Abstract:
The present invention relates to acyclic and cyclic amine derivatives for treating or preventing neuronal damage associated with neurological diseases. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation and claims priority to co-pending International Patent Application PCT/US00/20491, filed Jul. 27, 2000, which claims priority of U.S. provisional application 60/146,582, which was filed Jul. 30, 1999. 
    
    
     TECHNICAL FIELD OF THE INVENTION 
     The present invention relates to acyclic and cyclic amine derivatives for treating or preventing neuronal damage associated with neurological diseases. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage. 
     BACKGROUND OF THE INVENTION 
     Neurological diseases are associated with the death of or injury to neuronal cells. Typical treatment of neurological diseases involves drugs capable of inhibiting neuronal cell death. A more recent approach involves the promotion of nerve regeneration by promoting neuronal growth. 
     Neuronal growth, which is critical for the survival of neurons, is stimulated in vitro by nerve growth factors (NGF). For example, Glial Cell Line-Derived Neurotrophic Factor (GDNF) demonstrates neurotrophic activity both, in vivo and in vitro, and is currently being investigated for the treatment of Parkinson&#39;s disease. Insulin and insulin-like growth factors have been shown to stimulate growth of neurites in rat pheochromocytoma PC12 cells and in cultured sympathetic and sensory neurons [Recio-Pinto et al.,  J. Neurosci ., 6, pp. 1211-1219 (1986)]. Insulin and insulin-like growth factors also stimulate the regeneration of injured motor nerves in vivo and in vitro [Near et al.,  Proc. Natl. Acad. Sci ., pp. 89, 11716-11720 (1992); and Edbladh et al.,  Brain Res ., 641, pp. 76-82 (1994)]. Similarly, fibroblast growth factor (FGF) stimulates neural proliferation [D. Gospodarowicz et al.,  Cell Differ ., 19, p. 1 (1986)] and growth [M. A. Walter et al.,  Lymphokine Cytokine Res ., 12, p. 135 (1993)]. 
     There are, however, several disadvantages associated with the use of nerve growth factors for treating neurological diseases. They do not readily cross the blood-brain barrier. They are unstable in plasma and they have poor drug delivery properties. 
     Recently, small molecules have been shown to stimulate neurite outgrowth in vivo. In individuals suffering from a neurological disease, this stimulation of neuronal growth protects neurons from further degeneration, and accelerates the regeneration of nerve cells. For example, estrogen has been shown to promote the growth of axons and dendrites, which are neurites sent out by nerve cells to communicate with each other in a developing or injured adult brain [(C. Dominique Toran-Allerand et al.,  J. Steroid Biochem. Mol. Biol ., 56, pp. 169-78 (1996); and B. S. McEwen et al.,  Brain Res. Dev. Brain. Res ., 87, pp. 91-95 (1995)]. The progress of Alzheimer&#39;s disease is slowed in women who take estrogen. Estrogen is hypothesized to complement NGF and other neurotrophins and thereby help neurons differentiate and survive. 
     Other target sites for the treatment of neurodegenerative disease are the immunophilin class of proteins. Immunophilins are a family of soluble proteins that mediate the actions of immunosuppressant drugs such as cyclosporin A, FK506 and rapamycin. Of particular interest is the 12 kDa immunophilin, FK-506 binding protein (FKBP12). FKBP12 binds FK-506 and rapamycin, leading to an inhibition of T-cell activation and proliferation. Interestingly, the mechanism of action of FK-506 and rapamycin are different. For a review, see, S. H. Solomon et al.,  Nature Med ., 1, pp. 32-37 (1995). It has been reported that compounds with an affinity for FKBP12 that inhibit that protein&#39;s rotomase activity possess nerve growth stimulatory activity. [Lyons et al.,  Proc. Natl. Acad. Sci. USA , 91, pp. 3191-3195 (1994)]. Many of these such compounds also have immunosuppressive activity. 
     FK506 (Tacrolimus) has been demonstrated to act synergistically with NGF in stimulating neurite outgrowth in PC12 cells as well as sensory ganglia [Lyons et al. (1994)]. This compound has also been shown to be neuroprotective in focal cerebral ischemia [J. Sharkey and S. P. Butcher,  Nature , 371, pp. 336-339 (1994)] and to increase the rate of axonal regeneration in injured sciatic nerve [B. Gold et al.,  J. Neurosci ., 15, pp. 7509-16 (1995)]. 
     The use of immunosuppressive compounds, however, has drawbacks in that prolonged treatment with these compounds can cause nephrotoxicity [Kopp et al.,  J. Am. Soc. Nephrol ., 1, p. 162 (1991)], neurological deficits [P. C. DeGroen et al.,  N. Eng. J. Med ., 317, p. 861 (1987)] and vascular hypertension [Kahan et al.,  N. Eng. J. Med ., 321, p. 1725 (1989)]. 
     More recently, sub-classes of FKBP binding compounds which inhibit rotomase activity, but which purportedly lack immunosuppressive function have been disclosed for use in stimulating nerve growth [see, U.S. Pat. No. 5,614,547; WO 96/40633; WO 96/40140; WO 97/16190; J. P. Steiner et al.,  Proc. Natl. Acad. Sci. USA , 94, pp. 2019-23 (1997); and G. S. Hamilton et al.,  Bioorg. Med. Chem. Lett ., 7, pp. 1785-90 (1997)]. 
     Stimulation of neural axons in nerve cells by piperidine derivatives is described in WO 96/41609. Clinical use of the piperidine and pyrrolidine derivatives known so far for stimulating axonal growth has not been promising, as the compounds are unstable in plasma and do not pass the blood-brain barrier in adequate amounts. 
     Though a wide variety of neurological degenerative diseases may be treated by promoting repair of neuronal damage, there are relatively few agents known to possess these properties. Thus, there remains a need for new compounds and compositions that have the ability to either prevent or treat neuronal damage associated with neuropathologic disorders. 
     SUMMARY OF THE INVENTION 
     The invention provides compounds of formula 
                        
 
and pharmaceutically acceptable derivatives thereof, wherein:
     X is selected from —CH 2 CH 2 —, —CH═CH—, —C(OH)CH 2 —, —CH 2 C(OH)—, ═C(F)CH 2 —, —C(F)═CH 2 —, —NHC(O)—, —P(O)(OH)CH 2 —, —CH 2 S(O) 2 —, —C(S)NR 1 —, —C(O)CH 2 CH(OH)—, —C(OH)CF 2 —, —C(O)CF 2 —, —CH(F)CH 2 —, —C(F) 2 CH 2 —, —CH 2 CH(F)—, —CH 2 C(F) 2 —
                         
   A, B and R 1  are independently E, (C 1 -C 10 )-straight or branched alkyl, (C 2 -C 10 )-straight or branched alkenyl or alkynyl, or (C 5 -C 7 )-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (C 5 -C 7 )-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the —CH 2 — groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O) 2 —, ═N—, —N═ or —N(R 3 )—;   or, B and R 1  are independently hydrogen;   R 3  is hydrogen, (C 1 -C 4 )-straight or branched alkyl, (C 3 -C 4 )-straight or branched alkenyl or alkynyl, or (C 1 -C 4 ) bridging alkyl, wherein a bridge is formed between the nitrogen atom to which said R 3  is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, and wherein said ring is optionally benzofused;   E is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 ), O, S, S(O), or S(O) 2 ; and wherein no more than 4 ring atoms are selected from N, N(R 3 ), O, S, S(O), or S(O) 2 ;   wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO 3 H, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl, O—[(C 1 -C 6 )-straight or branched alkyl], O—[(C 3 -C 6 )-straight or branched alkenyl], (CH 2 ) n —N(R 4 )(R 5 ), (CH 2 ) n —NH(R 4 )—(CH 2 ) n -Z, (CH 2 ) n —N(R 4 —(CH 2 ) n -Z)(R 5 —(CH 2 ) n -Z), (CH 2 ) n -Z, O—(CH 2 ) n -Z, (CH 2 ) n —O-Z, S—(CH 2 ) n -Z, CH═CH-Z, 1,2-methylenedioxy, C(O)OH, C(O)O—[(C 1 C 6 )-straight or branched alkyl], C(O)O—(CH 2 ) n -Z or C(O)—N(R 4 )(R 5 );   each of R 4  and R 5  are independently hydrogen, (C 1 -C 6 )-straight or branched alkyl, (C 3 -C 5 )-straight or branched alkenyl, or wherein R 4  and R 5 , when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, N(R 3 ), O, S, S(O), or S(O) 2 ; wherein said alkyl, alkenyl or alkynyl groups in R 4  and R 5  are optionally substituted with Z.   each n is independently 0 to 4;   each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 ), O, S, S(O), or S(O) 2 ; and wherein no more than 4 ring atoms are selected from N, N(R 3 ), O, S, S(O), or S(O) 2 ;   wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(O)OH, (C 1 -C 3 )-straight or branched alkyl, O—(C 1 -C 3 )-straight or branched alkyl, C(O)O—[(C 1 -C 3 )-straight or branched alkyl], amino, NH[(C 1 -C 3 )-straight or branched alkyl], or N—[(C 1 -C 3 )-straight or branched alkyl] 2 ;   J is H, methyl, ethyl or benzyl;   K and K 1  are independently selected from (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E;   wherein K and K 1  are independently and optionally substituted with up to 3 substituents selected from halogen, OH, O—(C 1 -C 6 )-alkyl, O—(CH 2 )n-Z, NO 2 , C(O)OH, C(O)—O—(C 1 -C 6 )-alkyl, C(O)NR 4 R 5 , NR 4 R 5  and (CH 2 ) n -Z; or,   J and K, taken together with the nitrogen and carbon atom to which they are respectively bound, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R 3 ), O, S, S(O), or S(O) 2 , wherein 1 to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH 2 — group in said alkyl, alkenyl or alkynyl substituent is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O 2 )—, ═N—, —N═, or —N(R 3 )—; and wherein said heterocyclic ring is optionally fused with E;   G, when present, is —S(O) 2 —, —C(O)—, —S(O) 2 —Y—, —C(O)—Y—, —C(O)—C(O)—, or —C(O)—C(O)—Y—;   Y is oxygen, or N(R 6 );   wherein R 6  is hydrogen, E, (C 1 -C 6 )-straight or branched alkyl, (C 3 -C 6 )-straight or branched alkenyl or alkynyl; or wherein R 6  and D are taken together with the atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, N(R 3 ), SO, or SO 2 ; and wherein said ring is optionally benzofused;   D is hydrogen, (C 1 -C 7 )-straight or branched alkyl, (C 2 -C 7 )-straight or branched alkenyl or alkynyl, (C 5 -C 7 )-cycloalkyl or cycloalkenyl optionally substituted with (C 1 -C 6 )-straight or branched alkyl or (C 2 -C 7 )-straight or branched alkenyl or alkynyl, [(C 1 -C 7 )-alkyl]-E, [(C 2 -C 7 )-alkenyl or alkynyl]-E, or E;   wherein 1 to 2 of the CH 2  groups of said alkyl, alkenyl or alkynyl chains in D is optionally replaced by —O—, —S—, —S(O)—, —S(O 2 )—, ═N—, —N═, or —N(R 3 );   provided that when J is hydrogen or G is selected from —S(O) 2 —, C(O)C(O)—, SO 2 —Y, C(O)—Y, or C(O)C(O)—Y, wherein Y is O; then D is not hydrogen; and   x is 0 or 1.   

     In another embodiment, the invention provides pharmaceutical compositions comprising the compounds of formula (I). These compositions may be utilized in methods treating various neurological diseases which are influenced by neuronal regeneration and axon growth or for stimulating neuronal regeneration in an ex vivo nerve cell. Examples of such diseases include peripheral nerve destruction due to physical injury or diseases such as diabetes; physical injuries to the central nervous system (e.g., brain or spinal cord); stroke; neurological disturbances due to nerve degeneration, such as Parkinson&#39;s disease, Alzheimer&#39;s disease, and amylotrophic lateral sclerosis. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention provides compounds of formula (I): 
                        
 
and pharmaceutically acceptable derivatives thereof, wherein:
     X is selected from —CH 2 CH 2 —, —CH═CH—, —C(OH)CH 2 —, —CH 2 C(OH)—, ═C(F)CH 2 —, —C(F)═CH 2 —, —NHC(O)—, —P(O)(OH)CH 2 —, —CH 2 S(O) 2 —, —C(S)NR 1 —, —C(O)CH 2 CH(OH)—, —C(OH)CF 2 —, —C(O)CF 2 —, —CH(F)CH 2 —, —C(F) 2 CH 2 —, —CH 2 CH(F)—, —CH 2 C(F) 2 —, 
                         
   A, B and R 1  are independently E, (C 1 -C 10 )-straight or branched alkyl, (C 2 -C 10 )-straight or branched alkenyl or alkynyl, or (C 5 -C 7 )-cycloalkyl or cycloalkenyl; wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (C 5 -C 7 )-cycloalkyl or cycloalkenyl; and wherein 1 to 2 of the —CH 2 — groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O) 2 —, ═N—, —N═ or —N(R 3 )—;   or, B and R 1  are independently hydrogen;   R 3  is hydrogen, (C 1 -C 4 )-straight or branched alkyl, (C 3 -C 4 )-straight or branched alkenyl or alkynyl, or (C 1 -C 4 ) bridging alkyl, wherein a bridge is formed between the nitrogen atom to which said R 3  is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, and wherein said ring is optionally benzofused;   E is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 ), O, S, S(O), or S(O) 2 ; and wherein no more than 4 ring atoms are selected from N, N(R 3 ), O, S, S(O), or S(O) 2 ;   wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO 3 H, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl, O—[(C 1 -C 6 )-straight or branched alkyl], O—[(C 3 -C 6 )-straight or branched alkenyl], (CH 2 ) n —N(R 4 )(R 5 ), (CH 2 ) n —NH(R 4 )—(CH 2 ) n -Z, (CH 2 ) n —N(R 4 —(CH 2 ) n -Z)(R 5 —(CH 2 ) n -Z), (CH 2 ) n -Z, O—(CH 2 ) n -Z, (CH 2 ) n —O-Z, S—(CH 2 ) n -Z, CH═CH-Z, 1,2-methylenedioxy, C(O)OH, C(O)O—[(C 1 -C 6 )-straight or branched alkyl], C(O)O—(CH 2 ) n -Z or C(O)—N(R 4 )(R 5 );   each of R 4  and R 5  are independently hydrogen, (C 1 -C 6 )-straight or branched alkyl, (C 3 -C 5 )-straight or branched alkenyl, or wherein R 4  and R 5 , when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, N(R 3 ), O, S, S(O), or S(O) 2 ; wherein said alkyl, alkenyl or alkynyl groups in R 4  and R 5  are optionally substituted with Z.   each n is independently 0 to 4;   each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, N(R 3 ), O, S, S(O), or S(O) 2 ; and wherein no more than 4 ring atoms are selected from N, N(R 3 ), O, S, S(O), or S(O) 2 ;   wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(O)OH, (C 1 -C 3 )-straight or branched alkyl, O—(C 1 -C 3 )-straight or branched alkyl, C(O)O—[(C 1 -C 3 )-straight or branched alkyl], amino, NH[(C 1 -C 3 )-straight or branched alkyl], or N—[(C 1 -C 3 )-straight or branched alkyl] 2 ;   J is H, methyl, ethyl or benzyl;   K and K 1  are independently selected from (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E;   wherein K and K 1  are independently and optionally substituted with up to 3 substituents selected from halogen, OH, O—(C 1 -C 6 )-alkyl, O—(CH 2 )n-Z, NO 2 , C(O)OH, C(O)—O—(C 1 -C 6 )-alkyl, C(O)NR 4 R 5 , NR 4 R 5  and (CH 2 ) n -Z; or,   J and K, taken together with the nitrogen and carbon atom to which they are respectively bound, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R 3 ), O, S, S(O), or S(O) 2 , wherein 1 to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH 2 — group in said alkyl, alkenyl or alkynyl substituent is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O 2 )—, ═N—, —N═, or —N(R 3 )—; and wherein said heterocyclic ring is optionally fused with E;   G, when present, is —S(O) 2 —, —C(O)—, —S(O) 2 —Y—, —C(O)—Y—, —C(O)—C(O)—, or —C(O)—C(O)—Y—;   Y is oxygen, or N(R 6 );   wherein R 6  is hydrogen, E, (C 1 -C 6 )-straight or branched alkyl, (C 3 -C 6 )-straight or branched alkenyl or alkynyl; or wherein R 6  and D are taken together with the atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, N(R 3 ), SO, or SO 2 ; and wherein said ring is optionally benzofused;   D is hydrogen, (C 1 -C 7 )-straight or branched alkyl, (C 2 -C 7 )-straight or branched alkenyl or alkynyl, (C 5 -C 7 )-cycloalkyl or cycloalkenyl optionally substituted with (C l -C 6 )-straight or branched alkyl or (C 2 -C 7 )-straight or branched alkenyl or alkynyl, [(C 1 -C 7 )-alkyl]-E, [(C 2 -C 7 )-alkenyl or alkynyl]-E, or E;   wherein 1 to 2 of the CH 2  groups of said alkyl, alkenyl or alkynyl chains in D is optionally replaced by —O—, —S—, —S(O)—, —S(O 2 )—, ═N—, —N═, or —N(R 3 );   provided that when J is hydrogen or G is selected from —S(O) 2 —, C(O)C(O)SO 2 —Y, C(O)—Y, or C(O)C(O)—Y, wherein Y is O; then D is not hydrogen; and   x is 0 or 1.   

     According to a preferred embodiment, each of A and B in formula (I) is (C 1 -C 10 ) straight or branched alkyl, wherein 1-2 hydrogen atoms in said alkyl are optionally substituted with E. 
     In another preferred embodiment, B is hydrogen. 
     According to another preferred embodiment, each of A and B in formula (I) is —CH 2 —CH 2 —E or —CH 2 —CH 2 —CH 2 —E. 
     According to another preferred embodiment, D in formula (I) is (C 1 -C 7 ) straight or branched alkyl, E or [(C 1 -C 6 )-straight or branched alkyl]-E. 
     According to a more preferred embodiment, D is an aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5-7 ring atoms independently selected from C, N, O or S, and wherein no more than 4 ring atoms are selected from N, O or S. 
     According to an even more preferred embodiment, D is phenyl or C 1 -C 7  straight or branched alkyl group. 
     According to another preferred embodiment, E in formula (I) is a monocyclic or bicyclic aromatic ring system, wherein said ring comprises 5-7 ring atoms independently selected from C, N, N(R 3 ), O, S, S(O), or S(O) 2 , and wherein 1 to 4 ring atoms are independently selected from N, N(R 3 ), O, S, S(O), or S(O) 2 . 
     Preferred embodiments of E include phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isothiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, 1,3,5-trazinyl, 1,3,5-trithianyl, benzo[b]furanyl, benzo[b]thiophenyl, purinyl, cinnolinyl, phthalazinyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolinyl, indolizinyl, isoindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phnazinyl, phenothiazinyl, phenoxazinyl and benzothiazolyl, wherein E is optionally substituted as described above. 
     More preferred embodiments of E include phenyl, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, triazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, and benzothiazolyl, wherein E is optionally substituted as described above. 
     According to another preferred embodiment, J is H, methyl, ethyl or benzyl; and 
     K is selected from (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E. 
     According to another preferred embodiment, J and K, taken together with the nitrogen atom, form a 5-7 membered heterocyclic ring, optionally containing up to 3 additional heteroatoms selected from N, N(R 3 ), O, S, S(O), or S(O) 2 , wherein 1 to 4 hydrogen atoms in said heterocyclic ring are optionally and independently replaced with (C 1 -C 6 )-straight or branched alkyl, (C 2 -C 6 )-straight or branched alkenyl or alkynyl, oxo, hydroxyl or Z; and wherein any —CH 2 — group said heterocyclic ring is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O 2 )—, ═N—, —N═, or —N(R 3 )—; and wherein said heterocyclic ring is optionally fused with E. 
     According to yet another preferred embodiment, X is selected from —CH 2 CH 2 —, —CH═CH—, —C(OH)CH 2 —, —CH 2 C(OH)—, —C(F)═CH 2 —, —CH 2 S(O) 2 —, —C(S)NR 1 —, —C(O)CH 2 CH(OH)—, —C(OH)CF 2 —, —C(O)CF 2 —, —CH(F)CH 2 —, —C(F) 2 CH 2 —, —CH 2 CH(F)—, —CH 2 C(F) 2 —, or 
                        
 
     The compounds of formula (I) may be stereoisomers, geometric isomers or stable tautomers. The invention envisions all possible isomers, such as E and Z isomers, S and R enantiomers, diastereoisomers, racemates, and mixtures of those. It is preferred that the substituent in the 2 position have the S configuration. 
     The compounds of the present invention may be readily prepared using known synthetic methods. For synthetic methods for the preparation of X, which are amide bond bioisosteres see: “Peptidomimetics Protocols” in Methods on Molecular Medicine, Vol 30, 1999, Humana Press, Totowa N.J., Kazmierski, W. M., Ed. 
     Examples of synthetic schemes that may be used to produce the compounds of this invention are set forth in Schemes 1 through 6 below. 
                        
                         
                         
                         
                         
                         
 
     One of skill in the art will also be well aware of analogous synthetic methods for preparing compounds of formula (I). 
     According to another embodiment, this invention provides compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. 
     Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxy methylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. 
     In another embodiment, the pharmaceutical composition of the present invention is comprised of a compound of formula (I), a pharmaceutically acceptable carrier, and a neurotrophic factor. 
     The term “neurotrophic factor,” as used herein, refers to compounds which are capable of stimulating growth or proliferation of nervous tissue. Numerous neurotrophic factors have been identified in the art and any of those factors may be utilized in the compositions of this invention. These neurotrophic factors include, but are not limited to, nerve growth factor (NGF), insulin-like growth factor (IGF-1) and its active truncated derivatives such as gIGF-1 and Des(1-3)IGF-I, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factors (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3)and neurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factor in the compositions of this invention is NGF. 
     As used herein, the described compounds used in the pharmaceutical compositions and methods of this invention, are defined to include pharmaceutically acceptable derivatives thereof. A “pharmaceutically acceptable derivative” denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of a compound of this invention or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to promote repair or prevent damage of neurons from disease or physical trauma. 
     If pharmaceutically acceptable salts of the described compounds are used, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. 
     The described compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. 
     The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. 
     Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. 
     The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. 
     Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. 
     The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. 
     Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used. 
     For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. 
     For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. 
     The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. 
     The amount of both a described compound and the optional neurotrophic factor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the described compound can be administered. If a neurotrophic factor is present in the composition, then a dosage of between 0.01 μg-100 mg/kg body weight/day of the neurotrophic factor can be administered to a patient receiving these compositions. 
     It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredients will also depend upon the particular described compound and neurotrophic factor in the composition. 
     According to another embodiment, this invention provides methods for promoting repair or preventing neuronal damage or neurodegeneration in vivo or in an ex vivo nerve cell. Such methods comprise the step of treating nerve cells with any of the compounds described above. Preferably, this method promotes repair or prevents neuronal damage or neurodegeneration in a patient, and the compound is formulated into a composition additionally comprising a pharmaceutically acceptable carrier. The amount of the compound utilized in these methods is between about 0.01 and 100 mg/kg body weight/day. 
     According to an alternate embodiment, the method of promoting repair or preventing neuronal damage or neurodegeneration comprises the additional step of treating nerve cells with a neurotrophic factor, such as those contained in the pharmaceutical compositions of this invention. This embodiment includes administering the compound and the neurotrophic agent in a single dosage form or in separate, multiple dosage forms. If separate dosage forms are utilized, they may be administered concurrently, consecutively or within less than about 5 hours of one another. 
     Preferably, the methods of this invention are used to stimulate axonal growth in nerve cells. The compounds are, therefore, suitable for treating or preventing neuronal damage caused by a wide variety of diseases or physical traumas. These include, but are not limited to, Alzheimer&#39;s disease, Parkinson&#39;s disease, ALS, Huntington&#39;s disease, Tourette&#39;s syndrome, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, spinal cord injuries and facial nerve crush. 
     In a particularly preferred embodiment of the invention, the method is used to treat a patient suffering from trigeminal neuralgia, glosspharyngeal neuralgia, Bell&#39;s Palsy, myasthenia gravis, muscular dystrophy, muscle injury, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured, or prolapsed invertebrae disk syndrome&#39;s, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathies, such as those caused by lead, dapsone, ticks, or porphyria, other peripheral myelin disorders, Alzheimer&#39;s disease, Gullain-Barre syndrome, Parkinson&#39;s disease and other Parkinsonian disorders, ALS, Tourette&#39;s syndrome, multiple sclerosis, other central myelin disorders, stroke and ischemia associated with stroke, neural paropathy, other neural degenerative diseases, motor neuron diseases, sciatic crush, neuropathy associated with diabetes, spinal cord injuries, facial nerve crush and other trauma, chemotherapy- and other medication-induced neuropathies, and Huntington&#39;s disease. 
     More preferably, the compositions of the present invention are used for treating Parkinson&#39;s disease, amylotrophic lateral sclerosis, Alzheimer&#39;s disease, stroke, neuralgias, muscular atrophies, and Guillain-Barré syndrome. 
     For use of the compounds according to the invention as medications, they are administered in the form of a pharmaceutical preparation containing not only the active ingredient but also carriers, auxiliary substances, and/or additives suitable for enteric or parenteral administration. Administration can be oral or sublingual as a solid in the form of capsules or tablets, as a liquid in the form of solutions, suspensions, elixirs, aerosols or emulsions, or rectal in the form of suppositories, or in the form of solutions for injection which can be given subcutaneously, intramuscularly, or intravenously, or which can be given topically or intrathecally. Auxiliary substances for the desired medicinal formulation include the inert organic and inorganic carriers known to those skilled in the art, such as water, gelatin, gum arabic, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The medicinal formulations may also contain preservatives, stabilizers, wetting agents, emulsifiers, or salts to change the osmotic pressure or as buffers. 
     Solutions or suspensions for injection are suitable for parenteral administration, and especially aqueous solutions of the active compounds in polyhydroxy-ethoxylated castor oil. 
     Surface-active auxiliary substances such as salts of gallic acid, animal or vegetable phospholipids, or mixtures of them, and liposomes or their components, can be used as carrier systems. 
     The neurotrophic effect of the compounds of formula (I) of the present invention and their physiologically acceptable salts can be determined by the methods of W. E. Lyons et al.,  Proc. Natl. Acad. Sci. USA , Vol. 91, pp. 3191-3195 (1994) and W. E. Lyons et al.,  Proc. Natl. Acad. Sci. USA , Vol. 91, pages 3191-3195 (1994), the disclosures of which are herein incorporated by reference. 
     In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. 
     EXAMPLE 1 
     Compounds 100-295 
     Compounds 101-296 are synthesized via the method set forth in Scheme 1, above. In all of the examples, “Ph” is phenyl. 
     Compounds 100-148 have the formula: 
                        
 
with the individual variables defined in the table below.
 
                                                   Cmpd #                                 —(G) x —D                                100                                 —CH 3         101   Same as above   —CH 2 CH 3         102   Same as above   —C(═O)—CH 3         103   Same as above   —CH 2 —Ph       104   Same as above   —C(═O)—Ph       105   Same as above   —C(═O)—O—CH 2 —Ph       106   Same as above   —C(═O)—C(═O)—Ph       107                                 —CH 3         108   Same as above   —CH 2 CH 3         109   Same as above   —C(═O)—CH 3         110   Same as above   —CH 2 —Ph       111   Same as above   —C(═O)—Ph       112   Same as above   —C(═O)—O—CH 2 —Ph       113   Same as above   —C(═O)—C(═O)—Ph       114                                 —CH 3         115   Same as above   —CH 2 CH 3         116   Same as above   —C(═O)—CH 3         117   Same as above   —CH 2 —Ph       118   Same as above   —C(═O)—Ph       119   Same as above   —C(═O)—O—CH 2 —Ph       120   Same as above   —C(═O)—C(═O)—Ph       121                                 —CH 3         122   Same as above   —CH 2 CH 3         123   Same as above   —C(═O)—CH 3         124   Same as above   —CH 2 —Ph       125   Same as above   —C(═O)—Ph       126   Same as above   —C(═O)—O—CH 2 —Ph       127   Same as above   —C(═O)—C(═O)—Ph       128                                 —CH 3         129   Same as above   —CH 2 CH 3         130   Same as above   —C(═O)—CH 3         131   Same as above   —CH 2 —Ph       132   Same as above   —C(═O)—Ph       133   Same as above   —C(═O)—O—CH 2 —Ph       134   Same as above   —C(═O)—C(═O)—Ph       135                                 —CH 3         136   Same as above   —CH 2 CH 3         137   Same as above   —C(═O)—CH 3         138   Same as above   —CH 2 —Ph       139   Same as above   —C(═O)—Ph       140   Same as above   —C(═O)—O—CH 2 —Ph       141   Same as above   —C(═O)—C(═O)—Ph       142                                 —CH 3         143   Same as above   —CH 2 CH 3         144   Same as above   —C(═O)—CH 3         145   Same as above   —CH 2 —Ph       146   Same as above   —C(═O)—Ph       147   Same as above   —C(═O)—O—CH 2 —Ph       148   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 149-197 have the formula: 
                          
with the individual variables defined in the table below.
 
                                                   Cmpd #                                 —(G) x —D                                149                                 —CH 3         150   Same as above   —CH 2 CH 3         151   Same as above   —C(═O)—CH 3         152   Same as above   —CH 2 —Ph       153   Same as above   —C(═O)—Ph       154   Same as above   —C(═O)—O—CH 2 —Ph       155   Same as above   —C(═O)—C(═O)—Ph       156                                 —CH 3         157   Same as above   —CH 2 CH 3         158   Same as above   —C(═O)—CH 3         159   Same as above   —CH 2 —Ph       160   Same as above   —C(═O)—Ph       161   Same as above   —C(═O)—O—CH 2 —Ph       162   Same as above   —C(═O)—C(═O)—Ph       163                                 —CH 3         164   Same as above   —CH 2 CH 3         165   Same as above   —C(═O)—CH 3         166   Same as above   —CH 2 —Ph       167   Same as above   —C(═O)—Ph       168   Same as above   —C(═O)—O—CH 2 —Ph       169   Same as above   —C(═O)—C(═O)—Ph       170                                 —CH 3         171   Same as above   —CH 2 CH 3         172   Same as above   —C(═O)—CH 3         173   Same as above   —CH 2 —Ph       174   Same as above   —C(═O)—Ph       175   Same as above   —C(═O)—O—CH 2 —Ph       176   Same as above   —C(═O)—C(═O)—Ph       177                                 —CH 3         178   Same as above   —CH 2 CH 3         179   Same as above   —C(═O)—CH 3         180   Same as above   —CH 2 —Ph       181   Same as above   —C(═O)—Ph       182   Same as above   —C(═O)—O—CH 2 —Ph       183   Same as above   —C(═O)—C(═O)—Ph       184                                 —CH 3         185   Same as above   —CH 2 CH 3         186   Same as above   —C(═O)—CH 3         187   Same as above   —CH 2 —Ph       188   Same as above   —C(═O)—Ph       189   Same as above   —C(═O)—O—CH 2 —Ph       190   Same as above   —C(═O)—C(═O)—Ph       191                                 —CH 3         192   Same as above   —CH 2 CH 3         193   Same as above   —C(═O)—CH 3         194   Same as above   —CH 2 —Ph       195   Same as above   —C(═O)—Ph       196   Same as above   —C(═O)—O—CH 2 —Ph       197   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 198-246 have the formula: 
                          
with the individual variables defined in the table below.
 
                                                   Cmpd #                                 —(G) x —D                                198                                 —CH 3         199   Same as above   —CH 2 CH 3         200   Same as above   —C(═O)—CH 3         201   Same as above   —CH 2 —Ph       202   Same as above   —C(═O)—Ph       203   Same as above   —C(═O)—O—CH 2 —Ph       204   Same as above   —C(═O)—C(═O)—Ph       205                                 —CH 3         206   Same as above   —CH 2 CH 3         207   Same as above   —C(═O)—CH 3         208   Same as above   —CH 2 —Ph       209   Same as above   —C(═O)—Ph       210   Same as above   —C(═O)—O—CH 2 —Ph       211   Same as above   —C(═O)—C(═O)—Ph       212                                 —CH 3         213   Same as above   —CH 2 CH 3         214   Same as above   —C(═O)—CH 3         215   Same as above   —CH 2 —Ph       216   Same as above   —C(═O)—Ph       217   Same as above   —C(═O)—O—CH 2 —Ph       218   Same as above   —C(═O)—C(═O)—Ph       219                                 —CH 3         220   Same as above   —CH 2 CH 3         221   Same as above   —C(═O)—CH 3         222   Same as above   —CH 2 —Ph       223   Same as above   —C(═O)—Ph       224   Same as above       225   Same as above   —C(═O)—C(═O)—Ph       226                                 —CH 3         227   Same as above   —CH 2 CH 3         228   Same as above   —C(═O)—CH 3         229   Same as above   —CH 2 —Ph       230   Same as above   —C(═O)—Ph       231   Same as above   —C(═O)—O—CH 2 —Ph       232   Same as above   —C(═O)—C(═O)—Ph       233                                 —CH 3         234   Same as above   —CH 2 CH 3         235   Same as above   —C(═O)—CH 3         236   Same as above   —CH 2 —Ph       237   Same as above   —C(═O)—Ph       238   Same as above   —C(═O)—O—CH 2 —Ph       239   Same as above   —C(═O)—C(═O)—Ph       240                                 —CH 3         241   Same as above   —CH 2 CH 3         242   Same as above   —C(═O)—CH 3         243   Same as above   —CH 2 —Ph       244   Same as above   —C(═O)—Ph       245   Same as above   —C(═O)—O—CH 2 —Ph       246   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 247-295 have the formula: 
                          
with the individual variables defined in the table below.
 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 Cmpd # 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —(G) x —D 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 247 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 248 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 249 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 250 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 251 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 252 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 253 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 254 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 255 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 256 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 257 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 258 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 259 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 260 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 261 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 262 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 263 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 264 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 265 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 266 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 267 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 268 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 269 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 270 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 271 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 272 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 273 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 274 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 275 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 276 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 277 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 278 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 279 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 280 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 281 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 282 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 283 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 284 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 285 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 286 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 287 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 288 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 289 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 290 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 291 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 292 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 293 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 294 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 295 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 2 
     Compounds 296-519 
     Compounds 296-519 are synthesized via the method set forth in Scheme 2, above. 
     Compounds 296-407 have the formula: 
                        
 
with the individual variables defined in the table below.
 
                                                           Cmpd #                                 R 1     —(G) x —D                                296                                 H   —CH 3         297   Same as above   H   —CH 2 CH 3         298   Same as above   H   —C(═O)—CH 3         299   Same as above   H   —CH 2 —Ph       300   Same as above   H   —C(═O)—Ph       301   Same as above   H   —C(═O)—O—CH 2 —Ph       302   Same as above   H   —C(═O)—C(═O)—Ph       303   Same as above   CH 3     —CH 3         304   Same as above   CH 3     —CH 2 CH 3         305   Same as above   CH 3     —C(═O)—CH 3         306   Same as above   CH 3     —CH 2 —Ph       307   Same as above   CH 3     —C(═O)—Ph       308   Same as above   CH 3     —C(═O)—O—CH 2 —Ph       309   Same as above   CH 3     —C(═O)—C(═O)—Ph       310   Same as above   CH 2 CH 3     —CH 3         311   Same as above   CH 2 CH 3     —CH 2 CH 3         312   Same as above   CH 2 CH 3     —C(═O)—CH 3         313   Same as above   CH 2 CH 3     —CH 2 —Ph       314   Same as above   CH 2 CH 3     —C(═O)—Ph       315   Same as above   CH 2 CH 3     —C(═O)—O—CH 2 —Ph       316   Same as above   CH 2 CH 3     —C(═O)—C(═O)—Ph       317   Same as above   CH 2 Ph   —CH 3         318   Same as above   CH 2 Ph   —CH 2 CH 3         319   Same as above   CH 2 Ph   —C(═O)—CH 3         320   Same as above   CH 2 Ph   —CH 2 —Ph       321   Same as above   CH 2 Ph   —C(═O)—Ph       322   Same as above   CH 2 Ph   —C(═O)—O—CH 2 —Ph       323   Same as above   CH 2 Ph   —C(═O)—C(═O)—Ph       324                                 H   —CH 3         325   Same as above   H   —CH 2 CH 3         326   Same as above   H   —C(═O)—CH 3         327   Same as above   H   —CH 2 —Ph       328   Same as above   H   —C(═O)—Ph       329   Same as above   H   —C(═O)—O—CH 2 —Ph       330   Same as above   H   —C(═O)—C(═O)—Ph       331   Same as above   CH 3     —CH 3         332   Same as above   CH 3     —CH 2 CH 3         333   Same as above   CH 3     —C(═O)—CH 3         334   Same as above   CH 3     —CH 2 —Ph       335   Same as above   CH 3     —C(═O)—Ph       336   Same as above   CH 3     —C(═O)—O—CH 2 —Ph       337   Same as above   CH 3     —C(═O)—C(═O)—Ph       338   Same as above   CH 2 CH 3     —CH 3         339   Same as above   CH 2 CH 3     —CH 2 CH 3         340   Same as above   CH 2 CH 3     —C(═O)—CH 3         341   Same as above   CH 2 CH 3     —CH 2 —Ph       342   Same as above   CH 2 CH 3     —C(═O)—Ph       343   Same as above   CH 2 CH 3     —C(═O)—O—CH 2 —Ph       344   Same as above   CH 2 CH 3     —C(═O)—C(═O)—Ph       345   Same as above   CH 2 Ph   —CH 3         346   Same as above   CH 2 Ph   —CH 2 CH 3         347   Same as above   CH 2 Ph   —C(═O)—CH 3         348   Same as above   CH 2 Ph   —CH 2 —Ph       349   Same as above   CH 2 Ph   —C(═O)—Ph       350   Same as above   CH 2 Ph   —C(═O)—O—CH 2 —Ph       351   Same as above   CH 2 Ph   —C(═O)—C(═O)—Ph       352                                 H   —CH 3         353   Same as above   H   —CH 2 CH 3         354   Same as above   H   —C(═O)—CH 3         355   Same as above   H   —CH 2 —Ph       356   Same as above   H   —C(═O)—Ph       357   Same as above   H   —C(═O)—O—CH 2 —Ph       358   Same as above   H   —C(═O)—C(═O)—Ph       359   Same as above   CH 3     —CH 3         360   Same as above   CH 3     —CH 2 CH 3         361   Same as above   CH 3     —C(═O)—CH 3         362   Same as above   CH 3     —CH 2 —Ph       363   Same as above   CH 3     —C(═O)—Ph       364   Same as above   CH 3     —C(═O)—O—CH 2 —Ph       365   Same as above   CH 3     —C(═O)—C(═O)—Ph       366   Same as above   CH 2 CH 3     —CH 3         367   Same as above   CH 2 CH 3     —CH 2 CH 3         368   Same as above   CH 2 CH 3     —C(═O)—CH 3         369   Same as above   CH 2 CH 3     —CH 2 —Ph       370   Same as above   CH 2 CH 3     —C(═O)—Ph       371   Same as above   CH 2 CH 3     —C(═O)—O—CH 2 —Ph       372   Same as above   CH 2 CH 3     —C(═O)—C(═O)—Ph       373   Same as above   CH 2 Ph   —CH 3         374   Same as above   CH 2 Ph   —CH 2 CH 3         375   Same as above   CH 2 Ph   —C(═O)—CH 3         376   Same as above   CH 2 Ph   —CH 2 —Ph       377   Same as above   CH 2 Ph   —C(═O)—Ph       378   Same as above   CH 2 Ph   —C(═O)—O—CH 2 —Ph       379   Same as above   CH 2 Ph   —C(═O)—C(═O)—Ph       380                                 H   —CH 3         381   Same as above   H   —CH 2 CH 3         382   Same as above   H   —C(═O)—CH 3         383   Same as above   H   —CH 2 —Ph       384   Same as above   H   —C(═O)—Ph       385   Same as above   H   —C(═O)—O—CH 2 —Ph       386   Same as above   H   —C(═O)—C(═O)—Ph       387   Same as above   CH 3     —CH 3         388   Same as above   CH 3     —CH 2 CH 3         389   Same as above   CH 3     —C(═O)—CH 3         390   Same as above   CH 3     —CH 2 —Ph       391   Same as above   CH 3     —C(═O)—Ph       392   Same as above   CH 3     —C(═O)—O—CH 2 —Ph       393   Same as above   CH 3     —C(═O)—C(═O)—Ph       394   Same as above   CH 2 CH 3     —CH 3         395   Same as above   CH 2 CH 3     —CH 2 CH 3         396   Same as above   CH 2 CH 3     —C(═O)—CH 3         397   Same as above   CH 2 CH 3     —CH 2 —Ph       398   Same as above   CH 2 CH 3     —C(═O)—Ph       399   Same as above   CH 2 CH 3     —C(═O)—O—CH 2 —Ph       400   Same as above   CH 2 CH 3     —C(═O)—C(═O)—Ph       401   Same as above   CH 2 Ph   —CH 3         402   Same as above   CH 2 Ph   —CH 2 CH 3         403   Same as above   CH 2 Ph   —C(═O)—CH 3         404   Same as above   CH 2 Ph   —CH 2 —Ph       405   Same as above   CH 2 Ph   —C(═O)—Ph       406   Same as above   CH 2 Ph   —C(═O)—O—CH 2 —Ph       407   Same as above   CH 2 Ph   —C(═O)—C(═O)—Ph                    
Compounds 408-519 have the formula: 
                          
with the individual variables defined in the table below.
 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                 Cmpd # 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 R 1   
                 —(G) x —D 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 408 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 —CH 3   
               
               
                 409 
                 Same as above 
                 H 
                 —CH 2 CH 3   
               
               
                 410 
                 Same as above 
                 H 
                 —C(═O)—CH 3   
               
               
                 411 
                 Same as above 
                 H 
                 —CH 2 —Ph 
               
               
                 412 
                 Same as above 
                 H 
                 —C(═O)—Ph 
               
               
                 413 
                 Same as above 
                 H 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 414 
                 Same as above 
                 H 
                 —C(═O)—C(═O)—Ph 
               
               
                 415 
                 Same as above 
                 CH 3   
                 —CH 3   
               
               
                 416 
                 Same as above 
                 CH 3   
                 —CH 2 CH 3   
               
               
                 417 
                 Same as above 
                 CH 3   
                 —C(═O)—CH 3   
               
               
                 418 
                 Same as above 
                 CH 3   
                 —CH 2 —Ph 
               
               
                 419 
                 Same as above 
                 CH 3   
                 —C(═O)—Ph 
               
               
                 420 
                 Same as above 
                 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 421 
                 Same as above 
                 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 422 
                 Same as above 
                 CH 2 CH 3   
                 —CH 3   
               
               
                 423 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 CH 3   
               
               
                 424 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—CH 3   
               
               
                 425 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 —Ph 
               
               
                 426 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—Ph 
               
               
                 427 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 428 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 429 
                 Same as above 
                 CH 2 Ph 
                 —CH 3   
               
               
                 430 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 CH 3   
               
               
                 431 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—CH 3   
               
               
                 432 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 —Ph 
               
               
                 433 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—Ph 
               
               
                 434 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 435 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—C(═O)—Ph 
               
               
                 436 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 —CH 3   
               
               
                 437 
                 Same as above 
                 H 
                 —CH 2 CH 3   
               
               
                 438 
                 Same as above 
                 H 
                 —C(═O)—CH 3   
               
               
                 439 
                 Same as above 
                 H 
                 —CH 2 —Ph 
               
               
                 440 
                 Same as above 
                 H 
                 —C(═O)—Ph 
               
               
                 441 
                 Same as above 
                 H 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 442 
                 Same as above 
                 H 
                 —C(═O)—C(═O)—Ph 
               
               
                 443 
                 Same as above 
                 CH 3   
                 —CH 3   
               
               
                 444 
                 Same as above 
                 CH 3   
                 —CH 2 CH 3   
               
               
                 445 
                 Same as above 
                 CH 3   
                 —C(═O)—CH 3   
               
               
                 446 
                 Same as above 
                 CH 3   
                 —CH 2 —Ph 
               
               
                 447 
                 Same as above 
                 CH 3   
                 —C(═O)—Ph 
               
               
                 448 
                 Same as above 
                 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 449 
                 Same as above 
                 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 450 
                 Same as above 
                 CH 2 CH 3   
                 —CH 3   
               
               
                 451 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 CH 3   
               
               
                 452 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—CH 3   
               
               
                 453 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 —Ph 
               
               
                 454 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—Ph 
               
               
                 455 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 456 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 457 
                 Same as above 
                 CH 2 Ph 
                 —CH 3   
               
               
                 458 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 CH 3   
               
               
                 459 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—CH 3   
               
               
                 460 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 —Ph 
               
               
                 461 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—Ph 
               
               
                 462 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 463 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—C(═O)—Ph 
               
               
                 464 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 —CH 3   
               
               
                 465 
                 Same as above 
                 H 
                 —CH 2 CH 3   
               
               
                 466 
                 Same as above 
                 H 
                 —C(═O)—CH 3   
               
               
                 467 
                 Same as above 
                 H 
                 —CH 2 —Ph 
               
               
                 468 
                 Same as above 
                 H 
                 —C(═O)—Ph 
               
               
                 469 
                 Same as above 
                 H 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 470 
                 Same as above 
                 H 
                 —C(═O)—C(═O)—Ph 
               
               
                 471 
                 Same as above 
                 CH 3   
                 —CH 3   
               
               
                 472 
                 Same as above 
                 CH 3   
                 —CH 2 CH 3   
               
               
                 473 
                 Same as above 
                 CH 3   
                 —C(═O)—CH 3   
               
               
                 474 
                 Same as above 
                 CH 3   
                 —CH 2 —Ph 
               
               
                 475 
                 Same as above 
                 CH 3   
                 —C(═O)—Ph 
               
               
                 476 
                 Same as above 
                 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 477 
                 Same as above 
                 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 478 
                 Same as above 
                 CH 2 CH 3   
                 —CH 3   
               
               
                 479 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 CH 3   
               
               
                 480 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—CH 3   
               
               
                 481 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 —Ph 
               
               
                 482 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—Ph 
               
               
                 483 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 484 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 485 
                 Same as above 
                 CH 2 Ph 
                 —CH 3   
               
               
                 486 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 CH 3   
               
               
                 487 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—CH 3   
               
               
                 488 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 —Ph 
               
               
                 489 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—Ph 
               
               
                 490 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 491 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—C(═O)—Ph 
               
               
                 492 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 H 
                 —CH 3   
               
               
                 493 
                 Same as above 
                 H 
                 —CH 2 CH 3   
               
               
                 494 
                 Same as above 
                 H 
                 —C(═O)—CH 3   
               
               
                 495 
                 Same as above 
                 H 
                 —CH 2 —Ph 
               
               
                 496 
                 Same as above 
                 H 
                 —C(═O)—Ph 
               
               
                 497 
                 Same as above 
                 H 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 498 
                 Same as above 
                 H 
                 —C(═O)—C(═O)—Ph 
               
               
                 499 
                 Same as above 
                 CH 3   
                 —CH 3   
               
               
                 500 
                 Same as above 
                 CH 3   
                 —CH 2 CH 3   
               
               
                 501 
                 Same as above 
                 CH 3   
                 —C(═O)—CH 3   
               
               
                 502 
                 Same as above 
                 CH 3   
                 —CH 2 —Ph 
               
               
                 503 
                 Same as above 
                 CH 3   
                 —C(═O)—Ph 
               
               
                 504 
                 Same as above 
                 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 505 
                 Same as above 
                 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 506 
                 Same as above 
                 CH 2 CH 3   
                 —CH 3   
               
               
                 507 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 CH 3   
               
               
                 508 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—CH 3   
               
               
                 509 
                 Same as above 
                 CH 2 CH 3   
                 —CH 2 —Ph 
               
               
                 510 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—Ph 
               
               
                 511 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—O—CH 2 —Ph 
               
               
                 512 
                 Same as above 
                 CH 2 CH 3   
                 —C(═O)—C(═O)—Ph 
               
               
                 513 
                 Same as above 
                 CH 2 Ph 
                 —CH 3   
               
               
                 514 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 CH 3   
               
               
                 515 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—CH 3   
               
               
                 516 
                 Same as above 
                 CH 2 Ph 
                 —CH 2 —Ph 
               
               
                 517 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—Ph 
               
               
                 518 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 519 
                 Same as above 
                 CH 2 Ph 
                 —C(═O)—C(═O)—Ph 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 3 
     Compounds 520-561 
     Compounds 520-561 are synthesized via the method set forth in Scheme 3, above. 
     Compounds 520-540 have the formula: 
                        
 
with the individual variables defined in the table below.
 
                                                   Cmpd #                                 —(G) x —D                                520                                 —CH 3         521   Same as above   —CH 2 CH 3         522   Same as above   —C(═O)—CH 3         523   Same as above   —CH 2 —Ph       524   Same as above   —C(═O)—Ph       525   Same as above   —C(═O)—O—CH 2 —Ph       526   Same as above   —C(═O)—C(═O)—Ph       527                                 —CH 3         528   Same as above   —CH 2 CH 3         529   Same as above   —C(═O)—CH 3         530   Same as above   —CH 2 —Ph       531   Same as above   —C(═O)—Ph       532   Same as above   —C(═O)—O—CH 2 —Ph       533   Same as above   —C(═O)—C(═O)—Ph       534                                 —CH 3         535   Same as above   —CH 2 CH 3         536   Same as above   —C(═O)—CH 3         537   Same as above   —CH 2 —Ph       538   Same as above   —C(═O)—Ph       539   Same as above   —C(═O)—O—CH 2 —Ph       540   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 541-561 have the formula: 
                          
with the individual variables defined in the table below.
 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                 Cmpd # 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —(G) x —D 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 541 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 542 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 543 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 544 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 545 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 546 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 547 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 548 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 549 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 550 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 551 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 552 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 553 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 554 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 555 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 556 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 557 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 558 
                 Same as above 
                 —CH 2 —Ph 
               
               
                 559 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 560 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 561 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 4 
     Compounds 562-771 
     Compounds 562-771 are synthesized via the method set forth in Scheme 4 or Scheme 6, above. 
     Compounds 562-596 have the formula: 
                        
 
with the individual variables defined in the table below.
 
                                                   Cmpd #   A   —(G) x —D                                562                                 —CH 3         563   Same as above   —CH 2 CH 3         564   Same as above   —C(═O)—CH 3         565   Same as above   —CH 2 —Ph       566   Same as above   —C(═O)—Ph       567   Same as above   —C(═O)—O—CH 2 —Ph       568   Same as above   —C(═O)—C(═O)—Ph       569                                 —CH 3         570   Same as above   —CH 2 CH 3         571   Same as above   —C(═O)—CH 3         572   Same as above   —CH 2 —Ph       573   Same as above   —C(═O)—Ph       574   Same as above   —C(═O)—O—CH 2 —Ph       575   Same as above   —C(═O)—C(═O)—Ph       576                                 —CH 3         577   Same as above   —CH 2 CH 3         578   Same as above   —C(═O)—CH 3         579   Same as above   —CH 2 —Ph       580   Same as above   —C(═O)—Ph       581   Same as above   —C(═O)—O—CH 2 —Ph       582   Same as above   —C(═O)—C(═O)—Ph       583                                 —CH 3         584   Same as above   —CH 2 CH 3         585   Same as above   —C(═O)—CH 3         586   Same as above   —CH 2 —Ph       587   Same as above   —C(═O)—Ph       588   Same as above   —C(═O)—O—CH 2 —Ph       589   Same as above   —C(═O)—C(═O)—Ph       590                                 —CH 3         591   Same as above   —CH 2 CH 3         592   Same as above   —C(═O)—CH 3         593   Same as above   —CH 2 —Ph       594   Same as above   —C(═O)—Ph       595   Same as above   —C(═O)—O—CH 2 —Ph       596   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 597-631 have the formula: 
                          
with the individual variables defined in the table below.
 
                                                   Cmpd #   A   —(G) x —D                                597                                 —CH 3         598   Same as above   —CH 2 CH 3         599   Same as above   —C(═O)—CH 3         600   Same as above   —CH 2 —Ph       601   Same as above   —C(═O)—Ph       602   Same as above   —C(═O)—O—CH 2 —Ph       603   Same as above   —C(═O)—C(═O)—Ph       604                                 —CH 3         605   Same as above   —CH 2 CH 3         606   Same as above   —C(═O)—CH 3         607   Same as above   —CH 2 —Ph       608   Same as above   —C(═O)—Ph       609   Same as above   —C(═O)—O—CH 2 —Ph       610   Same as above   —C(═O)—C(═O)—Ph       611                                 —CH 3         612   Same as above   —CH 2 CH 3         613   Same as above   —C(═O)—CH 3         614   Same as above   —CH 2 —Ph       615   Same as above   —C(═O)—Ph       616   Same as above   —C(═O)—O—CH 2 —Ph       617   Same as above   —C(═O)—C(═O)—Ph       618                                 —CH 3         619   Same as above   —CH 2 CH 3         620   Same as above   —C(═O)—CH 3         621   Same as above   —CH 2 —Ph       622   Same as above   —C(═O)—Ph       623   Same as above   —C(═O)—O—CH 2 —Ph       624   Same as above   —C(═O)—C(═O)—Ph       625                                 —CH 3         626   Same as above   —CH 2 CH 3         627   Same as above   —C(═O)—CH 3         628   Same as above   —CH 2 —Ph       629   Same as above   —C(═O)—Ph       630   Same as above   —C(═O)—O—CH 2 —Ph       631   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 632-666 have the formula: 
                          
with the individual variables defined in the table below.
 
                                     Cmpd #   A   —(G) x —D                   632                                 —CH 3         633   Same as above   —CH 2 CH 3         634   Same as above   —C(═O)—CH 3         635   Same as above   —CH 2— Ph       636   Same as above   —C(═O)—Ph       637   Same as above   —C(═O)—O—CH 2 —Ph       638   Same as above   —C(═O)—C(═O)—Ph       639                                 —CH 3         640   Same as above   —CH 2 CH 3         641   Same as above   —C(═O)—CH 3         642   Same as above   —CH 2— Ph       643   Same as above   —C(═O)—Ph       644   Same as above   —C(═O)—O—CH 2 —Ph       645   Same as above   —C(═O)—C(═O)—Ph       646                                 —CH 3         647   Same as above   —CH 2 CH 3         648   Same as above   —C(═O)—CH 3         649   Same as above   —CH 2— Ph       650   Same as above   —C(═O)—Ph       651   Same as above   —C(═O)—O—CH 2 —Ph       652   Same as above   —C(═O)—C(═O)—Ph       653                                 —CH 3         654   Same as above   —CH 2 CH 3         655   Same as above   —C(═O)—CH 3         656   Same as above   —CH 2— Ph       657   Same as above   —C(═O)—Ph       658   Same as above   —C(═O)—O—CH 2 —Ph       659   Same as above   —C(═O)—C(═O)—Ph       660                                 —CH 3         661   Same as above   —CH 2 CH 3         662   Same as above   —C(═O)—CH 3         663   Same as above   —CH 2— Ph       664   Same as above   —C(═O)—Ph       665   Same as above   —C(═O)—O—CH 2 —Ph       666   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 667-701 have the formula: 
                          
with the individual variables defined in the table below.
 
                                     Cmpd #   A   —(G) x —D                   667                                 —CH 3         668   Same as above   —CH 2 CH 3         669   Same as above   —C(═O)—CH 3         670   Same as above   —CH 2— Ph       671   Same as above   —C(═O)—Ph       672   Same as above   —C(═O)—O—CH 2 —Ph       673   Same as above   —C(═O)—C(═O)—Ph       674                                 —CH 3         675   Same as above   —CH 2 CH 3         676   Same as above   —C(═O)—CH 3         677   Same as above   —CH 2— Ph       678   Same as above   —C(═O)—Ph       679   Same as above   —C(═O)—O—CH 2 —Ph       680   Same as above   —C(═O)—C(═O)—Ph       681                                 —CH 3         682   Same as above   —CH 2 CH 3         683   Same as above   —C(═O)—CH 3         684   Same as above   —CH 2— Ph       685   Same as above   —C(═O)—Ph       686   Same as above   —C(═O)—O—CH 2 —Ph       687   Same as above   —C(═O)—C(═O)—Ph       688                                 —CH 3         689   Same as above   —CH 2 CH 3         690   Same as above   —C(═O)—CH 3         691   Same as above   —CH 2— Ph       692   Same as above   —C(═O)—Ph       693   Same as above   —C(═O)—O—CH 2 —Ph       694   Same as above   —C(═O)—C(═O)—Ph       695                                 —CH 3         696   Same as above   —CH 2 CH 3         697   Same as above   —C(═O)—CH 3         698   Same as above   —CH 2— Ph       699   Same as above   —C(═O)—Ph       700   Same as above   —C(═O)—O—CH 2 —Ph       701   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 702-736 have the formula: 
                          
with the individual variables defined in the table below.
 
                                     Cmpd #   A   —(G) x —D                   702                                 —CH 3         703   Same as above   —CH 2 CH 3         704   Same as above   —C(═O)—CH 3         705   Same as above   —CH 2— Ph       706   Same as above   —C(═O)—Ph       707   Same as above   —C(═O)—O—CH 2 —Ph       708   Same as above   —C(═O)—C(═O)—Ph       709                                 —CH 3         710   Same as above   —CH 2 CH 3         711   Same as above   —C(═O)—CH 3         712   Same as above   —CH 2— Ph       713   Same as above   —C(═O)—Ph       714   Same as above   —C(═O)—O—CH 2 —Ph       715   Same as above   —C(═O)—C(═O)—Ph       716                                 —CH 3         717   Same as above   —CH 2 CH 3         718   Same as above   —C(═O)—CH 3         719   Same as above   —CH 2— Ph       720   Same as above   —C(═O)—Ph       721   Same as above   —C(═O)—O—CH 2 —Ph       722   Same as above   —C(═O)—C(═O)—Ph       723                                 —CH 3         724   Same as above   —CH 2 CH 3         725   Same as above   —C(═O)—CH 3         726   Same as above   —CH 2— Ph       727   Same as above   —C(═O)—Ph       728   Same as above   —C(═O)—O—CH 2 —Ph       729   Same as above   —C(═O)—C(═O)—Ph       730                                 —CH 3         731   Same as above   —CH 2 CH 3         732   Same as above   —C(═O)—CH 3         733   Same as above   —CH 2— Ph       734   Same as above   —C(═O)—Ph       735   Same as above   —C(═O)—O—CH 2 —Ph       736   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 737-771 have the formula: 
                          
with the individual variables defined in the table below.
 
     
       
         
               
               
               
             
           
               
                   
               
               
                 Cmpd # 
                 A 
                 —(G) x —D 
               
               
                   
               
             
             
               
                 737 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 738 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 739 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 740 
                 Same as above 
                 —CH 2— Ph 
               
               
                 741 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 742 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 743 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 744 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 745 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 746 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 747 
                 Same as above 
                 —CH 2— Ph 
               
               
                 748 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 749 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 750 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 751 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 752 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 753 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 754 
                 Same as above 
                 —CH 2— Ph 
               
               
                 755 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 756 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 757 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 758 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 759 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 760 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 761 
                 Same as above 
                 —CH 2— Ph 
               
               
                 762 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 763 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 764 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 765 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 766 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 767 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 768 
                 Same as above 
                 —CH 2— Ph 
               
               
                 769 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 770 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 771 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                   
               
             
          
         
       
     
     EXAMPLE 5 
     Compounds 772-967 
     Compounds 772- are synthesized via the method set forth in Scheme 5, above.
 
Compounds 772-820 have the formula: 
                        
 
with the individual variables defined in the table below
 
                                     Cmpd #                                 —(G) x —D                   772                                 —CH 3         773   Same as above   —CH 2 CH 3         774   Same as above   —C(═O)—CH 3         775   Same as above   —CH 2— Ph       776   Same as above   —C(═O)—Ph       777   Same as above   —C(═O)—O—CH 2 —Ph       778   Same as above   —C(═O)—C(═O)—Ph       779                                 —CH 3         780   Same as above   —CH 2 CH 3         781   Same as above   —C(═O)—CH 3         782   Same as above   —CH 2— Ph       783   Same as above   —C(═O)—Ph       784   Same as above   —C(═O)—O—CH 2 —Ph       785   Same as above   —C(═O)—C(═O)—Ph       786                                 —CH 3         787   Same as above   —CH 2 CH 3         788   Same as above   —C(═O)—CH 3         789   Same as above   —CH 2 Ph       790   Same as above   —C(═O)—Ph       791   Same as above   —C(═O)—O—CH 2 —Ph       792   Same as above   —C(═O)—C(═O)—Ph       793                                 —CH 3         794   Same as above   —CH 2 CH 3         795   Same as above   —C(═O)—CH 3         796   Same as above   —CH 2— Ph       797   Same as above   —C(═O)—Ph       798   Same as above   —C(═O)—O—CH 2 —Ph       799   Same as above   —C(═O)—C(═O)—Ph       800                                 —CH 3         801   Same as above   —CH 2 CH 3         802   Same as above   —C(═O)—CH 3         803   Same as above   —CH 2— Ph       804   Same as above   —C(═O)—Ph       805   Same as above   —C(═O)—O—CH 2 —Ph       806   Same as above   —C(═O)—C(═O)—Ph       807                                 —CH 3         808   Same as above   —CH 2 CH 3         809   Same as above   —C(═O)—CH 3         810   Same as above   —CH 2— Ph       811   Same as above   —C(═O)—Ph       812   Same as above   —C(═O)—O—CH 2 —Ph       813   Same as above   —C(═O)—C(═O)—Ph       814                                 —CH 3         815   Same as above   —CH 2 CH 3         816   Same as above   —C(═O)—CH 3         817   Same as above   —CH 2— Ph       818   Same as above   —C(═O)—Ph       819   Same as above   —C(═O)—O—CH 2 —Ph       820   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 821-869 have the formula: 
                          
with the individual variables defined in the table below
 
                                     Cmpd #                                 —(G) x —D                   821                                 —CH 3         822   Same as above   —CH 2 CH 3         823   Same as above   —C(═O)—CH 3         824   Same as above   —CH 2— Ph       825   Same as above   —C(═O)—Ph       826   Same as above   —C(═O)—O—CH 2 —Ph       827   Same as above   —C(═O)—C(═O)—Ph       828                                 —CH 3         829   Same as above   —CH 2 CH 3         830   Same as above   —C(═O)—CH 3         831   Same as above   —CH 2— Ph       832   Same as above   —C(═O)—Ph       833   Same as above   —C(═O)—O—CH 2 —Ph       834   Same as above   —C(═O)—C(═O)—Ph       835                                 —CH 3         836   Same as above   —CH 2 CH 3         837   Same as above   —C(═O)—CH 3         838   Same as above   —CH 2— Ph       839   Same as above   —C(═O)—Ph       840   Same as above   —C(═O)—O—CH 2 —Ph       841   Same as above   —C(═O)—C(═O)—Ph       842                                 —CH 3         843   Same as above   —CH 2 CH 3         844   Same as above   —C(═O)—CH 3         845   Same as above   —CH 2— Ph       846   Same as above   —C(═O)—Ph       847   Same as above   —C(═O)—O—CH 2 —Ph       848   Same as above   —C(═O)—C(═O)—Ph       849                                 —CH 3         850   Same as above   —CH 2 CH 3         851   Same as above   —C(═O)—CH 3         852   Same as above   —CH 2— Ph       853   Same as above   —C(═O)—Ph       854   Same as above   —C(═O)—O—CH 2 —Ph       855   Same as above   —C(═O)—C(═O)—Ph       856                                 —CH 3         857   Same as above   —CH 2 CH 3         858   Same as above   —C(═O)—CH 3         859   Same as above   —CH 2— Ph       860   Same as above   —C(═O)—Ph       861   Same as above   —C(═O)—O—CH 2 —Ph       862   Same as above   —C(═O)—C(═O)—Ph       863                                 —CH 3         864   Same as above   —CH 2 CH 3         865   Same as above   —C(═O)—CH 3         866   Same as above   —CH 2— Ph       867   Same as above   —C(═O)—Ph       868   Same as above   —C(═O)—O—CH 2 —Ph       869   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 870-918 have the formula: 
                          
with the individual variables defined in the table below
 
                                     Cmpd #                                 —(G) x —D                   870                                 —CH 3         871   Same as above   —CH 2 CH 3         872   Same as above   —C(═O)—CH 3         873   Same as above   —CH 2— Ph       874   Same as above   —C(═O)—Ph       875   Same as above   —C(═O)—O—CH 2 —Ph       876   Same as above   —C(═O)—C(═O)—Ph       877                                 —CH 3         878   Same as above   —CH 2 CH 3         879   Same as above   —C(═O)—CH 3         880   Same as above   —CH 2— Ph       881   Same as above   —C(═O)—Ph       882   Same as above   —C(═O)—O—CH 2 —Ph       883   Same as above   —C(═O)—C(═O)—Ph       884                                 —CH 3         885   Same as above   —CH 2 CH 3         886   Same as above   —C(═O)—CH 3         887   Same as above   —CH 2— Ph       888   Same as above   —C(═O)—Ph       889   Same as above   —C(═O)—O—CH 2 —Ph       890   Same as above   —C(═O)—C(═O)—Ph       891                                 —CH 3         892   Same as above   —CH 2 CH 3         893   Same as above   —C(═O)—CH 3         894   Same as above   —CH 2— Ph       895   Same as above   —C(═O)—Ph       896   Same as above   —C(═O)—O—CH 2 —Ph       897   Same as above   —C(═O)—C(═O)—Ph       898                                 —CH 3         899   Same as above   —CH 2 CH 3         900   Same as above   —C(═O)—CH 3         901   Same as above   —CH 2— Ph       902   Same as above   —C(═O)—Ph       903   Same as above   —C(═O)—O—CH 2 —Ph       904   Same as above   —C(═O)—C(═O)—Ph       905                                 —CH 3         906   Same as above   —CH 2 CH 3         907   Same as above   —C(═O)—CH 3         908   Same as above   —CH 2— Ph       909   Same as above   —C(═O)—Ph       910   Same as above   —C(═O)—O—CH 2 —Ph       911   Same as above   —C(═O)—C(═O)—Ph       912                                 —CH 3         913   Same as above   —CH 2 CH 3         914   Same as above   —C(═O)—CH 3         915   Same as above   —CH 2— Ph       916   Same as above   —C(═O)—Ph       917   Same as above   —C(═O)—O—CH 2 —Ph       918   Same as above   —C(═O)—C(═O)—Ph                    
Compounds 919-967 have the formula: 
                          
with the individual variables defined in the table below
 
     
       
         
               
               
               
             
           
               
                   
               
               
                 Cmpd # 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —(G) x —D 
               
               
                   
               
             
             
               
                 919 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 920 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 921 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 922 
                 Same as above 
                 —CH 2— Ph 
               
               
                 923 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 924 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 925 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 926 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 927 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 928 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 929 
                 Same as above 
                 —CH 2— Ph 
               
               
                 930 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 931 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 932 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 933 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 934 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 935 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 936 
                 Same as above 
                 —CH 2— Ph 
               
               
                 937 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 938 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 939 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 940 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 941 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 942 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 943 
                 Same as above 
                 —CH 2— Ph 
               
               
                 944 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 945 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 946 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 947 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 948 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 949 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 950 
                 Same as above 
                 —CH 2— Ph 
               
               
                 951 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 952 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 953 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 954 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 955 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 956 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 957 
                 Same as above 
                 —CH 2— Ph 
               
               
                 958 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 959 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 960 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                 961 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 —CH 3   
               
               
                 962 
                 Same as above 
                 —CH 2 CH 3   
               
               
                 963 
                 Same as above 
                 —C(═O)—CH 3   
               
               
                 964 
                 Same as above 
                 —CH 2— Ph 
               
               
                 965 
                 Same as above 
                 —C(═O)—Ph 
               
               
                 966 
                 Same as above 
                 —C(═O)—O—CH 2 —Ph 
               
               
                 967 
                 Same as above 
                 —C(═O)—C(═O)—Ph 
               
               
                   
               
             
          
         
       
     
     While we have described a number of embodiments of this invention, it is apparent that our basic constructions may be altered to provide other embodiments which utilize the products, processes and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific embodiments which have been presented by way of example.