WO2000016603A2 - Bridged heterocyclic derivatives - Google Patents

Description

BRIDGED HETEROCYCLIC 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.

Description 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) 31:384-400.

The PPIase, cyclophilin A, was found to be the 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., Bura off, S.J., Crabtree, G., Schreiber, S.L., Proc . Na tl . Acad. Sci . USA (1990) 87:9231-9235; Liu, J. , Farmer, J.D., Lane, .S., Friedman, J. , Weissman, I., Schreiber, S.L.; Cell (1991) 66:807-815.

Neither FK506 or FKBP alone appreciably inhibits calcineurin¹ 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 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. Na ture (1994) 369:756-758; Brown, E.J., Beal, P. A., Keith, C.T., Chen, J. , Shin, T.B., Schreiber, S.L., Na ture (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., Na ture (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 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., Na ture (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., Na ture (1992) 358:584-587. One of the proteins affected by FK506 treatment, GAP-43, 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 on 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, .E., George, E.B., Dawson, T.M., Steiner, J.P., Snyder, S.H., Proc. Na tl . 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 . (1995) 15:7509-7516. See, also, Snyder, S.H., Sabatini, D.M., Na ture Medicine (1995) 1:32-37 (regeneration of lesioned facial nerves in rats augmented by FK506 ) .

Besides FK506, rapamycin and cyclosporin also produced potent neurotrophic effects in vi tro 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., Durette, 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., Na ture Medicine (1997) 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/Liαands 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. 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 (K_χ 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. ., Brandt, M., Bossard, M.J., Levy, M.A., Eggleston, D.S., Liang, J. , Schultz, L. .; 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 vi tro 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 vi tro assay to measure the ability of compounds to promote neurite outgrowth (fiber extension) in 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., Na ture 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 (50% 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 (25% and 5% 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. Several of these compounds were shown to promote recovery of lesioned central dopaminergic 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-l,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 60-70% 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 vi tro, 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 . Na tl . Acad. Sci . USA (1997) 94:2019-2024. In rats lesioned with PCA, cortical density of serotonin fibers was reduced 90% 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 75-80% deafferentiation of the hippocampus. Subcutaneous administration of the FBKP12 ligand produced a four-fold sprouting of spared residual processes in the CAl, 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) , glial 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. 317:861); 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 Promoting 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 . Derma tol . , 1994, 102, 160-164; Jiang et al., J. Invest . Derma tol . 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 FK506 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 Physi cians ' 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 "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 or 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. O'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-α, 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 -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 nonimmunosuppressive 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 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 SUMMARY 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 neuronal 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 compound (s) 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 μM 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 90% of the shaved area is covered with new hair growth.

FIG. 3 is a photograph of mice treated with 30 μM 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 nonimmunosuppressive 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 5C 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 S0₂. For example, carbon 2 of 4-pentene can be replaced with 0 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, C;,-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 0, NH, S, or S0₂. For example, carbon 2 of n-pentyl can be replaced with 0 to form propyloxymethyl .

It should be kept in mind that, throughout this application, "R" or "R_n", 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 R_λ may be a branched alkyl in one context does not require that R_x be the same branched alkyl, and does not prohibit that R_± be, for example, a straight chain alkenyl, in another context in the same molecule. It is intended that all "R_n" are selected independently of all other "R_n", 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. ^λAlkyl/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_n", 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 is intended that all "Ar_n" are selected independently of all other "Ar_n", 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 atom(s) 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:

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-C₈ 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, tetrahydrof ranyl, 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, 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 -dioxopent yl ) -2- pyrrolidinecarboxylate of formula

"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 point (s) 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:

CO CO CO

α> > oo

"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(0)R³, -CONHNHS0₂R³, -COHNS0₂R³, and -CONR³CN, wherein R³ is hydrogen, hydroxy, halo, halo-C₁-C₆-alkyl, thiocarbonyl, C_λ- C₆-alkoxy, C₂-C₆-alkenoxy, Ci-Cg-alkylaryloxy, aryloxy, aryl- Ci-Cg-alkyloxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino- C_x-C₆-alkyl, sulfhydryl, thio- C-Cg-alkyl, Cι-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 C;,-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 invention:

and -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-Ci-Cg-alkyl, thiocarbonyl,

C₂-C₆- alkenoxy, Cx-Cg-alkylaryloxy, aryloxy, aryl- cyano, nitro, imino,

amin

sulfhydryl, thio-

Cj-Cg-alkylthio, sulfonyl, C_x- 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 Ci-Cg 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 R_lf 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 maintain (s) 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, maleic, 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- ( (C_x-C₄) alkyloxy) ethyl; for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso- propoxyethyl, etc.; 2-oxo-l, 3-dioxolen-4-ylmethyl groups, such as 5-methyl-2-oxo-l, 3, dioxolen-4-ylmethyl, etc.; C-_L-C_;, 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 Edi tion, 6: 41 (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:

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

Treating 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 neuropathies. 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.

Treating 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 forces; 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, 1 6th Edi tion, 6: 41 (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 kerat oconj unct i vit is , 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 Edi tion, 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 Edi tion , 217:2362-2363 (1992).

An inventive compound may be administered in combination with an effective amount of one or more factor (s) useful in treating vision disorder, improving vision, treating memory impairment, or enhancing memory performance.

In a preferred embodiment, the factor (s) 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 product (s) 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, polyglycolic 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, polyvinylpyrrolidone, b-cyclodextrin or hydroxypropyl-b- cyclodextrin. The buffers can be conventional buffers such as borate, citrate, phosphate, bicarbonate, or tris-HCl.

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 (e.g. , 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 phosphate; 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 factor (s) 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 factor (s) 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, int raperitoneal , 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.

Dosage

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 vi tro 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 agent (s) 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 agent (s) 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, C_x or C₂ alkyl, or benzyl and B is C_x-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(R_X)₂, S(0)_p, N, NR_Xι 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 0, CH₂ or S; m is 0 or 1; G is

R_x is independently hydrogen,

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, Ar_x, Ar₄, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar_x, 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 C^^ alkoxy, (Ar_x)_n, halo, halo-

Ci-Cg-alkyl, carbonyl, thiocarbonyl, Ci-Cg thioester, cyano, i ino, COOR₆ in which R₆ is independently Cx-Cc, straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, Cx-Cg alkoxy, C₂-C₄ alkenyloxy,

Ci-Cg alkylaryloxy Cx-Cg aryloxy, aryl- (C_x-C₆) - alkyloxy, phenoxy, benzyloxy, thio- (C^Cg) -alkyl,

C_x-C₆-alkylthio, sulfhydryl, sulfonyl, amino, (C_x-

C₆₎-mono- or di-alkylamino, amino- (C_x-C₆) -alkyl, aminocarboxy, C₃-C₈ cycloalkyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl optionally substituted with (Ar_x)_n,

C₃-C₈ cycloalkyl, Ci-Cg 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 0, NR₅, or S(0)_p;

Ar_x 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, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, C_x-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 heteroato (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, R_x is independently a moiety of the formula:

wherein:

R₃ is independently C^Cg straight or branched chain alkyl which is optionally substituted with C₃-C₈ cycloalkyl or Ar_x;

X₂ is 0 or NR₆, wherein R₆ is independently selected from the group consisting of hydrogen, Cj-Cg straight or branched chain alkyl, and C₂-C₆ straight or branched chain alkenyl;

R₄ is independently selected from the group consisting of phenyl, benzyl, Ci-Cs straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, CT-C_S 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 Ci-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of C_x-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, (Ar_x)_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, 0- (C_x-C₄ straight or branched chain alkyl), O- (C₂-C₄ straight or branched chain alkenyl) , Cx-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with C_x-C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (C_!-C₄ alkyl or C₂-C₄ alkenyl) -Ar₅, or Ar₅. 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 Ar₄, C₃-C₈ cycloalkyl, Ci-Cg 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, C₃- C₁₀ cycloalkyl, a C₇-C₁₂ bi- or tricyclic carbocycle, C;,-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, imi da z o 1 i d i ne , pyrazolidine, piperidine, and piperazine . W and Y, independently, are 0, S, CH₂ or H₂; Z is C(R_X)₂, 0, S, a direct bond or NR_X; or, Z-R_x is independently

wherein: C and D are, independently, hydrogen, Ar₄,

Ar_X/ C_x-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, Ar_x and Ar₄; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C_x-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, C_x-C₆ ester, C_x-C₆ thioester, C_x-C₆ alkoxy, C_x-C₆ alkenoxy, cyano, nitro, imino, C_x-C₆ alkylamino, amino- (C_x-C₆) alkyl, sulfhydryl, thio- (C_x-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 0, NR₅, or (S0)_p; C and D' are independently hydrogen, Ar₅,

C_x-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 S0₂ in chemically reasonable substitution patterns, or

w h e r e i n

Q is hydrogen, C_x-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, 0-(C_x-C₄ alkyl), 0- (C₂-C₄ alkenyl) , and carbonyl, J is 0, NR_X, S, or (CR_X)₂;

K is a direct bond, C_x-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 C_x-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 C_x-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(0)_p, wherein R' ' ' is selected from the group consisting of hydrogen, C_x-

C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, and C_x-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, C_x-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(0)_p;

K' ' is C(R_X)₂, 0, S, a direct bond or NR_X.

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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NR_xR_yR₂, wherein R_x, R_y, and R_z are independently selected from the group consisting of C_x-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 C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar₃; wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or Ar₃ is optionally substituted with C_x-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' , S(0)_p;

L' is a direct bond, C_x-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(0)_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, C_x-C₉ straight or branched chain alkyl, C_x-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 0, 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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (C_x-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, C_x-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, and C_x-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 Ar_x group. Additionally, the invention provides 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 formulations as described above,

I. HETEROCYCLIC THIOESTERS AND KETONES FORMULA I In particular, the bridged heterocyclic derivative may be a compound of formula I

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, S0₂, 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;

Z is either S, CH₂, CHR_X or CR_XR₃;

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

R_x and R₃ are independently C_x-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 (Ar_x)_n, C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_n, C₃-C₈ cycloalkyl, C_x-C₆ straight or branched chain alkyl or C₂-C₅ straight or branched chain alkenyl substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, and Ar₂; n is 1 or 2;

R₂ is independently C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 C_x-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, a bridged ring moiety, and hydroxy; and Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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.

FORMULA II The bridged heterocyclic derivative may also be a compound of formula

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=l) 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 0 or S; Z is selected from the group consisting of S, CH₂, CHR_X, and CR_XR₃;

R_x and R₃ are independently selected from the group consisting of C_x-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, and Ar_x, wherein said alkyl, alkenyl or Ar_x is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, nitro, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, a bridged ring moiety, hydroxy, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, amino, and Ar_x;

R₂ is independently selected from the group consisting of C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, and Ar_x; and

Ar_x is independently phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said Ar_x is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.

Preferred compounds of formula II are presented in TABLE I.

TABLE I

No n X z R, R,

1 1 0 CH₂ 3-Phenylpropyl 1 , 1 -Dimethylpropyl

2 1 0 CH₂ 3-(3-Pyridyl)propyl 1 , 1 -Dimethylpropyl

3 1 o CH₂ 3-Phenylpropyl tert-Butyl

4 1 0 CH₂ 3-(3-Pyridyl)propyl tert-Butyl

5 1 0 CH₂ 3-(3-Pyridyl)propyl Cyclohexyl

6 1 0 CH₂ 3-(3-Pyridyl)propyl Cyclopentyl

7 1 0 CH₂ 3-(3-Pyridyl)propyl Cycloheptyl

8 1 0 CH₂ 2-(9-Fluorenyl)ethyl 1 , 1 -Dimethylpropyl

9 1 0 S 2-Phenethyl 1 , 1 -Dimethylpropyl

10 2 0 S 2-Phenethyl 1 , 1 -Dimethylpropyl

11 1 0 S Methyl(2-thioindole) 1 , 1 -Dimethylpropyl

12 1 0 S 2-Phenethyl Cyclohexyl

13 2 0 S 2-Phenethyl rt-Butyl

14 2 0 S 2-Phenethyl Phenyl

15 1 0 CH₂ 3-(4-Methoxyphenyl)propyl 1 , 1 -Dimethylpropyl

16 2 0 CH₂ 4-(4-Methoxyphenyl)butyl 1 , 1 -Dimethylpropyl

17 2 0 CH₂ 4-Phenylbutyl 1 , 1 -Dimethylpropyl

18 2 o CH₂ 4-Phenylbutyl Phenyl

19 2 0 CH₂ 4-Phenylbutyl Cyclohexyl

20 1 s CH₂ 3-Phenylpropyl 1 , 1 -Dimethylpropyl

21 1 s S 2-Phenethyl 1 , 1 -Dimethylpropyl

22 2 s CH₂ 3-Phenylpropyl 1 , 1 -Dimethylpropyl

23 2 s S 2-Phenethyl 1 , 1 -Dimethylpropyl

24 2 0 CHR, 3-Phenylρropyl 1 , 1 -Dimethylpropyl

25 2 o CHR, 3-Phenylpropyl Cyclohexyl

26 2 0 CHR, 3-Phenylpropyl Phenyl

27 2 0 CHR, 3-Phenylpropyl 3 ,4,5-Trimethoxyphenyl

28 1 0 S 2-Phenethyl Cyclopentyl n X z R, R,

2 O s 3-Phenylpropyl tert-Butyl

1 o s 3-Phenylpropyl 1 , 1 -Dimethylpropyl

1 0 s 3-(3-Pyridyl)propyl 1 , 1 -Dimethylpropyl

1 0 s 3-Phenylpropyl Cyclohexyl

1 O s 4-Phenylbutyl Cyclohexyl

1 0 s 4-Phenylbutyl 1 , 1 -Dimethylpropyl

1 o s 3-(3-Pyridyl)propyl Cyclohexyl

1 o s 3 , 3-Diphenylpropyl 1 , 1 -Dimethylpropyl

1 0 s 3 , 3-Diphenylpropyl Cyclohexyl

1 o s 3-(4-Methoxyphenyl)propyl 1 , 1 -Dimethylpropyl

2 0 s 4-Phenylbutyl tert-Butyl

2 o s 1 ,5-Diphenylpentyl 1 , 1 -Dimethylpropyl

2 o s 1 ,5-Diphenylpentyl Phenyl

2 0 s 3-(4-Methoxyphenyl)propyl 1 , 1 -Dimethylpropyl

2 o s 3-(4-Methoxyphenyl) propyl Phenyl

2 0 s 3-( 1 -Naphthy propyl 1 , 1 -Dimethylpropyl

1 0 s 3 , 3-Di(4-fluoro)phenyl-propyl 1 , 1 -Dimethylpropyl

1 0 s 4 , 4-Di(4-fluoro)phenylbutyl 1 , 1 -Dimethylpropyl

1 0 s 3-( 1 -Naphthyl)propyl 1 , 1 -Dimethylpropyl

1 0 s 2,2-Diphenylethyl 1 , 1 -Dimethylpropyl

2 0 s 2,2-Diphenylethyl 1 , 1 -Dimethylpropyl

2 0 s 3 , 3-Diphenylpropyl 1 , 1 -Dimethylpropyl

1 0 s 3-(4-{Trifluoromethyl}phenyl)propyl 1 , 1 -Dimethylpropyl

1 0 s 3-(2-Naphthyl)propyl 1 , 1 -Dimethylpropyl

2 o s 3-(l-Naphthyl)propyl 1 , 1 -Dimethylpropyl

1 0 s 3-(3-Chloro)phenylpropyl 1 , 1 -Dimethylpropyl

1 0 s 3-(3-{Trifluoromethyl}phenyl)propyl 1 , 1 -Dimethylpropyl

1 0 s 3-(2-Biphenyl)propyl 1 , 1 -Dimethylpropyl

1 0 s 3-(2-Fluorophenyl)propyl 1 , 1 -Dimethylpropyl

1 0 s 3-(3-Fluorophenyl)propyl 1 , 1 -Dimethylpropyl

2 o s 4-Phenylbutyl 1 , 1 -Dimethylpropyl

2 0 s 3-Phenylpropyl 1 , 1 -Dimethylpropyl

1 0 s 3-(2-Chloro)phenylpropyl 1 , 1 -Dimethylpropyl

2 0 s 3-(3-Chloro)phenylpropyl 1 , 1 -Dimethylpropyl

2 0 s 3-(2-Fluoro)phenylpropyl 1 , 1 -Dimethylpropyl

2 0 s 3-(3-Fluoro)phenylpropyl 1 , 1 -Dimethylpropyl

1 0 s 3-(2,5-Dimethoxyphenyl)propyl 1 , 1 -Dimethylpropyl

1 0 CH₂ 3-Phenylpropyl Cyclohexyl

1 0 CH₂ 3-Phenylethyl tert-Butyl

2 0 CH₂ 4-Phenylbutyl Cyclohexyl

2 0 CHR, 2-Phenylethyl tert-Butyl

1 0 CH₂ 3 , 3-Di(4-fluorophenyl)propyl 1 , 1 -Dimethylpropyl

2 0 CH₂ 3-Phenylpropyl 1 , 1 -Dimethylpropyl

Preferred compounds of TABLE I are named as follows (25) -2- ( { l-Oxo-5-phenyl}-pentyl-l- (3, 3-dimethyl- 1, 2-dioxopentyl) pyrrolidine

3, 3-Dimethyl-l- [ (2S) -2- (5- (3-pyridyl) pentanoyl) 1-pyrrolidine] -1, 2-pentanedione

(25) -2- ( {l-Oxo-4-phenyl}-butyl-l- (3, 3-dimethyl- 1, 2-dioxobutyl) pyrrolidine

2-Phenyl-l-ethyl (25) -1- ( 3 , 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarbothioate

0 2-Phenyl-l-ethyl 1 - ( 3 , 3 -dime t hy 1 - 1 , 2 dioxopentyl) -2-piperidinecarbothioate

1 (3-Thioindolyl) methyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl ) -2-pyrrolidinecarbothioate

2 2-Phenyl-l-ethyl (2S) -1- (2-cyclohexyl-l, 2- dioxoethyl) -2-pyrrolidinecarbothioate

4 2-Phenyl-l-ethyl 1- (2-phenyl-l , 2-dioxoethyl) -2- piperidinecarbothioate

///

2-Phenyl-l-ethyl (25) -1- ( 1-cyclopentyl-l, 2- dioxoethyl) -2-pyrrolidinecarbothioate

3-Phenyl-l-propyl 1- ( 3 , 3-dimethyl- 1 , 2 - dioxobutyl) -2-piperidinecarbothioate

3-Phenyl-l-ρropyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarbothioate

3- (3-Pyridyl) -1-propyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl ) -2-pyrrolidinecarbothioate

3-Phenyl-l-propyl (2S) -1- (2-cyclohexyl-l, 2- dioxoethyl) -2-pyrrolidinecarbothioate

4-Phenyl-l-butyl (2S) -1- (2-cyclohexyl-l, 2- dioxoethyl ) -2-pyrrolidinecarbothioate

4-Phenyl-l-butyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarbothioate

3- (3-Pyridyl) -1-propyl (25) -1- (2-cyclohexyl-l, 2- dioxoethyl ) -2-pyrrolidinecarbothioate

3, 3-Diphenyl-l-proρyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl ) -2-pyrrolidinecarbothioate

3,3-Diphenyl-l-propyl (25) -1- (2-cyclohexyl-l, 2- dioxoethyl) -2-pyrrolidinecarbothioate

3- (para-Methoxyphenyl) -1-propyl (2S)-l-(3,3- dimethyl-1, 2 -dioxopentyl) -2-pyrrolidinecarbothioate

4-Phenyl-l-butyl 1- (1, 2-dioxo-3, 3-dimethylbutyl)

-2 -piper idinecarbothioate

1, 5-Diphenyl-3-pentyl 1- (3, 3-dimethyl-l, 2- dioxopentyl) -2 -piper idinecarbothioate 1, 5-Diphenyl-3-mercaptopentyl 1- (3-phenyl-l, 2- dioxoethyl) -2-piperidinecarbothioate

3- (para-Methoxyphenyl) -1-propyl 1- (1, 2-dioxo- 3, 3-dimethylpentyl) piperidine-2-carbothioate

3- (para-Methoxyphenyl) -1-propyl 1- (2-phenyl-l, 2- dioxoethyl) piperidine-2-carbothioate

3- (1-Naphthyl) -1-propyl 1- (3, 3-dimethyl-l, 2- dioxopentyl) piperidine-2-carbothioate

3, 3-Di (para-fluoro) phenyl-1-propyl (2S)-l-(3,3- dimethyl-1, 2 -dioxopentyl) -2-pyrrolidinecarbothioate

4, 4-Di (para-f luorophenyl) butyl 1- (3, 3-dimethyl- 2-oxopentanoyl) -2-pyrrolidinecarbothioate

3- (1-Naphthyl) propyl (2S) -1- (3, 3-dimethyl-2- oxopentanoyl) -2-pyrrolidinecarbothioate

2,2-Diphenylethyl (2S) -1- ( 3, 3-dimethyl-2- oxopentanoyl) tetrahydro-lH-2 -pyrrol idine- carbothioate

2,2-Diphenylethyl (25) -1- ( 3 , 3-dimethyl-2- oxopentanoyl ) -2-piperidinecarbothioate

3 , 3 -Diphenylpropy 1 1 - ( 3 , 3 -dime thy 1-2 oxopentanoyl) -2-piperidinecarbothioate

3- [4- (Trifluoromethyl) phenyl] propyl (2S)-l-(3,3- dimethyl-2 -oxopentanoyl) -2 -pyrrolidine- carbothioate

3- (2-Naphthyl) propyl (25) -1- (3, 3-dimethyl-2- oxopentanoyl ) -2-pyrrolidinecarbothioate

3- (2-Naphthyl) propyl (2R, 5) -1- (3, 3-dimethyl-2- oxopentanoyl ) -2-piperidinecarbothioate 3- (3-Chlorophenyl) propyl (25) -1- (3, 3-dimethyl-2- oxopentanoyl ) -2-pyrrolidinecarbothioate

3- [3- (Trifluoromethyl) phenyl] propyl (25)-l-(3,3- dimethyl- 2 -oxopentanoyl ) -2 -pyrrol idinecarbothioate

3- (1-Biphenyl) propyl (2S) -1- (3, 3-dimethyl-2- oxopentanoyl) -2-pyrrolidinecarbothioate

3- (2-Fluorophenyl) propyl (2S) -1- (3, 3-dimethyl-2- oxopentanoyl) -2-pyrrolidinecarbothioate

3- (3-Fluorophenyl) propyl (25) -1- (3, 3-dimethyl-2- oxopentanoyl ) -2-pyrrolidinecarbothioate

4-Phenylbutyl 1- (3, 3-dimethyl-2-oxopentanoyl) piperidinecarbothioate

3-Phenylpropyl 1- (3, 3-dimethyl-2-oxopentanoyll 2-piperidinecarbothioate

3- (2-Chlorophenyl) propyl (25) -1- (3, 3-dimethyl-2- oxopentanoyl) -2-pyrrolidinecarbothioate

3- (2-Chlorophenyl) propyl 1- (3, 3-dimethyl-2- oxopentanoyl) -2-piperidinecarbothioate

3- (2-Fluorophenyl) propyl 1- (3, 3-dimethyl-2- oxopentanoyl ) -2-piperidinecarbothioate

3- (3-Fluorophenyl) propyl 1- (3, 3-dimethyl-2- oxopentanoyl) -2-piperidinecarbothioate

3- (3,4-Dimethoxyphenyl)propyl (25) -1- (3,3- d i m e t h y l - 2 - o x o p e n t a n o y l ) - 2 - pyrrol idinecarbothioate 66 (2S)-2- ({l-0xo-4-phenyl}-butyl-l- (2-Cyclohexyl- 1, 2-dioxoethyl) pyrrolidine

67 2- ({l-Oxo-4-phenyl} -butyl-1- (3, 3-dimethyl-l, 2- dioxobutyl) pyrrolidine

68 2- ( { l-0xo-6-phenyl}-hexyl-l- (2-Cyclohexyl-l, 2- dioxoethyl) piperidine

69 2- ({1-Oxo- [2-{2'-phenyl}ethyl]-4-phenyl}-butyl- 1- (3, 3-dimethyl-l, 2-dioxobutyl) piperidine

70 l-{ (25) -2- [5, 5-di (4-Fluorophenyl) pentanoyl] -2- pyrrolidine}-3, 3-dimethyl-l, 2-pentanedione

71 D i m e t h y l - 1 - [ 2 - ( 4 - phenylpentanoyl) piperidino] -1, 2-pentanedione

FORMULA III

Furthermore, the bridged heterocyclic derivative may be a compound of formula III:

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

A, B, and C are independently CH₂, 0, S, SO, S0₂, 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure; X is 0 or S;

Z is S, CH₂, CHR_X or CR_XR₃;

R_x and R₃ are independently C_x-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 (Ar_x)_n, a bridged ring moiety, C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_n, C₃-C₈ cycloalkyl, C_x-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 C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 C_x-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and

Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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.

Preferred compounds of formula III are presented in TABLE II:

R₂

TABLE II

No. A B C X Z R, R₂

72 CH₂ S CH₂ O S 2-phenethyl 1 , 1 -dimethylpropyl 73 CH₂ s CH₂ O CH₂ 3-phenylpropyl 1 , 1 -dimethylpropyl 74 CH₂ CH₂ NH O S 2-phenethyl 1 , 1 -dimethylpropyl 75 CH₂ s CH₂ S S 2-phenethyl 1 , 1 -dimethylpropyl

FORMULA IV

Alternatively, the bridged heterocyclic derivative may be a compound of formula IV:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: A, B, C and D are independently CH₂, 0, S, SO, S0₂, 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

X is 0 or S;

Z is S, CH₂, CHR_X or CR_XR₃;

R_x and R₃ are independently C_x-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 (Ar_x)_n, C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_n, C₃-C₈ cycloalkyl, C_x-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 C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, bridged ring moiety, or Ar_x, 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, C_x-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, bridged ring moiety, and hydroxyl; and Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-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.

Preferred compounds of formula IV are presented in TABLE III.

TABLE I I I

No A B C D X Z R, R,

76 CH₂ CH₂ O CH₂ 0 CH₂ 3-phenylpropyl 1 , 1 -dimethylpropyl

77 CH₂ CH₂ O CH₂ 0 S 2-phenethyl 1, 1 -dimethylpropyl

78 CH₂ CH₂ S CH₂ 0 CH₂ 3-phenylpropyl 1 , 1 -dimethylpropyl

79 CH₂ CH₂ S CH₂ 0 S 2-phenethyl 1 , 1 -dimethylpropyl

FORMULA V

The bridged heterocyclic derivative may further be a compound of formula 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, S0₂, N, NH, and NR₄; 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;

R₄ is independently either C_x-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 R₄ is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, halo-C_x-C₆-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio-C_x-C₆-alkyl, C_x-C₆-alkylthio, sulfhydryl, amino, C_x-C₆- alkylamino, amino-C_x-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

R_x, 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:

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, S0₂, N, NH, and NR_X; 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 0 or S;

Z is 0, NH or NR_X; W and Y are independently 0, S, CH₂ or H₂; R_x is independently C_x-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 (Ar_x)_n, C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with

(Ar_x)_n, C₃-C₈ cycloalkyl, C_x-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 C_x-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 Ar_x, 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 C_x-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and

Ar_x 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_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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:

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

A, B and C are independently CH₂, 0, S, SO, S0₂, NH or

NR_X; 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

R_x is C_x-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 (Ar_x)_n and C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_n; n is 1 or 2;

R₂ is independently either C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x; and

Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-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.

A preferred compound of formula VII is:

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;

R_x is independently selected from the group consisting of 3-phenylpropyl and 3- (3-pyridyl) propyl; and R₂ is independently selected from the group consisting of 1, 1-dimethylpropyl, cyclohexyl, and tert-butyl.

Specific examples of this embodiment are presented in TABLE IV:

///

TABLE IV

80 CH₂ S CH₂ 3-phenylpropyl 1 , 1 -dimethylpropyl

81 CH₂ s CH₂ 3-(3-pyridyl)propyl 1 , 1-dimethylpropyl

82 CH₂ s CH₂ 3-phenylpropyl cyclohexyl

83 CH₂ s CH₂ 3-phenylpropyl tert-butyl

84 CH₂ CH₂ NH 3-phenylpropyl 1 , 1-dimethylpropyl

85 CH₂ CH₂ NH 3-phenylpropyl cyclohexyl

86 CH₂ CH₂ NH 3-phenylpropyl tert-butyl

FORMULA VI I I

In a further embodiment of this invention, the bridged heterocyclic derivative may be a compound of formula VIII:

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

A, B, C and D are independently CH₂, 0, S, SO, S0₂, NH or NR_X; 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure; R_x is independently C_x-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 (Ar_x)_n and C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_n; n is 1 or 2;

R₂ is independently either C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x; and

Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-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.

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;

R_x 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.

TABLE V

No. A B C D R. R₂

87 CH₂ CH₂ S CH₂ 3-phenylpropyl 1 , 1-dimethylpropyl

88 CH₂ CH₂ O CH₂ 3-phenylpropyl 1, 1-dimethylpropyl

89 CH₂ CH₂ s CH₂ 3-phenylpropyl cyclohexyl

90 CH₂ CH₂ O CH₂ 3-phenylpropyl cyclohexyl

91 CH₂ CH₂ s CH₂ 3-phenylpropyl phenyl

92 CH₂ CH₂ O CH₂ 3-phenylpropyl phenyl

93 CH₂ CH₂ NH CH₂ 3-phenylpropyl 1 , 1-dimethylpropyl

94 CH₂ CH₂ NH CH₂ 3-phenylpropyl phenyl

FORMULA IX

Additionally, the bridged heterocyclic derivative may be a compound of formula 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, SO, 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 C_x-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-C_x-C₆- alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio-C_x-C₆-alkyl, C_x-C₆-alkylthio, sulfhydryl, amino, C_x-C₆-alkylamino, amino-C_x-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 NR_X;

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

R_x is independently C_x-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 (Ar_x)_n, C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_n, C₃-C₈ cycloalkyl, C_x-C₅ 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 C_x-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 Ar_x, 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 C_x-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, and hydroxyl; and

Ar_x 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_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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.

N-OXIDES OF HETEROCYCLIC ESTERS, AMIDES, THIOESTERS AND KETONES

FORMULA X

The bridged heterocyclic derivative may further be a compound of formula 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 0, S, SO, S0₂, N, NH, and NR_X; 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 0, S, CH₂, or H₂;

R is independently C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, which is optionally substituted with one or more substituent (s ) independently selected from the group consisting of C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, and Ar₂;

Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR_X, S, CH, CR_X, or CR_XR₃;

Y is a direct bond, C_x-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 C_x-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 C_x-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 0, NH, NR₂, S, SO, or S0₂;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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 C_x-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 C_x-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 C_x-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 0, NH, NR_X, S, SO, or S0₂;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R_x and R₃ are independently hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ 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 :

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

E, F, G and J are independently CH₂, 0, S, SO, S0₂, NH or NR_X; 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

W is 0, S, CH₂, or H₂;

R is independently C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, and Ar_x;

Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, NH, NR_X, S, CH, CR_X, or CR_XR₃;

Y is a direct bond, C_x-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 C_x-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 C_x-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 0, NH, NR₂, S, SO, or S0₂;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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 C_x- 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 C_x-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 C_x-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 0, NH, NR_X, S, SO, or S0₂;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R_x and R₃ are independently hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, or Y-Z.

FORMULA XII

Furthermore, the bridged heterocyclic derivative may be a compound of formula XII:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH₂, 0, S, SO, S0₂, NH or NR_X; 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

W is 0, S, CH₂, or H₂;

R is independently C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, and Ar_x; Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR_X, S, CH, CR_X, or CR_XR₃; Y is a direct bond, C_x-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 - Ill - more substituent (s) independently selected from the group consisting of C_x-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 C_x-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 0, NH, NR₂, S, SO, or S0₂; R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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 C_x- 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 C_x-C₆ straight or branched chain alkyl, C₆-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 C_x-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 0, NH, NR_X, S, SO, or S0₂;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R_x and R₃ are independently hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ 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:

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 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 0, S, CH₂, or H₂; R is independently C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, and Ar_x;

Ar_x 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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR_X, S, CH, CR_X, or CR_XR₃;

Y is a direct bond, C_x-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 C_x-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 C_x-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 0, NH, NR₂, S, SO, or S0₂;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-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 C_x- 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 C_x-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 C_x-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 0, NH, NR_X, S, SO, or S0₂;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R_x and R₃, independently, are hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, or Y-Z.

Examples of the compounds of formula XIII when W is 0 are presented in TABLE VI:

TABLE VI

No. n X Y Z R

95 ] 0 (CH₂)₃ 3-Pyridyl N-oxide 1 , 1-dimethylpropyl

96 ] I O (CH^ 2-Pyridyl N-oxide 1, 1-dimethylpropyl

97 ] L O (CH₂)₃ 4-Pyridyl N-oxide 1, 1-dimethylpropyl

98 ] [ O (CH₂)₃ 2-Quinolyl N-oxide 1,1 -dimethylpropyl

99 ] 1 O (CH₂)₃ 3-Quinolyl N-oxide 1, 1-dimethylpropyl

100 ] I 0 (CH₂)₃ 4-Quinolyl N-oxide 1 , 1 -dimethylpropyl

Preferred compounds of formula XIII may be selected from the group consisting of:

3- (2-Pyridyl) -1-propyl (25) -1- (1, 1-Dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (3-Pyridyl) -1-propyl (2S) -1- (1, 1-Dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (4-Pyridyl) -1-propyl (2S)-1-(1, 1-Dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (2-Quinolyl) -1-propyl (25) -1- (1, 1-Dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide; 3- (3-Quinolyl) -1-propyl (2S) -1- (1, 1-Dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide;

3- (4-Quinolyl) -1-propyl (25) -1- (1, 1-Dimethyl-l, 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:

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, SO, 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 C_x-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-C_x-C₆-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, a bridged ring moiety, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio-C_x-C₆-alkyl, C_x-C₆- alkylthio, sulfhydryl, amino, C_x-C₆-alkylamino, amino-C_x-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 0, 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:

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, S0₂, 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, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, i ino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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, C_x-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 C_x-C₆-alkylamino, amido, amino, amino-C_x-C₆- alkyl, azo, benzyloxy, C_x-C₉ straight or branched chain alkyl,

alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, C_x-C₆-ester, formanilido, halo, halo-C_x-C₆-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C_x-C₆-alkyl, thiocarbonyl, thiocyano, thio-C_x-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 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, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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;

C and D are independently hydrogen, Ar, C_x-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 C_x-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆- ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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 0, NH, NR₃, S, SO, or S0₂;

W is 0 or S; and U is either 0 or N, provided that: when U is 0, then R_x is a lone pair of electrons and R₂ is selected from the group consisting of Ar, C₃-C₈ cycloalkyl, a bridged ring moiety, C_x-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 R_x and R₂ are independently selected from the group consisting of hydrogen, Ar, C₃-C_x0 cycloalkyl, a bridged ring moiety, C₇-C_X2 bi- or tri-cyclic carbocycle, C_x-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 R_x 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 :

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

E, F, G and J are independently CH₂, 0, S, SO, S0₂, 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

X is either 0 or S; Y is a direct bond, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 C_x-C₆-alkylamino, amido, amino, amino-C_x-C₆- alkyl, azo, benzyloxy, C_x-C₉ straight or branched chain alkyl, C_x-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, C_x-C₆-ester, formanilido, halo, halo-C₁-C₆-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C_x-C₆-alkyl, thiocarbonyl, thiocyano, thio-C_x-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, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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;

C and D are independently hydrogen, Ar, C_x-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 C_x-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆- ester, thio-C_x-C₆-ester, Ci-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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 0, NH, NR₃, S, SO, or S0₂; W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_x is a lone pair of electrons and R₂ is selected from the group consisting of Ar, C₃-C₈ cycloalkyl, a bridged ring moiety, C_x-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 R_x and R, are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C₃-C₁₀ cycloalkyl, C₇-C_X2 bi- or tri-cyclic carbocycle, C_x-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 R_x 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:

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

E, F, and G are independently CH₂, 0, S, SO, S0₂, 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

X is either 0 or S;

Y is a direct bond, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 C_x-C₆-alkylamino, amido, amino, amino-C_x-C₆- alkyl, azo, benzyloxy, C_x-C₉ straight or branched chain alkyl, C_x-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, Cj-Cg-ester, formanilido, halo, halo-C_x-C₆-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C_x-C₆-alkyl, thiocarbonyl, thiocyano, thio-C_x-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, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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;

C and D are independently hydrogen, Ar, C_x-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 C_x-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆- ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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 0, NH, NR₃, S, SO, or S0₂;

W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_x is a lone pair of electrons and R₂ is selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_x-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 R_x and R₂ are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C₇-C_X2 bi- or tri-cyclic carbocycle, C_x-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 R_x 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:

(xviii:

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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure; X is either 0 or S;

Y is a direct bond, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 C_x-C₆-alkylamino, amido, amino, amino-C_x-C₆- alkyl, azo, benzyloxy, C_x-C₉ straight or branched chain alkyl, C_x-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, C_x-C₆-ester, formanilido, halo, halo-C_x-C₆-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-C_x-C₆-alkyl, thiocarbonyl, thiocyano, thio-C_x-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, C_x-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-C_x-C₆-alkyl, thiocarbonyl, Ci-Cg-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy₍ C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-Cj-Cg-alkyl, sulfhydryl, thio-Ci-Cg-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; C and D are independently hydrogen, Ar, C_x-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 C_x-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆- ester, thio-C_x-C₆-ester, alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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 0, NH, NR₃, S, SO, or S0₂;

W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_x is a lone pair of electrons and R₂ is selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_x-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 R_x and R₂ are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C₃-C₁₀ cycloalkyl, C₇-C_X2 bi- or tri-cyclic carbocycle, C_x-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 R_x 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.

TABLE VII

No. n W Y Z C D ^Rl R₂

101 1 0 (CH₂)₂ CH 3-Pyridyl H H 2-Methylbutyl

102 1 0 (CH₂)₂ CH 3-Pyridyl H H 1 , 1 -dimethylpropyl

103 1 o (CH₂)₂ CH 4-Methoxyphenyl H H 1 , 1 -dimethylpropyl

104 1 0 CH₂ CH Phenyl H H 1 , 1 -dimethylpropyl

105 1 s (CH₂)₂ CH 4-Methoxyphenyl H H Cyclohexyl

106 1 0 (CH₂)₂ CH 3-Pyridyl H H Cyclohexyl

107 1 s (CH₂)₂ CH 3-Pyridyl H H Cyclohexyl

108 1 s (CH₂)₂ CH 3-Pyridyl H H 1 -Adamantyl

109 1 s (CH₂)₂ CH 3-Pyridyl H H 1 , 1 -dimethylpropyl

110 1 0 (CH₂)₂ CH Phenyl Phenyl H 1,1 -dimethylpropyl

111 2 0 (CH₂)₂ CH Phenyl H H 1 , 1-dimethylρropyl

112 2 0 (CH₂)₂ CH Phenyl H H Phenyl

113 2 0 Direct CH 2-Phenylethyl 2-Phenylethyl H Phenyl bond

114 2 0 Direct CH 2-Phenylethyl 2-Phenylethyl H Cyclohexyl bond

115 2 s Direct CH 2-Phenylethyl 2-Phenylethyl H Cyclohexyl bond

116 2 0 (CH₂)₂ CH 4-Methoxyphenyl H 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 ) l-propyl-2S- 1- [ ( 1 * , 1 '

Dimethylpropyl) carbamoyl] pyrrolidine-2 carboxylate;

3- (3-Pyridyl) -l-propyl-2S-l- [ (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:

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

V is CH, N, or S;

Y is a direct bond, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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, C_x-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 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, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-Cj-Cg-alkyl, sulfhydryl, thio-C_x-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;

C and D are independently hydrogen, Ar, C_x-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 C_x-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆- ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino-Cj-Cg-alkyl, sulfhydryl, thio-Cj-Cg-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 0, NH, NR₃, S, SO, or S0₂; and

A, B, R_x, 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:

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, S0₂, 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, C_x-C₆ straight or branched chain alkyl, δr 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-C_x-C₆-alkyl, thiocarbonyl_, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 0, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N- oxide;

Z is a direct bond, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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, SO, or S0₂;

C and D are independently hydrogen, Ar, C_x-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 C_x-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆- ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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 0, NH, NR₂, S, SO, or S0₂; and

R_x is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_x-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-C_x- C₆-alkyl, hydroxy, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆- ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x- C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-C₆- alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, or S0₂.

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 C₄-C₇ branched chain alkyl, C₄-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 (25) -N- (benzenesulfonyl) pyrrolidine-2-carboxylate;

3- (para-Methoxyphenyl) -1-propylmercaptyl (25) -N- (a-toluenesulfonyl) pyrrolidine-2-carboxylate;

3- (para-Methoxyphenyl) -1-propylmercaptyl (2S) -N- (a-toluenesulfonyl) pyrrolidine-2-carboxylate;

1, 5-Diphenyl-3-pentylmercaptyl N- (pa ra - toluenesulfonyl) pipecolate; and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA XXI

Moreover, the bridged heterocyclic derivative may be a compound of formula XXI :

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

E, F, G and J are independently CH₂, 0, S, SO, S0₂, 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

X is either 0 or S;

Y is a direct bond, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₅-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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 S0₂;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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, C_x-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-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆- alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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, SO, or S0₂;

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, C_x-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-C-, cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C_x-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_x-C₆-alkyl, thiocarbonyl, C_x-C₆- ester, thio-C_x-C₆-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-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 0, NH, NR₂, S, SO, or S0₂; and R_x is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_x-C₆ straight or branched chain alkyl, and C₂-C₅ 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-C_x- C₆-alkyl, hydroxy, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, C_x-C₆-ester, thio-C_x-C₆- ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x- C₆-alkylamino, amino-C_x-C₆-alkyl, sulfhydryl, thio-C_x-C₆- alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, or S0₂.

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:

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F, and G are independently CH₂, 0, S, SO, S0₂, 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, 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 0 or S;

Y is a direct bond, C_x-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- (C_x-C₆) -alkyl, thiocarbonyl, (C_x-C₆) -ester, thio- (C_x-C₆) - ester, (C_x-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (C_x-C₆) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio- (C_x-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 S0₂;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 0, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N- oxide;

Z is a direct bond, C_x-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- (C_x-C₆) -alkyl, thiocarbonyl, (C_x-C₆) -ester, thio- (C_x-C₆) - ester, (C_x-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (Cj-Cg) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio- (C_x-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, SO, or S0₂;

C and D are independently hydrogen, Ar, C_x-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 C_x-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 0, NH, NR₂, S, SO, or S0₂; and

R_x is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_x-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- (C_x-C₆) -alkyl, hydroxy, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, (C_x-C₆) -ester, thio- (C_x-C₆) - ester, (C_x-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino,

(C_x-C₆) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio-

(C_x-C₆) -alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S,

SO, or S0₂. 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:

(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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure; X is either 0 or S;

Y is a direct bond, C_x-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- (C_x-C₆) -alkyl, thiocarbonyl, (C_x-C₆) -ester, thio- (C_x-C₆) - ester, (C_x-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (C_x-C₆) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio- (C_x-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 S0₂;

Z is a direct bond, C_x-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- (C_x-C₆) -alkyl, thiocarbonyl, (C_x-C₆) -ester, thio- (C_x-C₆) - ester, (C_x-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (C_x-C₆) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio- (C_x-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, SO, or S0₂;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 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, C_x-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 C_x-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 0, NH,

NR₂, S, SO, or S0₂; and

R_x is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_x-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-

(C_x-C₆) -alkyl, hydroxy, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, (C_x-C₆) -ester, thio- (C_x-C₆) - ester, (C_x-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (Cj-Cg) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio- (C_x-C₆) -alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, 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:

TABLE VIII

No. n Y Z C D R,

117 CH₂ CH Phenyl H Phenyl

118 CH₂ CH Phenyl H a-Methylphenyl

119 CH₂ CH Phenyl H 4-Methylphenyl

120 (CH₂)₂ CH /?-Methoxyphenyl H Phenyl

121 (CH₂)₂ CH p-Methoxyphenyl H a-Methylphenyl

122 (CH,), CH />-Methoxyphenyl H 4-Methylphenyl

123 (CH₂)₂ CH Phenyl Phenyl Phenyl

124 (CH,), CH Phenyl Phenyl a-Methylphenyl

125 (CH,), CH Phenyl Phenyl 4-Methylphenyl

126 2 (CH,)₃ CH Phenyl H Phenyl

127 2 (CH,)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-Phenylpropyl 3-Phenylpropyl Phenyl bond

132 2 Direct CH 3-Phenylpropyl 3-Phenylpropyl a-Methylphenyl bond

133 2 Direct CH 3-Phenylpropyl 3-Phenylpropyl 4-Methylphenyl bond 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 selected from the group consisting of:

3- (para-Methoxyphenyl) -1-propylmercaptyl (25) -N- (benzenesulfonyl) pyrrolidine-2-carboxylate;

3- (para-Methoxyphenyl) -1-propylmercaptyl (25) -N- (a-toluenesulfonyl) pyrrolidine-2-carboxylate;

3- (para-Methoxyphenyl) -1-propylmercaptyl (25) -N- (a-toluenesulfonyl) pyrrolidine-2-carboxylate;

1, 5-Diphenyl-3-pentylmercaptyl N- (pa ra- toluenesulfonyl) pipecolate;

and pharmaceutically acceptable salts, esters, and solvates thereof.

FORMULA XXIV

Moreover, the bridged heterocyclic derivative may be a compound of formula XXIV:

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

V is CH, N, or S;

A, B, C, D, R_x, 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:

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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

R_x is independently C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said R_x is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C_x-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, a bridged ring moiety, and Ar₂;

Ar_x 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 Ar_x is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, S, CH₂ or H₂;

Y is 0 or NR₂, wherein R₂ is a direct bond to a Z, hydrogen or C_x-C₆ alkyl; and each Z, independently, is Cj-Cg 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 Ar_x, C₃-C₈ cycloalkyl, and C_x-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 C_x-C₉ straight or branched chain alkyl which is unsubstituted or substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x;

X₂ is 0 or NR₅, wherein R₅ is independently selected from the group consisting of hydrogen, C_x-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, C_x-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, C_x-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.

In a preferred embodiment of formula XXV, Z and R_x are lipophilic.

In another preferred embodiment of formula XXV, the compound is selected from the group consisting of:

3-phenyl-l-propyl (2S) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3-phenyl-l-prop-2- (E) -enyl (25) -1- (3, 3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboxylate;

3-(3,4,5-trimethoxyphenyl)-l-propyl (25) -1- (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate;

3- (3, , 5-trimethoxyphenyl ) -l-prop-2- (E) -enyl (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarboxylate ;

3- (4, 5-dichlorophenyl) -1-propyl (2S)-l-(3,3- d i m e t h y l - 1 , 2 - d i o x o p n t y 1 ) - 2 - pyrrol idinecarboxylate;

3- (4, 5-dichlorophenyl) -l-prop-2- (E) -enyl (25) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate;

3- (4, 5-methylenedioxyphenyl) -1-propyl (25) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate;

3- (4, 5-methylenedioxyphenyl) -l-prop-2- (E) -enyl (25) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarboxylate;

3-cyclohexyl-l-propyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3-cyclohexyl-l-prop-2- (E)-enyl (25) -1- (3,3- d i m e t h y l - 1 , 2 - d i o x o p e n t y l ) - 2 - pyrrolidinecarboxylate;

(IR) -1, 3-diphenyl-l-propyl (25) -1- (3, 3-dimethyl- 1, 2-dioxopentyl) -2-pyrrolidinecarboxylate;

(IR) -1, 3-diphenyl-l-prop-2- (E) -enyl (25) -1- (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate;

(IR) -l-cyclohexyl-3-phenyl-l-propyl (25) -1- (3,3- dimethyl-1, 2-dioxopentyl) -2 -pyrrol idine- carboxylate;

(IR) -l-cyclohexyl-3-phenyl-l-prop-2- (E) -enyl

(25) -1- ( 3, 3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarboxylate;

(IR) -1- (4, 5-dichlorophenyl) -3-phenyl-l-propyl (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidine-carboxylate ;

3-phenyl-l-propyl (25) -l-(l,2-dioxo-2' cyclohexyl) ethy 1-2 -pyrrolidinecarboxylate;

3-phenyl-l-propyl (25)-l- (l,2-dioxo-4 cyclohexyl) ut yl-2 -pyrrolidinecarboxylate; 3-phenyl-l-propyl (2S) -1- ( 1, 2-dioxo-2- [2- furanyl] ) ethyl-2-pyrrolidinecarboxylate;

3-phenyl-l-propyl ( 2 S) -1- ( 1, 2-dioxo-2- [2- thienyl] ) ethyl-2-pyrrolidinecarboxylate;

3-phenyl-l-propyl (25) -1- ( 1 , 2-dioxo-2- [2- thiazolyl] ) ethyl-2-pyrrolidinecarboxylate;

3-phenyl-l-propyl ( 2 S) -1- ( 1 , 2-dioxo-2- phenyl) ethyl-2-pyrrolidinecarboxylate;

1, 7-diphenyl-4-heptyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3-phenyl-l-propyl (2S) -1- (3, 3-dimethyl-l, 2- dioxo-4-hydroxybutyl) -2-pyrrolidinecarboxylate;

3-phenyl-l-propyl (2S) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxamide;

1- [1- (3, 3-dimethyl-l, 2-dioxopentyl) -L-proline] L-phenylalanine ethyl ester;

1- [1- (3, 3-dimethyl-l, 2-dioxopentyl) -L-proline] L-leucine ethyl ester;

1- [1- (3, 3-dimethyl-l, 2-dioxopentyl) -L-proline] L-phenylglycine ethyl ester;

1- [1- (3, 3-dimethyl-l, 2-dioxopentyl) -L-proline] L-phenylalanine phenyl ester;

1- [1- (3, 3-dimethyl-l, 2-dioxopentyl) -L-proline] - L-phenylalanine benzyl ester;

1- [1- (3, 3-dimethyl-l, 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 :

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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

R_x is independently C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said R_x is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C_x-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, a bridged ring moiety, and Ar₂; Ar, 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 Ar_x is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; Z is C_x-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 Ar_x, C₃-C₈ cycloalkyl, and C_x-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 C_x-C₉ straight or branched chain alkyl which is unsubstituted or substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x; X₂ is 0 or NR₅, wherein R₅ is independently selected from the group consisting of hydrogen, C_x-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, C_x-C₅ straight or branched chain alkyl,

C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, C_x-C₅ straight or branched chain alkyl substituted with phenyl, and C₂-C₅ straight or branched chain alkenyl substituted with phenyl.

In a preferred embodiment of formula XXVI, R_x is independently selected from the group consisting of C_x-C₉ straight or branched chain alkyl, 2-cyclohexyl, 4- cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4- hydroxybutyl .

In another preferred embodiment of formula XXVI, Z and R_x are lipophilic.

FORMULA XXVII

Furthermore, the bridged heterocyclic derivative may be a compound of formula XXVII:

(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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure; Z' is the fragment

wherein: R₃ is independently C_x-C₉ straight or branched chain alkyl or unsubstituted Ar_x, wherein said alkyl is unsubstituted or substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x;

X₂ is 0 or NR₅, wherein R₅ is independently selected from the group consisting of hydrogen, C_x-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, C_x-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, C_x-C₅ straight or branched chain alkyl substituted with phenyl, and C₂-C₅ straight or branched chain alkenyl substituted with phenyl; and

Ar_x 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:

(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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

R_x is independently C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₆ cycloalkyl, a bridged ring moiety, or Ar_x, wherein said alkyl or alkenyl is unsubstituted or substituted with C₃-C₆ cycloalkyl or Ar₂;

Ar_x 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 C_x-C₆ alkyl; each Z, independently, is hydrogen, C_x-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 C_x-C₄ alkoxy; and n is 1 or 2.

In a preferred embodiment of formula XXVIII, Z and R_x are lipophilic. In another preferred embodiment of formula XXVIII, the compound is selected from the group consisting of:

3- (2, 5-dimethoxyphenyl) -1-propyl (25) -1- (3,3- dime t hy l - 1 , 2 - d i o x op e n t y l ) - 2 - pyrrolidinecarboxylate;

3- (2, 5-dimethoxyphenyl) -l-prop-2- (E) -enyl (2S) - 1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate;

2-(3,4,5-trimethoxyphenyl)-l-ethyl (25) -1- (3,3- d ime t hyl - 1 , 2 - d i o x op e n t y l ) - 2 - pyrrolidinecarboxylate;

3- (3-pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3- (2-pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3- (4-pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3-phenyl-l-propyl (25) -1- (2-tert-butyl-1, 2- dioxoethyl) -2-pyrrolidinecarboxylate;

3-phenyl-l-propyl (25) -1- (2-cyclohexylethyl-l, 2- dioxoethyl) -2-pyrrolidinecarboxylate; 3- (3-pyridyl) -1-propyl ( 2 S) - 1 - ( 2 - cyclohexylethyl-1 , 2-dioxoethyl) -2-pyrrolidinecarboxylate;

3- (3-pyridyl) -1-propyl (2S) -1- (2-tert-butyl-l, 2- dioxoethyl) -2-pyrrolidinecarboxylate;

3, 3-diphenyl-l-propyl (25) -1- ( 3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3- (3-pyridyl) -1-propyl (2S) -1- (2-cyclohexyl-l, 2- dioxoethyl ) -2-pyrrolidinecarboxylate ;

3- (3-pyridyl) -1-propyl (25) -N- ( [2-thienyl] glyoxyl) pyrrolidinecarboxylate;

3, 3-diphenyl-l-propyl (25) -1- (3, 3-dimethyl-l, 2- dioxobutyl) -2-pyrrolidinecarboxylate;

3, 3-diphenyl-l-propyl (25) -1-cyclohexylglyoxyl- 2-pyrrolidinecarboxylate;

3, 3-diphenyl-l-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 (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3- (2-pyridyl) -1-propyl (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-pyrrolidinecarboxylate;

3- (3-pyridyl) -1-propyl (25) -1- (2-cyclohexyl-l, 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:

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, SO, 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 C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein R is independently either unsubstituted of substituted with one or more substituent (s) independently selected from the group consisting of halo, halo- (C_x-C₆) - alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio- (C_x-C₆) -alkyl, alkylthio, sulfhydryl, amino, (C_x-C₆) -alkylamino, amino- (C_x-C₆) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar₂; R_x is independently C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said R_x is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C_x-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, a bridged ring moiety, and Ar₂;

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

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 167

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-l, 2 , 4-triazoline-3 , 5-dione with rapamycin.

FORMULA (XXX)

^λWAY-124,466'

COMPOUND 168

Chakraborty et al. , Chemistry and Biology (1995) 2 : 157-161, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XXXI.

FORMULA (XXXI)

RAP-Pa

COMPOUNDS 169-171

Ikeda et al. , J Aπu Chem. Soc. (1994) 11_6: 143-4144 , 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 COMPOUNDS 172-175

Wang et al. , Bioorαanic &. 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 CH₂ 174 X H, CH₃ 175 X O

COMPOUND 176

Birkenshaw et al.. , Bioorαanic &. Medicinal Chemistry Letters (1994) 4 (21) :2501-2506, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XXXIV:

FORMULA ( XXXIV )

COMPOUNDS 177-187

Holt et al. , CL 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 R,

10

COMPOUNDS 188-196 Caffery et al. , Bioorganic &_. Medicinal Chemistry Letters (1994) 4 (21) :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 = l 189 y = 2 190 y = 3

FORMULA XXXVII

TABLE XVI I

Compound Structure

191 n = 1 192 n = 2 193 n = 3 FORMULA XXXVI I I

TABLE XVII I

Compound Structure

194 n = 1 195 n = 2 196 n = 3

COMPOUND 197

Teague et al. , Bioorganic &_. Medicinal Chemistry Letters (1993) 3(10) :1947-1950, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XXXIX.

FORMULA XXXIX

COMPOUNDS 198-200

Yamashita et al. , Bioorganic &. 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

TABLE XIX

Compound Structure

198 R = phenyl 199 R = N(allyl)₂

COMPOUNDS 201-221

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

TABLE XX

Compound No. R

202 A Mθ

A

203

208

209 Compound No. R

212

Table XXI I

Compound No. Structure

COMPOUNDS 222-234 Holt et al . , Bioorganic &_. 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 XXI I I

Compound Structure

222 X = OH

10 223 X = OMe 224 X = O-iso-Pr 225 X = OBn 226 X = OCH (Me)Ph 227 X = OCH₂CHCHPh

15 228 X = OCH₂CH₂CH₂(3,4-OMe₂)Ph 229 X = NHBn 230 X = NHCH,CH,CH,Ph

FORMULA XLIII

TABLE XXIV

Compound Structure

30 231 R = Me 232 R = Bn TABLE XXV

Compound Structure

COMPOUNDS 235-249

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

TABLE XXVI

Compound Structure

O-tert-butyl

R₂= Phe- O-tert-butyl

FORMULA XLV

TABLE XXVII

Compound Structure

237 R, = m-OCH₃Ph R₃ = Val-O-tert-butyl

238 R, = -OCH₃Ph

R₃ = Leu-O-tert-butyl

239 R, = -OCH₃Ph

R₃ = Ileu-O-tert-butyl 240 R, = m-OCH₃Ph

R₃ = hexahydro-Phe-O-tert-butyl

R₃ = allylalanine-O-tert-butyl

242 R, = b-naphthyl

R₃ = Val-O-tert-butyl

FORMULA XLVI

TABLE XXVI I I

Compound Structure

243 R, = CH₂(CO)- -OCH₃Ph R₄ = CH₂Ph R₅ = OCH₃

244 R, = CH₂(CO)-b-naphthyl R₄ = CH₂Ph R₅ = OCH₃

FORMULA XLVII

TABLE XXIX

Compound Structure

245 R, = m-OCH₃Ph X = trans-CH=CH- R₄ = H Y = OC(O)Ph

246 R, = m-OCH₃Ph X = trans-CH=CH R₄ = H Y = OC(O)CF₃

247 R, = m-OCH₃Ph X = trans-CH=Cli- R₄ = - Y = -

248 R, = -OCH₃Ph X = trans-CH=CH- R₄ ⁼ H Y = OCH₂CH=CH₂

249 R, = -OCH₃Ph X = C=O

R₄ = H

Y = Ph

COMPOUND 250

Teague et al. , Bioorganic &. Med. Chem. Letters (1994) 4(13) : 1581-1584, incorporated herein by reference, discloses an exemplary pipecolic acid derivative represented by Formula XLVIII.

FORMULA XLVIII

SLB506

COMPOUNDS 251-254

Stocks et al. , Bioorganic &_. Med. Chem. Letters (1994) 4 (12 ) : 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

FORMULA XLIX

TABLE XXXI

Compound Structure

252 R_r = H R₂ = OMe R₃ = CH₂Ome

253 R, = H R₂ = H

R, = H

254 R, = Me R₂ = H R₃ = H

COMPOUNDS 255-276

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

FORMULA L

TABLE XXXI I

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 XXXI I I

Compound Structure

260 R = 4-(p-Methoxy)butyl 261 R = 3-Phenylpropyl 262 R = 3-(3-Pyridyl)propyl

FORMULA LI I

TABLE XXXIV

Compound Structure

263 R = 3-(3-Pyridyl)propyl

264 R = l,7-Diphenyl-4-heptyl 265 R = 4-(4-Methoxy)butyl 266 R = l-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 LI I I

TABLE XXXV

Compound Structure

270 R = 4-(4-Methoxy)butyl

271 R = 3-Cyclohexylpropyl

272 R = 3-Phenylpropyl

FORMULA LIV

TABLE XXXVI

Compound Structure

273 R = 3-Cyclohexylpropyl 274 R = 3-Phenylpropyl 275 R = 4-(4-Methoxy)butyl 276 R = l,7-Diphenyl-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, , 5- trimethoxyphenyl) acetyl] hexahydro-2- pyridinecarboxylate

173 4- (4-methoxyphenyl) butyl (2S) -1- [2- (3, 4, 5- trimethoxyphenyl) acryloyl] hexahydro-2- pyridinecarboxylate

174 4- (4-methoxyphenyl) butyl (2S) -1- [2- (3, 4, 5- trimethoxyphenyl)propanoyl] hexahydro-2- pyridinecarboxylate

175 4- (4-methoxyphenyl) utyl (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) exahydro-2-pyridinecarboxylate

179 3- (3,4, 5-trimethoxyphenyl) propyl (2S)-l-(3,3- dimethyl-2-oxopentanoyl) hexahydro-2- pyridinecarboxylate

180 (lR)-2,2-dimethyl-l-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 (lR)-l-cyclohexyl-3-phenylpropyl (2S)-l-(3,3- dimethyl-2-oxopentanoyl) hexahydro-2- pyridinecarboxylate

183 (IS) -1, 3-diphenylpropyl (2S) -1- (3, 3-dimethyl-2- oxopentanoyl) hexahydro-2-pyridinecarboxylate

184 (lS)-l-cyclohexyl-3-phenylpropyl (2S)-l-(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 l-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-l-thioxopentyl) -2- piperidinecarboxylate

218 3-phenylpropyl 1- (2-hydroxy-3, 3-dimethyl- pentanoyl) -2-piperidinecarboxylate

219 (IR) -l-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 l-(2-[ (2R,3R, 6S)-6-[ (2S, 3E, 5E, 7E, 9S, 11R) -2, 13- dimethoxy-3, 9, ll-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, ll-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,llR)-2,13-dimethoxy-3,9,ll- 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, , ll-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-l- (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 l-(3,3- dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate

232 (E) -3- (3, , 5-trimethoxyphenyl) -2-propenyl 1- (3, 3-dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate

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- (l,3-benzodioxol-5-yl) -2-propenyl l-(3,3- dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate 236 4- (4-methoxyphenyl) butyl l-(2-oxo-2- phenylacetyl) -2-piperidinecarboxylate

237 3-phenylpropyl 1- (2-oxo-2-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-l- (3-phenylpropyl) butyl l-(3,3- dimethyl-2-oxopentanoyl ) -2-piperidinecarboxylate

241 4- (4-methoxyphenyl) butyl 1- (3, 3-dimethyl-2- oxopentanoyl) -2-piperidinecarboxylate

242 1- (4-methoxyphenethyl) -4-phenylbutyl l-(3,3- dimethyl-2-oxopentanoyl) -2-piperidinecarboxylate 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 l-phenethyl-3-phenylpropyl 1- (3, 3-dimethyl-2- oxopentanoyl) -2-piperidinecarboxylate

246 4- (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-l- (3-phenylpropyl) butyl l-(3,3- dimethyl-2-oxobutanoyl) -2-piperidine-carboxylate

FORMULA LV In yet a further embodiment, there is provided a compound of formula LV:

pharmaceut ca y acceptable salt, or solvate thereof, wherein: m is 0-3;

A is CH₂, 0, NH, or N-(C₁-C₄ alkyl);

B and D are independently hydrogen, Ar, C₅-C₇ cycloalkyl substituted C_λ-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkenyl substituted Ci-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl, or Ar substituted Ci-Cg 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 S0₂ in chemically reasonable substitution patterns, or the fragment

wherein Q is hydrogen, Ci-Cg 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, 0-(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, Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C₁-C₄ straight or branched chain alkyl), 0-(C₂-C₄ 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, 0-(C_!-C₄ straight or branched chain alkyl), 0-(C₂-C₄ straight or branched chain alkenyl), Ci-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cj-C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (C_α-C₄ alkyl or C₂- C₄ alkenyl) -Ar, or Ar;

J is hydrogen, C_x or C₂ alkyl, or benzyl; K is Ci-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 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:

TABLE XXXVI I I

Cpd. n m B D L

253 2 0 3-Phenylpropyl 3-(3-Pyridyl)propyl Phenyl

254 2 0 3-Phenylpropyl 3-(2-Pyridyl)propyl Phenyl

255 2 0 3-Phenylpropyl 2-(4-Methoxyphenyl)ethyl Phenyl

256 2 0 3-Phenylpropyl 3-Phenylpropyl Phenyl

257 2 0 3-Phenylpropyl 3-Phenylpropyl 3,4,5 -Trimethoxyphenyl

258 2 0 3-Phenylpropyl 2-(3-Pyridyl)propyl 3,4,5 -Trimethoxyphenyl

259 2 0 3-Phenylpropyl 3-(2-Pyridyl)propyl 3,4,5 -Trimethoxyphenyl

260 2 0 3-Phenylpropyl 3-(4-Methoxyphenyl)propyl 3,4,5 -Trimethoxyphenyl

261 2 0 3-Phenylpropyl 3-(3-Pyridyl) propyl 3-wσ-propoxyphenyl

FORMULA (LVD

U.S. Patent No. 5,330,993, incorporated herein by reference, discloses an exemplary pipecolic acid derivative of formula LVI :

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

A is 0, NH, or N- (C₁-C₄ alkyl);

B is hydrogen, CHL-Ar, Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, Ar substituted Ci-Cg alkyl or C₂-C₆ alkenyl, or

wherein L and Q are independently hydrogen, Ci-Cg 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, 0-(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, 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, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C₁-C₄ straight or branched chain alkyl), 0-(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, 0-(C₁-C₄ straight or branched chain alkyl), 0-(C₂-C₄ straight or branched chain alkenyl),

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇-cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cj-C,, straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, 2-indolyl, 3- indolyl, (C_x-C₄ alkyl or C₂-C₄ alkenyl) -Ar, or Ar; J is hydrogen, C_x or C₂ alkyl, or benzyl; K is Ci-C₄ 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, SO, or S0₂, 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:

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 atom(s) 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; 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

264 4-(4-Methoxyphenyl) butyl Phenyl 2

265 4-Phenylbutyl Phenyl 2

266 Phenethyl Phenyl 2

267 4-Cyclohexylbutyl Phenyl 2

268 Benzyl Methoxy 2

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

273 3-Phenoxybenzyl 3 ,4 , 5-Trimethoxyphenyl 2

274 4-Phenylbutyl 3,4,5- -Trimethoxyphenyl 2

275 3-(3-Indolyl)propyl 3 , 4 , 5-Trimethoxypheny 1 2

276 4-(4-Methoxyphenyl)butyl 3 ,4,5-Trimethoxyphenyl 2

FORMULA LVII I

The bridged heterocyclic derivative may also be a compound of formula LVIII:

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, SO, S0₂, 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 C-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar-_L, 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, i-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C^d alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio- (Ci-Cg) -alkyl, (Ci-Cg) -alkylthio, sulfhydryl, amino, (Ci-Cg) -alkylamino, amino- (Ci-Cg) -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 0, N, and S; A, B, D, L, M, and 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:

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

A is CH₂, 0, NH, or N-(C₁-C₄ alkyl);

B and D are independently Ar, hydrogen, Ci-Cg 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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, C^Cg 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-C₄ alkyl), 0-(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, ^-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C-C₄ straight or branched chain alkyl), 0-(C₂-C₄ straight or branched chain alkenyl), 0-benzyl, O-phenyl, 1, 2-methylenedioxy, amino, carboxyl, and phenyl;

E is C-Cg straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with

straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl,

(C₂-C₄ alkyl or C₂-C₄ alkenyl) -Ar, or Ar;

J is hydrogen, C_x or C₂ alkyl, or benzyl; K is C_J-C_J 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 0,

S, 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; 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:

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=l) 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; 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, 4- methylphenyl, 4-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 :

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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

B and D are independently Ar, hydrogen, Cx-Cg 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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Ci-Cg 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- (Ci-C₄ alkyl), 0-(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, -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, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C_!-C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl) , 0-benzyl, 0-phenyl,

1, 2-methylenedioxy, amino, carboxyl, and phenyl;

E is Ci-Cg 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.

FORMULA LXII A further exemplary bridged heterocyclic derivative is a compound of Formula LXII:

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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

B and D are independently Ar, hydrogen, C_α-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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Ci-Cg 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-C₄ alkyl), 0-(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, Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (C^ , straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl) , 0-benzyl, 0-phenyl,

1, 2-methylenedioxy, amino, carboxyl, and phenyl; E is Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Ci-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.

FORMULA LXII I A further exemplary bridged heterocyclic derivative is a compound of LXIII:

(LXIII)

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, SO, S0₂, 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 C^Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_l 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, Cχ-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C^C,, alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio- (C_x-C₆) -alkyl, (C_x-C₆) -alkylthio, sulfhydryl, amino, (Ci-Cg) -alkylamino, amino- (Cj-Cg) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar₂;

Ar_x 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

(benzylsulfonyl) - (2R, S) -2-pipecolinate

diphenyl-

3-pentyl-N- (a-toluenesulfonyl) -pipecolate

4-heptyl-N- (para-toluene-sulfonyl) pipecolate Cpd . Structure and name

1-propyl- (2S) -N- (a-toluenesulfonyl) -pyrrolidine-

2-carboxylate

yl-1-butyl-N- (para-toluenesulf onyl ) pipecolate

pheny

1-1-butyl-N- (benzenesulfonyl) -pipecolate Cpd. Structure and name

1-butyl-N- (a-toluenesulfonyl) pipecolate

VII. CARBOXYLIC ACID ISOSTERES Another preferred embodiment of the invention is a compound of formula 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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

X is either 0 or S;

R-_L is independently selected from the group consisting of Ci-Cg 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 C^C^ 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.

Preferred embodiments of this invention are where 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 invention are where R₂ is independently selected from the group below:

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-Ci-Cg-alkyl, thiocarbonyl, Cj-Cg-alkoxy, C₂-C₆- alkenoxy, Ci-Cg-alkylaryloxy, aryloxy, aryl- C-_L-Cg-alkyloxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino- C_j-Cg-alkyl, sulfhydryl, thio- Ci-Cg-alkyl, Ci-Cg-alkylthio, sulfonyl, C_α- 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 R⁴ is hydrogen or C_:-C₉ straight or branched chain alkyl or alkenyl . Preferred embodiments of this invention are: (2S)-1-

(1, 2-dioxo-3, 3-dimethylpentyl) -2-hydroxymethyl pyrrolidine;

( 2 S ) -1- (1, 2-dioxo-3, 3-dimethylpentyl) - 2 - pyrrolidinetetrazole; (2S)-l-(l,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_λ is 1, 1, 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.

10 Table XLI when D is a bond and R2 is COOH,

285 O 1 3,4,5 -trimethylpheny 1

286 O 2 3 ,4,5-trimethylphenyl

15 287 O 1 tert-butyl

287 O 3 tert-butyl

288 O 1 cyclopentyl

289 O 2 cyclopentyl

290 O 3 cyclopentyl

20 291 O 1 cyclohexyl

292 O 2 cyclohexyl

293 O 3 cyclohexyl

294 O 1 cycloheptyl

295 O 2 cycloheptyl

25 296 O 3 cycloheptyl

297 O 1 2-thienyl

298 O 2 2-thienyl

299 O 3 2-thienyl

300 O 1 2-furyl

30 301 O 2 2-ruryl

302 O 3 2-furyl

303 O 3 phenyl

304 O 1 1 , 1 -dimethylpentyl

305 O 2 1,1-dimethylhexyl

35 306 O 3 ethyl

307

TABLE XLI I

No. X n R, D

308 s 1 , 1 -dimethyl propyl CH₂ COOH

309 s 1 , 1 -dimethyl propyl bond COOH

310 O 1 , 1 -dimethyl propyl CH₂ OH

311 O 1 , 1 -dimethyl propyl bond SO₃H

312 O 1 , 1 -dimethyl propyl CH₂ CN

313 O 1 , 1 -dimethyl propyl bond CN

314 O 1 , 1 -dimethyl propyl bond tetrazolyl

315 s phenyl (CH₂)₂ COOH

316 s phenyl (CH₂)₃ COOH

317 s 2 phenyl CH₂ COOH

318 O 1 1 , 1 -dimethyl propyl bond CONH₂

319 O 2 1,1 -dimethyl propyl bond CONH₂

320 s 2 2-furyl bond PO₃H₂

321 O 2 propyl (CH₂)₂ COOH

322 O 1 propyl (CH₂)₃ COOH

323 O 1 tert-butyl (CH₂)₄ COOH

324 O 1 methyl (CH₂)₅ COOH

325 O 2 phenyl (CH₂)₆ COOH

326 O 2 3,4,5- trimethoxy- phenyl CH₂ COOH

327 O 2 3,4,5- trimethoxy- phenyl CH₂ tetrazolyl TABLE XLIII

No. n X D R₂ R>

328 s bond COOH Phenyl

329 O bond COOH a-MethylBenzyl

330 2 O bond COOH 4-MethylBenzyl

331 O bond Tetrazole Benzyl

332 O bond SO₃H a-MethylBenzyl

333 O CH₂ COOH 4-MethylBenzyl

334 O bond SO₂HNMe Benzyl

335 O bond CN a-MethylBenzyl

336 O bond PO₃H₂ 4-MethylBenzyl

337 2 O bond COOH Benzyl

338 2 O bond COOH a-MethylBenzyl

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 PO₂HEt i-propyl

343 2 O bond PO₃HPropyl ethyl

344 2 O bond PO₃(Et)₂ Methyl

345 2 O bond OMe tert-butyl

346 1 O bond OEt n-pentyl

347 2 O bond OPropyl n-hexyl

348 O bond OButyl Cyclohexyl

349 O bond OPentyl cyclopentyl

350 O bond OHexyl n-heptyl

351 O bond SMe n-octyl

352 O bond SEt n-nonyl

353 2 O bond SPropyl 2-indolyl

354 2 O bond SButyl 2-furyl

355 2 O bond NHCOMe 2-thiazolyl

356 2 0 bond NHCOEt 2-thienyl

357 1 O CH₂ N(Me)₂ 2-pyridyl

358 1 O (CH,), N(Me)Et 1 , 1-dimethylpropyl

359 1 O (CHz)₃ CON(Me)₂ 1 , 1-dimethylpropyl

360 1 0 (CH₂)₄ CONHMe 1 , 1-dimethylpropyl 361 1 O (CH,)₅ CONHEt 1, 1-dimethylpropyl

362 1 I O (CH,)₆ CONHPropyl 1 , 1-dimethylpropyl

363 1 L O bond CONH(O)Me Benzyl

364 1 O bond CONH(O)Et a-Methylphenyl

365 1 . O bond CONH(O)Propyl 4-Methylphenyl

366 1 O (CH,), COOH Benzyl

367 1 O bond COOH a-Methylphenyl

368 1 O bond COOH 4-Methylphenyl

369 1 O CH, COOH 1, 1-dimethylpropyl

370 1 O (CH,), COOH 1, 1-dimethylbutyl

371 1 O (CH,)₃ COOH 1,1-dimethylpentyl

372 1 O (CH,)₄ COOH 1,1-dimethylhexyl

373 ] O (CH,)₅ COOH 1, 1-dimethylethyl

374 ] L O (CH_Z)₆ COOH iso-propyl

375 ] O (CH,)₇ COOH tert-butyl

376 ] O (CH,)₈ COOH 1 , 1-dimethylpropyl

311 } I O (CH,)₉ COOH benzyl

378 ] O (CH,)₁₀ COOH 1 , 1-dimethylpropyl

379 1 L O C,xτ., COOH cyclohexylmethyl

380 1 O 2-OH,Et COOH 1 , 1 -dimethylpropyl

381 1 [ O 2-butylene COOH 1 , 1-dimethylpropyl

382 ] 1 s z^'-Pro COOH 1, 1-dimethylpropyl

383 . > s t-Bu COOH phenyl

384 : I O 2-NO,-hexyl COOH 1, 1-dimethylpropyl

385 ] I O (CH,), CN 1,1 -dimethylpropyl

386 1 I O (CH,)₃ CN 1, 1-dimethylpropyl

387 : 3 O bond CONHNHSO,Me Benzyl

388 : 5 O bond CONHNHSO,Et a-Methylphenyl

389 : 5 O bond CONHSO,Me 4-Methylphenyl

390 I O bond CONHNHSO,Et Phenyl

391 . I 0 bond CON(Me)CN a-Methylphenyl

392 1 0 bond CON(Et)CN 4-Methylphenyl

393 I 0 (CH,), COOH methyl

394 [ 0 (CH,)₃ COOH ethyl

395 [ 0 (CH,)₄ COOH n-propyl

396 [ 0 (CH,)₅ COOH t-butyl

397 I O (CH,)₆ COOH Pentyl

398 I O (CH,)₇ COOH Hexyl

399 I O (CH,)₈ COOH Heptyl

400 I O (CH,)₉ COOH Octyl

401 I 0 C,H, COOH Cyclohexyl

402 O bond 1 , 1-dimethylpropyl

\

403 1 O bond 1 , 1 -dimethylpropyl

404 1 O bond 1 , 1-dimethylpropyl

405 1 O bond 1 , 1-dimethylpropyl

% If

406 1 O bond 1,1 -dimethylpropyl

407 1 O bond 1 , 1 -dimethylpropyl

408 1 O bond 1 , 1 -dimethylpropyl

409 1 O bond 1,1 -dimethylpropyl

No. n X D R_? R_j

410 1 O bond 1,1 -dimethylpropyl

411 1 O bond 1,1 -dimethylpropyl

412 1 O bond 1, 1-dimethylpropyl

413 1 O bond 1,1 -dimethylpropyl

414 1 O bond 1,1 -dimethylpropyl

415 1 O bond _{\ ^}„ 1, 1-dimethylpropyl

416 1 O bond 1,1 -dimethylpropyl

417 1 0 bond 1, 1-dimethylpropyl

No. n X D R, R,

418 1 O bond 1 , 1 -dimethylpropyl

419 1 O bond 1 , 1 -dimethylpropyl

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:

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 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 _{l r} L₂, L₃, or L₄, in which

and R₁ and E, independently, are selected from the group consisting of hydrogen, C^Cg 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 (Ci-Cg) -alkyl, thiocarbonyl, (Ci-Cg) -alkoxy, (C₂-C₆) -alkenoxy, (Ci-Cg) -alkylaryloxy, aryloxy, aryl- (C-Cg) - alkyloxy, cyano, nitro, imino, (C^Cg)- alkylamino, amino- (C^Cg) -alkyl, sulfhydryl, thio- (Ci-Cg) -alkyl, (C^Cg) -alkylthio, sulfonyl, Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or C0₂R⁴ where R⁴ is hydrogen or Cj-Cg 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:

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.

Preferred embodiments of this embodiment are the 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:

in which the atoms of said ring structure may be optionally substituted at one or more positions with R³ wherein R³ is hydrogen, hydroxy, halo, halo-C;,-C₆-alkyl, thiocarbonyl, C_λ- C₆-alkoxy, C₂-C₆-alkenoxy, Ci-Cg-alkylaryloxy, aryloxy, aryl- Ci-Cg-alkyloxy, cyano, nitro, imino, C-_L-Cg-alkylamino, amino- Ci-Cg-alkyl, sulfhydryl, thio-

sulfonyl, Cj-Cg 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 R⁴ is hydrogen or Ci-Cg 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 atom(s) 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, Ri is 1, 1, dimethylpropyl, and R₂ is -CN, is named ( 2 S ) -1- (l,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

No. n D R, A Y R,

423 bond COOH H S Benzyl

424 bond COOH H S a-MethylBenzyl

425 bond COOH H S 4-MethylBenzyl

426 bond Tetrazole H S Benzyl

427 bond SO₃H H O a-MethylBenzyl

428 CH, COOH H O 4-MethylBenzyl

429 bond SO,HNMe H O Benzyl

430 bond CN H N a-MethylBenzyl

431 bond PO₃H, H N 4-MethylBenzyl

432 2 bond COOH H N Benzyl

433 2 bond COOH H S a-MethylBenzyl

434 2 bond COOH H S 4-MethylBenzyl

435 2 bond COOH H s 3,4,5 -trimethoxy-pheny 1

436 2 bond COOH H s Cyclohexyl

437 2 bond PO,HEt H 0 i-propyl

438 2 bond PO₃HPropyl H 0 ethyl

439 2 bond PO₃(Et), H N Methyl

440 2 bond OMe H s tert-butyl

441 2 bond OEt H s n-pentyl

442 2 bond OPropyl H s n-hexyl

443 1 bond OButyl H O Cyclohexyl

444 1 bond OPentyl H N cyclopentyl

445 1 bond OHexyl H s n-heptyl

446 1 bond SMe H s n-octyl

447 1 bond SEt H O n-nonyl

448 2 bond SPropyl H N 2-indolyl

449 2 bond SButyl H O 2-furyl

450 2 bond NHCOMe H s 2-thiazolyl

451 2 bond NHCOEt H s 2-thienyl

452 1 CH, N(Me), H N 2-pyridyl

453 1 (CH,), N(Me)Et H s 1,1 -dimethylpropyl

454 1 (CH,)₃ CON(Me), H 0 1, 1-dimethylpropyl

455 1 (CH,)₄ CONHMe H N 1 , 1 -dimethylpropyl No. n D R, A Y R,

456 1 (CH,)₅ CONHEt H S 1 , 1 -dimethylpropyl

457 1 (CH,)₆ CONHPropyl H S 1, 1-dimethylpropyl

TABLE XLV

No. n D R, 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-Methylphenyl

461 2 bond COOH S Benzyl

462 2 bond COOH O a-Methylphenyl

463 2 bond COOH O 4-Methylphenyl

464 CH, COOH N benzyl

465 (CH,), COOH N benzyl

466 (CH,)₃ COOH N benzyl

467 (CH,)₄ COOH S benzyl

468 (CH,)₅ COOH s benzyl

469 (CH,)₆ COOH s benzyl

470 (CH,)₇ COOH s benzyl

471 (CH,)₈ COOH O benzyl

472 (CH,)₉ COOH O benzyl

473 (CH,)_I0 COOH O benzyl

474 C,.H, COOH N benzyl

475 2-OH,Et COOH N benzyl

476 2butylene COOH s benzyl

477 i-Pro COOH s benzyl

478 tert-Bu COOH s benzyl

479 2-nitro COOH s benzyl Hexyl

480 3 (CH,), CN s benzyl

481 1 (CH,)₃ CN s benzyl

482 3 bond CONHNHSO,Me N Benzyl

483 3 bond CONHNHSO,Et N a-Methylphenyl 484 \ bond CONHSO,Me N 4-Methylphenyl

485 1 I bond CONHNHSO,Et N Phenyl

486 2 bond CON(Me)CN O a-Methylphenyl

487 2 bond CON(Et)CN O 4-Methylphenyl

488 1 (CH,), COOH O methyl

489 1 (CH,)₃ COOH 0 ethyl

490 1 (CH,)₄ COOH N n-propyl

491 1 (CH_Z)₅ COOH N t-butyl

492 1 (CH,)₆ COOH N Pentyl

493 1 (CH,)₇ COOH S Hexyl

494 1 (CH,)₈ COOH s Heptyl

495 1 (CH,)₉ COOH s Octyl

496 1

COOH s Nonyl

497 1 C,H, COOH s Cyclohexyl

TABLE XLVI

No. n X D R₇ R.

498 1 O bond O 1 ,1 -dimethylpropyl

499 1 O bond S 1,1 -dimethylpropyl

500 1 O bond S 1, 1 -dimethylpropyl

501 1 O bond O 1, 1 -dimethylpropyl

No. n X D R, R,

502 1 O bond N 1,1 -dimethylpropyl

503 1 O bond S 1,1 -dimethylpropyl

504 1 O bond N 1,1 -dimethylpropyl

505 1 O bond N 1,1 -dimethylpropyl

506 1 O bond S 1,1 -dimethylpropyl

507 1 O bond O 1,1 -dimethylpropyl

508 1 O bond S 1,1 -dimethylpropyl

509 1 O bond S 1,1 -dimethylpropyl

O 1,1 -dimethylpropyl

No. n X D R, R,

511 1 O bond 1 , 1-dimethylpropyl

512 1 O bond O 1 , 1-dimethylpropyl

513 1 O bond 1,1 -dimethylpropyl

514 1 O bond N 1 , 1-dimethylpropyl

515 1 O bond O 1, 1-dimethylpropyl

516 1 O bond 1 , 1 -dimethylpropyl

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, R_{l r} 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, R_x is 1, 1-dimethylpropyl, D is a bond, R₂ is COOH. Exemplary compound 612 is defined where 0 is located at the 2-position of the heterocyclic ring (2- oxopentanoyl) , n is 1, R_x 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 0, N, and S.

TABLE XLVII

613 1 CH₂ OH 1, 2-dioxoethyl benzyl

614 1 bond -CN 1, 2-dioxoethyl 1 , 1-dimethylpropyl

615 1 bond tetrazole 1, 2-dioxoethyl 1 , 1-dimethylpropyl

616 2 bond CONH, 1, 2-dioxoethyl 1 , 1 -dimethylpropyl

617 1 bond COOH 1, 2-dioxoethyl 1 , 1-dimethylpropyl

618 2 bond COOH 1, 2-dioxoethyl 1 , 1-dimethylpropyl

FORMULA LXVI

In another embodiment of the invention, there is provided a compound of formula LXVI :

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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure;

Ri and A are independently selected from the group consisting of hydrogen, Cι-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 C^C_K, straight or branched chain alkyl, C₂-Cι₀ alkenyl or C₂-Cι₀ 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 (Cι~C₆) -alkyl, thiocarbonyl, (C^Cg) -alkoxy, (C₂-C₆) -alkenoxy, (C_x-C₆) -alkylaryloxy, aryloxy, aryl- (Cι-C₆) - alkyloxy, cyano, nitro, imino₍ (Cι-C₆) -alkylamino, amino-

-alkyl, sulfhydryl, thio- (Cι-C₆) - alkyl, (Cι-C₆) -alkylthio, sulfonyl, Cj-Cg 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 R⁴ is hydrogen or C_λ- 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:

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 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(0)R³, -CONHNHS0₂R³, -COHNS0₂R³, and -CONR³CN wherein R³ is hydrogen, hydroxy, halo, halo-Cι-C₆-alkyl, thiocarbonyl, Ci-Cg-alkoxy, C₂-C₆-alkenoxy,

aryloxy, aryl- Ci-C₈- alkyloxy, cyano, nitro, imino, Cι-C₆-alkylamino, amino- Cι~ Cg-alkyl, sulfhydryl, thio- Cj-Cg-alkyl, Cι-C₆-alkylthio, sulfonyl, Cj-Cg 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 R⁴ is hydrogen or C^Cg 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*.

where the atoms of said ring structure may be optionally substituted at one or more positions with R³ wherein R³ is hydrogen, hydroxy, halo, halo-Ci-Cg-alkyl, thiocarbonyl, C_x- Cg-alkoxy, C₂-C₆-alkenoxy, Cι-C₆-alkylaryloxy, aryloxy, aryl-

cyano, nitro, imino, C_ι-C₆-alkylamino, amino- Ci-Cg-alkyl, sulfhydryl, thio- C_x-C₆-alkyl, Ci-Cg-alkylthio, sulfonyl, C^Cg 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 R⁴ is hydrogen or Cι-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 R³ substituents upon a carbocyclic or heterocyclic carboxylic acid isostere shall not be permitted at one or more atom(s) which maintain (s) 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, R_λ is 1, 1, 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.

TABLE XLVIII

No. n D R, R,

619 1 bond COOH H cyclohexyl

620 1 bond COOH H a-MethylBenzyl

621 1 bond COOH H 4-MethylBenzyl No. n D R, A R,

622 bond Tetrazole H Benzyl

623 bond SO₃H H a-MethylBenzyl

624 CH, COOH H 4-MethylBenzyl

625 bond SO,HNMe H Benzyl

626 bond CN H a-MethylBenzyl

627 bond PO₃H, H 4-MethylBenzyl

628 2 bond COOH H Benzyl

629 2 bond COOH H a-MethylBenzyl

630 2 bond COOH H 2-butyl

631 2 bond COOH H 2-butyl

632 2 bond COOH H Cyclohexyl

633 2 bond PO,HEt H i-propyl

634 2 bond PO₃HPropyl H ethyl

635 2 bond PO₃(Et), 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

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

645 2 bond NHCOMe H n-hexyl

646 2 bond NHCOEt H 2-thienyl

647 CH, N(Me), H adamantyl

648 (CH,), N(Me)Et H adamantyl

649 (CH,)₃ CON(Me), H adamantyl

650 (CH,)₄ CONHMe H adamantyl

651 (CH,)₅ CONHEt H adamantyl

652 (CH,)₆ CONHPropyl H adamantyl

653 bond CONH(O)Me H Benzyl

654 bond CONH(O)Et H a-methylphenyl

655 bond CONH(O)Propyl H 4-Methylphenyl

657 2 bond COOH H Benzyl

658 2 bond COOH H a-Methylphenyl

659 2 bond COOH H 4-Methylphenyl

660 1 CH, COOH Me cyclohexyl

661 1 (CH,), COOH Et cyclohexyl

662 1 (CH,)₃ COOH Prop cyclohexyl

663 1 (CH,)₄ COOH But cyclohexyl No. r l D R, A R,

664 1 (CH,)₅ COOH H cyclohexyl

665 1 (CH,)₆ COOH H cyclohexyl

666 1 (CH,)₇ COOH H cyclohexyl

667 1 (CH,)₈ COOH H cyclohexyl

668 1 (CH,)₉ COOH H cyclohexyl

669 1 (CH,)₁₀ COOH H cyclohexyl

670 1 C,H, COOH H cyclohexyl

671 1 2-OH,Et COOH H cyclohexyl

672 1 2-butylene- COOH H cyclohexyl

673 ] L i-Pro COOH H cyclohexyl

674 ] tert-Bu COOH H cyclohexyl

675 ] 2-nitro Hexyl COOH H cyclohexyl

676 : 5 (CH,), CN H cyclohexyl

677 1 I (CH₂)₃ CN H cyclohexyl

678 : 5 bond CONHNHSO,Me H Benzyl

679 : 5 bond CONHNHSO,Et H a-Methylphenyl

680 : ) bond CONHSO,Me H 4-Methylphenyl

681 . I bond CONHNHSO,Et H Phenyl

682 ; I bond CON(Me)CN H a-Methylphenyl

683 : I bond CON(Et)CN H 4-Methylphenyl

684 L (CH,), COOH H methyl

685 I (CH,)₃ COOH H ethyl

686 I (CH,)₄ COOH H n-propyl

687 I (CH,)₅ COOH H t-butyl

688 I (CH,)₆ COOH H Pentyl

689 1 (CH,)₇ COOH H Hexyl

690 I (CH,)₈ COOH H Heptyl

691 I (CH,)₉ COOH H Octyl

692 (CH^₁₀ COOH H Nonyl

693 L C,H, COOH H Cyclohexyl

694 1 bond H cyclohexyl

H cyclohexyl

696 1 bond H cyclohexyl

No. D R, R,

697 bond H cyclohexyl

698 bond H cyclohexyl

699 bond H cyclohexyl

700 bond H cyclohexyl

701 bond H cyclohexyl

702 bond H cyclohexyl

703 bond H cyclohexyl

704 1 bond H cyclohexyl

No. D R, R,

705 bond H cyclohexyl

\

/

706 bond H cyclohexyl

707 bond H cyclohexyl

708 bond H cyclohexyl

709 bond Me

<f H cyclohexyl

710 bond H cyclohexyl

711 1 bond H cyclohexyl

712 1 bond H cyclohexyl

TABLE IL

No. n D R, L R,

713 1 CH, OH 1, 2-dioxoethyl benzyl

714 1 bond -CN 1, 2-dioxoethyl 1 , 1 -dimethylpropyl

715 1 bond tetrazole 1, 2-dioxoethyl 1 , 1-dimethylpropyl

716 2 bond CONH₂ 1, 2-dioxoethyl 1 , 1-dimethylpropyl

717 1 bond COOH 1, 2-dioxoethyl 1 , 1 -dimethylpropyl

718 2 bond COOH 1, 2-dioxoethyl 1, 1-dimethylpropyl

FORMULA LXVII Another preferred embodiment of the invention is a compound of the formula LXVII:

ILXVII :

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 atom(s) other than a bond which do(es) not comprise a part of the primary ring structure; R_λ is independently selected from the group consisting of hydrogen, Cι~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 Cι~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- (Ci-Cg) -alkoxy, thiocarbonyl, (C^ C₆) -alkoxy, (C₂-C₆) -alkenyloxy, (C^Cg)- alkylaryloxy, aryloxy, aryl- (Cι-C₆) -alkyloxy, cyano, nitro, imino, (Cι-C₆) -alkylamino, amino- (Ci-Cβ) -alkyl, sulfhydryl, thio- (C^Cg) alkyl, (C_x- C₆) -alkylthio, sulfonyl, Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or C0₂R⁴ where R⁴ is hydrogen or Cι~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 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:

in which 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, -C0N(R³)₂, -CONH(0)R³, -C0NHNHS0₂R³, -COHNS0₂R³, and -CONR³CN .

Preferred embodiments of this invention are the 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(0)R³, -CONHNHS0₂R³, -COHNS0₂R³, and -CONR³CN, wherein R³ is hydrogen, hydroxy, halo, halo-C-Cg-alkyl, thiocarbonyl, C_x- C₆-alkoxy, C₂-C₆-alkenoxy, C_ι-C₆-alkylaryloxy, aryloxy, aryl-

cyano, nitro, imino,

amino- Ci-Cg-alkyl, sulfhydryl, thio- Ci-Cg-alkyl, C_ι-C₆- alkylthio, sulfonyl, Cj-Cg 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 R⁴ is hydrogen or Ci-Cg 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.

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 atom(s) 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, R_τ 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

No. D R, R,

719 ] bond COOH Benzyl

720 1 I bond COOH a-MethylBenzyl

721 ] [ bond COOH 4-MethylBenzyl

722 1 I bond Tetrazole Benzyl

723 I bond SO₃H a-MethylBenzyl

724 [ CH, COOH 4-MethylBenzyl

725 ] I bond SO,HNMe Benzyl

726 1 bond CN a-MethylBenzyl No. n D R₂ R,

727 1 bond PO₃H, 4-MethylBenzyl

728 2 bond COOH Benzyl

729 2 bond COOH a-MethylBenzyl

730 2 bond COOH 4-MethylBenzyl

731 2 bond COOH 3 ,4,5-trimethoxy-phenyl

732 2 bond COOH Cyclohexyl

733 2 bond PO,HEt i-propyl

734 2 bond PO₃HPropyl ethyl

735 2 bond PO₃(Et), Methyl

736 2 bond OMe tert-butyl

737 2 bond OEt n-pentyl

738 2 bond OPropyl n-hexyl

739 bond OButyl Cyclohexyl

740 bond OPentyl cyclopentyl

741 bond OHexyl n-heptyl

742 bond SMe n-octyl

743 bond SEt n-nonyl

744 2 bond SPropyl 2-indolyl

745 2 bond SButyl 2-furyl

746 2 bond NHCOMe 2-thiazolyl

747 2 bond NHCOEt 2-thienyl

748 CH, N(Me), 2-pyridyl

749 (CH,), N(Me)Et benzyl

750 (CH,)₃ CON(Me), benzyl

751 (CH,)₄ CONHMe benzyl

752 (CH,)₅ CONHEt benzyl

753 (CH,)₆ CONHPropyl 1 , 1-dimethylpropyl

754 bond CONH(O)Me Benzyl

755 bond CONH(O)Et a-Methylphenyl

756 bond CONH(O)Propyl 4-Methylphenyl

757 2 bond COOH Benzyl

758 2 bond COOH a-Methylphenyl

759 2 bond COOH 4-Methylphenyl

760 CH, COOH benzyl

761 (CH,), COOH benzyl

762 (CH,)₃ COOH benzyl

763 (CH,)₄ COOH benzyl

764 (CH,)₅ COOH benzyl

765 (CH,)₆ COOH benzyl

766 (CH₂)₇ COOH benzyl

767 (CH,)₈ COOH benzyl

768 (CH,)₉ COOH benzyl No. n D R₂ R,

769 (CH,)₁₀ COOH benzyl

770 C,H, COOH benzyl

771 2-hydroxyethyl COOH benzyl

772 2-butylene COOH benzyl

773 i-Propyl COOH benzyl

774 tert-Butyl COOH benzyl

775 2-nitrohexyl COOH benzyl

776 3 (CH,), CN benzyl

111 1 (CH,)₃ CN benzyl

778 3 bond CONHNHSO,Me Benzyl

779 3 bond CONHNHSO,Et a-Methylphenyl

780 3 bond CONHSO,Me 4-Methylphenyl

781 2 bond CONHNHSO,Et Phenyl

782 2 bond CON(Me)CN a-Methylphenyl

783 2 bond CON(Et)CN 4-Methylphenyl

784 (CH,), COOH methyl

785 (CH,)₃ COOH ethyl

786 (CH,)₄ COOH n-propyl

787 (CH,)₅ COOH t-butyl

788 (CH,)₆ COOH Pentyl

789 (CH,)₇ COOH Hexyl

790 (CH,)₈ COOH Heptyl

791 (CH,)₉ COOH Octyl

792 (CH,)₁₀ COOH Nonyl

793 C,H, COOH Cyclohexyl

794 bond benzyl

795 bond benzyl

796 bond benzyl

797 bond benzyl

No. D R, R,

798 bond benzyl

799 1 bond benzyl

800 bond benzyl

801 bond benzyl

802 bond benzyl

803 bond benzyl

804 bond benzyl

No. D R, R,

805 bond benzyl

\

/

806 bond benzyl

807 1 bond benzyl

-Et

808 bond benzyl

809 bond benzyl

810 bond benzyl

811 bond benzyl

No. D R, A.

812 bond benzyl

813 1 bond CH,OH benzyl

814 1 bond CONH₂ benzyl

815 1 bond CN benzyl

TABLE LI

No. n D R, L R,

816 1 CH, OH 1, 2-dioxoethyl benzyl

817 1 bond -CN 1, 2-dioxoethyl 1 , 1-dimethylpropyl

818 1 bond tetrazole 1, 2-dioxoethyl 1, 1-dimethylpropyl

819 2 bond CONH, 1, 2-dioxoethyl 1 , 1-dimethylpropyl

820 1 bond COOH 1, 2-dioxoethyl 1 , 1-dimethylpropyl

821 2 bond COOH 1, 2-dioxoethyl 1 , 1-dimethylpropyl

Synthesis 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. After the desired reactions are complete, or at any desired time, normally such protecting groups will be removed by, for example, hydrolytic or hydrogenolytic means. Such protection and deprotection steps are conventional in organic chemistry. One skilled in the art is referred to "Protective Groups in Organic Chemistry," McOmie, ed., Plenum Press, New York, New York; and "Protective Groups in Organic Synthesis," Greene, ed., John Wiley & Sons, New York, N.Y. (1981) for the teaching of protective groups which may be useful in the preparation of compounds of the present invention.

The product and intermediates may be isolated or purified using one or more standard purification techniques, including, for example, one or more of simple solvent evaporation, recrystallization, distillation, sublimation, filtration, chromatography, including thin- layer chromatography, HPLC (e.g. reverse phase HPLC) , column chromatography, flash chromatography, radial chromatography, trituration, and the like.

As described by Scheme I, cyclic amino acids 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 may be reacted with a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively.

SCHEME I

Isocyanates (R'NCO) or isothiocyanates (R'NCS) 4 may be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophosgene, as depicted in Scheme II.

SCHEME II

Thiols R-SH may be conveniently prepared from the corresponding readily available alcohols or halides via a two step replacement of halide by sulfur, as described in Scheme III. Halides may be reacted with thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide thiols RSH. If alcohols are used as the starting materials, they may be first converted to the corresponding halides by standard methods. SCHEME I I I

The compounds of formulas XX to XXIV may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathway depicted below. As described by Scheme IV, cyclic amino acids 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 may be reacted with various sulfonyl chlorides 4 to provide final products 5 in good to excellent yield.

SCHEME IV

Thiols R-SH may be conveniently prepared from the corresponding readily available alcohols or halides via a two step replacement of halogen by sulfur, as described in Scheme V. Halides may be reacted with thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide thiols RSH. If alcohols are used as the starting materials, they may be first converted to the corresponding halides by standard methods.

SCHEME V

The compounds of formulas XXV to XXIX may be prepared by a variety of synthetic sequences that utilize established chemical transformations. The general pathway to the present compounds is described in Scheme VI. N- glyoxylproline derivatives may be prepared by reacting L- proline methyl ester with methyl oxalyl chloride as shown in Scheme VI. The resulting oxamates may be reacted with a variety of carbon nucleophiles to obtain intermediates compounds. These intermediates are then reacted with a variety of alcohols, amides, or protected amino acid residues to obtain the propyl esters and amides of the invention .

SCHEME VI

The substituted alcohols may be prepared by a number of methods known to those skilled in the art of organic synthesis. As described in Scheme VII, alkyl or aryl aldehydes may be homologated to phenyl propanols by reaction with methyl (triphenyl-phosphoranylidene) acetate to provide a variety of traΛs-cinnamates; these latter compounds may be reduced to the saturated alcohols by reaction with excess lithium aluminum hydride, or sequentially by reduction of the double bond by catalytic hydrogenation and reduction of the saturated ester by appropriate reducing agents. Alternatively, the trans- cinnamates may be reduced to (E)-allylic alcohols by the use of diisobutylaluminum hydride.

SCHEME VI I

Longer chain alcohols may be prepared by homologation of benzylic and higher aldehydes. Alternatively, these aldehydes may be prepared by conversion of the corresponding phenylacetic and higher acids, and phenethyl and higher alcohols. The general synthesis of the carboxylic acid isosteres of Formula LXV is outlined in Scheme VIII and IX:

N-glyoxylproline derivatives may be prepared by reacting L-proline methyl ester with methyl oxalyl chloride as shown in Scheme VIII. The resulting oxamates may be reacted with a variety of carbon nucleophiles to obtain compounds used in the present invention, as in Scheme IX.

SCHEME VIII

SCHEME IX

The compounds of formulae LXV may be readily prepared by standard techniques of organic chemistry, utilizing the general synthetic pathways depicted in Scheme X for di-keto derivatives, sulfonamide derivatives, and urea or carbamate derivatives .

Cyclic amino acids 1 protected by suitable blocking groups P on the amino acid nitrogen may be reacted with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 may be reacted with a variety of isocyanates or isothiocyanates to provide final ureas or thioureas, respectively.

SCHEME X

Another scheme for preparing ureas or carbamates is set forth below in Scheme XI.

SCHEME XI

Isocyanates (R'NCO) or isothiocyanates (R'NCS) may be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophosgene, as depicted below.

SCHEME XI I

Thiols R-SH may be conveniently prepared from the corresponding readily available alcohols or halides via a two step replacement of halide by sulfur, as described below. Halides may be reacted with thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide thiols RSH. If alcohols are used as the starting materials, they may be first converted to the corresponding halides by standard methods.

SCHEME XIII

N-glyoxylproline derivatives may be prepared by reacting L-proline methyl ester with methyl oxalyl chloride as shown below. The resulting oxamates may be reacted with a variety of carbon nucleophiles to obtain compounds of the present invention or useful for preparing compounds of the present invention. SCHEME XIV

Synthetic schemes for preparing sulfonamide derivatives are known in the art and compounds of the present invention may be synthesized using schemes such as are set forth below. SCHEME XV

SCHEME XVI

The general synthesis of the carboxylic acid isosteres of Formula LXVI may be completed by a variety of synthetic sequences that utilize established chemical transformations. An exemplary general pathway to synthesize the present compounds is described in Scheme XVII. SCHEME XVI I

The compounds of formula LXVI I may be prepared by a variety of synthetic sequences that utilize established chemical transformations. Exemplary general pathways to these compounds is described in Schemes XVIII, XVI and XX.

SCHEME XVIII

SCHEME XIX

SCHEME XX

Affinity for FKBP12

The compounds used in the inventive methods and pharmaceutical compositions may have an affinity for the FK506 binding protein, particularly FKBP12. The inhibition of the prolyl peptidyl cis-trans isomerase activity of FKBP may be measured as an indicator of this affinity.

K_r Test Procedure

The binding to FBKP12 and inhibition of the peptidyl- prolyl isomerase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al. , Na ture, 1989, 341:758-760; Holt et ai. J. Am . Chem . Soc , 115:9923-9938). These values are obtained as apparent K ' s and are presented for representative compounds in TABLES IX to XVI.

The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p- nitroanilide, is monitored spectrophotometrically in a chymotrypsin-coupled assay, which releases para- nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K, values. In a plastic cuvette are added 950 mL of ice cold assay buffer (25 M HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol) , 25 mL of chymotrypsin (50 mg/ml in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe- para-nitroanilide, 5 mg/mL in 2.35 mM LiCl in trifluoroethanol) . The absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance versus time data files.

TABLE LII

In Vitro Test Results • - Formulas I to XIV

Compound K_j diM)

1 31

2 210

3 85

9 104

10 12

11 299

12 442

14 313

28 108

29 59

30 11

31 8.7

32 362

33 1698

34 34

35 62

36 7

37 68

38 8.9

39 347

40 1226

41 366 ComDound K_j faM)

42 28

43 259

44 188

45 31

46 757

47 21

48 127

49 1334

50 55

10 51 33

52 6

53 261

54 37

55 30

15 56 880

57 57

58 79

59 962

60 90

20 61 139

62 196

63 82

64 163

65 68

25 66 306

67 177

68 284

69 49

70 457

30 71 788

80 215

81 638

Parent (unoxidized) 7.5 compound of Example 6

35 95 (Example 6) 225

TABLE LI I I

In Vitro Test Results - Formulas XV to XXIV Compound K_t (nM)

101 + + +

102 + +

103 + +

104 + +

105 + +

106 +

107 ++

108 +++

109 + + +

110 + + +

111 + +

112 +++

113 + + +

114 + + +

115 + + +

116 ++

117 +++

118 + +

119 + +

120 + +

121 ++

122 +

123 + +

124 + + +

125 + + +

126 +++

127 + +

128 + + +

129 + + +

130 +++

131 +++

132 + +

Relative potencies of compounds are ranked according to the following scale: ++++ denotes K or ED50 < 1 nM; +++ denotes K, or ED50 of 1-50 nM; ++ denotes K_x or ED 50 of 51-200 nM; + denotes K, or ED of 201-500 nM. TABLE LIV

In Vitro Test Results - Formulas XXV to XXIX o. Z R, K,

137 1, 1-dimethylpropyl 3-phenylpropyl 42

138 1, 1-dimethylpropyl 3-phenyl-prop-2-(E)-enyl 125

139 1, 1-dimethylpropyl 3-(3,4,5-trimethoxyphenyl)propyl 200

140 1, 1-dimethylpropyl 3-(3,4,5-trimethoxyphenyl)-prop-2-(E)-enyl 65

141 1, 1-dimethylpropyl 3-(4,5-methylenedioxy)-phenylpropyl 170

142 1 , 1-dimethylpropyl 3-(4,5-methylenedioxy)phenylprop-2-(E)-enyl 160

143 1 , 1 -dimethylpropyl 3-cyclohexylpropyl 200

144 1, 1-dimethylpropyl 3-cyclohexylprop-2-(E)-enyl 600

145 1, 1-dimethylpropyl (1R)-1, 3-diphenyl-l-propyl 52

146 2-furanyl 3-phenylpropyl 4000

147 2-thienyl 3-phenylpropyl 92

148 2-thiazolyl 3-phenylpropyl 100

149 phenyl 3-phenylpropyl 1970

150 1, 1-dimethylpropyl 3-(2,5-dimethoxy)phenylpropyl 250

151 1, 1-dimethylpropyl 3-(2,5-dimethoxy)phenylprop-2-(E)-enyl 450

152 1, 1-dimethylpropyl 2-(3 , 4 , 5-trimethoxyphenyl)ethy 1 120

153 1, 1-dimethylpropyl 3-(3-pyridyl)propyl 5

154 1 , 1 -dimethylpropyl 3-(2-pyridyl)propyl 195

155 1, 1-dimethylpropyl 3-(4-pyridyl)propyl 23

156 cyclohexyl 3-phenylpropyl 82

157 tert-butyl 3-phenylpropyl 95

158 cyclohexylethyl 3-phenylpropyl 1025

159 cyclohexylethyl 3 -(3 -pyridyl)propy 1 1400

160 tert-butyl 3-(3-pyridyl)propyl 3

161 1, 1-dimethylpropyl 3, 3-diphenylpropyl 5

162 cyclohexyl 3-(3-pyridyl)propyl 9

163 2-thienyl 3-(3-pyridyl)propyl 1000

164 tert-butyl 3 , 3-diphenylpropyl 5 o. Z R_j K_j_

165 cyclohexyl 3, 3-diphenylpropyl 20

166 2-thienyl 3, 3-diphenylpropyl 150

TABLE LV In Vitro Test Results FORMULA XXXIII-LIV

Compound K, (mM)

172 140 175 13 177 170 178 250 179 25 181 17 185 12 202 > 10,000 207 1300 216 > 10,000 255 1800 256 28 257 39 258 75 259 70 260 165 261 740 262 725 263 130 264 30 265 60 266 15 267 12 268 120 269 20 270 103 271 760 272 210 273 32 274 2 275 24 276 5 MPTP Model of Parkinson' s Disease in Mice

MPTP lesioning of dopaminergic neurons in mice was used as an animal model of Parkinson's Disease. Four week old male CD1 white mice were dosed i.p. with 30 mg/kg of MPTP for 5 days. Inventive compounds (4 mg/kg), or vehicle, were administered s.c. along with the MPTP for 5 days, as well as for an additional 5 days following cessation of MPTP treatment. At 18 days following MPTP treatment, the animals were sacrificed and the striata were dissected and homogenized. Immunostaining was performed on saggital and coronal brain sections using anti-tyrosine hydoxylase Ig to quantitate survival and recovery of dopaminergic neurons. In animals treated with MPTP and vehicle, a substantial loss of functional dopaminergic terminals was observed as compared to non-lesioned animals. In another protocol, test compounds were administered only subsequent to MPTP-induced lesioning. Thus, after animals were treated with MPTP for 5 days, an additional 3 days passed before beginning oral drug treatment on day 8. Animals were treated with inventive compounds (0.4 mg/kg), administered orally, once a day for 5 days total. On day 18, the animals were sacrificed and analyzed as described above. Table LVI presents the percent recovery of dopaminergic neurons in the first (concurrent dosing) paradigm in animals receiving carboxylic acid or carboxylic acid isostere compounds.

Table LVI, below, shows the remarkable neuroregenerative effects of the inventive carboxylic acid or carboxylic acid isostere related compounds illustrating the neurotrophic capability of carboxylic acid isosteres as a class showing that lesioned animals receiving the carboxylic acid or carboxylic acid isostere compounds provide a remarkable recovery of TH-stained dopaminergic neurons . Table LVI - MPTP Neurodegenerative Model % Recovery

Compound A 26.7 % Compound B ND Compound C 24.4 % Compound D 23.2 % Compound E 19.6 % Compound F 34.1 % Compound G 46.5 % Compound H 14.0 % Compound I ND

Percent striatal innervation density was quantitated in brain sections with an anti-tyrosine hydroxylase immunoglobulin, which is indicative of functional dopaminergic neurons. The striatal innervation density of 23% for animals pretreated with only a vehicle and administered a vehicle orally during treatment, is indicative of normal non-lesioned striatal tissue. Striatal innervation density is reduced to 5% for animals pretreated with MPTP and administered a vehicle orally during treatment, and is indicative of MPTP-induced lesioning. Surprisingly, striatal innervation density is increased 8%- 13% for animals pretreated with MPTP and administered 0.4 mg/kg orally during treatment, indicating substantial neuronal regeneration after induction of MPTP-derived lesions .

EXAMPLES

The following examples are illustrative of the present invention and are not intended to be limitations thereon. Unless otherwise indicated, all percentages are based upon 100% by weight of the final composition.

EXAMPLE 1 Synthesis of (2S) -2- ( { l-oxo-5-phenyl } -pentyl-1- (3 , 3- dimethyl-1, 2-dioxopentyl) pyrrolidine (1)

(25) -2- (l-oxo-4-phenyl) utyl-N-benzylpyrroIidine l-chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 mL of THF was added to 0.24 g (10 mmol) of magnesium turnings in 50 mL of refluxing THF. After the addition was complete, the mixture was refluxed for an additional 5 hours, and then added slowly to a refluxing solution of N- benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 L of THF. After 2 hours of further reflux, the mixture was cooled and treated with 5 mL of 2 N HCl. The reaction mixture was diluted with ether (100 mL) and washed with saturated NaHC0₃, water and brine. The organic phase was dried, concentrated and chromatographed, eluting with 5:1 CH₂C1₂: EtOAc to obtain 2.05 g (64%) of the ketone as an oil. ^XH NMR (CDC1₃; 300 MHz): d 1.49-2.18 (m, 8H) ; 2.32- 2.46 (m, IH) ; 2.56-2.65 (m, 2H) ; 2.97-3.06 (m, IH) ; 3.17- 3.34 (m, IH) ; 3.44-3.62 (m, IH) ; 4.02-4.23 (m, 2H) ; 7.01- 7.44 ( , 10H) . (25) -2- (l-oxo-4-phenyl) butylpyrrolidine

The ketone compound (500 mg) and palladium hydroxide (20% on carbon, 50 mg) was hydrogenated at 40 psi in a Paar shaker overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The free amine was obtained as a yellow oil (230 mg; 100%) . ^lR NMR (CDC1₃; 300 MHz): d 1.75-2.34 (m, 10H) ; 2.55 (m, 2H) ; 2.95 (dm, IH) ; 3.45-3.95 ( , IH) ; 4.05 (m, IH) ; 7.37 (m, 5H) . (25) -2- (l-oxo-4-phenyl)butyl-l- (1, 2-dioxo-2- methoxyethyl) pyrrolidine To a solution of (25) -2- (l-oxo-4-phenyl) butylpyrrolidine (230 mg; 1.0 mmol) in CH₂C1₂(20 mL) at 0°C was added dropwise methyloxalyl chloride (135 mg; 1.1 mmol) . After stirring at 0°C for 3 hours, the reaction was quenched with saturated NH₄C1 and the organic phase was washed with water and brine and dried and concentrated. The crude residue was purified on a silica gel column, eluting with 20:1 CH₂C1₂: EtOAc to obtain 300 mg of the oxamate as a clear oil (98%) . ^XH NMR (CDC1₃; 300 MHz) : d 1.68 (m, 4H) ; 1.91-2.38 (m, 4H) ; 2.64 (t, 2H) ; 3.66-3.80 (m, 2H) ; 3.77, 3.85 (s, 3H total); 4.16 ( , 2H) ; 4.90 (m, IH) ; 7.16 (m, 3H) ; 7.27 (m, 2H) .

(25) -2- ( ( l-oxo-5-phenyll-pentyl-l- (3.3 -dimethyl -1 , 2- dioxopentyl) pyrrolidine (1)

To a solution of the oxamate above (250 mg; 0.79 mmol) in anhydrous ether (15 mL) , cooled to -78°C, was added 1, 1-dimethylpropyl-magnesium chloride (0.8 mL of a

1.0 M solution in ether; 0.8 mmol). After stirring the resulting mixture at -78 °C for 2 hours, the reaction was quenched by the addition of 2 mL of saturated NH₄C1, followed by 100 mL of EtOAc. The organic phase was washed with brine, dried, concentrated, and purified on a silica gel column, eluting with 50:1 CH_?C1₂: EtOAc. Compound 1 was obtained as a clear oil, 120 mg. *H NMR (CDC1₃, 300 MHz) : d 0.87 (t, 3H, J = 7.5); 1.22 (s, 3H) ; 1.25 (s, 3H) ; 1.67 (m, 4H) ; 1.70-2.33 (m, 6H) ; 2.61 (t, 2H, J = 7.1); 3.52 (m, 2H) ; 4.17 (t, 2H, J = 6.2); 4.52 (m, IH) ; 7.16-7.49 (m, 5H) . Analysis calculated for C₂₂H₃₁N0₃ - H₂0: C, 70.37; H, 8.86; N, 3.73. Found: 70.48; H, 8.35; N, 3.69.

EXAMPLE 2

Synthesis of 2-phenyl-l-ethyl 1- (3, 3-dimethyl-l, 2- dioxopentyl) -2-piperidinecarbothioate (10)

Methyl ( 25) -1- ( 1 , 2-dioxo-2-methoxyethyl ) -2- pyrrolidinecarboxylate

A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry ethylene chloride was cooled to 0°C and treated with triethylamine (3.92 g; 38.74 mmol;

2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 min, a solution of methyl oxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over MgS0₄ and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. ^λE NMR (CDC1₃) : d 1.93 (dm, 2H) ; 2.17 (m, 2H) ; 3.62 ( , 2H); 3.71 (s, 3H) ; 3.79, 3.84 (s, 3H total) ; 4.86 (dd, IH, J = 8.4, 3.3) .

Methyl (25) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarboxylate

A solution of methyl (2S) -1- ( 1, 2-dioxo-2- methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 L of tetrahydrofuran (THF) was cooled to -78 °C and treated with 14.2 mL of a 1.0 M solution of 1,1- dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 °C for three hours, the mixture was poured into saturated ammonium chloride

(100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil. ^XH NMR (CDC1₃) : d 0.88 (t, 3H) ; 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H) ; 1.87-2.10 (m, 3H) ; 2.23 (m, IH) ; 3.54 (m, 2H) ; 3.76 (s, 3H) ; 4.52 (dm, IH, J = 8.4, 3.4) . (25) -1- (1, 2-dioxo-3, 3-dimethylpentyl ) -2-pyrrolidine- carboxylic acid

A mixture of methyl (2S) -1- ( 1, 2-dioxo-3, 3- dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL) , and methanol (50 mL) was stirred at 0°C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. ^λR NMR

(CDC1₃) : d 0.87 (t, 3H) ; 1.22, 1.25 (s, 3H each); 1.77

(dm, 2H) ; 2.02 (m, 2H) ; 2.17 (m, IH) ; 2.25 (m, IH) ; 3.53

(dd, 2H, J = 10.4, 7.3); 4.55 (dd, IH, J = 8.6, 4.1).

2-phenyl-1-ethyl 1- (3, 3-dimethyl-l, 2-dioxopentyl ) -2- piperidinecarbothioate (10)

To a solution of (25) -1- (1, 2-dioxo-3, 3- dimethylpentyl) -2-pyrrolidinecarboxylic acid (241 mg; 1.0 mmol) in CH₂C1₂ (10 mL) was added dicyclohexylcarbodiimide

(226 mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes, the solution was cooled to 0°C and treated with a solution of phenyl mercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 ml of CH₂C1₂. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo; the crude residue was purified by flash chromatography (10:1 hexane: EtOAc) to obtain 302 mg (84%) of compound 10 as an oil. ^:H NMR (CDCI₃, 300 MHz): d 0.85 (t, 3H, J = 7.5); 1.29 (s, 3H) ; 1.31 (s, 3H) ; 1.70-2.32 (m, 6H) ; 2.92 (t, 2H, J = 7.4) ; 3.22 (t, 2H, J = 7.4) ; 3.58 (m, 2H) ; 4.72 (m, IH) ; 7.23-7.34 ( , 5H) . Analysis calculated for C₂₀H₂₇NO₃S - 0.4 H₂0: C, 65.15; H, 7.60; N, 3.80. Found: C, 65.41; H, 7.49; N, 3.72.

EXAMPLE 3

Synthesis of 2-phenyl-l-ethvI (2S)-l-(3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarbothioate (9) Methyl 1- ( 1 , 2 -dioxo-2 -methoxyethyl ) -2-piperidinecarboxylate A solution of methyl pipecolate hydrochloride (8.50 g; 47.31 mmol) in dry methylene chloride (100 L) was cooled to 0°C and treated with triethylamine (10.5 g; 103 mmol; 2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (8.50 g; 69.4 mmol) in methylene chloride (75 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1,5 hours. After filtering to remove solids, the organic phase was washed with water, dried over MgS0₄ and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 9.34 g (86%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. ^:H NMR (CDC1₃) : d 1.22-1.45 (m, 2H) ; 1.67- 1.78 (m, 3H) ; 2.29 (m, IH) ; 3.33 (m, IH) ; 3.55 (m, IH) ; 3.76 (s, 3H); 3.85, 3.87 (s, 3H total) ; 4.52 (dd, IH) .

Methyl 1- (1, 2-dioxo-3, 3-dimethylpentyl ) -2-piperidine- carboxylate

A solution of methyl 1- (1, 2-dioxo-2-methoxyethyl) -2- piperidinecarboxylate (3.80 g; 16.57 mmol) in 75 mL of tetrahydrofuran (THF) was cooled to -78 °C and treated with 20.7 mL of a 1.0 M solution of 1, 1-dimethyl-propylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 °C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 3.32 g (74%) of the oxamate as a colorless oil. *H NMR (CDC1₃) : d 0.88 (t, 3H) ; 1.21, 1.25 (s, 3H each); 1.35-1.80 (m, 7H) ; 2.35 (m, IH) ; 3.24 (m, IH) ; 3.41 (m, IH) ; 3.76 (s, 3H) ; 5.32 (d, IH) . 1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-piperidine-carboxylic acid A mixture of methyl 1- ( 1, 2-dioxo-3, 3-dimethylpentyl) - 2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 mL) , and methanol (60 mL) was stirred at 0°C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification. *H NMR (CDC1₃) : d 0.89 (t, 3H) ; 1.21, 1.24 (s, 3H each); 1.42-1.85 (m, 7H) ; 2.35 (m, IH) ; 3.22 (d, IH) ; 3.42 ( , IH) ; 5.31 (d, IH) .

2-phenyl-l-ethyl (25) -1- (3, 3-dimethyl-l , 2-dioxopentyl) -2- pyrrolidinecarbothioate (9)

To a solution of 1- (1, 2-dioxo-3, 3-dimethylpentyl) -2- piperidine-carboxylic acid (255 mg; 1.0 mmol) in CH₂C1₂ (10 mL) was added dicyclohexylcarbodiimide (226 mg; 1.1 mmol) . After stirring the resulting mixture for 5 minutes, the solution was cooled to 0°C and treated with a solution of phenyl mercaptan (138 mg; 1.0 mmol) and 4- dimethylaminopyridine (6 mg) in 5 ml of CH₂C1₂. The mixture was allowed to warm to room temperature with stirring overnight. The solids were removed by filtration and the filtrate was concentrated in vacuo; the crude residue was purified by flash chromatography (10:1 hexane: EtOAc) to obtain 300 mg (80%) of compound 9 as an oil. ^XH NMR (CDC1₃, 300 MHz): d 0.94 (t, 3H, J = 7.5); 1.27 (s, 3H) ; 1.30 (s, 3H) ; 1.34-1.88 (m, 7H) ; 2.45 (m, IH) ; 2.90 (t, 2H, J = 7.7) ; 3.26 (t, 2H, J = 7.7) ; 3.27 (m, IH) ; 3.38 ( , IH) ; 5.34 (m, IH) ; 7.24-7.36 (m, 5H) . Analysis calculated for C₂₁H₂₉N0₃S : C, 67.17; H, 7.78; N, 3.73. Found: C, 67.02; H, 7.83; N, 3.78.

EXAMPLE 4 Synthesis of 3-phenyl-l-propyl (2S) -1- (3 , 3-dimethyl-l, 2- dioxopentyl) -2- (4-thiazolidine) carboxylate (80) 1- (1, 2-dioxo-2-methoxyethyl) 2- (4-thiazolidine) -carboxylate A solution of L-thioproline (1.51 g; 11.34 mmol)in 40 mL of dry methylene chloride was cooled to 0°C and treated with 3.3 mL (2.41 g; 23,81 mmol) of triethylamine . After stirring this mixture for 30 minutes, a solution of methyl oxalyl chloride (1.81 g; 14.74 mmol) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hours, filtered through Celite to remove solids, dried and concentrated. The crude material was purified on a silica gel column, eluting with 10% MeOH in methylene chloride, to obtain 2.0 g of the oxamate as an orange-yellow solid. 3-phenyl-l-propyl (25) -1- (1 , 2-dioxo-2-methoxyethyl ) 2- (4- thiazolidine) carboxylate

1- (1, 2 -dioxo-2-methoxyethyl) 2- (4-thiazolidine) - carboxylate (500 mg; 2.25 mmol), 3-phenyl-l-propanol (465 mg; 3.42 mmol), dicyclohexylcarbodiimide (750 mg; 3.65 mmol), 4-dimethylaminopyridine (95 mg; 0.75 mmol) and camphorsulfonic acid (175 mg; 0.75 mmol) in 30 mL of methylene chloride were stirred together overnight. The mixture was filtered through Celite to remove solids and chromatographed (25% ethyl acetate/hexane) to obtain 690 mg of material. ²H NMR (CDC1₃, 300 MHz): d 1.92-2.01 (m, 2H) ; 2.61-2.69 (m, 2H) ; 3.34 (m, IH) ; 4.11-4.25 (m, 2H) ; 4.73 (m, IH) ; 5.34 ( , IH) ; 7.12 ( , 3H) ; 7.23 ( , 2H) . 3-phenyl-l-propyl (25) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2- (4-thiazolidine) carboxylate (80)

A solution of 3-phenyl-l-propyl (25) -1- ( 1, 2-dioxo-2- methoxyethyl) 2- (4-thiazolidine) carboxylate (670 mg; 1.98 mmol) in tetrahydrofuran (10 mL) was cooled to -78 °C and treated with 2.3 mL of a 1.0 M solution of 1,1- dimethylpropylmagnesium chloride in ether. After stirring the mixture for 3 hours, it was poured into saturated ammonium chloride, extracted into ethyl acetate, and the organic phase was washed with water, dried and concentrated. The crude material was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 380 mg of the compound of Example 4 as a yellow oil. *H NMR (CDC1₃, 300 MHz): d 0.86 (t, 3H) ; 1.21 (s, 3H) ; 1.26 (s, 3H) ; 1.62-1.91 (m, 3H) ; 2.01 ( , 2H) ; 2.71 (m, 2H) ; 3.26-3.33 (m, 2H) ; 4.19 (m, 2H) ; 4.58 (m, IH) ; 7.19 (m, 3H) ; 7.30 (m, 2H) . Analysis calculated for C₂₀H₂₇NO₄S: C, 63.63; H, 7.23; N, 3.71. Found: C, 64.29; H, 7.39; N, 3.46.

EXAMPLE 5

Synthesis of 3- (3-pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl- 1, 2-dioxopentyl) -2- (4-thiazolidine) carboxylate (81) The compound of Example 5 was prepared according to the procedure of Example 4, using 3- (3-pyridyl) -1-propanol in the final step, to yield 3- (3-pyridyl) -1-propyl (25) -1- ( 3 , 3-dimethyl-l , 2-dioxopentyl ) - 2 - ( 4 - thiazolidine) carboxylate. ^XH NMR (CDC1₃, 300 MHz) : d 0.89 (t, 3H, J = 7.3); 1.25 (s, 3H) ; 1.28 (s, 3H) ; 1.77 (q, 2H, J = 7.3); 2.03 (tt, 2H, J = 6.4, 7.5); 2.72 (t, 2H, J = 7.5); 3.20 (dd, IH, J = 4.0, 11.8); 3.23 (dd, IH, J = 7.0,

11.8); 4.23 (t, 2H, J = 6.4); 4.55 (d, 2H, J = 8.9); 5.08

(dd, IH, J = 4.0, 7.0); 7.24 (m, IH) ; 8.48 (m, 2H) .

Analysis calculated for C₁₉H₂₆N₂0₄S - 0.5 H₂0: C, 58.89; H,

7.02; N, 7.23. Found: C, 58.83; H, 7.05; N, 7.19.

EXAMPLE 6

Synthesis of 3- (3-pyridyl) -1-propyl (2S)-l-(3,3- Dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, N- oxide (95) Methyl (25) -1- (1, 2-dioxo-2-methoxyethyl) -2- pyrrolidinecarboxylate

A solution of L-proline methyl ester hydrochloride

(3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0°C and treated with triethylamine (3.92 g; 38.74 mmol; 2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 L) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over MgS0₄ and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. ^XH NMR (CDC1₃) : d 1.93 (dm, 2H) ; 2.17 (m, 2H) ; 3.62 ( , 2H) ; 3.71 (s, 3H) ; 3.79, 3.84 (s, 3H total); 4.86 (dd, IH, J = 8.4, 3.3) .

Methyl (25) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarboxylate A solution of methyl (2S) -1- (1, 2-dioxo-2- methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78 °C and treated with 14.2 mL of a 1.0 M solution of 1,1- dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 °C for three hours, the mixture was poured into saturated ammonium chloride

(100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil. ^XH NMR (CDC1₃) : d 0.88 (t, 3H) ; 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H) ; 1.87-2.10 (m, 3H) ; 2.23 (m, IH) ; 3.54 (m, 2H) ; 3.76 (s, 3H) ; 4.52 (dm, IH, J= 8.4, 3.4).

( 25) -1 - ( 1 , 2 -dioxo-3 , 3-dimethylpentyl ) - 2 - pyrrolidinecarboxylic acid

A mixture of methyl (2S) -1- ( 1 , 2-dioxo-3, 3- dimethylpentyl-2-pyrrolidine-carboxylate (2.10 g; 8.23 mmol) , 1 N LiOH (15 L) , and methanol (50 L) was stirred at 0°C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. ¹H NMR (CDC1₃) : d 0.87 (t, 3H) ; 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H) ; 2.02 (m, 2H) ; 2.17 (m, IH) ; 2.25 (m, IH) ; 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, IH, J = 8.6, 4.1). 3-(3-Pyridyl)-l-propyl(25)-l-(3,3-dimethyl-l,2- dioxopentyl) -2-pyrrolidinecarboxylate

A mixture of (25) -1- ( 1, 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarboxylic acid (4.58 g; 19 mmol), 3- pyridinepropanol (3.91 g; 28.5 mmol), dicyclohexylcarbodiimide (6.27 g; 30.4 mmol), camphorsulfonic acid (1.47 g; 6.33 mmol) and 4-dimethyl aminopyridine (773 mg; 6.33 mmol) in methylene chloride (100 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo. The crude material was triturated with several portions of ether, and the ether portions were filtered through Celite to remove solids and concentrated in vacuo. The concentrated filtrate was purified on a flash column (gradient elution, 25% ethyl acetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of GPI 1046 as a colorless oil (partial hydrate) . ^ NMR (CDCI₃, 300 MHz): d 0.85 (t, 3H) ; 1.23, 1.26 (s, 3H each); 1.63-1.89 (m, 2H) ; 1.90-2.30 (m, 4H) ; 2.30-2.50 (m, IH) ; 2.72 (t, 2H) ; 3.53 (m, 2H) ; 4.19 (m, 2H) ; 4.53 (m, IH) ; 7.22 (m, IH) ; 7.53 (dd, IH) ; 8.45. Analysis calculated for C₂₀H₂₈NO₄ - 0.25 H₂0: C, 65.82; H, 7.87; N, 7.68. Found: C, 66.01; H, 7.85; N, 7.64. 3- (3-Pyridyl) -1-propyl (25) -1- (3, 3-dimethyl-1 , 2- dioxopentyl) -2-pyrrolidinecarboxylate, N-oxide (95) A solution of 3- (3-pyridyl) -1-propyl (2S)-l-(3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate (190 mg; 0.52 mmol) and m-chloroperbenzoic acid (160 mg of 57%-86% material, 0.53 mmol) was stirred in methylene chloride (20 mL) at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride and washed twice with 1 N NaOH. The organic extract was dried and concentrated, and the crude material was chromatographed, eluting with 10% methanol in ethyl acetate, to obtain 130 mg of the Compound 95 of Example 6. ^XH NMR (CDC1₃, 300 MHz): d 0.83 (t, 3H); 1.21 (s, 3H) ; 1.25 (s, 3H) ; 1.75-2.23 (m, 8H) ; 2.69 (t, 2H, J = 7.5) ; 3.52 (t, 2H, J = 6.3) ; 4.17 (dd, 2H, J = 6.3); 4.51 (m, IH) ; 7.16-7.22 (m, 2H) ; 8.06-8.11 (m, 2H) . Analysis calculated for C₂₀H₂₈N₂O₅ - 0.75 H₂0: C, 61.60; H, 7.63; N, 7.18. Found: C, 61.79; H, 7.58; N, 7.23.

EXAMPLE 7 Synthesis of 3- (3-Pyridyl) -1-propylmercaptyl 2S-l-[(2- methylbutyl) carbamoyll pyrrolidine-2-carboxylate (101) 3- (3-Pyridyl) -1-propylchloride

To a solution of 3- (3-pyridyl) -1-propanol (10 g; 72.4 mmol) in chloroform (100 mL) was added dropwise a solution of thionyl chloride (12.9 g; 108.6 mmol) in chloroform (50 mL) . The resulting mixture was refluxed for 1 hour, then poured into ice-cold 50% aqueous potassium hydroxide (150 mL) . The layers were separated, and the organic phase was dried, concentrated, and purified on a silica gel column, eluting with 40% ethylacetate in hexane, to obtain 10 g (65%) of the chloride as a clear oil. ^XH NMR (300 MHz, CDC1₃) : d 2.02-2.11 (m, 2H) ; 2.77 (m, 2H) ; 3.51 (m, 2H) ; 7.20 (m, IH) ; 7.49 ( , IH) ; 8.45 (m, 2H) . 3- (3-Pyridyl) -1-propylmercaptan

A mixture of 3- (3-pyridyl) -1-propylchloride (3 g; 19.4 mmol) and thiourea (1.48 g; 19.4 mmol) in ethanol (10 mL) was refluxed for 24 hours. Aqueous sodium hydroxide, 15 L of a 0.75 N solution, was added, and the mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed in vacuo . Chromatographic purification of the crude thiol on a silica gel column eluting with 50% ethyl acetate in hexane delivered 1.2 g of 3- (3-Pyridyl) -1-propylmercaptan as a clear liquid. *H NMR (300 MHz, CDC1₃) : d 1.34 (m, IH) ; 1.90 (m, 2H) ; 2.52 (m, 2H) ; 2.71 (m, 2H) ; 7.81 (m, IH) ; 7.47 (m, IH) ; 8.42 (m, 2H) .

3- (3-Pyridyl) -1-propylmercaptyl N - ( tert- butyloxycarbonyl) pyrrolidine-2-carboxylate

A mixture of N- ( ert-butyloxycarbonyl) - (5) -proline (3.0 g; 13.9 mmol); 3- (3-Pyridyl) -1-propylmercaptan (3.20 g; 20.9 mmol), dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid (1.08 g; 4.63 mmol), and 4- dimethylaminopyridine (0.60 g; 4.63 mmol) in dry methylene chloride (100 mL) was stirred overnight. The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL) , and the layers were separated. The organic phase was washed with water (3 x 100 mL) , dried over magnesium sulfate, and concentrated, and the crude residue was purified on a silica gel column eluting with ethyl acetate to obtain 4.60 g (95%) of the thioester as a thick oil. ^XH NMR (300 MHz, CDC1₃) : d 1.45 (s, 9H) ; 1.70-2.05 (m, 5H) ; 2.32 ( , IH) ; 2.71 (t, 2H) ; 2.85 (m, 2H) ; 3.50 (m, 2H) ; 4.18 (m, IH) ; 7.24 (m, IH) ; 7.51 (m, IH) ; 8.48 ( , 2H) . 3- (3-Pyridyl) -1-propylmercaptyl pyrrolidine-2-carboxylate A solution of 3- (3-Pyridyl) -1-mercaptyl N- ( ert- butyloxycarbonyl) pyrrolidine-2-carboxylate (4.60 g; 13.1 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x) . The combined organic extracts were dried and concentrated to yield 2.36 g (75%) of the free amine as a thick oil. ^λH NMR (300 MHz, CDC1₃) : d 1.87-2.20 (m, 6H) ; 2.79 (m, 2H) ; 3.03-3.15 ( , 4H total); 3.84 (m, IH) ; 7.32 (m, IH) ; 7.60 (m, IH) ; 8.57 (m, 2H) .

3-(3-Pyridyl)-l-propylmercaptyl 2S-1-I^" ( 2 -methyl - butyl) carbamoyll pyrrolidine-2-carboxylate (101) A solution of 2-methylbutylamine (113 mg; 1.3 mmol) and triethylamine (132 mg; 1.3 mmol) in methylene chloride (5 mL) was added to a solution of triphosgene (128 mg; 0.43 mmol) in methylene chloride (5 mL) . The resulting mixture was refluxed for 1 hour and then cooled to room temperature. 3- (3-Pyridyl) -1-propylmercaptyl pyrrolidine-2- carboxylate (300 mg; 1.3 mmol) in 5 L of methylene chloride was added and the resulting mixture was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography

(50% ethyl acetate/hexane) to obtain 250 mg (55%) of the compound of Example 7 (Compound 101, Table VII) as an oil. ^XH NMR (CDC1₃, 300 MHz): d 0.89-0.93 (m, 6H) ; 1.10-1.20 ( , IH) ; 1.27 (s, IH) ; 1.36-1.60 (m, 2H) ; 1.72 (s, 2H 1.97-2.28 (m, 6H) ; 2.70-2.75 (m, 2H) ; 2.92-3.54 (m, 6H 4.45-4.47 (m, IH) ; 7.21-7.29 ( , IH) ; 7.53-7.56 (dd, IH 8.46-8.48 (s, 2H) .

EXAMPLE 8

Synthesis of 3- (3-Pyridyl) -1-propyl 2S-1- (1 ' , 1 ' -

Dimethylpropyl) carbamoyll pyrrolidine-2-carboxylate (102) Reaction of 3- ( 3-pyridyl ) -1-propylmercaptyl pyrrolidine-2-carboxylate with the isocyanate generated from tert-amylamine and triphosgene, as described for

Example 7, provided the compound of Example 8 (Compound

102, Table VII) in 62% yield. ^XH NMR (CDC1₃, 300 MHz) : d 0.83 (t, 3H) ; 1.27 (s, 6H) ; 1.64-1.71 (m, 2H) ; 1.91-2.02 ( , 7H) ; 2.66-2.71 (t, 2H) ; 2.85 ( , 2H) ; 3.29-3.42 ( , 2H) ; 4.11 (br, IH) ; 4.37-4.41 (m, IH) .

EXAMPLE 9 Synthesis of 3- (3-pyridyl) -1-propylmercaptyl 2S-1- f (cyclohexyl) thiocarbamoyll -pyrrolidine-2-carboxyIate

(107)

A mixture of cyclohexylisothiocyanate (120 mg; 0.9 mmol), 3- (3-pyridyl) -1-propylmercaptyl pyrrolidine-2- carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg;

0.9 mmol) in 20 mL of methylene chloride was stirred for

1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 160 mg (47%) of the compound of Example 9 (Compound 107, Table VII) . H NMR

(CDC1₃, 300 MHz): d 1.16-1.40 ( , 6H) ; 1.50-1.71 ( , 4H) ;

1.95-2.08 (m, 7H) ; 2.70-2.75 (t, 2H) ; 3.03 (m, 2H) ; 3.40-

3.60 (m, 2H) ; 4.95-4.98 (d, IH) ; 5.26-5.29 (d, IH) ; 7.17- 7.25 (m, IH) .

EXAMPLE 10 Synthesis of 3- (para-Methoxyphenyl ) -1- propylmercaptyl (2S) -N- (benzenesulfonyl) pyrrolidine-2- carboxylate (120)

3- (p-Methoxyphenyl) -1-propylbromide

To a solution of 3- (p-methoxyphenyl) -1-propanol (16.6 g; 0.1 mol) in 250 mL of toluene, cooled to 0°C, was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition, the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3x) and brine (3x) . The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10% EtOAc/hexane, to obtain 14 g (61%) of 3- (p- methoxyphenyl) -1-propylbromide . 3- (p-Methoxyphenyl) -1-propylmercaptan A mixture of 3- (p-methoxyphenyl) -1-propylbromide (14 g; 61 mmol) and thiourea (5.1 g; 67 mmol) in ethanol (150 mL) was refluxed for 48 hours. Evaporation of the solvent provided a clear glassy compound, which was dissolved in 50 mL of water and treated with 100 mL of 40% aqueous sodium hydroxide. After stirring the resulting mixture for two hours, the product was extracted into ether (3x) , and the combined organic extracts were washed with sodium bicarbonate and brine, dried, and concentrated. Chromatographic purification of the crude thiol on a silica gel column eluting with 2% either in hexane delivered 10.2 g of 3- (p-methoxyphenyl) - 1-propylmercaptan as a clear liquid. ^XH NMR (300 MHz, CDC1₃) : d 1.34 (t, IH) ; 1.88-1.92 (m, 2H) ; 2.49-2.53 (m, 2H) ; 2.64-2.69 ( , 2H) ; 3.77 (s, 3H); 6.80-6.84 (m, 2H) ; 7.06-7.24 (m, 2H) . 3- (p-Methoxyphenyl) -1-mercaptyl N - ( t e r t - butyloxycarbonyl ) pyrrolidine-2-carboxylate

A mixture of N- ( tert-butyloxycarbonyl )-( 5) -proline (2.0 g; 9.29 mmol), 3- (p-methoxyphenyl) -1-propylmercaptan (1.86 g; 10.22 mmol), 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (1.96 g; 10.22 mmol), and 4-dimethylaminopyridine (catalytic) in dry methylene chloride (50 mL) was stirred overnight. The reaction mixture was diluted with methylene chloride (50 L) and water 100 (mL) , and the layers were separated. The organic phase was washed with water (3 x 100 mL) , dried over magnesium sulfate, and concentrated to provide 3.05 g of the product (100%) as a thick oil. ^XH NMR (300 MHz, CDC1₃) : d 1.15 (s, 9H) ; 1.84-2.31 (m, 6H) ; 2.61 (m, 2H) ; 2.83 (m, 2H) ; 3.51 (m, 2H) ; 3.75 (s, 3H) ; 6.79 (d, 2H, J = 8.04) ; 7.05 (m, 2H) . 3- (p-Methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate A solution of 3- (p-methoxyphenyl) -mercaptyl N- ( ert- butyloxycarbonyl) pyrrolidine-2-carboxylate (3.0 g; 8.94 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x) . The combined organic extracts were dried and concentrated to yield 1.73 g (69%) of the free amine as a thick oil. *H NMR (300 MHz, CDC1₃) : d 1.80-2.23 (m, 6H) ; 2.62 (m, 2H) ; 2.81 (m, 2H) ; 3.01 ( , 2H) ; 3.75 (s, 3H) ; 3.89(m, IH) ; 6.81 ( , 2H) ; 7.06 (m, 2H) .

3- (para-Methoxyphenyl) -1-propylmercaptyl (25) -N-

(benzenesulfonyl) yrrolidine-2-carboxylate (120) A solution of 3- (p-methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate (567 mg; 2.03 mmol) and benzenesulfonyl chloride (358 mg; 2.03 mmol) in methylene chloride (5 mL) was treated with diisopropylethylamine (290 mg; 2.23 mmol) and stirred overnight at room temperature. The reaction mixture was filtered to remove solids and applied directly to a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 540 mg of Compound 120 (Table VIII) as a clear oil. ^XH NMR (300 MHz, CDC1₃) : d 1.65-1.89 (m, 6H) ; 2.61 (t, 2H, J = 7.3); 2.87 (t, 2H, J = 7.6); 3.26 ( , IH) ; 3.54 (m, IH) ; 3.76 (s, 3H) ; 4.34 (dd, IH, J = 2.7, 8.6); 6.79 (d, 2H, J = 8.7); 7.06 (d, 2H, J = 8.6); 7.49-7.59 (m, 3H) ; 7.86 (dd, 2H, J = 1.5, 6.8).

EXAMPLE 11 Synthesis of 3- (para-Methoxyphenyl) -1- propylmercaptyl (2S) -N- (a-toluenesulfonyl) pyrrolidine-2- carboxylate (121) A solution of 3- (p-Methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate (645 mg; 2.30 mmol) and a- toluenesulfonyl chloride (440 mg; 2.30 mmol) in methylene chloride (5 mL) was treated with diisopropylethylamine (330 mg; 2.53 mmol) and stirred overnight at room temperature. Purification as described for Example 10 provided the compound of Example 11 (Compound 121, Table VIII) as a clear oil. ^XH NMR (300 MHz, CDC1₃) : d 1.65-2.25 (m, 8H) ; 2.65 (t, 2H) ; 2.89-2.96 (m, 2H) ; 3.55-3.73 (m, 2H) ; 3.80 (s, 3H) ; 4.32 (s, 2H) ; 4.70-4.81 (m, IH) ; 6.83 (d, 2H) ; 7.09 (d, 2H) ; 7.14 (m, 3H) ; 7.26 (m, 2H) .

EXAMPLE 12

Synthesis of 3- (para-Methoxyphenyl) -1- propylmercaptyl (2S) -N- (a-toluenesulfonyl) pyrrolidine-2- carboxylate (122) A solution of 3- (p-methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate (567 mg; 2.30 mmol) and p- toluenesulfonyl chloride (425 mg; 2.23 mmol) in methylene chloride (5 mL) was stirred overnight at room temperature. Purification as described for Example 10 provided the compound of Example 12 (Compound 122, Table VIII) as a clear oil. ^XH NMR (300 MHz, CDC1₃) : d 1.67-1.94 ( , 6H) ; 2.40 (s, 3H) ; 2.61 (t, 2H, J = 7.3) ; 2.84 (m, 2H, J = 7.2) ; 3.22 (m, IH) ; 3.52 ( , IH) ; 3.76 (s, 3H) ; 4.32 (dd, IH, J- 2.9, 8.5); 6.79 (d, 2H, J = 6.5); 7.07 (d, 2H, J = 6.5); 7.29 (d, 2H, J = 6.5); 7.74 (d, 2H, J = 6.5).

EXAMPLE 13 Synthesis of 1, 5-Diphenyl-3-pentylmercaptyl N- (para- toluenesulfonyl) pipecolate (134) 3-Phenyl-1-propanal Oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride (50 mL) , cooled to -78°C, was treated with dimethylsulfoxide (3.4 mL) in 10 mL of methylene chloride. After stirring for 5 min, 3-phenyl-l-propanol (2.72 g; 20 mmol) in 20 mL of methylene chloride was added, and the resulting mixture was stirred at -78°C for 15 min, treated with 14 mL of triethylamine, stirred an additional 15 min, and poured into 100 mL of water. The layers were separated, the organic phase was dried and concentrated, and the crude residue was purified on a silica gel column, eluting with 10% ethyl acetate in hexane, to obtain 1.27 g (47%) of the aldehyde as a clear oil. ^XH NMR (300 MHz, CDC1₃) : d 2.80 (m, 2H) ; 2.98 (m, 2H) ; 7.27 (m, 5H) ; 9.81 (2, IH) . 1, 5-Diphenyl-3-pentanol A solution of 2- (bromoethyl) benzene (1.73 g; 9.33 mmol) in diethylether (10 mL) was added to a stirred slurry of magnesium turnings (250 mg; 10.18 mmol) in 5 mL of ether. The reaction was initiated with a heat gun, and after the addition was complete the mixture was heated on an oil bath for 30 min. 3-Phenyl-l-propanal (1.25 g; 9.33 mmol) was added in 10 mL of ether, and reflux was continued for 1 hour. The reaction was cooled and quenched with saturated ammonium chloride, extracted into 2x ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) delivered 1.42 g(63%) of the diphenyl alcohol. ^XH NMR (300 MHz, CDC1₃) : d 1.84 (m, 4H) ; 2.61-2.76 (m, 4H) ; 3.65 (m, IH) ; 7.19-7.29 (m, 10H) . 1, 5-Diphenyl-3-bromopentane

To a solution of 1, 5-diphenyl-3-pentanol (1.20 g (5 mmol) and carbon tetrabromide (1.67 g; 5 mmol) in methylene chloride (20 mL) was added triphenylphosphine (1.31 g; 5 mmol) portionwise, at 0°C. After stirring at room temperature for 18 hours, the mixture was concentrated, triturated with ether, and the solids removed by filtration. The filtrate was passed through a plug of silica gel, eluting with hexane :methylene chloride, 10:1, to give 1.35 g (90%) of the bromide as an oil which was used without further purification. H NMR (300 MHz, CDC1₃) : d 2.11-2.18 ( , 4H) ; 2.73 (m, 2H) ; 2.86 ( , 2H) ; 3.95 (m, IH) ; 7.16-7.30 (m, 10H) . 1 , 5-Diphenyl-3-pentylmercaptan

Using the procedure described in Example 10 for the conversion of bromides to thiols, 1, 5-diphenyl-3- bromopentane was converted to 1, 5-diphenyl-3- pentylmercaptan in 35% overall yield. ^:H NMR (300 MHz, CDC1₃) : d 1.79 (m, 2H) ; 1.98 (m, 2H) ; 2.71 (m, 3H) ; 2.80 (m, 2H) ; 7.16-7.28 (m, 10H) . 1 , 5 - D i p h e n y l - 3 - p e n t y l m e r c a p t v l N - ( t e r t - butyloxycarbonyl ) pyrrolidine-2-carboxylate

A mixture of N- ( tert-butyloxycarbonyl) - (S) -pipecolic acid (2.11 g; 9.29 mmol), 1, 5-diphenyl-3-pentylmercaptan (2.58 g; 10.22 mmol), 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (1.96 g; 10.22 mmol) and 4-dimethylaminopyridine (catalytic) in dry methylene chloride (50 mL) was stirred overnight. the reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL) , and the layers were separated. The organic phase was washed with water (3 x 100 mL) , dried over magnesium sulfate, and concentrated to provide 870 mg (20%) of the product as a thick oil, which was used without further purification. 1, 5-Diphenyl-3-pentylmercaptyl pyrrolidine-2-carboxylate A solution of 1, 5-diphenyl-3-pentylmercaptyl N- ( ert- butyloxycarbonyl) pyrrolidine-2-carboxylate (850 mg; 1.8 mmol) in methylene chloride (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for three hours. Saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride. The combined organic extracts were dried and concentrated to yield 480 mg (72%) of the free amine as a thick oil, which was used without further purification. 1 , 5-Diphenyl-3-pentylmercaptyl N - ( p a r a - toluenesulf onyl) pipecolate (134)

1, 5-Diphenyl-3-pentylmercaptyl N- (para- toluenesulf onyl) pipecolate (18 ) was prepared from 1,5- diphenyl-3-pentylmercaptyl pyrrolidine-2-carboxylate and para-toluenesulfonyl chloride as described for Example 12, in 65% yield. *H NMR (CDC1₃, 300 MHz) : d 0.80 (m, 4H) ; 1.23-1.97 (m, 5H) ; 2.15 (d, IH) ; 2.61-2.69 (m, 4H) ; 3.23 (m, IH) ; 3.44 (dm, IH) ; 4.27 (s, 2H) ; 4.53 (d, IH, J = 4.5) ; 5.06 (m, IH) ; 7.16-7.34 (m, 15H) .

EXAMPLE 14

Synthesis of 3-phenyl-l-propyl (2S) -1- (3.3-dimethyl-l , 2- dioxopentyl) -2-pyrrolidinecarboxylate (137 ) Methyl (25) -1- (1, 2 -dioxo-2 -methoxyethyl) -2- pyrrolidinecarboxylate

A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0°C and treated with triethylamine (3.92 g; 38.74 mmol; 2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 min, a solution of methyl oxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hour. After filtering to remove solids, the organic phase was washed with water, dried over MgS0₄ and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. ^XH NMR (CDC1₃) : d 1.93 (dm, 2H) ; 2.17 (m, 2H) ; 3.62 (m, 2H) ; 3.71 (s, 3H) ; 3.79, 3.84 (s, 3H total); 4.86 (dd, IH, J = 8.4, 3.3) .

Methyl (25)-l-(l,2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarboxylate A solution of methyl (2S) -1- (1, 2-dioxo-2- methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78°C and treated with 14.2 mL of a 1.0 M solution of 1,1- dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78°C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil. ^XH NMR (CDC1₃) : d 0.88 (t, 3H) ; 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H) ; 1.87-2.10 (m, 3H) ; 2.23 (m, IH) ; 3.54 (m, 2H) ; 3.76 (s, 3H) ; 4.52 (dm, IH, J = 8.4, 3.4) .

Synthesis of (25) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarboxylic acid

A mixture of methyl (25) -1- ( 1 , 2-dioxo-3, 3- dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 mL) , and methanol (50 L) was stirred at 0°C for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. ^XH NMR (CDC1₃) : d 0.87 (t, 3H) ; 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H) ; 2.02 (m, 2H) ; 2.17 (m, IH) ; 2.25 (m, IH) ; 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, IH, J = 8.6, 4.1).

3-Phenyl-l-propyl (25) -1- (3, 3-dimethyl-l , 2-dioxopentyl) -2- pyrrolidinecarboxylate (137)

A mixture of (25) -1- ( 1, 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidine-carboxylic acid (600 mg; 2.49 mmol), 3-phenyl- 1-propanol (508 mg; 3.73 mmol), dicyclohexylcarbodiimide (822 mg; 3.98 mmol), camphorsulfonic acid (190 mg; 0.8 mmol) and 4-dimethylaminopyridine (100 mg; 0.8 mmol) in methylene chloride (20 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain 720 mg (80%) of Example 14 as a colorless oil. ^XH NMR (CDC1₃) : d 0.84 (t, 3H) 1.19 (s, 3H) ; 1.23 (s, 3H) ; 1.70 (dm, 2H) ; 1.98 (m, 5H) 2.22 (m, IH) ; 2.64 (m, 2H) ; 3.47 (m, 2H) ; 4.14 (m, 2H) 4.51 (d, IH) ; 7.16 (m, 3H) ; 7.26 (m, 2H) .

EXAMPLE 15 The method of Example 14 was utilized to prepare the following illustrative compounds.

Compound 138: 3-phenyl-l-prop-2- (E) -enyl (25) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 80%. ^XH NMR (360 MHz, CDC1₃) : d 0.86 (t, 3H) ; 1.21 (s, 3H); 1.25 (s, 3H) ; 1.54-2.10 ( , 5H) ; 2.10-2.37 ( , IH) ; 3.52-3.55 ( , 2H) ; 4.56 (dd, IH, J = 3.8, 8.9); 4.78-4.83 (m, 2H) ; 6.27 (m, IH) ; 6.67 (dd, IH, J = 15.9); 7.13-7.50 (m, 5H) .

Compound 139: 3- (3, 4 , 5-trimethoxyphenyl) -1-propyl (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 61%. ^XH NMR (CDC1₃) : d 0.84 (t, 3H) ; 1.15 (s, 3H) ; 1.24 (s, 3H) ; 1.71 (dm, 2H) ; 1.98 ( , 5H) ; 2.24 (m, IH) ; 2.63 (m, 2H) ; 3.51 (t, 2H) ; 3.79 (s, 3H) ; 3.83 (s, 3H) ; 4.14 (m, 2H) ; 4.52 (m, IH) ; 6.36 (s, 2H) .

Compound 140: 3- (3, 4 , 5-trimethoxyphenyl) -l-prop-2-

(E)-enyl (2S)-l-(3, 3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidine carboxylate, 66%. ^XH NMR (CDC1₃) : d 0.85 (t, 3H) ; 1.22 (s, 3H) ; 1.25 (s, 3H) ; 1.50-2.11 (m, 5H) ; 2.11- 2.40 (m, IH) ; 3.55 (m, 2H) ; 3.85 (s, 3H) ; 3.88 (s, 6H) ; 4.56 (dd, IH); 4.81 (m, 2H) ; 6.22 (m, IH) ; 6.58 (d, IH, J = 16) ; 6.63 (s, 2H) .

Compound 141: 3- (4 , 5-methylenedioxyphenyl ) -1-propyl

(25) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 82%. ^αH NMR (360 MHz, CDC1₃) : d 0.86 (t, 3H) ; 1.22 (s, 3H) ; 1.25 (s, 3H) ; 1.60-2.10 (m, 5H) ; 3.36- 3.79 (m, 2H) ; 4.53 (dd, IH, J = 3.8, 8.6) ; 4.61-4.89 (m, 2H) ; 5.96 (s, 2H) ; 6.10 (m, IH) ; 6.57 (dd, IH, J = 6.2,

15.8) ; 6.75 (d, IH, J = 8.0) ; 6.83 (dd, IH, J = 1.3, 8.0) ; 6.93 (s, IH) .

Compound 142: 3- (4, 5-methylenedioxyphenyl) -l-prop-2- (E)-enyl ( 2S) - 1- ( 3 , 3-dimethyl-l , 2-dioxopentyl ) -2- pyrrolidinecarboxylate, 82%. *H NMR (360 MHz, CDC1₃) : d 0.86 (t, 3H) ; 1.22 (s, 3H) ; 1.25 (s, 3H) ; 1.60-2.10 (m, 5H) ; 2.10-2.39 (m, IH) ; 3.36-3.79 (m, 2H) ; 4.53 (dd, IH, J = 3.8, 8.6) ; 4.61-4.89 (m, 2H) ; 5.96 (s, 2H) ; 6.10 (m, IH) ; 6.57 (dd, IH, J = 6.2, 15.8) ; 6.75 (d, IH, J = 8.0) ;

6.83 (dd, IH, J = 1.3, 8.0) ; 6.93 (s, IH) .

Compound 144: 3-cyclohexyl-l-prop-2- (E) -enyl (2S)-1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidine-carboxylate, 92%. ^XH NMR (360 MHz, CDC1₃) : d 0.86 (t, 3H) ; 1.13-1.40

(m + 2 singlets, 9H total); 1.50-1.87 (m, 8H) ; 1.87-2.44 (m, 6H) ; 3.34-3.82 (m, 2H) ; 4.40-4.76 (m, 3H) ; 5.35-5.60 (m, IH) ; 5.60-5.82 (dd, IH, J = 6.5, 16) .

Compound 145: ( IR) -1, 3-Diphenyl-l-propyl (25) -1-

(3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 90%. ^}H NMR (360 MHz, CDC1₃) : d 0.85 (t, 3H) ; 1.20 (s, 3H) ; 1.23 (s, 3H) ; 1.49-2.39 (m, 7H) ; 2.46-2.86 (m, 2H) ; 3.25-3.80 ( , 2H) ; 4.42-4.82 ( , IH) ; 5.82 (td, IH, J = 1.8, 6.7) ; 7.05-7.21 (m, 3H) ; 7.21-7.46 (m, 7H) . Compound 146: 3-phenyl-l-propyl (25) -1- ( 1, 2-dioxo-2-

[2-furanyl] ) ethyl-2-pyrrolidinecarboxylate, 99%. H NMR

(300 MHz, CDC1₃) : d 1.66-2.41 (m, 6H) ; 2.72 (t, 2H, J =

7.5); 3.75 (m, 2H) ; 4.21 (m, 2H) ; 4.61 (m, IH) ; 6.58 (m, IH) ; 7.16-7.29 (m, 5H) ; 7.73 ( , 2H) .

Compound 147: 3-phenyl-l-propyl (25) -1- ( 1, 2-dioxo-2-

[2-thienyl] ) ethyl-2-pyrrolidinecarboxylate, 81%. ^λR NMR

(300 MHz, CDC1₃) : d 1.88-2.41 (m, 6H) ; 2.72 (dm, 2H) ; 3.72 (m, 2H) ; 4.05 (m, IH) ; 4.22 (m, IH) ; 4.64 (m, IH) ; 7.13-

7.29 (m, 6H) ; 7.75 (dm, IH) ; 8.05 (m, IH) .

Compound 149: 3-phenyl-l-propyl (25) -1- ( 1, 2-dioxo-2- phenyl) ethyl-2-pyrrolidinecarboxylate, 99%. ¹H NMR (300 MHz, CDC1₃) : d 1.97-2.32 (m, 6H) ; 2.74 (t, 2H, J = 7.5);

3.57 (m, 2H) ; 4.24 ( , 2H) ; 4.67 (m, IH) ; 6.95-7.28 (m,

5H) ; 7.51-7.64 (m, 3H) ; 8.03-8.09 ( , 2H) .

Compound 150: 3- (2, 5-dimethoxyphenyl) -1-propyl (2S)- 1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 99%. ^XH NMR (300 MHz, CDC1₃) : d 0.87 (t, 3H) ; 1.22 (s, 3H) ; 1.26 (s, 3H) ; 1.69 (m, 2H) ; 1.96 (m, 5H) ; 2.24 (m, IH) ; 2.68 ( , 2H) ; 3.55 (m, 2H) ; 3.75 (s, 3H) ; 3.77 (s, 3H) ; 4.17 ( , 2H) ; 4.53 (d, IH) ; 6.72 (m, 3H) .

Compound 151: 3- (2, 5-dimethoxyphenyl) -l-prop-2- (E) - enyl (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 99%. ^XH NMR (300 MHz, CDC1₃) : d 0.87 (t, 3H) ; 1.22 (s, 3H) ; 1.26 (s, 3H) ; 1.67 (m, 2H) ; 1.78 ( ,

IH) ; 2.07 (m, 2H) ; 2.26 (m, IH) ; 3.52 (m, 2H) ; 3.78 (s, 3H) ; 3.80 (s, 3H) ; 4.54 (m, IH) ; 4.81 (m, 2H) ; 6.29 (dt, IH, J = 15.9) ; 6.98 (s, IH) . Compound 152: 2- ( 3, 4 , 5-trimethoxyphenyl) -1-ethyl (2S) -1- ( 3 , 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 97%. ^lH NMR (300 MHz, CDC1₃) : d 0.84 (t, 3H) ; 1.15 (s, 3H) ; 1.24 (s, 3H) ; 1.71 (dm, 2H) ; 1.98 (m, 5H) ; 2.24 (m, IH) ; 2.63 (m, 2H) ; 3.51 (t, 2H) ; 3.79 (s, 3H) ; 3.83 (s, 3H) ; 4.14 (m, 2H) ; 4.52 (m, IH) ; 6.36 (s, 2H) .

Compound 153: 3- (3-Pyridyl) -1-propyl (25) -1- (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 80%. ^XH NMR (CDC1₃, 300 MHz): d 0.85 (t, 3H) ; 1.23, 1.26 (s, 3H each); 1.63-1.89 (m, 2H) ; 1.90-2.30 (m, 4H) ; 2.30-2.50 (m, IH) ; 2.72 (t, 2H) ; 3.53 (m, 2H) ; 4.19 ( , 2H) ; 4.53 (m, IH) ; 7.22 (m, IH) ; 7.53 (dd, IH) ; 8.45.

Compound 154: 3- (2-Pyridyl) -1-propyl (25) -1- (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 88% . ^XH NMR (CDC1₃, 300 MHz): d 0.84 (t, 3H) ; 1.22, 1.27 (s, 3H each); 1.68-2.32 (m, 8H) ; 2.88 (t, 2H, J = 7.5); 3.52 (m, 2H) ; 4.20 (m, 2H) ; 4.51 (m, IH) ; 7.09-7.19 (m, 2H) ; 7.59 (m, IH) ; 8.53 (d, IH, J = 4.9) .

Compound 155: 3- (4-Pyridyl) -1-propyl (25) -1- (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 91%. *H NMR (CDCI₃, 300 MHz): d 6.92-6.80 (m, 4H) ; 6.28 (m, IH) ; 5.25 (d, IH, J = 5.7); 4.12 (m, IH) ; 4.08 (s, 3H) ; 3.79 (s, 3H) ; 3.30 (m, 2H) ; 2.33 (m, IH) ; 1.85-1.22 (m, 7H) ; 1.25 (s, 3H) ; 1.23 (s, 3H) ; 0.89 (t, 3H, J = 7.5).

Compound 156: 3-phenyl-l-propyl (2S)-l-(2- cyclohexyl-1, 2-dioxoethyl) -2-pyrrolidinecarboxylate, 91% . ^XH NMR (CDC1₃, 300 MHz): d 1.09-1.33 (m, 5H) ; 1.62-2.33 (m, 12H); 2.69 (t, 2H, J = 7.5); 3.15 (dm, IH) ; 3.68 (m, 2H) ; 4 . 16 (m, 2H) ; 4 . 53 , 4 . 84 (d, IH total ) ; 7 . 19 (m, 3H) ;

7 . 29 (m, 2H) .

Compound 157: 3-phenyl-l-propyl (25) -1- (2- tert- butyl-1, 2-dioxoethyl) -2-pyrrolidinecarboxylate, 92%. ^XH

NMR (CDC1₃, 300 MHz): d 1.29 (s, 9H) ; 1.94-2.03 (m, 5H) ;

2.21 (m, IH) ; 2.69 (m, 2H) ; 3.50-3.52 (m, 2H) ; 4.16 (m,

2H) ; 4.53 (m, IH) ; 7.19 (m, 3H) ; 7.30 (m, 2H) .

Compound 158: 3-phenyl-l-propyl (2S)-l-(2- cyclohexyl- ethyl-1, 2-dioxoethyl) -2-pyrrolidinecarboxylate, 97%. ^XH NMR (CDCI₃, 300 MHz): d 0.88 (m, 2H) ; 1.16 (m, 4H) ; 1.43-1.51 (m, 2H) ; 1.67 ( , 5H) ; 1.94-2.01 (m, 6H) ; 2.66-2.87 ( , 4H) ; 3.62-3.77 (m, 2H) ; 4.15 (m, 2H) ; 4.86 (m, IH) ; 7.17-7.32 (m, 5H) .

Compound 159: 3- (3-pyridyl) -1-propyl (25) -1- (2- cyclo- hexylethyl-1, 2-dioxoethyl) -2-pyrrolidinecarboxylate,

70%. ^XH NMR (CDCI₃, 300 MHz): d 0.87 (m, 2H) ; 1.16 (m, 4H) ; 1.49 (m, 2H) ; 1.68 (m, 4H) ; 1.95-2.32 (m, 7H) ; 2.71

(m, 2H) ; 2.85 (m, 2H) ; 3.63-3.78 ( , 2H) ; 4.19 (m, 2H) ;

5.30 (m, IH) ; 7.23 (m, IH) ; 7.53 (m, IH) ; 8.46 (m, 2H) .

Compound 160: 3- (3-pyridyl) -1-propyl (2S) -1- (2- tert- butyl-1, 2-dioxoethyl) -2-pyrrolidinecarboxylate, 83%. ^XH

NMR (CDCI₃, 300 MHz): d 1.29 (s, 9H) ; 1.95-2.04 (m, 5H) ;

2.31 (m, IH) ; 2.72 (t, 2H, J = 7.5); 3.52 (m, 2H) ; 4.18 (m, 2H) ; 4.52 (m, IH) ; 7.19-7.25 (m, IH) ; 7.53 (m, IH) ; 8.46 (m, 2H) .

Compound 161: 3, 3-diphenyl-l-propyl (25) -1- (3,3- dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 99% . ^XH NMR (CDCI₃, 300 MHz): d 0.85 (t, 3H) ; 1.21, 1.26 (s, 3H each); 1.68-2.04 (m, 5H) ; 2.31 (m, IH) ; 2.40 (m, 2H) ; 3.51 (m, 2H) ; 4.08 (m, 3H) ; 4.52 (m, IH) ; 7.18-7.31 (m, 10H) . Compound 162: 3- (3-pyridyl) -1-propyl (2S)-l-(2- cyclo- hexyl-1, 2-dioxoethyl) -2-pyrrolidinecarboxylate, 88%. *H NMR (CDC1₃, 300 MHz): d 1.24-1.28 (m, 5H) ; 1.88-2.35 ( , 11H); 2.72 (t, 2H, J = 7.5); 3.00-3.33 (dm, IH) ; 3.69 (m, 2H); 4.19 (m, 2H) ; 4.55 (m, IH) ; 7.20-7.24 (m, IH) ; 7.53 (m, IH) ; 8.47 (m, 2H) .

Compound 163: 3- (3-Pyridyl) -1-propyl (2S)-N-([2- thienyl] glyoxyl) pyrrolidinecarboxylate, 49%. ¹H. NMR (CDCI₃, 300 MHz): d 1.81-2.39 (m, 6H) ; 2.72 (dm, 2H) ; 3.73

(m, 2H) ; 4.21 (m, 2H) ; 4.95 (m, IH) ; 7.19 (m, 2H) ; 7.61 (m,

IH) ; 7.80 (d, IH) ; 8.04 (d, IH) ; 8.46 (m, 2H) .

Compound 164: 3, 3-Diphenyl-l-propyl (25) -1- (3,3- dimethyl-1, 2-dioxobutyl) -2-pyrrolidinecarboxylate, 99%.

^XH NMR (CDCI₃, 300 MHz): d 1.27 (s, 9H) ; 1.96 ( , 2H) ;

2.44 (m, 4H) ; 3.49 (m, IH) ; 3.64 (m, IH) ; 4.08 (m, 4H) ;

4.53 (dd, IH) ; 7.24 (m, 10H) .

Compound 165: 3, 3-Diphenyl-l-propyl (25) -1- cyclohexyl glyoxyl-2-pyrrolidinecarboxylate, 91%. ¹H NMR (CDCI₃, 300 MHz): d 1.32 (m, 6H) ; 1.54-2.41 (m, 10H) ; 3.20 (dm, IH) ; 3.69 (m, 2H) ; 4.12 (m, 4H) ; 4.52 (d, IH) ; 7.28 (m, 10H) .

Compound 166: 3, 3-Diphenyl-l-propyl (25) -1- (2- thienyl) glyoxyl-2-pyrrolidinecarboxylate, 75%. ¹R NMR (CDCI₃, 300 MHz): d 2.04 (m, 3H) ; 2.26 (m, 2H) ; 2.48 ( , IH) ; 3.70 (m, 2H) ; 3.82-4.18 (m, 3H total); 4.64 (m, IH) ; 7.25 (m, 11H) ; 7.76 (dd, IH) ; 8.03 (m, IH) .

EXAMPLE 16 General procedure for the synthesis of acrylic esters, exemplified for methyl (3, 3, 5-trimethoxy) - trans- cinnamaτe. A solution of 3, 4 , 5-trimethoxybenzaldehyde (5.0 g; 25.48 mmol) and methyl (triphenyl-phosphoranyl- idene) acetate (10.0 g; 29.91 mmol) in tetrahydrofuran (250 mL) was refluxed overnight. After cooling, the reaction mixture was diluted with 200 mL of ethyl acetate and washed with 2 x 200 mL of water, dried, and concentrated in vacuo. The crude residue was chromatographed on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 5.63 g (88%) of the cinnamate as a white crystalline solid. ^λR NMR (300 MHz; CDC1₃) : d 3.78 (s, 3H) ; 3.85 (s, 6H) ; 6.32 (d, IH, J = 16); 6.72 (s, 2H) ; 7.59 (d, IH, J = 16) .

EXAMPLE 17 General procedure for the synthesis of saturated alcohols from acrylic esters, exemplified for (3,4,5- tri ethoxy) phenylpropanol .

A solution of methyl (3, 3, 5-trimethoxy) - trans- cinnamate (1.81 g; 7.17 mmol) in tetrahydrofuran (30 mL) was added in a dropwise manner to a solution of lithium aluminum hydride (14 mmol) in THF (35 mL) , with stirring and under an argon atmosphere. After the addition was complete, the mixture was heated to 75°C for 4 hours. After cooling, it was quenched by the careful addition of 15 mL of 2 N NaOH followed by 50 mL of water. The resulting mixture was filtered through Celite to remove solids, and the filter cake was washed with ethyl acetate. The combined organic fractions were washed with water, dried, concentrated in vacuo, and purified on a silica gel column, eluting with ethyl acetate to obtain 0.86 g (53%) of the alcohol as a clear oil. *H NMR (300 MHz; CDC1₃) : d 1.23 (br, IH) ; 1.87 (m, 2H) ; 2.61 (t, 2H, J = 7.1); 3.66 (t, 2H) ; 3.80 (s, 3H) ; 3.83 (s, 6H) ; 6.40 (s, 2H) .

EXAMPLE 18 General procedure for the synthesis of trans-allylic alcohols from acrylic esters, exemplified for (3,4,5- trimethoxy) phenylprop-2- (E) -enol .

A solution of methyl (3, 3, 5-trimethoxy) - trans- cinnamate (1.35 g; 5.35 mmol) in toluene (25 mL) was cooled to -10°C and treated with a solution of diisobutylaluminum hydride in toluene (11.25 mL of a 1.0 M solution; 11.25 mmol) . The reaction mixture was stirred for 3 hours at 0°C and then quenched with 3 mL of methanol followed by 1 N HCl until the pH was 1. The reaction mixture was extracted into ethyl acetate and the organic phase was washed with water, dried and concentrated. Purification on a silica gel column eluting with 25% ethyl acetate in hexane furnished 0.96 g (80%) of a thick oil. ^XH NMR (360 MHz; CDC1₃) : d 3.85 (s, 3H) ; 3.87 (s, 6H) ; 4.32 (d, 2H, J = 5.6); 6.29 (dt, IH, J = 15.8, 5.7), 6.54 (d, IH, J = 15.8); 6.61 (s, 2H) .

EXAMPLE 19 Synthesis of (2S) -1- (3 , 3-dimethyl-l , 2-dioxopentyl) -2- pyrrolidinecarboxylate (421)

Synthesis of (2S) -1- ( 1 , 2-dioxo-2-methoxyethyl ) -2- pyrrolidinecarboxylate .

A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in dry methylene chloride was cooled to 0°C and treated with triethylamine (3.92 g; 38.74 mmol; 2.1 eq) . After stirring the formed slurry under a nitrogen atmosphere for 15 min, a solution of methyl oxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) was added dropwise. The resulting mixture was stirred at 0°C for 1.5 hr . After filtering to remove solids, the organic phase was washed with water, dried over MgS0₄ and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data for trans rotamer given. ^lH NMR (CDC1₃) : d 1.93 (dm, 2H) ; 2.17 (m, 2H) ; 3.62 (m, 2H); 3.71 (s, 3H) ; 3.79, 3.84 ( s, 3H total); 4.86 (dd, IH, J = 8.4, 3.3) . Synthesis of methyl (2S) -1- ( 1 , 2-dioxo-3 , 3-dimethylpentyl) - 2-pyrrolidinecarboxylate .

A solution of methyl (2S) -1- (1, 2-dioxo-2-methoxyethyl) -2- pyrrolidinecarboxylate (2.35 g; 10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78°C and treated with 14.2 mL of a 1.0 M solution of 1, 1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78°C for three hours, the mixture was poured into saturated ammonium chloride (100 mL) and extracted into ethyl acetate. The organic phase was washed with water, dried, and concentrated, and the crude material obtained upon removal of the solvent was purified on a silica gel column, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%) of the oxamate as a colorless oil. ^lH NMR (CDC1₃) : d 0.88 (t, 3H) ; 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H) ; 1.87-2.10 (m, 3H) ; 2.23 (m, IH) ; 3.54 (m, 2H) ; 3.76 (s, 3H) ; 4.52 (dm, IH, J = 8.4, 3.4) .

Synthesis of (2S) -1- (1 , 2-dioxo-3 , 3-dimethylpentyl) -2- pyrrolidinecarboxylic acid A mixture of methyl (2S) -1- ( 1, 2-dioxo-3, 3-dimethylpentyl) - 2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 L) , and methanol (50 mL) was stirred at 0°C for 30 min and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification. ^XH NMR (CDC1₃) : d 0.87 (t, 3H) ; 1.22, 1.25

(s, 3H each); 1.77 (dm, 2H) ; 2.02 (m, 2H) ; 2.17 (m, IH) ; 2 . 25 (m, IH ) ; 3 . 53 ( dd, 2H , J = 10 . 4 , 7 . 3 ) ; 4 . 55 ( dd, IH , J = 8 . 6 , 4 . 1 ) .

EXAMPLE 20 Synthesis of (2S) -1- (1 , 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarboxamide (318)

Isobutyl chloroformate (20 mmol, 2.7 mL) was added to a solution containing (2S ) -1- ( 1 , 2-dioxo-3 , 3- dimethylpentyl) -2-pyrrolidinecarboxylic acid (4.89 g, 20 mmol) (from Example 19) in 50 mL methylene chloride at -10°C with stirring. After 5 minutes, ammonia was added dropwise

(20 mmol, 10 mL of 2 M ethyl alcohol solution) . The reaction was warmed up to room temperature after stirring at -10 °C for 30 minutes. The mixture was diluted with water, and extracted into 200 mL methylene chloride. The organic extract was concentrated and further purified by silica gel to give 4.0 g of product as a white solid (81.8% yield). ^XH NMR (CDC1₃) : d 0.91 (t, 3H, J= 7.5); 1.28 (s,

6H, each); 1.63-1.84 (m, 2H) ; 1.95-2.22 (m, 3H) ; 2.46 (m, IH) ; 3.55-3.67 (m, 2H) ; 4.67 (t, IH, J= 7.8); 5.51-5.53

(br, IH, NH) ; 6.80 (br, IH, NH) .

EXAMPLE 21 Synthesis of (2S) -1- ( 1 , 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarbonitrile (313)

To a solution of 0.465 mL DMF (6 mmol) in 10 mL acetonitrile at 0°C was added 0.48 mL (5.5 mmol) of oxalyl chloride. A white precipitate formed immediately and was accompanied by gas evolution. When complete, a solution of 1.2 g (5 mmol) of (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) - 2-pyrrolidinecarboxamide (from Example 20) in 2.5 L acetonitrile was added. When the mixture became homogeneous, 0.9 mL (11 mmol) pyridine was added. After 5 min., the mixture was diluted into water and extracted by 200 mL ethyl acetate. The organic layer was concentrated and further purified by silica gel to give 0.8 g product as a white solid (72% yield) . ^lH NMR (CDC1₃) : d 0.87 (t, 3H, J= 7.5); 1.22 (s, 3H) ; 1.24 (s, 3H) ; 1.80 (m, 2H) ; 2.03-2.23 (m, 4H) ; 3.55 (m, 2H) ; 4.73 (m, IH) .

EXAMPLE 22 Synthesis of (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinetetrazole (314) A mixture of (2S) -1- (1> 2-dioxo-3, 3-dimethylpentyl) -2- pyrrolidinecarbonitrile (222 mg, 1 mmol) (from Example 21), NaN₃ (81 mg, 1.3 mmol) and NH₄C1 (70 mg, 1.3 mmol) in 3 mL DMF was stirred at 130°C for 16 hours. The mixture was concentrated and purified by silica gel to afford 200 mg product as white solid (75.5% yield). ^XH NMR (CDC1₃) : d 0.88 (t, 3H, J= 7.5); 1.22 (s, 6H) ; 1.68 (m, 2H) ; 2.05-2.36 (m, 3H) ; 2.85 (m, IH) ; 3.54 (m, IH) ; 3.75 (m, IH) ; 5.40 (m, IH) .

EXAMPLE 23 Synthesis of 3- (3 , 3-dimethyl-2-oxopentanoyl) -1, 3- oxazolidine-4-carboxylic acid (612) Methyl 1, 3-oxazolidine-4-carboxylate

This compound was synthesized according to the procedure found in J_^ Med. Chem. (1990) 3_3: 1459-1469. Methyl 2- \ 4 - (methoxycarbonyl) (1, 3-oxazolidin-3-yl) 1 -2- oxoacetate

To an ice cooled solution of methyl 1, 3-oxazolidine- 4-carboxylate (0.65 g, 4.98 mM) were added triethylamine (0.76 ml, 5.45 mM) and methyl oxalyl chloride (0.5 ml, 5.45 mM) . This mixture was stirred at 0°C for 2 hours. After this time the mixture was washed with water, then brine, dried with anhydrous magnesium sulfate, filtered and evaporated. The resulting pale yellow oil was flash chromatographed eluting with 30% EtOAc/hexane, 50% EtOAc/hexane, and finally 75% EtOAc/hexane . A clear oil of product (0.52 g, 48%) was obtained. Anal. (C₈H_uN0₆)C,H,N; ^JH NMR (CDC1₃, 400 MHz): d (2 rotamers 1:1) 3.78 (s, 1.5H); 3.79 (s, 1.5H); 3.87 (s, 1.5H); 3.91 (s, 1.5H); 4.14-4.36 (m, 2H) ; 4.70 (dd, 0.SH, J=4.1, 6.8); 5.08 (dd,0.5H, J=3.1,6.7); 5.10 (d, 0.5H, J=5.9); 5.27 (d, 0.5H, J=5.8); 5.36 (dd, IH, J=5.3, 17.8).

Methyl 3- (3, 3-dimethyl-2-oxopentanoyl ) -1, 3-oxazolidine-4- carboxylate

To a solution of methyl 2- [4- (methoxycarbonyl) - (1, 3- oxazolidin-3-yl) ] -2-oxoacetate (0.84 g, 3.87 mM) in THF (50 ml) cooled to -78°C was added 1, 1-dimethylpropyl-magnesium chloride (IM in THF, 8ml, 8 mM) . After 3 hrs. at -78 °C the mixture was quenched with saturated NH₄C1 (50 ml) and extracted with ethyl acetate (100 ml) . The organic layer separated, washed with brine (100 ml) , dried with anhydrous magnesium sulfate, filtered and evaporated. The resulting pale yellow oil was flash chromatographed eluting with 20% EtOAc/hexane. A clear oil (3) (0.61 g, 61%) was obtained. *H NMR (CDC1₃, 400 MHz): d 0.85 (t, 3H, J=7.5); 1.25 (s, 3H) ; 1.26 (s, 3H) ; 1.67-1.94 (m, 2H) ; 3.79 (s, 3H) ; 4.12- 4.31 (m, 2H) ; 4.64 (dd, IH, J=4.1, 6.8); 5.04 (dd, 2H, J=4.9, 9.4) .

3- (3, 3-dimethyl-2-oxopentanoyl) -1, 3-oxazolidine-4- carboxylic acid (612) Methyl 3- ( 3 , 3-dimethyl-2-oxopent anoyl ) - 1 , 3- oxazolidine-4-carboxylate (3) (0.6 g, 2.33 mM) was dissolved in MeOH (25 ml) and added LiOH (IM in water, 10 ml, 10 mM) . This mixture was stirred overnight at room temperature. The residues were evaporated and partitioned between EtOAc (50 ml) and 2N HCl (50 mL) . The aqueous layer was extracted twice more with EtOAc (2 x 25 ml) . The extracts were washed with brine (50 ml) , dried with anhydrous magnesium sulfate, filtered and evaporated. A clear oil product (0.49 g, 86%) was obtained. Anal. (C H₁₇N0₅) C, H, N; 'H NMR (CDC1₃, 400 MHz): d 0.84 (t, 3H, J=7.5); 1.25 (s, 6H) ; 1.70-1.95 (m, 2H) ; 4.22-4.29 (m, 2H) ; 4.66 (dd, IH, J=4.6, 6.5); 5.04 (dd, 2H, J=5.0, 8.9); 7.67 (bs, IH) .

EXAMPLE 24

Synthesis of (2S) -1- (N-cvclohexylcarbamoyl) pyrrolidine-2-carboxylic acid (619)

Methyl (2S) -1- (N-cyclohexylcarbamoyl ) pyrrolidine-2- carboxylate . A mixture of cyclohexyl isocyanate (3.88 g; 31 mmol), L-proline ester hydrochloride (5.0 g; 30.19 mmol), and triethylamine (9 mL) in methylene chloride (150 ml) was stirred overnight at room temperature. The reaction mixture was washed with 2 x 100 ml of 1 N HCL and 1 x 100 ml of water. The organic phase was dried, concentrated and purified on a silica gel column (50 % EtOAc/hexane) to yield the urea as a thick oil, ^XH NMR (CDC1₃, 400 MHz) : d

1.09-1.15 (m, 3H) ; 1.33 (m, 2H) ; 1.68 (m, 3H) ; 1.93-2.05

(m, 6H) ; 3.33 (m, IH) ; 3.43 (m, IH) ; 3.46 (m, IH) ; 3.73 (s, 3H); 4.39 (m, IH) ; 4.41 (m, IH) .

(2S) -1- (N-cyclohexylcarbamoyl) pyrrolidine-2-carboxylic acid (619)

Methyl (2S) -1- (N-cyclohexylcarbamoyl) pyrrolidine-2- carboxylate (3.50 g) was dissolved in methanol (60 ml), cooled to 0°C, and treated with 2N LiOH (20 ml) . After stirring overnight, the mixture was partitioned between ether and water. The ether layer was discarded and the aqueous layer was made acidic (pH 1) with IN HCl and extracted with methylene chloride. Drying and removal of the solvent provided 2.20 g of the product as a white solid, ^lH NMR (CDC1₃, 400 MHz): d 1.14-1.18 (m, 3H) ; 1.36- 1.38 (m, 2H); 1.71-1.75 ( , 3H) ; 1.95-2.04 (m, 5H) ; 2.62 (m, IH) ; 3.16 (m, IH) ; 3.30-3.33 (m, IH) ; 3.67 (m, IH) ; 4.38 (br, IH) ; 4.46 ( , IH) . EXAMPLE 25 Synthesis of (2S) -N- (benzylsulfonyl) -2- pyrrolidinecarboxylic acid (719) To a cooled (0°C) solution of proline methyl ester hydrochloride salt (5.0 g; 30.19 mmol) in 200 mL of methylene chloride was added triethylamine (35mL) and benzenesulfonyl chloride (5.75 g; 30.19 mmol) . The mixture was stirred for one hour at 0°C and then washed with 2 x 100 mL of water. The ^■ organic phase was dried and concentrated. Chromatography eluting with 50% EtOAc/hexane delivered 8.14 g (5%) of the N-sulfonamide methyl ester, which was dissolved in 120 mL of methanol, cooled to 0°C, and treated with 40 mL of 1 N lithium hydroxide. The mixture was stirred for 1 hour at 0°C and then overnight at room temperature. After making the reaction mixture acidic (pH 1) with 1 N HCl, the product was extracted into methylene chloride and dried and concentrated to yield 4.25 g of (2S) -N- (benzylsulfonyl) -2-pyrrolidinecarboxylic acid (A) as a white solid, ^τH NMR (CDC1₃, 400 MHz): d 1.85-1.90 (m, 2H) ; 2.08 ( , IH) ; 2.18 (m, IH) ; 3.04 (m, IH) ; 3.27 (m, IH) ; 4.32-4.35 (m, 2H) ; 4.45 (m, IH) ; 4.45 (m, 2H) ; 7.36 (m, 3H) ; 7.48 (m, 2H) ; 10.98 (br, IH) .

EXAMPLE 26 Synthesis of (2S) -1- (phenylmethylsulfonyl) -2- hydroxymethyl pyrrolidine (813)

To a solution of (S) - (+) -2-pyrrolidinemethanol (1.01 g, 10 mmol) and triethylamine (1.5 ml, 11 mmol) in 30 ml methylene chloride was added 1.9 g (10 mmol) a- toluenesulfonyl chloride at 0°C with stirring. The reaction was gradually warmed up to room temperature and stirred overnight. The mixture was diluted with water, and extracted into 200 ml methylene chloride. The organic extract was concentrated and further purified by silica gel to give 1.5 g product as a white solid (58.9% yield). ^XH NMR (CDCI₃) : d 01.71-1.88 (m, 4H) ; 2.05 (br, IH, OH); 3.22 (m, 2H); 3.47 (m, 2H) ; 3.67 (m, IH) ; 4.35 (s, 2H) ; 7.26- 7.44 (m, 5H, aromatic).

EXAMPLE 27

Synthesis of (2S) -1- (phenylmethyl) sulfonyl-2- pyrrolidinecarboxamide (814) To a solution of L-prolinamide (2.28 g, 20 mmol) and triethylamine (5.76 ml, 42 mmol) in 40 ml methylene chloride was added 3.92 g (20 mmol) a-toluenesulfonyl chloride at 0°C with stirring. The reaction was gradually warmed up to room temperature and stirred overnight. The mixture was diluted with water, and extracted into 200 ml methylene chloride. The organic extract was concentrated and further purified by silica gel to give 3.0 g product as a white solid (55.7% yield). ^XH NMR (CDC1₃) : d 01.89 (m, 3H) ; 2.25 (m, IH) ; 3.40 (m, IH) ; 3.50 (m, IH) ; 3.96 (m, IH) ; 4.35 (s, 2H) ; 7.39-7.45 (m, 5H, aromatic).

EXAMPLE 28

Synthesis of (2S) -1- (phenylmethyl) sulfonyl-2- pyrrolidinecarbonitrile (815) To a solution of 0.67 ml DMF (8.7 mmol) in 10 ml acetonitrile at 0°C was added 0.70 ml (8.0 mmol) oxalyl chloride. A white precipitate was formed immediately and was accompanied by gas evolution. When complete, a solution of 2.0 g (7.5 mmol) of (2S)-1-

(phenylmethyl) sulfonyl-2-pyrrolidine-carboxamide in 5.0 ml acetonitrile was added. When the mixture became homogeneous, 1.35 ml (16.5 mmol) pyridine was added. After 5 min., the mixture was diluted with water, and extracted by 200 ml ethyl acetate. The organic layer was concentrated and further purified by silica gel to give 1.5 g product as a white solid (80% yield) . ^XH NMR (CDC1₃) : d 1.92 (m, 2H) ; 2.01 (m, IH) ; 2.11 ( , IH) ; 3.45 (m, 2H) ; 4.35 (s, 2H) ; 4.65 (m, IH) ; 7.26-7.45 ( , 5H, aromatic).

EXAMPLE 29 Synthesis of (2S) -1- (phenylmethyl) sulfonyl-2- pyrrolidinetetrazole (722). A mixture of (2S) -1- (phenylmethyl) sulfonyl-2- pyrrolidinecarbonitrile (250 mg, 1 mmol), NaN₃ (81 mg, 1.3 mmol) and NH₄C1 (70 mg, 1.3 mmol) in 3 ml DMF was stirred at 130 °C for 16 hours. The mixture was concentrated and purified by silica gel to give 120 mg product as a white solid (41.1% yield). ^λH NMR (CDC1₃) : d 01.95 (m, 2H) ; 2.21 (m, IH) ; 2.90 ( , IH) ; 3.40 (m, 2H) ; 4.27 (s, 2H) ; 5.04 (m, IH) ; 7.36-7.41 (m, 5H, aromatic); 8.05 (s, IH, NH) .

EXAMPLE 30 The FKBP Neuroimmunophilin Ligand GPI-1046 Enhances Retinal Ganglion Cell Survival and Arrests Axonal Dying Back Following Optic Nerve Transection

Transection of the mammalian optic nerve results in a brief period of abortive regeneration, but the majority of axotomized neurons die and the axons from many persisting ganglion cells die back beyond the optic nerve head. The present Example was designed to examine the neuroprotective effects of GPI-1046 following optic nerve transection.

Retinal ganglion cells in adult male Sprague Dawley rats were retrogradely labeled by fluorogold injection in the LGNd and four days later the optic nerves were transected 5 mm behind the globe. Groups of animals received either GPI-1046 lOmg/kg/day s.c. or vehicle for 28 days. All experimental animals and controls were sacrificed 90 days after transection. By 90 days only - 10% of the FG labeled ganglion cell population survived but less than half of these neurons maintained axons that extended past the optic nerve head, as detected with RT97 neurofilament immunohistochemisty . GPI-1046 treatment produced a moderate degree of perikaryal neuroprotection, sparing 25% of the ganglion cell population, and preserved the axons of virtually all protected neurons in the proximal stump of the transected nerve. These results indicate that treatment with the FKBP neuroimmunophilin ligand GPI-1046 produces a fundamental alteration in the pathological process following injury to CNS tracts.

These results also demonstrate that the small molecule FKBP neuroimmunophilin ligand GPI 1046 enhances neurite outgrowth in culture, enhance peripheral nerve regeneration, and stimulate sprouting within the CNS following partial deafferentation.

EXAMPLE 31 Neuroimmunophilin Ligands Promote Recovery from the Peripheral Sensory Neuropathy Associated with Streptozotocin-induced Diabetes

Peripheral neuropathy is a common debilitating complication of Type 2 diabetes in some 30-40% of diabetic patients. Neurotrophic factors such as nerve growth factor (NGF) are known to promote survival of developing and adult neurons of the peripheral nervous system (PNS) , and have also been evaluated as treatments for diabetic peripheral neuropathy. Some of the selective ligands of the neuroimmunophilin FKBP-12 such as the small molecule GPI- 1046, have also been shown to promote repair and regeneration in the central and peripheral nervous systems (Proc. Nat'l. Acad. Sci. USA 94, 019-2024, 1997). In this Example the potential therapeutic effects of GPI-1046 were evaluated for its ability to improve sensory function in the streptozotocin-induced diabetic rat. The procedure involved using Male Wistar rats which were given a single injection of streptozotocin (65 mg/kg i.v.). Blood glucose levels were determined weekly for the first three weeks and on the last week of the experiment. Animals were evaluated weekly for signs of sensory neuropathy using the conventional hot plate and tail flick apparatus test procedures. After six weeks, treatment either with GPI-1046 or vehicle was initiated.

The results demonstrated that behavioral testing using the hot plate and the tail flick apparatus indicated improvement in latency in lesioned animals treated for 6 weeks with GPI-1046 at 10 mg/kg s.c. The results also showed that GPI-1046 ameliorates the behavioral sequelae of diabetic sensory neuropathy and may offer some relief for patients suffering from diabetic peripheral neuropathy.

EXAMPLE 32 In Vivo Hair Generation Tests With C57 Black 6 Mice

Experiment A: C57 black 6 mice were used to demonstrate the hair revitalizing properties of an N- heterocyclic derivative non-immunosuppressive neuroimmunophilin FKBP ligand, GPI 1046. Referring now to FIGS. 1 and 2 of the drawings, C57 black 6 mice, approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers. The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIGS. 2, 3 and 4, four animals per group were treated by topical administration with 20% propylene glycol vehicle (FIG. 2), 10 μM GPI 1046

(FIG. 3) or 30 μM GPI 1046 (FIG. 4) dissolved in the vehicle. The animals were treated with vehicle or GPI 1046 every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.

FIG. 2 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth. In contrast, FIG. 3 shows that animals treated with 10 μM GPI 1046 exhibited dramatic hair growth, covering greater than 90% of the shaved area in all animals. Further, FIG. 4 shows that mice treated with 30 μM GPI 1046 exhibited essentially complete hair regrowth and their shaved areas were indistinguishable from unshaven C57 black 6 mice.

Experiment B: C57 Black 6 mice were used to demonstrate the hair revitalizing properties of various low molecular weight, small molecule, N-heterocyclic derivative non-immunosuppressive neuroimmunophilin FKBP ligands. C57 Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. The animals were in anagen growth phase when shaved. Five animals per group were treated by topical administration with a vehicle, FK506, or one of the low molecular weight, small molecule, non-immunosuppressive N-heterocyclic derivative neuroimmunophilin FKBP ligands (GPI 1605, GPI 1046, GPI 1312, GPI 1572, GPI 1389, GPI 1511, or GPI 1234) to the shaved area. The animals were treated three times per week, and hair growth was evaluated 14 days after initiation of treatment. Hair growth was quantitated by the percent of shaved area covered by new hair growth, as scored by a blinded observer, on a scale of 0 (no growth) to 5 (complete hair regrowth in shaved area) . FIG. 5 shows that after 14 days, the animals treated with vehicle exhibited the beginning of hair growth in small tufts. By contrast, most of the animals treated with the low molecular weight, small molecule, non- immunosuppressive N-heterocyclic derivative neuroimmunophilin FKBP ligands exhibited dramatic hair growth.

EXAMPLE 33 In Vivo Hair Generation Test With C57 Black 6 Mice C57 black 6 mice are used to demonstrate the hair revitalizing properties of N-heterocyclic derivatives. Referring now to FIGS. 1 and 2 of the drawings, C57 black 6 mice, approximately 7 weeks old, had an area of about 2 inches by 2 inches on their hindquarters shaved to remove all existing hair. Care was taken not to nick or cause abrasion to the underlaying dermal layers. The animals were in anagen growth phase, as indicated by the pinkish color of the skin. Referring now to FIG. 2, four animals per group were treated by topical administration with 20% propylene glycol vehicle (FIG. 2), or related compounds dissolved in the vehicle. The animals were treated with vehicle or an N-heterocyclic derivative every 48 hours (3 applications total over the course of 5 days) and the hair growth was allowed to proceed for 6 weeks. Hair growth was quantitated by the percent of shaved area covered by new hair growth during this time period.

FIG. 2 shows that animals treated with vehicle exhibited only a small amount of hair growth in patches or tufts, with less than 3% of the shaved area covered with new growth.

In contrast, FIG. 3 shows that animals treated for 2 weeks with an N-heterocyclic derivative compound, i.e. compound A, compound B, and compound G, exhibited dramatic hair growth, covering greater than 25% of the shaved area in all animals for two of the compounds. FIG. 3 shows the relative hair growth on shaven C57 black 6 mice 14 days after being treated with N- carboxylic acids or carboxylic acid isosteres. The mice had a 2 x 2 inch region on their backside shaved to remove all hair. Care was taken not to nick or cause abrasion to the underlying dermal layers. Compounds at a concentration of 1 μmole per milliliter were carefully applied to the shaved area of the mice (5 mice per group) three times per week. Hair growth was evaluated 14 days after initiation of drug treatment. The relative scale for assessing hair growth is as follows:

0 = no growth;

1 = beginning of growth in small tufts;

2 = hair growth covering over <25% of shaved area; 3 = hair growth covering over >25% of shaved area, but less than 50% of shaved area;

4 = hair growth covering over >50% of shaved area, but less than 75% of shaved area;

5 = complete hair growth of shaved area.

EXAMPLE 34 In Vivo Retinal Ganglion Cell and Optic Nerve Axon Tests The extent of degeneration reduction or prevention in retinal ganglion cells and optic nerve axons was determined in a vision loss model utilizing surgical optic nerve transection to simulate mechanical damage to the optic nerve. The effects of several N-heterocyclic derivative neuroimmunophilin FKBP ligands on retinal ganglion cells neuroprotection and optic nerve axon density was determined experimentally, comparing 14 day and 28 day N-heterocyclic derivative neuroimmunophilin FKBP ligand treatments. The effects of treatment with N-heterocyclic derivative neuroimmunophilin FKBP ligands on retinal ganglion cells and optic nerve axons was correlated. Surgical Procedures

Adult male Sprague Dawley rats (3 months old, 225-250 grams) were anesthetized with a ketamine (87mg/kg) and xylazine (13mg/kg) mixture. Retinal ganglion cells were pre-labeled by bilateral stereotaxic injection of the fluorescent retrogradely transported marker fluoro-gold (FG, 0.5 microliters of 2.5% solution in saline) at the coordinates of the LGNd (4.5 millimeters post β, 3.5 millimeters lateral, 4.6 millimeters below dura). Four days later, FG labeled rats underwent a second surgery for microsurgical bilateral intraorbital optic nerve transection 4-5 millimeters behind the orbit.

Experimental animals were divided into six experimental groups of six rats (12 eyes) per group. One group received an N-heterocyclic derivative neuroimmunophilin FKBP ligand (10 milligrams per kg per day sc in PEG vehicle (20 percent propylene glycol, 20 percent ethanol, and 60 percent saline)) for 14 days. A second group received the same N-heterocyclic derivative neuroimmunophilin FKBP ligand dose for 28 days. Each treated group had a corresponding sham/surgery and transection control group which received corresponding 14 or 28 day dosing with the vehicle only.

All animals were sacrificed 90 days after optic nerve transection and perfused pericardially with formalin. All eyes and optic nerves stumps were removed. Cases were excluded from the study if the optic nerve vasculature was damaged or if FG labeling was absent in the retina. Retinal Ganglion Cell Counts Retinas were removed from eyes and prepared for wholemount analysis. For each group, five eyes with dense and intense FG labeling were selected for quantitative analysis using a 20 power objective. Digital images were obtained from five fields in the central retina (3-4 millimeters radial to optic nerve head) . FG labeled Large (>18 μm) , medium (12-16 μm) , and small (<10 μm) ganglion cells and microglia were counted in five 400 μm by 400 μm fields per case, 5 cases per group. Examination of Optic Nerves Proximal and distal optic nerve stumps were identified, measured, and transferred to 30% sucrose saline. The proximal stumps of five nerves were blocked and affixed to a chuck, and 10 micron cross sections were cut on a cryostat; one in ten sections were saved per set. Sections including the region 1-2 mm behind the orbit were reacted for RT97 neurofilament immunohistochemistry . Analysis of optic nerve axon density was performed using a 63 power oil immersion lens, a Dage 81 camera, and the Simple Image Analysis program. RT97 positive optic nerve axons were counted in three 200 μm by 200 μm fields per nerve. The area of the nerve was also determined for each case at 10 power.

As depicted graphically in Table I&II, the 14 day course of treatment with an N-heterocyclic derivative neuroimmunophilin FKBP ligand provided moderate neuroprotection of retinal ganglion cells observed 28 days after optic nerve transection. However, by 90 days after transection, only 5% of the ganglion cell population remained viable. 90 days after optic nerve transection the number of axons persisting in the proximal stump of the optic nerve represented approximately one half of the number of surviving ganglion cells in groups of animals that received vehicle alone or the 14 day course of treatment with an N- heterocyclic derivative neuroimmunophilin FKBP ligand. These results indicate that over half of the transected ganglion cell axons retract beyond the optic nerve head, and that treatment with an N-heterocyclic derivative neuroimmunophilin FKBP ligand during the first 14 days after optic nerve transection is not sufficient to arrest this retraction.

As depicted graphically in Table I&II, more prolonged treatment with an N-heterocyclic derivative neuroimmunophilin FKBP ligand during the 28 day course of treatment produced a moderate increase in retinal ganglion cell neuroprotection. Approximately 12% of the vulnerable retinal ganglion cell population was protected. A similar proportion (~50%) of optic nerve axon density sparing was also observed. These results demonstate the startling result that extending the duration of treatment with an N- heterocyclic derivative neuroimmunophilin FKBP ligand to 28 days after transection completely arrests the regression of damaged axons for essentially the entire surviving population of retinal ganglion cells.

Additional results are set forth in Tables III and IV, and Figures 5-13.

[insert blank pages for Tables I-IV, renumber tables]

Figure 5. GPI 1046 protects retinal ganglion cells against degeneration following retinal ischemia.

Retinal ganglion cells were retrogradely labeled in adult rats by bilateral injection of fluorogold in their lateral geniculate nuclei. Labeled ganglion cells in the normal rat retina appear as white profiles against the dark background (Figure 5A) . Complete retinal ischemia was produced by infusing normal saline solution into the retinal vitreous cavity of each eye until the intraocular pressure exceeded arterial blood pressure. 28 days after the ischemic episode extensive degeneration of retinal ganglion cell was evidenced by massive reduction in the density of fluorogold labeled cells (Figure 5B) . Administration of GPI 1046 (lOmg/kg, s.c.) 1 hour prior to the ischemic episode and at lOmg/kg/day for the next four days produced noticeable protection of a large proportion of the vulnerable ganglion cell population (Figure 5C) .

Figure 6. GPI 1046 prevents degeneration of optic nerve axons and myelin following retinal ischemia

Examination of the optic nerves from the same retinal ischemia cases reveals that GPI 1046 produces dramatic protection of optic nerve element from ischemic degeneration. Toluidine blue staining of epon embedded optic nerve cross sections revealed the detail of myelin sheaths (white circles) and optic nerve axons (black centers) in the normal rat optic nerve. Optic nerves from vehicle treated cases examined 28 days after a 1 hour retinal ischemic episode are characterized by a decreased density of optic nerve axons and the appearance of numerous degenerating myelin figures

(bright white filled circles) . Treatment with GPI 1046 protected the majority of optic nerve axons from degeneration and also dramatically decreased the density of degenerating myelin figures.

Figure 7. GPI 1046 provides moderate protection against retinal ganglion cell death after optic nerve transection

Complete transection of the optic nerve 5 mm from the eyeball produces massive degeneration of retinal ganglion cells, representing loss of >87% of the normal ganglion cell population 90 days after the injury (Table 1) . Few spared fluorogold pre labeled ganglion cells are present in vehicle treated cases (large white figures) among a population of small microglia that digest the debris of the degenerating cells and take up the fluorogold label (Figure 7A) . Treatment with GPI 1046 for 14 days resulted in a small but not significant increase in the density of retinal ganglion cells that survived 90 days after transection (Table 1) but treatment with GPI 1046 for the first 28 days after transection produced moderate but significant protection of 12.6% of the vulnerable ganglion cell population (Table 1, Figure 7B) .

Figure 8. GPI 1046 treatment duration significantly affects the process of optic nerve axonal degeneration after transection . Examination of optic nerve axon density in the proximal stump of the optic nerve from the same cases revealed a more dramatic protection afforded by GPI 1046 treatment. 90 days after transection few ganglion cell axons remain within the optic nerve (Figure 8B) , representing only 5.6% of the normal population. The loss of axons reflects both the death of retinal ganglion cells and the regression or "dying back" of the axons of ~ 70% of the small surviving ganglion cell population into the retina itself (Table 1) . Treatment with GPI 1046 for the first 14 days after optic nerve transection produced a small but significant 5.3% protection of optic nerve axons (Figure 8D, Table 1) , but treatment with the same dose of GPI 1046 for 28 days resulted in the protection of optic nerve axons for the vast majority (81.4%) of spared retinal ganglion cells (Figure 8C, Table 1) .

Figure 9. GPI 1046 treatment produces a greater effect on optic nerve axons than ganglion cell bodies

This summary figure shows data from Figure 7 ganglion cell protection and higher power photomicrographs of optic nerve axon protection (Figure 9A&B, upper panels). 28 day treatment with GPI 1046 produced a significant increase in the density of large, and particularly medium and small caliber optic nerve axons (Figure 9C&D, lower panels) .

Figure 10. GPI 1046 treatment for 28 days after optic nerve transection prevents myelin degeneration in the proximal s ump

Myelin basic protein immunohistochemistry labels fascicles (darker labeled 'islands') of myelinated axons in the normal optic nerve (Figure 10A, upper left) . 90 days after transection extensive degeneration of myelin is evident in vehicle treated cases, characterized by the loss of fascicular organization and the appearance of numerous large dense degenerating myelin figures (Figure 10B, upper right) . Treatment with GPI 1046 for the first 14 days after optic nerve transection did not alter the pattern of myelin degeneration (Figure IOC, lower left panel) , and yielded an insignificant 1.6% quantitative recovery in myelin density (Table 1) . Extending the GPI 1046 treatment course through the first 28 days after optic nerve transection produced a dramatic preservation of the fascicular staining pattern for myelin basic protein in the proximal stump of the optic nerve and decreased the density of degenerating myelin figures

(Figure 10D, lower right panel), representing a '70% recovery of myelin density (Table 1) .

Figure 11. 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.

Figure 12. GPI 1046 treatment for 28 days after optic nerve transection prevents myelin degeneration in the distal stump . Complete transection of the optic nerve leads to degeneration of the distal segments (axon fragments disconnected from the ganglion cell bodies) , and the degeneration of their myelin sheaths. 90 days after transection (Figure 12B) myelin basic protein immunohistochemistry reveals the near total loss of fascicular organization (present in the normal optic nerve, Figure 12A) and the presence of numerous dense degenerating myelin figures. Quantitation reveals that the cross sectional area of the transected distal stump shrinks by 31% and loses approximately 1/2 of its myelin (Table 1) . Treatment with GPI 1046 for the first 14 days after transection did not protect against shrinkage of the distal stump but did slightly increase the density of myelin, though the density of degenerating myelin figures remained high (Figure 12C, Table 1) . GPI 1046 treatment through the first 28 days produced dramatic protection of the fascicular pattern of myelin labeling, decreased the density of degenerating myelin figures, prevented cross sectional shrinkage of the distal stump of the transected nerve and maintained the myelin levels at ~99% of normal levels (Figure 12D, Table 1) .

Figure 13. 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.

Negative images of cresyl violet stained tangential retinal sections reveals perikarya in the three cellular layers (Figure 13A) . The retinae of streptozotocin treated animals administered only vehicle (Figure 13B) exhibited loss of cells from the ONL and INL, decreased thickness of the Outer plexiform layer (the dark area between ONL and INL) and a dramatic increase in the size and density of retinal blood vessels (large black circular outlines) in the INL, OPL, ONL and the photoreceptor layer (PR, the gray fuzzy area above the ONL) . GPI 1046 treatment reduced neovascularization (i.e. ' prevented the proliferation of blood vessels) in the PR, ONL, OPL and INL. Although GPI 1046 did not appear to protect against neuronal loss in the ONL, it appeared to decrease the loss of neurons in both the INL and GCL compared to streptozotocin/vehicle treated controls.

EXAMPLE 35 Efficacy of representative compounds from different immunophilin ligand series in protecting retinal ganglion cell axons from degeneration following optic nerve transection is set forth in Table V.

TABLE V Efficacy of Representative Compounds from Different Immunophilin Ligand

Series in Protecting Retinal Ganglion

Cell Axons from Degeneration Following

Optic Nerve Transection

EXAMPLE 36 Morris Watermaze/Aσing and Memory Test Procedure Aged rodents exhibit marked individual differences in performance on a variety of behavioral tasks , including two- choice spatial discrimination in a modified T-maze , spatial discrimination in a circular platform task, passive avoidance , radial maze tasks , and spatial navigation in a water pool . In all of these tasks, a proportion of aged rats or mice perform as well as the vast majority of young control animals, while other animals display severe impairments in memory function compared to young animals. For example, Fischer and colleagues showed that the proportion of rats displaying significant impairments in spatial navigation increases with age, (Fischer et al . 1991b) with 8% of all 12 month old, 45% of 18 month old, 53% of 24 month old, and 90% of all 30 month old rats displaying impairments in spatial acquisition of the Morris watermaze task relative to young controls .

Specifically, rodent spatial learning and memory decline during aging has been accepted by many investigators as an intriguing correlative animal model of human senile dementia. Cholinergic function in the hippocampus has been extensively studied as a component of spatial learning in rodents, and declining hippocampal cholinergic function has been noted in parallel with the development of learning and memory impairments. In addition, other neurotransmitter systems have been shown to contribute to spatial learning, and to decline with age, such as the dopaminergic and noradrenergic, serotonergic, and glutamatergic systems.

Also, reports on age-related deficits of hippocampal long-term potentiation (LTP) -induction, a reduction in theta rhythm frequency, a loss of experience-dependent plasticity of hippocampal place-units, and reductions in hippocampal protein kinase C are in keeping with the concept that no single underlying pathology can be identified as the cause of age-related behavioral impairment in rodents. However, the various experimental therapeutic approaches that have been undertaken to improve memory function in aged rodents have been somewhat slanted towards the cholinergic hypothesis. The Morris watermaze is widely used for assessing spatial memory formation and retention in experimental animals. The test depends on the animal's ability to utilize spatial visual information in order to locate a submerged escape platform in a water tank. It is important that the tank itself be as devoid of specific visual features as possible - thus, it is always circular in shape, the sides are kept smooth and in uniform dull colors, and the water is rendered opaque with nontoxic watercolour pigment or powdered milk. This is to ensure that the animal navigates only by the use of more distant visual cues, or by the use of intra- maze cues specifically provided by the experimenter.

The tank is filled to a level which forces the animal to swim actively. Normal mice and rats react aversively to the swimming part of the test and will climb onto, and remain on, an escape platform from which they are removed to a heated resting cage.

If the platform is visible (i.e. above the surface), animals placed in the tank will quickly learn to home in on the platform and climb out onto it. Testing with a visible platform will also ensure that the experimental animals are not blind and show sufficient motivation and stamina to perform the task, which can be important in experiments involving aged rodents. If the platform is invisible (i.e. submerged just below the surface) , normal animals learn to use distant visual cues in the test room for orientation in the test tank, and, when placed in the tank, will quickly home in on the approximate location of the platform and circle in that area until the platform is found. The animals' path, speed, and swim time are tracked with a ceiling camera for later computerized analysis. Over the course of several successive trials, spatial learning can therefore be defined as a drop of distance swum, or time elapsed, from placement in the tank until escape onto the invisible platform.

The test can be adapted to assess several aspects of spatial memory: a) acquisition of a cued task, where the animal's ability to link one visual cue directly with the escape platform depends on cortical function (i.e. a ball is suspended over the escape platform and the animal learns to follow this cue to find the platform) ; b) acquisition of a spatial task, where the animal's ability to learn the location of a submerged escape platform based on a combination of distant visual cues is dependent upon hippocampal function (i.e. the animal learns to triangulate its position in the tank by visually aligning the paper-tower dispenser with the door and ceiling lamp) ; c) retention of a successfully acquired spatial task, which is predominantly dependant on cortical function (i.e. the animal must remember the spatial location of the platform over several weeks) ; d) a hippocampus-dependant reversal task where the animals must reacquire a new spatial platform location (i.e. the platform is moved to a new location between swim trials and the animal must abandon its previous search strategy and acquire a new one) .

These different modifications of the Morris watermaze procedure can be applied in sequence to the same set of experimental animals and allow for a thorough characterization of their spatial memory performance and its decline with normal ageing. Moreover, such a series of sequential memory tests sheds some light on the functional integrity of the specific brain systems involved in the acquisition and retention of spatial memory (e.g. rats with cholinergic lesions of the hippocampus may remember a platform location acquired weeks before, but persevere over the old platform location after the platform is moved) .

EFFECTS OF CHRONIC GPI-1046 ADMINISTRATION ON SPATIAL LEARNING AND MEMORY IN AGED RODENTS

This Example shows the effects of chronic treatment with the systemically available FKBP-ligand GPI-1046 on spatial learning and memory in aged rodents.

The procedure involved using three-month old (young) and 18-19 month old male C57BL/6N-Nia (aged) mice which habituated to the well known and conventional Morris watermaze during a 4 trials/day, 3-4 day visible platform training phase. Subsequent spatial acquisition testing was conducting as follows: All mice were given 4 trials/day (block), for 5 days. Maximum swim time was 90 seconds. Aged mice were allocated to an "aged impaired" group if their performance during blocks 4 or 5 of the acquisition phase was >1 S.D. above the mean of "young" mice, and to an "aged non- impaired" group if their performance was < 0.5 S.D. above the mean of "young" mice. Aged groups were then split into statistically similar "GPI-1046" and "vehicle" groups.

Daily treatment with lOmg/kg GPI-1046 was initiated 3 days after the end of acquisition training, and continued through retention testing. Retention testing began after 3 weeks of dosing using the same methods as the acquisition phase. Swim Distances (cm) were analyzed in a 7 X 5 ANOVA including Groups and Blocks (1-5) as factors in the analysis, treating Blocks as a repeated measure.

The results showed that planned contrasts revealed that there were significant differences between the "young", and "aged impaired-vehicle and GPI-1046" treated groups at the end of the acquisition phase, F_{1 58} = 26.75, P=0.0001, and F_1-5g = 17.70, P=0.0001 respectively. While there were no significant differences between the two "aged impaired" groups, F_1-58 = 0.67, P = 0.42. During retention testing, however, "aged impaired-vehicle" treated animals performed significantly poorer than "aged impaired - GPI-1046", and "young" animals, F_lι69 = 8.11, P = 0.006, and F_1<69 = 25.45, P = 0.0001 respectively. There was no longer any statistically significant difference between the "young" and "aged impaired" - GPI-1046" treated groups during the retention phase, F_1-69 = 3.09, P = 0.08. In summary, systemic treatment with GPI-1046 significantly enhanced spatial memory performance of mice with age-related spatial memory impairments .

EXAMPLE 37

A patient is suffering from alopecia senilis. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same, may be administered to the patient.

Increased hair growth is expected to occur following treatment.

EXAMPLE 38 A patient is suffering from male pattern alopecia. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same, or a pharmaceutical composition comprising the same may be administered to the patient. Increased hair growth is expected to occur following treatment.

EXAMPLE 39 A patient is suffering from alopecia areata. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment .

EXAMPLE 40

A patient is suffering from hair loss caused by skin lesions. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

EXAMPLE 41

A patient is suffering from hair loss caused by tumors. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

EXAMPLE 42 A patient is suffering from hair loss caused by a systematic disorder, such as a nutritional disorder or an internal secretion disorder. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

EXAMPLE 43

A patient is suffering from hair loss caused by chemotherapy. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same, may be administered to the patient. Increased hair growth is expected to occur following treatment.

EXAMPLE 44 A patient is suffering from hair loss caused by radiation. A bridged heterocyclic derivative, or a pharmaceutical composition comprising the same may, be administered to the patient. Increased hair growth is expected to occur following treatment.

EXAMPLE 45

A patient is suffering from a neurodegenerative disease.

A bridged heterocyclic derivative or a pharmaceutical composition comprising the same is administered. It would be expected that the patient would improve their condition or recover.

EXAMPLE 46 A patient is suffering from a neurological disorder. A bridged heterocyclic derivative or pharmaceutical compositions comprising same is administered. It would be expected that the patient would improve their condition or recover.

EXAMPLE 47 A patient is suffering from stroke. A bridged heterocyclic derivative or pharmaceutical compositions comprising same is administered. It would be expected that the patient would improve their condition or recover.

EXAMPLE 48

A patient is suffering from Parkinson's Disease. A carboxylic acid or carboxylic acid isostere of an N- heterocyclic ring or pharmaceutical compositions comprising same is administered. It would be expected that the patient would improve their condition or recover. EXAMPLE 4 9

A patient is suffering from Alzheimer's Disease. A bridged heterocyclic derivative or pharmaceutical compositions comprising same is administered. It would be expected that the patient would improve their condition or recover.

EXAMPLE 50 A patient is suffering from a peripheral neuropathy. A bridged heterocyclic derivative or pharmaceutical compositions comprising same is administered. It would be expected that the patient would improve their condition or recover.

EXAMPLE 51

A patient is suffering from amyotrophic lateral sclerosis. A bridged heterocyclic derivative or pharmaceutical compositions comprising same is administered. It would be expected that the patient would improve their condition or recover.

EXAMPLE 52 A patient is suffering from a spinal injury. A bridged heterocyclic derivative or pharmaceutical compositions comprising same is administered. It would be expected that the patient would improve their condition or recover.

EXAMPLE 53 A patient is at risk of suffering from a neurodegenerative disease or neurological disorder. A bridged heterocyclic derivative or a pharmaceutical composition comprising the same is prophelactically administered. It would be expected that the patient would be prevented from some or all of the effects of the disease or disorder, or would significantly improve their condition or recover over patients who were not pre-treated.

EXAMPLE 54 A patient is suffering from macular degeneration. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment.

EXAMPLE 55 A patient is suffering from glaucoma, resulting in cupping of the optic nerve disc and damage to nerve fibers. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment.

EXAMPLE 56 A patient is suffering from cataracts requiring surgery. Following surgery, a pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment .

EXAMPLE 57 A patient is suffering from an impairment or blockage of retinal blood supply relating to diabetic retinopathy, ischemic optic neuropathy, or retinal artery or vein blockage. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment .

EXAMPLE 58 A patient is suffering from a detached retina. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment.

EXAMPLE 59

A patient is suffering from tissue damage caused by inflammation associated with uveitis or conjunctivitis. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment.

EXAMPLE 60 A patient is suffering from photoreceptor damage caused by chronic or acute exposure to ultraviolet light. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment.

EXAMPLE 61 A patient is suffering from optic neuritis. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment.

EXAMPLE 62

A patient is suffering from tissue damage associated with a "dry eye" disorder. A pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur following treatment. EXAMPLE 63 A topical lotion comprising the following composition may be prepared.

Into 95% ethanol are added a non-immunosuppressive N- heterocyclic derivative neuroimmunophilin FKBP ligand, α- tocopherol acetate, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye. The resulting mixture is stirred and dissolved, and purified water is added to the mixture to obtain a transparent liquid lotion.

5 ml of the lotion may be applied once or twice per day to a site having marked baldness or alopecia.

EXAMPLE 64 A topical lotion comprising the following composition shown may be prepared.

Into 95% ethanol are added a non-immunosuppressive N- heterocyclic derivative neuroimmunophilin FKBP ligand, hinokitol, ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and a dye. The resulting mixture is stirred, and purified water is added to the mixture to obtain a transparent liquid lotion.

The lotion may be applied by spraying once to 4 times per day to a site having marked baldness or alopecia.

EXAMPLE 65 An emulsion may be prepared from A phase and B phase having the following compositions.

Purified water 69.0

Perfume, dye, and preservative q.s.

The A phase and the B phase are respectively heated and melted and maintained at 80°c. Both phases are then mixed and cooled under stirring to normal temperature to obtain an emulsion.

The emulsion may be applied by spraying once to four times per day to a site having marked baldness or alopecia.

EXAMPLE 66 A cream may be prepared from A phase and B phase having the following compositions.

The A phase is heated and melted, and maintained at 70°c. The B phase is added into the A phase and the mixture is stirred to obtain an emulsion. The emulsion is then cooled to obtain a cream.

The cream may be applied once to 4 times per day to a site having marked baldness or alopecia.

EXAMPLE 67 A topical liquid comprising the following composition may be prepared.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, a non- immunosuppressive N-heterocyclic derivative neuroimmunophilin FKBP ligand, and perfume. The resulting mixture is stirred, and purified water is added to the mixture to obtain a liquid.

The liquid may be applied once to 4 times per day to a site having marked baldness or alopecia. EXAMPLE 68 A shampoo comprising the following composition may be prepared.

Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betaine lauryldimethyl-aminoacetate . Then a mixture obtained by adding 5.0 g of a non-immunosuppressive N- heterocyclic derivative neuroimmunophilin FKBP ligand, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycol distearate to 2.0 g of ethanol, followed by stirring, and 0.3 g of perfume are successively added. The resulting mixture is heated and subsequently cooled to obtain a shampoo .

The shampoo may be used on the scalp once or twice per day. This page intentionally left blank.

Claims

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 0, C(R_!)₂, S(0)_p, N, NR_1# or NR₅ atoms; V is CH, S, or N;

X is 0, CH₂ or S; m is 0 or 1;

G is

R_λ is independently hydrogen, C^Cg 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, Ar_x, Ar₄, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar_lr 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 C^C,, alkoxy, (Ar_x)_n, halo, halo- C-Cg-alkyl, carbonyl, thiocarbonyl, C^Cg thioester, cyano, imino, COOR₆ in which R₆ is independently C_x-C₉ straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, C-Cg alkoxy, C₂-C₄ alkenyloxy, Ci-Cg alkylaryloxy C^Cg aryloxy, aryl- (Ci-Cg) - alkyloxy, phenoxy, benzyloxy, thio- (C_x-C₆) -alkyl, C₁-C₆-alkylthio, sulfhydryl, sulfonyl, amino, (C₁-C₆₎-mono- or di-alkylamino, amino- (C-Cg) - alkyl, aminocarboxy, C₃-C₈ cycloalkyl, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl optionally substituted with (Arj)., C₃-C₈ cycloalkyl, Cj-Cg 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 0, NR₅, or S(0)_p; Ar_x 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, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, C^^ 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 0, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; or, R is independently a moiety of the formula:

wherein:

R₃ is independently C-C₉ straight or branched chain alkyl which is optionally substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x;

X₂ is 0 or NR₆, wherein R₆ is independently selected from the group consisting of hydrogen, C-Cg straight or branched chain alkyl, and C₂-C₆ straight or branched chain alkenyl;

R₄ is independently selected from the group consisting of phenyl, benzyl, C_!-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, C^Cs 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 C_:-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, (Ar ,, 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-C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl) ,

C-_L-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with C_x-C₄ straight or branched chain alkyl or

C₂-C₄ straight or branched chain alkenyl, (C^C, alkyl or C₂-C₄ alkenyl) -Ar₅, or Ar₅. 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 Ar₄, a bridged ring moiety, C₃-C₈ cycloalkyl, C-_L-CC, 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 subs ituent ( s ) independently selected from the group consisting of Ar₄ and C₃-C_P 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, Ci-Cg 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, imida zol idine , py r a z o 1 i dine , piperidine, and piperazine.

W and Y, independently, are 0, S, CH₂ or H₂; Z is C (R₁ ) _{2 r} 0, S, a direct bond or NR^ or, Z-Ri is independently

wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar₄, Ar_1# C^Cg straight or branched chain alkyl, or C₂-C_D 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, Ar_x and Ar₄; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C^C_g alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, -Cg ester, C_x-C₆ thioester, Cj-Cg alkoxy, C₁-C₆ alkenoxy, cyano, nitro, imino, C-Cg alkylamino, amino- ( C_λ- C₆) alkyl, sulfhydryl, thio- (C-Cg) 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 0, NR₅, or (S0)_p;

C and D' are independently hydrogen, a bridged ring moiety, Ar₅, Cj-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 S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Cj-Cg 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, 0- (C^^ alkyl), 0- (C₂-C₄ alkenyl) , and carbonyl,

J is 0, NR_l S, or (CR₁)₂;

K is a direct bond, Ci-Cg 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 Ci-Cg 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(0)_p, wherein R' ' ' is selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-

C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_!-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, Ci-Cg 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(0)_p;

K' ' is C(R₁)₂, 0, S, a direct bond or NR_1;

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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl,

C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NR_xR_yR_E, wherein R_x, R_y, and R_z are independently selected from the group consisting of Ci-Cg 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 C-_L-Cg 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 C_x-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' , S(0)_p;

L' is a direct bond, Ci-Cg 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(0)_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, Ci-Cg straight or branched chain alkyl, C^C_g 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 0, 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 heteroato (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, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C_!-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, C-Cg straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Ci-C,, 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 Ar_x 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 0, S, SO, S0₂, N, NH, and NR₂;

X is either 0 or S;

Z is either S, CH₂, CHRi or CR_XR₃;

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

R_λ and R₃ are independently Ci-Cg 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 (Ar_x)_n, Cj-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with ( r _n, C₃-C₈ cycloalkyl, C-Cg straight or branched chain alkyl or C₂-C₅ straight or branched chain alkenyl substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, and Ar₂; n is 1 or 2; R₂ is independently C^Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 C_x-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, a bridged ring moiety, and hydroxy; and

Ar_x 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,

straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C^C, 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.

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=l) 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 0 or S;

Z is selected from the group consisting of S, CH₂,

Ri and R₃ are independently selected from the group consisting of C^Cs straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, and Ar_{l r} wherein said alkyl, alkenyl or Ax₁ is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, nitro, C-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, a bridged ring moiety, hydroxy, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, amino, and Ar^

R₂ is independently selected from the group consisting of Ci-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C cycloalkyl, C,-C, cycloalkenyl, a bridged ring moiety, and Ar^- and

Ar_x is independently phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, wherein said z_λ is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, C^C_g straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-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, 0, S, SO, S0₂, 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 0 or S;

Z is S , CH₂ , CHRj or CR₁R₃ ;

R_α and R₃ are independently Ci-Cg 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 (Ar_x)_n, a bridged ring moiety, Cj-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Αr_λ ) _n, C₃-C₈ cycloalkyl, C^Cg 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 Ci-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 Α _λ 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, Cj-Cg 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.

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, 0, S, SO, S0₂, 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 0 or S;

Z is S, CH₂, CHR_X or CR₁R₃;

R_x and R₃ are independently Ci-Cg 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 (Αr₁ ) _n , Ci-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_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 straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_l 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, C_:-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and

Ar_x 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, C-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_}-^ 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.

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 0, S, SO, S0₂, N, NH, and NR₄; X is either 0 or S; Z is either S, CH₂, CHR or CR_XR₃;

W and Y are independently 0, S, CH₂ or H₂; R₁ and R₃ are independently Ci-Cg 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 (Ar_:)_n, C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar ,,, C₃-C₈ cycloalkyl, C_:-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 Ci-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 C_J-C_J straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, a bridged ring moiety, and hydroxy;

R₄ is independently either Ci-Cg 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 R₄ is either unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of halo, halo-Cj-Cg-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_!-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio-Ci-Cg-alkyl, Ci-Cg-alkylthio, sulfhydryl, amino, C^C₈- alkylamino, amino-Cj-Cg-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 ring; wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroato (s) independently selected from the group consisting of 0, 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 0, S, SO, S0₂, N, NH, and NR_X;

X is 0 or S; Z is 0, NH or F^;

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

R_x is independently Cj-Cg 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 (Ar ,,, Cj-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar ., C₃-C₈ cycloalkyl, Ci-Cg 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 C^Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain or alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 Cj-C,, straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, a bridged ring moiety, and hydroxyl; and

Ar_x 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, C-^C_^j 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.

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, 0, S, SO, S0₂, NH or NR_ι;

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;

R_λ is Ci-Cs 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 (Ar_x)_n and C^Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar^,,; n is 1 or 2;

R₂ is independently either C-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar-,; and

Ar_x 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, Ci-C₈ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_:-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.

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;

R_x 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, 0, S, SO, S0₂, NH or NR_:;

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;

Ri is independently

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 ( r^ and C^Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with (Ar_x)_n; n is 1 or 2 ;

R, is independently either Cj-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_l- and

Ar_x 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, C^C_g straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-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.

12. The compound of Claim 11, wherein: A is CH₂;

B is CH₂;

C is S, 0 or NH;

D is CH₂;

R_λ 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 0, S, SO, S0₂, N, NH, and NR;

R is independently ^Cg 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,

alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl,

Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C-C,, alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy,

sulfhydryl, amino,

amino-C_x-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;

W and Y are independently 0, S, CH₂ or H₂; R_λ is independently C-^Cg 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 (Ar _n, Cj-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chai ι_ni alkenyl substituted with (Rr^ _n, C₃-C₈ cycloalkyl, C_j-C -6_f 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 C^Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain or alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Arj, 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 Cj-C₄ straight or branched chain alkyl, C₂-C₄ straight or branched chain alkenyl, and hydroxyl; and hr₁ 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^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C^C₎ 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.

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 0, S, SO, S0₂, N, NH, and NR^- W is 0, S, CH₂, or H₂;

R is independently Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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; Ar_x 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, Cj-Cg straight or branched chain alkyl, C₂- C₅ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR_X, S, CH, CR₂, or CR^; Y is a direct bond, C_:-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 Cj-Cg 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 C^d 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, Ci-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C^d 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, Cx-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, d-C, 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 C^Cg 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 d-C₈ straight or branched chain alkyl, C,-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 C^C,. 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_X, S, SO, or S0₂;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and Rj and R₃ are independently hydrogen, C_α-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, 0, S, SO, S0₂, 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;

W is 0, S, CH₂, or H₂; R is independently d-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C_x-C₄ alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, and Ar ;

Ar_x 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, d-Cg straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR_{l f} S, CH, CR_{l f} or CR^;

Y is a direct bond, d-C 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 C-Cg 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 Cj-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 0, NH, NR₂, S, SO, or S0₂; R₂ is independently selected from the group consisting of hydrogen, C^d straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Ci-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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C^d 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 _λ- 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

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 C^d 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_l S, SO, 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^d 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, 0, S, SO, S0₂, NH or NR_:;

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 0, S, CH₂, or H₂;

R is independently C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 Ar_x; Ar_x 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 0, NH, NR_lf S, CH, CR₂, or CR^;

Y is a direct bond, C_x- ₆ straight or branched chain alkyl, or C,-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

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 d-C, 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, C^d straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_λ-C 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, C^C_g straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, Ci-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 C_λ- 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 d-Cg 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 C_x-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 0, NH, NR_X, S, SO, or S0₂;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and R_x 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 0, S, CH₂, or H₂; R is independently Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, 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 Ar_lf-

Ar_: 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, d-Cg straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NRj, S, CH, CR₂, or CR₁R₃;

Y is a direct bond, C^Cg 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

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 0, NH, NR₂, S, SO, or S0₂;

R₂ is independently selected from the group consisting of hydrogen, Ci-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C^d 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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C^d 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 C_x- 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 d-Cg 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 C^d 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_X, S, SO, or S0₂; Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R_: and R₃, independently, are hydrogen, d-C,, 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 0, S, SO, S0₂, N, NH, and NR₇; R₇ is independently either C^Cg 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-Ci-Cg-alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, a bridged ring moiety, C^d alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy,

alkylthio, sulfhydryl, amino, Ci-Cg-alkylamino,

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 0, N, and S ;

W is 0, S, CH₂, or H₂;

R is independently d-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_1Λ which is optionally substituted with one or more substituent (s) independently selected from the group consisting of C^d alkyl, C₂-C₄ alkenyl, hydroxy, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, and Ar₂;

Ar₂ 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, Cj-Cg straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

X is 0, NH, NR_X, S, CH, CR_lf or CR₁R₃;

Y is a direct bond, C^Cg 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 d-Cg 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 Cj-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 0, NH, NR₂, S, SO, or S0₂; R₂ is independently selected from the group consisting of hydrogen, C^d straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C^d 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, Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, Cx-C. alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; said tertiary amine is NR₄R₅R₆, wherein R₄, R₅, and R_fe are independently selected from the group consisting of a bridged ring moiety, or C^Cg 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 C^C_g 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 C_x-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 0, NH, NR_X, S, SO, or S0₂;

Ar is independently selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazyl, quinolinyl, and isoquinolinyl; and

R_: 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 1, 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 0, S, SO, SO,, N, NH, and NR₃;

X is either 0 or S;

Y is a direct bond, C^Cg 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-C_:-C₆-alkyl, thiocarbonyl,

ester,

C₂-C₅-alkenoxy, cyano, nitro, imino, d-Cg-alkylamino, amino-Cx-Cg-alkyl, sulfhydryl, thio-Ci-Cg- 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, C_λ-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Cι-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 Ci-Cg-alkylamino, amido, amino, amino-Cj-Cg- alkyl, azo, benzyloxy, d-Cg straight or branched chain alkyl,

alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo,

formanilido, halo,

hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-Ci-Cg-alkyl, thiocarbonyl, thiocyano, thio-Ci-Cg-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 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, C^Cg 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-C_x-C₆-alkyl, thiocarbonyl, Ci-Cg-ester, thio-d-Cg- ester, Cj-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino,

amino-d-Cg-alkyl, sulfhydryl, thio-C-Cg- 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;

C and D are independently hydrogen, Ar, Cj-Cg straight or branched chain alkyl, or C,-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, C₆- C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with d-Cg-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-Cj-Cg-alkyl, thiocarbonyl, C^Cg- ester, thio-Cj-Cg-ester, Cj-Cg-alkoxy, C,-C₆-alkenoxy, cyano, nitro, imino, C-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-Ci-Cg-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 0, NH, NR₃, S, SO, or S0₂; W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_λ is a lone pair of electrons and R₂ is selected from the group consisting of Ar, C₃-C₈ cycloalkyl, a bridged ring moiety, C_λ-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 R_x 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, Cx-Cg 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 R_λ 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, 0, S, SO, S0₂, 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 0 or S;

Y is a direct bond,

straight or branched chain alkyl, or C,-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,

thiocarbonyl, Cx-Cg-ester, thio-Cι-C₆- ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Cj-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-C_j-Cg- 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 SO,; R₃ is independently selected from the group consisting of hydrogen, C^d straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C^d 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 Cx-Cg-alkylamino, amido, amino, amino-C-C₈- alkyl, azo, benzyloxy, C^Cg straight or branched chain alkyl, C^Cg alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, Ci-Cg-ester, formanilido, halo, halo-Ci-Cg-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-Ci-Cg-alkyl, thiocarbonyl, thiocyano,

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, d-Cg straight or branched chain alkyl, or C,-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-Ci-Cg-alkyl, thiocarbonyl,

thio-Cj-Cg- ester, d-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-C-Cg-alkyl, sulfhydryl, thio-C^C₈- 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; C and D are independently hydrogen, Ar, C_j-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- C-₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with

C₂-C₆ alkenyl, hydroxy, amino, halo,

thiocarbonyl, C_j-Cg- ester, thio-Cj-Cg-ester, d-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Q-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-d-Cg-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 0, NH, NR₃, S, SO, or S0₂;

W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_x is a lone pair of electrons and R₂ is selected from the group consisting of Ar, C₃-C₈ cycloalkyl, a bridged ring moiety, d-Cg 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 R, and R₂ are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C₃-C₁₀ cycloalkyl, C₇-C₁₂ bi- or tricyclic carbocycle, Cj-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, 0, S, SO, S0₂, 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 0 or S;

Y is a direct bond, C_α-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,

thiocarbonyl, Cj-Cg-ester, thio-C_j-Cg- ester, d-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, d-Cg-alkylamino, amino-C-Cg-alkyl, sulfhydryl, thio-Ci-Cg- 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, Ci-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and d-C,, 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 Cj-Cg-alkylamino, amido, amino, amino-Ci-Cg- alkyl, azo, benzyloxy, C^Cg straight or branched chain alkyl, C_:-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, formanilido, halo, halo-Cj-C-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thio-Cx-Cg-alkyl, thiocarbonyl, thiocyano,

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, C_x-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-Ci-Cg-alkyl, thiocarbonyl, C-Cg-ester, thio-C_j-C₈- ester,

C,-C₆-alkenoxy, cyano, nitro, imino, C-Cg-alkylamino, amino-Cj-Cg-alkyl, sulfhydryl, thio-Ci-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 SO,;

C and D are independently hydrogen, Ar, C^C_g 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 d-Cg-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-Cx-Cg-alkyl, thiocarbonyl, C_ι-C_£- ester,

C,-C₆-alkenoxy, cyano, nitro, imino,

amino-Ci-Cg-alkyl, sulfhydryl, thio-Ci-Cg-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 0, NH, NR₃, S, SO, or S0₂; W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_x is a lone pair of electrons and R₂ is selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, d-Cg 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 R_x 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, C^Cg straight or branched chain alkyl, and C₂-C₅ 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

R_x 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:

(xviir

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 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-Ci-Cg-alkyl, thiocarbonyl,

thio-C_j-Cg- ester, Cj-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino,

sulfhydryl,

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, Cj-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C^d 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 Ci-Cg-alkylamino, amido, amino, amino-Ci-C₈- alkyl, azo, benzyloxy, Cj-Cc, straight or branched chain alkyl, d-Cg alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, Ci-Cg-ester, formanilido, halo, halo-d-Cg-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio,

thiocarbonyl, thiocyano, thio-Cj-Cg-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 C,-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-Ci-Cg-alkyl, thiocarbonyl,

thio-Ci-Cg- ester, d-Cg-alkoxy_, C₂-C₆-alkenoxy, cyano, nitro, imino, C_x- C₆-alkylamino, amino-C-Cg-alkyl, sulfhydryl, thio-Cj-Cg- 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;

C and D are independently hydrogen, Ar, C_j-Cg 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

C₂-C₆ alkenyl, hydroxy, amino, halo, halo-Ci-Cg-alkyl, thiocarbonyl, C_j-Cg- ester, thio-d-Cg-ester, alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Cj-Cg-alkylamino, amino-C-Cg-alkyl, sulfhydryl, thio-Cj-Cg-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 0, NH, NR₃, S, SO, or S0₂;

W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_x is a lone pair of electrons and R₂ is selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, d-Cg 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 R₂ and R₂ are, independently, selected from the group consisting of hydrogen, Ar, a bridged ring moiety, C₃-C₁₀ cycloalkyl, C₇-C₁₂ bi- or tricyclic carbocycle, C^Cg 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 R_λ 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 0, S, SO, S0₂, N, NH, and NR₃; X is either 0 or S; Y is a direct bond, C-Cg 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-Ci-Cg-alkyl, thiocarbonyl,

ester,

C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-C^C₈- 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 C^d 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

amido, amino, amino-C_j-C₈- alkyl, azo, benzyloxy, d-Cg straight or branched chain alkyl, Cj-Cg alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, C_j-C-ester, formanilido, halo, halo-C-Cg-alkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio,

thiocarbonyl, thiocyano, thio-Cj-Cg-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 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, d-Cg 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-Ci-Cg-alkyl, thiocarbonyl, Cj-Cg-ester, thio-Ci-Cg- ester, d-Cg-alkoxy, C,-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-Cj-Cg-alkyl, sulfhydryl, thio-C^C₈- 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;

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 d-Cg-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo,

ester, thio-C_x-C₆-ester,

C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-Cx-Cg-alkyl, sulfhydryl, thio-Cj-Cg-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 0, NH, NR₃, S, SO, or S0₂; W is 0 or S; and

U is either 0 or N, provided that: when U is 0, then R_τ is a lone pair of electrons and R₂ is selected from the group consisting of Ar, C₃-C₈ cycloalkyl, a bridged ring moiety, d-Cg 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 R_λ 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,

C_x-Cg 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 R_λ 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, d-Cg 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-Ci-Cg-alkyl, thiocarbonyl,

thio-C_j-Cg- ester, Ci-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-C^C₈- 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.

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 0, S, SO, S0₂, N, NH, and NR₂;

X is either 0 or S;

Y is a direct bond, C^Cg 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-Cx-Cg-alkyl, thiocarbonyl_,

thio-Cx-Cg-ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, C₁-C₆- alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-d-Cg-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;

R, is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 0, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C_α-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-Ci-Cg-alkyl, thiocarbonyl,

thio-Ci-Cg- ester,

C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-C_x-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, SO, or S0₂;

C and D are independently hydrogen, Ar, C^C_g 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, d-C₈- ester, thio-C₁-C₆-ester, d-Cg-alkoxy, C,-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-Cx-Cg-alkyl, sulfhydryl, thio-Ci-Cg-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 0, NH, NR₂, S, SO, or S0₂; and R_x is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, d-C₈ 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-C_x- Cg-alkyl, hydroxy, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl,

thio-C₁-C₆- ester,

C₂-C₆-alkenoxy, cyano, nitro, imino, amino-d-Cg-alkyl, sulfhydryl, thio-Ci-C₈- alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, or SO,

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, 0, S, SO, S0₂, 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 0 or S;

Y is a direct bond, C_x-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-C_x-Cg-alkyl, thiocarbonyl, Cj-Cg-ester, thio-d-Cg- ester, d-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Cx-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl,

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 S0₂;

R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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, C^Cg 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-Cj-Cg-alkyl, thiocarbonyl,

thio-C_x-C₆- ester, C_x-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, a ino-Ci-Cg-alkyl, sulfhydryl, thio-Ci-C₈- 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, SO, or S0₂; 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, C^Cg 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 d-Cg-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-Cj-Cg-alkyl, thiocarbonyl, C^C₈- ester, thio-Ci-Cg-ester, Cj-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Cj-Cg-alkylamino, amino-Ci-Cg-alkyl, sulfhydryl, thio-Cx-Cg-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 0, NH, NR₂, S, SO, or S0₂; and

R_x is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C^Cg 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-d- C₆-alkyl, hydroxy, trifluoromethyl, C_x-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl,

thio-d-Cg- ester, C_x-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Cj-Cg-alkylamino, amino-Cj-Cg-alkyl, sulfhydryl,

alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, or S0₂.

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, 0, S, SO, S0₂, 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 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- (Ci-Cg) -alkyl, thiocarbonyl, (Cx-Cg) -ester, thio- (C_α- C₆) -ester, (Cj-Cg) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (Ci-Cg) -alkylamino, amino- (C₁-C₆) -alkyl, sulfhydryl, thio- (Ci-Cg) -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 S0₂; R₂ is independently selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃-C_ζ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C₂-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 0, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, d-Cg 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- (Cj-Cg) -alkyl, thiocarbonyl, (C^Cg) -ester, thio- (C_x- C₆) -ester, (Cj-Cg) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (Cj-C ) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio- (Ci-Cg) -alkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR,, S, SO, or SO,;

C and D are independently hydrogen, Ar,

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 C_x-C₄ alkyl, C,-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 0, NH, NR₂ , S , SO , or SO, ; and

R_x is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_j-C₈ 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- (Ci-Cg) -alkyl, hydroxy, trifluoromethyl, Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, (Cj-Cg) -ester, thio-(C₁- C₆) -ester, (C^Cg) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (C_x-Cg) -alkylamino, amino- (Ci-Cg) -alkyl, sulfhydryl, thio- (Ci-Cg) -alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, or S0₂.

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:

(xxiir

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 0 or S; Y is a direct bond, Ci-Cg 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- (Ci-Cg) -alkyl, thiocarbonyl, (C_ι-C₆) -ester, thio-(C_ι- C₆) -ester, (Cι-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (Cj-Cg) -alkylamino, amino- (Cj-Cg) -alkyl, sulfhydryl, thio- (Ci-Cg) -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 S0₂; Z is a direct bond, d-Cg 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- (Ci-Cg) -alkyl, thiocarbonyl, (C_ι-C₆) -ester, thio- (C_x- C₆) -ester, (Cι-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (Cj-Cg) -alkylamino, amino- (Cj-Cg) -alkyl, sulfhydryl, thio- (Ci-Cg) -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, SO, or S0₂; R₂ is independently selected from the group consisting of hydrogen, C_α-C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Ci~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 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, Ci-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 C_x-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 0, NH, NR₂, S, SO, or S0₂; and

Rj is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₈ cycloalkyl, C_j-Cg 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-

(Cj-Cg) -alkyl, hydroxy, trifluoromethyl, Cj-Cg straight or branched chain alkyl, C,-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, (Cι-C₆) -ester, thio-(Cι~ C₆) -ester, (C_ι-C₆) -alkoxy, (C₂-C₆) -alkenoxy, cyano, nitro, imino, (Ci-C₆) -alkylamino, amino- (Cj-Cg) -alkyl, sulfhydryl, thio- (Cj-Cg) -alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, or S0₂.

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 0, S, SO, S0₂, N, NH, and NR₂;

X is either 0 or S;

Y is a direct bond, C_ι-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-Ci-Cg-alkyl, thiocarbonyl_, C_ι-C₆-ester, thio-Cι-C₆-ester, Ci-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Ci~C₆- alkylamino, amino-Cι-C₆-alkyl, sulfhydryl, thio-Cι-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 SO,; R, is independently selected from the group consisting of hydrogen, Ci~C₄ straight or branched chain alkyl, C₃-C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Ci-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 0, N, and S; wherein any aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, Ci-C₆ straight or branched chain alkyl, or C,-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-Cj-Cg-alkyl, thiocarbonyl, Cj-Cg-ester, thio-Ci-C₆- ester, Ci-Cg-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-C_ι-C₆-alkyl, sulfhydryl, thio-Ci-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, SO, or S0₂;

C and D are independently hydrogen, Ar, C_j-C₈ 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 Cι-C₆-alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, halo-C_ι-C₆-alkyl, thiocarbonyl, Cι~C₆- ester, thio-Ci-C₆-ester, Ci-C₆-alkoxy, C,-C₆-alkenoxy, cyano, nitro, imino, Ci-C₆-alkylamino, amino-Ci-C₆-alkyl, sulfhydryl, thio-Cι-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 0, NH, NR₂, S, SO, or S0₂; and Ri is independently selected from the group consisting of Ar, a bridged ring moiety, C₃-C₆ cycloalkyl, Cι~C₆ straight or branched chain alkyl, and C,-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-Cι~ Cg-alkyl, hydroxy, trifluoromethyl, C^Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl, Ci-C₆-ester, thio-Cι-C₆- ester, Ci-C₆-alkoxy, C₂-C₆-alkenoxy, cyano, nitro, imino, Ci-Cg-alkylamino, amino-Cj-Cg-alkyl, sulfhydryl, thio-Ci~C₆- alkyl, and sulfonyl, wherein any carbon atom of said alkyl or alkenyl is optionally replaced with 0, NH, NR₃, S, SO, or SO,.

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;

Ri is independently Cj-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said R_x is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cι-C₆ alkyl, C-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, a bridged ring moiety, and Ar₂;

Ari 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 Ar, is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cι-C₆ straight or branched chain alkyl, C₂- C₆ straight or branched chain alkenyl, C_j-C₄ alkoxy, C,-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is 0, S, CH₂ or H₂;

Y is 0 or NR₂, wherein R₂ is a direct bond to a Z, hydrogen or Ci-Cg alkyl; and each Z, independently, is C_ι-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 Ar_x, C₃-C₈ cycloalkyl, and C_j-Cg straight or branched chain alkyl or C,-C₆ straight or branched chain alkenyl substituted with C₃-C₆ cycloalkyl; or Z is the fragment

wherein:

R₃ is independently C_ι~C₉ straight or branched chain alkyl which is unsubstituted or substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x;

X₂ is 0 or NR₅, wherein R₅ is independently selected from the group consisting of hydrogen, C_ι-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, Cι-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, C_ι-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;

R_x is independently Cj-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_1Λ wherein said R_x is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C_ι-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, a bridged ring moiety, and Ar₂;

Ar_x 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 Ari is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, Cj-Cg straight or branched chain alkyl, C_>- C₆ straight or branched chain alkenyl, Ci-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

Z is Ci-Cg 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 Ar,, C₃-C₈ cycloalkyl, and Cj-Cg straight or branched chain alkyl or C,-C₆ straight or branched chain alkenyl substituted with C₃-C₈ cycloalkyl; or Z is the fragment

wherein:

R₃ is independently C_x-C₉ straight or branched chain alkyl which is unsubstituted or substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Arj,*

X₂ is 0 or NR₅, wherein R₅ is independently selected from the group consisting of hydrogen, C_ι~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, C_ι-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, C_ι~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: (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;

Z ' is the fragment

wherein:

R₃ is independently C_ι-C₉ straight or branched chain alkyl or unsubstituted Ar_x, wherein said alkyl is unsubstituted or substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x;

X₂ is 0 or NR₅, wherein R₅ is independently selected from the group consisting of hydrogen, Cj-Cg straight or branched chain alkyl, and C₂-C₆ straight or branched chain alkenyl;

R₄ is independently selected from the group consisting of phenyl, benzyl, C_ι-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, C_ι~C₅ straight or branched chain alkyl substituted with phenyl, and C₂-C₅ straight or branched chain alkenyl substituted with phenyl; and

Ar_x 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 Ar_x is unsubstituted or substituted with one or more substituent (s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, Ci~C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.

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

(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; Ri is independently C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₆ cycloalkyl, a bridged ring moiety, or Ar_x, wherein said alkyl or alkenyl is unsubstituted or substituted with C₃-C₆ cycloalkyl or Ar,; Ar_x and Ar, 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 Ci-Cg alkyl; each Z, independently, is hydrogen, Cι-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 Cj-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 0, S, SO, S0₂, N, NH, and NR;

R is independently either C_ι~C₉ straight or branched chain alkyl, C,-C₉ straight or branched chain alkenyl, C₃-C_& cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein R is independently either unsubstituted of substituted with one or more substituent (s) independently selected from the group consisting of halo, halo- (C_x-C₆) - alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_ι~C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio- (Cι-C₆) -alkyl, alkylthio, sulfhydryl, amino, (Cι-C₆) -alkylamino, amino- (C_x-C₆) -alkyl, aminocarboxyl, a bridged ring moiety, and Ar₂;

R_x is independently C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₅ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_:, wherein said R_λ is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Cι-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, a bridged ring moiety, and Ar₂; Ar_x 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 C_ι-C₆ alkyl; and each Z, independently, is C_ι-C₆ straight or branched chain alkyl, or C,-C₆ straight or branched chain alkenyl, wherein said Z is substituted with one or more substituent (s) independently selected from the group consisting of Ar_x, C₃-C₈ cycloalkyl, and C_x-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 Cj-Cg straight or branched chain alkyl which is unsubstituted or substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x;

X₂ is 0 or NR₅, wherein R₅ is independently selected from the group consisting of hydrogen, C_ι-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, C_ι-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, a bridged ring moiety, C_ι-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 i s CH₂ , 0 , NH , or N- ( C₁-C₄ al kyl ) ;

B and D are independently hydrogen, a bridged ring moiety, Ar, C₅-C₇ cycloalkyl substituted C_x-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkenyl substituted C_λ-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl, or Ar substituted C_ι-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 S0₂ in chemically reasonable substitution patterns, or the fragment

wherein Q is hydrogen, C_x-C₆ straight or branched chain alkyl, or C,-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, 0- (C_x-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, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (Cj-C, straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl) , 0-benzyl, O-phenyl, amino, 1, 2-methylenedioxy, carbonyl, and phenyl;

L is either hydrogen or ϋ; 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, 0- (Cι-C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl), Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cι~C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (C_j-C₄ alkyl or C₂-C₄ alkenyl) -Ar, or Ar;

J is hydrogen, C_x or C₂ alkyl, or benzyl; K is Cι~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 S0₂.

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

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

A is 0, NH, or N- (C_x-C₄ alkyl);

B is hydrogen, CHL-Ar, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, Ar substituted C_ι-C₆ alkyl or C₂-C₆ alkenyl, or

wherein L and Q are independently hydrogen, C_x-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, 0- (C_ι~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, 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, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (C_x-C₄ straight or branched chain alkyl), O- (C₂-C₄ straight or branched chain alkenyl), 0- 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, 0- (C_ι~C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl), C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C,-cycloalkyl, C₅-C₇ cycloalkenyl substituted with C_x-C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, 2-indolyl, 3- indolyl, (C_x-C₄ alkyl or C₂-C₄ alkenyl) -Ar, or Ar; J is hydrogen, C_x or C₂ alkyl, or benzyl;

K is C_x-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 S0₂.

45. The compound of claim 43, 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 atom(s) 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:

(LVIII)

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

V is CH, N, or S;

R is independently either C_x-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein R is independently either unsubstituted of substituted with one or more substituent (s) independently selected from the group consisting of halo, halo (C_x-C₆) - alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C_j-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_ι~C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio- (Cι-C₆) -alkyl, (Cι~C₆) -alkylthio, sulfhydryl, amino, (Cι-C₆) -alkylamino, amino- (Cι-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 heteroato (s) independently selected from the group consisting of 0, N, and S ; m is 0-3 ;

A is CH₂ , 0 , NH , or N- ( C_x-C₄ alkyl ) ;

B and D are independently hydrogen, a bridged ring moiety, Ar, C₅-C₇ cycloalkyl substituted C_j-Cg straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkenyl substituted C_ι-C₆ straight or branched chain alkyl or C₂-C₆ straight or branched chain alkenyl, or Ar substituted Cι-C₆ straight or branched chain alkyl or C,-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 S0₂ in chemically reasonable substitution patterns, or the fragment

wherein Q is hydrogen, Cι-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, 0- (Cι~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, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (C_x-C₄ straight or branched chain alkyl), 0- (C₂-C₄ 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, 0- (Cι~C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl), Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cι~C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (C_ι~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 S0₂.

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 , 0 , NH , or N- ( Cι-C₄ al kyl ) ;

B and D are independently Ar, a bridged ring moiety, hydrogen, Ci~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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Cι-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-(Ci-C₄ alkyl), 0-(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, Ci~C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (C_ι~C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl), 0-benzyl, O-phenyl, 1, 2-methylenedioxy, amino, carboxyl, and phenyl;

E is Ci-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with C_x-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 0, S, SO, or S0₂; 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=l) 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, Ci~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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Ci-Cg 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-(Ci-C₄ alkyl), 0- (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, Cι-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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Cι-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-C₄ alkyl), 0- (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, Cι~C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C_ι~C₄ straight or branched chain alkyl), 0-(C₂-C₄ straight or branched chain alkenyl), O-benzyl, O-phenyl, 1, 2-methylenedioxy, amino, carboxyl, and phenyl; E is Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cj-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, Cι-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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Cι-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- (Cι~C₄ alkyl), 0-(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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (C_x-C₄ straight or branched chain alkyl), 0-(C₂-C₄ straight or branched chain alkenyl), O-benzyl, O-phenyl, 1, 2-methylenedioxy, amino, carboxyl, and phenyl;

E is C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cι~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:

^'LXIII

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

V is CH, N, or S;

A is CH₂, 0, NH, or N- (C_x-C₄ alkyl);

B and D are independently Ar, a bridged ring moiety, hydrogen, C_x-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-C- 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 0, S, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, C_x-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- (C_x-C₄ alkyl), 0-(C₂-C₄ alkenyl), and carbonyl; provided that both B and D are not hydrogen;

R is independently either Cι-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein R is independently either unsubstituted of substituted with one or more substituent (s ) independently selected from the group consisting of halo, halo(C_x-C₆)- alkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thio- (Cι-C₆) -alkyl, (Cι-C₆) -alkylthio, sulfhydryl, amino, (C_ι-C₆) -alkylamino, amino- (C_x-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 0, N, and S; E is C_:-C₆ straight or branched chain alkyl, C,-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with C_x-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 containing one or more heteroato (s) selected from the group consisting of 0, S, SO, S0₂, 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 0 or S;

Ri is independently selected from the group consisting of Cj-Cg straight or branched chain alkyl, C,-C₉ straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, or heterocycle; D is a bond, or a C_x-Cι₀ straight or branched chain alkyl, C₂-Cι₀ alkenyl or C,-Cι₀ alkynyl; and

R, 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, -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-Ci-Cg-alkyl, thiocarbonyl, Cj-Cg-alkoxy, C₂-C₆- alkenoxy, C_x-C₆-alkylaryloxy, aryloxy, aryl- C_x-C₆-alkyloxy, cyano, nitro, imino, C_x-C₆-alkylamino, amino- C_x-C₆-alkyl, sulfhydryl, thio- C_x-C₆-alkyl, C_ι-C₆-alkylthio, sulfonyl, Ci-Cg 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 R⁴ is hydrogen or Cj-Cg 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, 0, 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 L,, L₂, L₃, or L₄, in which

and Ri and E, independently, are selected from the group consisting of hydrogen, Cι-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 (Cι~C₆) -alkyl, thiocarbonyl, (Cj-Cg) -alkoxy, (C₂-C₆) -alkenoxy, (Cj-Cg) -alkylaryloxy, aryloxy, aryl- (C_x-C₆) - alkyloxy, cyano, nitro, imino, (C_x-C₆)- alkylamino, amino- (Cι-C₆) -alkyl, sulfhydryl, thio- (Ci-Cg) -alkyl, (Cι-C₆) -alkylthio, sulfonyl, Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or CO,R⁴ where R⁴ is hydrogen or Cj-Cg 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;

Ri and A are independently selected from the group consisting of hydrogen, Cι-C₉ straight or branched chain alkyl, C,-C₉ straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, and heterocycle;

D is a bond, or a Cι-C₁₀ straight or branched chain alkyl, C₂-C₁₀ alkenyl or C₂-Cι₀ 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 (C_α-C₆) -alkyl, thiocarbonyl, (C_ι-C₆) -alkoxy, (C₂-C₆) -alkenoxy, (Ci-Cg) -alkylaryloxy, aryloxy, aryl- (C,-C₆) - alkyloxy, cyano, nitro, imino_, (C_x-C₆) - alkylamino, amino- (C_ι~C₆) -alkyl, sulfhydryl, thio- (Ci-Cg) -alkyl, (Cι-C₆) -alkylthio, sulfonyl, Ci-Cg 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 R⁴ is hydrogen or Cj-Cg 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:

(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;

Ri is independently selected from the group consisting of hydrogen, C_x-C₉ straight or branched chain alkyl, C,-C₉ straight or branched chain alkenyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, or heterocycle;

D is a bond, or a C_x-C_xo straight or branched chain alkyl, C₂-Cι₀ alkenyl or C₂-C_ι0 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- (C_ι-C₆) -alkoxy, thiocarbonyl, (C_x- C₆)-alkoxy, (C₂-C₆) -alkenyloxy, (C_x-C₆) - alkylaryloxy, aryloxy, aryl- (C_x-C₆) -alkyloxy, cyano, nitro, imino, (Ci~C₆) -alkylamino, amino- (C_x-C₆) -alkyl, sulfhydryl, thio- (C_x-C₆) alkyl, (C_x- C₆) -alkylthio, sulfonyl, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, aryl, heteroaryl, carbocycle, heterocycle, or C0₂R⁴ where R⁴ is hydrogen or C_x-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 0, C(R_ι)₂, S(0)_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

Ri is independently hydrogen, Cj-C₉ straight or branched chain alkyl, or C,-C₉ straight or branched chain alkenyl or alkynyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, a carboxylic acid or carboxylic acid isostere, N(R₄)_n, Ar_:, Ar₄, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar , 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 Cj-C₄ alkoxy, (Ar_ι)_n, halo, halo- Cj-Cg-alkyl, carbonyl, thiocarbonyl, C_j-Cg thioester, cyano, imino, COOR₆ in which R₆ is independently C_ι~C₉ straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, Cι-C₆ alkoxy, C₂-C₄ alkenyloxy, Ci-Cg alkylaryloxy Cι-C₆ aryloxy, aryl- (C_j-Cg) - alkyloxy, phenoxy, benzyloxy, thio- (C_x-C₆) -alkyl, Cj-Cg-alkylthio, sulfhydryl, sulfonyl, amino, (Ci-Cg_j-mono- or di-alkylamino, amino- (Cj-Cg) - alkyl, aminocarboxy, C₃-C₈ cycloalkyl, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl optionally substituted with ( r_ι)_n, C₃-C₈ cycloalkyl, Cι-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 0, NR₅, or S(0)_p;

Ari 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, Cι~C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, Cι~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 0, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; or, Ri is independently a moiety of the formula:

wherein:

R₃ is independently C_x-C₉ straight or branched chain alkyl which is optionally substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar ;

X₂ is 0 or NR₆, wherein R₆ is independently selected from the group consisting of hydrogen, Cj-Cg straight or branched chain alkyl, and C₂-C₆ straight or branched chain alkenyl;

R₄ is independently selected from the group consisting of phenyl, benzyl, Cι~C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, Cι-C₅ straight or branched chain alkyl substituted with phenyl, C₂-C straight or branched chain alkenyl substituted with phenyl, and a bridged ring moiety;

R₂ is independently Cj-Cg straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_:, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, (Ar_x)_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, 0-(Cj-C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl) ,

Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cι~C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (Cj-C₄ alkyl or C₂-C₄ alkenyl) -Ar₅, or Ar₅. 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 Ar₄, a bridged ring moiety, C₃-C₈ cycloalkyl, Ci-Cg 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-Cι₀ cycloalkyl, a C₇-Ci₂ bi- or tri-cyclic carbocycle,

Cι-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, imida zol idine , py r a z o 1 idine , piperidine, and piperazine. W and Y, independently, are 0, S, CH, or H₂; Z is C(Ri)₂, 0, S, a direct bond or NRi,- or, Z-R_j is independently

wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar₄, Ar_2, Cj-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, Ar_: and Ar₄; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cι-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, Cι-C₆ ester, Cι-C₆ thioester, Ci-Cg alkoxy, Cι-C₆ alkenoxy, cyano, nitro, imino, Cι-C₆ alkylamino, amino- (Ci- Cg) alkyl, sulfhydryl, thio- (Cι-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 0, NR₅, or (SO)_p;

C and D' are independently hydrogen, a bridged ring moiety, Ar₅, C_ι-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 heteroato (s) independently selected from the group consisting of oxygen, sulfur, SO, and S0₂ in chemically reasonable substitution patterns, or

wherein

Q is hydrogen, C_ι~C₆ straight or branched chain al kyl , 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, 0-(Cι~C₄ alkyl), 0-(C₂-C₄ alkenyl), and carbonyl,

K is a direct bond, Cι-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 Cj-Cg 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 Cι~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(0)_p, wherein R' ' ' is selected from the group consisting of hydrogen, Cj-C₄ straight or branched chain alkyl, C₃-

C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Cι-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, Cι-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(0)_p;

K" is C(Ri)₂, 0, S, a direct bond or Rι_;

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, Ci~C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl,

Ci~C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; and wherein said tertiary amine is NR_κR_yR_z, wherein R_x, R_y, and R_z are independently selected from the group consisting of Ci-Cg 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 Cι-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 C_x-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' , S(0)_p;

L' is a direct bond, Cι~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(0)_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, a ido, amino, aminoalkyl, azo, benzyloxy, Cj-Cg straight or branched chain alkyl, Cι-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 0, 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, Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0- (Cι~C₄ straight or branched chain alkyl), 0- (C₂- C₄ straight or branched chain alkenyl), O-benzyl, 0-phenyl, amino, 1, 2-methylenedioxy, carbonyl, and phenyl; and R₅ is independently selected from the group consisting of hydrogen, Cι-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Ci~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 Ar_x 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, C_x or C₂ alkyl, or benzyl and B is Ci-

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 0, C(Rι)₂, S(0)_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

Ri is independently hydrogen, C_ι-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, Ar_x, Ar₄, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Rr_{l r} 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 Cι~C₄ alkoxy, (Arι)_n, halo, halo- Ci-Cg-alkyl, carbonyl, thiocarbonyl, Cι-C₆ thioester, cyano, imino, COOR₆ in which R₆ is independently Cι-C₉ straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, Cι~C₆ alkoxy, C₂-C₄ alkenyloxy, Ci-Cg alkylaryloxy Cι-C₆ aryloxy, aryl- (Cι-C₆) - alkyloxy, phenoxy, benzyloxy, thio- (Cι-C₆) -alkyl, Ci-Cg-alkylthio, sulfhydryl, sulfonyl, amino, (Ci-Cg, -mono- or di-alkylamino, amino- (C_ι-C₆) - alkyl, aminocarboxy, C₃-C₈ cycloalkyl, C_ι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl optionally substituted with (Arι)_n, C₃-C₈ cycloalkyl, Cι-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 0, NR₅, or S(0)_p;

Αr₁ 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, Cι~C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, Ci~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 0, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; or, Ri is independently a moiety of the formula:

wherein :

R₃ is independently Cj-C₉ straight or branched chain alkyl which is optionally substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or Ar_x;

X₂ is 0 or NR₆, wherein R₆ is independently selected from the group consisting of hydrogen, Cι~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, Cι-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, Cj-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 Cι-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, (Ar₂)_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, 0-(Cι~C₄ straight or branched chain alkyl), 0-(C₂-C₄ straight or branched chain alkenyl) , Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cι~C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (C_α-C₄ alkyl or C₂-C₄ alkenyl) -Ar₅, or Ar₅.

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 Ar₄, a bridged ring moiety, C₃-C₈ cycloalkyl, Cj-Cg 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-Cι₀ cycloalkyl, a C₇-Cι₂ bi- or tri-cyclic carbocycle, Cι~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, imidazol idine , pyr a z o 1 i di ne , piperidine, and piperazine. W and Y, independently, are 0, S, CH₂ or H₂; Z is C(Rι)₂, 0, S, a direct bond or NR_X; or, Z-Ri is independently

wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar₄, Ar_lf Cι-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, Ar_x and Ar₄; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cι-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, Cι-C₆ ester, C_ι-C₆ thioester, Ci~C₆ alkoxy, Cι~C₆ alkenoxy, cyano, nitro, imino, Cι-C₆ alkylamino, amino- (Cι~ C₆) alkyl, sulfhydryl, thio- (Cι-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 0, NR₅, or

(SO)_p; C and D' are independently hydrogen, a bridged ring moiety, Ar₅, Cι~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 S0₂ in chemically reasonable substitution patterns, or

wherein

Q is hydrogen, C_ι-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, 0-(C_ι~C₄ alkyl), 0- (C₂-C₄ alkenyl) , and carbonyl,

K is a direct bond, Ci-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 C_ι~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 Cι~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(0)_p, wherein R' ' ' is selected from the group consisting of hydrogen, Cι~C₄ straight or branched chain alkyl, C₃-

C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Ci~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, Cj-Cg 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(0)_p; K" is C(Rι)₂, 0, S, a direct bond or NR_1;

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, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, Cι~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 Cj-Cg 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 Cι-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 C_ι~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' , S(0)_p;

L' is a direct bond, Cι~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(0)_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, C_ι-C₉ straight or branched chain alkyl, C_ι-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 0, 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, C_j-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C_x-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, Cι-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Cι~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 Ar_x 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.

64. 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, C_: or C₂ alkyl, or benzyl and B is C_ι~ 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 0, C(R_X)₂, S(0)_p, N, NR_X, or NR₅ atoms;

V is CH, S, or N;

X is 0, CH₂ or S; m is 0 or 1;

G is

Ri is independently hydrogen, C_ι~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, Ar_x, Ar₄, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, hr_{l r} 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 C_x-C₄ alkoxy, (Ar _n, halo, halo- Ci-Cg-alkyl, carbonyl, thiocarbonyl, Cι-C₆ thioester, cyano, imino, COOR₆ in which R₆ is independently Cι~C₉ straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, Cι-C₆ alkoxy, C₂-C₄ alkenyloxy, Ci-C₆ alkylaryloxy Cι-C₆ aryloxy, aryl- (Cι-C₆) - alkyloxy, phenoxy, benzyloxy, thio- (Cι-C₆) -alkyl, Cι-C₆-alkylthio, sulfhydryl, sulfonyl, amino, (Cι-C₆₎-mono- or di-alkylamino, amino- (C_ι~C₆) - alkyl, aminocarboxy, C₃-C₈ cycloalkyl, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl optionally substituted with (Arι)_n, C₃-C₈ cycloalkyl, Cj-Cg 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 0, NR₅, or S(0)_p;

Ar_x 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, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, Cj-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 0, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; or, Ri is independently a moiety of the formula:

wherein:

R₃ is independently C_ι~C₉ straight or branched chain alkyl which is optionally substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or

Ar_x;

X₂ is 0 or NR₆, wherein R₆ is independently selected from the group consisting of hydrogen, Cj-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, C_ι~C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, C_ι-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 Cj-C₉ straight or branched chain alkyl , C₂-C₉ straight or branched chain alkenyl , C₃-C₈ cycloalkyl , C₅-C₇ cycloalkenyl, a bridged ring moiety, or Ar_x, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, (Ar_j)_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, 0- (Cj-C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl), Ci-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cι~C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (Cj-C₄ alkyl or C₂-C₄ alkenyl) -Ar₅, or Ar₅. 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 Ar₄, a bridged ring moiety, C₃-C₈ cycloalkyl, Cι~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-C_ι0 cycloalkyl, a C₇-Ci₂ bi- or tri-cyclic carbocycle, Cι~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, imida zol idine , pyr a z o 1 i dine , piperidine, and piperazine. W and Y, independently, are 0, S, CH, or H₂; Z is C(Rj)₂, 0, S, a direct bond or NR_X; or, Z-Ri is independently

wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar₄, Ar_x, Cj-Cg 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, Ar_x and Ar₄; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cι-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, Cι-C₆ ester, Cι-C₆ thioester, Ci-C₆ alkoxy, Cj-Cg alkenoxy, cyano, nitro, imino, Cι~C₆ alkylamino, amino- (Ci- Cg) alkyl, sulfhydryl, thio- (C_x-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 0, NR₅, or (SO)_p;

C and D' are independently hydrogen, a bridged ring moiety, Ar₅, Cι-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 S0₂ in chemically reasonable substitution patterns, or

wherein Q is hydrogen, Cι-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, 0-(Cι~C₄ alkyl), 0-(C₂-C₄ alkenyl) , and carbonyl,

K is a direct bond, Cι-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 C_ι-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 Cι~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(0)_p, wherein R' ' ' is selected from the group consisting of hydrogen, Cι~C₄ straight or branched chain alkyl, C₃-

C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and Cj-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, Cι-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(0)_p;

K" is C(Ri)₂, 0, S, a direct bond or NR_1;

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, C_ι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl,

Cι~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 R₂ are independently selected from the group consisting of Ci-Cg 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 C_x-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 C_x-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' , S(0)_p;

L' is a direct bond, Cι-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(0)_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, Ci~C₉ straight or branched chain alkyl, C_j-C₈ 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 0, 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, C_ι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(Cι-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, Cι-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_ι~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 Ar₂ 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; 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.

79. The method of claim 74, which is improving naturally-occuring 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 0, C(R_ι)₂, S(0)_p, N, NR_lr or NR₅ atoms;

V is CH, S, or N;

X is 0, CH₂ or S; m is 0 or 1;

G is

Ri is independently hydrogen, C_t-Cg 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, Αr_{l r} Ar₄, a bridged ring moiety, or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl, alkynyl, alkenyl, Ar_x, 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 C_ι~C₄ alkoxy, (Arι)_n, halo, halo- Cj-Cg-alkyl, carbonyl, thiocarbonyl, Cι~C₆ thioester, cyano, imino, COOR₆ in which R₆ is independently Cj-C₉ straight or branched chain alkyl or alkenyl, hydroxy, nitro, trifluoromethyl, Cι~C₆ alkoxy, C₂-C₄ alkenyloxy, Ci-Cg alkylaryloxy Cι-C₆ aryloxy, aryl- (Cι-C₆) - alkyloxy, phenoxy, benzyloxy, thio- (Cι-C₆) -alkyl, Ci-Cg-alkylthio, sulfhydryl, sulfonyl, amino, (C_ι-C₆₎-mono- or di-alkylamino, amino- (Cι-C₆) - alkyl, aminocarboxy, C₃-C₈ cycloalkyl, Cι-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl optionally substituted with (Arι)_n, C₃-C₈ cycloalkyl, Cι-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 0, NR₅, or S(0)_p;

Ar_x 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, Cj-Cg straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, C_x-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 0, N, and S, and, wherein any aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; or, Ri is independently a moiety of the formula:

wherein: R₃ is independently C_ι~C₉ straight or branched chain alkyl which is optionally substituted with C₃-C₈ cycloalkyl, a bridged ring moiety, or

X₂ is 0 or NR₆, wherein R₆ is independently selected from the group consisting of hydrogen, C_ι~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, C_ι-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chain alkenyl, C_ι~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 C_ι-C₉ straight or branched chain alkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, a bridged ring moiety, or hr_{l r} wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl, or bridged ring moiety, is optionally substituted with one or more substituents selected from the group consisting of Ci-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, (Ar_x)_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, 0- (C_ι~C₄ straight or branched chain alkyl), 0- (C₂-C₄ straight or branched chain alkenyl) , Ci-C straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₅-C₇ cycloalkyl, C₅-C₇ cycloalkenyl substituted with Cι~C₄ straight or branched chain alkyl or C₂-C₄ straight or branched chain alkenyl, (Cι~C₄ alkyl or C₂-C₄ alkenyl) -Ar₅, or Ar₅. 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 Ar₄, a bridged ring moiety, C₃-C₈ cycloalkyl, Cι~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-C_ι0 cycloalkyl, a C₇-Ci₂ bi- or tri-cyclic carbocycle, C_ι~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, imi da zol idine , pyra z ol idine , piperidine, and piperazine. W and Y, independently, are 0, S, CH₂ or H₂;

Z is C(R_ι)₂, 0, S, a direct bond or NR_X; or, Z-Ri is independently

wherein:

C and D are, independently, hydrogen, a bridged ring moiety, Ar₄, Ar_lf C_ι-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, Ari and Ar₄; wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with Cι~C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, Cι~C₆ ester, Cι-C₆ thioester, Cι-C₆ alkoxy, Cι~C₆ alkenoxy, cyano, nitro, imino, Cι~C₆ alkylamino, amino- (C_x- C₆) alkyl, sulfhydryl, thio- (Cι-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 0, NR₅, or

(S0)_p; C and D' are independently hydrogen, a bridged ring moiety, Ar₅, Cι-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 S0₂ in chemically reasonable substitution patterns, or

wherein

Q is hydrogen, Cj-Cg 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, 0-(Cι~C₄ alkyl), 0- (C₂-C₄ alkenyl) , and carbonyl,

K is a direct bond, C_x-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 C_x-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 C_x-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(0)_p, wherein R" ' is selected from the group consisting of hydrogen, C_x-C₄ straight or branched chain alkyl, C₃- C₄ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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, C_ι-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(0)_p;

K" is C(Ri)₂, 0, S, a direct bond or NR_X. 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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C_x-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 C_x-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 C_x-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 C_x-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' , S(0)_p; L' is a direct bond, C_x-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(0)_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, C_x-C₉ straight or branched chain alkyl, C_x-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 0, 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, C_x-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chain alkenyl, 0-(C_x-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, C_x-C₆ straight or branched chain alkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, a bridged ring moiety, and C_x-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 Ar_x group.