one ring heteroatom. For example, the terms “heterocyclic” and “heterocyclyl” encompass an aromatic or nonaromatic ring containing one or more heteroatoms. The heteroatoms can be the same or different from each other. Examples of heteratoms include, but are not limited to nitrogen, oxygen and sulfur. Aromatic and nonaromatic heterocyclic rings are well-known in the art. Some nonlimiting examples of aromatic heterocyclic rings include pyridine, pyrimidine, indole, purine, quinoline and isoquinoline. Nonlimiting examples of nonaromatic heterocyclic compounds include piperidine, piperazine, morpholine, pyrrolidine and pyrazolidine. Examples of oxygen containing heterocyclic rings include, but not limited to furan, oxirane, 2H-pyran, 4H-pyran, 2H-chromene, and benzofuran. Examples of sulfur-containing heterocyclic rings include, but are not limited to, thiophene, benzothiophene, and parathiazine. Examples of nitrogen containing rings include, but not limited to, pyrrole, pyrrolidine, pyrazole, pyrazolidine, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, indole, purine, benzimidazole, quinoline, isoquinoline, triazole, and triazine. Examples of heterocyclic rings containing two different heteroatoms include, but are not limited to, phenothiazine, morpholine, parathiazine, oxazine, oxazole, thiazine, and thiazole.
The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formula:




wherein each R60 independently represent hydrogen, alkyl, alkenyl, —(CH2)m—R61, or both R60 taken together with the N atom to which they are attached form a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one R60 may be a carbonyl, e.g., both R60 and the nitrogen together do not form an imide. In other embodiments, each R60 independently represents a hydrogen, an alkyl, an alkenyl, or —(CH2)m—R61. Thus, the term “alkylamine” includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R60 is an alkyl group.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH2)m—R61, where m and R61 are described above.
The term “heteroarylmethyl” refers to a heteroaryl moiety that is linked to the rest of the compound via a methylene (e.g.,




where “Het” is a heterocycle and  represent the point of attachment to the rest of the compound. The term “4-(heteroaryl)benzyl” refers to a moiety of the structure:





Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. Accordingly, a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer. The term “substantially free of other stereoisomers” as used herein means less than 25% of other stereoisomers, less than 10% of other stereoisomers, less than 5% of other stereoisomers, or less than 2% of other stereoisomers.
If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound, as well as enantiomeric mixtures thereof.
As used herein, the term “IC50” refers to the concentration of a compound at which 50% of its maximal inhibitory effect is observed.
As used herein, the term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.
As used herein, the term “effective amount” refers to the amount of a compound (e.g., a compound of the present invention) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1-4 alkyl, and the like.
Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, NH4+, and NW4+ (wherein W is a C1-4 alkyl group), and the like.
For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
EXAMPLES
The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
Starting materials for the sythetic procedures can be obtained from commercial sources or prepared using literature procedures. Abbreviations as used herein include acetonitrile (ACN); alanine (Ala); allyloxy (CO2All); α-aminoisobutyric acid (Aib); arginine (Arg); asparagine (Asp); O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU); calculated (Calcd); N,N′-diisopropylcarbodiimide (DIC); diisopropylethylamine (DIPEA); dimethylaminopyridine (DMAP); dimethylformamide (DMF); 9-fluorenylmethoxycarbonyl (Fmoc); glutamine (Glu); glycine (Gly); hexafluoroisopropanol (HFIP); 1-hydroxy-7-azabenzotriazole (HOAt); acetic acid (HOAc); high resolution mass spectrometry (HRMS); high pressure liquid chromatography (HLPC); methanol (MeOH); 1-methyl-2-pyrrolidinone (NMP); methylene chloride (DCM); 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf); phenylalanine (Phe); serine (Ser); tert-butoxycarbonyl (Boc); tert-butyl (tBu); tetrahydrofuran (THF); thienylalanine (Tha); trifluoroacetic acid (TFA); trityl (TrT); tyrosine (Tyr); O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium Hexafluorophosphate (HBTU); 1-hydroxybenzotriazole (HOBt); 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU); 1-(2-Mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole (MSNT); 4-Hydroxymethylbenzoic acid PEGA resin (HMBA-PEGA); 4-methylmorpholine (NMM); Acetic Anhydride (Ac2O).
In each of the synthesis schemes set forth in the example Ra is —(CH2)n—RI, Rb is —(CH2)n—RII, Rc is —(CH2)n—RIII, and Rd is —(CR11R12)m—, wherein RI, RII, RIII, x and n are defined as set forth for a compound of Formula II, and R11, R12, and m are defined as set forth for a compound of Formula I.
Example 1
This example describes the synthesis and characterization of macrocyclic compounds. A general synthetic sequence for preparing the macrocyclic compounds is illustrated schematically below.










Compound 1

Step 1: Fmoc-Cl (27.6 g, 107.2 mmol) in 1,4-dioxane (950 mL) was added dropwise to a solution of (S)-methyl 2-amino-3-(4-nitrophenyl)propanoate (3A; 20 g, 89.3 mmol) and K2CO3 (14.8 g , 107.2 mmol) in water (80 mL) and 1,4-dioxane (150 mL) on an ice bath. After being stirred for 2 hours at room temperature, the mixture was poured into 1.2 L of water to precipitate a white solid, which was filtered and washed with cold water. The solid was dried under vacuum for 3 hours to give 40 g of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate 3B, which was directly used in step 2.
Step 2: In a hydrogenation reactor, (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoate (3B; 25 g, 56 mmol) was dissolved in THF (200 mL), and 15 mL of 4N HCl was added to the reaction mixture. Then, 10% Pd/C (2.5 g) was added to the reaction mixture. Hydrogen was introduced into the reactor until pressure reached 4 MPa. The reaction was stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with THF. The pH of the solution was adjusted to about 7 by adding saturated NaHCO3 (aq) while the solution was on an ice bath. The organic layer was separated, and the aqueous layer was washed with CH2Cl2 (2×15 mL). The combined organic fractions were dried with anhydrous Na2SO4 to give a solution of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-aminophenyl)propanoate 3C. The solution was used directly in step 3.
Step 3: Succinic anhydride (6.72 g, 67.2 mmol) was added to the solution of (S)-methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-aminophenyl)propanoate 3C from step 2. The reaction mixture was stirred at room temperature overnight. The solvent was removed, and the residual solid was washed with 30% ethyl acetate/petroleum ether (200 mL) and recrystallized in THF and 30% ethyl acetate/petroleum ether to give (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid 3D as a white solid (19 g, 66% yield). 1HNMR (DMSO-d6, 300 MHz) δ: 10-9.9 (s, 1H), 8.0-7.9 (m, 3H), 7.8-7.6 (m, 2H), 7.6-7.5(m, 2H), 7.5-7.4(m, 2H), 7.4-7.3(m, 2H), 7.3-7.1(d, 2H), 4.4-4.2 (m, 4H), 3.8-3.6 (s, 3H), 3.1-2.8 (m, 2H), 2.7-2.5 (m, 4H); ESI-MS: m/z 517.3 (M+H)+.
Step 4: (R)-2-(((9H-Fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid (3D; 4.40 g, 11.37 mmol) was dissolved in DCM (35 mL) and added to 2-chloro-trityl chloride resin 3E (5.14 g, 8.12 mmol). DIPEA (7.06 mL, 40.6 mmol) was added to the resin suspension. The mixture was agitated for 1 hour under argon. The resin was then washed with 3×30 mL of 1% DIPEA in DCM. This coupling of (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was repeated once. After washing the resin with 3×30 mL of 17:2:1 DCM:MeOH:DIPEA, 3×30 mL of DMF and 3×30 mL of 1% DIPEA in DCM, resin 3F was obtained.
Step 5: Resin 3F was treated with 35 mL of 20% piperidine in DMF for 20 min, washed with 2×30 mL DMF and treated with another 35 mL of 20% piperidine in DMF. The resin was then washed with 3×30 mL of DMF and 3×30 mL of 1% DIPEA in DCM. To the resulting resin, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid (4.20 g, 9.05 mmol), HATU (3.44 g, 9.05 mmol) and DIPEA (3.15 mL, 18.10 mmol) in 35 mL of NMP was added. The mixture was agitated under argon at room temperature for 1.5 hours. The resin was filtered and washed with 2×30 mL of NMP. This coupling of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was repeated once. After washing the resin with 2×30 mL NMP and 4×30 mL of 1% DIPEA in DCM, resin 3G was obtained.
Step 6: Resin 3G was treated with 35 mL of 20% piperidine in DMF for 20 min, washed with 2×30 mL DMF and treated with another 35 mL of 20% piperidine in DMF. The resin was then washed with 3×30 mL of DMF and 3×30 mL of 1% DIPEA in DCM. To the resulting resin, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid (2.67 g, 6.79 mmol), HATU (3.44 g, 9.05 mmol) and DIPEA (3.15 mL, 18.10 mmol) in 35 mL of NMP was added. The mixture was agitated under argon at room temperature for 1.5 hours. The resin was filtered and washed with 2×30 mL of NMP. This coupling of (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was repeated once. After washing the resin with 2×30mL NMP and 4×30 mL of 1% DIPEA in DCM, resin 3H was obtained.
Step 7: Resin 3H (2.569 g, 2.262 mmol) was treated with 35 mL of 20% piperidine in DMF for 20 min, washed with 2×30 mL DMF and treated with another 35 mL of 20% piperidine in DMF. The resin was then washed with 3×30 mL of DMF and 3×30 mL of 1% DIPEA in DCM. To the resulting resin, (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid (1.753 g, 3.39 mmol) and HATU (1.290 g, 3.39 mmol) in 30 mL of NMP was added. DIPEA (0.591 mL, 3.39 mmol) was then added to the reaction mixture/resin suspension while agitated under argon. The mixture was agitated at room temperature for 1 hour. The resin was filtered and washed with 2×30 mL of NMP. This coupling of (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was repeated once. After washing the resin with 2×30mL NMP and 4×30 mL of 1% DIPEA in DCM, resin 31 was obtained.
Step 8: Resin 3I was treated with 35 mL of 20% piperidine in DMF for 20 min, washed with 2×30 mL DMF and treated with another 35 mL of 20% piperidine in DMF. The resin was then washed with 3×30 mL of DMF and 3×30 mL of 1% DIPEA in DCM. The resin was then treated with 30 mL of 20% HFIP in DCM for 10 min four times. The resin was then washed with DCM (3×30mL). This cleaving solution was collected and evaporated to give 0.696 g of (R)-2-((S)-2-((R)-2-(4-(4-((S)-2-amino-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanamido)-3-(thiophen-2-yl)propanamido)-3-(biphenyl-4-yl)propanamido)-3-phenylpropanoic acid (3J). The product 3J was used without further purification in step 9.
Step 9: (R)-2-((S)-2-((R)-2-(4-(4-((S)-2-amino-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanamido)-3-(thiophen-2-yl)propanamido)-3-(biphenyl-4-yl)propanamido)-3-phenylpropanoic acid (696 mg, 0.851 mmol), HATU (647 mg, 1.702 mmol) and HOAt (232 mg, 1.702 mmol) were dissolved in anhydrous DMF (810 mL). DIPEA (0.741 mL, 4.26 mmol) was then added to the stirring solution. The mixture was stirred at room temperature for 2 hours. The solvent was then evaporated. MeOH was added to the residue and evaporated to yield a gel-like slurry, to which water was added. A solid precipitate formed and was collected by filtration. After washing the solid with water, 0.937 g of crude 3K was obtained as a white solid.
Step 10: 3K (0.937 g, crude product from step 9) was dissolved in 50 mL THF. A solution of lithium hydroxide (542 mg, 22.62 mmol) in 9 mL of H2O was then added. The reaction mixture was stirred at room temperature for 40 min, and reaction progress was monitored by LC/MS. Upon completion, the solution was neutralized with 5% HCl (3 mL). Solvents were evaporated and the crude product was purified by flash chromatography using a reverse-phase cartridge (20-65% ACN/water) to give compound 1 as an off-white solid (0.656 g, 71% yield). 1H-NMR (DMSO-d6, 400 MHz) δ (ppm): 8.65-8.55 (d, 1H), 8.55-8.5 (d, 1H), 7.85-7.75 (m, 2H), 7.65-7.55(d, 2H), 7.55-7.5 (d, 2H), 7.45-7.35 (t, 3H), 7.4-7.3 (t, 2H), 7.3-7.1 (m, 13H), 7.05-7.0 (d, 2H), 6.8-6.75 (m, 1H), 6.45-6.4 (d, 1H), 4.75-4.6 (td, 1H), 4.6-4.5 (td, 1H), 4.55-4.45 (td, 1H), 4.1-3.95 (q, 1H), 3.15-3.0 (m, 2H), 2.9-2.8 (dd, 1H), 2.8-2.7 (m, 1H), 2.65-2.55 (m, 1H), 2.45-2.35 (m, 2H), 2.25-2.15 (t, 1H), 2.15-2.05 (dd, 1H).
Compound 2
Compound 2 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5 and D-homophenylalanine was used as starting material at step 6.
Compound 3
Compound 3 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used at step 7.
Compound 4
Compound 4 was prepared according to the procedures used for the synthesis of Compound 1, except that (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7. 1H-NMR (400 MHz, DMSO-d6, δ): 12.72 (br s, 1H), 8.94 (s, 1H), 8.71 (d, J=9.2 Hz, 1H), 8.60 (d, J=9.3 Hz, 1H), 7.81 (d, J=7.2 Hz, 1H), 7.60 (m, 2H), 7.53 (d, J=8.3 Hz, 2H), 7.45-7.15 (m, 13H), 7.06 (d, J=8.5 Hz, 2H), 6.74 (dd, J=3.4, 5.1 Hz, 1H), 6.49 (d, J=4.4 Hz, 1H), 6.44 (d, J=2.7 Hz, 1H), 4.72 (td, J=3.3, 10.0 Hz, 1H), 4.60-4.52 (m, 2H), 4.49 (d, J=6.4 Hz, 1H), 4.02-3.93 (m, 2H), 3.19-2.95 (m, 4H), 2.82-2.60 (m, 3H), 2.25, (dd, J=11.0, 13.2 Hz, 1H).
Compound 5
Compound 5 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-3-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-3-oxopropanoic acid was used as starting material at step 7.
Compound 6
Compound 6 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-3-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)propanoic acid was used as starting material at step 7.
Compound 7
Compound 7 was prepared according to the procedures used for the synthesis of Compound 1, except that 4-(3-(((((9H-fluoren-9-yl)methoxy)carbonyl)(2-methoxy-2-oxoethyl)amino)methyl)benzylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 8
Compound 8 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 7.
Compound 9
Compound 9 was prepared according to the procedures used for the synthesis of Compound 1, except that (1R,2R)-2-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylcarbamoyl)cyclohexanecarboxylic acid was used as starting material at step 7.
Compound 10
Steps 1-10 of the procedures used in the synthesis of Compound 1 were performed.
Step 11: A stock solution of HATU (19.82 mg, 0.052 mmol) and HOAt (3.55 mg, 0.026 mmol) in 0.75 mL of DMF was prepared and added to compound 1 (10.24 mg, 0.013 mmol). If necessary, the resulting mixture was sonicated to form a solution. To this solution was added a solution of (S)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride (6.72 mg, 0.026 mmol) in 0.75 mL DMF, followed by DIPEA (0.023 mL, 0.130 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. Solvents were evaporated, and the solid was treated with 25% TFA in DCM. Reaction progress was monitored by LC/MS, and the solvents were removed upon reaction completion. The crude product was purified by preparative HPLC to give Compound 10 as a white solid (5.5 mg, 56% yield).
Compound 11
Compound 11 was prepared according to the procedures used in the synthesis of Compound 10, except that compound 2 was used as starting material at step 11.
Compound 12
Compound 12 was prepared according to the procedures used in the synthesis of Compound 10, except that Compound 3 was used as starting material at step 11.
Compound 13
Compound 13 was prepared according to the procedures used in the synthesis of Compound 10, except that Compound 3 and (R)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride were used as starting materials at step 11.
Compound 14
Compound 14 was prepared according to the procedures used in the synthesis of Compound 10, except that Compound 3 and tert-butyl 2-amino-2-methylpropanoate hydrochloride were used as starting materials at step 11.
Compound 15
Compound 15 was prepared according to the procedures used in the synthesis of Compound 10, except that Compound 3 and tert-butyl 3-aminopropanoate hydrochloride were used as starting materials at step 11.
Compound 16
Compound 16 was prepared according to the procedures used in the synthesis of Compound 10, except that Compound 4 and (R)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride were used as starting materials at step 11.
Compound 17
Steps 1-10 of the procedures used in the synthesis of Compound 1 were performed.
Step 11: A stock solution of HATU (17.0 mg, 0.045 mmol) and HOAt (3.05 mg, 0.022 mmol) in 0.7 mL of DMF was prepared and added to Compound 3 (8.8 mg, 0.011 mmol). If necessary, the resulting mixture was sonicated to form a solution. To this solution was added a solution of 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride (3.4 mg, 0.022 mmol) in 0.7 mL DMF, followed by DIPEA (0.0195 mL, 0.112 mmol). The reaction mixture was stirred at room temperature for 25 minutes, with reaction progress monitored by LC/MS. Upon completion, the solvents were evaporated, and the residue was dissolved in THF (458 μL). A solution of lithium hydroxide (2.63 mg, 0.110 mmol) in water (90 μL) was added and the reaction mixture was vortexed. A second portion of lithium hydroxide (2.63 mg, 0.110 mmol) in water (90 μL) was added after 1.5 hours, and vortexing continued for a total of 3.75 hours. Reaction progress was monitored by LC/MS and the solvents were removed upon reaction completion. The crude product was purified by preparative HPLC to give Compound 17 as a white solid (4.1 mg, 43% yield).
Compound 18
Compound 18 was prepared according to the procedures used in the synthesis of Compound 17, except that Compound 2 was used as starting material at step 11.
Compound 19
Compound 19 was prepared according to the procedures used in the synthesis of Compound 10, except that glycine tert-butyl ester was used as starting material at step 11.
Compound 20
Compound 20 was prepared according to the procedures used in the synthesis of Compound 10, except that L-alanine-t-butyl ester hydrochloride was used as starting material at step 11.
Compound 21
Compound 21 was prepared according to the procedures used in the synthesis of Compound 10, except that beta-alanine t-butyl ester hydrochloride was used as starting material at step 11.
Compound 22
Compound 22 was prepared according to the procedures used in the synthesis of Compound 10, except that H-Ser(tBu)-OtBu hydrochloride was used as starting material at step 11.
Compound 23
Compound 23 was prepared according to the procedures used in the synthesis of Compound 10, except that 4-piperidine-carboxylic acid t-butyl ester hydrochloride was used as starting material at step 11.
Compound 24
Compound 24 was prepared according to the procedures used in the synthesis of Compound 10, except that D-alanine-t-butyl ester hydrochloride was used as starting material at step 11.
Compound 25
Compound 25 was prepared according to the procedures used in the synthesis of Compound 10, except that H-Aib-OtBu hydrochloride was used as starting material at step 11.
Compound 26
Compound 26 was prepared according to the procedures used in the synthesis of Compound 10, except that L-valine t-butyl ester hydrochloride was used as starting material at step 11.
Compound 27
Compound 27 was prepared according to the procedures used in the synthesis of Compound 10, except that (S)-di-tert-butyl 2-aminosuccinate was used as starting material at step 11.
Compound 28
Compound 28 was prepared according to the procedures used in the synthesis of Compound 10, except that (S)-tert-butyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate was used as starting material at step 11.
Compound 29
Compound 29 was prepared according to the procedures used in the synthesis of Compound 10, except that (S)-4-tert-butyl 1-methyl 2-aminosuccinate was used as starting material at step 11.
Compound 30
Compound 30 was prepared according to the procedures used in the synthesis of Compound 10, except that tert-butyl 2-(methylamino)acetate was used as starting material at step 11.
Compound 31
Compound 31 was prepared according to the procedures used in the synthesis of Compound 10, except that (S)-tert-butyl pyrrolidine-2-carboxylate was used as starting material at step 11.
Compound 32
Compound 32 was prepared according to the procedures used in the synthesis of Compound 10, except that (R)-tert-butyl pyrrolidine-2-carboxylate was used as starting material at step 11.
Compound 33
Compound 33 was prepared according to the procedures used in the synthesis of Compound 10, except that (R)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material at step 11.
Compound 34
Compound 34 was prepared according to the procedures used in the synthesis of Compound 17, except that Compound 1 and 4-aminobutyrate acid ethyl ester hydrochloride were used as starting materials at step 11.
Compound 35
Compound 35 was prepared according to the procedures used in the synthesis of Compound 17, except that Compound 1 and (S)-methyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate were used as starting materials at step 11.
Compound 36
Compound 36 was prepared according to the procedures used in the synthesis of Compound 17, except that Compound 1 and methyl 2-(benzylamino)acetate were used as starting materials at step 11.
Compound 37
Compound 37 was prepared according to the procedures used in the synthesis of Compound 17, except that Compound 1 and (S)-ethyl piperidine-3-carboxylate were used as starting materials at step 11.
Compound 38
Compound 38 was prepared according to the procedures used in the synthesis of Compound 17, except that Compound 1 and (R)-ethyl piperidine-3-carboxylate were used as starting materials at step 11.
Compound 39
Compound 39 was prepared according to the procedures used in the synthesis of Compound 17, except that Compound 1 and 1-aminocyclopropane-1-carboxylic acid methyl ester hydrochloride were used as starting materials at step 11.
Compound 42
Steps 1-3 of the procedures used in the synthesis of Compound 1 were performed.
Step 4: Wang resin (0.5 g, 0.325 mmol) was swelled with DMF (5.0 mL). Fmoc-(R)-phenylalanine (1.26 g, 3.25 mmol) was dissolved in DMF (10.00 mL), filtered, and DIC (0.253 mL, 1.621 mmol) was then added to the solution. The solution was stirred at room temperature for 10 minutes, then was added into resin above. DMAP (3.97 mg, 0.033 mmol) was added as a solid, and the mixture was agitated at room temperature for 1 hour. The resin was filtered, then washed with DMF (15 mL×3) and DCM (15 ml×3). This coupling of Fmoc-(R)-phenylalanine step was repeated, and resin 42-F was obtained.
Steps 5-10: Compound 42 was prepared according to the procedures used in the synthesis of Compound 1, except that (S)-4-(5-(tert-butoxycarbonylamino)-6-methoxy-6-oxohexylamino)-4-oxobutanoic acid was used as starting material in step 7.
Compound 43
Steps 1-3 of the procedures used in the synthesis of Compound 1 were performed.
Step 4: Wang resin (0.5 g, 0.325 mmol) was swelled with DMF (5.0 mL). Fmoc-(R)-phenylalanine (1.26 g, 3.25 mmol) was dissolved in DMF (10.00 mL), filtered, and DIC (0.253 mL, 1.621 mmol) was then added to the solution. The solution was stirred at room temperature for 10 minutes, then was added into resin above. DMAP (3.97 mg, 0.033 mmol) was added as a solid, and the mixture was agitated at room temperature for 1 hour. The resin was filtered, then washed with DMF (15 mL×3) and DCM (15 ml×3). This coupling of Fmoc-(R)-phenylalanine step was repeated, and resin 43-F was obtained.
Steps 5-10: Compound 43 was prepared according to the procedures used in the synthesis of Compound 1, except that Fmoc-3-L-Ala(2-thienyl)-OH was used as starting material in step 6.
Compound 44
Compound 44 was prepared according to the procedures used in the synthesis of Compound 43, except that Fmoc-(R)-alanine was used as starting material in step 4.
Compound 45
Compound 45 was prepared according to the procedures used in the synthesis of Compound 43, except that Fmoc-L-alanine was used as starting material at step 5.
Compound 46
Compound 46 was prepared according to the procedures used in the synthesis of Compound 43, except that Fmoc-D-alanine was used as starting material in step 6.
Compound 156
Compound 156 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 145 and (S)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 157
Compound 157 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 146 and (S)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 158
Compound 158 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 144 and (S)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 162
Compound 162 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxyphenyl)propanoic acid was used as starting material at step 6.
Compound 163
Compound 163 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 6.
Compound 164
Compound 164 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(benzo[b]thiophen-3-yl)propanoic acid was used as starting material at step 6.
Compound 165
Compound 165 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(2,3-dihydro-1H-inden-2-yl)acetic acid was used as starting material at step 6.
Compound 166
Compound 166 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 6.
Compound 174
Compound 174 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 4 and (S)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 175
Compound 175 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 4 and tert-butyl 3-aminopropanoate hydrochloride was used as starting material.
Compound 176
Compound 176 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 4 and tert-butyl 2-amino-2-methylpropanoate hydrochloride was used as starting material.
Compound 184
Compound 184 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2S,3S)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 185
Compound 185 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 186
Compound 186 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and 4-(4-(((((9H-fluoren-9-yl)methoxy)carbonyl)(2-methoxy-2-oxoethyl)amino)methyl)benzylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 187
Compound 187 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (1 S,2R)-2-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylcarbamoyl)cyclohexanecarboxylic acid was used as starting material at step 7.
Compound 191
Compound 191 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-cyclohexylpropanoic acid was used as starting material at step 6.
Compound 192
Compound 192 was prepared according to steps 1 to 9 used for the synthesis of Compound 1.
Compound 193
Compound 193 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 1 and (9H-fluoren-9-yl)methyl 2-(2-aminoethoxy)ethylcarbamate was used as starting material.
Compound 194
Compound 194 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 195
Compound 195 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 197
Compound 197 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-cyclohexylpropanoic acid was used as starting material at step 6, and (S,Z)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobut-2-enoic acid was used as starting material at step 7.
Compound 198
Compound 198 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-tert-butoxy-4-oxobutanoic acid was used as starting material at step 6.
Compound 199
Compound 199 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 1 and (S)-tert-butyl pyrrolidine-2-carboxylate was used as starting material.
Compound 200
Compound 200 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 1 and methyl 1-aminocyclopropanecarboxylate was used as starting material.
Compound 201
Compound 201 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 85 and (S)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 202
Compound 202 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and (S)-methyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 205
Compound 205 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 1 and 2-aminoethanol was used as starting material and no TFA treatment was required.
Compound 206
Compound 206 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-tert-butoxy-4-oxobutanoic acid was used as starting material at step 6.
Compound 209
Compound 209 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 210
Compound 210 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 211
Compound 211 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 212
Compound 212 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 213
Compound 213 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 214
Compound 214 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 215
Compound 215 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 216
Compound 216 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6.
Compound 227
Compound 227 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and (R)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 228
Compound 228 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and (R)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 229
Compound 229 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and (S)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 230
Compound 230 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and (S)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 246
Compound 246 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6.
Compound 260
Compound 260 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-cyanophenyl)propanoic acid was used as starting material at step 6.
Compound 261
Compound 261 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 6.
Compound 262
Compound 262 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3,4-difluorophenyl)propanoic acid was used as starting material at step 6.
Compound 263
Compound 263 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 6.
Compound 264
Compound 264 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-p-tolylpropanoic acid was used as starting material at step 6.
Compound 268
Compound 268 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 269
Compound 269 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 270
Compound 270 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 271
Compound 271 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 272
Compound 272 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 273
Compound 273 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 274
Compound 274 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 275
Compound 275 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 276
Compound 276 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 277
Compound 277 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 278
Compound 278 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 279
Compound 279 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 280
Compound 280 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 281
Compound 281 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 282
Compound 282 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 262 and (S)-methyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 295
Compound 295 was prepared according to the procedures used for the synthesis of Compound 10, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6, and that (S)-tert-butyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate hydrochloride was used as starting material at step 11.
Compound 296
Compound 296 was prepared according to the procedures used for the synthesis of Compound 295, except that (2R,3R)-3-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)benzamido)-2,3-diacetoxypropanoic acid was used as starting material at step 7.
Compound 297
Compound 297 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and tert-butyl 2-amino-2-methylpropanoate was used as starting material.
Compound 298
Compound 298 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and tert-butyl 4-aminobutanoate was used as starting material.
Compound 299
Compound 299 was prepared according to the procedures used for the synthesis of Compound 17, except that comopund and methyl 1-aminocyclopropanecarboxylate was used as starting material.
Compound 300
Compound 300 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and (S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate was used as starting material.
Compound 301
Compound 301 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and tert-butyl 3-aminopropanoate was used as starting material.
Compound 302
Compound 302 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and (R)-tert-butyl 2-aminopropanoate was used as starting material.
Compound 303
Compound 303 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and (S)-tert-butyl pyrrolidine-2-carboxylate was used as starting material.
Compound 304
Compound 304 was prepared according to the procedures used for the synthesis of Compound 10, except that compound and (R)-tert-butyl pyrrolidine-2-carboxylate was used as starting material.
Compound 305
Compound 305 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and (S)-tert-butyl 2-aminopropanoate was used as starting material.
Compound 306
Compound 306 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and tert-butyl piperidine-4-carboxylate was used as starting material.
Compound 307
Compound 307 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and tert-butyl 2-amino-3-methylpentanoate was used as starting material.
Compound 308
Compound 308 was prepared according to the procedures used for the synthesis of Compound 10, except that comopund and di-tert-butyl 2-aminopentanedioate was used as starting material.
Compound 309
Compound 309 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-methoxy-4-oxobutyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 310
Compound 310 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (S)-2-(2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2-oxoethoxy)acetic acid was used as starting material at step 7.
Compound 311
Compound 311 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 312
Compound 312 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-phenylacetic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 313
Compound 313 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 314
Compound 314 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-cyanophenyl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 315
Compound 315 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-chlorophenyl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 316
Compound 316 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-cyanophenyl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 317
Compound 317 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methoxyphenyl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 318
Compound 318 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-3-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 319
Compound 319 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and tert-butyl 3-aminopropanoate was used as starting material.
Compound 320
Compound 320 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 145 and HCl salt of (S)-ethyl 2-amino-4-phenylbutanoate was used as starting material.
Compound 321
Compound 321 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 145 and HCl salt of tert-butyl 2-aminoacetate was used as starting material.
Compound 322
Compound 322 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 145 and ethanolamine was used as starting material and no TFA treatment was required.
Compound 323
Compound 323 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 145 and HCl salt of ethyl 2-(benzylamino)acetate was used as starting material.
Compound 324
Compound 324 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 145 and HCl salt of (R)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 325
Compound 325 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 145 and HCl salt of (S)-4-tert-butyl 1-methyl 2-aminosuccinate was used as starting material.
Compound 326
Compound 326 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and HCl salt of (S)-tert-butyl 2-aminopropanoate was used as starting material.
Compound 327
Compound 327 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and HCl salt of (S)-4-tert-butyl 1-methyl 2-aminosuccinate was used as starting material.
Compound 328
Compound 328 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and HCl salt of (S)-tert-butyl 2-amino-4-phenylbutanoate was used as starting material.
Compound 329
Compound 329 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and HCl salt of tert-butyl 2-aminoacetate was used as starting material.
Compound 338
Compound 338 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and HCl salt of tert-butyl 2-aminoacetate was used as starting material.
Compound 339
Compound 339 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and HCl salt of tert-butyl 3-aminopropanoate was used as starting material.
Compound 340
Compound 340 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 212 and ethyl 2-(benzylamino)acetate was used as starting material.
Compound 341
Compound 341 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 212 and HCl salt of (R)-tert-butyl 2-aminopropanoate was used as starting material.
Compound 342
Compound 342 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 212 and HCl salt of methyl 4-aminobutanoate was used as starting material.
Compound 343
Compound 343 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 212 and HCl salt of methyl 4-aminobutanoate was used as starting material.
Compound 344
Compound 344 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 212 and HCl salt of methyl 4-aminobutanoate was used as starting material.
Compound 345
Compound 345 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and HCl salt of (S)-4-tert-butyl 1-methyl 2-aminosuccinate was used as starting material.
Compound 350
Compound 350 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and (S)-methyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 351
Compound 351 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 117 and (R)-4-tert-butyl 1-methyl 2-aminosuccinate was used as starting material.
Compound 352
Compound 352 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and methyl 3-aminobenzoate was used as starting material.
Compound 353
Compound 353 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and methyl pyrrolidine-3-carboxylate was used as starting material.
Compound 354
Compound 354 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 117 and 4-tert-butoxybutanoic acid was used as starting material.
Compound 370
Compound 370 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 117 and dimethylamine hydrochloride was used as starting material and no TFA treatment was required.
Compound 383
Compound 383 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and HCl salt of tert-butyl 2-aminoacetate was used as starting material.
Compound 384
Compound 384 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and HCl salt of (R)-tert-butyl 2-aminopropanoate was used as starting material.
Compound 385
Compound 385 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and HCl salt of (S)-tert-butyl 2-aminopropanoate was used as starting material.
Compound 386
Compound 386 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and HCl salt of tert-butyl 4-aminobutanoate was used as starting material.
Compound 387
Compound 387 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and HCl salt of (S)-tert-butyl 2-amino-3-(4-tert-butoxyphenyl)propanoate was used as starting material.
Compound 388
Compound 388 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and HCl salt of (S)-5-tert-butyl 1-methyl 2-aminopentanedioate was used as starting material.
Compound 389
Compound 389 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and HCl salt of (S)-5-tert-butyl 1-methyl 2-aminopentanedioate was used as starting material.
Compound 390
Compound 390 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and ethanolamine was used as starting material and no TFA treatment was required.
Compound 391
Compound 391 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 214 and methyl 1-aminocyclopropanecarboxylate was used as starting material.
Compound 392
Compound 392 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 214 and ethyl 2-(benzylamino)acetate was used as starting material.
Compound 393
Compound 393 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 214 and (S)-ethyl 2-amino-4-phenylbutanoate was used as starting material.
Compound 395
Compound 395 was prepared according to the procedures used for the synthesis of Compound 17, except that comopund and methyl 6-aminohexanoate was used as starting material.
Compound 401
Compound 401 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and methyl 3-aminopropanoate was used as starting material.
Compound 402
Compound 402 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and methyl 4-aminobutanoate was used as starting material.
Compound 403
Compound 403 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and (S)-methyl 2-amino-3-(pyridin-3-yl)propanoate was used as starting material.
Compound 404
Compound 404 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 145 and ethyl 1-(aminomethyl)cyclopropanecarboxylate was used as starting material.
Compound 405
Compound 405 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and (S)-methyl 2-amino-3-(pyridin-3-yl)propanoate was used as starting material.
Compound 426
Compound 426 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 419 and (S)-methyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 440
Compound 440 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 111 and (S)-methyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 441
Compound 441 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 112 and (S)-methyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 442
Compound 442 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 330 and (S)-methyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 443
Compound 443 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 180 and (S)-methyl 2-amino-3-phenylpropanoate hydrochloride was used as starting material.
Compound 444
Compound 444 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and (R)-methyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 445
Compound 445 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and (S)-methyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 446
Compound 446 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and (R)-methyl 2-aminopropanoate was used as starting material.
Compound 447
Compound 447 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and (S)-methyl 2-aminopropanoate was used as starting material.
Compound 448
Compound 448 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and methyl 3-aminopropanoate was used as starting material.
Compound 449
Compound 449 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and methyl 4-aminobutanoate was used as starting material.
Compound 450
Compound 450 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 289 and tert-butyl 5-aminopentanoate was used as starting material.
Compound 451
Compound 451 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 289 and tert-butyl 1-aminocyclopropanecarboxylate was used as starting material.
Compound 452
Compound 452 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and methyl 2-amino-2-methylpropanoate was used as starting material.
Compound 453
Compound 453 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 289 and methyl 2-aminoacetate was used as starting material.
Compound 454
Compound 454 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 6, and L-AP succinate was used as starting material at step 7.
Compound 455
Compound 455 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 454 and (R)-methyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 456
Compound 456 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 454 and (S)-methyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 457
Compound 457 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 454 and (R)-methyl 2-aminopropanoate was used as starting material.
Compound 458
Compound 458 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 454 and (S)-methyl 2-aminopropanoate was used as starting material.
Compound 459
Compound 459 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 454 and methyl 3-aminopropanoate was used as starting material.
Compound 460
Compound 460 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 454 and methyl 4-aminobutanoate was used as starting material.
Compound 461
Compound 461 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 454 and tert-butyl 5-aminopentanoate was used as starting material.
Compound 462
Compound 462 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 454 and methyl 2-aminoacetate was used as starting material.
Compound 470
Compound 470 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and (S)-ethyl 2-amino-4-phenylbutanoate hydrochloride was used as starting material.
Compound 471
Compound 471 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 117 and (S)-neopentyl 2-amino-3-(4-tert-butoxyphenyl)propanoate hydrochloride was used as starting material.
Compound 472
Compound 472 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and HCl salt of tert-butyl 2-aminoacetate was used as starting material.
Compound 473
Compound 473 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and HCl salt of (S)-tert-butyl 2-aminopropanoate was used as starting material.
Compound 475
Compound 475 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and HCl salt of tert-butyl 4-aminobutanoate was used as starting material.
Compound 477
Compound 477 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and HCl salt of tert-butyl 2-amino-2-methylpropanoate was used as starting material.
Compound 478
Compound 478 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and HCl salt of tert-butyl 1-aminocyclopropanecarboxylate was used as starting material.
Compound 479
Compound 479 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 348 and HCl salt of methyl 2-(2-aminoacetamido)acetate was used as starting material.
Compound 480
Compound 480 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and HCl salt of (R)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 481
Compound 481 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and HCl salt of (S)-tert-butyl 2-amino-3-phenylpropanoate was used as starting material.
Compound 482
Compound 482 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and aminomethanesulfonic acid was used as starting material and no TFA treatment was required.
Compound 483
Compound 483 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and benzenesulfonamide and N,N-dimethylpyridin-4-amine was used as starting material and no TFA treatment was required.
Compound 484
Compound 484 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and N-(2-aminoethyl)-4-methylbenzenesulfonamide was used as starting material and no TFA treatment was required.
Compound 485
Compound 485 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and (S)-tert-butyl 3-amino-4-phenylbutanoate was used as starting material.
Compound 486
Compound 486 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and (S)-tert-butyl 2-amino-3-(trityloxy)propanoate was used as starting material.
Compound 487
Compound 487 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 348 and HCl salt of methyl 2-(2-aminoacetamido)acetate was used as starting material.
Compound 488
Compound 488 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-amino-4-oxobutanoic acid was used as starting material at step 6.
Compound 489
Compound 489 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 6.
Compound 490
Compound 490 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 6.
Compound 491
Compound 491 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(benzyloxy)phenyl)propanoic acid was used as starting material at step 6.
Compound 493
Compound 493 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 494
Compound 494 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 495
Compound 495 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 496
Compound 496 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6.
Compound 497
Compound 497 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 498
Compound 498 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 499
Compound 499 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 500
Compound 500 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 501
Compound 501 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 502
Compound 502 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 503
Compound 503 was prepared according to the procedures used for the synthesis of Compound 1, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 504
Compound 504 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and ethyl 2-(benzylamino)acetate was used as starting material.
Compound 505
Compound 505 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and (S)-methyl 2-amino-3-(4-(tert-butoxycarbonylamino)phenyl)propanoate was used as starting material and treatment with 25% TFA was required after treatment with lithium hydroxide in step 11.
Compound 528
Compound 505 (2.7 mg, 2.82 μmol) was dissolved in DCM (1 mL). Acetic Anhydride (20 uL, 212 μmol) and DIPEA (20 uL, 113 μmol) was added to the stirring mixture. The reaction was monitored by LC/MS and after 1 hour was complete. The reaction mixture was concentrated and the desired material was precipitated with 1.5 mL of water. The solids were pelleted and the water removed. The solids were washed with water (1 mL) and dried. The crude solid was purified by preparative HPLC to give Compound 528 as a white solid (0.5 mg, 0.45 umol, 90% yield).
Compound 542
Compound 542 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 117 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material.
Compound 543
Compound 543 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6, and (S)-4-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)butanoic acid was used as starting material at step 7.
Compound 544
Compound 544 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (S)-5-(1-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)pentanoic acid was used as starting material at step 7.
Compound 545
Compound 545 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (S)-4-(6-(2-(tert-butoxycarbonylamino)-3-ethoxy-3-oxopropyl)pyridin-3-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 546
Compound 546 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6, and (S)-4-(6-(2-(tert-butoxycarbonylamino)-3-ethoxy-3-oxopropyl)pyridin-3-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 547
Compound 547 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (S)-4-(6-(2-(tert-butoxycarbonylamino)-3-ethoxy-3-oxopropyl)pyridin-3-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 548
Compound 548 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6, and (S)-4-(6-(2-(tert-butoxycarbonylamino)-3-ethoxy-3-oxopropyl)pyridin-3-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 549
Compound 549 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (S)-4-(3-(4-(((9H-fluoren-9-yl)methoxy)carbonylamino)phenyl)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 550
Compound 550 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6, and (S)-4-(3-(4-(((9H-fluoren-9-yl)methoxy)carbonylamino)phenyl)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 551
Compound 551 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (S)-4-(3-(4-(((9H-fluoren-9-yl)methoxy)carbonylamino)phenyl)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 552
Compound 552 was prepared according to the procedures used for the synthesis of Compound 1, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 5, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 6, and (S)-4-(3-(4-(((9H-fluoren-9-yl)methoxy)carbonylamino)phenyl)-1-methoxy-1-oxopropan-2-ylamino)-4-oxobutanoic acid was used as starting material at step 7.
Compound 553
Compound 553 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and (R)-tent-butyl 2-amino-3-phenylpropanoate hydrochloride were used as starting materials.
Compound 554
Compound 554 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and (S)-tert-butyl 2-amino-3-phenylpropanoate hydrochloride were used as starting materials.
Compound 555
Compound 555 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and (R)-tert-butyl 2-amino-3-tert-butoxypropanoate hydrochloride were used as starting materials.
Compound 556
Compound 556 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and (S)-tert-butyl 2-amino-3-tert-butoxypropanoate hydrochloride were used as starting materials.
Compound 557
Compound 557 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and (R)-tert-butyl 2-aminopropanoate hydrochloride were used as starting materials.
Compound 558
Compound 558 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and tert-butyl 2-aminoacetate hydrochloride were used as starting materials.
Compound 559
Compound 559 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and tert-butyl 3-aminopropanoate hydrochloride were used as starting materials.
Compound 560
Compound 560 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and tert-butyl 4-aminobutanoate hydrochloride were used as starting materials.
Compound 561
Compound 561 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 674 and (S)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 562
Compound 562 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 674 and (R)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 563
Compound 563 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 346 and (S)-tert-butyl 2-amino-3-tert-butoxypropanoate were used as starting materials.
Compound 564
Compound 564 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 346 and tent-butyl 3-aminopropanoate were used as starting materials.
Compound 565
Compound 565 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 346 and (R)-tent-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 566
Compound 566 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 346 and aminomethanesulfonic acid were used as starting materials.
Compound 567
Compound 567 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and (S)-tert-butyl 2-amino-3-(4-tert-butoxyphenyl)propanoate were used as starting materials.
Compound 568
Compound 568 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and tert-butyl 4-aminobutanoate hydrochloride were used as starting materials.
Compound 569
Compound 569 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and tert-butyl 3-aminopropanoate hydrochloride were used as starting materials.
Compound 570
Compound 570 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and tert-butyl 2-aminoacetate hydrochloride were used as starting materials.
Compound 571
Compound 571 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and (R)-tent-butyl 2-amino-3-tert-butoxypropanoate hydrochloride were used as starting materials.
Compound 572
Compound 572 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and (S)-tert-butyl 2-aminopropanoate were used as starting materials.
Compound 573
Compound 573 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and (R)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 574
Compound 574 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and (S)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 575
Compound 575 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and (S)-tert-butyl 2-(methylamino)propanoate were used as starting materials.
Compound 576
Compound 576 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and (R)-tert-butyl 2-(methylamino)propanoate were used as starting materials.
Compound 577
Compound 577 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and (S)-tert-butyl 2-aminopropanoate were used as starting materials.
Compound 578
Compound 578 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and 2-aminoethanol were used as starting materials.
Compound 579
Compound 579 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and tert-butyl 3-aminopropanoate hydrochloride were used as starting materials.
Compound 580
Compound 580 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and tert-butyl 4-aminobutanoate hydrochloride were used as starting materials.
Compound 581
Compound 581 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and (S)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 582
Compound 582 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and (R)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 583
Compound 583 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and (S)-tert-butyl 2-amino-3-tert-butoxypropanoate were used as starting materials.
Compound 584
Compound 584 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and (R)-tert-butyl 2-amino-3-tert-butoxypropanoate were used as starting materials.
Compound 585
Compound 585 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and (S)-tert-butyl 2-amino-3-(4-tert-butoxyphenyl)propanoate were used as starting materials.
Compound 586
Compound 586 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and (R)-tert-butyl 2-amino-3-(4-tert-butoxyphenyl)propanoate were used as starting materials.
Compound 587
Compound 587 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 625 and (R)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 588
Compound 588 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 631 and (R)-tert-butyl 2-amino-3-phenylpropanoate were used as starting materials.
Compound 589
Compound 589 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and (S)-2-phenyl-1-(1-trityl-1H-tetrazol-5-yl)ethanamine were used as starting materials.
Compound 590
Compound 590 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and (S)-2-phenyl-1-(1-trityl-1H-tetrazol-5-yl)ethanamine were used as starting materials.
Compound 591
Compound 591 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and (1-trityl-1H-tetrazol-5-yl)methanamine were used as starting materials.
Compound 592
Compound 592 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and (S)-2-phenyl-1-(1-trityl-1H-tetrazol-5-yl)ethanamine were used as starting materials.
Compound 593
Compound 593 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 289 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 594
Compound 594 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 212 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 595
Compound 595 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 213 and aminoethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 596
Compound 596 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 214 and aminopropanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 597
Compound 597 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 598
Compound 598 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and aminoethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 599
Compound 599 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and aminopropanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 600
Compound 600 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and methanesulfonamide and DMAP were used as starting materials and no TFA treatment was required.
Compound 601
Compound 601 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and methanesulfonamide and DMAP were used as starting materials and no TFA treatment was required.
Compound 602
Compound 602 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and 2-aminoethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 603
Compound 603 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and aminopropanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 604
Compound 604 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 674 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 605
Compound 605 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and 2-(methylamino)ethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 606
Compound 606 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and 2-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-ylamino)ethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 607
Compound 607 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 608
Compound 608 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and aminoethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 609
Compound 609 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and aminopropanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 610
Compound 610 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and (1H-tetrazol-5-yl)methanamine hydrobromide were used as starting materials and no TFA treatment was required.
Compound 611
Compound 611 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 510 and 2-(1H-tetrazol-5-yl)ethanamine were used as starting materials and no TFA treatment was required.
Compound 612
Compound 612 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 625 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 613
Compound 613 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 631 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 614
Compound 614 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 633 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 615
Compound 615 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 348 and MeOH, DCC and DMAP were used as starting materials and no TFA treatment was required.
Compound 616
Compound 616 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and (1H-tetrazol-5-yl)methanamine hydrobromide were used as starting materials and no TFA treatment was required.
Compound 617
Compound 617 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 684 and aminomethanesulfonic acid were used as starting materials and no TFA treatment was required.
Compound 618
Compound 618 was prepared according to the procedures used for the synthesis of Compound 10, except that Compound 506 and (1H-tetrazol-5-yl)methanamine hydrobromide were used as starting materials and no TFA treatment was required.
Compound 619
Compound 619 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 506 and (R)-ethyl 2-amino-4-phenylbutanoate hydrochloride were used as starting materials.
Compound 620
Compound 620 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 510 and (S)-ethyl 2-amino-4-phenylbutanoate hydrochloride were used as starting materials.
Compound 621
Compound 621 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 348 and (S)-methyl 2-(methylamino)-3-phenylpropanoate were used as starting materials.
Compound 622
Compound 622 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 510 and (R)-ethyl 2-amino-4-phenylbutanoate hydrochloride were used as starting materials.
Compound 623
Compound 623 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 684 and (S)-ethyl 2-amino-4-phenylbutanoate were used as starting materials.
Compound 624
Compound 624 was prepared according to the procedures used for the synthesis of Compound 17, except that Compound 684 and (R)-ethyl 2-amino-4-phenylbutanoate were used as starting materials.
Example 2
This example describes the synthesis and characterization of additional macrocyclic compounds. A general synthetic sequence for preparing the macrocyclic compounds is illustrated schematically below.







Compound 47

Step 1: 2-Chloro-trityl chloride resin 3E (5.14 g, 8.12 mmol) was swelled in 40 mL DCM for 30 min and then filtered. Fmoc-L-Phe(4-Ph)-OH (5.27 g, 11.37 mmol) and DIPEA (7.06 mL, 40.6 mmol) was dissolved in 5 mL of NMP and 23 mL of DCM. The resulting solution was added to the swelled resin. The mixture was purged with argon and agitated for 1 hour. The resin was then washed with 3×30 mL of DCM. This coupling of Fmoc-L-Phe(4-Ph)-OH was repeated once. After washing the resin with 3×30 mL of DCM, resin 4B was obtained.
Step 2: Resin 4B was treated twice with 35 mL of 25% piperidine in DMF for 20 min. The resin was then washed 2-3 times with DMF and 3-5 times with 1% DIPEA in DCM. To the resulting resin, Fmoc-D-Tha (4.79 g, 12.18 mmol), HATU (6.18 g, 16.24 mmol) and DIPEA (5.66 mL, 32.5 mmol) in 25 mL of NMP was added. The mixture was agitated at room temperature for 1 hour. The resin was filtered and washed with 2×30 mL NMP, 2×30 mL DCM, 1×30 mL MeOH, and 1×30 mL DCM. This coupling of Fmoc-D-Tha was repeated once. After washing the resin with 3×30 mL of DCM, resin 4C was obtained.
Step 3: Resin 4C was treated twice with 35 mL of 25% piperidine in DMF for 20 min. The resin was then washed 2-3 times with DMF and 3-5 times with 1% DIPEA in DCM. To the resulting resin, (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid (5.27 g, 11.37 mmol) and HATU (6.18 g, 16.24 mmol) in 30 mL of NMP was added. DIPEA (7.06 mL, 40.6 mmol) was then added to the reaction mixture. The mixture was agitated at room temperature for 1 hour. The resin was filtered and washed with 2×30 mL NMP, 2×30 mL DCM, 1×30 mL MeOH, and 1×30 mL DCM. This coupling of (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was repeated once. After washing the resin with 3×30 mL of DCM, resin 4D was obtained.
Step 4: Resin 4D (100 mg) was treated twice with 2 mL of 25% piperidine in DMF for 20 min. The resin was then washed 2-3 times with DMF and 3-5 times with 1% DIPEA in DCM. To the resulting resin, Fmoc-D-HOPhe (0.175 g, 0.45 mmol), HATU (0.228 g, 0.60 mmol) and DIPEA (0.207, 1.2 mmol) in 2 mL of NMP was added. The mixture was agitated at room temperature overnight. The resin was filtered and washed with 2×5 mL NMP, 2×5 mL DCM, 1×5 mL MeOH, and 1×5 mL DCM. After washing the resin with 3×5 mL of DCM, resin 4E was obtained.
Step 5: Resin 4E was treated twice with 2 mL of 25% piperidine in DMF for 20 min. The resin was then washed 2-3 times with DMF and 3-5 times with 1% DIPEA in DCM. The resin was then treated with 2 mL of 25% TFA in DCM for 30 min. This cleaving solution was then collected by filtration and evaporated to give 75 mg of (S)-2-((R)-2-(4-(4-((S)-2-((R)-2-amino-4-phenylbutanamido)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanamido)-3-(thiophen-2-yl)propanamido)-3-(biphenyl-4-yl)propanoic acid (4F). The crude product 4F was used directly in step 6.
Step 6: (S)-2-((R)-2-(4-(4-((S)-2-((R)-2-amino-4-phenylbutanamido)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanamido)-3-(thiophen-2-yl)propanamido)-3-(biphenyl-4-yl)propanoic acid (75 mg, 0.092 mmol), HATU (25.1 mg, 0.184 mmol) and HOAt (25.1 mg, 0.184 mmol) were dissolved in anhydrous DMF (74 mL) and DCM (18 mL). DIPEA (0.080 mL, 0.461 mmol) was then added to the stirring solution. The mixture was stirred at room temperature for 2 hours. The solvents were evaporated. MeOH was added and evaporated to yield a gel-like slurry, to which water was added. A solid precipitate formed and was collected by filtration. After washing the solid with water, 0.1 g of crude 4G was obtained as a white solid.
Step 7: 4G (0.1 g, crude product from step 6) was dissolved in 4 mL of THF. Lithium hydroxide (29.4 mg, 1.229 mmol) in 0.87 mL of H2O was then added. The reaction mixture was stirred at room temperature for 40 min. The solution was then neutralized with 38% HCl (0.097 mL). The solvents were evaporated, and the crude product was purified by preparative HPLC to give Compound 47 as a white solid.
Compound 48
Compound 48 was prepared according to the procedures used in the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 4.
Compound 49
Compound 49 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-4-pyridyl-Ala was used as starting material at step 4.
Compound 50
Compound 50 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-4-pyridyl-Ala was used as starting material at step 4.
Compound 51
Compound 51 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-3-pyridyl-Ala was used as starting material at step 4.
Compound 52
Compound 52 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-3-pyridyl-Ala was used as starting material at step 4.
Compound 53
Compound 53 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-2-pyridyl-Ala was used as starting material at step 4.
Compound 54
Compound 54 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-Leucine-OH was used as starting material at step 4.
Compound 55
Compound 55 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-N-benzylglycine was used as starting material at step 4.
Compound 56
Compound 56 was prepared according to the procedures used in the synthesis of Compound 47a, except that (s)-3-(Fmoc-amino-)-4-phenylbutyric acid was used as starting material at step 4.
Compound 57
Compound 57 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-N-Me-Phe-OH was used as starting material at step 4.
Compound 58
Compound 58 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Tyr-OH was used as starting material at step 4.
Compound 59
Compound 59 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-Tyr-OH was used as starting material at step 4.
Compound 60
Compound 60 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Ser(TrT)-OH was used as starting material at step 4.
Compound 61
Compound 61 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Ser(TrT)-OH was used as starting material at step 4.
Compound 62
Compound 62 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Asp-OtBu was used as starting material at step 4.
Compound 63
Compound 63 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-Asp-OtBu was used as starting material at step 4.
Compound 64
Compound 64 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Asp-OtBu was used as starting material at step 4.
Compound 65
Compound 65 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-Asp-OtBu was used as starting material at step 4.
Compound 66
Compound 66 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Glu-OtBu was used as starting material at step 4.
Compound 67
Compound 67 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-Glu-OtBu was used as starting material at step 4.
Compound 68
Compound 68 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Glu-OtBu was used as starting material at step 4.
Compound 69
Compound 69 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-Glu-OtBu was used as starting material at step 4.
Compound 72
Compound 72 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-Arg(Pbf)-OH was used as starting material at step 4.
Compound 73
Compound 73 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-Arg(Pbf)-OH was used as starting material at step 4.
Compound 74
Compound 74 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-L-2-Furyl-Ala was used as starting material at step 4.
Compound 75
Compound 75 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-2-Furyl-Ala was used as starting material at step 4.
Compound 76
Compound 76 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-Phe-Gly was used as starting material at step 4.
Compound 77
Compound 77 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-2-CF3-Phe was used as starting material at step 4.
Compound 78
Compound 78 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-3-CF3-Phe was used as starting material at step 4.
Compound 79
Compound 79 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-4-CF3-Phe was used as starting material at step 4.
Compound 80
Compound 80 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-2-CH3-Phe was used as starting material at step 4.
Compound 81
Compound 81 was prepared according to the procedures used in the synthesis of Compound 47, except that Fmoc-D-4-Cl-Phe was used as starting material at step 4.
Compound 224
Compound 224 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 225
Compound 225 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-cyanophenyl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 226
Compound 226 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-chlorophenyl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 250
Compound 250 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and S-Fmoc-Proline-OH was used as starting material at step 4.
Compound 251
Compound 251 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and S-Fmoc-Proline-OH was used as starting material at step 4.
Compound 252
Compound 252 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and S-Fmoc-Proline-OH was used as starting material at step 4.
Compound 253
Compound 253 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(benzyl)amino)acetic acid was used as starting material at step 4.
Compound 254
Compound 254 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 255
Compound 255 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and S-Fmoc-Proline-OH was used as starting material at step 4.
Compound 256
Compound 256 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-acetamidohexanoic acid was used as starting material at step 4.
Compound 257
Compound 257 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(benzyl)amino)acetic acid was used as starting material at step 4.
Compound 258
Compound 258 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-tert-butoxy-5-oxopentanoic acid was used as starting material at step 4.
Compound 259
Compound 259 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-tert-butoxy-5-oxopentanoic acid was used as starting material at step 4.
Compound 283
Compound 283 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 284
Compound 284 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 4.
Compound 285
Compound 285 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-cyanophenyl)propanoic acid was used as starting material at step 4.
Compound 286
Compound 286 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-chlorophenyl)propanoic acid was used as starting material at step 4.
Compound 287
Compound 287 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 4.
Compound 288
Compound 288 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 289
Compound 289 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 290
Compound 290 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-dihydroxy-4-oxobutanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 291
Compound 291 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-phenylacetic acid was used as starting material at step 4.
Compound 346
Compound 346 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 347
Compound 347 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 348
Compound 348 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 349
Compound 349 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-tert-butoxy-5-oxopentanoic acid was used as starting material at step 4.
Compound 368
Compound 368 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-phenylacetic acid was used as starting material at step 4.
Compound 369
Compound 369 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-acetamidohexanoic acid was used as starting material at step 4.
Compound 427
Compound 427 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 428
Compound 428 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 530
Compound 530 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 531
Compound 531 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 532
Compound 532 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 533
Compound 533 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 534
Compound 534 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxyphenyl)propanoic acid was used as starting material at step 4.
Compound 535
Compound 535 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 536
Compound 536 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 4.
Compound 537
Compound 537 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R,E)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-phenylpent-4-enoic acid was used as starting material at step 4.
Compound 538
Compound 538 was prepared according to the procedures used for the synthesis of Compound 47, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 625
Compound 625 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 626
Compound 626 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 627
Compound 627 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 628
Compound 628 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 629
Compound 629 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 630
Compound 630 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 631
Compound 631 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 632
Compound 632 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-2-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 633
Compound 633 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-3-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 634
Compound 634 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 635
Compound 635 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butylphenyl)propanoic acid was used as starting material at step 4.
Compound 636
Compound 636 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 637
Compound 637 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 638
Compound 638 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 639
Compound 639 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 640
Compound 640 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 4.
Compound 641
Compound 641 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-cyanophenyl)propanoic acid was used as starting material at step 4.
Compound 642
Compound 642 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 643
Compound 643 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-2-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 644
Compound 644 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-3-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 645
Compound 645 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 646
Compound 646 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 647
Compound 647 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 648
Compound 648 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 649
Compound 649 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 650
Compound 650 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichloro-phenyl)propanoic acid was used as starting material at step 4.
Compound 651
Compound 651 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-chloro-phenyl)propanoic acid was used as starting material at step 4.
Compound 652
Compound 652 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 653
Compound 653 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 4.
Compound 654
Compound 654 was prepared according to the procedures used for the synthesis of Compound 47, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 2, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 3, and (S)-3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Example 3
This example describes the synthesis and characterization of additional macrocyclic compounds. A general synthetic sequence for preparing the macrocyclic compounds is illustrated schematically below.







Compound 82

Step 1: 2-Chloro-trityl chloride resin 3E (4.00 g, 6.32 mmol) was swelled in 20 mL DCM for 30 min and then filtered. (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid (2.98 g, 7.58 mmol) and DIPEA (5.50 mL, 31.6 mmol) were dissolved in 40 mL of DCM. The resulting solution was added to the swelled resin. The mixture was purged with argon and agitated for 2 hours. The resin was then washed with (34 mL DCM, 4 mL MeOH, 2 mL DIPEA)×3; DCM (40 mL×3), DMF (40 mL×2), DCM (40 mL×2). After flushing with argon and drying under vacuum, resin 5B was obtained.
Step 2: Resin 5B was treated with 35 mL of 20% piperidine in DMF for 20 min, washed with 2×30 mL DMF, and treated with another 35 mL of 20% piperidine in DMF. The resin was then washed with 3×30 mL of DMF and 3×30 mL of 1% DIPEA in DCM. To the resulting resin, (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid (3.27 g, 6.33 mmol) and HATU (3.21 g, 8.44 mmol) in 30 mL of NMP were added. DIPEA (2.94 mL, 16.87 mmol) was then added to the reaction mixture. The mixture was agitated at room temperature for 1 hour. The resin was filtered and after washing with 2×30mL NMP and 4×30 mL of 1% DIPEA in DCM, resin 5C was obtained.
Step 3: Resin 5C was treated with 35 mL of 20% piperidine in DMF for 20 min, washed with 2×30 mL DMF, and treated with another 35 mL of 20% piperidine in DMF. The resin was then washed with 3×30 mL of DMF and 3×30 mL of 1% DIPEA in DCM. To the resulting resin, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid (4.9 g, 12.66 mmol), HATU (8.02 g, 21.1 mmol) and DIPEA (7.35, 42.2 mmol) in 30 mL of NMP were added. The mixture was agitated at room temperature overnight. The resin was filtered and after washing with 2×30mL NMP and 4×30 mL of 1% DIPEA in DCM, resin 5D was obtained.
Step 4: Resin 5D (150 mg) was treated with 2 mL of 20% piperidine in DMF for 20 min, washed with 2×4 mL DMF and treated with another 2 mL of 20% piperidine in DMF. The resin was then washed with 3×4 mL of DMF and 3×4 mL of 1% DIPEA in DCM. To the resulting resin, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3,4-dichlorophenyl)propanoic acid (0.115 g, 0.252 mmol) and HATU (0.16 g, 0.42 mmol) in 1.5 mL of NMP were added. DIPEA (0.147 mL, 0.84 mmol) was then added to the reaction mixture. The mixture was agitated at room temperature for 1 hour. After washing the resin with 2×5mL NMP and 4×5 mL of 1% DIPEA in DCM, resin 5E was obtained.
Step 5: Resin 5E was treated with 2 mL of 20% piperidine in DMF for 20 min, washed with 2×4 mL DMF and treated with another 2 mL of 20% piperidine in DMF. The resin was then washed with 3×4 mL of DMF and 3×4 mL of 1% DIPEA in DCM. The resin was treated with 3 mL of 20% HFIP in DCM for 10 min four times. The resin was then washed with DCM (3×3 mL). This cleaving solution was then collected by filtration. The solution was combined and evaporated to give 116 mg of (R)-2-(4-(4-((S)-2-((R)-2-((S)-2-amino-3-(2,4-dichlorophenyl)propanamido)-3-phenylpropanamido)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanamido)-3-(thiophen-2-yl)propanoic acid (5F). The crude product 5F was used directly in step 6.
Step 6: (R)-2-(4-(4-((S)-2-((R)-2-((S)-2-amino-3-(2,4-dichlorophenyl)propanamido)-3-phenylpropanamido)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanamido)-3-(thiophen-2-yl)propanoic acid (99 mg, 0.122 mmol), HATU (93 mg, 0.244 mmol) and HOAt (33 mg, 0.224 mmol) were dissolved in anhydrous DMF (80 mL). DIPEA (0.4 mL, 2.29 mmol) was then added to the stirring solution. The mixture was stirred at room temperature for 2 hours. The solvents were evaporated to give 80 mg of crude 5G as an orange solid.
Step 7: 5G (80 mg, 0.101 mmol) was dissolved in 4 mL of THF. A solution of lithium hydroxide (145 mg, 6.06 mmol) in 0.5 mL of H2O was then added. The reaction mixture was stirred at room temperature for 40 min. The solution was then neutralized with aqueous HCl. The solvents were evaporated, and the crude product was purified by preparative HPLC to give Compound 82 as a white solid.
Compound 83
Compound 83 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 84
Compound 84 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-cyclohexylpropanoic acid was used as starting material at step 4.
Compound 85
Compound 85 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 86
Compound 86 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 87
Compound 87 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxyphenyl)propanoic acid was used as starting material at step 4.
Compound 88
Compound 88 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 89
Compound 89 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 90
Compound 90 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butylphenyl)propanoic acid was used as starting material at step 4.
Compound 91
Compound 91 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 92
Compound 92 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(benzyloxy)phenyl)propanoic acid was used as starting material at step 4.
Compound 93
Compound 93 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3,4-dimethoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 94
Compound 94 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-cyanophenyl)propanoic acid was used as starting material at step 4.
Compound 95
Compound 95 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2′-methylbiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 96
Compound 96 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(nicotinamido)hexanoic acid was used as starting material at step 4.
Compound 97
Compound 97 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 98
Compound 98 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(methylsulfonyl)butanoic acid was used as starting material at step 4.
Compound 99
Compound 99 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(2,3-dihydro-1H-inden-2-yl)acetic acid was used as starting material at step 4.
Compound 100
Compound 100 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-methyl-1H-imidazol-4-yl)propanoic acid was used as starting material at step 4.
Compound 101
Compound 101 was prepared according to the procedures used in the synthesis of Compound 82, except that 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(benzyl)amino)acetic acid was used as starting material at step 4.
Compound 102
Compound 102 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-hydroxyphenyl)propanoic acid was used as starting material at step 4.
Compound 103
Compound 103 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methylphenyl)propanoic acid was used as starting material at step 4.
Compound 104
Compound 104 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxylphenyl)propanoic acid was used as starting material at step 4.
Compound 105
Compound 105 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-chlorophenyl)propanoic acid was used as starting material at step 4.
Compound 106
Compound 106 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 4.
Compound 107
Compound 107 was prepared according to the procedures used in the synthesis of Compound 82, except that (S)-3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 108
Compound 108 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(naphthalen-1-yl)propanoic acid was used as starting material at step 4.
Compound 109
Compound 109 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(naphthalen-2-yl)propanoic acid was used as starting material at step 4.
Compound 110
Compound 110 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; and (S)-2-(tert-butoxycarbonylamino)-3-(3′-methoxybiphenyl-4-yl)propanoic acid was used as starting material at step 4. In step 5, the Fmoc group was not removed. In addition, trifluoroacetic acid (1⁄3 volume of solution) was added to facilitate removal of the Boc group.
Compound 111
Compound 111 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material in step 2; and (S)-3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 112
Compound 112 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material in step 2; and (S)-3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 4.
Compound 113
Compound 113 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; and (S)-2-(tert-butoxycarbonylamino)-3-(biphenyl-3-yl)propanoic acid was used as starting material at step 4. In step 5, the Fmoc group was not removed. In addition, trifluoroacetic acid (1⁄3 volume of solution) was added to facilitate removal of the Boc group.
Compound 114
Compound 114 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyrimidin-2-yl)phenyl)propanoic acid was used as starting material at step 4. In step 5, the Fmoc group was not removed. In addition, trifluoroacetic acid (1⁄3 volume of solution) was added to facilitate removal of the Boc group.
Compound 115
Compound 115 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; and (S)-3-(4-(1H-pyrazol-1-yl)phenyl)-2-(tert-butoxycarbonylamino)propanoic acid was used as starting material at step 4. In step 5, the Fmoc group was not removed. In addition, trifluoroacetic acid (1⁄3 volume of solution) was added to facilitate removal of the Boc group.
Compound 116
Compound 116 was prepared according to the procedures used in the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material in step 1; and (S)-2-(tert-butoxycarbonylamino)-3-(4′-chlorobiphenyl-4-yl)propanoic acid was used as starting material at step 4. In step 5, the Fmoc group was not removed. In addition, trifluoroacetic acid (1⁄3 volume of solution) was added to facilitate removal of the Boc group.
Compound 167
Compound 167 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(2′-methoxybiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 168
Compound 168 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4′-methoxybiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 169
Compound 169 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(3′-hydroxybiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 170
Compound 170 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(2′-chlorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 171
Compound 171 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(3′-chlorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 172
Compound 172 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 173
Compound 173 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(benzyloxy)phenyl)propanoic acid was used as starting material at step 4.
Compound 177
Compound 177 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(benzyloxy)phenyl)propanoic acid was used as starting material at step 4.
Compound 178
Compound 178 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 180
Compound 180 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-chlorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 181
Compound 181 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(3′-fluorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 182
Compound 182 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(3′,5′-difluorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 183
Compound 183 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and 2-(4-bromophenyl)-2-(tert-butoxycarbonylamino)acetic acid was used as starting material at step 4.
Compound 188
Compound 188 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3′-hydroxybiphenyl-4-yl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 189
Compound 189 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 190
Compound 190 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 5, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 6, and (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 7.
Compound 203
Compound 203 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-6-(dimethylamino)hexanoic acid was used as starting material at step 4.
Compound 208
Compound 208 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 292
Compound 292 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 4.
Compound 293
Compound 293 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 294
Compound 294 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and 2-(4-bromophenyl)-2-(tert-butoxycarbonylamino)acetic acid was used as starting material at step 4.
Compound 330
Compound 330 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 332
Compound 332 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4′-(methoxycarbonyl)biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 333
Compound 333 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4′-methoxybiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 334
Compound 334 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4′-fluorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 335
Compound 335 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-3-(4′-(benzyloxycarbonyl)biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid was used as starting material at step 4.
Compound 336
Compound 336 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (2R,3R)-4-(4-((S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-2,3-diacetoxy-4-oxobutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-3-(4′-(benzyloxycarbonylamino)biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid was used as starting material at step 4.
Compound 355
Compound 355 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 356
Compound 356 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-chlorophenyl)propanoic acid was used as starting material at step 4.
Compound 357
Compound 357 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(naphthalen-1-yl)propanoic acid was used as starting material at step 4.
Compound 358
Compound 358 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 4.
Compound 359
Compound 359 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 361
Compound 361 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-4′-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-carboxyethyl)biphenyl-4-carboxylic acid was used as starting material at step 4.
Compound 362
Compound 362 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-(benzyloxycarbonylamino)biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 363
Compound 363 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-fluorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 364
Compound 364 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-methoxybiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 365
Compound 365 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-chlorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 366
Compound 366 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 367
Compound 367 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 4.
Compound 396
Compound 396 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-(benzyloxycarbonyl)biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 397
Compound 397 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 398
Compound 398 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 399
Compound 399 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 400
Compound 400 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 406
Compound 406 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3,4-dimethoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 407
Compound 407 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 408
Compound 408 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 419
Compound 419 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 525
Compound 525 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(4-bromophenyl)acetic acid was used as starting material at step 4.
Compound 526
Compound 526 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-(benzyloxycarbonyl)biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 527
Compound 527 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 539
Compound 539 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 540
Compound 540 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3,4-dimethoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 541
Compound 541 was prepared according to the procedures used for the synthesis of Compound 82, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 4.
Compound 655
Compound 655 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-fluorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 656
Compound 656 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4′-hydroxybiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 657
Compound 657 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(pyridin-3-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 658
Compound 658 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 659
Compound 659 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 660
Compound 660 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 661
Compound 661 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 662
Compound 662 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 663
Compound 663 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-2-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 664
Compound 664 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-2-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 665
Compound 665 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-3-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 666
Compound 666 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 667
Compound 667 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-2-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-2-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 668
Compound 668 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-3-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 669
Compound 669 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 4.
Compound 670
Compound 670 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-chlorophenyl)propanoic acid was used as starting material at step 4.
Compound 671
Compound 671 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 1, (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-methylpentanoic acid was used as starting material at step 4.
Compound 672
Compound 672 was prepared according to the procedures used for the synthesis of Compound 82, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 1, (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, and (R)-3-(4′-(benzyloxycarbonylamino)biphenyl-4-yl)-2-(tert-butoxycarbonylamino)propanoic acid was used as starting material at step 4.
Example 4
This example describes the synthesis and characterization of additional macrocyclic compounds. A general synthetic sequence for preparing the macrocyclic compounds is illustrated schematically below. The synthetic sequence involves attaching a substituted succinate to a solid support.










Compound 117

Step 1: 2-Chloro-trityl chloride resin (3E; 1.5 g, 2.37 mmol) was swelled in 20 mL DCM for 30 min and then filtered. (S)-4-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid (1.224 g, 2.37 mmol) and DIPEA (0.824 mL, 4.74 mmol) was dissolved in 12 mL of DCM. The resulting solution was added to the swelled resin. The mixture was purged with argon and agitated for 4 hours. The resin was then washed with 3×5 mL (17:2:1 DCM:MeOH:DIPEA), 3×5 mL 1% DIPEA in DCM, 2×5 mL DMF and 2×5 mL 1% DIPEA in DCM. After the resin was flushed with argon and dried under vacuum, resin 6B was obtained.
Step 2: Resin 6B (4×375 mg batches) Each batch was treated with 7 mL of 20% piperidine in DMF for 20 min, washed with 2×5 mL DMF and treated with another 7 mL of 20% piperidine in DMF. The resin was then washed with 3×5 mL DMF, 3×5 mL DCM and 2×5 mL NMP. To the resulting resin, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid (1.01 g, 2.61 mmol) and HATU (0.992 g, 2.61 mmol) in 12 mL of NMP were added evenly across the four batches of resin. DIPEA (0.908 mL, 5.22 mmol) was then added evenly across each batch. The four reaction mixtures were agitated at room temperature for 40 min. The combined resin was filtered and washed with 4×5 mL DMF and 4×5mL 1% DIPEA in DCM to give resin 6C.
Step 3: Resin 6C (4×375 mg batches) Each batch was treated with 4 mL of 20% piperidine in DMF for 20 min, washed with 2×5 mL DMF and treated with another 4 mL of 20% piperidine in DMF. The resin was then washed with 3×5 mL DMF, 3×5 mL DCM and 2×5 mL NMP. To the resulting resin, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid (1.210 g, 2.61 mmol), HATU (0.992 g, 2.61 mmol) and DIPEA (0.908 mL, 5.22 mmol) in 8 mL of NMP were added evenly across the four batches of resin. The four reaction mixtures were agitated at room temperature for one hour. The combined resin was filtered and washed with 3×5 mL DMF and 3×5 mL 1% DIPEA in DCM to give resin 6D.
Step 4: Resin 6D (200 mg) was treated with 4 mL of 20% piperidine in DMF for 20 min, washed with 2×5 mL DMF and treated with another 4 mL of 20% piperidine in DMF. The resin was then washed with 3×5 mL DMF, 3×5 mL 1% DIPEA in DCM and 2×5 mL NMP. To the resulting resin, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid (140 mg, 0.348 mmol), HATU (132 mg, 0.348 mmol) and DIPEA (0.121 mL, 0.696 mmol) in 1 mL of NMP were added. The mixture was agitated at room temperature for 1 hour. The resin was filtered and washed with 3×5 mL DMF and 3×5 mL 1% DIPEA in DCM to yield resin 6E.
Step 5: Resin 6E was treated with 4 mL of 20% piperidine in DMF for 20 min, washed with 2×5 mL DMF and treated with another 4 mL of 20% piperidine in DMF. The resin was then washed with 3×5 mL DMF, and 3×5 mL 1% DIPEA in DCM. The resin was treated with 5 mL of 2% TFA in DCM for 15 min and then collected by filtration. The cleaving reaction was repeated once. The filtrates were combined and evaporated to give 96 mg of 4-(4-((S)-2-((R)-2-((S)-2-((R)-2-amino-4-phenylbutanamido)-3-(biphenyl-4-yl)propanamido)-3-phenylpropanamido)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid (6F). The crude product 6F was used directly in step 6.
Step 6: 4-(4-((S)-2-((R)-2-((S)-2-((R)-2-amino-4-phenylbutanamido)-3-(biphenyl-4-yl)propanamido)-3-phenylpropanamido)-3-methoxy-3-oxopropyl)phenylamino)-4-oxobutanoic acid (96 mg, 0.116 mmol), HATU (88 mg, 0.232 mmol) and HOAt (31.6 mg, 0.232 mmol) were dissolved in anhydrous DMF (38.7 mL). DIPEA (0.101 mL, 0.581 mmol) was then added to the stirring solution. The mixture was stirred at room temperature for 20 min and progress was monitored by LC/MS. The solvents were evaporated to give 94 mg of crude 6G as a brown solid.
Step 7: 6G (94 mg, 0.116 mmol) was dissolved in 1.6 mL of THF. Lithium hydroxide (27.9 mg, 1.163 mmol) in 0.4 mL of H2O was then added. The reaction mixture was stirred at room temperature for 2 hours. The solution was then neutralized with aqueous HCl. The solvents were evaporated, and the crude product was purified by preparative HPLC to give Compound 117 as a white solid (14 mg, 15% yield).
Compound 118
Compound 118 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 119
Compound 119 was prepared according to the procedures used in the synthesis of Compound 117, except that 2-((((9H-fluoren-9-yl)methoxy)carbonyl)(benzyl)amino)acetic acid was used as starting material at step 4.
Compound 120
Compound 120 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-phenylacetic acid was used as starting material at step 4.
Compound 121
Compound 121 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxyphenyl)propanoic acid was used as starting material at step 4.
Compound 122
Compound 122 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-3-yl)propanoic acid was used as starting material at step 4.
Compound 123
Compound 123 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 4.
Compound 124
Compound 124 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-cyclohexylpropanoic acid was used as starting material at step 4.
Compound 125
Compound 125 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 4.
Compound 126
Compound 126 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-3-yl)propanoic acid was used as starting material at step 4.
Compound 127
Compound 127 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 4.
Compound 128
Compound 128 was prepared according to the procedures used in the synthesis of Compound 117, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 129
Compound 129 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-cyanophenyl)propanoic acid was used as starting material at step 4.
Compound 130
Compound 130 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-cyanophenyl)propanoic acid was used as starting material at step 4.
Compound 131
Compound 131 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-cyanophenyl)propanoic acid was used as starting material at step 4.
Compound 132
Compound 132 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-chlorophenyl)propanoic acid was used as starting material at step 4.
Compound 133
Compound 133 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-chlorophenyl)propanoic acid was used as starting material at step 4.
Compound 134
Compound 134 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 135
Compound 135 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3,4-difluorophenyl)propanoic acid was used as starting material at step 4.
Compound 136
Compound 136 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-phenylpentanoic acid was used as starting material at step 4.
Compound 137
Compound 137 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(benzyloxy)propanoic acid was used as starting material at step 4.
Compound 138
Compound 138 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 139
Compound 139 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-o-tolylpropanoic acid was used as starting material at step 4.
Compound 140
Compound 140 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3,3-diphenylpropanoic acid was used as starting material at step 4.
Compound 141
Compound 141 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-(3-(2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ylsulfonyl)guanidino)pentanoic acid was used as starting material at step 4.
Compound 142
Compound 142 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(naphthalen-1-yl)propanoic acid was used as starting material at step 4.
Compound 143
Compound 143 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3 and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(naphthalen-2-yl)propanoic acid was used as starting material at step 4.
Compound 144
Compound 144 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 145
Compound 145 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 146
Compound 146 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 147
Compound 147 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 148
Compound 148 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 149
Compound 149 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 150
Compound 150 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 151
Compound 151 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 152
Compound 152 was prepared according to the procedures used in the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 506
Compound 506 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 4.
Compound 507
Compound 507 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-phenylacetic acid was used as starting material at step 4.
Compound 508
Compound 508 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-acetamidohexanoic acid was used as starting material at step 4.
Compound 509
Compound 509 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-phenylpentanoic acid was used as starting material at step 4.
Compound 510
Compound 510 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 511
Compound 511 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 512
Compound 512 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 4.
Compound 513
Compound 513 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4.
Compound 514
Compound 514 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 515
Compound 515 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butylphenyl)propanoic acid was used as starting material at step 4.
Compound 517
Compound 517 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-(4-bromophenyl)acetic acid was used as starting material at step 4.
Compound 518
Compound 518 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 519
Compound 519 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 520
Compound 520 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 521
Compound 521 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxyphenyl)propanoic acid was used as starting material at step 4.
Compound 522
Compound 522 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 523
Compound 523 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 4.
Compound 524
Compound 524 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3,4-difluorophenyl)propanoic acid was used as starting material at step 4.
Compound 673
Compound 673 was prepared according to the procedures used for the synthesis of Compound 117, except that (R)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 674
Compound 674 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 675
Compound 675 was prepared according to the procedures used for the synthesis of Compound 117, except that (R)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 676
Compound 676 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 677
Compound 677 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 678
Compound 678 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 679
Compound 679 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-fluorophenyl)propanoic acid was used as starting material at step 4.
Compound 680
Compound 680 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 681
Compound 681 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-methoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 682
Compound 682 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-2-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 683
Compound 683 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-3-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 684
Compound 684 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(tert-butoxycarbonylamino)-3-(4-(pyridin-4-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 685
Compound 685 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(benzyloxy)phenyl)propanoic acid was used as starting material at step 4.
Compound 686
Compound 686 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid was used as starting material at step 4.
Compound 687
Compound 687 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 4.
Compound 688
Compound 688 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-chlorophenyl)propanoic acid was used as starting material at step 4.
Compound 689
Compound 689 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 690
Compound 690 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(3-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 691
Compound 691 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid was used as starting material at step 4.
Compound 692
Compound 692 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-p-tolylpropanoic acid was used as starting material at step 4.
Compound 693
Compound 693 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-phenyl-1H-1,2,3-triazol-4-yl)propanoic acid was used as starting material at step 4.
Compound 694
Compound 694 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(naphthalen-1-yl)propanoic acid was used as starting material at step 4.
Compound 695
Compound 695 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(naphthalen-2-yl)propanoic acid was used as starting material at step 4.
Compound 696
Compound 696 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiazol-4-yl)propanoic acid was used as starting material at step 4.
Compound 697
Compound 697 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 4.
Compound 698
Compound 698 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4′-fluorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 699
Compound 699 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 700
Compound 700 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(3′,5′-difluorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 701
Compound 701 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methylbutanoic acid was used as starting material at step 4.
Compound 702
Compound 702 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(tert-butoxycarbonylamino)-3-(4′-chlorobiphenyl-4-yl)propanoic acid was used as starting material at step 4.
Compound 703
Compound 703 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(methylsulfonyl)butanoic acid was used as starting material at step 4.
Compound 704
Compound 704 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(thiophen-2-yl)phenyl)propanoic acid was used as starting material at step 4.
Compound 705
Compound 705 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 4.
Compound 706
Compound 706 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1-methyl-1H-imidazol-4-yl)propanoic acid was used as starting material at step 4.
Compound 707
Compound 707 was prepared according to the procedures used for the synthesis of Compound 117, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-chlorophenyl)propanoic acid was used as starting material at step 4.
Example 5
This example describes the synthesis and characterization of additional macrocyclic compounds. A general synthetic sequence for preparing the macrocyclic compounds is illustrated schematically below. The synthetic sequence involves attaching a substituted succinate to a solid support.







Compound 217

Step 1: (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid (9.13 g, 21.13 mmol) was dissolved in DCM (65 mL) and followed by the addition of 1-(mesitylsulfonyl)-3-nitro-1H-1,2,4-triazole (6.26 g, 21.13 mmol) and 1-methyl-1H-imidazole (1.263 mL, 15.84 mmol). This solution was added to swelled Wang Resin (3E′; 6.5, 8.12 mmol) and agitated for 1 hour under argon. The resin was then washed with 5×50 mL of DCM, 5×50 mL of DMF, and 3×50 mL of DCM, then dried resulting in resin 7B.
Step 2: Resin 7B (150 mg, 0.071 mmol) was treated with 2 mL of 20% piperidine in DMF for 20 min, washed with 2×2 mL DMF and treated with another 2 mL of 20% piperidine in DMF. The resin was then washed with 3×2 mL of DMF and 3×2 mL of NMP. To the resulting resin, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid (86 mg, 0.21 mmol), HATU (133 mg, 0.35 mmol) and DIPEA (122 μL, 0.70 mmol) in 2 mL of NMP was added. The mixture was shook under argon at room temperature for 2 hours. The resin was filtered and washed with 3×2 mL of NMP, 3×2 mL of DMF, and 3×3 mL of DCM, resin 7C was obtained.
Step 3: Resin 7C was treated with 2 mL of 20% piperidine in DMF for 20 min, washed with 2×2 mL DMF and treated with another 2 mL of 20% piperidine in DMF. The resin was then washed with 3×2 mL of DMF and 3×2 mL of NMP. To the resulting resin, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid (97 mg, 0.21 mmol), HATU (133 mg, 0.35 mmol) and DIPEA (122 μL, 0.70 mmol) in 2 mL of NMP was added. The mixture was shook under argon at room temperature for 2 hours. The resin was filtered and washed with 3×2 mL of NMP, 3×2 mL of DMF, and 3×2 mL of DCM, resin 7D was obtained.
Step 4: Resin 7D was treated with 2 mL of 20% piperidine in DMF for 20 min, washed with 2×2 mL DMF and treated with another 2 mL of 20% piperidine in DMF. The resin was then washed with 3×2 mL of DMF and 3×2 mL of NMP. To the resulting resin, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid (83 mg, 0.21 mmol), HATU (133 mg, 0.35 mmol) and DIPEA (122 μL, 0.70 mmol) in 2 mL of NMP was added. The mixture was shook under argon at room temperature for 2 hours. The resin was filtered and washed with 3×2 mL of NMP, 3×2 mL of DMF, and 3×2 mL of DCM, resin 7E was obtained.
Step 5: Resin 7E was treated with a 0.7M Tin Chloride solution in DMF (2 mL, 1.4 mmol) and the mixture was shook under argon at room temperature for 16 hours. The resin was filtered and washed with 3×2 mL of DMF, and 3×2 mL of DCM, resin 7F was obtained.
Step 6: Resin 7F was treated with a 0.5M (3R,4R)-2,5-dioxotetrahydrofuran-3,4-diyl diacetate (3 mL, 1.5 mmol) and the mixture was shook under argon at room temperature for 4 hours. The resin was filtered and washed with 3×2 mL DCM, 3×2 mL of DMF, and 3×2 mL of DCM, resin 7G was obtained.
Resin 7G was treated with 2 mL of 2% piperidine, 2% DBU in DMF for 20 min, washed with 2×2 mL DMF and treated with another 2 mL of 2% piperidine, 2% DBU in DMF for 20 min. The resin was then washed with 5×2 mL of DMF and 5×2 mL of DCM and dried thoroughly. Perfluorophenyl diphenylphosphinate (81 mg, 0.21 mmol) and DIPEA (73 μL, 0.42 mmol) was dissolved in DMF (20 mL) and this was added to the resin and shook under argon at room temperature for 16 hours. The resin was filtered and washed with 3×2 mL of DMF, and 3×2 mL of DCM, resin 7H was obtained.
Resin 7H was swelled in DCM (1.8 mL) followed by the addition of triisopropyl silane (0.2 mL), and this mixture was rocked for 10 minutes. TFA (2 mL) was added and the solution was rocked for 2 hrs. The resin was filtered collecting the solution. The resin was then washed with a 50% TFA in DCM solution (4 mL×3), combining washes. Evaporation of volatiles left a crude oil which was purified by was purified by preparative HPLC to give Compound 217 (7I) as a white solid (4.5 mg, 7% overall).
Compound 153
Compound 153 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4, and maleic anhydride was used as starting material at step 6.
Compound 154
Compound 154 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 159
Compound 159 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4, and maleic anhydride was used as starting material at step 6.
Compound 160
Compound 160 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(furan-2-yl)propanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 196
Compound 196 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4, and maleic anhydride was used as starting material at step 6.
Compound 218
Compound 218 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 219
Compound 219 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 220
Compound 220 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 221
Compound 221 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 222
Compound 222 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 223
Compound 223 was prepared according to the procedures used for the synthesis of Compound 217, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 231
Compound 231 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 232
Compound 232 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 233
Compound 233 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 234
Compound 234 was prepared according to the procedures used for the synthesis of Compound 217, except that (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2,4-dichlorophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 235
Compound 235 was prepared according to the procedures used for the synthesis of Compound 217, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 4.
Compound 394
Compound 394 was prepared according to the procedures used for the synthesis of Compound 217, except that Fmoc PheWang Resin (Polymer Laboratories,a division of Varian, Inc., Palo Alto, Calif.; Cat #PL3463-47995) was used as starting resin at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 409
Compound 409 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 410
Compound 410 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin at step 1, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 411
Compound 411 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 412
Compound 412 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 413
Compound 413 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 414
Compound 414 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 415
Compound 415 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 416
Compound 416 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 417
Compound 417 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 418
Compound 418 was prepared according to the procedures used for the synthesis of Compound 217, except that Wang resin preloaded with L-phenylalanine was used as starting resin and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-nitrophenyl)propanoic acid was used as starting material at step 1, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-phenylpropanoic acid was used as starting material at step 2, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-bromophenyl)propanoic acid was used as starting material at step 3, and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 4.
Compound 708
Compound 708 was prepared according to the procedures used for the synthesis of Compound 217, except that 3-oxabicyclo[3.1.0]hexane-2,4-dione was used as starting material at step 6.
Compound 709
Compound 709 was prepared according to the procedures used for the synthesis of Compound 217, except that 3-oxabicyclo[3.2.0]heptane-2,4-dione was used as starting material at step 6.
Compound 710
Compound 710 was prepared according to the procedures used for the synthesis of Compound 217, except that (3aS,7aS)-hexahydroisobenzofuran-1,3-dione was used as starting material at step 6.
Compound 711
Compound 711 was prepared according to the procedures used for the synthesis of Compound 217, except that (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 5 and 3,3-dimethyldihydrofuran-2,5-dione was used as starting material at step 6.
Example 6
Compounds of formula 711 were coverted into the corresponding diols by_dissolving in THF (0.5 mL) followed by the addition of 40% methylamine/water (10 uL, 0.16 mmol). After vortexing for 30 minutes, volatiles were evaporated, and the resulting solid was washed with water (0.2 mL×2), put up in acetonitrile/water and lyophilized.
Compound 236
Compound 217 (1.5 mg, 1.6 μmol) (7I) was dissolved in THF (0.5 mL) followed by the addition of 40% methylamine/water (10 uL, 0.16 mmol). After vortexing for 30 minutes, volatiles were evaporated, and resulting solid was washed with water (0.2 mL×2), put up in acetonitrile/water and lyophilized, leaving Compound 236 as a white powder (0.72 mg, 0.87 μmol, 53%).
Compound 155
Compound 155 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 154 was used as starting material.
Compound 161
Compound 161 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 160 was used as starting material.
Compound 237
Compound 237 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 218 was used as starting material.
Compound 238
Compound 238 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 219 was used as starting material.
Compound 239
Compound 239 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 220 was used as starting material.
Compound 240
Compound 240 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 221 was used as starting material.
Compound 241
Compound 241 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 222 was used as starting material.
Compound 242
Compound 242 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 232 was used as starting material.
Compound 243
Compound 243 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 233 was used as starting material.
Compound 244
Compound 244 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 234 was used as starting material.
Compound 245
Compound 245 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 235 was used as starting material.
Compound 429
Compound 429 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 409 was used as starting material.
Compound 430
Compound 430 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 394 was used as starting material.
Compound 431
Compound 431 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 410 was used as starting material.
Compound 432
Compound 432 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 411 was used as starting material.
Compound 433
Compound 433 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 412 was used as starting material.
Compound 434
Compound 434 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 413 was used as starting material.
Compound 435
Compound 435 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 414 was used as starting material.
Compound 436
Compound 436 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 415 was used as starting material.
Compound 437
Compound 437 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 416 was used as starting material.
Compound 438
Compound 438 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 417 was used as starting material.
Compound 439
Compound 439 was prepared according to the procedures used for the synthesis of Compound 236 except that Compound 418 was used as starting material.
Example 7
This example describes the synthesis and characterization of additional macrocyclic compounds. A general synthetic sequence for preparing the macrocyclic compounds is illustrated schematically below.







Compound 247

Step 1: HMBA-PEGA Resin, 8A (0.74 mmol, 0.37 mmol/g) was swelled in 20 mL NMP for 30 min, washed with 2×20 mL DMF and 3×20 mL of DCM. A solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(tert-butoxycarbonylamino)phenyl)propanoic acid (1.08 g, 2.22 mmol),
Compound 713
Compound 713 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 714
Compound 714 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 715
Compound 715 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 716
Compound 716 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 717
Compound 717 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 718
Compound 718 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 719
Compound 719 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 720
Compound 720 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 721
Compound 721 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 722
Compound 722 was prepared according to the procedures used for the synthesis of Compound 712, except that (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 723
Compound 723 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 724
Compound 724 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 5.
Compound 725
Compound 725 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 5.
Compound 726
Compound 726 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(thiophen-2-yl)propanoic acid was used as starting material at step 5.
Compound 727
Compound 727 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 728
Compound 728 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 729
Compound 729 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 730
Compound 730 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 731
Compound 731 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 732
Compound 732 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 733
Compound 733 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 734
Compound 734 was prepared according to the procedures used for the synthesis of Compound 712, except that step 1 was omitted, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 735
Compound 735 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 736
Compound 736 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 737
Compound 737 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 738
Compound 738 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 739
Compound 739 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 740
Compound 740 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 741
Compound 741 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 742
Compound 742 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(2-fluorophenyl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 743
Compound 743 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 744
Compound 744 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 745
Compound 745 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(pyridin-4-yl)propanoic acid was used as starting material at step 5.
Compound 746
Compound 746 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-phenylbutanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Compound 747
Compound 747 was prepared according to the procedures used for the synthesis of Compound 712, except that was used as starting material at step 1, (S)-2-(4-(2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-methoxy-3-oxopropyl)phenoxy)acetic acid was used as starting material at step 2, (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 3, (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(biphenyl-4-yl)propanoic acid was used as starting material at step 4 and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-3-(1H-indol-3-yl)propanoic acid was used as starting material at step 5.
Example 10
The compounds listed in Table 2 below were assayed for ability to inhibit binding of TNFα to the TNFα receptor (TNFα R1/Fc). The assays were performed as described in the following procedure: TNFα (R&D Systems) was coated on high binding plate wells (Corning 96-well) at a single uniform concentration of 15 nM, 100 μL/well in PBS. The coating proceeded for 30 minutes at 37° C. then 10 minutes at 4° C. The coated plate was washed with PBST, then 250 μL/well of blocking solution (PBST 0.1% BSA, bovine serum albumin) was added and incubation proceeded for 30-45 minutes at room temperature with agitation. The solution phase competition proceeded separately with the dilutions of test compound in PBST (phosphate buffered saline with Tween 20), 2% DMSO in a polypropylene plate (Corning 96-well storage plate) with a single concentration, 8.33 nM of the high affinity receptor for TNFα (R&D Systems). This solution phase incubation proceeded for 30 minutes at room temperature with agitation and was then added to the washed TNFα coated assay plate, 100 μL/well, and was incubated for a further 30 minutes at room temperature with agitation. The assay plate was washed and 100 μL goat anti-human IgG (Fc) HRP labeled antibody in PBST, 13 pM, (KPL Cat#04-10-2) was added to each well. This incubation proceeded for 25-30 minutes at room temperature with agitation. Following this incubation step, the plate was washed and a 100 μL TMB solution (SUREBLUETM TMB Peroxidase substrate, KPL) was added per well and allowed to stand approximately 3-5 minutes for development. The TMB reaction was stopped with the addition of 0.5N HCl and then the plate was read for absorbance at 450 nm. IC50 values are reported as follows: + indicates an IC50 value greater than 100 μM or that the compound had no activity at the concentration tested, ++ indicates an IC50 value of 30 μM to 100 μM, +++ indicates an IC50 value of greater than 10 μM and less than 30 μM, ++++ indicates an IC50 value of 10 μM or less.










TABLE 2







Compound No.
Activity



















1
+++



2
+



3
+++



4
+++



5
++



6
+



7
+



8
++



9
+++



10
+++



11
++++



12
++++



13
+



14
++



15
+++



16
++++



17
+++



18
+++



19
+++



20
++++



21
++++



22
++



23
+



24
++



25
++++



26
+++



27
+



28
++++



29
++++



30
+++



31
+



32
+



33
++++



34
++++



35
+++



36
++++



37
+



38
++



39
++++



42
+



43
+



44
+



45
+



46
+



47
++++



48
+++



49
+



50
+



51
+



52
+



53
+



54
+



55
+



56
+



57
+



58
+



59
+



60
+



61
+



62
+



63
+



64
+



65
+



66
+



67
++



68
+



69
+



72
+



73
+



74
++



75
++



76
+++



77
++



78
+



79
+



80
+



81
+



82
+++



83
+



84
+



85
+++



86
+



87
+



88
+



89
+++



90
+



91
+



92
++



93
+



94
+



95
++



96
+



97
+



98
+



99
+



100
+



101
+



102
+



103
+



104
+



105
++



106
+



107
+



108
+++



109
+++



110
+++



111
+++



112
++++



113
+++



114
+



115
+



116
++++



117
++++



118
+++



119
++



120
+



121
+



122
++



123
++



124
+



125
+



126
+



127
+



128
++



129
++



130
+++



131
++



132
++



133
++



134
+



135
++



136
++



137
++



138
+



139
+



140
+



141
+



142
++



143
+



144
+++



145
+++



146
+++



147
++



148
++



149
+++



150
++



151
++



152
+



153
+



154
+



155
+



156
++++



157
++++



158
++++



159
+++



160
++



161
+



162
+



163
++



164
++



165
+



166
++



167
+



168
++



169
+



170
++



171
+



172
++++



173
+++



174
++++



175
++++



176
+



177
++



178
+



179
++++



180
++++



181
+++



182
++



183
+++



184
+



185
+



186
++



187
+



188
+



189
+



190
+++



191
++++



192
++++



193
++++



194
+



195
+



196
++++



197
++++



198
++++



199
+



200
++



201
++++



202
++++



203
+



205
+



206
+



208
+



209
+



210
+



211
++



212
++++



213
+



214
++++



215
++



216
+



217
++++



218
+++



219
++++



220
+++



221
++



222
+



223
++



224
+



225
+



226
+++



227
++++



228
++++



229
++++



230
+++



231
+



232
+



233
++



234
+



235
+++



236
++++



237
++++



238
++++



239
++++



240
+++



241
++



242
++



243
++



244
++



245
+++



246
++



247
+



248
++++



249
+



250
+



251
+



252
+



253
+



254
+++



255
+



256
+



257
+



258
+



259
++



260
++



261
++



262
+++



263
+



264
+



265
+



266
+



267
+



268
+



269
+



270
+



271
+



272
+



273
+



274
+



275
+



276
+



277
+



278
+



279
+



280
+



281
+



282
++++



283
++++



284
+++



285
++



286
+++



287
+++



288
+



289
++++



290
++++



291
+



292
+



293
+



294
++



295
+++



296
++



297
++++



298
++++



299
++++



300
++++



301
++++



302
++++



303
+++



304
+++



305
++++



306
++++



307
++++



308
+



309
+++



310
+



311
++



312
+



313
++++



314
+++



315
+++



316
+++



317
+++



318
++++



319
++++



320
++++



321
++++



322
+++



323
++++



324
++++



325
++++



326
++++



327
++++



328
++++



329
++++



330
++++



332
++++



333
++



334
++



335
+++



336
+++



337
+



338
+++



339
++++



340
++++



341
++++



342
++++



343
++++



344
++++



345
++



346
++++



347
++



348
++++



349
+++



350
++++



351
+++



352
+



353
+



354
+



355
+



356
+



357
+



358
+



359
+



360
+



361
+



362
++++



363
++++



364
++++



365
++



366
++++



367
+



368
+



369
+++



370
+



371
+



372
+



373
+



374
+



375
+



376
+++



377
+



378
+++



379
++++



380
++++



381
++++



382
++++



383
++++



384
++++



385
++++



386
++++



387
+



388
++++



389
+



390
++++



391
++++



392
+++



393
++++



394
++++



395
++++



396
++++



397
+



398
++++



399
+



400
++++



401
++++



402
+++



403
+



404
++++



405
+



406
+



407
+



408
+



409
++++



410
++++



411
+



412
++++



413
+



414
+



415
+



416
+



417
+



418
+



419
+++



420
+



421
++++



422
++++



423
++++



424
++++



425
++



426
++++



427
+



428
++++



429
++++



430
+++



431
+



432
++++



433
+



434
++++



435
++++



436
++++



437
+++



438
++++



439
++



440
+++



441
+++



442
++++



443
+++



444
++



445
+++



446
+



447
+



448
+++



449
+



450
++



451
++



452
+



453
+



454
+++



455
+



456
+



457
+



458
+



459
+



460
+



461
+



462
+



463
+



464
++++



465
++++



466
+



467
+



468
+



469
+



470
++++



471
++++



472
++++



473
++++



475
++++



477
++++



478
++++



479
++++



480
+++



481
++++



482
++++



483
+



484
+



485
+++



486
++++



487
+++



488
+



489
+



490
+



491
+



493
++++



494
+



495
+



496
+



497
+



498
+



499
+



500
+++



501
+



502
+



503
+



504
++++



505
+++



506
++++



507
+++



508
++++



509
++++



510
++++



511
++++



512
++++



513
++++



514
++++



515
+++



516
++



517
+++



518
++++



519
+++



520
++++



521
+



522
+



523
+



524
+++



525
++++



526
+



527
+



528
++++



529
+



530
+



531
+



532
+



533
+



534
+



535
+



536
++++



537
+



538
+



539
+



540
+



541
+



542
++++



543
+



544
++++



545
+++



546
++++



547
++++



548
++



549
+



550
++



551
++



552
+++



553
++++



554
++++



555
++++



556
++++



557
++++



558
++++



559
++++



560
++++



561
++++



562
++++



563
++



564
++++



565
++++



566
+++



567
++++



568
++



569
++++



570
+++



571
++++



572
++++



573
++++



574
+



575
++++



576
++++



577
++++



578
+



579
++++



580
++++



581
++++



582
++++



583
++++



584
++++



585
++++



586
++++



448
+++



449
+



450
++



451
++



452
+



453
+



454
+++



455
+



456
+



457
+



458
+



459
+



460
+



461
+



462
+



463
+



464
++++



465
++++



466
+



467
+



468
+



469
+



470
++++



471
++++



472
++++



473
++++



475
++++



477
++++



478
++++



479
++++



480
+++



481
++++



482
++++



483
+



484
+



485
+++



486
++++



487
+++



488
+



489
+



490
+



491
+



493
++++



494
+



495
+



496
+



497
+



498
+



499
+



500
+++



501
+



502
+



503
+



504
++++



505
+++



506
++++



507
+++



508
++++



509
++++



510
++++



511
++++



512
++++



513
++++



514
++++



515
+++



516
++



517
+++



518
++++



519
+++



520
++++



521
+



522
+



523
+



524
+++



525
++++



526
+



527
+



528
++++



529
+



530
+



531
+



532
+



533
+



534
+



535
+



536
++++



537
+



538
+



539
+



540
+



541
+



542
++++



543
+



544
++++



545
+++



546
++++



547
++++



548
++



549
+



550
++



551
++



552
+++



553
++++



554
++++



555
++++



556
++++



557
++++



558
++++



559
++++



560
++++



561
++++



562
++++



563
++



564
++++



565
++++



566
+++



567
++++



568
++



569
++++



570
+++



571
++++



572
++++



573
++++



574
+



575
++++



576
++++



577
++++



578
+



579
++++



580
++++



581
++++



582
++++



583
++++



584
++++



585
++++



586
++++



587
++++



588
++++



590
++++



591
++++



592
++++



593
++++



594
+



595
+



596
+



597
+++



598
++++



599
++++



600
+++



601
++++



602
++++



603
+



604
++++



605
++++



606
++++



607
+



608
+++



609
+++



610
++++



611
++++



612
+++



613
+



614
++++



615
+



616
++++



617
++++



618
++++



619
++++



620
+



621
++++



622
++++



623
++++



624
++++



625
++++



626
+



627
+



628
+



629
+++



630
+++



631
++++



632
++++



633
++++



634
++++



635
++++



636
++++



637
++++



638
++++



639
++++



640
++++



641
++++



642
+



643
++++



644
++++



645
++++



646
++++



647
++++



648
++++



649
++++



650
++++



651
+



652
++++



653
++++



654
+



655
++++



656
++++



657
++++



658
++++



659
++++



660
++++



661
++



662
++++



663
+



664
++



665
+++



666
+++



667
+



668
+



669
++++



670
+++



672
++++



673
++++



674
++++



675
+



676
++++



677
++++



678
++++



679
++++



680
++++



681
++++



682
++++



683
++++



684
++++



685
++++



686
++++



687
++++



688
++++



689
++++



690
+++



691
++++



692
++++



693
++++



694
++++



695
++++



696
++++



697
++++



698
++++



699
+



700
++++



701
++++



702
++++



703
++++



704
++++



705
++++



706
+++



707
++++



708
++++



709
++++



710
++++



711
++++



712
++++



713
++++



713
++++



714
++++



715
+++



715
+



716
++++



717
+++



718
++++



719
++++



720
++++



721
++++



722
++++



723
++++



724
++++



725
++++



726
++



727
++++



728
+++



729
+



730
++++



731
+++



732
+



733
++++



734
++++



735
+++



736
++++



737
++++



738
++++



739
++++



740
+++



741
++++



742
++++



743
++++



744
++++



745
+++



746
++++



747
++++










Example 10
Compounds 3, 4, 10 and 202 were tested in a rat paw edema model to determine anti-inflammatory activity. Seven groups (one for Vehicle A [15 mL PEG400, 3 mL Graves Grain alcohol (190 proof), 1.8 mL dimethylacetamide and 10.2 mL deionized water] alone as a negative control, one for Vehicle B [0.1M NaHCO3] alone as a negative control, one for each of the four test compounds dissolved in Vehicle A, and one for indomethacin dissolved in Vehicle B as a positive control), each group containing six Sprague-Dawley (SD) rats (180-200 g) randomized by weight. Initial paw volumes were measured by placing the right hind limb of the rat up to the top of the hock in a beaker of water sitting on a scale that had been tared to zero and recording the readout.
Rats were pre-treated with either i) one of the test compounds, or ii) a positive or negative control. Vehicle A alone and test compound dissolved in Vehicle A (Compound 3-1.0 mg/kg; Compound 4-0.4 mg/kg; Compound 10-0.5 mg/kg; Compound 202-0.3 mg/kg) were administered by intravenous injection. Vehicle B alone and indomethacin (5 mg/kg in 0.1M NaHCO3) was administered by intraperitoneal injection. Thirty minutes after this pretreatment, rats were anesthetized and injected with 0.1 mL of carrageenan (10 mg/mL in water) in the subplantar region of the right hind foot using a 1⁄2 inch 26 gauge needle attached to a 1 cc syringe.
At 2, 4 and 6 hours post-carrageenan injection, the right hind foot of each rat was measured for paw volume as described above. The results of this experiment are shown in Table 3, below.








TABLE 3








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle A alone (IV)
0
1.11 ± 0.23
1.55 ± 0.18
1.50 ± 0.12


Compound 3 (IV)
0
0.69 ± 0.14
1.16 ± 0.32
1.22 ± 0.31


Compound 4 (IV)
0
0.72 ± 0.13
1.16 ± 0.16
1.16 ± 0.25


Compound 10 (IV)
0
0.54 ± 0.23
1.11 ± 0.31
1.23 ± 0.28


Compound 202 (IV)
0
0.42 ± 0.20
1.01 ± 0.31
1.16 ± 0.20


Vehicle B alone (IP)
0
1.15 ± 0.16
1.76 ± 0.17
1.80 ± 0.15


Indomethacin (IP)
0
0.61 ± 0.10
0.92 ± 0.12
0.99 ± 0.10









The above experiment was repeated with Compounds 11, 33, 342 and 393 (each at 1 mg/kg intravenous doses. The results are set forth below in Table 4, below.








TABLE 4








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle A alone (IV)
0
1.26 ± 0.17
1.61 ± 0.18
1.66 ± 0.10


Compound 11 (IV)
0
1.37 ± 0.16
1.43 ± 0.13
1.45 ± 0.08


Compound 33 (IV)
0
1.10 ± 0.22
1.49 ± 0.11
1.46 ± 0.07


Compound 342 (IV)
0
1.36 ± 0.10
1.49 ± 0.20
1.51 ± 0.15


Compound 393 (IV)
0
1.24 ± 0.18
1.54 ± 0.25
1.56 ± 0.17


Indomethacin (IP)
0
0.61 ± 0.08
0.82 ± 0.05
0.90 ± 0.11









The experiment was again repeated with Compounds 362, 426, 442, 482 and 506 (each at 1 mg/kg intravenous doses). The results are set forth below in Table 5, below.








TABLE 5








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle A alone (IV)
0
1.56 ± 0.21
1.64 ± 0.19
1.54 ± 0.12


Compound 362 (IV)
0
1.17 ± 0.07
1.22 ± 0.21
1.15 ± 0.19


Compound 426 (IV)
0
0.90 ± 0.15
1.11 ± 0.18
1.11 ± 0.23


Compound 442 (IV)
0
0.86 ± 0.15
1.08 ± 0.16
1.01 ± 0.14


Compound 482 (IV)
0
0.73 ± 0.19
0.99 ± 0.34
0.86 ± 0.27


Compound 506 (IV)
0
0.74 ± 0.18
1.05 ± 0.17
0.86 ± 0.15


Indomethacin (IP)
0
0.82 ± 0.08
0.94 ± 0.10
0.87 ± 0.11









The experiment was again repeated with Compounds 330, 346, 348, and a re-test of 393 (each at 1 mg/kg intravenous doses). The results are set forth below in Table 6, below.








TABLE 6








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle A alone (IV)
0
1.46 ± 0.12
1.70 ± 0.26
1.57 ± 0.24


Compound 330 (IV)
0
1.20 ± 0.20
1.32 ± 0.17
1.33 ± 0.22


Compound 346 (IV)
0
1.17 ± 0.06
1.20 ± 0.09
1.34 ± 0.09


Compound 348 (IV)
0
1.13 ± 0.10
1.30 ± 0.20
1.32 ± 0.11


Compound 393 (IV)
0
1.27 ± 0.07
1.28 ± 0.08
1.42 ± 0.12


Indomethacin (IP)
0
0.63 ± 0.08
0.79 ± 0.17
0.82 ± 0.21









The experiment was again repeated with Compounds 156, 174, and 273 (each at 1 mg/kg intravenous doses). The results are set forth below in Table 7, below.








TABLE 7








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle A alone (IV)
0
1.52 ± 0.11
1.83 ± 0.21
1.84 ± 0.17


Compound 156 (IV)
0
1.49 ± 0.24
1.51 ± 0.12
1.81 ± 0.16


Compound 174 (IV)
0
1.22 ± 0.08
1.53 ± 0.13
1.70 ± 0.22


Compound 273 (IV)
0
1.13 ± 0.09
1.52 ± 0.12
1.59 ± 0.16


Indomethacin (IP)
0
0.75 ± 0.14
1.02 ± 0.09
1.07 ± 0.08









The experiment was again repeated with Compounds 419, 428, 493, and 500 (each at 1 mg/kg intravenous doses), as well as with an oral dose (3 mg/kg) of Compound 482. ENBREL® (etanercept) (30 mg/kg subcutaneous) was also used as another positive control. The results are set forth below in Table 8, below.








TABLE 8








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle A alone (IV)
0
1.35 ± 0.16
1.52 ± 0.13
1.32 ± 0.15


Compound 419 (IV)
0
1.22 ± 0.21
1.32 ± 0.18
1.16 ± 0.16


Compound 428 (IV)
0
1.27 ± 0.15
1.43 ± 0.22
1.39 ± 0.22


Compound 493 (IV)
0
1.04 ± 0.15
1.12 ± 0.10
1.03 ± 0.15


Compound 500 (IV)
0
0.98 ± 0.24
1.07 ± 0.21
0.98 ± 0.14


Compound 482 (3
0
1.13 ± 0.15
1.18 ± 0.10
1.14 ± 0.10


mg/kg PO)






Indomethacin (IP)
0
0.76 ± 0.13
0.92 ± 0.09
0.74 ± 0.08


ENBREL ® 
0
0.74 ± 0.18
1.07 ± 0.14
0.96 ± 0.12


(etanercept)






(30 mg/kg SC)









We next investigated the effect of varying intravenous doses of Compound 202 (0.05, 0.10, 0.30, and 1.00 mg/kg) in the same model using the same protocol (6 rats per group). These results are shown in FIG. 1 and in Table 9, below. We also investigated the affect of oral dosing (10 mg/kg) of Compound 202 in the same model. For oral dosing, a 2.5 mg/mL suspension of Compound 202 was prepared in Vehicle A. Rats were orally administered 4 mL/kg of that suspension. These results are also show in Table 9.








TABLE 9








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle B (IP)
0
1.52 ± 0.11
1.83 ± 0.21
1.84 ± 0.17


Indomethacin (IP)
0
0.75 ± 0.14
1.02 ± 0.09
1.07 ± 0.08


0.05 mg/kg
0
1.20 ± 0.09
1.56 ± 0.22
1.67 ± 0.18


Compound 202 (IV)






0.1 mg/kg
0
0.99 ± 0.15
1.41 ± 0.26
1.62 ± 0.19


Compound 202 (IV)






0.3 mg/kg
0
0.70 ± 0.13
1.09 ± 0.06
1.15 ± 0.12


Compound 202 (IV)






1.0 mg/kg
0
0.60 ± 0.04
0.98 ± 0.08
1.14 ± 0.05


Compound 202 (IV)






10 mg/kg
0
1.12 ± 0.15
1.35 ± 0.27
1.42 ± 0.22


Compound 202 (PO)









Oral dosing of Compound 202 at 0.3, 1, 3 and 10 mg/kg was further explored in a subsequent experiment in the same model using the same protocol (6 rats per group). The results are shown in Table 10, below.








TABLE 10








Change in Paw Volume (mL)











Treatment (n = 6)
0 h
2 h
4 h
6 h





Vehicle A alone (IV)
0
1.46 ± 0.12
1.70 ± 0.26
1.57 ± 0.24


Indomethacin (IP)
0
0.63 ± 0.08
0.79 ± 0.17
0.82 ± 0.21


0.3 mg/kg
0
1.49 ± 0.14
 1.59 ± 0013
1.65 ± 0.10


Compound 202 (PO)






1.0 mg/kg
0
1.43 ± 0.18
1.45 ± 0.16
1.62 ± 0.14


Compound 202 (PO)






3.0 mg/kg
0
1.25 ± 0.08
1.42 ± 0.09
1.50 ± 0.09


Compound 202 (PO)






10 mg/kg
0
1.17 ± 0.17
1.29 ± 0.06
1.51 ± 0.06


Compound 202 (PO)









Example 11
We used a human cell-based assay to determine the TNF-α antagonistic activity of the compounds of this invention based upon the ability of the compounds to inhibit the degradation of IkB in those cells. The assay was performed on either HeLa cells or A431 cells.
On Day 1, wells of a 24-well tissue culture plate were seeded with cells that had been harvested from cultures in T-75 flasks by standard trypsin/EDTA treatment. The harvested cells were suspended in EMEM/10% FBS/P/S (100,000 HeLa cells/mL or 200,000 A431 cells/mL) and 1 mL aliquots were placed into each well. The cells were incubated overnight at 37° C. in a humidified CO2 incubator. On day 2, the cells were approximately 95% confluent.
Test and control compounds were diluted to a 1 mM solution by dilution in DMSO. The assay was run in Costar tubes. Into each tube was placed 2.5 or 5.0 μL of test compound (for testing 5 μM and 10 μM concentrations, respectively), 2.5 μL of 100× TNF-α solution (200 ng/mL TNF-α in EMEM containing 1μg/mL cycloheximide) and, for those tubes containing 2.5 μL of compound, an additional 2.5 μL of DMSO. To each tube was then added 0.5 mL of EMEM containing 1μg/mL cycloheximide. Negative control tubes contained either a) no compound, or b) no TNF-α. Tubes were then incubated for 30 minutes at room temperature.
Once incubation had begun, the media was aspirated from the cells in the 24-well plates. Sufficient EMEM/10% FBS/P/S containing 1 ug/mL cycloheximide was then added to cover the cells (approximately 3 mL) and the cells were retuned to the 37° C. humidified CO2 incubator until compound incubation was completed. The media was then aspirated from the cells, 0.2 mL of the compound solution was added and the cells re-incubated at 37° C. for 30 minutes. The plates were then placed on ice, the compound solution was aspirated from each well, and the cells washed once with 1 mL of cold PBS. Cells were then fixed with 500 μL of 3.7% formaldehyde in PBS (“fix solution”) for 20 minutes at room temperature. The fix solution was decanted and the cells permeabilized by 4× washing with 500 uL PBS/0.1% Triton X-100. After the final permeabilization wash, the cells were treated with 500 uL of Odyssey blocking buffer (OBB) and incubated at room temperature with shaking for 90 minutes.
The OBB was decanted and then to each well was then added 125 μL each of mouse anti-IkB CST#4814 (diluted 1:200 in OBB) and rabbit anti-beta-tubulin CST#2146 (diluted 1:200 in OBB). Plates were sealed with parafin and incubated overnight at room temperature with shaking.
On day 3, the antibody solution was removed from the cells and the cells were washed 5× with 0.5 mL PBST for five minutes each on a shaker. To each well was then aded 125 μL of a secondary antibody solution containing goat anti-mouse IgG-IRDye 800 and goat anti-rabbit IgG-IRDye (each diluted 1:500 in OBB+0.2% Tween 20). The plates were covered with aluminum foil and incubated for 1 hour at room temperature with shaking. The secondary antibody solution was removed and the cells washed 3× with 0.5 mL PBST for five minutes each on a shaker. Cells were then scanned by LICOR with the following settings: 700 intensity=6.0, 800 intensity=6.5; microplate2 settings with 3.0 mm offset; 169 resolution. LICOR values were fitted to an equation for a sigmoidal curve and IC50 values calculated from the fitted parameters. These results are also show in Table 11, where + indicates less than 10% inhibition, ++ indicates 10% to less than 50% inhibition, +++ indicates 50% to 80% inhibition, and ++++ indicates greater than 80% inhibition. Blank cells indicate that the compound was not tested at that concentration. Certain compounds that were tested more than once and the values reflect the average of the multiple tests.









TABLE 11









Inhibition at Various



Compound Concentrations












Compound No.
25 μM
10 μM
5 μM
















1
++





3

+
+



4

+



10
++++



11

+++
++



12

++
++



15

+



16

+



18

++
+++



19
+



20
+



21
+



24
+



26
++



29
+



33

+++
++



34
+



35
+++



36
+
+++
++



39

++



43
+



47

+



82

+
+



85
+



89
+



111

+



112

+



116

+
++



117

+++
+



118

++



156

++++
+++



157

+++
++



158

+++
+++



174

++
+



180

+
+



194
+



196
+



198
+++



201

++



202

+++
++



212

+
+



217

+
+



236

++
++



237

+
+



239

+
+



248

++
+



273

+
++



282

++
+++



289

+
+



290

+
+



297

+
+



298

+
+



299

+
+



300

++



301

+
+



302

++
++



305

+



307

+



313

++
+



318

++
+



319

+
+



320

++++
++



321

++
+



323

++
++



324

++
++



325

+



326

++
++



327

+
++



328

++



330

++
++++



332


+



339

++
+



341

+



342

++
+



343

++
+



344

+++
++



346

+++
++++



348

+++
++



350

++
++



362

++
+



363

++
+++



364

++
+++



366

+
+



369

+
+



379

++
+++



380

+
+



381

+
+



382

+
++



384

+
+



385

++++
+++



386

+
+



388

++
+



390

+++
+



391

++
++



393

++++
++



395

+
+



396

+++
++



410

++
+



419

+
+



426

++
++



428

+
+



442

++
++



482

++
++










Incorporation by Reference

The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
Equivalents
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

## Claims

1. A compound represented by formula VII:




including pharmaceutically acceptable salts thereof, wherein:
R50 is benzyl, phenylethyl, indol-3-ylmethyl, thien-2-ylmethyl, biphenyl -4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, or 4-(pyridin-2-yl)benzyl, wherein the benzyl, biphenyl-4-yl or phenylethyl group in R50 is optionally substituted on a terminal phenyl ring with a single substituent selected from the group consisting of halo, methoxy, CF3, hydroxy, cyano, and C1-C4 alkyl; or is optionally substituted with chloro at each of the 2 and 4 positions of the terminal phenyl ring;
R51 is biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, or 4-(pyridin-3-yl)benzyl, wherein the biphenyl group in R51 is optionally monosubstituted at the 4-position of the terminal phenyl ring with amino, halo or hydroxy;
R52 is phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl, heteroarylmethyl, 4-(heteroaryl)benzyl, or biphenyl-4-ylmethyl, wherein the phenyl, naphthyl, benzyl, naphthylmethyl, phenylethyl or biphenyl-4-ylmethyl group in R52 is optionally on a terminal phenyl ring with 1 to 2 substituents independently selected from the group consisting of halo, methoxy, hydroxy, C1-C4 alkyl, and C1-C4 haloalkyl;
R53 is hydrogen or methyl;
X is —OH, —N(RW)—[C(RV)2]1-4—COOH, —N(RW)—[C(RV)2]1-3—SO3H, —N(RW)—[C(RV)2]0-4—S(O)2CH3, or —N(RW)—[C(RV)2]1-3-1H-tetrazol-5-yl, wherein:
RW represents hydrogen, methyl or benzyl; and
each RV independently represents hydrogen, —(C1-C6)-alkyl, —(C1-C6)-alkyl-heterocyclyl, —(C1-C6)-alkyl-carbocyclyl, or —CO2-alkyl, wherein each RV is optionally substituted with a substituent selected independently from the group consisting of —NH2, —NH—C(O)—(C1-C4)-alkyl and —OH; or
two RV are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkane ring,
the stereochemistry at (1) is the same as the stereochemistry at (3); and
the stereochemistry at (1) is opposite the stereochemistry at (2).

2. The compound of claim 1, wherein:
R50 is benzyl, 2-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2,4-dichlorobenzyl, 3-methoxybenzyl, 4-hydroxybenzyl, 4-cyanobenzyl, 4-methoxybenzyl, 4-t-butylbenzyl, phenylethyl, 2-fluorophenylethyl, indol-3-ylmethyl, thien-2-ylmethyl, biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, or 4-(pyridin-2-yl)benzyl;
R51 is biphenyl-4-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, 4-(4-aminophenyl)benzyl, 4-(4-bromophenyl)benzyl, 4-(4-fluorophenyl)benzyl, or 4-(4-hydroxyphenyl)benzyl;
R52 is 2,4-dichlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-hydroxybenzyl, 4-chlorobenzyl, 4-fluorobenzyl, 4-methylbenzyl, biphenyl-4-ylmethyl, indol-3-ylmethyl, thien-2-ylmethyl, 4-(pyridin-4-yl)benzyl, 4-(pyridin-3-yl)benzyl, 4-(pyridin-2-yl)benzyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, naphthyl, naphthylmethyl, phenylethyl, thiazol -3ylmethyl, 4-(thien-2-yl)benzyl, furan-2ylmethyl, N-phenyl-1H-triazol-4ylmethyl, 4-(4-fluorophenyl)benzyl, or 4-(4-chlorophenyl)benzyl; and
X is —N(CH3)CH2SO3H, —N(CH3)CH(benzyl)COOH, —N(CH3)CH(CH3)COOH, —NHCH2COOH, —NHCH2SO3H, —NHCH2-1H-tetrazol-5-yl, —NH(CH2)2COOH, —NH(CH2)2SO3H, —NH(CH2)3COOH, —NH(CH2)3SO3H, —NH(CH2)2-1H-tetrazol-5-yl, —NHCH(4-hydroxybenzyl)COOH, —NHCH(benzyl)COOH, —NHCH(benzyl)-1H-tetrazol-5-yl, —NHCH(CH2OH)COOH, —NHCH(phenylethyl)COOH, or —NHS(O)2CH3.

3. The compound of claim 1, wherein the compound is Compound 482:

4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.