Abstract:
Described herein are steroid derivatives of fullerene moieties, for example fullerene derivatives in which cholesterol, or a cholesterol moiety, is attached via ester, amide, or ether bonds to one of a variety of “linkers,” e.g., chemical groups including alkyl chains and aromatic groups, which are then connected to the fullerene moiety. The steroid moiety can confers useful solubility in components of biological fluids and/or pharmacologically acceptable carriers and can also affect the biodistribution of the fullerenes which makes the derivatives useful in imaging, diagnosis and the treatment or management of disease or complications of disease states.

Description:
RELATED APPLICATION 
       [0001]    This application claims priority to U.S. Application No. 60/904,402, filed Mar. 2, 2007, which is hereby incorporated by reference in its entirety for all purposes. 
     
    
     FIELD 
       [0002]    The invention relates to fullerene derivatives and methods for preparing fullerene derivatives. 
       BACKGROUND 
       [0003]    There remains a need in the art for modified fullerene molecules that have desirable characteristics of solubility in biological fluids, such as blood, other biological transport modes, such as lipoprotein complexes, or pharmacologically acceptable carriers, biodistribution, targeting to specific tissue components and the like. 
         [0004]    Cholesteryl esters of C 60  have been studied. Hummelen et al. (J. Org. Chem., 60:532-538, 1995) describe C 60  cholesterol ester linked via a diazo reaction. Cholesteryl fullerenes have been described in the preparation of liquid crystals. For example, Chuard &amp; Deschenaux ( J. Mat. Chem.,  12:1944-1951, 2002) describe a C 60  with two cholesterol esters attached via alkane linkers to one pole as unsuccessful attempts to form liquid crystals. The cholesterol in these instances was not attached to a fullerene modified to make it useful for biological applications. Steroid derivatives of fullerenes suitable for therapeutic or diagnostic applications have not been previously described. 
       SUMMARY 
       [0005]    The combination of fullerenes with steroids can provide improved properties for a variety of diagnostic and therapeutic purposes. For these agents to be effective in biological tissues it is desirable that the linkage of the steroid to the fullerene be stable to chemical and/or enzymatic breakdown and that the site of attachment not interfere with the biological activity of the steroid species. 
         [0006]    Among the exemplary embodiments described herein are molecules having the formula F*(PL i S j ) k ; where F* is a fullerene moiety, P is a connecting group, L is a linker, S is a steroid moiety; i=1 or 2; j=1-4, and k=1-5. F* is preferably a biologically functionalized fullerene derivative comprising a fullerene, F with even number of carbon atoms between 60 and 200, more generally, 60-120 and typically 60-90, to which one or more different groups are attached to the fullerene cage at locations different from P to provide water solubility and/or biological membrane compatibility. 
         [0007]    In some preferred embodiments, the fullerene is an endohedral metallofullerene A v @C m , where v=1 or 2, or a trimetal endohedral metallofullerene of the formula: F=A 3-n X n N@C m ; where A and X are metal atoms, n=0-3, and m can take on even values between about 60 and about 200. In this notation, all elements to the right of an @ symbol are part of the fullerene cage network and the linked groups, while all elements listed to the left are contained within the fullerene cage network. As an example, Sc 3 N@C 80 (PL i S j ) k  indicates that a Sc 3 N trimetallic nitride is situated within a C 80  fullerene cage with steroid moiety groups S attached through linkers L and connecting group P. 
         [0008]    In general, the linker can comprise alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl groups. 
         [0009]    In certain examples, A and/or X are rare earth elements and/or a group IIIB element, for example, A and/or X can be chosen from among the group consisting of Scandium, Yttrium, Lanthanum, Gadolinium, Holmium, Erbium, Thulium, and Ytterbium. 
         [0010]    Attachment of a steroid group and linker to a fullerene can be accomplished by reacting the electrons of a carbon-carbon double bond of the fullerene. For example, by forming a cyclic connecting group in which two carbons from the fullerene cage form a ring with atoms of the connecting group. The ring can consist of three atoms, e.g. a cyclopropane, or it can consist of four atoms, such as cyclobutane, five atoms or more. The atoms need not all be carbon. For example, aziridine may be formed having a nitrogen in place of a carbon. Five member rings can include oxygen, nitrogen or sulfur. 
         [0011]    Pyrrolidine is an example of a cyclic connecting group. Transition metals can also form cyclic additions. Alternatively attachment can be to a single carbon atom in the fullerene cage, such as by a connecting group comprising oxygen, nitrogen, sulfur, phosphorous, or silicon. Thus, in exemplary embodiments for purposes of illustrating the making of a steroid-fullerene derivative described herein, a fullerene derivative can compromise four units: a fullerene, a pyrrolidine or other cyclic connecting group, a linker, and steroid moiety such as cholesterol or a cholesterol derivative. In exemplary methods of synthesizing such embodiments, a cyclic addition group can be formed using a Prato reaction that connects the linker moiety to the fullerene. In another example, the linking group may comprise a phenyl alkyl group connected to the fullerene by a cycloalkyl connecting group such as cyclopropane and connected to the steroid group by an ether bond. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS  
         [0012]      FIG. 1  illustrates an exemplary steroid-fullerene derivative  1  comprising a fullerene, a steroid moiety derived from cholesterol, a pyrrolidine connecting group, and an aromatic ester linker between the pyrrolidine and the steroid moiety. As illustrated, the fullerene can be further biologically functionalized with hydroxyl groups for water solubility. 
           [0013]      FIG. 2  illustrates an exemplary steroid-fullerene derivative  2  comprising a fullerene, a steroid moiety derived from cholestanone, a pyrrolidine connecting group, and an aromatic amide linker between the pyrrolidine and the steroid moiety. As illustrated, the fullerene can be further biologically functionalized with hydroxyl groups for water solubility. 
           [0014]      FIG. 3  illustrates an exemplary steroid-fullerene derivative  3  comprising a fullerene, a cholesterol moiety derived from cholesterol, a pyrrolidine connecting group, and a hydrolytically stable ether group to link the cholesterol unit to the pyrrolidine via an alkyl chain. As illustrated, the fullerene can be further biologically functionalized with hydroxyl groups for water solubility. 
           [0015]      FIG. 4  illustrates an exemplary scheme for synthesis of 1. 
           [0016]      FIG. 5  illustrates an exemplary scheme for synthesis of 2. 
           [0017]      FIG. 6  illustrates an exemplary scheme for synthesis of 3. 
           [0018]      FIG. 7  illustrates another exemplary scheme for synthesis of steroid derivatives of fullerene using the Diazo reaction. 
           [0019]      FIG. 8 . Illustrates that the steroid-fullerene compound in  FIG. 6  can be biologically functionalized by reaction with activated PEG reagents, peptide reagents or carbohydrate (sugar) reagents to give the water soluble products shown. 
       
    
    
     DETAILED DESCRIPTION 
       [0020]    Various forms of fullerenes have properties that make them suited to use in imaging techniques, for example in conjunction with magnetic resonance, positron emission tomography, computer aided tomography, and other scanning methods, and in therapeutic compositions, for example in delivery of radionuclides and as scavengers of free radicals such as reactive oxygen species. 
         [0021]    Steroids are a category of biological molecules that have a broad variety of functions, ranging from structural components of membranes, e.g., cholesterol, to highly potent anti-inflammatory agents, e.g., glucocorticoids, to hormones, e.g., androgens and anabolic steroids. Cholesterol containing magnetic resonance contrast agents have been described. e.g., Platzek et al. (J. Mag. Res. Imag. 5:7-10, 1995) used gadolinium chelates to which cholesterol had been attached. 
         [0022]    Described herein are a steroid derivatives of fullerenes having the general formula 
         [0000]      F*(PL i S j ) k ;  (I) 
         [0000]    where P is a connecting group, L is a linker, S is a steroid moiety; i=1 or 2; j=1-4, and k=1-5; and wherein F* is a fullerene moiety comprising a fullerene, F, having an even number of carbon atoms between 60 and 200, typically between 60 and 120, or 60 and 96, or 60 and 84 carbons, such as C 60  or C 70 . The fullerene moiety F* can have one or more non-steroid groups attached to the cage at locations different from where P is attached to provide water solubility and/or biological membrane compatibility. In this respect, F* can be a biologically functionalized fullerene. 
         [0023]    In alternative embodiments, a molecule can have the formula F(-P i -L i -S i ) i ; where F is a fullerene, P i  is a connecting group, L i  is a linker, S i  is a steroid moiety; i=1 to about 20; and for each i&gt;1, (P i -L i -S i ) may be the same or different; and F is a fullerene; the linker can be connected to the steroid moiety via an amide, an ether, or an ester bond, the linker comprises an alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl group. 
         [0024]    Such fullerene derivatives can be prepared using organic synthesis methods such as illustrated below and methods known in the art. In preferred embodiments, F can be a fullerene biologically functionalized to make it more suitable for biological applications. In exemplary embodiments, connecting group P can represent a pyrrolidine or other cyclic addition connecting group. S represents a steroid such as a cholesteryl group or other derivative of cholesterol. 
         [0025]    In some embodiments, the fullerene is an endohedral metallofullerene A v @C m , where v=1 or 2, or F=A 3-n X n N@C m ; where A and X are metal atoms, n=0-3, and m can take on even values between about 60 and about 200 as described in U.S. Pat. No. 6,303,760. In this notation, elements to the right of an @ symbol are part of the fullerene cage network, while all elements listed to the left are contained within the fullerene cage network. As an example, Sc 3 N@C 80 (PL i S j ) k  indicates that a Sc 3 N trimetallic nitride is situated within a C 80  fullerene cage with S j  steroid moiety groups attached through linkers L. In certain examples, A and/or X are rare earth elements and/or a group IIIB element, for example, A and/or X can be chosen from among the group consisting of Scandium, Yttrium, Lanthanum, Gadolinium, Holmium, Erbium, Thulium, and Ytterbium. 
         [0026]    In exemplary embodiments, a fullerene derivative compromises four units: a functionalized fullerene, connecting group, linker, and steriod moiety. In exemplary synthetic methods, a pyrrolidine group connecting the linker to the fullerene may be formed using a Prato reaction. The linker may be connected to the steroid moiety via an amide, ester or an ether, linkage as exemplified below. In general the linker may comprise alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl groups. In particular embodiments, the linking group and connecting group may comprise, for example, polyethylene glycol moieties or peptide moieties. 
         [0027]    “Steroid moiety” refers to chemical groups having a polycyclic steroid backbone comprising a nucleus of three six-carbon rings and a five-carbon ring, e.g. a cyclophenanthrene nucleus, and preferably having substantially all the features of a cholesterol molecule, for example, the double-bond of a cholesterol. Alternative sterols and steroids comprising a cholesterol moiety include natural and synthetic anabolic steroids that interact with androgen receptors to increase muscle and bone synthesis, corticosteroids including glucocorticoid and mineralocorticoids, sex steroids (a subset of sex hormones that produce sex differences or support reproduction) including androgens, estrogens, and progestagens, phytosterols naturally occurring in plants, ergosterols occurring in fungi. The use of different steroid moieties can target the derivatives to particular biological compartments and tissues. More generally, a structural mimetic of a steroid may be substituted for a steroid moiety. Structural mimetics are molecular groups presenting a three-dimensional surface that mimics the structure of a steroid, but may contain atomic substitutions and/or backbone differences. 
         [0028]    “Biologically functionalized fullerene” means a fullerene that has been modified to make it suitable for biological applications, which can include diagnostic or therapeutic applications. 
         [0029]    Biologically functionalized fullerenes can include fullerene moieties having one or more hydroxyl groups; PEG groups; sugar groups; or peptide groups attached on its surface. In alternative embodiments, a biologically functionalized fullerene can incorporate a lipophilic moiety such as one or more acyl chains, diacyl glycerol, fatty acid, and the like. The usefulness of biologically functionalized fullerenes can be improved by providing one or more steroid addition groups at locations on the fullerene cage other than where the biological functionalization groups are attached. 
         [0030]    Biological functionalization groups can include hydrophilic groups that promote water solubility, or which, in conjunction with one or more steroid derivatives, are arranged to enhance uptake and intercalation into biological membranes. In preferred embodiments, the fullerene can be a C 70  to which one or more lipophilic biological functionalization groups are attached at or immediately proximate to an apical five member ring. Alternatively, a steroid derivative of a biologically functionalized fullerene can comprise a C 70  fullerene with one or more hydrophilic moiety at or near one apical ring and one or more steroid groups S connected through linker(s) L having a chain of 4-24 atoms, preferably comprising a saturated or unsaturated acyl chain of 10-18 carbons, and connecting group(s) P attached to an opposing apical ring. Such steroid derivative fullerene molecules are well suited to be taken up into lipoproteins such as LDL. These derivatives can also be taken up into biological membranes such as mitochondrial membranes where the fullerene can be positioned so as to block propagation of pathogenic radicals. Uptake into mitochondrial membranes can be meditated by choosing an appropriate steroid. 
         [0031]    Fullerenes functionalized for diagnostic applications include metallofullerenes that have been modified to enhance image quality for magnetic resonance imaging. Such modifications can include attachment of groups to the outside of the fullerene that facilitate magnetic coupling between entrapped metal atoms such as gadolinium and water protons and also water solubility or liposome compatibility. Such functionalizations are described in U.S. Patent Application No.: 60/960,962, which is hereby incorporated by reference in its entirety. An exemplary biologically functionalized fullerene, F*, of this type is an endohedral metallofullerene compound represented by the formula A k X n N i @C m *, wherein A and X represent identical or different elements in the Periodic Table of Elements, provided that at least one of A and X is paramagnetic, N represents a nitrogen atom; C m * represents a substituted C m ; C m  represents a fullerene comprising m carbon atoms; k represents an integer from 1 to 3; n represents an integer from 0 to 2, provided that 1≦k+n≦3; i represents an integer of 0 or 1; and m represents an even integer from about 60 to about 200, wherein the substituent(s) in C m * comprise one or more -Q-Z j G p D r , wherein Q represents an atom which is selected from the group consisting of N, O, S and P and is directly bonded to C m ; Z, G and D are different, and each comprises a hydrophilic moiety and each is directly bonded to Q; j represents an integer from 1 to 3; p represents an integer from 0 to 2; and r represents an integer from 0 to 2, provided that 1≦p+j+r≦3. Another exemplary embodiment is directed to an endohedral metallofullerene compound represented by the formula A k X n N i @C m **, wherein C m ** represents a substituted C m ; and A, X, N, k, n, I, and m have the same meanings as described above; wherein the substituent(s) in C m ** comprise one or more Z′ and optionally one or more Q′, wherein Z′ comprises a hydrophilic moiety and when there are more than one Z′s, Z′s are identical or different; and Q′ represents a group bonded to C m  via an atom which is selected from the group consisting of N, O, S and P, and when there are more than one Q′s, Q′s are identical or different. 
         [0032]    Steroid derivatives of these biologically active imaging agents can be designed to facilitate uptake in target cells or tissues. For example, cholesterol derivatives may facilitate uptake into atherosclerotic plaque to enhance magnetic resonance images of plaque buildup. In the same vein, estrogen derivatives may enhance uptake in metastatic breast cancer cells. Diagnostic applications may also include metallofullerenes that are suitable for x-ray contrast enhancement, where attachment of groups to enhance the water solubility of the fullerene moiety are necessary for biological activity. 
         [0033]    Therapeutic applications can include brachytherapy, in which radioactive metals are entrapped within the cage and the surface additions are such to facilitate distribution to a target. Other therapeutic applications include fullerenes that have been modified to juxtapose a radical scavenging zone near the source where free radicals are generated, such as within biological membranes of internal cell organelles. 
         [0034]    For the latter application, addition of hydrophilic and lipophilic groups may be useful. A therapeutic fullerene that has been modified to block pathogenic free radical propagation may be especially effective at blocking the inflammatory response that causes foam cells to take up cholesterol esters and stenose blood vessels. Thus a biologically functionalized fullerene cholesteryl derivative can be selectively taken up by foam cells where it may reach sufficient concentration to effectively block plaque from growing larger. 
         [0035]    “Alkyl” refers to alkyl groups preferably having from 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n -heptyl, octyl, dodecyl and the like. 
         [0036]    “Substituted alkyl” refers to an alkyl group, preferably of from 1 to 20 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted aryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/substituted alkyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic, and —SO 2 NRR where R is hydrogen or alkyl. 
         [0037]    “Alkoxy” refers to the group “alkyl-O—” which includes, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. 
         [0038]    “Substituted alkoxy” refers to the group “substituted alkyl-O—”. 
         [0039]    “Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)— cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O), heterocyclic-C(O)—, and substituted heterocyclic-C(O)— wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. 
         [0040]    “Acylamino” refers to the group —C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0041]    “Thiocarbonylamino” refers to the group —C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0042]    “Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0043]    “Alkenyl” refers to alkenyl group preferably having from 2 to 20 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. 
         [0044]    “Substituted alkenyl” refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic, and —SO 2 NRR where R is hydrogen or alkyl. 
         [0045]    “Alkenyloxy” refers to the group —O-alkenyl. 
         [0046]    “Substituted alkenyloxy” refers to the group —O-substituted alkenyloxy. 
         [0047]    “Alkynyl” refers to alkynyl group preferably having from 2 to 20 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. 
         [0048]    “Substituted alkynyl” refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic, and —SO 2 NRR where R is hydrogen or alkyl. 
         [0049]    “Alkylene” refers to a divalent alkylene group preferably having from 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (—CH 2 —), ethylene (—CH 2 CH 2 —), the propylene isomers (e.g., —CH 2 CH 2 CH 2 — and —CH(CH 3 )CH 2 —) and the like. 
         [0050]    “Substituted alkylene” refers to alkylene groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic, and —SO 2 NRR where R is hydrogen or alkyl. 
         [0051]    “Alkenylene” refers to a divalent alkenylene group preferably having from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms and having from 1 to 2 sites of alkenyl unsaturation. This term is exemplified by groups such as ethenylene (—CH═CH—), propenylene (—CH 2 CH═CH—), and the like. 
         [0052]    “Substituted alkenylene” refers to alkenylene groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic, and —SO 2 NRR where R is hydrogen or alkyl. 
         [0053]    “Alkynylene” refers to a divalent alkynylene group preferably having from 2 to 20 carbon atoms and more preferably 1 to 6 carbon atoms and having from 1 to 2 sites of alkynyl unsaturation. This term is exemplified by groups such as ethynylene, propynylene and the like. 
         [0054]    “Substituted alkynylene” refers to alkynylene groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and substituted alkenyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkenyl/substituted alkenyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic, and —SO 2 NRR where R is hydrogen or alkyl. 
         [0055]    “Amidino” refers to the group H 2 NC(═NH)— and the term “alkylamidino” refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC(═NH)—). 
         [0056]    “Thioamidino” refers to the group RSC(═NH)— where R is hydrogen or alkyl. 
         [0057]    “Aminoacyl” refers to the groups —NRC(O)alkyl, —NRC(O)substituted alkyl, —NRC(O)cycloalkyl, —NRC(O)substituted cycloalkyl, —NRC(O)alkenyl, —NRC(O)substituted alkenyl, —NRC(O)alkynyl, —NRC(O)substituted alkynyl, —NRC(O)aryl, —NRC(O)substituted aryl, —NRC(O)heteroaryl, —NRC(O)substituted heteroaryl, —NRC(O)heterocyclic, and —NRC(O)substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0058]    “Aminocarbonyloxy” refers to the groups —NRC(O)O-alkyl, —NRC(O)O-substituted alkyl, —NRC(O)O-alkenyl, —NRC(O)O-substituted alkenyl, —NRC(O)O-alkynyl, —NRC(O)O-substituted alkynyl, —NRC(O)O-cycloalkyl, —NRC(O)O-substituted cycloalkyl, —NRC(O)O-aryl, —NRC(O)O-substituted aryl, —NRC(O)O-heteroaryl, —NRC(O)O-substituted heteroaryl, —NRC(O)O-heterocyclic, and —NRC(O)O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0059]    “Oxycarbonylamino” refers to the groups —OC(O)NH 2 , —OC(O)NRR, —OC(O)NR-alkyl, —OC(O)NR-substituted alkyl, —OC(O)NR-alkenyl, —OC(O)NR-substituted alkenyl, —OC(O)NR-alkynyl, —OC(O)NR-substituted alkynyl, —OC(O)NR-cycloalkyl, —OC(O)NR-substituted cycloalkyl, —OC(O)NR-aryl, —OC(O)NR-substituted aryl, —OC(O)NR-heteroaryl, —OC(O)NR-substituted heteroaryl, —OC(O)NR-heterocyclic, and —OC(O)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0060]    “Oxythiocarbonylamino” refers to the groups —OC(S)NH 2 , —OC(S)NRR, —OC(S)NR-alkyl, —OC(S)NR-substituted alkyl, —OC(S)NR-alkenyl, —OC(S)NR-substituted alkenyl, —OC(S)NR-alkynyl, —OC(S)NR-substituted alkynyl, —OC(S)NR-cycloalkyl, —OC(S)NR-substituted cycloalkyl, —OC(S)NR-aryl, —OC(S)NR-substituted aryl, —OC(S)NR-heteroaryl, —OC(S)NR-substituted heteroaryl, —OC(S)NR-heterocyclic, and —OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0061]    “Aminocarbonylamino” refers to the groups —NRC(O)NRR, —NRC(O)NR-alkyl, —NRC(O)NR-substituted alkyl, —NRC(O)NR-alkenyl, —NRC(O)NR-substituted alkenyl, —NRC(O)NR-alkynyl, —NRC(O)NR-substituted alkynyl, —NRC(O)NR-aryl, —NRC(O)NR-substituted aryl, —NRC(O)NR-cycloalkyl, —NRC(O)NR-substituted cycloalkyl, —NRC(O)NR-heteroaryl, and —NRC(O)NR-substituted heteroaryl, —NRC(O)NR-heterocyclic, and —NRC(O)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0062]    “Aminothiocarbonylamino” refers to the groups —NRC(S)NRR, —NRC(S)NR-alkyl, —NRC(S)NR-substituted alkyl, —NRC(S)NR-alkenyl, —NRC(S)NR-substituted alkenyl, —NRC(S)NR-alkynyl, —NRC(S)NR-substituted alkynyl, —NRC(S)NR-aryl, —NRC(S)NR-substituted aryl, —NRC(S)NR-cycloalkyl, —NRC(S)NR-substituted cycloalkyl, —NRC(S)NR-heteroaryl, and —NRC(S)NR-substituted heteroaryl, —NRC(S)NR-heterocyclic, and —NRC(S)NR-substituted heterocyclic where each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. 
         [0063]    “Aryl” or “Ar” refers to a monovalent unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7yl, and the like). Preferred aryls include phenyl and naphthyl. 
         [0064]    “Substituted aryl” refers to aryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —S(O) 2 -alkyl, —S(O) 2 -substituted alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -substituted cycloalkyl, —S(O) 2 -alkenyl, —S(O) 2 -substituted alkenyl, —S(O) 2 -aryl, —S(O) 2 -substituted aryl, —S(O) 2 -heteroaryl, —S(O) 2 -substituted heteroaryl, —S(O) 2 -heterocyclic, —S(O) 2 -substituted heterocyclic, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with —SO 2 NRR where R is hydrogen or alkyl. 
         [0065]    “Arylene” refers to a divalent unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenylene) or multiple condensed rings (e.g., naphthylene or anthrylene) which condensed rings may or may not be aromatic. Preferred arylenes include phenylene and naphthylene. 
         [0066]    Substituted arylene refers to arylene groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —S(O) 2 -alkyl, —S(O) 2 -substituted alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -substituted cycloalkyl, —S(O) 2 -alkenyl, —S(O) 2 -substituted alkenyl, —S(O) 2 -aryl, —S(O) 2 -substituted aryl, —S(O) 2 -heteroaryl, —S(O) 2 -substituted heteroaryl, —S(O) 2 -heterocyclic, —S(O) 2 -substituted heterocyclic, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS (O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS (O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —SO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with —SO 2 NRR where R is hydrogen or alkyl. 
         [0067]    “Aryloxy” refers to the group aryl-O— which includes, by way of example, phenoxy, naphthoxy, and the like. 
         [0068]    “Substituted aryloxy” refers to substituted aryl-O— groups. 
         [0069]    “Aryloxyaryl” refers to the group -aryl-O-aryl. 
         [0070]    “Substituted aryloxyaryl” refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —S(O) 2 -alkyl, —S(O) 2 -substituted alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -substituted cycloalkyl, —S(O) 2 -alkenyl, —S(O) 2 -substituted alkenyl, —S(O) 2 -aryl, —S(O) 2 -substituted aryl, —S(O) 2 -heteroaryl, —S(O) 2 -substituted heteroaryl, —S(O) 2 -heterocyclic, —S(O) 2 -substituted heterocyclic, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OS 0   2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with —SO 2 NRR where R is hydrogen or alkyl. 
         [0071]    “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. This definition also includes bridged groups such as bicyclo [2.2.1] heptane and bicyclo [3.3.1] nonane. 
         [0072]    “Cycloalkyloxy” refers to —O-cycloalkyl. 
         [0073]    “Cycloalkenyl” refers to cyclic alkenyl groups of frm 3 to 10 carbon atoms having a single cyclic ring. 
         [0074]    “Cycloalkenyloxy” refers to —O-cycloalkenyl. 
         [0075]    “Substituted cycloalkyl” and “substituted cycloalkenyl” refers to an cycloalkyl or cycloalkenyl group, preferably of from 3 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (═O), thioxo(═S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, 
         [0076]    carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, 
         [0077]    carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic and —SO 2 NRR where R is hydrogen or alkyl. 
         [0078]    “Substituted cycloalkyloxy” and “substituted cycloalkenyloxy” refers to —O-substituted cycloalkyl and —O-substituted cycloalkenyloxy respectively. 
         [0079]    “Cycloalkylene” refers to divalent cyclic alkylene groups of from 3 to 10 carbon atoms having a single cyclic ring including, by way of example, cyclopropylene, cyclobutylene, cyclopentylene, cyclooctylene and the like. 
         [0080]    “Cycloalkenylene” refers to a divalent cyclic alkenylene groups of from 3 to 10 carbon atoms having a single cyclic ring. 
         [0081]    “Substituted cycloalkylene” and “substituted cycloalkenylene” refers to a cycloalkylene or cycloalkenylene group, preferably of from 3 to 8 carbon atoms, having from 1 to 5 substituents selected from the group consisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic and —SO 2 NRR where R is hydrogen or alkyl. 
         [0082]    “Cycloalkoxy” refers to —O-cycloalkyl groups. 
         [0083]    “Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups. 
         [0084]    “Guanidino” refers to the groups —NRC(═NR)NRR, —NRC(═NR)NR-alkyl, —NRC(═NR)NR-substituted alkyl, —NRC(═NR)NR-alkenyl, —NRC(═NR)NR-substituted alkenyl, —NRC(═NR)NR-alkynyl, —NRC(═NR)NR-substituted alkynyl, —NRC(═NR)NR-aryl, —NRC(═NR)NR-substituted aryl, —NRC(═NR)NR-cycloalkyl, —NRC(═NR)NR-heteroaryl, —NRC(═NR)NR-substituted heteroaryl, —NRC(═NR)NR-heterocyclic, and —NRC(═NR)NR-substituted heterocyclic where each R is independently hydrogen and alkyl as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. 
         [0085]    “N,N-Dimethylcarbamyloxy” refers to the group —OC(O)N(CH 3 ) 2 . 
         [0086]    “Guanidinosulfone” refers to the groups —NRC(═NR)NRSO 2 -alkyl, —NRC(═NR)NRSO 2 -substituted alkyl, —NRC(═NR)NRSO 2 -alkenyl, —NRC(═NR)NRSO 2 -substituted alkenyl, —NRC(═NR)NRSO 2 -alkynyl, —NRC(═NR)NRSO 2 -substituted alkynyl, —NRC(═NR)NRSO 2 -aryl, —NRC(═NR)NRSO 2 -substituted aryl, —NRC(═NR)NRSO 2 -cycloalkyl, —NRC(═NR)NRSO 2 -substituted cycloalkyl, —NRC(═NR)NRSO 2 -heteroaryl, and —NRC(═NR)NRSO 2 -substituted heteroaryl, —NRC(═NR)NRSO 2 -heterocyclic, and —NRC(═NR)NRSO 2 -substituted heterocyclic where each R is independently hydrogen and alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein. 
         [0087]    “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo. 
         [0088]    “Heteroaryl” refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl. 
         [0089]    “Substituted heteroaryl” refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —S(O) 2 -alkyl, —S(O) 2 -substituted alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -substituted cycloalkyl, —S(O) 2 -alkenyl, —S(O) 2 -substituted alkenyl, —S(O) 2 -aryl, —S(O) 2 -substituted aryl, —S(O) 2 -heteroaryl, —S(O) 2 -substituted heteroaryl, —S(O) 2 -heterocyclic, —S(O) 2 -substituted heterocyclic, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with —SO 2 NRR where R is hydrogen or alkyl. 
         [0090]    “Heteroarylene” refers to a divalent aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroarylene groups can have a single ring (e.g., pyridylene or furylene) or multiple condensed rings (e.g., indolizinylene or benzothienylene). Preferred heteroarylenes include pyridylene, pyrrolylene, indolylene and furylene. 
         [0091]    “Substituted heteroarylene” refers to heteroarylene groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, carboxylamido, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —S(O) 2 -alkyl, —S(O) 2 -substituted alkyl, —S(O) 2 -cycloalkyl, —S(O) 2 -substituted cycloalkyl, —S(O) 2 -alkenyl, —S(O) 2 -substituted alkenyl, —S(O) 2 -aryl, —S(O) 2 -substituted aryl, —S(O) 2 -heteroaryl, —S(O) 2 -substituted heteroaryl, —S(O) 2 -heterocyclic, —S(O) 2 -substituted heterocyclic, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and amino groups on the substituted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or substituted with —SO 2 NRR where R is hydrogen or alkyl. 
         [0092]    “Heteroaryloxy” refers to the group —O-heteroaryl and “substituted heteroaryloxy” refers to the group —O-substituted heteroaryl. 
         [0093]    “Heterocycle” or “heterocyclic” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be aryl or heteroaryl. 
         [0094]    “Substituted heterocyclic” refers to heterocycle groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS (O) 2 -substituted heteroaryl, —OS (O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic and —SO 2 NRR where R is hydrogen or alkyl. 
         [0095]    Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. 
         [0096]    “Heterocyclene” refers to a divalent saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be aryl or heteroaryl. 
         [0097]    “Substituted heterocyclene” refers to heterocyclene groups which are substituted with from 1 to 3 substituents selected from the group consisting of oxo (═O), thioxo (═S), alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, substituted thioheterocyclic, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, —C(O)O-aryl, —C(O)O-substituted aryl, heterocyclyloxy, substituted heterocyclyloxy, oxycarbonylamino, oxythiocarbonylamino, —OS(O) 2 -alkyl, —OS(O) 2 -substituted alkyl, —OS(O) 2 -aryl, —OS(O) 2 -substituted aryl, —OS(O) 2 -heteroaryl, —OS(O) 2 -substituted heteroaryl, —OS(O) 2 -heterocyclic, —OS(O) 2 -substituted heterocyclic, —OSO 2 —NRR where R is hydrogen or alkyl, —NRS(O) 2 -alkyl, —NRS(O) 2 -substituted alkyl, —NRS(O) 2 -aryl, —NRS(O) 2 -substituted aryl, —NRS(O) 2 -heteroaryl, —NRS(O) 2 -substituted heteroaryl, —NRS(O) 2 -heterocyclic, —NRS(O) 2 -substituted heterocyclic, —NRS(O) 2 —NR-alkyl, —NRS(O) 2 —NR-substituted alkyl, —NRS(O) 2 —NR-aryl, —NRS(O) 2 —NR-substituted aryl, —NRS(O) 2 —NR-heteroaryl, —NRS(O) 2 —NR-substituted heteroaryl, —NRS(O) 2 —NR-heterocyclic, —NRS(O) 2 —NR-substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substituted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl/substituted alkynyl groups substituted with —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -cycloalkyl, —SO 2 -substituted cycloalkyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, —SO 2 -substituted heterocyclic and —SO 2 NRR where R is hydrogen or alkyl. 
         [0098]    “Heterocyclyloxy” refers to the group —O-heterocyclic and “substituted heterocyclyloxy” refers to the group —O-substituted heterocyclic. 
         [0099]    “Thiol” refers to the group —SH. 
         [0100]    “Thioalkyl” refers to the groups —S-alkyl. 
         [0101]    “Substituted thioalkyl” refers to the group —S-substituted alkyl. 
         [0102]    “Thiocycloalkyl” refers to the groups —S-cycloalkyl. 
         [0103]    “Substituted thiocycloalkyl” refers to the group —S-substituted cycloalkyl. 
         [0104]    “Thioaryl” refers to the group —S-aryl and “substituted thioaryl” refers to the group —S-substituted aryl. 
         [0105]    “Thioheteroaryl” refers to the group —S-heteroaryl and “substituted thioheteroaryl” refers to the group —S-substituted heteroaryl. 
         [0106]    “Thioheterocyclic” refers to the group —S-heterocyclic and “substituted thioheterocyclic” refers to the group —S-substituted heterocyclic. 
         [0107]    “Amino” refers to the —NH 2  group. 
         [0108]    “Substituted amino” refers to the —NR′R″ group wherein R′ and R″ are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic or where R′ and R″, together with the nitrogen atom pendent thereto, form a heterocyclic ring. 
         [0109]    “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of Formula (I), which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. 
         [0110]    “Pharmaceutically acceptable carrier” refers to a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable carrier” as used in the specification and claims includes both one and more than one such carrier. 
         [0111]    “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. 
         [0112]    A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease or condition, is sufficient to effect a desirable treatment for the disease or condition. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. A “therapeutically effective amount” need not represent a complete cure, but may provide partial relief of one or more symptoms or retard the progression of a disease or condition. 
         [0113]    The steroid derivatives of fullerene, such as the biologically functionalized fullerene moieties, described above may be used to treat or manage oxidative damage to tissues. A method of treating or managing oxidative damage to tissues can comprise administering a therapeutically effective amount of a steroid derivative of a fullerene moiety. In preferred embodiments of treatment methods, the steroid derivatives of fullerene moieties can function therapeutically by neutralizing oxidative species present in cells, tissue, or biological fluids. 
         [0114]    The steroid derivatives of fullerene moieties described above may also, or alternatively, be used to enhance imaging techniques, for example by acting to increase contrast in magnetic resonance, CAT or PET scanning techniques. A method of imaging a subject can comprise administering an effective amount of a fullerene derivative before or during an imaging procedure. In preferred examples of methods of enhancing imaging, the fullerene is a metal containing fullerene and/or the cholesterol moiety is capable of binding preferentially in the tissue or to a carrier in biological fluid in the region of interest. 
         [0115]    In preferred therapeutic compositions the number of (PLS) groups is from about 0 to 5, more preferably the number of groups attached to each fullerene is substantially uniform. This may be accomplished by controlling reaction conditions and timing, by post synthetic purification, or a combination. 
         [0116]    The following examples provide non-limiting demonstration of schemes for synthesizing cholesteryl derivatives of fullerenes. 
       EXAMPLES 
     Example 1 
       [0117]    As illustrated in  FIG. 4 , a steroid derivative of fullerene such as Compound 1 in  FIG. 1  can be synthesized as follows: P-carboxybenzaldehyde is reacted with thionyl chloride to produce the corresponding acid chloride. The acid chloride is reacted without purification with an equivalent amount of cholesterol in toluene at either room temperature or with heating to provide the cholesterol ester. Fullerene C m , A i @C m , or A 3-n X n N@C m , e.g. C 60 , is treated with an excess (2-100 fold depending on the fullerene) of the cholesterol aldehyde and either sarcosine (or other N-alkyl glycine) at elevated temperatures refluxing toluene, xylene, or ODCB. Heating is continued until the reaction is complete. After cooling the reaction mixture is concentrated, the solvent evaporated, and the residue chromatographed to provide pure steroid-fullerene compound. To increase water solubility for some biological applications, the compound can then be reacted with tetrabutylammonium hydroxide under phase transfer conditions to produce polyhydroxy steroid-fullerene compound 1. 
       Example 2 
       [0118]    As illustrated in  FIG. 5 , a steroid derivative of fullerene such as Compound 2 can be synthesized as follows: Cholestanone is reacted with (CH 3 O)(CH 2 ) 3 NH 2  and TiCl 4  to prepare the imine. Reduction of the imine to the secondary amine is carried out with NaBH 4 . The amine is then acylated with the acid chloride of p-carboxybenzaldehyde (prepared in example above) to produce an amide. The amide aldehyde is subjected to a Prato reaction in the following way. The fullerene C m , X i @C m , or A 3-n X n N@C m , e.g. C 60 , is treated with an excess (2-100 fold depending on the fullerene) of the cholestane amide aldehyde and either sarcosine (or other N-alkyl glycine) at elevated temperatures refluxing toluene, xylene, or ODCB. Heating is continued until the reaction is complete. After cooling the reaction mixture is concentrated, the solvent evaporated, and the residue chromatographically purified to provide pure steroid fullerene compound. To increase water solubility for some biological applications, the compound can then be reacted with tetrabutylammonium hydroxide under phase transfer conditions to produce polyhydroxy steroid-fullerene compound 2. 
       Example 3 
       [0119]    As illustrated in  FIG. 6 , a steroid derivative of fullerene such as Compound 3 can be synthesized as follows: Cholesterol tosylate is heated with 1,n-alkane diol (for example 1,12-dihydroxydodecane) in refluxing dioxane for 4-12 hours. After chromatography and recrystalization, pure hydroxy alkyl ether is formed. Oxidation of the cholesterol ether with PCC gave the corresponding aldehyde, a precursor for the typical Prato reaction conditions. The Prato reaction is carried out by treating fullerene, e.g. C 60 , with an excess (2-100 fold depending on the fullerene) of the aldehyde and either sarcosine (or other N-alkyl glycine) at elevated temperatures refluxing toluene, xylene, or ODCB. Heating is continued until the reaction is complete. After cooling the reaction mixture is concentrated, the solvent evaporated, and the residue chromatographically purified to provide pure steroid fullerene compound. To increase water solubility for some biological applications, the compound can then be reacted with tetrabutylammonium hydroxide under phase transfer conditions to produce polyhydroxy steroid-fullerene compound 3. 
       Example 4 
       [0120]    As illustrated in  FIG. 7 , a steroid derivative of fullerene can also be synthesized as follows: Cholesterol tosylate is heated with 1,4-butane diol (similar to the example above) to produce a cholesterol hydroxy alkyl ether The produced alcohol is converted to the aldehyde with PCC, phenyl lithium is added to produce the secondary alcohol which is subsequently oxidized with PCC to the phenyl ketone. The ketone is reacted with tosylhydrazine to produce the tosylhydrazone which is reacted with NaOCH 3/ pyridine (to prepare the diazo compound) followed by heating fullerene C m , X i @C m , or A 3-n X n N@C m , e.g. C 60 , in ODCB. The final product is purified by column chromatography to yield the parent steroid-fullerene compound. To increase water solubility for some biological applications, the compound can then be reacted with tetrabutylammonium hydroxide under phase transfer conditions to produce the polyhydroxy steroid-fullerene compound shown in  FIG. 7 . Using a similar reaction scheme, cholesterol fullerene linked by varying number of carbons may also be prepared, for example using linkers comprising 4 to 24 carbons, more preferably 11 or 12 any number up to about 18 carbons. 
       Example 5 
       [0121]    As illustrated in  FIG. 8  the steroid-fullerene compound 3 can be further functionalized with PEG amine groups, peptide groups, or sugar groups to produce water soluble compound. Thus, the fullerene portion of the molecule can be a biologically functionalized fullerene moiety for improved performance in certain biological applications