CA2344376A1 - Bridged heterocyclic derivatives - Google Patents

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r a DEMANDES OU BREVETS VOLUMINEUX

COMPREND PLUS D'UN TOME.
CECt EST LE TOME '/ DE y NOTE: ~ Pour les tomes additionels, veuillez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS

THAN ONE VOLUME
THtS IS VOLUME ~ , OF
NOTE: For additional volumes please contact the Canadian Patent Office - I -BRIDGED HETEROCYCI~IC DERIVATIVES
This application claims the benefit of the filing date of Provisional U.S. Patent Application No. 60/101,077, filed on September 18, 1998, and U.S. Patent Application No. 09/159,105, filed September 23, 1998, the entire contents of which are herein incorporated by reference.
BACKGROUND OF THE INVENTION
Field of Invention This invention relates generally to novel bridged heterocyclic compounds, and their preparation and use for preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases; for treating alopecia and promoting hair growth;
for treating vision disorders and/or improving vision; and for treating memory impairment and/or enhancing memory performance in an animal requiring or benefitting from such treatment, using low molecular weight, small molecule bridged heterocyclic derivative compounds.
Descris~tion of Related Art A. Neuroimmunophilins The peptidyl-prolyl isomerases ("PPIases") are a family of ubiquitous enzymes which catalyze the interconversion of cis and trans amide bond rotamers adjacent to proline residues in peptide substrates. See, for example, Galat, A., Eur. J. Biochem. (1993) 216:689-707 and Kay, J.E., Biochem. J. (1996) 314:361-385. The PPIases have been referred to as "immunophilins" because of their interaction with certain immunosuppressant drugs.
Schreiber, S.L., Science (1991) 251:283-287; Rosen, M.K.
and Schreiber, S.L., Angew. Chem. Intl. Ed. Engi. (1992) 31:389-400.
The PPIase, cyclophilin A, was found to be the

- 2 -intracellular protein target for the potent immunosuppressant drug cyclosporin A. Subsequently, the structurally unrelated macrolide immunosuppressant FK506 was discovered to bind to a different PPIase enzyme which was named FK506-binding protein, or FKBP. Rapamycin, another macrolide drug which is a structural analogue of FK506, also interacts with FKBP.
All three of these drugs bind to their respective immunophilins and inhibit the respective PPIase activities.
However, inhibition of immunophilin enzymatic activity is not the cause of the observed immunosuppressive effects.
Binding of the drugs to the immunophilins results in the formation of "activated complexes", which interact with downstream proteins to inhibit proliferation of T-lymphocytes. Schreiber, supra; Rosen, et al., supra. In the case of FK506, binding to FKBP results in a drug-protein complex which is a potent inhibitor of the calcium-calmodulin-dependent protein phosphatase, calcineurin.
Bierer, B.E., Mattila, P.S., Standaert, R.F., Herzenberg, L.A., Burakoff, S.J., Crabtree, G., Schreiber, S.L., Proc.
Natl. Acad. Sci. USA (1990) 87:9231-9235; Liu, J., Farmer, J.D., Lane, W.S., Friedman, J., Weissman, I., Schreiber, S.L.; Cell (1991) 66:807-815.
Neither FK506 or FKBP alone appreciably inhibits calcineurin's activity. Inhibiting calcineurin blocks the signaling pathway by which the activated T-cell receptor causes transcription of the gene for interleukin-2, inhibiting the immune response. Despite the structural dissimilarity between FK506 and cyclosporin A (and cyclophilin and FKBP), the cyclosporin A-cyclophilin complex also inhibits calcineurin, and thus cyclosporin A
and FK506 have the same mechanism of action.
On the other hand, while rapamycin and FK506 have similar structures and bind to the same immunophilin (FKBP), rapamycin's mechanism of action is different from

3 PCT/US98/25577 that of FK506. The complex of FKBP12 with rapamycin interacts with a protein called FRAP, or RAFT, and in so doing blocks the signal pathway leading from the IL-2 receptor on the surface of T-cells to promotion of entry into the cell cycle in the nucleus. Sabatini, D.M., Erdjument-Bromage, H., Lui, M.; Tempst, P., Snyder, S.H., Cell (1994) 78:35-43; Brown, E.J., Albers, M.W., Shin, T.B., Ichikawa, K., Keith, C.T., Lane, W.S., Schreiber, S.L. Nature (1994) 369:75-758; Brown, E.J., Beal, P.A., Keith, C.T., Chen, J., Shin, T.B., Schreiber, S.L., Nature (1995) 377:441-446.
Thus, all three drugs produce the same effect --suppression of T-cell proliferation -- but do so by inhibiting distinct signal transduction pathways. The introduction of cyclosporin("CsA") marked a breakthrough in organ transplantation, and the drug became a major pharmaceutical product. The subsequent discovery of rapamycin ("Rapamycin") and FK506 further fueled interest in the cellular basis of the actions of these drugs. The discovery of the interaction of the immunophilins with CsA, FK506 and Rapamycin led to research on the mechanistic basis of immunophilin-mediated immunosuppression.
B. Immunophilins and the Nervous System Because the initial interest in the immunophilins was largely driven by their role in the mechanism of action of the immunosuppressant drugs, most of the original studies of these proteins and their actions focused on the tissues of the immune system. In 1992, it was reported that levels of FKBP12 in the brain were 30 to 50 times higher than in the immune tissues. Steiner, J.P., Dawson, T.M., Fotuhi, M., Glatt, C.E., Snowman, A.M., Cohen, N., Snyder, S.H., Nature (1992) 358:584-587. This finding suggested a role for the immunophilins in the functioning of the nervous system. Both FKBP and cyclophilin were widely distributed in the brain and were found almost. exclusively within

- 4 -neurons. The distribution of the immunophilins in the brain closely resembled that of calcineurin, suggesting a potential neurological link. Steiner, J.P., Dawson, T.M., Fotuhi, M., Glatt, C.E., Snowman, A.M., Cohen, N., Snyder, S.H., Nature (1992) 358:584-587; Dawson, T.M., Steiner, J.P., Lyons, W.E., Fotuhi, M., Blue, M., Snyder, S.H., Neuroscience (1994) 62:569-580.
Subsequent work demonstrated that the phosphorylation levels of several known calcineurin substrates were altered in the presence of FK506. Steiner, J.P., Dawson, T.M., Fotuhi, M., Glatt, C.E., Snowman, A.M., Cohen, N., Snyder, S.H., Nature (1992) 358:584-587. One of the proteins affected by FK506 treatment, GAP-93, mediates neuronal process elongation. Lyons, W.E., Steiner, J.P., Snyder, S.H., Dawson, T.M., J. Neurosci. (1995) 15:2985-2994. This research revealed that FKBP12 and GAP-43 were upregulated in damaged facial or sciatic nerves in rats. Also, FKBP12 was found in very high levels in the growth cones of neonatal neurons. FK506 was tested to determine whether or not it might have an effect an nerve growth or regeneration. In cell culture experiments with PC12 cells or sensory neurons from dorsal root ganglia, FK506 promoted process (neurite) extension with subnanomolar potency.
Lyons, W.E., George, E.B., Dawson, T.M., Steiner, J.P., Snyder, S.H., Proc. Natl. Acad. Sci. USA (1994) 91:3191-3195. Gold et al. demonstrated that FK506 functioned as a neurotrophic agent .in vivo. In rats with crushed sciatic nerves, FK506 accelerated nerve regeneration and functional recovery. Gold, B.G., Storm-Dickerson, T., Austin, D.R., Restorative Neurol. Neurosci., (1994) 6:287; Gold, B.G., Katoh, K., Storm-Dickerson, T.J, Neurosci. (I995) 15:7509-7516. See, also, Snyder, S.H., Sabatini, D.M., Nature Medicine (1995) 1:32-37 (regeneration of lesioned facial nerves in rats augmented

- 5 -by FK506).
Besides FK506, rapamycin and cyclosporin also produced potent neurotrophic effects in vitro in PC12 cells and chick sensory neurons. Steiner, J.P., Connolly, M.A., Valentine, H.L., Hamilton, G.S., Dawson, T.M., Hester, L., Snyder, S.H., Nature Medicine (1997) 3:421-428. As noted above, the mechanism for immunosuppression by rapamycin is different than that of FK506 or cyclosporin. The observation that rapamycin exerted neurotrophic effects similar to FK506 and cyclosporin suggested that the nerve regenerative effects of the compounds are mediated by a different mechanism than that by which they suppress T-cell proliferation.
Analogues of FK506, rapamycin, and cyclosporin which bind to their respective immunophilins, but are devoid of immunosuppressive activity, are known in the art. Thus, the FK506 analogue L-685,818 binds to FKBP but does not interact with calcineurin, and is therefore nonimmunosuppressive. Dumont, F.J., Staruch, M.J., Koprak, S.L., J. Exp. Med. (1992) 176:751-760.
Similarly, 6-methyl-alanyl cyclosporin A (6-[Me]-ala-CsA) binds to cyclophilin but likewise lacks the ability to inhibit calcineurin. The rapamycin analogue WAY-124,466 binds FKBP but does not interact with RAFT, and is likewise nonimmunosuppressive. Ocain, T.D., Longhi, D., Steffan, R.J., Caccese, R.G., Sehgal, S.N., Biochem. Biophys. Res.
Commun. (1993) 192:1340-1346; Sigal, N.H., Dumont, F., burette, P., Siekierka, J.J., Peterson, L., Rich, D., J.
Exp. Med. (1991) 173:619-628. These nonimmunosuppressive compounds were shown to be potent neurotrophic agents in vitro, and one compound, L-685,818, was as effective as FK506 in promoting morphological and functional recovery following sciatic nerve crush in rats. Steiner, J.P., Connolly, M.A., Valentine, H.L., Hamilton, G.S., Dawson, T.M., Hester, L., Snyder, S.H., Nature Medicine (1997)

- 6 -3:421-428. These results demonstrated that the neurotrophic properties of the immunosuppressant drugs could be functionally dissected from their immune system effects.
Published work by researchers studying the mechanism of action of FK506 and similar drugs had shown that the minimal FKBP-binding domain of FK506 (as formulated by Holt et al., BioMed. Chem. Lett. (1994) 4:315-320) possessed good affinity for FKBP. Hamilton et al. proposed that the neurotrophic effects of FK506 resided within the immunophilin binding domain, and synthesized a series of compounds which were shown to be highly effective in promoting neurite outgrowth from sensory neurons, often at picomolar concentrations. Hamilton, G.S., Huang, W., Connolly, M.A., Ross, D.T., Guo, H., Valentine, H.L., Suzdak, P.D., Steiner, J.P.; BioMed. Chem. Lett. (1997).
These compounds were shown to be effective in animal models of neurodegenerative disease.
C. FKBP12 Inhibitors/Liaands A number of researchers in the early 1990s explored the mechanism of immunosuppression by FK506, cyclosporin and rapamycin, and sought to design second-generation immunosuppressant agents that lacked the toxic side effects of the original drugs. A pivotal compound, 506BD (for "FK506 binding domain"--see Bierer, B.E., Somers, P.K., Wandless, T-J., Burakoff, S.J., Schreiber, S.L., Science (1990) 250:556-559), retained the portion of FK506 which binds FKBP12 in an intact form, while the portion of the macrocyclic ring of FK506 which extends beyond FKBP12 in the drug-protein complex was significantly altered. The finding that 506BD was a high-affinity ligand for, and inhibitor of, FK506, but did not suppress T-cell proliferation was the first demonstration that the immunosuppressant effects of FK506 were not simply caused by rotamase activity inhibition.

WO 00/16603 PCT/US9$/25577 In addition to various macrocyclic analogues of FK506 and rapamycin, simplified compounds which represent the excised FKBP binding domain of these drugs were synthesized and evaluated. Non-macrocyclic compounds with the FKBP-binding domain of FK506 excised possess lower affinity for FKBP12 than the parent compounds. Such structures still possess nanomolar affinity for the protein. See, e.g., Hamilton, G.S., Steiner, J.P., Curr. Pharm. Design (1997) 3:405-428; Teague, S.J., Stocks, M.J., BioMed.
Chem. Lett., (1993) 3:1947-1950; Teague, S.J., Cooper, M.E., Donald, D.K., Furber, M., BioMed. Chem. Lett. (1994) 4:1581-1584.
Holt et al. published several studies of simple pipecolate FKBP12 inhibitors which possessed excellent affinity for FKBP12. In initial studies, replacement of the pyranose ring of FK506 mimetics demonstrated that simple alkyl groups such as cyclohexyl and dimethylpentyl worked well in this regard. Holt et al., BioMed. Chem.
Lett. (1994) 4:315-320. Simple compounds possessed good affinity for FKBP12 (Ki values of 250 and 25 nM, respectively). These structures demonstrated that these simple mimics of the binding domain of FK506 bound to the immunophilin in a manner nearly identical to that of the corresponding portion of FK506. Holt, D.A., Luengo, J.I., Yamashita, D.S., Oh, H.J., Konialian, A.L., Yen, H.K., Rozamus, L.W., Brandt, M., Bossard, M.J., Levy, M.A., Eggleston, D.S., Liang, J., Schultz, L.W.; Stout, T.J.;
Clardy, I., J. Am. Chem. Soc. (1993) 115:9925-9938.
Armistead et al. also described several pipecolate FKBP12 inhibitors. X-ray structures of the complexes of these molecules with FKBP also demonstrated that the binding modes of these simple structures were related to that of FK506. Armistead, D.M., Badia, M.C., Deininger, D.D., Duffy, J.P., Saunders, J.O., Tung, R.D., Thomson, J.A.; DeCenzo, M.T.; Futer, 0., Livingston, D.J., Murcko, _ $ _ M.A., Yamashita, M.M., Navia, M.A., Acta Cryst. (1995) D51:522-528.
As expected from the noted effector-domain model, FKBP12 ligands lacking an effector element were inactive as immunosuppressant agents, failing to suppress lymphocyte proliferation both in vitro and in vivo.
D. Neuroprotective/Neuroregenerative Effects of FKBP12 Ligands Steiner et al., U.S. Patent No. 5,696,135 (issued December 9, 1997) describe the neurotrophic actions of a large number of compounds such as those described above.
Cultured chick sensory neurons were used as an in vitro assay to measure the ability of compounds to promote neurite outgrowth (fiber extension) i.n neurons. Compounds were also tested for their ability to bind to FKBP12 and inhibit its enzymatic (rotamase) activity. As the data demonstrate, many of these compounds were found to be , extremely potent nerve growth agents, promoting fiber extension from cultured neurons with half-maximal effects seen in some cases at picomolar concentrations. The effects of these simple FKBP12 ligands on nervous tissue are comparable to, or in some cases more potent than, FK506 itself.
Some of the compounds were also shown to promote regrowth of damaged peripheral nerves in vivo. Steiner, J.P., Connolly, M.A., Valentine, H.L., Hamilton, G.S., Dawson, T.M., Hester, L., Snyder, S.H., Nature Medicine (1997) 3:421-428. In whole-animal experiments in which the sciatic nerves of rats were crushed with forceps and animals treated with these compounds subcutaneously, there was found significant regeneration of damaged nerves relative to control animals, resulting in both more axons in drug-treated animals and axons with a greater degree of myelination. Lesioning of the animals treated only with vehicle caused a significant decrease in axon number (500 decrease compared to controls) and degree of myelination (90% decrease compared to controls). Treatment with the FKBP12 ligands resulted in reduction in the decrease of axon number (25o and 5o reduction, respectively, compared to controls) and in the reduction of myelination levels (65% and 50~ decrease compared to controls). Similar results were subsequently reported by Gold et al. Gold, B.G., Zeleney-Pooley, M., Wang, M.S., Chaturvedi, P.;
Armistead, D.M., Exp. Neurobiol. (1997) 147:269-278.
ZO Several of these compounds were shown to promote recovery of lesioned central dopami.nergic neurons in an animal model of Parkinson's Disease. Hamilton, G.S., Huang, W., Connolly, M.A., Ross, D.T., Guo, H., Valentine, H.L., Suzdak, P.D., Steiner, J.P., BioMed. Chem. Lett.
(1997). N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (~~MPTP") is a neurotoxin which selectively destroys dopaminergic neurons. Gerlach, M., Riederer, P., Przuntek, H., Youdim, M.B., Eur. J. Pharmacol. (1991) 208:273-286.
The nigral-striatal dopaminergic pathway in the brain is responsible for controlling motor movements.
Parkinson's Disease is a serious neurodegenerative disorder resulting from degeneration of this motor pathway.
Lesioning of the nigral-striatal pathway in animals with MPTP has been utilized as an animal model of Parkinson's Disease. In mice treated with MPTP and vehicle, a substantial loss of 60-700 of functional dopaminergic terminals was observed as compared to non-lesioned animals.
Lesioned animals receiving FKBP12 ligands concurrently with MPTP showed a striking recovery of TH-stained striatal dopaminergic terminals, as compared with controls, suggesting that FKBP12 ligands may possess potent neuroprotective and neuro-regenerative effects on both peripheral as well as central neurons.
Other compounds which have an affinity for FKBP12 may also possess neurotrophic activities similar to those described above. For example, one skilled in the art is referred to the following patents and patent applications for their teaching of neurotrophic compounds which are lacking immunosuppressive activity:
Hamilton et al., U.S. Patent No. 5,614,547 (March 25, 1997);
Steiner et al., U.S. Patent No. 5,696,135 (Dec.
9, 1997 ) ;
Hamilton et al., U.S. Patent No. 5,721,256 (Feb.
24, 1998);
Hamilton et al., U.S. Patent No. 5,786,378 (July 28, 1998);
Hamilton et al., U.S. Patent No. 5,795,908 (Aug.
18, 1998);
Steiner et al., U.S. Patent No. 5,798,355 (August 25, 1998);
Steiner et al., U.S. Patent No. 5,801,197 (Sept.
1, 1998); and Li et al., U.S. Patent No. 5,801,187 (Sept. 1, 1998) These molecules are effective ligands for, and inhibitors of, FKBP12 and are also potent neurotrophic agents in vitro, promoting neurite outgrowth from cultured sensory neurons at nanomolar or subnanolar dosages.
Additionally, as noted, compounds which possess immunosuppressive activity, for example, FK506, CsA and Rapamycin, among others, also may possess a significant level of neurotrophic activity. Thus, to the extent that such compounds additionally may possess activities, including neurotrophic activities, such compounds are intended to be included within the term "sensorineurotrophic compound" as used herein. The following publications provide disclosures of compounds which presumably possess immunosuppressive activities, as well as possibly other activities, and are likewise intended to be included within the term "sensorineurotrophic compound" as used herein:
Armistead et al., U.S. Patent No. 5,192,773 (March 9, 1993);
Armistead et al., U.S. Patent No. 5,330,993 (July 19, 1994);
Armistead et al., U.S. Patent No. 5,516,797 (May 14, 1996);
Armistead et al., U.S. Patent No. 5,620,971 (Apr. 15, 1997);
Armistead et al., U.S. Patent No. 5,622,970 (Apr. 22, 1997);
Armistead et al., U.S. Patent No. 5,665,774 (Sept. 9, 1997); and Zelle et al., U.S. Patent No. 5,780,484 (July 14, 1998) .
The neuroregenerative and neuroprotective effects of FKBP12 ligands are not limited to dopaminergic neurons in the central nervous system. In rats treated with para-chloro-amphetamine ("PCA"), an agent which destroys neurons which release serotonin as a neurotransmitter, treatment with an FKBP ligand was reported to exert a protective effect. Steiner, J.P., Hamilton, G.S., Ross, D.T., Valentine, H.L., Guo, H., Connolly, M.A., Liang, S., Ramsey, C., Li, J.H., Huang, W., Howorth, P.; Soni, R., Fuller, M., Sauer, H., Nowotnick, A., Suzdak, P.D., Proc.
Natl. Acad. Sci. USA (1997) 94:2019-2024. In rats lesioned with PCA, cortical density of serotonin fibers was reduced 90o relative to controls. Animals receiving the ligand showed a greater serotonin innervation in the cortex-serotonergic innervation in the somatosensory cortex was increased more than two-fold relative to lesioned, non-drug treated animals.
Similarly, such ligands have been shown to induce sprouting of residual cholinergic axons following partial transection of the fimbria fornix in rats. Guo, H., Spicer, D.M., Howorth, P., Hamilton, G.S., Suzdak, P.D, Ross, D.T., Soc. Neurosci. Abstr. (1997) 677.12. The transection produced a 75-80o deafferentiation of the hippocampus. Subcutaneous administration of the FBKP12 ligand produced a four-fold sprouting of spared residual processes in the CA1, CA3 and dentate gyrus regions of the hippocampus, resulting in significant recovery of cholinergic innervation in all three regions as quantitated by choline acetyltransferase (ChAT) density.
Taken together, the data in the noted references indicate that certain ligands for FKBP 12, preferably those which are non-immunosuppressive, comprise a class of potent active neurotrophic compounds which have been referred to as "neuroimmunophilins" or "neuroimmunophilin ligands" with potential for therapeutic utility in the treatment or prevention of neurodegenerative diseases. Thus, in the context of the present invention, a sensorineurotrophic compound is meant to encompass those compounds which have been designated as neuroimmunophilins and which also may have, but are not required to have, binding affinity for an FKBP. The ultimate mechanism of action and whether or not such compounds also possess other activity such as, for example, immunosuppressive activity, is not determinative of whether the compound is neurotrophic, promotes hair growth, regenerates vision, or improves memory for purposes of the invention, as long as the compound in question possesses the desired effect on nerve cells, hair follicles, eye tissues, or brain cells.
Until the present invention, none of the prior work disclosed the use of the disclosed compounds in the treatment or prevention of neurological disorders, alopecia, vision disorders, memory impairment, and associated diseases. As described in more detail below, the present invention is directed to such uses. To better understand the invention, the following discussion on preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases, and for treating memory impairment and/or enhancing memory performance; for treating alopecia and promoting hair growth; and for treating vision disorders and/or improving vision; is provided:
1. Preventing And/or Treating Neurological Disorders It has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite outgrowth in PC12 cells and sensory nervous, namely dorsal root ganglion cells (DRGs). Lyons et al., supra. In whole animal experiments, FK506 has been shown to stimulate nerve regeneration following facial nerve injury and results in functional recovery in animals with sciatic nerve lesions.
Several neurotrophic factors effecting specific neuronal populations in the central nervous system have been identified. For example, it has been hypothesized that Alzheimer' s disease results from a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat Alzheimer's patients with exogenous nerve growth factor or other neurotrophic proteins such as brain derived nerve factor (BDNF), filial derived nerve factor, ciliary neurotrophic factor, and neurotropin-3 to increase the survival of degenerating neuronal populations.
Clinical application of these proteins in various neurological disease states is hampered by difficulties in the delivery and bioavailability of large proteins to nervous system targets. By contrast, immunosuppressant drugs with neurotrophic activity are relatively small and display excellent bioavailability and specificity.
However, when administered chronically, immunosuppressants exhibit a number of potentially serious side effects including nephrotoxicity, such as impairment of glomerular filtration and irreversible interstitial fibrosis (Kopp et al., 1991, J. Am. Soc. Nephrol. 1:162); neurological deficits, such as involuntary tremors, or non-specific cerebral angina such as non-localized headaches (De Groen et al., 1987, N. Engl. J. Med. 31'7:861); and vascular hypertension with complications resulting therefrom (Kahan et al., 1989 N. Engl. J. Med. 321: 1725).
Accordingly, there is a need for small-molecule compounds which are useful for neurotrophic effects and for treating neurodegenerative disorders.
2. Treating Alopecia and Promotina Hair Growth Hair loss occurs in a variety of situations. These situations include male pattern alopecia, alopecia senilis, alopecia areata, diseases accompanied by basic skin lesions or tumors, and systematic disorders such as nutritional disorders and internal secretion disorders. The mechanisms causing hair loss are very complicated, but in some instances can be attributed to aging, genetic disposition, the activation of male hormones, the loss of blood supply to hair follicles, and scalp abnormalities.
The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against graft rejection after organ transplantation. It has been reported that topical, but not oral, application of FK506 (Yamamoto et al., J. Invest. Dermatol., 1994, 102, 160-164;
Jiang et al., J. Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in a dose-dependent manner.
One form of hair loss, alopecia areata, is known to be associated with autoimmune activities; hence, topically administered immunomodulatory compounds are expected to demonstrate efficacy for treating that type of hair loss.
The hair growth stimulating effects of FK506 have been the subject of an international patent filing covering FK506 and structures related thereto for hair growth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al. discloses the use of relatively large tricyclic compounds, known for their immunosuppressive effects, as hair revitalizing agents.
The hair growth and revitalization effects of FK506 and related agents are disclosed in many U.S. patents (Goulet et al., U.S. Patent No. 5,258,389; Luly et al., U.S. Patent No. 5,457,111;~Goulet et al., U.S. Patent No.
5, 532, 248; Goulet et al. , U. S. Patent No. 5, 189, 042; and Ok et al., U.S. Patent No. 5,208,241; Rupprecht et al., U.S.
Patent No. 5,284,840; Organ et al., U.S. Patent No.
5,284,877). These patents claim FK506 related compounds.
Although they do not claim methods of hair revitalization, they disclose the known use of FK50Fi for effecting hair growth. Similar to FK506 (and the claimed variations in the Honbo et al. patent), the compounds claimed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds for use in autoimmune related diseases, for which FK506's efficacy is well known.
Other U.S. patents disclose the use of cyclosporin and related compounds for hair revitalization (Hauer et al., U.S. Patent No. 5,342,625; Eberle, U.S. Patent No.
5,284,826; Hewitt et al., U.S. Patent No. 4,996,193).
These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin and related immunosuppressive compounds for hair growth.
However, immunosuppressive compounds by definition suppress the immune system and also exhibit other toxic side effects. Accordingly, there is a need for non immunosuppressant, small molecule compounds which are useful as hair revitalizing compounds.
Hamilton and Steiner disclose in U.S. Patent No.
5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects . Unexpectedly, it has been discovered that these non-immunosuppressant compounds promote hair growth with an efficacy similar to FK506. Yet their novel small molecule structure and non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.
3. Treating Vision Disorders And/or Improving Vision The visual system is composed of the eyes, ocular adnexa and the visual pathways. Dysfunction of the visual system may lead to permanent or temporary visual impairment, i.e, a deviation from normal in one or more functions of the eye. Visual impairment manifests itself in various ways and includes a broad range of visual dysfunctions and disturbances. Without limitation, these dysfunctions and disturbances include partial or total loss of vision, the need for correction of visual acuity for objects near and far, loss of visual field, impaired ocular motility without diplopia (double vision), impaired or skewed color perception, limited adaptation to light and dark, diminished accommodation, metamorphopsic distortion, impaired binocular vision, paresis of accommodation, iridoplegia, entropion, ectropion, epiphora, lagophthalmos, and scarring. See Physicians' Desk Reference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988). The visual system may be adversely affected by various ophthalmologic disorders, diseases, injuries, and complications, including, without limitation, genetic disorders; disorders associated with aging or degenerative diseases; disorders correlating to physical injury to the eye, head, or other parts of the body resulting from external forces; disorders resulting from environmental factors; disorders resulting from a broad range of diseases; and combinations of any of the above.
The visual system is a complex system composed of numerous components. Visual impairment can involve the entire visual system, any one component, or any combination of components, depending upon the precise nature of the circumstances. The eye is composed of a lens, which is suspended in the zonules of Zinn and is focused by the ciliary body. The ciliary body also secretes aqueous humor, which fills the posterior chamber, passes through the pupil into the anterior chamber, then drains primarily via the canal of Schlemm. The iris regulates the quantity of light entering the eye by adjusting the size of its central opening, the pupil. A visual image is focused onto the retina, the fovea centralis being the retinal area of sharpest visual acuity. The conjunctiva is the mucus membrane which lines the eyelids and the eyeball, and ends abruptly at the limbus conjunctivae, the edge of the conjunctiva overlapping the cornea. The cornea is the clear, transparent anterior portion of the fibrous coat of the eye; it is important in light refraction and is covered with an epithelium that differs in many respects from the conjunctival epithelium.
The retina is the innermost, light sensitive portion of the eye, containing two types of photoreceptors, cones, which are responsible for color vision in brighter light, and rods, which are essential for vision in dim light but do not perceive colors. After light passes through the cornea, lens system, and the vitreous humor, it enters the retina from the inside; that is, it passes through the ganglion cells and nerve fibers, the inner and outer plexiform layers, the inner and outer nuclear layers, and the internal and external limiting membranes before it finally reaches the layer of photoreceptors located near the outside of the retina, just inside the outermost pigment epithelium layer. The cells of the pigment epithelium layer act as an anatomical barrier to liquids and substances located outside of the eye, forming the WO 00/16603 fCT/US98/25577 "blood-retina" barrier, and provide nourishment, oxygen, a source of functionally useful substances like vitamin A, and phagocytosis of decomposition products to photoreceptor cells. There is no anatomical connection between the pigment epithelium and the photoreceptor layer, permitting separation of the layers in some pathological situations.
When rods or cones are excited by light, signals are transmitted through successive neurons in the retina itself, into the optic nerve fibers, and ultimately to the cerebral cortex. Both rods and cones contain molecules that decompose on exposure to light and, in the process, excite the nerve fibers leading from the eye. The molecule in rods is rhodopsin. The three light-sensitive molecules in cones, collectively called iodopsin, have compositions only slightly different from that of rhodopsin and are maximally excited by red, blue, or green light, respectively.
Neither rods nor cones generate action potentials.
Rather, the light-induced membrane hyperpolarization generated in the outer, photosensitive segment of a rod or cone cell is transmitted from the outer segment through the inner segment to the synaptic body by direct conduction of the electrical voltage itself, a process called electrotonic conduction. At the synaptic body, the membrane potential controls the release of an unknown transmitter molecule. In low light, rod and cone cell membranes are depolarized and the rate of transmitter release is greatest. Light-induced hyperpolarization causes a marked decrease in the release of transmitter molecules.
The transmitters released by rod and cone cells induce signals in the bipolar neurons and horizontal cells. The signals in both these cells are also transmitted by electrotonic conduction and not by action potential.
The rod bipolar neurons connect with as many as 50 rod cells, while the dwarf and diffuse bipolar cells connect with one or several cone cells. A depolarizing bipolar cell is stimulated when its connecting rods or cones are exposed to light. The release of transmitter molecules inhibits the depolarizing bipolar cell. Therefore, in the dark, when the rods and cones are secreting large quantities of transmitter molecules, the depolarizing bipolar cells are inhibited. In the light, the decrease in release of transmitter molecules from the rods and cones reduces the inhibition of the bipolar cell, allowing it to become excited. In this manner, both positive and negative signals can be transmitted through different bipolar cells from the rods and cones to the amacrine and ganglion cells .
As their name suggests, horizontal cells project horizontally in the retina, where they may synapse with rods, cones, other horizontal cells, or a combination of cells types. The function of horizontal cells is unclear, although some mechanism in the convergence of photoreceptor signaling has been postulated.
All types of bipolar cells connect with ganglion cells, which are of two primary types. A-type ganglion cells predominately connect with rod bipolar cells, while B-type ganglion cells predominately connect with dwarf and diffuse bipolar cells. It appears that A-type ganglion cells are sensitive to contrast, light intensity, and perception of movement, while B-type ganglion cells appear more concerned with color vision and visual acuity.
Like horizontal cells, the Amacrine cells horizontally synapse with several to many other cells, in this case bipolar cells, ganglion cells, and other Amacrine cells.
The function of Amacrine cells is also unclear.
The axons of ganglion cells carry signals into the nerve fiber layer of the eye, where the axons converge into fibers which further converge at the optic disc, where they exit the eye as the optic nerve. The ganglion cells transmit their signals through the optic nerve fibers to the brain in the form of action potentials. These cells, even when unstimulated, transmit continuous nerve impulses at an average, baseline rate of about 5 per second. The visual signal is superimposed onto this baseline level of ganglion cell stimulation. It can be either an excitatory signal, with the number of impulses increasing above the baseline rate, or an inhibitory signal, with the number of nerve impulses decreasing below the baseline rate.
As part of the central nervous system, the eye is in some ways an extension of the brain; as such, it has a limited capacity for regeneration. This limited regeneration capacity further complicates the challenging task of improving vision, resolving dysfunction of the visual system, and/or treating or preventing ophthalmologic disorders. Many disorders of the eye, such as retinal photic injury, retinal ischemia-induced eye injury, age-related macular degeneration, free radical-induced eye diseases, as well as numerous other disorders, are considered to be entirely untreatable. Other ophthalmologic disorders, e.g., disorders causing permanent visual impairment, are corrected only by the use of ophthalmic devices and/or surgery, with varying degrees of success.
The immunosuppressant drugs FK506, rapamycin, and cyclosporin are well known as potent T-cell specific immunosuppressants, and are effective against autoimmunity, transplant or graft rejection, inflammation, allergic responses, other autoimmune or immune-mediated diseases, and infectious diseases. It has been disclosed that application of Cyclosporin, FK-506, Rapamycin, Buspirone, Spiperone, and/or their derivatives are effective in treating some ophthalmologic disorders of these types.
Several ophthalmologic disorders or vision problems are known to be associated with autoimmune and immunologically-mediated activities; hence, immunomodulatory compounds are expected to demonstrate efficacy for treating those types of ophthalmologic disorders or vision problems.
The effects of FK506, Rapamycin, and related agents in the treatment of ophthalmologic diseases are disclosed in several U.S. patents (Goulet et al., U.S. Patent No.
5,532,248; Mochizuki et al., U.S. Patent No. 5,514,686;
Luly et al., U.S. Patent No. 5,457,111; Russo et al., U.S.
Patent No. 5, 441, 937; Kulkarni, U. S. Patent No. 5, 387, 589;
Asakura et al., U.S. Patent No. 5,368,865; Goulet et al., U.S. Patent No. 5,258,389; Armistead et al., U.S. Patent No. 5, 192, 773; Goulet et al. , U. S. Patent No. 5, 189, 042;
and Fehr, U.S. Patent No. 5,011,844). These patents claim FK506 or Rapamycin related compounds and disclose the known use of FK506 or Rapamycin related compounds in the treatment of ophthalmologic disorders in association with the known immunosuppressive effects of FK506 and Rapamycin.
The compounds disclosed in these patents are relatively large. Further, the cited patents relate to immunomodulatory compounds limited to treating autoimmunity ar related diseases, or immunologically-mediated diseases, for which the efficacy of FK506 and Rapamycin is well known.
Other U.S. patents disclose the use of cyclosporin, Spiperone, Buspirone, their derivatives, and other immunosuppressive compounds for use in the treatment of ophthalmologic diseases (Sharpe et al., U.S. Patent No.
5,703,088; Sharpe et al., U.S. Patent No. 5,693,645;
Sullivan, U.S. Patent No. 5,688,765; Sullivan, U.S. Patent No. 5, 620, 921; Sharpe et al. , U. S. Patent No. 5, 574, 041;
Eberle, U.S. Patent No. 5,284,826; Sharpe et al., U.S.
Patent No. 5,244,902; Chiou et al., U.S. Patent Nos.
5,198,454 and 5,194,434; and Kaswan, U.S. Patent No.
4,839,342). These patents also relate to compounds useful for treating autoimmune diseases and cite the known use of cyclosporin, Spiperone, Buspirone, their derivatives, and other immunosuppressive compounds in treating ocular inflammation and other immunologically-mediated ophthalmologic diseases.
The immunosuppressive compounds disclosed in the prior art suppress the immune system, by definition, and also exhibit other toxic side effects. Accordingly, there is a need for non-immunosuppressant, small molecule compounds, and compositions and methods for use of such compounds, that are useful in improving vision; preventing, treating, and/or repairing visual impairment or dysfunction of the visual system; and preventing, treating, and/or resolving ophthalmologic disorders.
There are also a number of patents on non immunosuppressive compounds disclosing methods of use for permitting or promoting wound healing (whether from injury or surgery); controlling intraocular pressure (often resulting from glaucoma); controlling neurodegenerative eye disorders, including damage or injury to retinal neurons, damage or injury to retinal ganglion cells, and macular degeneration; stimulating neurite outgrowth; preventing or reducing oxidative damage caused by free radicals; and treating impaired oxygen and nutrient supply, as well as impaired waste product removal, resulting from low blood flow. These non-immunosuppressive substances fall into one of two general categories: naturally occurring molecules, such as proteins, glycoproteins, peptides, hormones, and growth factors; and synthetic molecules.
Within the group of naturally occurring non immunosuppressive molecules, several hormones, growth factors, and signaling molecules have been patented for use as supplements to naturally occurring quantities of such molecules, as well as for targeting of specific cells where the particular molecule does not naturally occur in a mature individual. These patents generally claim methods of use for reducing or preventing the symptoms of ocular disease, or arresting or reversing vision loss.
Specifically, Louis et al., U.S. Patent Nos. 5,736,516 and 5,641,749, disclose the use of a glial cell line derived neurotrophic factor (GDNF) to stop or reverse the degeneration of retinal neurons (i.e. photoreceptors) and retinal ganglion cells caused by glaucoma, or other degenerative or traumatic retinal diseases or injuries.
0'Brien, et al., U.S. Patent Nos. 5,714,459 and 5,700,909, disclose the use of a glycoprotein, Saposin, and its derivatives for stimulating neurite outgrowth and increasing myelination. To stop or reverse degeneration of retinal neurons, LaVail et al., U.S. Patent No. 5,667,968, discloses the use of a variety of neurotrophic proteins, including brain-derived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-3 or neurotrophin-4, acidic or basic fibroblast growth factors, interleukin, tumor necrosis factor-a, insulin-like growth factor-2 and other growth factors. Wong et al., U.S. Patent No.
5,632,984, discloses the use of interferons, especially interferon a-2a, for treating the symptoms of macular degeneration by reducing hemorrhage and limiting neovascularization. Finally, Wallace et al., U.S. Patent No. 5,441,937, discloses the use of a lung-derived neurotrophic factor (NTF) to maintain the functionality of ciliary ganglion and parasympathetic neuron cells.
A key characteristic of factors derived from specific cell lines is their localization to specific cell lines or tissues; systemic treatment with these molecules would run a substantial risk of unintended, and potentially dangerous, effects in cell lines where the genes encoding these molecules are inactive. Similarly, hormones and growth factors often activate a large number of genes in many cell lines; again, non-localized application of these molecules would run a substantial risk of provoking an inappropriate, and potentially dangerous, response.
Within the category of synthetic molecules, most of the patented compounds are immunosuppressive and disclose uses in treating inflammatory, autoimmune, and allergic responses, as discussed above. A few others are non-immunosuppressive and claim the ability to treat cellular degeneration, and in some cases promote cellular regeneration, most often in the context of their antioxidant properties.
Specifically, Tso et al., U.S. Patent No. 5,527,533, discloses the use of astaxanthin, a carotenoid antioxidant, for preventing or reducing photoreceptor damage resulting from the presence of free radicals. Similarly, Babcock et al., U.S. Patent No. 5,252,319, discloses the use of antioxidant aminosteroids for treating eye disease and injury, by increasing resistance to oxidative damage.
Freeman, U.S. Patent No. 5,468,752, discloses the use of the antiviral phosphonylmethoxyalkylcytosines to reduce abnormally increased intraocular pressure.
Hamilton and Steiner disclose in U.S. Patent No.
5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressant compounds promote improvements in vision and resolve ophthalmologic disorders. Yet their novel small molecule structure and non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art.
Further, these compounds may be differentiated from the non-immunosuppressive compounds used to treat vision disorders by their novel small molecule structure and their lack of general, systemic effects. Naturally occurring hormones, growth factors, cytokines, and signaling molecules are generally multifunctional and activate many WO 00/16603 PCT/US9$/25577 genes in diverse cell lines. The present compounds do not, thus avoiding the unexpected, and potentially dangerous, side effects of systemic use. Similarly, the present compounds also avoid the potential unexpected side effects of introducing cell line-specific molecules into other cell lines were they do not naturally occur.
Regardless of the cause, there exists a need to prevent or treat neurological disorders, including physically damaged nerves and neurodegenerative diseases;
for treat alopecia and promote hair growth; treat vision disorders and/or improve vision; and treat memory impairment and/or enhance memory performance. The present invention provides such methods.
BRIEF SU~RY OF THE INVENTION
The present invention is based on the discovery that bridged heterocyclic derivative compounds may be useful for treating neurodegenerative disorders, for treating alopecia and related hair loss disorders, for treating vision disorders and/or improving vision, and for treating memory impairment and/or enhancing memory performance.
Accordingly, a novel class of heterocyclic derivative compounds, containing one or more bridged moieties in the central structure and/or its substituents, is provided.
These compounds stimulate neuranal regeneration and outgrowth and as such are useful for treating neurological disorders and neurodegenerative diseases. These compounds also promote hair growth and as such are useful for treating hair loss disorders. These compounds also are useful for treating vision disorders, improving vision, treating memory impairment, or enhancing memory performance. A preferred feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity and/or are non-immunosuppressive.
In particular, the present invention provides methods for treating neurodegenerative disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention. By way of example, the disorder to be treated may be associated with injury or cellular degeneration.
Thus, a therapeutically effective amount of a compound of the invention may be administered to promote the protection, survival, or regeneration of certain nerve, hair, eye, or brain cells.
The present invention further relates to a pharmaceutical composition which comprises:
(i) an effective amount of a bridged heterocyclic derivative compound, containing one or more bridged moieties in the central structure or its substituents, for treating neurodegenerative disorders, for treating alopecia and related hair loss disorders, for treating vision disorders and/or improving vision, or for treating memory impairment and/or enhancing memory performance in an animal; and (ii) a pharmaceutically acceptable carrier.
It is further contemplated that a compound of the invention may be administered separately, sequentially, or simultaneously in combination or conjunction with an effective amount of a second therapeutic agent or any other agent useful for the treatment of the disorders enumerated herein.
The invention also provides for the use of compound ( s ) of the invention in the manufacture of a medicament or pharmaceutical composition for the treatment of the disorders enumerated herein. Such pharmaceutical compositions include, as appropriate to the specific disorder, topical, systemic, oral or injectable formulations. It is further contemplated that the WO 00/16603 PCT/US98/2557~

compounds) of the invention may be administered with an effective amount of a second therapeutic agent for the treatment of the enumerated disorders. A variety of pharmaceutical formulations and different delivery techniques are described in further detail below.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a photograph of mice treated with a vehicle after six weeks. FIG. 1 shows that less than 3% of the shaved area is covered with new hair growth when the vehicle (control) is administered.
FIG. 2 is a photograph of mice treated with 10 uM of a related compound, GPI 1046, after six weeks. FIG. 2 shows the remarkable effects of N-heterocyclic derivative non-immunosuppressive neuroimmunophilin FKBP ligands wherein 900 of the shaved area is covered with new hair growth.
FIG. 3 is a photograph of mice treated with 30 uM of GPI 1046 after six weeks. FIG. 3 shows the remarkable ability of N-heterocyclic derivative non-immunosuppressive neuroimmunophilin FKBP ligands to achieve, essentially, complete hair regrowth in the shaved area.
FIG. 4 is a bar graph depicting the relative hair growth indices of mice treated with a vehicle, FK506, and various related N-heterocyclic derivative non immunosuppressive neuroimmunophilin FKBP ligands 14 days after treatment with each identified compound. FIG. 4 demonstrates the remarkable early hair growth promoted by N-heterocyclic derivative non-immunosuppressive neuroimmunophilin FKBP ligands.
FIGS. 5A, 5B, and SC show that GPI 1046 protects retinal ganglion cells against degeneration following retinal ischemia.
FIG. 6 shows that GPI 1046 prevents degeneration of optic nerve axons and myelin following retinal ischemia.

FIG. 7 shows that GPI 1046 provides moderate protection against retinal ganglion cell death after optic nerve transection.
FIG. 8 shows that GPI 1046 treatment duration significantly affects the process of optic nerve axonal degeneration after transection.
FIG. 9 shows that GPI 1046 treatment produces a greater effect on optic nerve axons than ganglion cell bodies.
FIG. 10 shows that GPI 1046 treatment for 28 days after optic nerve transection prevents myelin degeneration in the proximal stump.
FIG. 11 shows that FKBP-12 immunohistochemistry labels oligodendroglia (large dark cells with fibrous processes), the cells which produce myelin, located between the fascicles of optic nerve fibers, and also some optic nerve axons.
FIG. 12 shows GPI 1046 treatment for 28 days after optic nerve transection prevents myelin degeneration in the distal stump.
FIG. 13 shows that 28 day treatment with GPI 1046 treatment beginning 8 weeks after onset of streptozotocin induced diabetes decreases the extent of neovascularization in the inner and outer retina and protects neurons in the inner nuclear layer (INL) and ganglion cell layer (GCL) from degeneration.
DETAILED DESCRIPTION OF THE INVENTION
Definitions ~~Alkenyl" means a branched or unbranched unsaturated hydrocarbon chain comprising a designated number of carbon atoms. For example, C2-C6 straight or branched alkenyl hydrocarbon chain contains 2 to 6 carbon atoms having at least one double bond, and includes but is not limited to substituents such as ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, and the like. It is also contemplated as within the scope of the present invention that "alkenyl" may also refer to an unsaturated hydrocarbon chain wherein any of the carbon atoms of said alkenyl are optionally replaced with 0, NH, S, or 502. For example, carbon 2 of 4-pentene can be replaced with O to form (2-propene)oxymethyl.
"Alkoxy" means the group -OR wherein R is alkyl as herein defined. Preferably, R is a branched or unbranched saturated hydrocarbon chain containing 1 to 6 carbon atoms .
"Alkyl" means a branched or unbranched saturated hydrocarbon chain comprising a designated number of carbon atoms. For example, C1-C6 straight or branched alkyl hydrocarbon chain contains 1 to 6 carbon atoms, and includes but is not limited to substituents such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. It is also contemplated as within the scope of the present invention that "alkyl" may also refer to a hydrocarbon chain wherein any of the carbon atoms of said alkyl are optionally replaced with O, NH, S, or S02. For example, carbon 2 of n-pentyl can be replaced with O to form propyloxymethyl.
It should be kept in mind that, throughout this application, "R" or "R~", where n is a number, is used to designate various alkyl (and other) substituents. As indicated throughout, these R groups are independently selected. Thus, for example, the fact that R1 may be a branched alkyl in one context does not require that R1 be the same branched alkyl, and does not. prohibit that R1 be, for example, a straight chain alkenyl, in another context in the same molecule . It is intended that all "R~" are selected independently of all other "R~", whether or not the term "independently selected" is used or is inadvertently omitted.
"Alopecia" refers to deficient hair growth and partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness), toxic alopecia, alopecia senilis, alopecia areata, alopecia pelada and trichotillomania. Alopecia results when the pilar cycle is disturbed. The most frequent phenomenon is a shortening of the hair growth or anagen phase due to cessation of cell proliferation. This results in an early onset of the catagen phase, and consequently a large number of hairs in the telogen phase during which the follicles are detached from the dermal papillae, and the hairs fall out. Alopecia has a number of etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental stresses, hormonal problems, and secondary effects of drugs.
"Aralkyl" refers to alkyl or alkylene (alkenyl) chain which is substituted with aryl, heteroaryl, carbocycle or heterocycle, or alternatively one or more aryl, heteroaryl, carbocycle, or heterocycle(s) which is/are substituted with alkyl or alkenyl, i.e. 'Alkyl/alkylene which is substituted with Ar' or 'Ar which is substituted with alkyl/alkylene'.
"Aryl" or "aromatic" refers to an aromatic carbocyclic or heterocyclic group having a single ring, for example a phenyl ring; multiple rings, for example biphenyl; or multiple condensed rings in which at least one ring is aromatic, for example naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl, or phenanthryl, which can be unsubstituted or substituted with one or more other substituents as defined above. The substituents attached to a phenyl ring portion of an aryl moiety in the compounds of the invention may be configured in the ortho-, meta-, or para- orientations orientations, with the para- orientation being preferred.
Examples of typical aryl moieties included in the scope of the present invention may include, but are not limited to, the following:

/ ~ / ~ / ~ \
\ \ \ /
/ ~ / ~ \ \
\ \ / /
/ \ /
/ \ / \
It should be kept in mind that, throughout this application, "Ar" or "Ar"", where n is a number, is used to designate various cyclic (and other) substituents. As indicated throughout, these Ar groups are independently selected. Thus, for example, the fact that Ar2 may be phenyl in one context does not require that Ar2 be phenyl, nor prohibit that Ar2 be, for example, pyridyl, in another context in the same molecule. It i.s intended that all "Arn" are selected independently of all other "Ar~", whether or not the term "independently selected" is used or is inadvertently omitted.
"Bridged ring" or "bridged ring moiety" refers to a carbocyclic or heterocyclic moiety where two or more atoms are shared between two or more ring structures, where any such shared atom is C, N, S, or other heteroatom arranged in a chemically reasonable substitution pattern.
Alternatively, a "bridged" compound also refers to a carbocyclic or heterocyclic ring structure where one atom at any position of a primary ring is bonded to a second atom on the primary ring through either a chemical bond or atoms) other than a bond which do not comprise a part of the primary ring structure. The first and second atom may or may not be adjacent to one another in the primary ring.
Illustrated below are specific nonlimiting examples of bridged ring structures contemplated by the present invention:
N~ _~," N -~," N~ _w,, N
N
N~ ~ N~ ~
N N N
N , N
~/~~III,,,,~~__''~~,, N"'M N"'M N
N
The present invention also contemplates other carbocyclic or heterocyclic bridged ring structures, including bridged rings wherein the bridging atoms are C or heteroatom(s) arranged in chemically reasonable substitution patterns, which are not described herein.
"Carbocycle" or "carbocyclic" refers to an organic cyclic moiety in which the cyclic skeleton is comprised of only carbon atoms, whereas the term "heterocycle" or "heterocyclic" refers to an organic cyclic moiety in which the cyclic skeleton contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur, and which may or may not include carbon atoms. The term "carbocycle" refers to a carbocyclic moiety containing the indicated number of carbon atoms. The term "C3-Cg cycloalkyl", therefore, refers to an organic cyclic substituent in which three to eight carbon atoms form a three, four, five, six, seven, or eight-membered ring, including, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring.
"Carbocyclic" or "heterocyclic" each includes within its scope a single ring system, multiple fused rings (for example, bicyclic, tricyclic, or other similar bridged ring systems or substituents, e.g. adamantyl) or multiple condensed ring systems. One skilled in the art, therefore, will appreciate that in the context of the present invention, a cyclic structure formed by A and B (or J and K) as described herein may comprise bi-, or tri-, or multiple condensed and/or bridged ring systems.
Examples of preferred carbocyclic and heterocyclic moieties include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinalizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and adamantyl.

"Enhancing memory performance" refers to improving or increasing the mental faculty by which to register, retain or recall past experiences, knowledge, ideas, sensations, thoughts or impressions.
"Eye" refers to the anatomical structure responsible for vision in humans and other animals, and encompasses the following anatomical structures, without limitation: lens, vitreous body, ciliary body, posterior chamber, anterior chamber, pupil, cornea, iris, canal of Schlemm, zonules of Zinn, limbus, conjunctiva, choroid, retina, central vessels of the retina, optic nerve, fovea centralis, macula lutea, and sclera.
"GPI 1046" refers to the related N-heterocyclic derivative neuroimmunophilin FKBP ligand 3-(3-pyridyl)-1-propyl (2s)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate of formula N
~O /
I ~II(N

"Halo" means at least one fluoro, chloro, bromo, or iodo moiety.
"Heterocycle" or "heterocyclic", as used herein, refers to a saturated, unsaturated or aromatic carbocyclic group having a single ring, multiple fused rings(for example, bicyclic, tricyclic, or other similar bridged ring systems or substituents), or multiple condensed rings, and having at least one hetero atom such as nitrogen, oxygen or sulfur within at least one of the rings. This term also includes "Heteroaryl" which refers to a heterocycle in which at least one ring is aromatic. Any heterocyclic or heteroaryl group can be unsubstituted or optionally substituted with one or more groups, as defined above.

Further, bi- or tricyclic heteroaryl moieties may comprise at least one ring which is either completely or partially saturated.
In the context of the invention, useful carbo- and heterocyclic rings include, for example and without limitation, phenyl, benzyl, naphthyl., indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.
As one skilled in the art will appreciate, such heterocyclic moieties may exist in several isomeric forms, all of which are encompassed by the present invention . For example, a 1,3,5-triazine moiety is isomeric to a 1,2,4-triazine group. Such positional isomers are to be considered within the scope of the present invention.
Likewise, the heterocyclic or heteroaryl groups can be bonded to other moieties in the compounds of the present invention. The points) of attachment to these other moieties is not to be construed as limiting on the scope of the invention. Thus, by way of example, a pyridyl moiety may be bound to other groups through the 2-, 3-, or 4 position of the pyridyl group. All such configurations are to be construed as within the scope of the present invention.

Examples of heterocyclic or heteroaryl moieties included in the scope of the present invention may include, but are not limited to, the following:
C> C> U L=
C~C~C~C~rJ' ,o ~~~c»?o C~ r.~. C~ C~ C~ C
~5 I ~ ~ I
~~ N oc ~
N
,) N ~ S ~O
H
20 I ~ ~ I
~N
O N O
a? ~'~
"Isomers" are different compounds that have the same molecular formula and includes cyclic isomers such as (iso}indole and other isomeric forms of cyclic moieties.
"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. "Diastereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers.
"Non-racemic mixture" is a mixture containing unequal parts of individual enantiomers or stereoisomers.
"Isosteres" are different compounds that have different molecular formulae but exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated by the present invention include -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 ( R3 ) 2, -OR3, -SR3, -NHCOR3, -N ( R3 ) 2, -CON ( R3 ) 2, -CONH ( O ) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN, wherein R3 is hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, Cl-C6-alkoxy, C2-C6-alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl-C1-C6-alkyloxy, cyano, nitro, imino, C1-C6-alkylamino, amino- C1-C6-alkyl, sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, and C02R9 where R9 is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl. In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of preferred carbocyclic and heterocyclic isosteres contemplated by this invention:

N ~ /N N
/ ~~N ~N OH
N
HN
HN~~ HOOC H N-N
H ~ O OH O
~N ~ \
N \NH ~ N NH
NON S ~~ HN

\ O /N ~ N
N / O
NH HN
O O ~ S
~N \N
s OH
N N N
O O I ~ ( /N
O ~ HS H F H
OH

O
S
OH
2 5 ~- NH
.J
O ~OH
O
and -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -30 SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (0) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN, wherein R3 is hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-alkoxy, C2-C6-alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl- C1-C6-alkyloxy, cyano, nitro, imino, C1-C6-alkylamino, amino- C1-C6-alkyl, 35 sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, aryl, heteroaryl, carbocycle, heterocycle, and C02R4 where R4 is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl and where the atoms of said ring structure may be optionally substituted at one or more positions with R1, as defined herein. The present invention contemplates that when chemical substituents are added to a carboxylic isostere then the inventive compound retains the properties of a carboxylic isostere.
The present invention contemplates that when a carboxylic isostere is optionally substituted with one or more moieties selected from R3, as defined herein, then the substitution cannot eliminate the carboxylic acid isosteric properties of the inventive compound. The present invention contemplates that the placement of one or more R3 substituents upon a carbocyclic or heterocyclic carboxylic acid isostere shall not be permitted at one or more atom ( s ) which maintains) or is/are integral to the carboxylic acid isosteric properties of the inventive compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the inventive compound.
Other carboxylic acid isosteres not specifically exemplified or described in this specification are also contemplated by the present invention.
"Memory impairment" refers to a diminished mental registration, retention or recall of past experiences, knowledge, ideas, sensations, thoughts or impressions.
Memory impairment may affect short and long-term information retention, facility with spatial relationships, memory (rehearsal) strategies, and verbal retrieval and production. Common causes of memory impairment are age, severe head trauma, brain anoxia or ischemia, alcoholic-nutritional diseases, and drug intoxications. Examples of memory impairment include, without limitation, benign forgetfulness, amnesia and any disorder in which memory deficiency is present, such as Korsakoff's amnesic psychosis, dementia and learning disorders.
"Neopsic factors" or "neopsics" refers to compounds useful in treating vision loss, preventing vision degeneration, or promoting vision regeneration.
"Neopsis" refers to the process of treating vision loss, preventing vision degeneration, or promoting vision regeneration.
"Neurotrophic" as used herein includes without limitation the ability to stimulate neuronal regeneration or growth, and/or the ability to prevent or treat neurodegeneration.
"Non-immunosuppressive" as used herein refers to the inability of the compounds of the present invention to trigger an immune response when compared to a control such as FK506 or cyclosporin A. Assays for determining immunosuppression are well known to those of ordinary skill in the art. Specific, non-limiting examples of well known assays include PMA and OKT3 wherein mitogens are used to stimulate proliferation of human peripheral blood lymphocytes (PBC) and the compounds are evaluated on their ability to inhibit such proliferation.

"Ophthalmological" refers to anything about or concerning the eye, without limitation, and is used interchangeably with "ocular," "ophthalmic,"
"ophthalmologic," and other such terms, without limitation.
"Pharmaceutically acceptable carrier" as used herein refers to any carrier, diluent, excipient, suspending agent, lubricating agent, adjuvant, vehicle, delivery system, emulsifier, disintegrant, absorbant, preservative, surfactant, colorant, flavorant, or sweetener. For these purposes, the compounds of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneally, intrathecally, intraventricularly, intrasternal and intracranial injection or infusion techniques.
"Pharmaceutically acceptable salt", as used herein, refers to an organic or inorganic salt which is useful in the treatment of a warm-blooded animal in need thereof.
Such salts can be acid or basic addition salts, depending on the nature of the inventive compound to be used.
In the case of an acidic moiety in an inventive compound, a salt may be formed by treatment of the inventive compound with a basic compound, particularly an inorganic base. Preferred inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Preferred organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts. Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
Other suitable base salts, esters, or solvates include magnesium salts; salts with organic bases, such as dicyclohexylamine salts; and N-methyl-D-glucamine. An especially preferred salt is a sodium or potassium salt of an inventive compound.
With respect to basic moieties, a salt is formed by the treatment of the desired inventive compound with an acidic compound, particularly an inorganic acid. Preferred inorganic salts of this type may include, for example, the hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric or the like salts. Preferred organic salts of this type, may include, for example, salts formed with formic, acetic, succinic, citric, lactic, malefic, fumaric, palmitic, cholic, pamoic, mucic, d-glutamic, d-camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, para-toluenesulfonic, sorbic, puric, benzoic, cinnamic and the like organic acids. Other suitable acids are adipate, alginate, aspartate, benzenesulfonate, bisulfate, butyrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycero-phosphate, hemisulfate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. An especially preferred salt of this type is a hydrochloride or sulfate salt of the desired inventive compound. Also, the basic nitrogen-containing groups can be quarternized with such agents as: 1) lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; 2) dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; 3) long chain alkyls such as decyl, lauryl, myristyl and stearyl substituted with one or more halide such as chloride, bromide and iodide; and 4) aralkyl halides like benzyl and phenethyl bromide and others.
Also encompassed in the scope of the present invention are pharmaceutically acceptable esters of a carboxylic acid or hydroxyl containing group, including a metabolically labile ester or a prodrug form of an inventive compound.
A metabolically labile ester is one which may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound. A prodrug form is one which is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydrolytic cleavage. Esters of an inventive compound may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety. Metabolically labile esters, may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, a-methoxyethyl, groups such as a-((C1-C9)alkyloxy)ethyl; for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethyl groups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C1-C3 alkylthiomethyl groups, for example, methylthio-methyl, ethylthiomethyl, isopropylthio-methyl, etc.; acyloxymethyl groups, for example, pivaloyloxy-methyl, a-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; or a-acyloxy-a-substituted methyl groups, for example a-acetoxyethyl.
Further, the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as ethanol, N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms of the compounds of the invention may exist as solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention.
"Pilar cycle" refers to the life cycle of hair follicles, and includes three phases:
(1) the anagen phase, the period of active hair growth which, insofar as scalp hair is concerned, lasts about three to five years;
(2) the catagen phase, the period when growth stops and the follicle atrophies which, insofar as scalp hair is concerned, lasts about one to two weeks; and (3) the telogen phase, the rest period when hair progressively separates and finally falls out which, insofar as scalp hair is concerned, lasts about three to four months.
Normally 80 to 90 percent of the follicles are in the anagen phase, less than 1 percent being in the catagen phase, and the rest being in the telogen phase . In the telogen phase, hair is uniform in diameter with a slightly bulbous, non-pigmented root. By contrast, in the anagen phase, hair has a large colored bulb at its root.
"Preventing neurodegeneration" as used herein includes the ability to inhibit or prevent neurodegeneration in patients newly diagnosed as having a neurodegenerative disease, or at risk of developing a new degenerative disease and for inhibiting or preventing further neurodegeneration in patients who are already suffering from or have symptoms of a neurodegenerative disease when the compounds are given concurrently.
"Preventing vision degeneration" as used herein includes the ability to prevent degeneration of vision in patients newly diagnosed as having a degenerative disease affecting vision, or at risk of developing a new degenerative disease affecting vision, and for preventing further degeneration of vision in patients who are already suffering from or have symptoms of a degenerative disease affecting vision.
"Primary ring structure" refers to a 5-, 6-, or 7 membered ring structure which is depicted in the formula drawings herein, or otherwise referred to by a designation such as "...A and B (or J and K), taken together with the atoms to which they are attached...". Such definition shall apply to only one ring structure in any molecule described in this application, regardless of the number or confirmation of any substituent cyclic structures.
"Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating, or revitalizing the germination of hair.
"Promoting vision regeneration" refers to maintaining, improving, stimulating or accelerating recovery of, or revitalizing one or more components of the visual system in a manner which improves or enhances vision, either in the presence or absence of any ophthalmologic disorder, disease, or injury.
"Treating" or "treatment" as used herein covers any treatment of a disease and/or condition in an animal, particularly a human, and includes:
(i) preventing a disease and/or condition from occurring in a subject which may be predisposed to the disease and/or condition but has not yet been diagnosed as having it;
(ii) inhibiting the disease and/or condition, i.e., arresting its development; or (iii) relieving the disease and/or condition, i.e., causing regression of the disease and/or condition.
"Treating alopecia" refers to:
(i) preventing alopecia in an animal which may be predisposed to alopecia; and/or (ii) inhibiting, retarding or reducing alopecia;
and/or (iii) promoting hair growth; and/or (iv) prolonging the anagen phase of the hair cycle;
and/or (v) converting vellus hair to growth as terminal hair.
Terminal hair is coarse, pigmented, long hair in which the bulb of the hair follicle is seated deep in the dermis.
Vellus hair, on the other hand, is fine, thin, non pigmented short hair in which the hair bulb is located superficially in the dermis. As alopecia progresses, the hairs change from the terminal to the vellus type.
"Vision", as used herein, refers to the ability of humans and other animals to process images, and is used interchangeably with "sight", "seeing", and other such terms, without limitation.
"Vision disorder" refers to any disorder that.affects or involves vision, including without limitation visual impairment, orbital disorders, disorders of the lacrimal apparatus, disorders of the eyelids, disorders of the conjunctiva, disorders of the cornea, cataracts, disorders of the uveal tract, disorders of the optic nerve or visual pathways, free radical induced eye disorders and diseases, immunologically-mediated eye disorders and diseases, eye injuries, and symptoms and complications of eye disease, eye disorder, or eye injury.
"Visual impairment" refers to any dysfunction in vision including without limitation disturbances or diminution in vision (e. g., binocular, central, peripheral, scotopic), visual acuity for objects near and for, visual field, ocular motility, color perception, adaptation to light and dark, accommodation, refraction, and lacrimation.
See Physicians' Desk Reference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988) .
"Warm-blooded animal" includes a mammal, including a member of the human, equine, porcine, bovine, murine, canine or feline species. In the case of a human, the term "warm-blooded animal" may also be referred to as a "patient". Further, as used herein, "a warm blooded animal in need thereof" refers to a warm-blooded animal which is susceptible to a disorder due to genetic or environmental conditions or predispositions. This term also refers to a warm blooded animal which has already suffered some degree of injury or damage because of genetic or environmental conditions to which the animal has been exposed or to which it has been predisposed. Environmental conditions can include treatment with a therapeutic compound, as well as other types of injury or insult.
Further, as used throughout the teaching of the invention, a designation of:
C_W or C'Y
wherein W or Y is H2, or similar designations, is meant to denote that two hydrogen atoms are attached to the noted carbon and that the bonds to each hydrogen are single bonds.
Compounds of the Invention The present invention relates to the surprising discovery that the inventive compounds are neurotrophic, are able to treat alopecia, and are able to treat vision and memory disorders. Accordingly, a novel class of bridged heterocyclic compounds are provided. A preferred feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity.
Methods of the Present Invention Treatinct Neurotrophic Disorders. The present invention relates to the use of any of the compounds described herein in the preparation of a medicament for the treatment of a disease such as peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.
The present invention also relates to the use of carboxylic acid and carboxylic acid isostere compounds for treating the above-mentioned neuropathies, neurological disorders, and neurological damage.
As neurotrophic agents, the compounds of this invention can be periodically administered to a patient undergoing treatment for neurological disorders or for other reasons in which it is desirable to stimulate neuronal regeneration and growth, such as in various peripheral neuropathic and neurological disorders relating to neurodegeneration. The compounds of this invention can also be administered to mammals other than humans for treatment of various mammalian neurological disorders.
The novel compounds of the present invention possess an excellent degree of neurotrophic activity. This activity is useful in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and in the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropath:ies. The neurological disorders that may be treated include but are not limited to: trigeminal neuralgia, glossopharyngeal neuralgia, Bell's Palsy, myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar inherited muscular atrophy, herniated, ruptured or prolapsed invertebrate disk syndromes, cervical spondylosis, plexus disorders, thoracic outlet destruction syndromes, peripheral neuropathic such as those caused by lead, dapsone, ticks, prophyria, or Gullain-Barre syndrome, Alzheimer's disease, and Parkinson's disease.
Treatincr Alopecia and Promoting Hair Growth. The present invention also relates to a method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of an inventive compound. The present invention also relates to using the inventive compounds and compositions in the preparation of a medicament for the treatment of alopecia or promoting hair growth in an animal.
The inventive method is particularly useful for treating male pattern alopecia, alopecia senilis, alopecia areata, alopecia resulting from skin lesions or tumors, alopecia resulting from cancer therapy such as chemotherapy and radiation, and alopecia resulting from systematic disorders such as nutritional disorders and internal secretion disorders.
Treating Vision and Memory Disorders. The present invention provides a method for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance in an animal by administering to a patient a therapeutically effective amount of an inventive compound.
The inventive methods are particularly useful for treating various eye disorders including, but not limited to visual disorders, diseases, injuries, and complications, genetic disorders; disorders associated with aging or degenerative vision diseases; vision disorders correlating to physical injury to the eye, head, or other parts of the body resulting from external forcesa disorders resulting from environmental factors; disorders resulting from a broad range of diseases; and combinations of any of the above.
In particular, the compositions and methods of the present invention are useful for improving vision, or correcting, treating, or preventing visual (ocular) impairment or dysfunction of the visual system, including permanent and temporary visual impairment, without limitation. The present invention is also useful in preventing and treating ophthalmologic diseases and disorders, treating damaged and injured eyes, and preventing and treating diseases, disorders, and injuries which result in vision deficiency, vision loss, or reduced capacity to see or process images, and the symptoms and complications resulting from same. The eye diseases and disorders which may be treated or prevented by the compositions and methods of the present invention are not limited with regard to the cause of said diseases or disorders. Accordingly, said compositions and methods are applicable whether the disease or disorder is caused by genetic or environmental factors, as well as any other influences. The compositions and methods of the present invention are particularly useful for eye problems or vision loss or deficiency associated with all of the following, without limitation: aging, cellular or physiological degeneration, central nervous system or neurological disorder, vascular defects, muscular defects, and exposure to adverse environmental conditions or substances.
The compositions and methods of the present invention are particularly useful in correcting, treating, or improving visual impairment, without limitation. Visual impairment in varying degrees occurs in the presence of a deviation from normal in one or more functions of the eye, including (1) visual acuity for objects at distance and near; (2) visual fields; and (3) ocular motility without diplopia. See Physicians' Desk Reference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988). Vision is imperfect without the coordinated function of all three.
Id.

Said compositions and methods of use are also useful in correcting, treating, or improving other ocular functions including, without limitation, color perception, adaptation to light and dark, accommodation, metamorphopsia, and binocular vision. The compositions and methods of use are particularly useful in treating, correcting, or preventing ocular disturbances including, without limitation, paresis of accommodation, iridoplegia, entropion, ectropion, epiphora, lagophthalmos, scarring, vitreous opacities, non-reactive pupil, light scattering disturbances of the cornea or other media, and permanent deformities of the orbit.
The compositions and methods of use of the present invention are also highly useful in improving vision and treating vision loss. Vision loss ranging from slight loss to absolute loss may be treated or prevented using said compositions and methods of use. Vision may be improved by the treatment of eye disorders, diseases, and injuries using the compositions and methods of the invention.
However, improvements in vision using the compositions and methods of use are not so limited, and may occur in the absence of any such disorder, disease, or injury.
The compositions and methods of the present invention are also useful in the treatment or prevention of the following non-limiting exemplary diseases and disorders, and symptoms and complications resulting therefrom.
Vision disorders include but are not limited to the following:
visual impairment, such as diminished visual acuity for objects near and far, visual fields, and ocular motility;
orbital disorders, such as orbital cellulitis, periorbital cellulitis, cavernous sinus thrombosis, and exophthalmos (proptosis);
disorders of the lacrimal apparatus, such as dacryostenosis, congenital dacryostenosis, and dacryocystitis (acute or chronic);
disorders of the eyelids, such as lid edema, blepharitis, ptosis, Bell's palsy, blepharospasm, hordeolum (stye), external hordeolum, internal hordeolum (meibomian stye), chalazion, entropion (inversion of the eyelid), ectropion (eversion of the eyelid), tumors (benign and malignant), xanthelasma, basil cell carcinoma, squamous cell carcinoma, meibomian gland carcinoma, and melanoma;
disorders of the conjunctiva, such as pinguecula, pterygium, and other neoplasms, acute conjunctivitis, chronic conjunctivitis, adult gonococcal conjunctivitis, neonatal conjunctivitis, trachoma (granular conjunctivitis or Egyptian ophthalmia), inclusion conjunctivitis (inclusion blenorrhea or swimming pool conjunctivitis), neonatal inclusion conjunctivitis, adult inclusion conjunctivitis, vernal keratoconjunctivitis, keratoconjunctivitis sicca (keratitis sicca or dry eye syndrome), episcleritis, scleritis, cicatricial pemphigoid (ocular cicatricial pemphigoid or benign mucous membrane pemphigoid), and subconjunctival hemorrhage;
disorders of the cornea, such as superficial punctate keratitis, corneal ulcer, indolent ulcer, recurrent corneal erosion, corneal epithelial basement membrane dystrophy, corneal endothelial cell dystrophy, herpes simplex keratitis (herpes simplex keratoconjunctivitis), dendritic keratitis, disciform keratitis, ophthalmic herpes zoster, phlyctenular keratoconjunctivitis (phlyctenular or eczematous conjunctivitis), interstitial keratitis (parenchymatous keratitis), peripheral ulcerative keratitis (marginal keratolysis or peripheral rheumatoid ulceration), keratomalacia (xerotic keratitis), xerophthalmia, keratoconus, bullous keratopathy;
cataracts, including developmental or congenital cataracts, juvenile or adult cataracts, nuclear cataract, posterior subcapsular cataracts;
disorders of the uveal tract, such as uveitis (inflammation of the uveal tract or retina), anterior uveitis, intermediate uveitis, posterior uveitis, iritis, cyclitis, choroiditis, ankylosing spondylitis, Reiter's syndrome, pars planitis, toxoplasmosis, cytomegalovirus (CMV), acute retinal necrosis, toxocariasis, birdshot choroidopathy, histoplasmosis (presumed ocular histoplasmosis syndrome), Behcet's syndrome, sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, sarcoidosis, reticulum cell sarcoma, large cell lymphoma, syphilis, tuberculosis, juvenile rheumatoid arthritis, endophthalmitis, and malignant melanoma of the choroid;
disorders of the retina, such as vascular retinopathies (e.g., arteriosclerotic retinopathy and hypertensive retinopathy), central and branch retinal artery occlusion, central and branch retinal vein occlusion, diabetic retinopathy (e. g., proliferative retinopathy and non-proliferative retinopathy), macular degeneration of the aged (age-related macular degeneration or senile macular degeneration), neovascular macular degeneration, retinal detachment, retinitis pigmentosa, retinal photic injury, retinal ischemia-induced eye injury, and glaucoma (e. g., primary glaucoma, chronic open-angle glaucoma, acute or chronic angle-closure, congenital (infantile) glaucoma, secondary glaucoma, and absolute glaucoma);
disorders of the optic nerve or visual pathways, such as papilledema (choked disk), papillitis (optic neuritis), retrobulbar neuritis, ischemic optic neuropathy, toxic amblyopia, optic atrophy, higher visual pathway lesions, disorders of ocular motility (e. g., third cranial nerve palsies, fourth cranial nerve palsies, sixth cranial nerve palsies, internuclear ophthalmoplegia, and gaze palsies);
free radical induced eye disorders and diseases; and immunologically-mediated diseases, such as Graves' ophthalmopathy, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, and sarcoidosis. See The Merck Manual, Sixteenth Edition, 217:2365-2397 (1992) and The Eye Book, Cassel, Billig, and Randall, The Johns Hopkins University Press (1998).
The compositions and methods of the present invention are also useful in the treatment of the following non limiting eye injuries, and symptoms and complications resulting therefrom: conjunctival and corneal foreign body injuries, corneal abrasion, intraocular foreign body injuries, lacerations, lid lacerations, contusions, lid contusions (black eye), trauma to the globe, laceration of the iris, cataract, dislocated lens, glaucoma, vitreous hemorrhage, orbital-floor fractures, retinal hemorrhage or detachment, and rupture of the eyeball, anterior chamber hemorrhage (traumatic hyphema), burns, eyelid burns, chemical burns, chemical burns of the cornea and conjunctiva, and ultraviolet light burns (sunburn). See The Merck Manual, Sixteenth Edition, 217:2364-2365 (1992).
The compositions and methods of the present invention are also useful in treating and/or preventing the following non-limiting exemplary symptoms and complications of eye disease, eye disorder or eye injury: subconjunctival hemorrhages, vitreous hemorrhages, retinal hemorrhages, floaters, retinal detachments, photophobia, ocular pain, scotomas (negative and positive), errors of refraction, emmetropia, ametropia, hyperopia (farsightedness), myopia (nearsightedness), astigmatism, anisometropia, aniseikonia, presbyopia, bleeding, recurrent bleeding, sympathetic ophthalmia, inflammation, swelling, redness of the eye, irritation of the eye, corneal ulceration and scarring, iridocyclitis, perforation of the globe, lid deformities, exophthalmos, impaired mobility of the eye, lid swelling, chemosis, loss of vision, including partial or total blindness, optic neuritis, fever, malaise, thrombophlebitis, cavernous sinus thrombosis, panophthalmitis, infection of the meninges and brain, papilledema, severe cerebral symptoms (headache, decreased level of consciousness, and convulsions), cranial nerve palsies, epiphora (chronic or persistent tearing), copious reflux of mucus or pus, follicular subconjunctival hyperplasia, corneal vascularization, cicatrization of the conjunctiva, cornea, and lids, pannus, hypopyon, lagophthalmos, phlyctenules, rubeosis iridis, bitemporal hemianopia, and homonymous hemianopia. See The Merck Manual, Sixteenth Edition, 217:2362-2363 (1992).
An inventive compound may be administered in combination with an effective amount of one or more factors) useful in treating vision disorder, improving vision, treating memory impairment, or enhancing memory performance.
In a preferred embodiment, the factors) to be combined with an inventive compound is/are selected from the group consisting of immunosuppressants for treating autoimmune, inflammatory, and immunologically-mediated disorders; wound healing agents for treating wounds resulting from injury or surgery; antiglaucomatous medications for treating abnormally elevated intraocular pressure; neurotrophic factors and growth factors for treating neurodegenerative disorders or stimulating neurite outgrowth; compounds effective in limiting or preventing hemorrhage or neovascularization for treating macular degeneration; and antioxidants for treating oxidative damage to eye tissues.
Pharmaceutical Compositions of the Present Invention The present invention relates to a pharmaceutical composition comprising:

(i) an effective amount of a bridged heterocyclic compound; and (ii) a pharmaceutically acceptable carrier.
The general discussion above, relating to the utility and administration of the compounds of the present invention, also applies to the pharmaceutical compositions of the present invention.
Pharmaceutical compositions typically include a therapeutically effective amount of an inventive compound described herein in admixture with one or more pharmaceutically and physiologically acceptable formulation materials. Suitable formulation materials include, but are not limited to, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants. For example, a suitable vehicle may be water for injection, physiological saline solution, or artificial perilymph, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
The primary solvent in a vehicle may be either aqueous or non-aqueous in nature. In addition, the vehicle may contain other pharmaceutically-acceptable excipients for modifying, modulating or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation. Similarly, the vehicle may contain still other pharmaceutically-acceptable excipients for modifying or maintaining the rate of release of the therapeutic product(s), or for promoting the absorption or penetration of the therapeutic products) across the tympanic membrane. Such excipients are those substances usually and customarily employed to formulate dosages for administration in either unit dose or multi-dose form.
Once the therapeutic composition has been formulated, it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready to use form or in a form, e.g., lyophilized, requiring reconstitution prior to administration.
The optimal pharmaceutical formulations will be determined by one skilled in the art depending upon considerations such as the route of administration and desired dosage. See, for example, "Remington's Pharmaceutical Sciences", 18th ed. (1990, Mack Publishing Co., Easton, PA 18042), pp. 1435-1712, the disclosure of which is hereby incorporated by reference. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the present therapeutic agents of the invention.
Other effective administration forms, such as ocular slow-release formulations, inhalant mists, or orally active formulations are also envisioned. For example, in a sustained release formulation, an inventive compound may be bound to or incorporated into particulate preparations of polymeric compounds (such as polylactic acid, palyglycolic acid, etc.) or liposomes. Hylauronic acid may also be used, and this may have the effect of promoting sustained duration in the circulation. Such therapeutic compositions are typically in the form of a pyrogen-free, aqueous solution comprising the inventive compound in a pharmaceutically acceptable vehicle. One preferred vehicle is sterile distilled water.
Certain formulations containing an inventive compound may be administered orally. An inventive compound which is administered in this fashion may be encapsulated and may be formulated with or without those carriers customarily used in the compounding of solid dosage forms. The capsule may be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional excipients may be included to facilitate absorption of the inventive compound. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.
The formulation of topical preparations, including solutions, suspensions, and ointments is well known to those skilled in the art (see, for example, "Remington's Pharmaceutical Sciences", 18th Edition, Chapter 86, pp.
1581-1592, Mack Publishing Company, 1990). Other modes of administration are available, including injections.
Methods and means for producing preparations suitable for such modes of administration are also well known.
In the treatment of ocular or neuronal disease or injury it is also advantageous that a topically applied formulation include an agent to promote the penetration or transport of the therapeutic agent to the appropriate site.
Such agents are known in the art. Yet another preparation may involve the formulation of an inventive compound with an agent, such as injectable microspheres or liposomes, that provides for the slow or sustained release of the molecules which may then be delivered as a depot injection.
Other suitable means for the introduction of an inventive compound include implantable drug delivery devices which contain the inventive compound, or an implant including a tunnel through which the inventive compound can be continuously delivered.
The preparations of the present invention, particularly topical preparations, may include other components, for example acceptable preservatives, tonicity agents, cosolvents, complexing agents, buffering agents or other pH controlling agents, antimicrobials, antioxidants and surfactants, as are well known in the art. Suitable preservatives include, but are not limited to, benzalkonium chloride, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid and the like.
Hydrogen peroxide may also be used as preservative.
Suitable cosolvents include, but are not limited to, glycerin, propylene glycol and polyethylene glycol.
Suitable complexing agents include caffeine, polyvinyl-pyrrolidone, b-cyclodextrin or hydroxypropyl-b-cyclodextrin. The buffers can be conventional buffers such as borate, citrate, phosphate, bicarbonate, or tris-HC1.
Additional formulation components may include materials which prolong the residence of the administered therapeutic agent, particularly to maximize the topical contact and promote absorption of the therapeutic agent.
Suitable materials may include polymers or gel forming materials which increase the viscosity of the preparation.
The suitability of the formulations of the instant invention for controlled release (era., sustained and prolonged delivery) can be determined by various procedures known in the art. Yet another preparation may involve an effective quantity of an inventive compound in admixture with non-toxic treatment acceptable excipients. For example, the inventive compound may be prepared in tablet form. By dissolving the tablets in sterile water, or other appropriate vehicle, treatment solutions can be prepared in unit dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphates or binding agents, such as starch, gelatin, or acacia.
Neurotrophic Disorders. The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of a bridged heterocyclic compound for treating neurodegenerative diseases, neurological disorders, and nerve damage, or promoting nerve growth in an animal;
and (ii) a pharmaceutically acceptable carrier.
As neurotrophic agents, the compounds can be administered with other neurotrophic agents such as neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, insulin growth factor and active truncated derivatives thereof, acidic fibroblast growth factor, basic fibroblast growth factor, platelet-derived growth factors, neurotropin-3 and neurotropin 4/5. The dosage level of other neurotrophic drugs will depend upon the factors previously stated and the neurotrophic effectiveness of the drug combination.
The neurotrophic compounds of this invention can be periodically administered to a patient undergoing treatment for neurological disorders or for other reasons in which it is desirable to stimulate neuronal regeneration and growth, such as in various peripheral neuropathic and neurological disorders relating to neurodegeneration. The compounds of this invention can also be administered to mammals other than humans for treatment of various mammalian neurological disorders.
Alopecia and Hair Growth. The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of a bridged heterocyclic compound for treating alopecia or promoting hair growth in an animal; and (ii) a pharmaceutically acceptable carrier.
An inventive compound may be administered in combination with an effective amount of one or more factors) useful in treating alopecia or promoting hair growth.
Vision and Memory Disorders. The present invention also relates to a pharmaceutical composition comprising:
(i) an effective amount of a bridged heterocyclic compound for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance in an animal; and (ii) a pharmaceutically acceptable carrier.
An inventive compound may be administered in combination with an effective amount of one or more factors) useful in treating vision disorder, improving vision, treating memory impairment, or enhancing memory performance.
Routes of Administration The compounds of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion techniques.
For oral administration, the compounds of the present invention may be provided in any suitable dosage form known in the art. For example, the compositions may be incorporated into tablets, powders, granules, beads, chewable lozenges, capsules, liquids, aqueous suspensions or solutions, or similar dosage forms, using conventional equipment and techniques known in the art. Tablet dosage forms are preferred. Tablets may contain carriers such as lactose and corn starch, and/or lubricating agents such as magnesium stearate. Capsules may contain diluents including lactose and dried corn starch. Aqueous suspensions may contain emulsifying and suspending agents combined with the active ingredient.
When preparing dosage form incorporating the compositions of the invention, the compounds may also be blended with conventional excipients such as binders, including gelatin, pregelatinized starch, and the like;
lubricants, such as hydrogenated vegetable oil, stearic acid, and the like; diluents, such as lactose, mannose, and sucrose; disintegrants, such as carboxymethylcellulose and sodium starch glycolate; suspending agents, such as povidone, polyvinyl alcohol, and the :Like; absorbants, such as silicon dioxide; preservatives, such as methylparaben, propylparaben, and sodium benzoate; surfactants, such as sodium lauryl sulfate, polysorbatE 80, and the like;
colorants such as F.D.& C. dyes and lakes; flavorants; and sweeteners.
The compounds of the present invention may be administered in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally-acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally employed as solvents or suspending mediums. 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, including olive oil and castor oil, especially in their polyoxyethylated versions, are useful in the preparation of injectables.
These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.
The compounds of this invention may also be administered topically, especially when the conditions addressed for treatment involve areas or organs readily accessible by topical application, including neurological disorders of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas.
For topical application to the eye, or ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively for the ophthalmic uses the compounds may be formulated in an ointment such as petrolatum.
For topical application to the skin, the compounds can be formulated in a suitable ointment containing the compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Topical application for the lower intestinal tract an be effected in a rectal suppository formulation (see below) or in a suitable enema formulation.
The compounds of this invention may also be administered rectally in the form of suppositories. These compositions can be prepared by mixing the drug 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.
Compositions and methods of the invention also may utilize controlled release technology. Thus, for example, the inventive compounds may be incorporated into a hydrophobic polymer matrix for controlled release over a period of days. Such controlled release films are well known to the art. Particularly preferred are transdermal delivery systems. Other examples of polymers commonly employed for this purpose that may be used in the present invention include nondegradable ethylene-vinyl acetate copolymer and degradable lactic acid-glycolic acid copolymers which may be used externally or internally.
Certain hydrogels such as poly(hydroxyethylmethacrylate) or poly(vinylalcohol) also may be useful, but for shorter release cycles then the other polymer releases systems, such as those mentioned above.
It is envisioned that the continuous administration or sustained delivery of sensorineurotrophic compound may be advantageous for a given condition. While continuous administration may be accomplished via a mechanical means, such as with an infusion pump, it is contemplated that other modes of continuous or near continuous administration may be practiced. For example, such administration may be by subcutaneous or muscular injections as well as oral pills and ear drops.
Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible particles or beads and depot injections, are also known to those skilled in the art.
To be effective therapeutically as central nervous system targets, the compounds of the present invention should readily penetrate the blood-brain barrier when peripherally administered. Compounds which cannot penetrate the blood-brain barrier can be effectively administered by an intraventricular route or other appropriate delivery system suitable for administration to the brain.
To effectively treat alopecia or promote hair growth, the compounds used in the inventive methods and pharmaceutical compositions must readily affect the targeted areas. For these purposes, the compounds are preferably administered topically to the skin.
For topical application to the skin, the compounds can be formulated into suitable ointments containing the compounds suspended or dissolved in, for example, mixtures with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds can be formulated into suitable lotions or creams containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds can be administered with other hair revitalizing agents. Specific dose levels for the other hair revitalizing agents will depend upon the factors previously stated and the effectiveness of the drug combination. Other routes of administration known in the pharmaceutical art are also contemplated by this invention.
For the treatment of ocular conditions, the sensorineurotrophic compound may be administered orally, systemically, or directly into the eye, especially in those situations where an invasive surgical procedure has already taken place, or by topical application, inserts, injection or implants. For example, slow-releasing implants containing the molecules embedded in a biodegradable polymer matrix can be used to deliver an inventive compound. As noted, an inventive compound may be administered in the eye, or it may be administered topically in connection with one or more agents capable of promoting penetration or transport of the inventive compound across the membranes of the eye. The frequency of dosing will depend on the pharmacokinetic parameters of the inventive compound as formulated, and the route of administration.
The final dosage regimen involved in a method for treating the above-described conditions will be determined by the attending physician, considering various factors which modify the action of drugs, e.g., the age, condition, body weight, sex and diet of the patient, the severity of the condition, time of administration and other clinical factors familiar to one skilled in the art.
Other routes of administration known in the pharmaceutical art are also contemplated by this invention.
DosacL,e dosage levels on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination;
the severity of the particular disease or disorder being treated; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art .
The specific dose may be calculated according to considerations of body weight, body surface area or organ size. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed, especially in light of the dosage information and assays disclosed herein.
Appropriate dosages may be determined using established assays in conjunction with appropriate dose-response data.
One skilled in the art will appreciate that the dosage used in localized formulations of the invention normally will be smaller as compared to that used in a systemic injection or oral administration.
The compounds can be administered with other agents) for preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases; for treating alopecia and promoting hair growth;
for treating vision disorders and/or improving vision; and for treating memory impairment and/or enhancing memory performance. Specific dose levels for such other agents) will depend upon the factors previously stated and the effectiveness of the drug combination.
The compounds described in Formulas I-LXVII, below, possess asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers. The individual stereoisomers may be obtained by using an optically active starting material, by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolving the compounds of Formulas I-LXLVII. It is understood that the compounds of Formulas I-LXVII encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, S-stereoisomers are used in the pharmaceutical compositions and methods of the present invention.
The compounds useful in the invention comprise a variety of structural families. As noted, the primary consideration is that the compounds possess the desired activity described herein. By way of description and not limitation, therefore, the following structural formulae are provided as exemplary of the compounds useful in preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases; in treating alopecia and promoting hair growth;
in treating vision disorders and/or improving vision; and in treating memory impairment and/or enhancing memory performance:
The invention provides a compound of formula I'' or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A is hydrogen, C1 or C2 alkyl, or benzyl and B is C1-C4 straight or branched chain alkyl, benzyl, or cyclohexylmethyl; or, A and B, taken together with the atoms to which they are attached, form a 5-7 membered saturated, unsaturated, or aromatic heterocylic or carbocyclic ring which contains one or more 0, C (R1) 2, S (0) P, N, NR1, or NR5 atoms; or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
V is CH, S, or N;

X is O, CH2 or S;
m is 0 or 1;
G is Y R\
w W , O= i =O , or U ~''W .
R2 R~ R .
R1 is independently hydrogen, C1-C9 straight or branched chain alkyl, or C2-C9 straight or branched chain alkenyl or alkynyl, C3-C9 cycloalkyl, CS-C7 cycloalkenyl, a carboxylic acid or carboxylic acid isostere, N (R4) ~, Arl, Ar4, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Arl, Ar4, or bridged ring moiety, is optionally substituted with one or more substituent(s) independently selected from the group consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6 cycloalkyl wherein said furyl, thienyl, pyridyl, phenyl or cycloalkyl group optionally is substituted with C1-C9 alkoxy, (Arl) ", halo, halo-C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6 thioester, cyano, imino, COOR6 in which R6 is independently Ci-C9 straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy, C1-C6 alkylaryloxy C1-C6 aryloxy, aryl- (C1-C6) -alkyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, C1-C6-alkylthio, sulfhydryl, sulfonyl, amino, (C1-C6~-mono- or di-alkylamino, amino- (C1-C6) -alkyl, aminocarboxy, C3-Ce cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl optionally substituted with (Arl)", C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, C3-CB

cycloalkyl, and Ar2, and, wherein any carbon atom of an alkyl or alkenyl group may optionally replaced with O, NRS, or S (0) P;
Arl or Ar2, independently, is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, C1-CQ alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring contains 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;
or, R1 is independently a moiety of the formula:
i x2 wherein:
R3 is independently C1-C9 straight or branched chain alkyl which is optionally substituted with C3-C$
cycloalkyl or Arl;
X2 is 0 or NR6, wherein R6 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R9 is independently selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, C2-CS straight or branched chain alkenyl substituted with phenyl, and a bridged ring moiety,;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cyc:Loalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-CB
cycloalkyl, CS-C7 cycloalkenyl, (Arl) ~ and hydroxy; or, R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that if R2 is hydrogen, then Y is CH-P, or if Y is oxygen then R2 is P;
P is hydrogen, 0- (C1-CQ straight or branched chain alkyl) , O- (C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, CS-C7 cycloalkenyl substituted with C,-Cq straight or branched chain alkyl or C2-C9 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 al kenyl ) -Ars, or Ars;

U is either 0 or N, provided that:

when U is 0, then R' is a lone pair of electrons and R " is selected from the group consisting of Ar9, C3-C8 cycloalkyl, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-CB cycloalkyl; and when U is N, then R' and R"

are, independently, selected from the group consisting of hydrogen, Ar4, C3-Clo cycloalkyl, a C7-C12 bi- or tri-cyclic carbocycle, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-CB cycloalkyl; or R' and R"

are taken together to form a heterocyclic 5- or 6-membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

W and Y, independently, are 0, S, CH2 or H2;

Z is C (Rl) 2, 0, S, a direct bond or NRl; or, Z-R1 is independently /C C.
J-K-L J K'---L! , or K"
'' D t D' wherein:
C and D are, independently, hydrogen, Ar9, Arl, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-CB

cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, Arl and Ar4; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6 thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano, nitro, imino, C1-C6 alkylamino, amino- (C1-C6) alkyl, sulfhydryl, thio- (C1-C6) alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NRS, or ( SO ) P;

C' and D' are independently hydrogen, ArS, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with CS-C7 cycloalkyl, CS-C7 cycloalkenyl, or Ars, wherein, one or two carbon atoms) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and S02 in chemically reasonable substitution patterns, or T
Q
whe rei n Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
and T is Ars or CS-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, 0- (C1-C9 alkyl} , O- (C2-C4 alkenyl), and carbonyl, J is 0, NR1, S, or (CR1 } 2 K is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C, cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally substituted with C1-CQ alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally replaced with 0, NR" ', or S(0)p, wherein R " ' is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, and C1-C9 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar3 group;

K' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, vitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NRS, S (0) p:

K" is C (Rl) 2, 0, S, a direct bond or NRl;

L is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine being selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, said aromatic amine being optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NRXRYRZ, wherein RX, Ry, and RZ are independently selected from the group consisting of C1-C6 straight or branched chain alkyl and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar3;

wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally substituted with C1-C9 alkyl, C2-CQ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally replaced with O, NR', S(0)p;

L' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NRS, S (O) p;

n is 1 or 2;

p is 0, 1, or 2;

t is 0, 1, 2, 3, or 9;

_ 77 _ Ar3 is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-Cg straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties; wherein the individual alicyclic or aromatic ring contains 5-8 members and wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Ars is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2 thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ars optionally contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-CQ straight or branched chain alkyl) , O- (C2-CQ straight _ 78 _ or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl; and RS is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar4 or Arl group.
Additionally, the invention pravides methods for the preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases; in treating alopecia and promoting hair growth;
in treating vision disorders and/or improving vision; and in treating memory impairment and/or enhancing memory performance by administering a compound of Formula I' to a patient in need thereof.
Also provided are compounds of Formula I' for use in the preparation of a medicament for preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases; in treating alopecia and promoting hair growth; in treating vision disorders and/or improving vision; and in treating memory impairment and/or enhancing memory performance.
Additionally, there is provided a formulation adapted for use in preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases; in treating alopecia and promoting hair growth; in treating vision disorders and/or improving vision; and in treating memory impairment and/or enhancing memory performance, which comprises a compound of Formula I' associated with a pharmaceutically acceptable carrier, diluent or excipient therefor.
More specifically, the invention provides the compounds described below, as well as methods, uses, and .

_ 79 _ formulations as described above.
I. HETEROCYCLIC THIOESTERS AND KETONES
FORMULA I
In particular, the bridged heterocyclic derivative may be a compound of formula I
B
A Z
'R~
(~>
Y X
\W

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of 0, S, S0, S02, N, NH, arid NR~;
or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
X is either 0 or S:
Z is either S, CH2, CHR1 or CR1R3;
W and Y are independently 0, S, CH2 or H2;
R, and R3 are independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) ", C1-C6 straight or branched chain alkyl or CZ-C6 straight or branched chain alkenyl substituted with (Arl) ~, C3-Cg cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-CB cycloalkyl, a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-Cq straight or branched chain alkenyl, a bridged ring moiety, and hydroxy; and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C,-C9 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.
FORMULA II
The bridged heterocyclic derivative may also be a compound of formula 8~.. I I
.~CH2)n N Z
Q X
R2 (II) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1 or 2~
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring (when n=1) or the piperidine ring (when n=2) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is 0 or S;
Z is selected from the group consisting of S, CH2, CHR1, and CR1R3;
R1 and R3 are independently selected from the group consisting of C1-CS straight or branched chain alkyl, C2-CS
straight or branched chain alkenyl, a bridged ring moiety, and Arl, wherein said alkyl, alkenyl or Arl is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, a bridged ring moiety, hydroxy, C1-C9 alkoxy, C2-CQ alkenyloxy, phenoxy, benzyloxy, amino, and Arl;
R2 is independently selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-CB cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, and Arl; and Arl is independently phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said Arl is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-CQ alkoxy, C2-Cq alkenyloxy, phenoxy, benzyloxy, and amino.
Preferred compounds of formula II are presented in TABLE I.
(CH2)n N Z~~
i O O X
R2 (II) TABLE I
No n X Z R, RZ

1 1 O CHZ 3-Phenylpropyl 1,1-Dimethylpropyl 2 1 O CHZ 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 3 1 O CHZ 3-Phenylpropyl tent-Butyl 4 1 O CHZ 3-(3-Pyridyl)propyl tert-Butyl 5 1 O CHZ 3-(3-Pyridyl)propyl Cyclohexyl 2 6 1 O CHZ 3-(3-Pyridyl)propyl Cyclopentyl

7 1 O CHZ 3-(3-Pyridyl)propyl Cycloheptyl

8 1 O CHZ 2-(9-Fluorenyl)ethyl 1,1-Dimethylpropyl

9 1 O S 2-Phenethyl 1,1-Dimethylpropyl

10 2 O S 2-Phenethyl 1,1-Dimethylpropyl 2 11 1 O S Methyl(2-thioindole) l , l-Dimethylpropyl 12 1 O S 2-Phenethyl Cyclohexyl 13 2 O S 2-Phenethyl tert-Butyl 14 2 O S 2-Phenethyl Phenyl 15 1 O CHZ 3-(4-Methoxyphenyl)propyl1,1-Dimethylpropyl 3 16 2 O CH2 4-(4-Methoxyphenyl)butyl1,1-Dimethylpropyl 17 2 O CH2 4-Phenylbutyl 1,1-Dimethylpropyl 18 2 O CHZ 4-Phenylbutyl Phenyl 19 2 O CHZ 4-Phenylbutyl Cyclohexyl 20 1 S CHz 3-Phenylpropyl 1,1-Dimethylpropyl 3 21 1 S S 2-Phenethyl 1,1-Dimethylpropyl 22 2 S CHZ 3-Phenylpropyl 1,1-Dimethylpropyl 23 2 S S 2-Phenethyl 1,1-Dimethylpropyl 24 2 O CHR, 3-Phenylpropyl 1,1-Dimethylpropyl 25 2 O CHR, 3-Phenylpropyl Cyclohexyl 4 26 2 O CHR, 3-Phenylpropyl Phenyl 27 2 O CHR, 3-Phenylpropyl 3,4,5-Trimethoxyphenyl 28 1 O S 2-Phenethyl Cyclopentyl No n X Z R, 29 2 O S 3-Phenylpropyl tent-Butyl 30 1 O S 3-Phenylpropyl 1,1-Dimethylpropyl 31 1 O S 3-(3-Pyridyl)propyl 1,1-Dimethylpropyl 32 1 O S , 3-Phenylpropyl Cyclohexyl 33 1 O S 4-Phenylbutyl Cyclohexyl 34 1 O S 4-Phenylbutyl 1,1-Dimethylpropyl 35 1 O S 3-(3-Pyridyl)propyl Cyclohexyl 36 1 O S 3,3-Diphenylpropyl 1,1-Dimethylpropyl 37 1 O S 3,3-Diphenylpropyl Cyclohexyl 38 1 O S 3-(4-MethoxyphenyI)propyl1,1-Dimethylpropyl 39 2 O S 4-Phenylbutyl ten-Butyl 40 2 O S 1,5-Diphenylpentyl 1,1-Dimethylpropyl 41 2 O S 1,5-Diphenylpentyl Phenyl 42 2 O S 3-(4-Methoxyphenyl)propyl1,1-Dimethylpropyl 43 2 O S 3-(4-Methoxyphenyl) propylPhenyl 44 2 O S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 45 1 O S 3,3-Di(4-fluoro)phenyl-propyl1,1-Dimethylpropyl 46 1 O S, 4,4-Di(4-fluoro)phenylbutyl1,1-Dimethylpropyl 47 1 O S 3-(1-Naphthyl)propyl 1,1-Dimethylpropyl 2 48 1 O S 2, 2-Diphenylethyl 1, i-Dimethylpropyl 49 2 O S 2,2-Diphenylethyl 1,1-Dimethylpropyl 50 2 O S 3,3-Diphenylpropyl 1,I-Dimethylpropyl 51 1 O S 3-(4-{Trifluoromethyl}phenyl)propyl1,1-Dimethylpropyl 52 1 O S 3-(2-Naphthyl)propyl 1,1-Dimethylpropyl 2 53 2 O S 3-( 1-Naphthyl)propyl 1,1-Dimethylpropyl 54 1 O S 3-(3-Chloro)phenylpropyl 1,1-Dimethylpropyl 55 1 O S 3-(3-{Trifluoromethyl}phenyl)propyl1,1-Dimethylpropyl 56 1 O S 3-(2-Biphenyl)propyl 1,1-Dimethylpropyl 57 1 O S 3-(2-Fluorophenyl)propyl 1,1-Dimethylpropyl 3 58 1 O S 3-(3-Fluorophenyl)propyl 1,1-Dimethylpropyl 59 2 O S 4-Phenylbutyl 1,1-Dimethylpropyl 60 2 O S 3-Phenylpropyl 1,1-Dimethylpropyl 61 1 O S 3-(2-Chloro)phenylpropyl 1,1-Dimethylpropyl 62 2 O S 3-(3-Chloro)phenylpropyl 1,1-Dimethylpropyl 3 63 2 O S 3-(2-Fluoro)phenylpropyl 1,1-Dimethylpropyl 64 2 O S 3-(3-Fluoro)phenylpropyl 1,1-Dimethylpropyl 65 1 O S 3-(2,5-Dimethoxyphenyl)propyl1,1-Dimethylpropyl 66 1 O CH2 3-Phenylpropyl Cyclohexyl 67 1 O CHZ 3-Phenylethyl ten-Butyl 4 68 2 O CHz 4-Phenylbutyl Cyclohexyl 69 2 O CHR, 2-Phenylethyl tent-Butyl 70 1 O CHZ 3,3-Di(4-fluorophenyl)propyl1,1-Dimethylpropyl 71 2 O CHZ 3-Phenylpropyl 1,1-Dimethylpropyl 45 Preferred compounds of TABLE I are named as follows:

1 (2S)-2-((1-Oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine 2 3,3-Dimethyl-1-[(2S)-2-(5-(3-pyridyl)pentanoyl)-1-pyrrolidine]-1,2-pentanedione 3 (2S)-2-({1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine 9 2-Phenyl-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 10 2-Phenyl-1-ethyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate

11 (3-Thioindolyl)methyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate

12 2-Phenyl-1-ethyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 14 2-Phenyl-1-ethyl 1-(2-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate //

_ 85 -28 2-Phenyl-1-ethyl (2S)-1-(1-cyclopentyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 29 3-Phenyl-1-propyl 1-(3,3-dimethyl-1,2-dioxobutyl)-2-piperidinecarbothioate 30 3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 31 3-(3-Pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 32 3-Phenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 33 4-Phenyl-1-butyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 34 4-Phenyl-1-butyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 35 3-(3-Pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 36 3,3-biphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate 37 3,3-biphenyl-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarbothioate 38 3- (para-Methoxyphenyl) -1-propyl (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carbothioate 39 4-Phenyl-1-butyl 1-(1,2-dioxo-3,3-dimethylbutyl) -2-piperidinecarbothioate 1,5-biphenyl-3-pentyl 1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate 41 1,5-biphenyl-3-mercaptopentyl 1-(3-phenyl-1,2-dioxoethyl)-2-piperidinecarbothioate 42 3-(para-Methoxyphenyl)-1-propyl 1-(1,2-dioxo-3,3-dimethylpentyl)piperidine-2-carbothioate 43 3-(para-Methoxyphenyl)-1-propyl 1-(2-phenyl-1,2-dioxoethyl)piperidine-2-carbothioate 44 3-(1-Naphthyl)-1-propyl 1-(3,3-dimethyl-1,2 dioxopentyl)piperidine-2-carbothioate 45 3,3-Di(para-fluoro)phenyl-1-propyl (2S)-1-(3,3 dimethyl-1,2-dioxopentyl)-2-pyrrolidine carbothioate 46 4,4-Di(para-fluorophenyl)butyl 1-(3,3-dimethyl 2-oxopentanoyl)-2-pyrrolidinecarbothioate 47 3-(1-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 48 2,2-Diphenylethyl (2S)-1-(3,3-dimethyl-2 oxopentanoyl)tetrahydro-1H-2-pyrrolidine carbothioate 49 2,2-Diphenylethyl (2S)-l-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 50 3,3-Diphenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 51 3- [4- (Trifluoromethyl) phenyl) propyl (2S) -1- (3, 3 dimethyl-2-oxopentanoyl)-2-pyrrolidine carbothioate 52 3-(2-Naphthyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 53 3- ( 2-Naphthyl ) propyl ( 2R, S) -1- ( 3, 3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate - 87 _ 54 3-(3-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 55 3- [3- (Trifluoromethyl) phenyl] propyl (2S) -1- (3, 3-dimethyl-2-oxopentanoyl)-2-pyrrolidine-carbothioate 56 3-(1-Biphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 57 3-(2-Fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 58 3-(3-Fluorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 59 4-Phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 60 3-Phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 61 3-(2-Chlorophenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)-2-pyrrolidinecarbothioate 62 3-(2-Chlorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 63 3-(2-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 64 3-(3-Fluorophenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarbothioate 65 3-(3,4-Dimethoxyphenyl)propyl (2S)-1-(3,3-d i m a t h y 1 - 2 - o x o p a n t a n o y 1 ) - 2 -pyrrolidinecarbothioate 88 _ 66 (2S)-2-((1-Oxo-4-phenyl}-butyl-1-(2-Cyclohexyl-1,2-dioxoethyl)pyrrolidine 67 2-((1-Oxo-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)pyrrolidine 68 2-({1-Oxo-6-phenyl}-hexyl-1-(2-Cyclohexyl-1,2-dioxoethyl)piperidine 69 2-((1-Oxo-[2-~2'-phenyl}ethyl]-4-phenyl}-butyl-1-(3,3-dimethyl-1,2-dioxobutyl)piperidine 70 1-( (2S) -2- [5, 5-di (4-Fluorophenyl) pentanoyl] -2 pyrrolidine}-3,3-dimethyl-1,2-pentanedione 71 3 , 3 - D i m a t h y 1 - 1 - [ 2 - ( 4 -phenylpentanoyl)piperidino]-1,2-pentanedione FORMULA III
Furthermore, the bridged heterocyclic derivative may be a compound of formula III:
Rr (III) Rz or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, and C are independently CH2, 0, S, S0, 502, NH or NR2;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of A, B, and C are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is O or S;
Z is S, CH2, CHR1 or CR1R3;
Rl and R3 are independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) ~, a bridged ring moiety, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl)n, C3-Ca cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-CQ straight or branched chain alkyl, C2-CQ
straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C~-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.
Preferred compounds of formula III are presented in TABLE II:
Br,;,;~~C
A v. Z
N ~ \R~
O O X

TABLE II
No. A B C X Z R, R2 72 CHZ S CHZ O S 2-phenethyl 1,1-dimethylpropyl 73 CHZ S CHZ O CH2 3-phenylpropyl1,1-dimethylpropyl , 74 CHZ CHz NH O S 2-phenethyl 1,1-dimethylpropyl 75 CHZ S CHZ S S 2-phenethyl 1,1-dimethylpropyl FORMULA IV
Alternatively, the bridged heterocyclic derivative may be a compound of formula IV:
Br;,, C
,.>'...~
D
,, 2 5 A~ Z~
Ri O O X
(IV) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

_ 91 _ A, B, C and D are independently CH2, 0, S, S0, 502, NH
or NR2;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of A, B, C and D are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is O or S;
Z is S, CH2, CHR1 or CR1R3;
Rl and R3 are independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl) ~, C3-Ce cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-Ce cycloalkyl, a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, bridged ring moiety, or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or mr,rP
substituent(s) independently selected from the group consisting of C3-Ce cycloalkyl, C1-Cq straight or branched chain alkyl, C2-CQ straight or branched chain alkenyl, bridged ring moiety, and hydroxyl; and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoro-methyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkPr,«i r _r- ~, v...... ,.
alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.
Preferred compounds of formula IV are presented in TABLE III.
Br;, C
Z
\R1 TABLE III
No A B C D X Z R

76 CHZ CHZ O CHZ O CHZ 3-phenylpropyl1,1-dimethylpropyl 77 CHZ CHZ O CHZ O S 2-phenethyl 1,1-dimethylpropyl 78 CHz CHZ S CHZ O CH2 3-phenylpropyl1,1-dimethylpropyl 2 5 79 CHZ CH2 S CH2 O S 2-phenethyl 1,1-dimethylpropyl FORMULA V
The bridged heterocyclic derivative may further be a compound of formula V:

~B
Z
I
Y
(V) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring one or more heteroatom(s) independently selected from the group consisting of 0, S, SO, 502, N, NH, and NR9; or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R9 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety,, or Ar3, wherein RQ is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, halo-C1-C6-alkyl, carbonyl, carboxy, hydroxy, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-CQ alkenylaxy, phenoxy, benzyloxy, thio-C1-C6-alkyl, C1-C6-alkylthio, sulfhydryl, amino, C1-C6-alkylamino, amino-C1-C6-alkyl, aminocarboxyl, a bridged ring moiety, and Ar9;
Ar3 and Ar4 are independently an alicyclic ar aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;
wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; and R1, R2, W, X, Y, and Z are as defined in Formula I
above.
II. HETEROCYCLIC ESTERS AND AMIDES
FORMULA VI
Additionally, the bridged heterocyclic derivative may be a compound of formula VI:
A Z
\N y Y
,. W X
(VI) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of 0, S, SO, 502, N, NH, and NR1;
or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
X is O or S;
Z is 0, NH or NRI;
W and Y are independently O, S, CH2 or H2;

Rl is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, which is substituted with one or more substituent(s) independently selected from the group consisting of (Arl)", C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl)~, C3-Ce cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-Cg cycloalkyl, a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain or alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-CQ straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.
Suitable carbo- and heterocyclic rings include without limitation naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.

FORMULA VII
The bridged heterocyclic derivative may also be a compound of formula VII:
Br; _,,$-,,,,~ _ .
O -Ri O
\ O
~O
R2 (VII) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B and C are independently CH2, 0, S, SO, S02, NH or NR1;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of A, B and C are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
R1 is C1-C5 straight or branched chain alkyl, C2-CS
straight or branched chain alkenyl, or a bridged ring moiety, which is substituted with one or more substituent(s) independently selected from the group consisting of (Arl)n and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl)~%
n is 1 or 2;
R2 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-CB
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Arl; and Arl is independently an alicyclic or aromatic, mono-, bi~- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, Cz-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.
A preferred compound of formula VII is:
13r In a particularly preferred embodiment of formula VII
compounds:
A is CH2;
B is CH2 or S;
C is CH2 or NH;
two or more of A, B, and C, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R1 is independently selected from the group consisting of 3-phenylpropyl and 3-(3-pyridyl)propyl; and _ 98 _ R2 is independently selected from the group consisting of l,l-dimethylpropyl, cyclohexyl, and tert-butyl.
Specific examples of this embodiment are presented in TABLE IV:
Br._ ..
-R~

IO

TABLE IV
No. A B C R~ Rz 80 CHz S CHz 3-phenylpropyl 1,1-dimethylpropyl 81 CHz S CHz 3-(3-pyridyl)propyll , l-dimethylpropyl 82 CHz S CHz 3-phenylpropyl cyclohexyl 83 CHz S CHz 3-phenylpropyl tert-butyl 84 CHz CHz NH 3-phenylpropyl 1,1-dimethylpropyl 85 CHz CHz NH 3-phenylpropyl cyclohexyl 86 CHz CHz NH 3-phenylpropyl tent-butyl FORMULA VIII
In a further embodiment of this invention, the bridged heterocyclic derivative may be a compound of formula VIII:
Br ~' C
B~, ;wD
O~R~
O
O
~O

(VIII) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, C and D are independently CH2, 0, S, SO, 502, NH
or NR1;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of A, B, C and D are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;

Rl is independently C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Arl)n and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl)~%
n is 1 or 2;
R2 is independently either C,-C~ straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C, cycloalkenyl, a bridged ring moiety, or Arl; and Arl is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-CA alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s} independently selected from the group consisting of 0, N, and S.
In a particularly preferred embodiment of formula VIII
compounds:
A is CH2;
B is CH2;
C is S, 0 or NH;
D is CH2;
Two or more of A, B, C, and D, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R1 is independently selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy)phenylpropyl; and R2 is independently selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and 3,4,5-trimethoxyphenyl.
Specific examples of this embodiment are presented in TABLE V.
Br, ,,, C
D
ANN i O~R~
O
TABLE V
No. A B C D R, Rz 87 CH2 CH2 S CH2 3-phenylpropyl1,1-dimethylpropyl 88 CH2 CHz O CHZ 3-phenylpropyl1,1-dimethylpropyl 89 CH2 CHz S CHZ 3-phenylpropylcyclohexyl 2 0 90 CHZ CHz O CHZ 3-phenylpropylcyclohexyl 91 CHZ CHZ S CHZ 3-phenylpropylphenyl 92 CHZ CHz O CH2 3-phenylpropylphenyl 93 CHZ CHZ NH CHZ 3-phenylpropyl1,1-dimethylpropyl 94 CHZ CH2 NH CHZ 3-phenylpropylphenyl FORMULA IX
Additionally, the bridged heterocyclic derivative may be a compound of formula IX:

~B
Z\
Y
(IX) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of 0, S, S0, 502, N, NH, and NR; or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-Cg cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Ar3, wherein R is independently either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, halo-C1-C6-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-CQ alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio-C1-C6-alkyl, CI-C6-alkylthio, sulfhydryl, amino, C1-C6-alkylami no, amino-C1-C6-alkyl, aminocarboxyl, a bridged ring moiety, and Ar4;
Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;
wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; and X is 0 or S;
Z is 0, NH or NRl;
W and Y are independently O, S, CH2 or H2;
R1 is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Arl) n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Arl) n, C3-Ce cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-Ca cycloalkyl, and Ar2;
n is 1 or 2;
R2 is independently C1-Cg straight or branched chain alkyl, C2-C9 straight or branched chain or alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, and hydroxyl; and Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C,-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S.
N-OXIDES OF HETEROCYCLIC ESTERS AMIDES
THIOESTERS AND KETONES
FORMULA X
The bridged heterocyclic derivative may further be a compound of formula X:
g X~Y/Z
I
O
(X) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, 502, N, NH, and NR1;
or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C~
cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C,-Cq alkyl, C2-CQ alkenyl, hydroxy, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, and Ar2 ;
Arl and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C.A alkenyloxy, phenoxy, benzyloxy, and amino;
X is 0, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C$ cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-CQ alkyl, C~-Cq alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR." S, SO, or S02;
R2 is independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C3-C9 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NR4RSR~, wherein R4, R5, and R6 are independently selected from the group consisting of a bridged ring moiety, or C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl optionally substituted with one or more substituent(s) independently I5 selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-Cq alkyl, C2-C9 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, S0, or 502;
Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C1-C9 straight or branched chain alkyl, C3-CQ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.
FORMULA XI
Moreover, the bridged heterocyclic derivative may be a compound of formula XI:

Bf, . ..~W
X~Y/Z
(XI) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, G and J are independently CH2, O, S, S0, S02, NH
or NRl;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, G and J are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
W is 0, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-CB
cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-Cq alkyl, C2-Cq alkenyl, hydroxy, C3-C~
cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, and Arl ;
Arl is independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR~R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C?
cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-CQ alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR2, S, S0, or 502;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-CQ
straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-Ca bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl, quin-olinyl, and isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C~
alkenyloxy, phenoxy, benzyloxy, and amino;

said tertiary amine is NR9RSR6, wherein R4, R5, and RE
are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, a bridged ring moiety, and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C;, cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C9 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR"
S, SO, or 502 Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C1-C4 straight or branched chain alkyl, C3-CQ straight or branched chain alkenyl or alkynyl, or Y-Z.
FORMULA XII
Furthermore, the bridged heterocyclic derivative may be a compound of formula XII:
Bf, .,, E-G
..
E\N X\Y/Z
O O
(XII) R
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

E, F, and G are independently CH2, 0, S, S0, 502, NH or NRl;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, and G are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C$
cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-CQ alkyl, C2-C4 alkenyl, hydroxy, C3-C$
cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and Arl ;
Arl is independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain al~:enyl, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
X is 0, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-CB cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C9 alkyl, C2-C9 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR2, S, S0, or S02;
IO R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-CQ
straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NRQRSR6, wherein R9, R5, and R6 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl,a bridged ring moiety, and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C, cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-CQ
alkyl, C2-C9 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, S0, or S02;
Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C,-Cq straight or branched chain alkyl, C3-C9 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.
FORMULA XIII
The bridged heterocyclic derivative may also be a compound of formula XIII:
Q.
X~Y/Z
(XIII) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1, 2, or 3, forming a 5-7 member heterocyclic ring;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1, 2, or 3) are bonded to each other thraugh either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
W is 0, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 alkyl, C2-C9 alkenyl, hydroxy, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, and Arl;
Arl is independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-CQ alkenyloxy, phenoxy, benzyloxy, and amino;
X is 0, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-CB cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-Cq alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR2, S, SO, or S02;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C9 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NRQRSR~, wherein R4, R5, and R6 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, a bridged ring moiety, and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-CB cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C9 alkyl, C2-CQ alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with 0, NH, NR1, S, S0, or S02;
Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3, independently, are hydrogen, C1-Cq straight or branched chain alkyl, C3-C9 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.
Examples of the compounds of formula XIII when W is O are presented in TABLE VI:
Br . \N X\Y/Z
O~ ~ O
TABLE VI
No. n X Y Z R

95 1 O (CH~3 3-Pyridyl N-oxide1,1-dimethylpropyl 96 1 O (CH~3 2-Pyridyl N-oxide1,1-dimethylpropyl 97 1 O (CHz)3 4-Pyridyl N-oxide1,1-dimethylpropyl 98 1 O (CH,~3 2-Quinolyl N-oxide1,1-dimethylpropyl 99 1 O (CH~3 3-Quinolyl N-oxide1,1-dimethylpropyl 100 1 O (CH~3 4-Quinolyl N-oxide1,1-dimethylpropyl Preferred compounds of formula XIII may be selected from the group consisting of:
3-(2-Pyridyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(3-Pyridyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(9-Pyridyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(2-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;

3-(3-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;
3-(4-Quinolyl)-1-propyl(2S)-1-(1,1-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide;
and pharmaceutically acceptable salts, esters, and solvates thereof.
FORMULA XIV
Additionally, the bridged heterocyclic derivative may be a compound of formula XIV:
B
A
\V X~Y/Z
O O
(XIV) R
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, together with V and the carbon atom to which they are respectively attached, form a 5-7 memberPC~
saturated or unsaturated heterocyclic ring cantaining one or more heteroatom(s) independently selected from the group consisting of O, S, S0, S02, N, NH, and NR7; or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R7 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, CS-C, cycloalkenyl, a bridged ring moiety, or Ar3, wherein R7 is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, halo-C1-C6-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, a bridged ring moiety, C1-C4 alkoxy, C2-CQ
alkenyloxy, phenoxy, benzyloxy, thio-C1-C6-alkyl, C1-C6-alkylthio, sulfhydryl, amino, C1-C6-alkylamino, amino-C1-C6-alkyl, aminocarboxyl, and Ar4;
Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;
wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and R, W, X, Y, and Z are as defined in Formula X above.
IV. N-LINKED UREAS AND CARBAMATES OF HETEROCYCLIC
THIOESTERS
The bridged heterocyclic derivative may further be a compound of formula XV:
B
A S-~Y-Z
\N 1 \D
X
R1 (xv) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, 502, N, NH, and NR3;
or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
X is either 0 or S;
Y is a direct bond., C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-CE,-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or S02;
R3 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-Cq bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with.one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C,-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C,.-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, vitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thin-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, vitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, SO, or 502;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl; CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl_ or cycloalkenyl is optionally substituted with C1-Cf;-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, vitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, S0, or S02;
W is O or S; and U is either 0 or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-Ce cycloalkyl, a bridged ring moiety, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-Ce cycloalkyl; and when U is N, then R1 and R2 are independently selected from the group consisting of hydrogen, Ar, C3-Clo cycloalkyl, a bridged ring moiety, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
In a preferred embodiment of formula XV, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
FORMULA XVI
Moreover, the bridged heterocyclic derivative may be a compound of formula XVI:
Br ;;'F~G~ J
'~, N ~ \
D
X
(XVI) Ri or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, G and J are independently CH2, O, S, S0, 502, NH, or NR3;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, G and J are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is either 0 or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C~-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502;
R3 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl. or alkynyl, a bridged ring moiety, and C1-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-CB cycloalkyl, CS-C, cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; and wherein any aromatic or tertiary alkyl .amine is optionally oxidized to a corresponding N-oxide Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-Cb-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-Ce cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-Cl-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkyl amino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, S0, or S02;
4V is 0 or S; and U is either 0 or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-CB cycloalkyl, a bridged ring moiety, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-CB cycloalkyl; and when U is N, then R1 and R2 are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C3-Clo cycloalkyl, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-CB cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
In a preferred embodiment of formula XVI, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
FORMULA XVII
The bridged heterocyclic derivative may also be a compound of formula XVII:
Br;;~~~ c E ' \N S\Y~z~D
3 0 RZ \ /~
a w (XVII) R~

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, and G are independently CH2, O, S, S0, 502, NH, and NR3;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, and G are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is either 0 or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, Cl-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkyl amino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or S02;
R3 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C9 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkyl amino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-CB cycloalkyl, CS-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitrosa, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position (s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-CB cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or W is 0 or S; and U is either 0 or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, a bridged ring moiety, C3-Cg cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R1 and R2 are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C3-C8 cycloalkyl, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-CB cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
In a preferred embodiment of formula XVII, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
FORMULA XVIII
The bridged heterocyclic derivative may further be a compound of formula XVIII:
(CHy)n C
','N S\Y~Z~D
R2~ X
U W
(XVIII) Ry or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1, 2 or 3;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1, 2 or 3) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;

X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkeny.l is optionally replaced with 0, NH, NR3, S, S0, or 502;
R3 is independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C3-Cq straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C~-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position (s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-Ce cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-Cf;-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, S0, or S02 ;
W is O or S: and U is either 0 or N, provided that:

when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, a bridged ring moiety, C3-CB
cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-CB cycloalkyl; and when U is N, then R1 and R2 are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C3-Clo cycloalkyl, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
In a preferred embodiment of formula XVIII, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
Exemplary compounds in which U is N and X is 0 of formula XVIII are presented in TABLE VII.

Br Rz\
c \Y/Z\D
TABLE VII
No. n W Y Z C D R R

101 1 O (CHZ)2CH 3-Pyridyl H H 2-Methylbutyl 102 1 O (CH2)2CH 3-Pyridyl H H 1,1-dimethylpropyl 103 1 O (CHZ)2CH 4-MethoxyphenylH H 1,1-dimethylpropyl 104 1 O CHz CH Phenyl H H I ,1-dimethylpropyl 105 1 S (CHZ)zCH 4-MethoxyphenylH H Cyclohexyl 106 1 O (CHZ)ZCH 3-Pyridyl H H Cyclohexyl 107 I S (CHZ)ZCH 3-Pyridyl H H Cyclohexyl 108 1 S (CHZ)2CH 3-Pyridyl H H 1-Adamantyl 109 1 S (CH2)ZCH 3-Pyridyl H H 1,1-dimethylpropyl 110 1 O (CH2)2CH Phenyl Phenyl H 1,1-dimethyipropyl 111 2 O (CHZ)2CH Phenyl H H 1,1-dimethylpropyl 112 2 O (CH2)ZCH Phenyl H H Phenyl 2 0 113 2 O DirectCH 2-Phenylethyl2-PhenylethylH Phenyl bond 114 2 O DirectCH 2-Phenylethyl2-PhenylethylH Cyclohexyl bond 115 2 S DirectCH 2-Phenylethyl2-PhenylethylH Cyclohexyl bond 116 2 O (CHZ)ZCH 4-MethoxyphenylH H Cyclohexyl The most preferred compounds of formula XVIII are selected from the group consisting of:
3-(3-Pyridyl)-1-propyl-2S-1-[(2-methylbutyl) carbamoyl]pyrrolidine-2-carboxylate;
3-(3-Pyridyl)-1-propyl-2S-1-[(1',1'-Dimethylpropyl) carbamoyl]pyrrolidine-2-carboxylate;
3-(3-Pyridyl)-1-propyl-2S-1-[(cyclohexyl) thiocarbamoyl]pyrrolidine-2-carboxylate;

and pharmaceutically acceptable salts, esters, and solvates thereof.
FORMULA XIX
Additionally, the bridged heterocyclic derivative may be a compound of formula XIX:
B C
,4 S i \V ~Y/ \D
R2 ~ X
U W
(XIX) R~
o r a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S:
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkeny:l is optionally replaced with 0, NH, NR3, S, S0, or 502;
R3 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C,-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5 8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-Ce cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, Cz-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-CI-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, S0, or 502; and A, B, Rl, R2, U, W, and X are as otherwise defined in formula XV.
V. N-LINKED SULFONAMIDES OF HETEROCYCLIC THIOESTERS
FORMULA XX
The bridged heterocyclic derivative may further be a compound of formula XX:
B C
\N \Y/ \D
I~O
R, (XX) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a S-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, 502, N, NH, and NR2;
or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
X is either 0 or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, Ci-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, S0, or 502;
R2 is independently selected from the group consisting of hydrogen, C1-CQ straight or branched chain alkyl, C3-CQ
straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions} with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, S0, Or 502 C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-Ce cycloalkyl, CS-C, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-Cb-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkyl amino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, S0, or S02; and Rl is independently selected from the group consisting of Ar, a bridged ring moiety, C3-Ce cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-CB cycloalkyl, amino, halo, halo-C1-C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thin-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502.
In a preferred embodiment of formula XX, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
In another preferred embodiment of formula XX, A and B, together with the nitrogen and carbon atoms to which they are respectfully attached, form a 6 membered saturated or unsaturated heterocyclic ring or heterocyclic bridged ring moiety: and R2 is CQ-C7 branched chain alkyl, C9-C7 cycloalkyl, phenyl, or 3,4,5-trimethoxyphenyl.
In another preferred embodiment of formula XX, the compound is selected from the group consisting of:
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate;
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(a-toluenesulfonyl)pyrrolidine-2-carboxylate;
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(a-toluenesulfonyl)pyrrolidine-2-carboxylate;
1,5-biphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate;
and pharmaceutically acceptable salts, esters, and solvates thereof.
FORMULA XXI
Moreover, the bridged heterocyclic derivative may be a compound of formula XXI:
Br: ;,,F'~G\~ c E S\Y/Z\D
ii \o X (XXI ) Ri or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, G and J are independently CH2, 0, S, SO, 502, NH
or NR2;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, G and J are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is either 0 or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or 502;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C9 straight or branched chain alkeny:L or alkynyl, a bridged ring moiety, and C1-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is a direct bond, C,-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-CE-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C,-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, S0, or 502;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-Ce cycloalkyl, C,-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or S02; and Rl is independently selected from the group consisting of Ar, a bridged ring moiety, C3-CB cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-C1-C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thin-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C,-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502.
In a preferred embodiment of formula XXI, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
FORMULA XXII
The bridged heterocyclic derivative may also be a compound of formula XXII:
Br; ., F- c c ,,,, E~N S\Y/Z\D
p' \o R~ (XXII) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

E, F, and G are independently CH2, 0, S, S0, 502, NH or the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, and G are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is either 0 or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position (s) with amino, halo, halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenaxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio-(C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, S0, or 502;
R2 is independently selected from the group consisting of hydrogen, C1-CQ straight or branched chain alkyl, C3-C9 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C9 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N
oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C,-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio-(C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, S0, o.r 502;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-CB cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-CQ alkyl, C2-CQ alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or 502; and R1 is independently selected from the group consisting of Ar, a bridged ring moiety, C3-Cg cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-(C1-C6) -alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio-(C1-C6) -alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or 502.
In a preferred embodiment of formula XXII, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
FORMULA XXIII
Additionally, the bridged heterocyclic derivative may be a compound of formula XXIII:
Br c Y~Z~D
(XXIII) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1, 2 or 3;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1, 2 or 3) are bonded to each other through either a chemical bond or atoms} other than a bond which doles) not comprise a part of the primary ring structure;
X is either 0 or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo- (C1-C6} -alkyl, thiocarbonyl, (C,-C6} -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio-(C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, SO, or 502;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with amino, halo, halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio-(C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, S0, or 502;
R2 is independently selected from the group consisting of hydrogen, C1-CQ straight or branched chain alkyl, C3-CQ
straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C,-CQ bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-CB cycloalkyl, CS-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-Cq alkyl, C2-C9 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more positions) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR2, S, S0, or S02; and R1 is independently selected from the group consisting of Ar, a bridged ring moiety, C3-Ce cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-Cg cycloalkyl, amino, halo,-halo-(C1-C6) -alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, CZ-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio-(C1-C6) -alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR3, S, S0, or S02.
In a preferred embodiment of formula XXIII, Ar is independently selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.
Exemplary compounds of formula XXIII are presented in TABLE VIII:
Br c Y'~Z~D
TABLE VIII
No. n Y Z C D R, 117 1 CHZ CH Phenyl H Phenyl 118 1 CH2 CH Phenyl H a-Methylphenyl 2 0 119 1 CHZ CH Phenyl H 4-Methylphenyl 120 1 (CH~Z CH p-MethoxyphenylH Phenyl 121 1 (CH~2 CH p-MethoxyphenylH a-Methylphenyl 122 1 (CH~z CH p-MethoxyphenylH 4-Methylphenyl 123 1 (CH~Z CH Phenyl Phenyl Phenyl 124 1 (CH~2 CH Phenyl Phenyl a-Methylphenyl 125 1 (CH~2 CH Phenyl Phenyl 4-Methylphenyl 126 2 (CH~3 CH Phenyl H Phenyl 127 2 (CH2)3 CH Phenyl H a-Methylphenyl 128 2 (CH~3 CH Phenyl H 4-Methylphenyl 129 2 (CH~3 CH Phenyl H 3,4,5-trimethoxyphenyl 130 2 (CH~3 CH Phenyl H Cyclohexyl 131 2 Direct CH 3-Phenylpropyl3-PhenylpropylPhenyl bond 132 2 Direct CH 3-Phenylpropyl3-Phenylpropyla-Methylphenyl bond 133 2 Direct CH 3-Phenylpropyl3-Phenylpropyl4-Methylphenyl bond 3 5 134 2 Direct CH 3-Phenylethyl 3-Phenylethyl 4-Methylphenyl bond 135 2 Direct CH 3-(4-Methoxy 3-Phenylpropyl 4-Methylphenyl bond phenyl)propyl 136 2 Direct CH 3-(2-Pyridyl) 3-Phenylpropyl 4-Methylphenyl bond propyl The most preferred compounds of formula XXIII are 40 selected from the group consisting of:
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate;
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-45 (a-toluenesulfonyl)pyrrolidine-2-carboxylate;
3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(a-toluenesulfonyl)pyrrolidine-2-carboxylate;
50 1,5-biphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate;
and pharmaceutically acceptable salts, esters, and solvates thereof.
FORMULA XXIV
Moreover, the bridged heterocyclic derivative may be a compound of formula XXIV:
C
A\V S\Y/Z\D
~S\ O X
(XXIV) R~

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A, B, C, D, Rl, X, Y, and Z are as defined in formula XX above.
PYRROLIDINE DERIVATIVES
FORMULA XXV
The bridged heterocyclic derivative may also be a compound of formula XXV:
Q
Y
~~Z~n (XXV) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when t is 1, 2 or 3) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
R1 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein said Rl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, CS-C7 cycloalkenyl, hydroxy, a bridged ring moiety, and Ar2;
Arl and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Arl is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 al.koxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
X is 0, S, CH2 or H2;
Y is O or NR2, wherein R2 is a direct bond to a Z, hydrogen or C1-C6 alkyl; and each Z, independently, is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with nt'1P nr mnro substituent(s) independently selected from the group consisting of Arl, C3-Ce cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-Ce cycloalkyl; or Z is the fragment O
CH
X2 Ra wherein:
R3 is independently C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-CB

cycloalkyl,a bridged ring moiety, or Arl;
X2 is 0 or NRS, wherein RS is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R9 is independently selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, a bridged ring moiety, C1-CS straight or branched chain alkyl substituted with phenyl, and C2-CS straight or branched chain alkenyl substituted with phenyl;
n is 1 or 2, and;
t is 1, 2 or 3.
In a preferred embodiment of formula XXV, Z and R1 are lipophilic.
In another preferred embodiment of formula XXV, the compound is selected from the group consisting of:
3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3,4,5-trimethoxyphenyl)-1-propyl (2S)-1-(3,3 dimethyl-1,2-dioxopentyl)-2-pyrrolidine carboxylate;
3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2 pyrrolidinecarboxylate;
3-(4,5-dichlorophenyl)-1-propyl (2S)-1-(3,3-d i m a t h y 1 - 1 , 2 - d i o x o p a n t y 1 ) - 2 -pyrrolidinecarboxylate;
3- (4, 5-dichlorophenyl) -1-prop-2- (E) -enyl (2S) -1-(3,3-dimethyl-1,2-dioxopentyl}-2-pyrrolidine-carboxylate;
3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1 (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine carboxylate;
3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2 pyrrolidinecarboxylate;
3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-cyclohexyl-1-prop-2-(E}-enyl (2S)-1-(3,3-d i m a t h y 1 - 1 , 2 - d i o x o p a n t y 1 ) - 2 -pyrrolidinecarboxylate;
( 1R) -l, 3-diphenyl-1-propyl (2S) -1- ( 3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1,3-Biphenyl-1-prop-2-(E)~enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate;
(1R}-1-cyclohexyl-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate;
(1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl ( 2 S) -1- ( 3, 3-dimethyl-1, 2-dioxopentyl ) -2-pyrrolidine-carboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate;

3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;
1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxamide;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglycine ethyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester;
and pharmaceutically acceptable salts, esters, and solvates thereof.
FORMULA XXVI
Additionally, the bridged heterocyclic derivative may be a compound of formula XXVI:
Rr (XXVI) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure R1 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-CB
cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety,. or Arl, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-CE
cycloalkyl, CS-C7 cycloalkenyl, hydroxy, a bridged ring moiety, and Ar2;
Ar, and Ar2 are independently selected fram the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Arl is unsubstituted or substituted with one or more substituent(s} independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-CQ alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
Z is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Arl, C3-Ce cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-CB cycloalkyl;
or Z is the fragment O
CH

wherein:
R3 is independently C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Arl;
X2 is O or NRS, wherein RS is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and RQ is independently selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, a bridged ring moiety, C1-CS straight or branched chain alkyl substituted with phenyl, and C2-CS straight or branched chain alkenyl substituted with phenyl.
In a preferred embodiment of formula XXVI, R1 is independently selected from the group consisting of C1-C9 straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 9-hydroxybutyl.
In another preferred embodiment of formula XXVI, Z and R1 are lipophilic.
FORMULA XXVII
Furthermore, the bridged heterocyclic derivative may be a compound of formula XXVII:
Q r (XXVII) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
Z' is the fragment O
CH

wherein:
R3 is independently C1-C9 straight or branched chain alkyl or unsubstituted Arl, wherein said alkyl is unsubstituted or substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Arl;
X2 is 0 or NRS, wherein RS is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R9 is independently selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, a bridged ring moiety, C1-CS straight or branched chain alkyl substituted with phenyl, and C2-CS straight or branched chain alkenyl substituted with phenyl; and Arl is as defined in formula XXVI.
In a preferred embodiment of formula XXVII, Z' is lipophilic.

FORMULA XXVIII
The bridged heterocyclic derivative may also be a compound of formula XXVIII:
Q r Y (Z)"
(XXVIII) wherein:
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
R1 is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C6 cycloalkyl, a bridged ring moiety, or Arl, wherein said alkyl or alkenyl is unsubstituted or substituted with C3-C6 cycloalkyl or Ar2;
Arl and Ar2 are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl;
X is selected from the group consisting of oxygen and sulfur;
Y is oxygen or NR2, wherein R2 is independently a direct bond to a Z, hydrogen or C1-C6 alkyl;
each Z, independently, is hydrogen, C1-C6 straight or branched chain alkyl, or CZ-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of 2-furyl, 2-thienyl, C3-C6 cycloalkyl, pyridyl, and phenyl, each having one or more substituent(s) independently selected from the group consisting of hydrogen and C1-C9 alkoxy; and n is 1 or 2.
In a preferred embodiment of formula XXVIII, Z and R1 are lipophilic.
In another preferred embodiment of formula XXVIII, the compound is selected from the group consisting of:
3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-d i m a t h y 1 - 1 , 2 - d i o x o p a n t y 1 ) - 2 -pyrrolidinecarboxylate;
3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrralidine-carboxylate;
2-(3,4,5-trimethoxyphenyl)-1-ethyl (2S)-1-(3,3-d i m a t h y 1 - 1 , 2 - d i o x o p a n t y 1 ) - 2 -pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (2-pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidine-carboxylate;
3- (3-pyridyl) -1-propyl (2S) -1- (2-tert-butyl-l, 2 dioxoethyl)-2-pyrrolidinecarboxylate;
3,3-Biphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (3-pyridyl) -1-propyl (2S) -1- (2-cyclohexyl-1, 2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-N-([2-thienyl]
glyoxyl)pyrrolidinecarboxylat.e;
3,3-Biphenyl-1-propyl (2S)-1-(3,3-dimethyl-1~,2-dioxobutyl)-2-pyrrolidinecarboxylate;
3,3-Biphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate;
3,3-Biphenyl-1-propyl (2S)-1-{2-thienyl)glyoxyl-2-pyrrolidinecarboxylate;
and pharmaceutically acceptable salts, esters, and solvates thereof.
In another preferred embodiment of formula XXVIII, the compound is selected from the group consisting of:
3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (2-pyridyl ) -1-propyl (2S) -1-~ ( 3, 3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
and pharmaceutically acceptable salts, esters, and solvates thereof.
In another preferred embodiment of formula XXVIII, the compound is 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, and pharmaceutically acceptable salts, esters, and solvates thereof.
FORMULA XXIX
Additionally, the bridged heterocyclic derivative may be a compound of formula XXIX:
Y (Z)n (XXIX) R~
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) independently selected from the group consisting of 0, S, S0, S02, N, NH, and NR; or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or 3-(3-pyridyl)-1-p Arl, wherein R is independently either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, halo- (C1-C6) -alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, thio-(C1-C6)-alkyl, alkylthio, sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar2;
R1 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-Ce cycloalkyl, CS-C7 cycloalkenyl, hydroxy, a bridged ring moiety, and Ar2;
Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S;
X is 0, S, CH2 or H2;
Y is 0 or NR2, wherein R2 is a direct bond to a Z, hydrogen or C1-C6 alkyl; and each Z, independently, is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Arl, C3-Ce cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-Ce cycloalkyl; or Z is the fragment O
CH
~ X2 R4 wherein: Rs R3 is independently C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-CB
cycloalkyl, a bridged ring moiety, or Arl;
X2 is O or NRS, wherein RS is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is independently selected from the group consisting of phenyl, benzyl, C1-CS straight or branched chain alkyl, C2-CS straight or branched chain alkenyl, a bridged ring moiety, C1-CS straight or branched chain alkyl substituted with phenyl, and C2-CS straight or branched chain alkenyl substituted with phenyl; and, n is 1 or 2.
Other compounds which are bridged heterocyclic derivatives within the scope of the present invention are those compounds which may possess immunosuppressive, non-immunosuppressive, or other activities as long as they also are useful in preventing and/or treating neurological disorders, including physically damaged nerves and neurodegenerative diseases; in treating alopecia and promoting hair growth; in treating vision disorders and/or improving vision; and in treating memory impairment and/or enhancing memory performance. For example, such compounds may include, but are not limited to those below:

COMPOUND 16?
Ocain et al., Biochemical and Biophysical Research Communications (1993) 3:192, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XXX. This compound is prepared by reacting 4-phenyl-1,2,4-triazoline-3,5-dione with rapamycin.
FORMULA (XXX) h ~'QMe "WAY-124,466"

Chakraborty et al., Chemistrv and Bioloav (1995) 2:157-161, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XXXI.
FORMULA (XXXI) RAP-Pa Ikeda et al., J. Am. Chem. Soc. (1994) II6:4143-4144, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XXXII and Table XII.
FORMULA (XXXII) TABLE XII
Compound Structure 169 n = 1 170 n = 2 171 n = 3 Wang et al., Biooraanic & Medicinal Chemistry Letters (1994) 4:1161-1166, 9, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XXXIII and Table XIII.
FORMULA (XXXIII) TABLE XIII
Compound Structure 172 X=H,H

173 X = CHZ

174 X = H, CH3 175 X=O

Birkenshaw et al., Bioor anic & Medicinal Chemistry Letters (1994) 4(21):2501-2506, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XXXIV:
OH
OMe OMe FORMULA (XXXIV) Holt et al., J. Am. Chem. Soc.(1993) 115:9925-9938, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XXXV and Tables XIV and XV.
FORMULA (XXXV) TABLE XV
Compound RZ

Me 179 / OMe OMe - ls9 -lgs Caffery et al., Bioorctanic & Medicinal Chemistry Letters (1994) 4121):2507-2510, Incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas XXXVI-XXXVIII and Tables XVI-XVIII.
FORMULA XXXVI

TABLE XVI
Compound Structure 188 y = 1 189 y = 2 190 y = 3 FORMULA XXXVII

N
O
O
O O
TABLE XVII
Compound Structure 191 n = 1 192 n=2 193 n=3 FORMULA XXXVIII

N
O
O
H
O Oi .._.
TABLE XVIII
Compound Structure 194 n = 1 195 n = 2 196 n=3 Teague et al., Bioor a~ & Medicinal Chemistry Letters (1993) 3110):1947-1950, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XXXIX. Ho.
FORMULA XXXIX
~a ~R

Yamashita et al., Bioorcranic & Medicinal Chemistry Letters (1994) 4(2):325-328, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XL and Table XIX.
FORMULA XL
~O R
' IIvIIN

~O
TABLE XIX
Compound Structure 198 R = phenyl 199 R = N(allyl)2 Holt et al., Bioorganic & Medicinal Chemistry Letters(1994) 4(2):315-320, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XLI and Tables XX-XXII.
FORMULA XLI
R
TABLE XX
Compound No.

i Compound No.

Table XXII
Compound No. Structure Holt et al., Bioorcranic & Medicinal Chemistry Letters (1993) 3(10)_:1977-1980, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas XLII and XLIII and Tables XXIII-XXV.
FORMULA XLII

TABLE XXIII
Compound Structure 222 X = OH

223 X = OMe 224 X = O-iso-Pr 225 X = OBn 226 X = OCH (Me)Ph 227 X = OCH~CHCHPh 228 X = OCHzCH2CH2(3,4-OMez)Ph 229 X = NHBn 230 X = NHCHzCHZCH2Ph FORMULA XLIII

TABLE XXIV
Compound Structure 3 0 231 R = Me 232 R = Bn TABLE XXV
Compound Structure Ho. , ~

HO.

p ~ ~ OH
N
O
O MeO....
O O
OMe 1~

Hauske et al., J. Med. Chem. (1992) 35:4284-4296, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formulas XLIV
XLVII and Tables XXVI-XXIX.
FORMULA XLIV
O
N \R2 R~

TABLE XXVI
Compound Structure 235 ~=2 O OH
S
''~'Cfh RZ=Phe-O-tert-butyl 236 ~=2 OcH, i RZ= Phe-O-tert-butyl FORMULA XLV
R, TABLE XXVII
Compound Structure 237 R, = m-OCH3Ph R3 = Val-O-tert-butyl 238 R, = m-OCH3Ph R3 = Leu-O-tert-butyl 2 0 239 R, = m-OCH3Ph R3 = Ileu-O-tert-butyl 240 R, = m-OCH3Ph R3 = hexahydro-Phe-O-tert-butyl 241 R, = m-OCH3Ph 2 5 R3 = allylalanine-O-tert-butyl 242 R, = b-naphthyl R3 = Val-O-tert-butyl TABLE XXVIII
Compound Structure 243 R, = CHZ(CO)-m-OCH3Ph R, = CH2Ph 4 0 RS = OCH3 244 R, = CHZ(CO)-b-naphthyl R4 = CHZPh RS = OCH3 FORMULA XLVII
~R, H

TABLE XXIX
Compound Structure 245 R, = m-OCH3Ph X = traps-CH=CH-R, = H
Y = OC(O)Ph 246 R,. = m-OCH3Ph X = traps-CH=CH
~=H
Y = OC(O)CF3 247 R, = m-OCH3Ph X = traps-CH=CH-R4=_ y=_ 248 R, = m-OCH3Ph X = traps-CH=CH-R, = H
Y = OCHzCH=CHZ
249 R, = m-OCH3Ph X=C=O
R4=H
Y=Ph Teague et al., Biooraanic & Med. Chem. Letters (1994) 4(13):1581-1584, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XLVIII.
FORMULA XLVII:I

OH

Stocks et al., Bioor anic & Med. Chem. Letters (1994) 4112):1457-1460, incorporated herein by reference, discloses exemplary pipecolic acid derivatives represented by Formula XLIX and Tables XXX and XXXI.
TABLE XXX
Compound No. Structure 2 51 Ho_ Me0 FORMULA XLIX

Compound Structure 252 R, = H
RZ = OMe R3 = CHZOme 253 R, = H
RZ=H
R3=1-I
254 R, = Me Rz=H
R3=H

Additional exemplary pipecolic acid derivatives are represented by Formulas L-LIV and Tables XXXII-XXXVI.
FORMULA L

TABLE XXXII
Compound Structure 255 R = 3,4-dichloro 256 R = 3,4,5-trimethoxy 257 R=H
258 R = 3-(2,5-Dimethoxy)phenylpropyl 259 R = 3-(3,4-Methylenedioxy)phenylpropyl FORMULA LI

TABLE XXXIII
Compound Structure 260 R = 4-(p-Methoxy)butyl 261 R = 3-Phenylpropyl 2 0 262 R = 3-(3-Pyridyl)propyl FORMULA LII
TABLE XXXIV
Compound Structure 3 0 263 R = 3-(3-Pyridyl)propyl 264 R = 1,7-biphenyl-4-heptyl 265 R = 4-(4-Methoxy)butyl 266 R = 1-Phenyl-6-(4-methoxyphenyl)-4-hexyl 267 R = 3-(2,5-Dimethoxy)phenylpropyl 268 R = 3-(3,4-Methylenedioxy)phenylpropyl 269 R = 1, 5-Diphenylpentyl FORMULA LIII
TABLE XXXV
Compound Structure 270 R = 4-(4-Methoxy;)butyl 271 R = 3-Cyclohexylpropyl 272 R = 3-Phenylpropyl FORMULA LIV
TABLE XXXV:I
Compound Structure 273 R = 3-Cyclohexylpropyl 274 R = 3-Phenylpropyl 3 0 275 R = 4-(4-Methoxy)butyl 276 R = 1,7-biphenyl-4-heptyl The names of some of the compounds identified above are provided below in Table XXXVII.
TABLE XXXVII
Compound Name of Species 172 4-(4-methoxyphenyl)butyl (2S)-1-[2-(3,4,5-trimethoxyphenyl)acetyl]hexahydro-2-pyridinecarboxylate 173 4-(4-methoxyphenyl)butyl (2S)-1-[2-(3,4,5-trimethoxyphenyl)acryloyl]hexahydro-2-pyridinecarboxylate 179 4-(4-methoxyphenyl)butyl (2S)-1-[2-(3,4,5-trimethoxyphenyl)propanoyl]hexahydro-2-pyridinecarboxylate 175 4-(4-methoxyphenyl)butyl (2S)-1-[2-oxo-2-(3,4,5-trimethoxyphenyl)acetyl]hexahydro-2-pyridinecarboxylate 177 3-cyclohexylpropyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate 178 3-phenylpropyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate 179 3-(3,4,5-trimethoxyphenyl)propyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate 180 (1R)-2,2-dimethyl-1-phenethyl-3-butenyl (2S)-1-(3,3-dimethyl-2-oxopentan-oyl)hexahydro-2-pyridinecarboxylate 181 (1R)-1,3-diphenylpropyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate 182 (1R)-1-cyclohexyl-3-phenylpropyl (2S)-1-(3,.3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate 183 (1S)-1,3-diphenylpropyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate 184 (1S)-1-cyclohexyl-3-phenylpropyl (2S)-1-(3,3-dimethyl-2-oxopentanoyl)hexahydro-2-pyridinecarboxylate Compound Name of Species 185 (22aS)-15,15-dimethylperhydropyrido[2,1-c][1,9,4]dioxazacyclononadecine-1,12,16,17-tetraone 186 (24aS)-17,17-dimethylperhydropyrido(2,1-c][1,9,4]dioxazacyclohenicosine-1,14,18,19-tetraone 201 ethyl 1-(2-oxo-3-phenylpropanoyl)-2-piperidinecarboxylate 202 ethyl 1-pyruvoyl-2-piperidinecarboxylate 203 ethyl 1-(2-oxobutanoyl)-2-piperidine-carboxylate 204 ethyl 1-(3-methyl-2-oxobutanoyl)-2-piperidinecarboxylate 205 ethyl 1-(4-methyl-2-oxopentanoyl)-2-piperidinecarboxylate 206 ethyl 1-(3,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate 207 ethyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate 208 4-[2-(ethyloxycarbonyl)piperidino]-2,2-dimethyl-3,4-dioxobutyl acetate 209 ethyl 1-[2-(2-hydroxytetrahydro-2H-2-pyranyl)-2-oxoacetyl]-2-piperidinecarboxylate 210 ethyl 1-[2-(2-methoxytetrahydro-2H-2-pyranyl)-2-oxoacetyl]-2-piperidinecarboxylate 211 ethyl 1-[2-(1-hydroxycyclohexyl)-2-oxoacetyl]-2-piperidinecarboxylate 212 ethyl 1-[2-(1-methoxycyclohexyl)-2-oxoacetyl]-2-piperidinecarboxylate 213 ethyl 1-(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate 214 ethyl 1-(2-oxo-2-piperidinoacetyl)-2-piperidinecarboxylate 215 ethyl 1-(2-(3,4-dihydro-2H-6-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate Compound Name of Species 216 ethyl 1-(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate 217 ethyl 1-(4-methyl-2-oxo-1-thioxopentyl)-2-piperidinecarboxylate 218 3-phenylpropyl 1-(2-hydroxy-3,3-dimethyl-pentanoyl)-2-piperidinecarboxylate 219 (1R)-1-phenyl-3-(3,4,5-trimethoxy-phenyl)propyl 1-(3,3-dimethylbutanoyl)-2-piperidinecarboxylate 220 (1R)-1,3-diphenylpropyl 1-(benzylsulfonyl)-2-piperidinecarboxylate 221 3-(3,4,5-trimethoxyphenyl)propyl 1-(benzylsulfonyl)-2-piperidinecarboxylate 222 1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylic acid 223 methyl 1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyl-tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate 224 isopropyl 1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyl-tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate 225 benzyl 1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyl-tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate 226 1-phenylethyl 1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyl-tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate Compound Name of Species 227 (Z)-3-phenyl-2-propenyl 1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate 228 3-(3,4-dimethoxyphenyl)propyl 1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl)-2-hydroxy-3-methyl-tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate 229 N2-benzyl-1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,'13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyl-tetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate 230 N2-(3-phenylpropyl)-1-(2-[(2R,3R,6S)-6-[(2S,3E,5E,7E,9S,11R)-2,:13-dimethoxy-3,9,11-trimethyl-12-oxo-3,5,7-tridecatrienyl]-2-hydroxy-3-methyltetrahydro-2H-2-pyranyl)-2-oxoacetyl)-2-piperidinecarboxylate.
231 (E)-3-(3,4-dichlorophenyl)-2-propenyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-carboxylate 232 (E)-3-(3,4,5-trimethoxyphenyl)-2-propenyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-carboxylate 233 (E)-3-phenyl-2-propenyl 1-(3,3-dimethyl-2-oxo pentanoyl}-2-piperidinecarboxylate 234 (E)-3-((3-(2,5-dimethoxy)-phenylpropyl)-phenyl)-2-propenyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate 235 (E)-3-(1,3-benzodioxol-5-yl)-2-propenyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-carboxylate 236 4-(4-methoxyphenyl)butyl 1-(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate 237 3-phenylpropyl 1-(2-oxo-~-phenylacetyl)-2-piperidinecarboxylate 238 3-(3-pyridyl)propyl 1-(2-oxo-2-phenylacetyl)-2-piperidinecarboxylate Compound Name of Species 239 3-(3-pyridyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate 240 4-phenyl-1-(3-phenylpropyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-carboxylate 241 4-(4-methoxyphenyl)butyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate 242 1-(4-methoxyphenethyl)-4-phenylbutyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-carboxylate 243 3-(2,5-dimethoxyphenyl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate 244 3-(1,3-benzodioxol-5-yl)propyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidine-carboxylate 245 1-phenethyl-3-phenylpropyl 1-(3,3-dimethyl-2-oxopentanoyl)-2-piperidinecarboxylate 246 9-(4-methoxyphenyl)butyl 1-(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate 247 3-cyclohexylpropyl 1-(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate 248 3-phenylpropyl 1-(2-cyclohexyl-2-oxoacetyl)-2-piperidinecarboxylate 249 3-cyclohexylpropyl 1-(3,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate 250 3-phenylpropyl 1-(3,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate 251 4-(4-methoxyphenyl)butyl 1-(3,3-dimethyl-2-oxobutanoyl)-2-piperidinecarboxylate 252 4-phenyl-1-(3-phenylpropyl)butyl 1-(3,3-dimethyl-2-oxobutanoyl)-2-piperidine-carboxylate FORMULA LV
In yet a further embodiment, there is provided a compound of formula LV:

K
J
B
N A
M
O O m ~ (LV) o r a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
m is 0-3;
A is CH2, 0, NH, or N-(C1-C9 alkyl) ;
B and D are independently hydrogen, Ar, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, CS-C, cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, or Ar substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein in each case, one or two carbon atoms) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, S0, and S02 in chemically reasonable substitution patterns, or the fragment T
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or CS-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C~ alkyl) , O- (C2-C9 alkenyl), and carbonyl;
Ar is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, vitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O- (C1-C9 straight or branched chain alkyl), O-(C2-C9 straight or branched chain alkenyl), 0-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U;
U is hydrogen, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, CS-C7 cycloalkenyl substituted with C1-CQ straight or branched chain alkyl or C2-CQ straight or branched chain alkenyl, (C,-Cq alkyl or CZ-CQ alkenyl)-Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl;
K is C1-C9 straight or branched chain alkyl, benzyl or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, SO, or S02, or J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety.
Representative species of Formula LV are presented in Table XXXVIII:

s m ~D
)n O
N
hi O
O
~O
L
TABLE XXXVIII
Cpd. n m B D L

253 2 0 3-Phenylpropyl3-(3-Pyridyl)propylPhenyl 254 2 0 3-Phenylpropyl3-(2-Pyridyl)propylPhenyl 255 2 0 3-Phenylpropyl2-(4-Methozyphenyl)ethylPhenyl 1 5 256 2 0 3-Phenylpropyl3-Phenylpropyl Phenyl 257 2 0 3-Phenylpropyl3-Phenylpropyl 3,4,5-Trimethozyphenyl 258 2 0 3-Phenylpropyl2-(3-Pyridyl)propyl3,4,5-Trimethozyphenyl 259 2 0 3-Phenylpropyl3-(2-Pyridyl)propyl3,4,5-Trimethozyphenyl 260 2 0 3-Phenylpropyl3-(4-Methozyphenyl)propyl3,4,5-Trimethozyphenyl 2 0 261 2 0 3-Phenylpropyl3-(3-Pyridyl) propyl3-iso-propozyphenyl FORMULA (LVI) U.S. Patent No. 5,330,993, incorporated herein by reference, discloses an exemplary pipecolic acid derivative 25 of formula LVI:
B
A
30 (LVI) D
or a pharmaceutically acceptable salt, ester, or solvate 35 thereof, wherein:
A is 0, NH, or N- (C1-CQ alkyl) ;
B is hydrogen, CHL-Ar, C,-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, CS-C7 cycloalkyl, CS-C7 cycloalkenyl, Ar substituted C1-C6 alkyl or C2-C6 alkenyl, or T
Q t wherein L and Q are independently hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or CS-C, cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, 0-(C1-CQ alkyl), 0-(C2-C9 alkenyl) , and carbonyl;
Ar is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, CF3, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, 0-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, 0-phenyl, amino, and phenyl.
D is hydrogen or U; E is oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen, then D is U;
U is hydrogen, O-(C1-C9 straight or branched chain alkyl) , 0- (C2-Cq straight or branched chain alkenyl) , C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, CS-C7-cycloalkyl, CS-C7 cycloalkenyl substituted with C1-CQ straight or branched chain alkyl or C2-Cq straight or branched chain alkenyl, 2-indolyl, 3-indolyl, (C1-CQ alkyl or C2-CQ alkenyl ) -Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl;

K is C1-CQ straight or branched chain alkyl, benzyl or cyclohexylethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with oxygen, sulfur, S0, or 502; or in the bridged heterocyclic derivative of the present invention J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety.
FORMULA LVII
A preferred bridged heterocyclic derivative is a compound of Formula LVII:
BI
(LVII) or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 2;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the piperidine ring (when n=2) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl; and B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropy:l, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl)butyl;
provided that:
when D is phenyl, then B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, or 4-cyclohexylbutyl;
when D is methoxy, B is benzyl, 4-cyclohexylbutyl, 3-cyclohexylpropyl, or 3-cyclopentylpropyl;
when D is 2-furyl, then B is benzyl; and when D is 3,4,5-trimethoxyphenyl, then B is 4-cyclohexylbutyl, 3-phenoxybenzyl, 4-phenylbutyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl)butyl.
Representative species of Formula LVII are presented in Table XXXIX.
TABLE XXXIX
Cpd. B D n 262 Benzyl Phenyl 2 263 3-Phenylpropyl Phenyl 2 2 0 264 4-(4-Methoxyphenyl} Phenyl 2 butyl 265 4-Phenylbutyl Phenyl 2 266 Phenethyl Phenyl 2 267 4-Cyclohexylbutyl Phenyl 2 268 Benzyl Methoxy 2 2 5 269 4-Cyclohexylbutyl Methoxy 2 269 3-Cyclohexylpropyl Methoxy 2 270 3-Cyclopentylpropyl Methoxy 2 271 Benzyl 2-Furyl 2 272 4-Cyclohexylbutyl 3,4,5-Trimethoxyphenyl 2 30 273 3-Phenoxybenzyl 3,4,5-Trimethoxyphenyl 2 274 4-Phenylbutyl 3,4,5-Trimethoxyphenyl 2 275 3-(3-Indolyl)propyl 3,4,5-Trimethoxyphenyl 2 276 4-(4-Methoxyphenyl)butyl3,4,5-Trimethoxyphenyl 2 The bridged heterocyclic derivative may also be a compound of formula LVIII:

B
A
(LVIII) m D
o r a pnarmaceutic ally acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S
J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) selected from the group consisting of 0, S, S0, 502, N, NH, and NR, or J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein R is independently either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, halo(C,-C6)-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-Cq alkenyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, (C1-C6) -alkylthio, sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar2;
Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;
wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S;

A, B, D, L, M, and m are as defined in Formula LV, above.
VI. SMALL MOLECULE SULFONAMIDES
FORMULA LIX
In an additional embodiment of the invention, there is provided a compound of formula LIX:
K B
A
\ n D
O
(LIX) or a pharmaceutically acceptable salt, ester or solvate thereof, wherein:
A is CH2, O, NH, or N-(C1-C9 alkyl);
B and D are independently Ar, hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with CS-C7 cycloalkyl, CS-C7 cycloalkenyl or Ar, and wherein one or two carbon atoms) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of 0, S, SO, and S02 in chemically reasonable substitution patterns, or T
Q
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or CS-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, 0- (C1-C9 alkyl), 0-(C2-CQ alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain aikenyl, O- (C1-C4 straight or branched chain alkyl) , O- (C2-C9 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, CS-C7 cycloalkyl, CS-C, cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-CQ straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl ) -Ar, or Ar;
J is hydrogen, C1 or CZ alkyl, or benzyl; K is C1-C4 straight or branched chain alkyl, benzyl, or cyclohexylmethyl; or J and K are taken together to form a 5-7 membered heterocyclic ring which is substituted with O, S, S0, or S02, or J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
n is 0 to 3; and the stereochemistry at carbon positions 1 and 2 is R
or S.

FORMULA LX
In a preferred embodiment of Formula LIX, J and K are taken together and the bridged heterocyclic derivative is a compound of Formula LX:

D
(LX) or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring (when n=1) or the piperidine ring (when n=2) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure; and m is 0 or 1.
In a more preferred embodiment, B is selected from the group consisting of hydrogen, benzyl, 2-phenylethyl, and 3 phenylpropyl;
D is selected from the group consisting of phenyl, 3-phenylpropyl, 3-phenoxyphenyl, and 4-phenoxyphenyl; and E is selected from the group consisting of phenyl, 9 methylphenyl, 9-methoxyphenyl, 2-thienyl, 2,4,6 triisopropylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 2 methoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N,N-dimethylamino) naphthyl, 4-iodophenyl, 2,4,6-trimethylphenyl, benzyl, 4 nitrophenyl, 2-nitrophenyl, 4-chlorophenyl, and E-styrenyl.

FORMULA LXI
Another exemplary bridged heterocyclic derivative is a compound of formula LXI:
Br E, _ ( LX I ) or a pharmaceutically acceptable salt, ester or solvate thereof, wherein:
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary piperidine ring are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
B and D are independently Ar, hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with CS-C7 cycloalkyl, CS-C7 cycloalkenyl or Ar, and wherein one or two carbon atoms) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of 0, S, S0, and S02 in chemically reasonable substitution patterns, or T
Q

wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or CS-C, cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, 0 (C1-C4 alkyl) , O- (C2-C4 alkenyl) , and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2 thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of 0, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, 0- (C1-C9 straight or branched chain alkyl) , O- (C2-C4 straight or branched chain alkenyl), 0-benzyl, 0-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, CS-C7 cyclaalkyl, CS-C, cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C9 alkyl or C2-Cq alkenyl)-Ar, or Ar; and m is 0 to 3.
FORMULA LXII
A further exemplary bridged heterocyclic derivative is a compound of Formula LXII:

WO 00!16603 PCT/US98/25577 a Br m (LXII) t or a pharmaceutically acceptable salt thereof, wherein:
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary pyrrolidine ring are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
B and D are independently Ar, hydrogen, C,-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with CS-C7 cycloalkyl, CS-C7 cycloalkenyl, or Ar, and wherein one or two carbon atoms) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of 0, S, S0, and S02 in chemically reasonable substitution patterns, or T
wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, 0-(C1-C9 alkyl), 0-(C2-C9 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic.heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, vitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, 0- (C1-CQ straight or branched chain alkyl) , O- (C2-C4 straight or branched chain alkenyl), O-benzyl, 0-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, CS-C7 cycloalkyl, CS-C7 cycloalkenyl substituted with C1-CQ straight or branched chain alkyl or C2-C9 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar; and m is 0 to 3.
FORMULA LXIII
A further exemplary bridged heterocyclic derivative is a compound of LXIII:
K
J~ A
D

(LXIII) E

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
J and K, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatom(s) selected from the group consisting of 0, S, S0, 502, N, NH, and NR, or J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety;
R is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, CS-C7 cycloalkenyl, a bridged ring moiety, or Arl, wherein R is independently either unsubst~.tuted of substituted with one or more substituent(s) independently selected from the group consisting of halo, halo(C1-C6)-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-CQ alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, (Cz-C6) -alkylthio, sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C,-C6) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar2;
Arl and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring;
wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of 0, N, and S;
A, B, D, E, and n are as defined in Formula LIX above.
Representative species of Formulas LIX-LXIII are presented in Table XL.
TABLE XL

Cpd. Structure and name 4-phenyl-1-butyl-1-(benzylsulfonyl)-(2R,S)-2-pipecolinate 1, 5-diphenyl-3-pentyl-N-(a-toluenesulfonyl)-pipecolate 1, 7-diphenyl-4-heptyl-N-(para-toluene-sulfonyl)pipecolate Cpd. Structure and name 3- ( 3-pyridyl)-1-propyl-(2S)-N-(a-toluenesulfonyl)-pyrrolidine-2-carboxylate phen yl-1-butyl-N-(para-toluenesulfonyl)pipecolate pheny 1-1-butyl-N-(benzenesulfonyl)-pipecolate Cpd. Structure and name phenyl-1-butyl-N-(a-toluenesulfonyl)pipecolate VII. CARBOXYLIC ACID ISOSTERES
Another preferred embodiment of the invention is a compound of formula LXIV:
Q.

(LXIV) in which:
n is 1-3;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1-3) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
X is either 0 or S;
R1 is independently selected from the group consisting of C1-C9 straight or branched chain alkyl, CZ-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-Clo straight or branched chain alkyl, C2-Clo alkenyl or C2-Clo alkynyl; and R2is independently a carboxylic acid or a carboxylic acid isostere;
or a pharmaceutically acceptable salt, ester, or solvate thereof.
Preferred embodiments of this invention are where R2 is independently a carbocycle or heterocycle containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions with R3.
Especially preferred embodiments of this invention are where R2 is "~ ~ " OH independently H ~ ( N HN~ ~ ~ selected from " HOOC H
the group H ° °H ° below:
~"-" NH I N NH
~N~ 6 ~~ HN
O O
O /N
NH ~~ HN
N ~ S N

O
OH
N / ~ ~~N ~ N
° °
O ~ HS H F H
OH
O
OH
NH ~ ~ ~ I
.J
3 5 '~°H
°

where the atoms of said ring structure may be optionally substituted at one or more positions with R3.
Another preferred embodiment of this invention is where R2 is independently selected from the group consisting of -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3} 2, -OR3, -SR3, -NHCOR3, -N ( R3 ) 2, -CON ( R3 ) 2, -CONH ( 0 } R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN wherein R3 is hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-alkoxy, C2-C6-alkenoxy, C,-C6-alkylaryloxy, aryloxy, aryl- C1-C6-alkyloxy, cyano, nitro, imino, C1-C6-alkylamino, amino- C1-C6-alkyl, sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and COzR~ where R4 is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl.
Preferred embodiments of this invention are: (2S)-1-(Z,2-dioxo-3,3-dimethylpentyl)-2-hydroxymethyl pyrrolidine;
(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinetetrazole; (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarbonitrile; and (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-aminocarbonyl piperidine.
A compound of the present invention, especially formula LXIV, wherein n is 1, X is 0, D is a bond. R, is l,l,dimethylpropyl, and R2 is -CN, is named (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carbonitrile.
Specific embodiments of the inventive compounds are presented in Tables XLI, XLII, and XLIII. The present invention contemplates employing the compounds of Tables XLI, XLII and XLIII, below.

~CH2)n / Rz N D
X
Table XLI
when D is a bond and R2 is COOH, No. X n _ R, _ 285 O 1 3,4,5-trimethylphenyl 286 O 2 3,4,5-trimethylphenyl 287 O 1 tent-butyl 287 O 3 tert-butyl 288 O 1 cyclopentyl 289 O 2 cyclopentyl 290 O 3 cyclopentyl 2 0 291 O 1 cyclohexyl 292 O 2 cyclohexyl 293 O 3 cyclohexyl 294 O 1 cycloheptyl 295 O 2 cycloheptyl 296 O 3 cycloheptyl 297 O 1 2-thienyl 298 O 2 2-thienyl 299 O 3 2-thienyl 300 O 1 2-furyl 301 O 2 2-furyl 302 O 3 2-furyl 303 O 3 phenyl 304 O 1 1,1-dimethylpentyl 305 O 2 l,l-dimethylhexyl 306 O 3 ethyl ~CH2)n N D
X
TABLE XLII
No. X n R, D RZ

308 S 1 1,1-dimethyl propyl CHz COOH

309 S 1 1, I-dimethyl propyl bond COOH

310 O 1 I, I-dimethyl propyl CHZ OH

311 O 1 1,1-dimethyl propyl bond S03H

312 O 1 1,1-dimethyl propyl CH2 CN

313 O 1 1,1-dimethyl propyl bond CN

314 O 1 1,1-dimethyl propyl bond tetrazolyl 315 S 1 phenyl (CH2)2 COON

316 S 1 phenyl (CHZ)3 COOH

2 317 S 2 phenyl CHZ COOH

318 O 1 1,1-dimethyl propyl bond CONHZ

319 O 2 1,1-dimethyl propyl bond CONHZ

320 S 2 2-furyl bond P03H2 321 O 2 propyl (CH2)2 COOH

2 322 O 1 propyl (CHZ)3 COOH

323 O 1 tert-butyl (CH )4 COON
z 324 O 1 methyl (CHAS COOH

325 O 2 phenyl (CH2)6 COON

326 O 2 3,4,5- trimethoxy- CHZ COON
phenyl 30 327 O 2 3,4,5- trimethoxy- CHz tetrazolyl phenyl TABLE XLIII
/ Rz D
R~
No. n X D RZ R, 328 1 S bond COOH Phenyl 329 1 O bond COOH a-MethylBenzyl 330 2 O bond COOH 4-MethylBenzyl 331 1 O bond Tetrazole Benzyl 332 1 O bond S03H a-MethyIBenzyl 333 1 O CHZ COOH 4-MethylBenzyl 334 1 O bond S02HNMe Benzyl 335 1 O bond CN a-MethylBenzyl 336 1 O bond P03Hz 4-MethylBenzyl 337 2 O bond COOH Benzyl 338 2 O bond COOH a-MethylBenzyl 2 339 2 O bond COOH 4-MethylBenzyl 340 2 S bond COOH 3,4,5-trimethoxyphenyl 341 2 O bond COOH Cyclohexyl 342 2 O bond P02HEt i-propyl 343 2 O bond P03HPropyl ethyl 2 344 2 O bond P03(Et)2 Methyl 345 2 O bond OMe tert-butyl 346 I O bond OEt n-pentyl 347 2 O bond OPropyl n-hexyl 348 1 O bond OButyl Cyclohexyl 30 349 1 O bond OPentyl cyclopentyl 350 1 O bond OHexyl n-heptyl 351 1 O bond SMe n-octyl 352 1 O bond SEt n-nonyl 353 2 O bond SPropyl 2-indolyl 3 354 2 O bond SButyl 2-furyl 355 2 O bond NHCOMe 2-thiazolyl 356 2 O bond NHCOEt 2-thienyl 357 1 O CHZ N(Me)Z 2-pyridyl 358 1 O (CH~2 N(Me)Et 1,1-dimethylpropyl 40 359 1 O (CH~3 CON(Me)2 1,1-dimethylpropyl 360 1 O (CH~4 CONHMe 1,1-dimethylpropyl 361 1 O (CHAS CONHEt 1,1-dimethylpropyl 362 1 O (CH~6 CONHPropyl 1,1-dimethylpropyl 363 1 O bond CONH(O)Me Benzyl 364 1 O bond CONH(O)Et a-Methylphenyl 365 1 . bond CONH(O)Propyl 4-Methylphenyl O

366 1 O (CH2)2 COOH Benzyl 367 1 O bond COOH a-Methylphenyl 368 1 O bond COOH 4-Methylphenyl 369 1 O CH2 , COOH 1,1-dimethylpropyl 370 1 O (CH~Z COOH 1,1-dimethylbutyl 371 1 O (CH~3 COOH l, l-dimethylpentyl 372 1 O (CH~4 COOH 1,1-dimethylhexyl 373 1 O (CHs COOH 1,1-dimethylethyl 374 1 O (CH~6 COOH iso-propyl 375 1 O (CHI, COOH tert-butyl 376 1 O (CH~$ COOH 1,I-dimethylpropyl 377 1 O (CH~9 COOH benzyl 378 1 O (CH~,a COOH 1,1-dimethylpropyl 2 379 1 O C2H2 COOH cyclohexylmethyl 380 1 O 2-OH,Et COOH 1,1-dimethylpropyl 381 1 O 2-butylene COOH 1,1-dimethylpropyl 382 1 S i-Pro COOH 1,1-dimethylpropyl 383 2 S t-Bu COOH phenyl 2 384 2 O 2-NOZ-hexylCOOH 1,1-dimethylpropyl 385 1 O (CH~z CN 1,1-dimethylpropyl 386 1 O (CH~3 CN 1,1-dimethylpropyl 387 3 O bond CONHNHSOZMe Benzyl 388 3 O bond CONHNHSOzEt a-Methylphenyl 3 389 3 O bond CONHSOZMe 4-Methylphenyl 390 1 O bond CONHNHSOZEt Phenyl 391 2 O bond CON(Me)CN a-Methylphenyl 392 1 O bond CON(Et)CN 4-Methylphenyl 393 1 O (CH~2 COOH methyl 35 394 1 O (CH~3 COOH ethyl 395 1 O (CH~4 COON n-propyl 396 1 O (CHs COOH t-butyl 397 1 O (CH~6 COOH Pentyl 398 1 O (CHI, COOH Hexyl 4 399 1 O (CH~B COOH Heptyl 400 1 O (CH~9 COOH Octyl 401 1 O CZH2 COOH Cyclohexyl No. n X D R, R~
402 2 O bond ~~~ 1,1-dimethylpropyl N
HN~ ~~
N
403 1 O bond ~ N 1,1-dimethylpropyl 'N
HOOG~ 'N
404 1 O bond ~~N 1,1-dimethylpropyl ,_N
~//N
H~C~
~?
405 I O bond ~~p~«, 1,1-dimethylpropyl H-N
406 1 O bond ~ ~" 1,1-dimethylpropyl N
\
N\NI
407 1 O bond ~ ° I ,1-dimethylpropyl NH

°
408 1 O bond s °" 1,1-dimethylpropyl ,N
/O
409 1 O bond ~ ° 1,1-dimethylpropyl ~NH
HN
\\\\O

-No. n X D R R~

410 1 O bond ~ 1,1-dimethylpropyl , N

~

OH

411 I O bond ~ 1,1-dimethylpropyl "

412 1 O bond ~ 1,1-dimethylpropyl N
'\

N

H

413 1 O bond ~ 1,1-dimethylpropyl ~~

N

F
H

414 1 O bond ~ 1,1-dimethylpropyl ~

\

_NH
_~/O

O

415 1 O bond ~~N 1,1-dimethylpropyl ~Et ~~N
416 1 O bond ~~N l , l-dimethylpropyl HN' ~\'\\S
4I7 1 O bond ~ 1,1-dimethylpropyl ,.N
I~/
AY
B~N

No. n X D RZ R, 418 1 O bond f ° 1,1-dimethylpropyl °
419 1 O bond ~ 1,1-dimethylpropyl . ~ ~
i 420 1 O bond ° 1,1-dimethylpropyl 421 1 O bond COOH 1,1-dimethylpropyl 422 2 O bond COOH 1,1-dimethylpropyl FORMULA LXV
Another preferred embodiment of this aspect of the invention is a compound of the formula LXV:
Br (LXV) in which X, Y, and Z are independently selected from the group consisting of C, 0, S, or N, provided that X, Y, and Z are not all C;
n is 1-3~
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1-3) are bonded to each other through either a chemical bond or atoms) other than a bond which dales) not comprise a part of the primary ring structure;
A is selected from the group consisting of L1, L2, L3.
or L4, in which O
O \
L~ is ~O , L2 is ~s R~ R~
E\
=O , and L4 is \N
L3 is ~ o R' R~
and R1 and E, independently, are selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbacycle, and heterocycle;
R2is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, where R3 is hydrogen, hydroxy, halo, halo (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, (C1-C6) -alkylaryloxy, aryloxy, aryl- (C1-C6) alkyloxy, cyano, nitro; imino, (C1-C6) alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio- (C1-C6) -alkyl, (C1-C6) -alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or C02R' where R' is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate thereof.
Preferred embodiments of this embodiment of the invention are those in which R2 is independently a carbocycle or heterocycle containing any combination of CH2, 0, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions with R3.
Especially preferred embodiments of this aspect of the invention are the use of those compounds in which R2 is independently selected from the group below:

H
\ / N OH
N \N N
HN
HN\ N HOOC H N-N
H ~ O H O
N
N ~NH ~ I ~ N NH
S ~~ HN
° O
O
N
/ ~ ~ /N
N~ ~ O
NH ~ HN
° °\ ~ S\
N ~ N
S
°
OH
v ~O O ( ~N I ~N
N HS H F H
O H
2 0 °H

OH
NH ~ ~ ~
I .aJ
2 5 0 °" o where the atoms of said ring structure may be optionally substituted at one or more positions with R3.
Another preferred embodiment of this invention is 30 where R2 is independently selected from the group consisting of -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (0) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN .
Preferred embodiments of this embodiment are the 35 compounds (2S)-1-(phenylmethyl)carbamoyl-2-hydroxymethyl (4-thiazolidine), (2S)-1-(1,1-dimethyl propyl)carbamoyl-2-(4-thiazolidine)tetrazole and (2S)-1-(phenylmethyl) carbamoyl-2-(4-thiazolidine) carbonitrile.
The following structures are non-limiting examples of preferred carbocyclic and heterocyclic isosteres contemplated by this aspect of the invention:
H
/N\ ~ ~ ~ /N~ ~ N OH
N N
I
HN\N "OOI: H ~ N-N
SH ~ 0 OH O
~N-C ~ ~ ~ ~
N NH f il N NH
N\NI ~ \O HN

~\ ///O, ' /"~ ~ N
N \ H ~ O
N ~~ HN
0 \N \N~
S

2 0 off N / ~~N ~~ ~ N
0 O ~ NI ~ N
0 ~ HS H F H
OH

S
2 5 °"
NH I ~ ~ I
.J
O ~OH
in which the atoms of said ring structure may be optionally 30 substituted at one or more positions with R3 wherein R3 is hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, C,-C6-alkoxy, C2-C6-alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl-C1-C6-alkyloxy, cyano, nitro, imino, C,-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, 35 sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and C02R' where R' is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl. The present invention contemplates that when chemical substituents are added to a carboxylic isostere then the compound retains the properties of a carboxylic isostere. Particularly, the present invention contemplates that when a carboxylic isostere is optionally substituted with one or more moieties selected from R3, then the substitution cannot eliminate the carboxylic acid isosteric properties of the compound. The present invention contemplates that the placement of one or more R3 substituents upon a carbocyclic or heterocyclic carboxylic acid isostere shall not be at an atoms) which maintains or is integral to the carboxylic acid isosteric properties of the inventive compound if such a substituent(s) would destroy the carboxylic acid isosteric properties of the inventive compound.
Other carboxylic acid isosteres not specifically exemplified or described in this specification are also contemplated by the present invention.
A compound for use in the present invention, especially formula LXV, wherein n is 1, X is 0, D is a bond, R1 is l,l,dimethylpropyl, and R2 is -CN, is named (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarbonitrile.
Specific embodiments of the inventive compounds are presented in Tables XLIV, XLV, and XLVI. The present invention contemplates employing the compounds of Tables XLIV, XLV, and XLVI, below, for use in compositions and methods of the invention.
TABLE XLIV

Y~~CH2)n ~R2 N D
A
~N o R~
No. n D R2 A y R~

423 1 bond COOH H S Benzyl 424 1 bond COOH H S a-MethylBenzyi 425 1 bond COON H S 4-MethylBenzyl 426 1 bond Tetrazole H S Benzyl 427 1 bond S03H H O a-MethylBenzyl 428 1 CHZ COOH H O 4-MethyIBenzyi 429 1 bond SOZHNMe H O Benryl 430 1 bond CN H N a-MethylBenzyl 431 1 bond P03HZ H N 4-MethylBenzyl 432 2 bond COOH H N Benzyl 433 2 bond COOH H S a-MethylBenzyl 2 434 2 bond COOH H S 4-MethyIBenzyl 435 2 bond COOH H S 3,4,5-trimethoxy-phenyl 436 2 bond COOH H S Cyclohexyi 437 2 bond POZHEt H O i-propyl 438 2 bond P03HPropyl H O ethyl 2 439 2 bond P03(Et)2 H N Methyl 440 2 bond OMe H S tert-butyl 441 2 bond OEt H S n-pentyl 442 2 bond OPropyi H S n-hexyl 443 1 bond OButyl H O Cyclohexyl 3 444 1 bond OPentyl H N cyciopentyl 445 1 bond OHexyl H S n-heptyl 446 1 bond SMe H S n-octyl 447 1 bond SEt H O n-nonyl 44.8 2 bond SPropyl H N 2-indolyl 35 449 2 bond SButyi H O 2-furyl 450 2 bond NHCOMe H S 2-thiazolyl 451 2 bond NHCOEt H S 2-thienyl 452 1 CHZ N(Me)Z H N 2-pyridyi 453 1 (CH~2 N(Me)Et H S 1,1-dimethylpropyl 4 454 I (CHZ)3 CON(Me)2 H O 1,1-dimethylpropyl 455 1 (CHZ)4 CONHMe H N 1,1-dimethylpropyl No. n D R2 A y R' 456 1 (CHAS CONHEt H S 1,1-dimethylpropyl 457 1 (CH~6 CONHPropyl H S 1,1-dimethylpropyl TABLE XLV
(CH2)n N /D
/$02 R/~
No. n D R2 Y R, 458 bond CONH(O)Me S Benzyl 459 bond CONH(O)Et S a-Methylphenyl 460 1 bond CONH(O)Propyl S 4-MethylphenyI

461 2 bond COOH S Benzyl 462 2 bond COOH O a-Methylphenyl 463 2 bond COOH O 4-Methylphenyl 2 464 1 CHZ COOH N benzyl 465 1 (CH~2 COON N benzyl 466 1 (CH~3 COOH N benzyl 467 1 (CH~4 COOH S benzyl 468 1 (CHAS COOH S benzyl 2 469 1 (CH~6 COOH S benzyl 470 1 (CH~7 COON S benzyl 471 1 (CH~g COOH O benzyl 472 1 (CH~9 COOH O benzyl 473 1 (CH~,o COOH O benzyl 3 474 1 CZHz COOH N benzyl 475 1 2-OH,Et COOH N benzyl 476 1 2butyleneCOOH S benzyl 477 1 i-Pro COOH S benzyl 478 1 tert-Bu COOH S benzyl 3 479 1 2-nitro COOH S benzyl Hexyl 480 3 (CH~Z CN S benzyl 481 1 (CHZ)3 CN S benzyl 482 3 bond CONHNHSOZMe N Benzyl 483 3 bond CONHNHS02Et N a-Methylphenyl 484 3 bond CONHSOZMe N 4-Methylphenyl 485 2 bond CONHNHSOZEt N Phenyl 486 2 bond CON(Me)CN O a-Methylphenyl 487 2 bond CON(Et)CN O 4-Methylphenyl 488 1 (CH~2 COOH O methyl 489 1 (CHZ)3 COOH O ethyl 490 1 (CH~4 COOH N n-propyl 491 1 (CHs COOH N t-butyl 492 1 (CH~6 COOH N Pentyl 493 1 (CHI, COOH S Hexyl 494 1 (CH~B COOH S Heptyl 495 1 (CH~9 COOH S Octyl 496 1 (CH~,o COOH S Nonyl 497 1 CZHZ COOH S Cyclohexyl TABLE XLVI
Y ~CH2)n No. n X D RZ Y R, 498 1 O bond ~ N off O 1,1-dimethylpropyl N-N
2 5 499 1 O bond ~ ~ S 1,1-dimethylpropyl N
N
N
500 1 O bond .~ S 1,1-dimethylpropyl N
HN~
N
501 1 O bond ~~N ~N O 1,1-dimethylpropyl --~~~N~
M ~ Me No. n X D R2 Y R, 502 1 O bond ~ N I, I-dimethylpropyl I 'N
HOOC H
503 1 O bond ~ ~N~ S I, I-dimethylpropyl OH
504 I O bond ~ °" N 1,1-dimethylpropyl i 505 1 O bond ~ N 1,1-dimethylpropyl ~~N
HS
506 1 O bond ~ S 1,1-dimethylpropyl I ~N
b 507 1 O bond ~ ° O 1, I-dimethylpropyl N' NH
O
508 1 O bond ~ ° S l,l-dimethylpropyl NH
S\ /
~\\O
509 1 O bond °" S 1,1-dimethylpropyl ~ ~ ~N
°
510 I O bond ~ ° O 1,1-dimethylpropyl NH
HN
~\(\\'O

No. n X D R2 Y R~
51 i 1 O bond ° S l, i-dimethylpropyl NH
O
512 1 O bond ~~ O 1,1-dimethylpropyl °H
513 1 O bond ~ S 1,1-dimethylpropyl 514 1 O bond ~N\ /E~ N 1,1-dimethylpropyl O- /~'N
S 15 1 O bond ~ ~ O 1,1-dimethylpropyl ,o H ~\\(N
s 516 1 O bond ~ S l, i-dimethylpropyl /j-'--Me S ~~~
N
Compounds 517-610 are also exemplified for use in the present invention, and are defined as where Y is located at the 3-position of the heterocyclic ring for compounds 423-516, and n, A, D, Y, X, R1, and R2 remain the same as defined for compounds 423-516 in Tables XLIV, XLV, and XLVI.
Exemplary compound 611 is defined where S is located at the 3-position of the heterocyclic ring (3-thiazolidine), n is 1, R1 is 1,1-dimethylpropyl, D is a bond, R2 i s COON .

Exemplary compound 612 is defined where 0 is located at the 2-position of the heterocyclic ring (2-oxopentanoyl), n is 1, R1 is 1,1-dimethylpropyl, D is a bond, R2 is COOH (i.e. 3-(3,3-dimethyl-2-oxopentanoyl)-1,3-oxazolidine-4-carboxylic acid).
The present invention also contemplates other ring locations for the heteroatoms 0, N, and S in heterocyclic compounds. Also contemplated by the present invention are heterocycles containing 3 or more heteroatoms chosen independently from O, N, and S.
TABLE XLVII
(CH2)n N D
L~
R~
No. n D R~ L R, 613 I CHZ OH 1,2-dioxoethylbenzyl 614 1 bond -CN 1,2-dioxoethylI,1-dimethylpropyl 615 1 bond tetrazole1,2-dioxoethyll,I-dimethylpropyl 616 2 band CONH2 1,2-dioxoethyl1,1-dimethylpropyl 617 I bond COOH 1,2-dioxoethyl1,1-dimethylpropyl 618 2 bond COOH 1,2-dioxoethyl1,1-dimethylpropyl FORMULA LXVI
In another embodiment of the invention, there is provided a compound of formula LXVI:

BP., ~CH2~~
~ RZ
N D
A
N O
(LXVI) R~
in which:
n is 1-3;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1-3) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;
R1 and A are independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, CZ-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, and heterocycle;
D is a bond, or a C1-Clo straight or branched chain alkyl, C2-Clo alkenyl or C2-C1o alkynyl;
R2 is independently carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, where R3 is hydrogen, hydroxy, halo, halo (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, (C1-C6) -alkylaryloxy, aryloxy, aryl- (C1-C6) -alkyloxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio- (C1-C6) -alkyl, (C1-C6) -alkylthio, sulfonyl, C1-C6 straight WO 00/16603 PCT/US98/2557?

or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and C02R4 where R' is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate thereof.
A preferred compound for use in this embodiment of this invention is (2S)-1-(cyclohexyl)carbamoyl-2 pyrrolidinecarboxylic acid.
Other preferred compounds for use in this embodiment of this invention are those in which R2 is independently a carbocycle or heterocycle containing any combination of CH2, 0, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions with R3.
Especially preferred embodiments of this aspect of the invention are those in which R2 is independently selected from the group below:

yi/ ~ ~N~ Y// N N OH
HN' ~ N ~ NI H
N HOOC _H N-N
H~ ° °
~N~
N ~ N NH
I
N\N ~ ~O
O O
O /
I NH ~~ HN
N S N
S
O
OH
/ N ~ ~~N
\° ~
'N
° ~l~ HS ~ F H
OH
O
OH
NH
2 0 ° °" °
where the atoms of said ring structure may be optionally substituted at one or more positions with R3.
Another preferred embodiment of this invention is where R2 is independently selected from the group consisting of -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, SR3, -NHCOR3, -N ( R3 ) 2, -CON ( R3 ) 2, -CONH ( 0 ) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN .
"Isosteres" are different compounds that have different molecular formulae but exhibit the same or 34 similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated by the present invention include -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 ( R3 ) 2, -OR3, -SR3, -NHCOR3, -N ( R3 ) 2, -CON ( R3 ) 2, -CONH (O) R3.
-CONHNHS02R3, -COHNS02R3, and -CONR3CN wherein R3 is hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-alkoxy, C2-C6-alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl- C1-C6-alkyloxy, cyano, nitro, imino, C1-C6-alkylamino, amino- C1-C6-alkyl, sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and C02R9 where RQ is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl.
In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, O, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of preferred carbocyclic and heterocyclic isosteres contemplated by this aspect of the invention:

H
~N~ ~ ~ ~ N OH
N N N
~~H~
HN\ ~ HOOC H ~ N-~N
sH ~ o off o NH - 'N
N NH
N S ~~ HN
O O
S) O
IO ~~N~ N /N~O ~ 'N
~NH H
0 \ S\
N
S
O
OH
I5 ~ O O /N ~ /N

OH
O

S
OH

O ~OH

where the atoms of said ring structure may be optionally substituted at one or more positions with R3 wherein R3 is 25 hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-alkoxy, C2-C6-alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl-C1-C6-alkyloxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio- C1-C6-alkyl; C1-C6-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 30 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and C02R9 where R° is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl. The present invention contemplates that when chemical substituents are added to a carboxylic isostere then the inventive compound retains the properties of a carboxylic isostere.
The present invention contemplates that when a carboxylic isostere is optionally substituted with one or more moieties selected from R3, then the substitution cannot eliminate the carboxylic acid isosteric properties of the inventive compound. The present invention contemplates that the placement of one or more Rj substituents upon a carbocyclic or heterocyclic carboxylic acid isostere shall not be permitted at one or more atoms) which maintains) or is/are integral to the carboxylic acid isosteric properties of the inventive compound, if such substituent(s) would destroy the carboxylic acid isosteric properties of the inventive compound.
A compound of the present invention, especially formula LXVI, wherein n is 1, X is 0, D is a bond, R1 is l,l,dimethylpropyl, and R2 is -CN, is named (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarbonitrile.
Specific embodiments of the inventive compounds are presented in Table XLVIII. The present invention contemplates employing the compounds of Table XLVIII, below, for use in compositions and methods of the invention.

No. n D RZ A R~

619 1 bond COOH I-f cyclohexyl 620 I bond COOH H a-MethylBenzyl 3 5 621 1 bond COOH H 4-MethylBenzyl TABLE XLVIII

No. n D R A

622 1 bond Tetrazole H Benzyl 623 1 bond S03H H a-MethylBenzyl 624 1 CH2 COOH H 4-MethylBenzyl 625 1 bond S02HNMe H Benzyl 626 1 bond CN H a-MethylBenzyl 627 1 bond P03H2 H 4-MethylBenzyl 628 2 bond COON H Benzyl 629 2 bond COOH H a-MethylBenzyl 630 2 bond COOH H 2-butyl 631 2 bond COON H 2-butyl 632 2 bond COOH H Cyclohexyl 633 2 bond POZHEt H i-propyl 634 2 bond P03HPropyl H ethyl 635 2 bond P03(Et)2 H Methyl 636 2 bond OMe H tert-butyl 637 2 bond OEt H n-pentyl 638 2 bond OPropyl H n-hexyl 639 1 bond OButyl H Cyclohexyl 639 1 bond OPentyl H cyclopentyl 2 640 1 bond OHexyl H heptyl 641 1 bond SMe H n-octyl 642 1 bond SEt H n-hexyl 643 2 bond SPropyl H n-hexyl 644 2 bond SButyl H n-hexyl 2 645 2 bond NHCOMe H n-hexyl 646 2 bond NHCOEt H 2-thienyl 647 1 CHz N(Me)2 H adamantyl 648 1 (CH~z N(Me)Et H adamantyl 649 1 (CH~3 CON(Me)Z H adamantyl 3 650 1 (CH~4 CONHMe H adamantyl 651 1 (CHAS CONHEt H adamantyl 652 1 (CH~6 CONHPropyl H adamantyl 653 1 bond CONH(O)Me H Benzyl 654 1 bond CONH(O)Et H a-methylphenyl.

3 655 1 bond CONH(O)Propyl H 4-Methylphenyl 657 2 bond COON H Benzyl 658 2 bond COOH H a-Methylphenyl 659 2 bond COOH H 4-Methylphenyl 660 1 CH2 COOH Me cyclohexyl 4 661 1 (CH~2 COOH Et cyclohexyl 662 1 (CH~3 COON Prop cyclohexyl 663 1 (CH~4 COOH But cyclohexyl No. n D R2 A R, 664 1 (CHs COOH H cyclohexyl 665 1 (CH~6 COOH H cyclohexyl 666 1 (CH~7 COOH H cyclohexyl 667 1 (CH~B COOH H cyclohexyl 668 1 (CH~9 COON H cyclohexyl 669 1 (CH~,o COOH H cyclohexyl 670 1 CZHZ COON H cyclohexyl 671 1 2-OH,Et COOH H cyclohexyl 672 1 2-butylene- COOH H cyclohexyl 673 1 i-Pro CbOH H cyclohexyl 674 1 tert-Bu COOH H cyclohexyl 675 1 2-nitro Hexyl COOH H cyclohexyl 676 3 (CH~}2 CN H cyclohexyl 677 1 (CH~3 CN H cyclohexyl I5 678 3 bond CONHNHSOZMe H Benzyl 679 3 bond CONHNHSOZEt H a-Methylphenyl 680 3 bond CONHSOZMe H 4-Methylphenyl 681 2 bond CONHNHS02Et H Phenyl 682 2 bond CON(Me)CN H a-Methylphenyl 2 0 683 2 bond CON(Et)CN H 4-Methylphenyl 684 1 (CH~2 COOH H methyl 685 1 (CH~3 COOH H ethyl 686 1 (CH~4 COOH H n-propyl 687 1 (CHAS COOH H t-butyl 2 5 688 1 (CHZ)6 COOH H Pentyl 689 1 (CHZ)7 COON H Hexyl 690 1 (CH~B COOH H Heptyl 691 1 (CH~9 COOH H Octyl 692 1 (CH~,o COOH H Nonyl 3 0 693 1 CZHZ COOH H Cyclohexyl 694 1 bond ,~ H cyclohexyl N
HN~
N
695 1 bond \ H cyclohexyl 'N
HOOC /H
696 1 bond ~~" ~N H cyclohexyl N
M ~ Me No. n D R p R
697 1 bond ~ " °" H cyclohexyl N-N
698 1 bond ~ " H cyclohexyl N
~N
N
699 1 bond ° H cyclohexyl ~NH
S
~\('\'0 700 1 bond °" H cyclohexyl ~N
O
701 1 bond ° H cyclohexyl NH
HN
~,('1'O
702 1 bond i ~ H cyclohexyl OH
703 1 bond o" H cyclohexyl NH
704 1 bond \ H cyclohexyl -N
'N
HS H

-No. n D

705 1 bond N H cyclohexyl ' N

N
F H

706 1 bond H cyclohexyl ~NH
HN' /
~( \'O

707 1 bond ~ H cyclohexyl \ /
N
Ifr' /r--Et O ~~~
N

708 1 bond ~ 'N H cyclohexyl HN' ~\('\'S
709 1 bond .~~N~Me H cyclohexyl -~\'S- ~N
710 1 bond ° H cyclohexyl a 711 1 bond ~~ H cyclohexyl s OH
712 1 bond H cyclohexyl OH
O

TABLE IL
(CHt)n /Ri N D
R~
No. n D R L R

713 1 CHZ OH I,2-dioxoethylbenzyl 714 1 bond -CN 1,2-dioxoethyl1,1-dimethylpropyl 715 1 bond tetrazole 1,2-dioxoethyl1,1-dimethylpropyl 716 2 bond CONH2 1,2-dioxoethylI,1-dimethylpropyl 717 1 bond COOH I,2-dioxoethyl1,1-dimethylpropyl 718 2 bond COOH 1,2-dioxoethylI,I-dimethylpropyl FORMULA LXVII
Another preferred embodiment of the invention is a compound of the formula LXVII:
Bf ~~; ,' (CHZ)n ~ ~Rz N D
O ~~O
(LXVII) in which:
n is 1-3;
the primary ring structure optionally includes Br, wherein Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is f-3) are bonded to each other through either a chemical bond or atoms) other than a bond which doles) not comprise a part of the primary ring structure;

R1 is independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-Clo straight or branched chain alkyl, C2-Clo alkenyl or C2-Clo alkynyl;
R2 is independently a carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, where R3 is independently hydrogen, hydroxy, halo, , halo- (C1-C6) -alkoxy, thiocarbonyl, (C1 C6) -alkoxy, (C2-C6) -alkenyloxy, (C1-C6) alkylaryloxy, aryloxy, aryl- (C1-C6) -alkyloxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino-(C1-C6) -alkyl, sulfhydryl, thio- (C1-C6) alkyl, (C1-C6) -alkylthio, sulfonyl, C1-Cf; straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or C02R9 where RQ is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester or solvate thereof.
A preferred embodiment of this invention is the use of a compound in which R2 is independently a carbocycle or heterocycle containing any combinatian of CHz, O, S, or N
in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions with R3.
Especially preferred embodiments of this aspect of the invention are the use of those compounds in which R2 is independently selected from the group below:

OH
N I ~N ~ N
HN~ ~ HN
N HOOC H N--N
~ H ~ H
N
N NH
N
N / S ~ /NH
N p HN\/
~\'O
O
IO p ~ N
~N~ / O
I NH ~ ~ HN
0\ S
N N
S
O
H

0 O ( /N ,N
O H HS H/ F /H
OH
OH
NH I ~ ~ ~ I
O OH

in which the atoms of said ring structure may be optionally substituted at one or more positions with R3.
Another preferred embodiment of this ;nvant;"n where R2 is independently selected from the group consisting of -COOH, -S03H, -S02HNR3, -P02.(R3) 2, -CN, -P03 ( R3 ) 2, -OR3, -SR3, -NHCOR3, -N ( R3 ) 2, -CON ( R3 ) 2, -CONH ( 0 ) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN .
Preferred embodiments of this i n«Pnt; ~n ~,-o +-~,..
following compounds: (2S)-1-(phenylmethyl)sulfonyl-2-hydroxymethyl pyrrolidine; (2S)-1-(phenylmethyl)-sulfonyl-2-pyrrolidinetetrazole; (2S)-1-(phenyl-methyl)-sulfonyl-2-pyrrolidine carbonitrile; and compounds 719-821.

"Isosteres" are different compounds that have different molecular formulae but exhibit the same or similar properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they both have very different molecular formulae. Tetrazole is one of many possible isosteric replacements for carboxylic acid. Other carboxylic acid isosteres contemplated by the present invention include -COOH, -S03H, -S02HNR3, -P02 (R3) 2, -CN, -P03 (R3) 2, -OR3, -SR3, -NHCOR3, -N (R3) 2, -CON (R3) 2, -CONH (O) R3, -CONHNHS02R3, -COHNS02R3, and -CONR3CN, wherein R3 is hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-alkoxy, C2-C6-alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl-C1-C6-alkyloxy, cyano, nitro, imino, C1-C6-alkylamino, amino- C1-C6-alkyl, sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and C02R4 where R' is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl.
In addition, carboxylic acid isosteres can include 5-7 membered carbocycles or heterocycles containing any combination of CH2, 0, S, or N in any chemically stable oxidation state, where any of the atoms of said ring structure are optionally substituted in one or more positions. The following structures are non-limiting examples of preferred carbocyclic and heterocyclic isosteres contemplated by this aspect of the invention.

N
N N N OH
HN~ ~ N~ HN
N HOOC H N-N
H ~ O H O
~N
N NH /N NH
N~ ~ S HN
N O
O
O
lO N
\N O ~"
O
NH
HN
N
S
O
off O ( N I N
O
O ~ HS H F H
OH

OH
NH ~ ~ I
~J
O OH
O
where the atoms of said ring structure may be optionally substituted at one or more positions with R3. The present invention contemplates that when chemical substituents are added to a carboxylic isostere then the inventive compound retains the properties of a carboxylic isostere. The present invention contemplates that when a carboxylic isostere is optionally substituted with one or more moieties selected from R3, then the substitution can not eliminate the carboxylic acid isosteric properties of the inventive compound. The present invention contemplates that the placement of one or more R3 substituents upon a carbocyclic or heterocyclic carboxylic acid isostere shall not be at an atoms) which maintains or is integral to the carboxylic acid isosteric properties of the inventive compound if such a substituent(s) would destroy the carboxylic acid isosteric properties of the inventive compound.
Other carboxylic acid isosteres not specifically exemplified or described in this specification are also contemplated by the present invention.
A compound of the present invention, especially formula LXVII, wherein n is 1, D is a bond, R1 is phenylmethyl, and R2 is -CN, is named (2S)-1-(phenylmethyl) sulfonyl-2-pyrrolidine carbonitrile.
Specific embodiments of the inventive compounds are presented in Tables L and LI. The present invention contemplates employing the compounds of Tables L and LI, below, for use in compositions and methods of the invention.
TABLE L
(CHZ)n N D
o '~o R~
No. n D RZ R, 719 1 bond COOH Benzyl 3 0 720 1 bond COOH a-MethylBenzyl 721 1 bond COOH 4-MethyIBenzyl 722 1 bond Tetrazole Benzyl 723 1 bond S03H a-MethyLBenzyl 724 1 CHZ COOH 4-MethylBenzyl 3 5 725 1 bond SOZHNMe Benzyl 726 1 bond CN a-MethylBenzyl No. n D R R, 727 1 bond P03Hz 4-MethylBenzyl 728 2 bond COOH Benzyl 729 2 bond COOH a-MethyIBenzyl 730 2 bond COOH 4-MethylBenzyl 731 2 bond COOH 3,4,5-trimethoxy-phenyl 732 2 bond COOH Cyclohexyl 733 2 bond POZHEt i-propyl 734 2 bond P03HPropyl ethyl 735 2 bond P03(Et)2 Methyl 736 2 bond OMe tert-butyl 737 2 bond OEt n-pentyl 738 2 bond OPropyl n-hexyl 739 1 bond OButyl Cyclohexyl 740 1 bond OPentyl cyclopentyl 741 1 bond OHexyl n-heptyl 742 1 bond SMe n-octyl 743 1 bond SEt n-nonyl 744 2 bond SPropyl 2-indolyl 745 2 bond SButyl 2-furyl 2 746 2 bond NHCOMe 2-thiazolyl 747 2 bond NHCOEt 2-thienyl 748 1 CHZ N(Me)Z 2-pyridyl 749 1 (CH~z N(Me)Et benzyl 750 1 (CH~3 CON(Me}2 benzyl 2 751 1 (CH~4 CONHMe benzyl 752 1 (CHAS CONHEt benzyl 753 1 (CH~6 CONHPropyl 1,1-dimethylpropyl 754 1 bond CONH(O)Me Benzyl 755 1 bond CONH(O)Et a-Methylphenyl 3 756 1 bond CONH(O)Propyl 4-Methylphenyl 757 2 bond COON Benzyl 758 2 bond COOH a-Methylphenyl 759 2 bond COOH 4-Methylphenyl 760 1 CH2 COOH benzyl .

3 761 1 (CH~2 COOH benzyl 762 1 (CH~3 COON benzyl 763 1 (CH~4 COOH benzyl 764 1 (CHs COOH benzyl 765 1 (CH~6 COOH benzyl 4 766 1 (CH~7 COOH benzyl 767 1 (CHZ)$ COOH benzyl 768 1 (CHZ)9 COOH benzyl No. n D R2 R, 769 1 (CH~,o COOH benzyl 770 1 C2H2 COOH benzyl 771 1 2-hydroxyethylCOOH benzyl 772 1 2-butylene COOH benzyl 773 1 i-Propyl COOH benzyl 774 1 tert-Butyl COOH benzyl 775 1 2-nitrohexyl COOH benzyl 776 3 (CH~Z CN benzyl 777 1 (CH~3 CN benzyl 778 3 bond CONHNHSOZMe Benzyl 779 3 bond CONHNHSOZEt a-Methylphenyl 780 3 bond CONHSOZMe 4-Methylphenyl 781 2 bond CONHNHSOZEt Phenyl 782 2 bond CON(Me)CN a-Methylphenyl 783 2 bond CON(Et)CN 4-Methylphenyl 784 1 (CHZ)Z COOH methyl 785 1 (CH~3 COOH ethyl 786 1 (CH~4 COON n-propyl 787 1 (CHAS COOH t-butyl 2 788 1 (CH~6 COOH Pentyl 789 1 (CHI, COOH Hexyl 790 1 (CH~g COOH Heptyl 791 1 (CH~9 COOH Octyl 792 1 (CH~,o COOH Nonyl 2 793 1 C2H2 COOH Cyclohexyl 794 1 bond benzyl \ 'N\
r' //N
I

HN '/~
N

795 1 bond benzyl ~N\
,N
N /~
H3C~

796 1 bond benzyl N
\\N
N
HOOC H
797 1 bond ~ " off benzyl N-N

No. n D R R
3 0 798 1 bond ~ S" benzyl N' ~N
N
N
799 1 bond ~ o l~~yl NH
S

800 1 bond S aH benzyl /N
O
801 1 bond ° benzyl ~NH
HN
O
802 1 bond ~ benzyl 'N\
\O
OH
3 5 803 1 bond benzyl 804 1 bond ~ benzyl N
~~N
N
HS H

No. n D Rz R, 805 1 bond ~ benzyl \

N

N
F H

806 1 bond ~ benzyl \ N

I NH
O

O

807 1 bond ~ benzyl N
~' /j--Et O
N
4 0 808 1 bond ~ benzyl \ / N' \O
HN
S
809 1 bond ~ ~~yl N
Ir' ir--Me S ~~~
N
810 1 bond ~ ° benzyl NH
O
811 1 bond ~~ benzyl s OH

No. n D R R
812 1 bond benzyl 813 1 bond CHZOH benzyl 814 1 bond CONHZ benzyl 815 1 bond CN benzyl TABLE LI
~CH2)n ~Rz ~ D
L\
R~
No. n D R L R

816 1 CHZ OH 1,2-dioxoethyl ~~yl 817 1 bond -CN 1,2-dioxoethyl 1,1-dimethylpropyl 818 1 bond tetrazole 1,2-dioxoethyl 1,1-dimethylpropyl 819 2 bond CONH2 1,2-dioxoethyl 1,1-dimethylpropyl 820 1 bond COOH 1,2-dioxoethyl 1,1-dimethylpropyl 821 2 bond COON 1,2-dioxoethyl 1,1-dimethylpropyl Svnthesis of Compounds of the Invention The compounds for use in the methods and compositions of the invention may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathways depicted below.
In the preparation of the compounds of the invention, one skilled in the art will understand that one may need to protect or block various reactive functionalities on the starting compounds or intermediates while a desired reaction is carried out on other portions of the molecule.

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CECI EST LE TOME '( DE
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THAN ONE VOLUME , THIS IS VOLUME ~ , OF
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Claims (80)

WE CLAIM:

1. A compound of formula I':

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which contains one or more O, C (R1)2, S (O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is R1 is independently hydrogen, C1-C9 straight or branched chain alkyl, or C2-C9 straight or branched chain alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a carboxylic acid or carboxylic acid isostere, N (R4)n, Ar1, Ar4, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or bridged ring moiety, is optionally substituted with one or more substituent(s) independently selected from the group consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6 cycloalkyl wherein said furyl, thienyl, pyridyl, phenyl or cycloalkyl group optionally is substituted with C1-C4 alkoxy, (Ar1) n, halo, halo-C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6 thioester, cyano, imino, COOR6 in which R6 is independently C1-C9 straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy, C1-C6 alkylaryloxy C1-C6 aryloxy, aryl- (C1-C6) -alkyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, C1-C6-alkylthio, sulfhydryl, sulfonyl, amino, (C1-C6)-mono- or di-alkylamino, amino- (C1-C6) -alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl optionally substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, C3-C8 cycloalkyl, and Ar2, and, wherein any carbon atom of an alkyl or alkenyl group may optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring contains 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;
or, R1 is independently a moiety of the formula:

wherein:

R3 is independently C1-C9 straight or branched chain alkyl which is optionally substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR6, wherein R6 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, C2-C5 straight or branched chain alkenyl substituted with phenyl, and a bridged ring moiety;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of C1-C6 straight or branched chain alkyl,C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and hydroxy: or, R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that if R2 is hydrogen, then Y is CH-P, or if Y is oxygen then R2 is P:
P is hydrogen, O- (C1-C4 straight or branched chain alkyl), O- (C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C6 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl) -Ar5, or Ar5;
U is either 0 or N, provided that:
when U is O, then R' is a lone pair of electrons and R" is selected from the group consisting of Ar4, a bridged ring moiety, C3-C8 cycloalkyl, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
and when U is N, then R' and R" are, independently, selected from the group consisting of hydrogen, Ar4, a bridged ring moiety, C3-C10 cycloalkyl, a C7-C12 bi- or tri-cyclic carbocycle, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to form a heterocyclic 5- or 6-membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C (R1) 2, O, S, a direct bond or NR1; or, Z-R1 is independently wherein:
C and D are, independently, hydrogen, a bridged ring moiety, Ar4, Ar1, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and Ar4; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6 thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano, nitro, imino, C1-C6 alkylamino, amino- (C1-C6) alkyl, sulfhydryl, thio- (C1-C6) alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, or (SO)p;
C' and D' are independently hydrogen, a bridged ring moiety, Ar5, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
and T is Ar5 or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl, J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally replaced with O, NR''', or S(O)p, wherein R''' is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar3 group;
K' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O)p;
K'' is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine being selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, said aromatic amine being optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NR x R y R z, wherein R k, R y, and R z are independently selected from the group consisting of C1-C6 straight or branched chain alkyl and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, a bridged ring moiety, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally substituted with C1-C9 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally replaced with O, NR', S(O)p;
L' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O)p:
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties: wherein the individual alicyclic or aromatic ring contains 5-8 members and wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar5 optionally contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl; and R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar4 or Ar1 group.

2. The compound of claim 1, wherein the compound is formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR2;
X is either O or S;
Z is either S, CH2, CHR1 or CR1R3;
W and Y are independently O, S, CH2 or H2;
R1 and R3 are independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, a bridged ring moiety, and hydroxy; and Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

3. The compound of claim 2, wherein the compound is formula II:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1 or 2;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring (when n=1) or the piperidine ring (when n=2) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is O or S;
Z is selected from the group consisting of S, CH2, CHR1, and CR1R3:
R1 and R3 are independently selected from the group consisting of C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, a bridged ring moiety, and Ar1, wherein said alkyl, alkenyl or Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, a bridged ring moiety, hydroxy, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, amino, and Ar1;
R2 is independently selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and Ar1; and Ar1 is independently phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino.

4. The compound of claim 2, wherein the compound is formula III:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, and C are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any two or more of A, B, and C are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is O or S;
Z is S, CH2, CHR, or CR1R3;
R1 and R3 are independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n, a bridged ring moiety, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

5. The compound of claim 2, wherein the compound is formula IV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, C and D are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any two or more of A, B, C and D are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is O or S;
Z is S, CH2, CHR1 or CR1R3;
R1 and R3 are independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein said ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, vitro, trifluoro-methyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

6. The compound of claim 1, wherein the compound is formula V:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR4;
X is either O or S;
Z is either S, CH2, CHR1 or CR1R3;
W and Y are independently O, S, CH2 or H2;
R1 and R3 are independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n, C3-C6 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C6 cycloalkyl, a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, a bridged ring moiety, and hydroxy;
R4 is independently either C1-C9, straight ar branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar3, wherein R4 is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, halo-C1-C6-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio-C1-C6-alkyl, C1-C6-alkylthio, sulfhydryl, amino, C1-C6-alkylamino, amino-C1-C6-alkyl, aminocarboxyl, a bridged ring moiety, and Ar4; and Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic rings wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

7. The compound of claim 1, wherein the compound is formula VI:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR1;
X is O or S;
Z is O, NH or NR1;
W and Y are independently O, S, CH2 or H2;
R1 is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, which is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, a bridged ring moiety, and Ar2;
n is 1 or 2;
R2 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain or alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

8. The compound of claim 7, wherein the compound is formula VII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B and C are independently CH2, O, S, SO, SO2, NH or NR1;
Br is a heterocylic bridged ring moiety, wherein any two or more of A, B and C are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
R1 is C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, or a bridged ring moiety, which is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n;
n is 1 or 2;
R2 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1; and Ar1 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

9. The compound of claim 8, wherein the compound is formula:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any two or more of A, B and C are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure.

10. The compound of Claim 8, wherein:
A is CH2;
B is CH2 or S;
C is CH2 or NH;
R1 is selected from the group consisting of 3-phenylpropyl and 3-(3-pyridyl)propyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, and tert-butyl.

11. The compound of claim 7, wherein the compound is formula VIII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A, B, C and D are independently CH2, O, S, SO, SO2, NH
or NR1;
Br is a heterocylic bridged ring moiety, wherein any two or more of A, B, C and D are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
R1 is independently C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n;
n is 1 or 2;
R2 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1; and Ar1 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

12. The compound of Claim 11, wherein:
A is CH2;
B is CH2;
C is S, O or NH;
D is CH2;
R1 is selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy)phenylpropyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and 3,4,5-trimethoxyphenyl.

13. The compound of claim 1, wherein the compound is formula IX:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR;
R is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar3, wherein R is independently either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, halo-C1-C6-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio-C1-C6-alkyl, C1-C6-alkylthio, sulfhydryl, amino, C1-C6-alkylamino, amino-C1-C6-alkyl, aminocarboxyl, a bridged ring moiety, and Ar4;
Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and X is O or S;
Z is O, NH or NR1;
W and Y are independently O, S, CH2 or H2;
R1 is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, or a bridged ring moiety, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of (Ar1)n, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, and Ar2;
n is 1 or 2;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain or alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 straight or branched chain alkyl, C2-C4 straight or branched chain alkenyl, and hydroxyl; and Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S.

14. The compound of claim 1, wherein the compound is formula X:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR1;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;

Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6 are independently selected from the group consisting of a bridged ring moiety, or C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, SO, or SO2;
Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.

15. The compound of claim 14, wherein the compound is formula XI:
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, G and J are independently CH2, O, S, SO, SO2, NH
or NR1;
Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, G and J are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and Ar1;
Ar1 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;

R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, a bridged ring moiety, and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, SO, or SO2;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.

16. The compound of claim 14, wherein the compound is formula XII:
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH
or NR1;
Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, and G are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and Ar1;

Ar1 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl,a bridged ring moiety, and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, SO, or SO2;
Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight: or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.

17. The compound of claim 14, wherein the compound is formula XIII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1, 2, or 3, forming a 5-7 member heterocyclic ring;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1, 2, or 3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and Ar1;
Ar1 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR1, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched .chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino said tertiary amine is NR4R5R6, wherein R4, R5, and R6 are independently selected from the group consisting of C1-C6 straight or branched chain alkyl, a bridged ring moiety, and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, SO, or SO2;
Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3, independently, are hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.

18. The compound of claim 1, wherein the compound is formula XIV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR7;
R7 is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar3, wherein R7 is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, halo-C1-C6-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, a bridged ring moiety, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio-C1-C6-alkyl, C1-C6-alkylthio, sulfhydryl, amino, C1-C6-alkylamino, amino-C1-C6-alkyl, aminocarboxyl, and Ar4;
Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
W is O, S, CH2, or H2;
R is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, which is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, hydroxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, and Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, having one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, NH, NR2, S, CH, CR1, or CR1R3;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;
wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide;
said aromatic amine is selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, or isoquinolinyl, which is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
said tertiary amine is NR4R5R6, wherein R4, R5, and R6 are independently selected from the group consisting of a bridged ring moiety, or C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar is optionally replaced with O, NH, NR1, S, SO, or SO2;
Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R1 and R3 are independently hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z..

19. The compound of claim l, wherein the compound is formula XV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR3;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties;
wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
W is O or S; and U is either O or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, a bridged ring moiety, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R1 and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C10 cycloalkyl, a bridged ring moiety, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

20. The compound of Claim 19 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

21. The compound of claim 19, wherein the compound is formula XVI:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, G and J are independently CH2, O, S, SO, SO2, NH, or NR3;
Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, G and J are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;

R3 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;

W is O or S; and U is either O or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, a bridged ring moiety, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R1 and R2 are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C3-C10 cycloalkyl, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

22. The compound of Claim 21 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

23. The compound of claim 19, wherein the compound is formula XVII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH, and NR3;
Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, and G are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C1-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thin-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position (s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
W is O or S; and U is either O or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and C1-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R1 and R2 are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C3-C8 cycloalkyl, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

24. The compound of Claim 23 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

25. The compound of claim 19, wherein the compound is formula XVIII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 1, 2 or 3;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1, 2 or 3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
W is O or S; and U is either O or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain or alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R1 and R2 are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C3-C10 cycloalkyl, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

26. The compound of Claim 25 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

27. The compound of claim 1, wherein the compound is formula XIX:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR3;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
R3 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of C1-C6-alkylamino, amido, amino, amino-C1-C6-alkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C6 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, C1-C6-ester, formanilido, halo, halo-C1-C6-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thin, thio-C1-C6-alkyl, thiocarbonyl, thiocyano, thio-C1-C6-ester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties;
wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C1-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;

W is O or S; and U is either O or N, provided that:
when U is O, then R1 is a lone pair of electrons and R2 is selected from the group consisting of Ar, C3-C8 cycloalkyl, a bridged ring moiety, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R1 and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C10 cycloalkyl, a bridged ring moiety, C7-C12 bi- or tri-cyclic carbocycle, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, and C3-C8 cycloalkyl; or R1 and R2 are taken together to form a heterocyclic 5 or 6 membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2.

28. The compound of claim 1, wherein the compound is formula XX:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR2;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C2-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2; and R1 is independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-C1-C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2.

29. The compound of claim 28 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

30. The compound of Claim 29 in which A and B, together with the nitrogen and carbon atoms to which they are respectfully attached, form a 6 membered saturated or unsaturated bridged heterocyclic ring; and R2 is C4-C7 branched chain alkyl, C4-C7 cycloalkyl, phenyl, or 3,4,5-trimethoxyphenyl.

31. The compound of claim 28, wherein the compound is formula XXI:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, G and J are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, G and J are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure:
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, vitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2; and R1 is independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-C1-C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2.

32. The compound of Claim 31 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

33. The compound of claim 28, wherein the compound is formula XXII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
E, F, and G are independently CH2, O, S, SO, SO2, NH
or NR2;
Br is a heterocylic bridged ring moiety, wherein any two or more of E, F, and G are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6)-ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkyl amino, amino- (C1-C6) -alkyl, sulfhydryl, thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2; and R1 is independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-(C1-C6) -alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio-(C1-C6)-alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2.

34. The compound of Claim 33 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

35. The compound of claim 28, wherein the compound is formula XXIII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

n is 1, 2 or 3;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1, 2 or 3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure:
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo- (C1-C6) -alkyl, thiocarbonyl, (C1-C6) -ester, thio- (C1-C6) -ester, (C1-C6) -alkoxy, (C2-C6) -alkenoxy, cyano, nitro, imino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, sulfhydryl, thio- (C1-C6) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, or hydroxy; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2; and R1 is independently selected from the group consisting of Ar, a bridged ring moiety, C3-C6 cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-(C1-C6)-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, (C1-C6)-ester, thio-(C1-C6)-ester, (C1-C6)-alkoxy, (C2-C6)-alkenoxy, cyano, nitro, imino, (C1-C6)-alkylamino, amino-(C1-C6)-alkyl, sulfhydryl, thio-(C1-C6)-alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2.

36. The compound of Claim 35 in which Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

37. The compound of claim 1, wherein the compound is formula XXIV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR2;
X is either O or S;
Y is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2;
R2 is independently selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar group;
Ar is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Z is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2;
C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6-alkyl, C2-C6 alkenyl, hydroxy, amino, halo, halo-C1-C6-alkyl., thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl; or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR2, S, SO, or SO2; and R1 is independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar, a bridged ring moiety, C3-C8 cycloalkyl, amino, halo, halo-C1-C6-alkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, carbonyl, thiocarbonyl, C1-C6-ester, thio-C1-C6-ester, C1-C6-alkoxy, C2-C6-alkenoxy, cyano, nitro, imino, C1-C6-alkylamino, amino-C1-C6-alkyl, sulfhydryl, thio-C1-C6-alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO, or SO2.

38. The compound of claim 1, wherein the compound is formula XXV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when t is 1, 2 or 3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
R1 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, a bridged ring moiety, and Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, S, CH2 or H2;
Y is O or NR2, wherein R2 is a direct bond to a Z, hydrogen or C1-C6 alkyl; and each Z, independently, is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Ar1, C3-C8 cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is the fragment wherein:
R3 is independently C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl,a bridged ring moiety, or Ar1;
X2 is O or NR5, wherein R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, a bridged ring moiety, C1-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl;
n is 1 or 2, and;
t is 1, 2 or 3.

39. The compound of claim 38, wherein the compound is formula XXVI:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
R1 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, a bridged ring moiety, and Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
Z is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Ar1, C3-C8 cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is the fragment wherein:

R3 is independently C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is 0 or NR5, wherein R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, a bridged ring moiety, C1-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

40. The compound of claim 38, wherein the compound is formula XXVII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
Z1 is the fragment wherein:
R3 is independently C1-C9 straight or branched chain alkyl or unsubstituted Ar1, wherein said alkyl is unsubstituted or substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR5, wherein R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, a bridged ring moiety, C1-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl; and Ar1 is selected from the group consisting of 1-napthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino.

41. The compound of claim 38, wherein the compound is formula XXVIII:

wherein:
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
R1 is independently C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C6 cycloalkyl, a bridged ring moiety, or Ar1, wherein said alkyl or alkenyl is unsubstituted or substituted with C3-C6 cycloalkyl or Ar2;

Ar1 and Ar2 are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl;
X is selected from the group consisting of oxygen and sulfur;
Y is oxygen or NR2, wherein R2 is independently a direct bond to a Z, hydrogen or C1-C6 alkyl;
each Z, independently, is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of 2-furyl, 2-thienyl, C3-C6 cycloalkyl, pyridyl, and phenyl, each having one or more substituent(s) independently selected from the group consisting of hydrogen and C1-C4 alkoxy; and n is 1 or 2.

42. The compound of claim 1, wherein the compound is formula XXIX:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) independently selected from the group consisting of O, S, SO, SO2, N, NH, and NR;
R is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein R is independently either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, halo-(C1-C6)-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C9 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, alkylthio, sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar2;
R1 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, a bridged ring moiety, and Ar2;
Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
X is O, S, CH2 or H2;
Y is O or NR2, wherein R2 is a direct bond to a Z, hydrogen or C1-C6 alkyl; and each Z, independently, is C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent(s) independently selected from the group consisting of Ar1, C3-C8 cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is the fragment wherein:

R3 is independently C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR5, wherein R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, a bridged ring moiety, C1-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl; and, n is 1 or 2.

43. The compound of claim 1, wherein the compound is formula LV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
m is 0-3;

A is CH2, O, NH, or N- (C1-C4 alkyl);
B and D are independently hydrogen, a bridged ring moiety, Ar, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, or Ar substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein in each case, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or the fragment wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting o f hydrogen, hydroxy, O-(C1-C4 alkyl), 0-(C2-C4 alkenyl), and carbonyl;
Ar is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl) , O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U;
U is hydrogen, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl;
K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylmethyl; or J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which is substituted with oxygen, sulfur, SO, or SO2.

44. The compound of claim 43, wherein the compound is formula LVI:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A is O, NH, or N- (C1-C4 alkyl);
B is hydrogen, CHL-Ar, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl, Ar substituted C1-C6 alkyl or C2-C6 alkenyl, or wherein L and Q are independently hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cyclohexyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
Ar is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, CF3, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O- (C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, and phenyl.

D is hydrogen or U; E is oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen, then D is U;
U is hydrogen, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7-cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, 2-indolyl, 3-indolyl, (C1-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar;
J is hydrogen, C1 or C2 alkyl, or benzyl;
K is C1-C4 straight or branched chain alkyl, benzyl or cyclohexylethyl; or J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which is substituted with oxygen, sulfur, SO, or SO2.

45. The compound of claim 93, wherein the compound is Formula LVII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
n is 2;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the piperidine ring (when n=2) are bonded to each other through either a chemical bond or atoms) other than a bond which do(es) not comprise a part of the primary ring structure;
D is phenyl, methoxy, 2-furyl, or 3,4,5-trimethoxyphenyl; and B is benzyl, 3-phenylpropyl, 4-(4-methoxyphenyl)butyl, 4-phenylbutyl, phenethyl, 3-cyclohexylpropyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, 4-cyclohexylbutyl, 3-phenoxybenzyl, 3-(3-indolyl)propyl, or 4-(4-methoxyphenyl)butyl.

46. The compound of claim 1, wherein the compound is formula LVIII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
R is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein R is independently either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, halo (C1-C6) -alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C6 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, (C1-C6) -alkylthio, sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar2;
Ar1 and Ar2 are independently an alicyclic or aromatiC7 mono-, bi- or tricycliC7 carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
m is 0-3;
A is CH2, O, NH, or N- (C1-C4 alkyl);
B and D are independently hydrogen, a bridged ring moiety, Ar, C5-C7 cycloalkyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkenyl substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, or Ar substituted C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl, wherein in each case, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or the fragment wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C9 alkyl), O- (C2-C4 alkenyl), and carbonyl;
Ar is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O- (C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl;
L is either hydrogen or U; M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U;
U is hydrogen, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar; and J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which is substituted with oxygen, sulfur, SO, or SO2.

47. The compound of claim 1, wherein the compound is formula LIX:

or a pharmaceutically acceptable salt, ester or solvate thereof, wherein:

A is CH2, O, NH, or N-(C1-C9 alkyl);
B and D are independently Ar, a bridged ring moiety, hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen., halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, (C2-C6 straight or branched chain alkenyl, O- (C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, (C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or (C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or (C2-C4 alkenyl)-Ar, or Ar;
J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which is substituted with O, S, SO, or SO2; and n is 0 to 3.

48. The compound of claim 47, wherein the compound is Formula LX:
or a pharmaceutically acceptable salt thereof, wherein:
n is 1 or 2;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the pyrrolidine ring (when n=1 ) or the piperidine ring (when n=2) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
B and D are independently Ar, a bridged ring moiety, hydrogen, C1-C6 straight or branched chain alkyl, or (C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or (C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen; and m is 0 or 1.

49. The compound of claim 47, wherein the compound is formula LXI:
or a pharmaceutically acceptable salt, ester or solvate thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary piperidine ring are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
B and D are independently Ar, a bridged ring moiety, hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom((s) independently selected from the group consisting of O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl), O- C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O- (C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl)-Ar, or Ar; and m is 0 to 3.

50. The compound of claim 49, wherein the compound is Formula LXII:
or a pharmaceutically acceptable salt thereof, wherein:
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary pyrrolidine ring are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
B and D are independently Ar, a bridged ring moiety, hydrogen, C1-C6 straight or branched chain alkyl, or (C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
Ar is independently selected from the group consisting of phenyl, 1-napthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein Ar contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, and phenyl;
E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C4 alkyl or C2-C4 alkenyl) -Ar, or Ar; and m is 0 to 3.

51. The compound of claim 1, wherein the compound is formula LXIII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is CH, N, or S;
A is CH2, O, NH, or N- (C1-C4 alkyl);
B and D are independently Ar, a bridged ring moiety, hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is unsubstituted or substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl or Ar, and wherein one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of O, S, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; and T is Ar or C5-C7 cycloalkyl substituted at positions 3 and 4 with one or more substituent(s) independently selected from the group consisting of hydrogen, hydroxy, O-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl;
provided that both B and D are not hydrogen;
R is independently either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein R is independently either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, halo (C1-C6) -alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, (C1-C6) -alkylthio, sulfhydryl, amino, (C1-C6) -alkylamino, amino- (C1-C6) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar2;
Ar, and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members;
wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; E is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C2-C9 alkyl or C2-C4 alkenyl)-Ar, or Ar;
J and K, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety containing one or more heteroatom(s) selected from the group consisting of O, S, SO, SO2, N, NH, and NR; and n is 0 to 3.

52. The compound of claim 1, wherein the compound is formula LXIV:

in which:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1-3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
X is either O or S;
R1 is independently selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, or heterocycle;

D is a bond, or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; and R2 is independently a carboxylic acid or a carboxylic acid isostere;
or a pharmaceutically acceptable salt, ester, or solvate thereof.

53. The compound of Claim 52 in which R2 is selected from the group consisting of:

-COOH, -SO3H, -SO2HNR3, -PO2(R3)2, -CN, -PO3(R3)2. -OR3, -SR3.
-NHCOR3, -N(R3)2, -CON(R3)2, -CONH(O)R3, -CONHNHSO2R3, -COHNSO2R3, and -CONR3CN wherein R3 is hydrogen, hydroxy, halo, halo-C1-C6-alkyl, thiocarbonyl, C1-C6-alkoxy, C2-C6-alkenoxy, C1-C6-alkylaryloxy, aryloxy, aryl- C1-C6-alkyloxy, cyano, nitro, imino, C1-C6-alkylamino, amino- C1-C6-alkyl, sulfhydryl, thio- C1-C6-alkyl, C1-C6-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and CO2R4 where R4 is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl.

54. The compound of claim 1, wherein the compound is formula LXV:

in which X, Y, and Z are independently selected from the group consisting of C, O, S, or N, provided that X, Y, and Z are not all C:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1-3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
A is selected from the group consisting of L1, L2, L3, or L4, in which and R1 and E, independently, are selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, and heterocycle;
R2 is carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, where R3 is hydrogen, hydroxy, halo, halo (C1-C6) -alkyl, thiocarbonyl, (C1-C6)-alkoxy, (C2-C6)-alkenoxy, (C1-C6)-alkylaryloxy, aryloxy, aryl-(C1-C6)-alkyloxy, cyano, nitro, imino, (C1-C6)-alkylamino, amino-(C1-C6)-alkyl, sulfhydryl, thio-(C1-C6)-alkyl, (C1-C6)-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4 where R4 is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl;

or a pharmaceutically acceptable salt, ester, or solvate thereof.

55. The compound of claim 54, wherein the compound is formula LXVI:

in which:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1-3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
R1 and A are independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, and heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl;
R2 is independently carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, where R3 is hydrogen, hydroxy, halo, halo(C1-C6)-alkyl, thiocarbonyl, (C1-C6)-alkoxy, (C2-C6)-alkenoxy, (C1-C6)-alkylaryloxy, aryloxy, aryl-(C1-C6)-alkyloxy, cyano, nitro, imino, (C1-C6)-alkylamino, amino-(C1-C6)-alkyl, sulfhydryl, thio-(C1-C6)-alkyl, (C1-C6)-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, and CO2R4 where R4 is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester, or solvate thereof.

56. The compound of claim 54, wherein the compound is formula LXVII:

in which:
n is 1-3;
Br is a heterocylic bridged ring moiety, wherein any two or more atoms of the primary ring (when n is 1-3) are bonded to each other through either a chemical bond or atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;
R1 is independently selected from the group consisting of hydrogen, C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, or heterocycle;
D is a bond, or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl;
R2 is independently a carboxylic acid or a carboxylic acid isostere;
wherein said alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, or carboxylic acid isostere is optionally substituted with one or more substituents selected from R3, where R3 is independently hydrogen, hydroxy, halo, , halo-(C1-C6)-alkoxy, thiocarbonyl, (C1-C6)-alkoxy, (C2-C6)-alkenyloxy, (C1-C6) -alkylaryloxy, aryloxy, aryl-(C1-C6)-alkyloxy, cyano, nitro, imino, (C1-C6)-alkyl amino, amino-(C1-C6)-alkyl, sulfhydryl, thio-(C1-C6)alkyl, (C1-C6)-alkylthio, sulfonyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or CO2R4 where R4 is hydrogen or C1-C9 straight or branched chain alkyl or alkenyl;
or a pharmaceutically acceptable salt, ester or solvate thereof.

57. A pharmaceutical composition, comprising:
a. an effective amount of a bridged heterocyclic derivative; and b. a pharmaceutically acceptable carrier.

58. The pharmaceutical composition of claim 57, wherein the bridged heterocyclic derivative is a compound of formula I':

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which contains one or more O, C (R1)2, S (O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is R1 is independently hydrogen, C1-C9 straight or branched chain alkyl, or C2-C9 straight or branched chain alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a carboxylic acid or carboxylic acid isostere, N (R4)n, Ar1, Ar4, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or bridged ring moiety, is optionally substituted with one or more substituent(s) independently selected from the group consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6 cycloalkyl wherein said furyl, thienyl, pyridyl, phenyl or cycloalkyl group optionally is substituted with C1-C4 alkoxy, (Ar1)n, halo, halo-C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6 thioester, cyano, imino, COOR6 in which R6 is independently C1-C9 straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy, C1-C6 alkylaryloxy C1-C6 aryloxy, aryl- (C1-C6)-alkyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, C1-C6-alkylthio, sulfhydryl, sulfonyl, amino, (C1-C6)-mono- or di-alkylamino, amino- (C1-C6)-alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl optionally substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, C3-C8 cycloalkyl, and Ar2, and, wherein any carbon atom of an alkyl or alkenyl group may optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring contains 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;

or, R1 is independently a moiety of the formula:

wherein:
R3 is independently C1-C9 straight or branched chain alkyl which is optionally substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR6, wherein R6 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, C2-C5 straight or branched chain alkenyl substituted with phenyl, and a bridged ring moiety;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of C1-C6 straight or branched chain alkyl,C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and hydroxy; or, R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that if R2 is hydrogen, then Y is CH-P, or if Y is oxygen then R2 is P;
P is hydrogen, O-(C1-C4 straight or branched chain alkyl) , O- (C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl) -Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone pair of electrons and R" is selected from the group consisting of Ar4, a bridged ring moiety, C3-C8 cycloalkyl, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent (s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
and when U is N, then R' and R" are, independently, selected from the group consisting of hydrogen, Ar4, a bridged ring moiety, G3-C10 cycloalkyl, a C7-C12 bi- or tri-cyclic carbocycle, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to form a heterocyclic 5- or 6-membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C (R1)2, O, S, a direct bond or NR1; or, Z-R1 is independently wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar4, Ar1, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and Ar4; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6 thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano, nitro, imino, C1-C6 alkylamino, amino- (C1-C6) alkyl, sulfhydryl, thio- (C1-C6) alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position (s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, or (SO) p;
C' and D' are independently hydrogen, a bridged ring moiety, Ar5, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
and T is Ar5 or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl, J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally substituted with C1-C4 alkyl, C2-C9 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally replaced with O, NR"' , or S(O) p, wherein R" ' is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar3 group;
K' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O) p;
K'' is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine being selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, said aromatic amine being optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C6 alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NRxRyRz, wherein Rx, Ry, and Rz are independently selected from the group consisting of C1-C6 straight or branched chain alkyl and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, a bridged ring moiety, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally replaced with O, NR', S(O)p;
L' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O)p;
n is 1 or 2;
p is 0, l, or 2;
t is 0, l, 2, 3, or 4;
Ar3 is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C3-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties; wherein the individual alicyclic or aromatic ring contains 5-8 members and wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar5 optionally contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), 0-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl; and R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar4 or Ar1 group.

59. A method of treating a neurological disorder in an animal, comprising:
administering to the animal an effective amount of a bridged heterocyclic derivative.

60. The method of claim 59, wherein the bridged heterocyclic derivative is a compound of formula I':
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A is hydrogen, C1 or C2 alkyl, or benzyl and B is C1-C4 straight or branched chain alkyl, benzyl, or cyclohexylmethyl; or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which contains one or more O, C(R1)2, S(O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is R1 is independently hydrogen, C1-C9 straight or branched chain alkyl, or C2-C9 straight or branched chain alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7, cycloalkenyl, a carboxylic acid or carboxylic acid isostere, N(R4)n, Ar1, Ar4, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or bridged ring moiety, is optionally substituted with one or more substituent(s) independently selected from the group consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6 cycloalkyl wherein said furyl, thienyl, pyridyl, phenyl or cycloalkyl group optionally is substituted with C1-C4 alkoxy, (Ar1)n, halo, halo-C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6 thioester, cyano, imino, COOR6 in which R6 is independently C1-C9 straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy, C1-C6 alkylaryloxy C1-C6 aryloxy, aryl-(C1-C6)-alkyloxy, phenoxy, benzyloxy, thio-(C1-C6)-alkyl, C1-C6-alkylthio, sulfhydryl, sulfonyl, amino, (C1-C6)-mono- or di-alkylamino, amino-(C1-C6)-alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl optionally substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, C3-C8 cycloalkyl, and Ar2, and, wherein any carbon atom of an alkyl or alkenyl group may optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring contains 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;
or, R1 is independently a moiety of the formula:
wherein:
R3 is independently C1-C9 straight or branched chain alkyl which is optionally substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR6, wherein R6 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, C2-C5 straight or branched chain alkenyl substituted with phenyl, and a bridged ring moiety;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and hydroxy; or, R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that if R2 is hydrogen, then Y is CH-P, or if Y is oxygen then R2 is P;
P is hydrogen, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl )-Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone pair of electrons and R'' is selected from the group consisting of Ar4, a bridged ring moiety, C3-C8 cycloalkyl, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
and when U is N, then R' and R'' are, independently, selected from the group consisting of hydrogen, Ar4, a bridged ring moiety, C3-C10 cycloalkyl, a C7-C12 bi- or tri-cyclic carbocycle, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to form a heterocyclic 5- or 6-membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C (R1)2, O, S, a direct bond or NR1; or, Z-R1 is independently J-K-L, wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar4, Ar1, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and Ar4; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6 thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano, nitro, imino, C1-C6 alkylamino, amino-(C1-C6)alkyl, sulfhydryl, thio-(C1-C6)alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, or (SO)p;
C' and D' are independently hydrogen, a bridged ring moiety, Ar5, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
and T is Ar5 or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl, J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally replaced with O, NR"' , or S (O)p, wherein R"' is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C9 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar3 group;
K' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O)p;
K" is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine being selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, said aromatic amine being optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight ar branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NR x R y R z, wherein R x, R y, and R z are independently selected from the group consisting of C1-C6 straight or branched chain alkyl and C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, a bridged ring moiety, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally replaced with O, NR', S(O)p;
L' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O)p;
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties wherein the individual alicyclic or aromatic ring contains 5-8 members and wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar5 optionally contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl) , O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl; and R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar4 or Ar1 group.

61. The method of claim 60, wherein the neurological disorder is selected from the group consisting of peripheral neuropathies cause by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegeneration.

62. The method of claim 60, wherein the neurological disorder is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis.

63. The method of claim 60, wherein the neurological disorder is Alzheimer's disease.

462 69. The method of claim 60, wherein the neurological disorder is Parkinson's disease.

65. The method of claim 60, wherein the neurological disorder is amyotrophic lateral sclerosis.

66. The method of claim 59, wherein the bridged heterocyclic derivative is non-immunosuppressive.

67. The method of claim 59, wherein the bridged heterocyclic derivative has an affinity for an FKBP-type immunophilin.

68. The method of claim 67, wherein the FKBP-type immunophilin is FKBP-12.

69. A method for treating alopecia or promoting hair growth in an animal, which comprises administering to said animal an effective amount of a bridged heterocyclic derivative.

70. The method of claim 69, wherein the bridged heterocyclic derivative is non-immunosuppressive.

71. The method of claim 69, wherein the bridged heterocyclic derivative has an affinity for an FKBP-type immunophilin.

72. The method of claim 71, wherein the FKBP-type immunophilin is FKBP-12.

73. The method of claim 69, wherein the bridged heterocyclic derivative is a compound of formula formula I':

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
A is hydrogen, C1 or C2 alkyl, or benzyl and B is C1-C4 straight or branched chain alkyl, benzyl, or cyclohexylmethyl; or, A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which contains one or more O, C (R1)2, S(O)p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is O, CH2 or S;
m is 0 or 1;
G is R1 is independently hydrogen, C1-C9 straight or branched chain alkyl, or C2-C9 straight or branched chain alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a carboxylic acid or carboxylic acid isostere, N(R4)n, Ar1, Ar4, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or bridged ring moiety, is optionally substituted with one or more substituent(s) independently selected from the group consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6 cycloalkyl wherein said furyl, thienyl, pyridyl, phenyl or cycloalkyl group optionally is substituted with C1-C9 alkoxy, (Ar1)n, halo, halo-C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6 thioester, cyano, imino, COOR6 in which R6 is independently C1-C9 straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy, C1-C6 alkylaryloxy C1-C6 aryloxy, aryl-(C1-C6)-alkyloxy, phenoxy, benzyloxy, thio-(C1-C6)-alkyl, C1-C6-alkylthio, sulfhydryl, sulfonyl, amino, (C1-C6)-mono- or di-alkylamino, amino-(C1-C6)-alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl optionally substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, C3-C8 cycloalkyl, and Ar2, and, wherein any carbon atom of an alkyl or alkenyl group may optionally replaced with O, NR5, or S(O)p;
Ar1 or Ar2, independently, is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino: wherein the individual ring contains 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;
or, R1 is independently a moiety of the formula:

wherein:
R3 is independently C1-C9 straight or branched chain alkyl. which is optionally substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR6, wherein R6 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, C2-C5 straight or branched chain alkenyl substituted with phenyl, and a bridged ring moiety;
R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and hydroxy; or, R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that if R2 is hydrogen, then Y is CH-P, or if Y is oxygen then R2 is P;
P is hydrogen, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl)-Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone pair of electrons and R'' is selected from the group consisting of Ar4, a bridged ring moiety, C3-C8 cycloalkyl, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
and when U is N, then R' and R'' are, independently, selected from the group consisting of hydrogen, Ar4, a bridged ring moiety, C3-C10 cycloalkyl, a C7-C12 bi- or tri-cyclic carbocycle, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar9 and C3-C8 cycloalkyl;
or R' and R'' are taken together to form a heterocyclic 5- or 6-membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C(R1)2, O, S, a direct bond or NR1; or, Z-R1 is independently J-K-L , wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar4, Ar1, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and Ar4; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6 thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano, nitro, imino, C1-C6 alkylamino, amino- (C1-C6)alkyl, sulfhydryl, thio- (C1-C6) alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, or (SO)p;
C' and D' are independently hydrogen, a bridged ring moiety, Ar5, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
and T is Ar5 or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O-(C1-C4 alkyl), O-(C2-C4 alkenyl), and carbonyl, J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally replaced with 0, NR''', or S(O) p, wherein R''' is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or.
alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar3 group;
K' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NR5, S(O) p;
K'' is C(R1)2, O, S, a direct bond or NR1;
L is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine being selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, said aromatic amine being optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NR xR yR z, wherein R x, R y, and R z, are independently selected from the group consisting of C1-C6 straight or branched chain alkyl and C2 C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, a bridged ring moiety, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally replaced with O, NR', S(O)P;
L' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O)p;
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties; wherein the individual alicyclic or aromatic ring contains 5-8 members and wherein said heterocyclic ring contains 1-6 heteratom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar5 optionally contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl) , O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl; and R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar4 or Ar1 group.

74. A method for treating a vision disorder, improving vision in an animal, treating age related memory impairment, enhancing memory performance, which comprises administering to said animal an effective amount of a bridged heterocyclic derivative.

75. The method of claim 74, wherein the bridged heterocyclic derivative is immunosuppressive or non-immunosuppressive.

76. The method of claim 74, wherein the bridged heterocyclic derivative has an affinity for an FKBP-type immunophilin.

77. The method of claim 76, wherein the FKBP-type immunophilin is FKBP-12.

78. The method of claim 74, wherein the vision disorder is selected from the group consisting of visual impairments; orbital disorders; disorders of the lacrimal apparatus; disorders of the eyelids; disorders of the conjunctiva; disorders of the cornea; cataracts; disorders of the uveal tract; disorders of the retina; disorders of the optic nerve or visual pathways; tree radical induced eye disorders and diseases; immunologically-mediated eye disorders and diseases; eye injuries; and symptoms and complications of eye disease, eye disorder, or eye injury.

79. The method of claim 79, which is improving naturally-occurring vision in an animal, in the absence of any ophthalmologic disorder, disease, or injury.

80. The method of claim 74, wherein the bridged heterocyclic derivative is a compound of formula I':

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:

A and B, taken together with the atoms to which they are attached, form a saturated, unsaturated, or aromatic heterocylic or carbocyclic bridged ring moiety which contains one or more O, C(R1)2, S(O) p, N, NR1, or NR5 atoms;
V is CH, S, or N;
X is 0, CH2 or S;
m is 0 or 1;
G is R1 is independently hydrogen, C1-C9 straight or branched chain alkyl, or C2-C9 straight or branched chain alkenyl or alkynyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, a carboxylic acid or carboxylic acid isostere, N(R4)n, Ar1, Ar4, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar1, Ar4, or bridged ring moiety, is optionally substituted with one or more substituent(s) independently selected from the group consisting of:
2-furyl, 2-thienyl, pyridyl, phenyl, C3-C6 cycloalkyl wherein said furyl, thienyl, pyridyl, phenyl or cycloalkyl group optionally is substituted with C1-C4 alkoxy, (Ar1)n, halo, halo-C1-C6-alkyl, carbonyl, thiocarbonyl, C1-C6 thioester, cyano, imino, COOR6 in which R6 is independently C1-C9 straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, C1-C6 alkoxy, C2-C4 alkenyloxy, C1-C6 alkylaryloxy C1-C6 aryloxy, aryl- (C1-C6) -alkyloxy, phenoxy, benzyloxy, thio- (C1-C6) -alkyl, C1-C6-alkylthio, sulfhydryl, sulfonyl, amino, (C1-C6)-mono- or di-alkylamino, amino- (C1-C6) -alkyl, aminocarboxy, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl optionally substituted with (Ar1)n, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl, C3-C8 cycloalkyl, and Ar2, and, wherein any carbon atom of an alkyl or alkenyl group may optionally replaced with O, NRS, or S(O)P;
Ar1 or Ar2, independently, is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; wherein the individual ring contains 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;
or, R1 is independently a moiety of the formula:

wherein:
R3 is independently C1-C9 straight or branched chain alkyl which is optionally substituted with C3-C8 cycloalkyl, a bridged ring moiety, or Ar1;
X2 is O or NR6, wherein R6 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is independently selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, C2-C5 straight or branched chain alkenyl substituted with phenyl, and a bridged ring moiety;

R2 is independently C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, or Ar1, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, (Ar1)n and hydroxy; or, R2 is independently either hydrogen or P;
Y is either oxygen or CH-P, provided that if R2 is hydrogen, then Y is CH-P, or if Y is oxygen then R2 is P;
P is hydrogen, O- (C1-C4 straight or branched chain alkyl), O-(C2-C4 straight or branched chain alkenyl), C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C5-C7 cycloalkyl, C5-C7 cycloalkenyl substituted with C1-C4 straight or branched chain alkyl or C2-C4 straight or branched chain alkenyl, (C1-C4 alkyl or C2-C4 alkenyl) -Ar5, or Ar5;
U is either O or N, provided that:
when U is O, then R' is a lone pair of electrons and R'' is selected from the group consisting of Ar4, a bridged ring moiety, C3-C8 cycloalkyl, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
and when U is N, then R' and R'' are, independently, selected from the group consisting of hydrogen, Ar4, a bridged ring moiety, C3-C10 cycloalkyl, a C7-C12 bi- or tri-cyclic carbocycle, C1-C9 straight or branched chain alkyl, and C2-C9 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of Ar4 and C3-C8 cycloalkyl;
or R' and R'' are taken together to form a heterocyclic 5- or 6-membered ring selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.
W and Y, independently, are O, S, CH2 or H2;
Z is C(R1)2, O, S, a direct bond or NR1; or, Z-R1 is independently wherein:
C and D are, independently, hydrogen, a bridged ring moiety, Ar4, Ar1, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, Ar1 and Ar4; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, C1-C6 ester, C1-C6 thioester, C1-C6 alkoxy, C1-C6 alkenoxy, cyano, nitro, imino, C1-C6 alkylamino, amino- (C1-C6) alkyl, sulfhydryl, thio-(C1-C6)alkyl, or sulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position (s) with oxygen to form a carbonyl;
or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, or (SO) p;
C' and D' are independently hydrogen, a bridged ring moiety, Ar5, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl is optionally substituted with C5-C7 cycloalkyl, C5-C7 cycloalkenyl, or Ar5, wherein, one or two carbon atom(s) of said alkyl or alkenyl may be substituted with one or two heteroatom(s) independently selected from the group consisting of oxygen, sulfur, SO, and SO2 in chemically reasonable substitution patterns, or wherein Q is hydrogen, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl;
and T is Ar5 or C5-C7 cycloalkyl substituted at positions 3 and 4 with substituents independently selected from the group consisting of hydrogen, hydroxy, O- (C1-C4 alkyl) , O- (C2-C4 alkenyl), and carbonyl, J is O, NR1, S, or (CR1)2;
K is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, a bridged ring moiety, hydroxy, carbonyl oxygen, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar3, is optionally replaced with O, NR''' , or S(O) p, wherein R''' is selected from the group consisting of hydrogen, C1-C4 straight or branched chain alkyl, C3-C4 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar3 group;
K' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S(O) p;
K'' is C(R1)2, O, S, a direct bond or NR1, L is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; said aromatic amine being selected from the group consisting of pyridyl, pyrimidyl, quinolinyl, and isoquinolinyl, said aromatic amine being optionally substituted with one or more substituent(s) independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NR xR yR z, wherein R x, R y, and R z are independently selected from the group consisting of C1-C6 straight or branched chain alkyl and C2 C6 straight or branched chain alkenyl; wherein said alkyl or alkenyl is optionally substituted with one or more substituent(s) independently selected from the group consisting of C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, a bridged ring moiety, and Ar3; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, hydroxy, or carbonyl oxygen; wherein any carbon atom of said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar3 is optionally replaced with O, NR', S(O) p;
L' is a direct bond, C1-C6 straight or branched chain alkyl, or C2-C6 straight or branched chain alkenyl, wherein any carbon atom of said alkyl or alkenyl is optionally substituted in one or more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of said alkyl or alkenyl is optionally replaced with O, NR5, S (O) p;
n is 1 or 2;
p is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
Ar3 is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl;
Ar4 is independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is optionally substituted with one or more substituent(s) independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C1-C9 straight or branched chain alkyl, C1-C9 alkoxy, C2-C9 alkenyloxy, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy; sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic moieties; wherein the individual alicyclic or aromatic ring contains 5-8 members and wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S; and wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;
Ar5 is independently selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which contain in either or both rings a total of 1-4 heteroatom(s) independently selected from the group consisting of oxygen, nitrogen and sulfur; wherein Ar5 optionally contains 1-3 substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxymethyl, nitro, CF3, trifluoromethoxy, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, O-(C1-C4 straight or branched chain alkyl ), O-(C2-C4 straight or branched chain alkenyl), O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl, and phenyl; and R5 is independently selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, C3-C6 straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C1-C4 bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl or alkenyl chain containing said heteroatom to form a ring, wherein said ring is optionally fused to an Ar9 or Ar1 group.