Receptor modulators and methods

Abstract

The present invention relates to compounds useful in the modulation of the sigma-1 receptor (S1R). The present invention also relates to the use of these compounds in the treatment of sigma-1 receptor (S1R) associated diseases and disorders, for instance, diseases and disorders associated with ER stress, and diseases and disorders which would benefit from sigma-1 receptor (S1R) activation.

Description

RECEPTOR MODULATORS AND METHODSFIELD

[0001] The present invention relates generally to compounds useful in the modulation of the sigma-1 receptor. The present invention also relates to the use of these compounds in the treatment of sigma-1 receptor mediated diseases and disorders, such as disorders associated with ER stress.DESCRIPTION OF RELATED ART

[0002] The sigma- 1 receptor (olR or SIR), one of two sigma receptor subtypes, is encoded by the SIGMAR1 gene and is located as a transmembrane protein in the endoplasmic reticulum (ER) membrane. The SIR has been described to be involved in a large number of cellular activities. Its most widely studied role is the regulation of cellular calcium levels. One such regulatory function relates to the phenomenon of store operated calcium entry (SOCE). Under conditions of depleted endogenous calcium stores (especially the endoplasmic reticulum), extracellular calcium will lead to a strong influx of calcium into the cytoplasm by opening the Orail calcium channel in the plasma membrane. In this scenario, SIR expression and / or activation by SIR agonists inhibits excessive calcium influx into the cytoplasm, while the absence of SIR or its inhibition by antagonists will increase calcium influx. The SIR has been associated with a variety of functions based on its chaperone activity that range from neuroprotection, protection against ER stress, supporting growth factor signalling, regulating immune function, to cellular ion homeostasis. Specifically, the SIR modulates Calcium ion (Ca2+) homeostasis by interacting with several calcium channels in the ER and plasma membranes such as ORAI1 channels and inositol 1,4,5-triphosphate (IP3) receptor. Ca2++ homeostasis plays a complex role in orchestrating diverse cellular processes, including cell death and survival.

[0003] The SIR is widely expressed in many different tissue types but is particularly concentrated in certain regions of the central nervous system. It has been implicated in several disease states and conditions, including cardiovascular dysfunction, neurodegenerative diseases, clinical depression, pain perception, virus infections, the effects of cocaine abuse, and cancer. SIR mutations have been described to cause neuromuscular disorders such as Juvenile Amyotrophic Lateral Sclerosis 16 (ALS16) and Autosomal Recessive Distal Hereditary Motor Neuronopathy 2 (HMNR2). SIGMAR1 knockout mice are viable and fertile, and do not display any overt phenotype compared to wildtype mice. However, mutant mice are associated withimpaired motor coordination and muscle weakness associated with denervation at the neuromuscular junction and loss of motor neurons in the spinal cord. Mutant cells display defective Ca2+signalling, Ca2+homeostasis and increased ER stress, resulting in motor neuron and axonal degeneration. This causative link was confirmed by intracellular Ca2+scavengers and ER stress inhibitors that were able to prevent motor neuron degeneration.

[0004] Endogenous ligands for the SIR have yet to be conclusively identified, but tryptaminergic trace amines and neuroactive steroids have been found to activate the receptor. Especially progesterone, but also testosterone, pregnenolone sulfate, and dehydroepiandrosterone sulfate (DHEA-S) bind to the SIR.

[0005] Allosteric SIR modulators are also postulated to be beneficial in treating and / or preventing diseases or onset of diseases / disorders associated with ER stress. Under physiologicalconditions, proteins synthesized at the endoplasmic reticulum (ER) are properly folded with the assistance of ER chaperones such as calnexin and calreticulin. While it is not entirely known how the SIR protects against ER stress it is known to downregulate CHOP protein (DNA damage-inducible transcript 3, also known as CZEBP homologous protein or CHOP) which is a marker of ER stress. Mai- or unfolded proteins are disposed of by ER- associated protein degradation (ERAD) referred to as an unfolded protein response (UPR). When the amount of unfolded protein exceeds the folding capacity of the ER, human cells activate a defense mechanism called the ER stress response, which induces expression of ER chaperones and ERAD components and transiently attenuates protein synthesis to decrease the burden on the ER. It has been reported that at least three independent response pathways separately regulate induction of the expression of chaperones, ERAD components, to attenuate protein translation. The ER represents one of the main intracellular Ca2+ stores. Therefore not surprising, Ca2+metabolism disruptors have been described as ER stressors. Under physiological conditions, the concentration of Ca2+in the ER is kept at a high level since ER chaperones such as BiP require Ca2+fortheir function. Conversely, chemicals that perturb Ca2+homeostasis in the ER (for example, thapsigargin), induce ER stress. It is postulated that SIR modulators would be beneficial in maintaining Ca2+homeostasis and as such may assist in reducing ER stress. A dysregulated ER stress response, for example caused by aging, genetic mutations, xenobiotics or environmental factors is thought to result in various diseases such as diabetes, inflammation, and neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and bipolar disorder, which are collectively known as ‘conformational diseases’.

[0006] Currently there are no selective SIR ligands available as most dedicated SIR ligands either have significant affinities to other receptors (i.e. Blarcamesine, Cutamesine) or affinity to the SIR has been described later for drugs that were never officially developed to bind the SIR (i.e. Fluvoxamine, Pentazocine). In addition, the widespread presence of off-target effects of known SIR ligands significantly limits their clinical usefulness.

[0007] There is a need for improved and specific therapies for the treatment of sigma-1 receptor (olR or SIR) associated diseases and disorders as well as with disease and disorders related to ER stress.SUMMARY OF THE INVENTION

[0008] The present invention provides for compounds of Formula (I) and Formula (II) and pharmaceutical compositions thereof which are useful in treating sigma-1 receptor (olR or SIR) associated diseases and disorders. Specifically the inventors have identified that the present compounds are useful not necessarily in treating diseases caused by SIR inactivation, such as ALS, but instead diseases that could benefit from SIR activation. The skilled person would understand that these diseases are not necessarily SIR mediated, the SIR activation provides benefits in these diseases but itself is not involved in the pathology and as such is useful in treating sigma-1 receptor (c I R or SIR) "associated" diseases. The skilled person would appreciate then that the present compounds could however be beneficial in diseases caused by a lack of SIR activation or SIR mutations in the ligand binding site where the presently identified different mode of action might even activate the mutated receptor.

[0009] The compounds of Formula (I) and Formula (II) have utility in the modulation of the sigma-1 receptor (c l R or SIR). In another embodiment, the compounds of Formula (I) and Formula (II) have sigma-1 receptor agonist utility. In another embodiment, the compounds of Formula (I) and Formula (II) have sigma-1 receptor antagonist utility. In still another embodiment, the compounds of Formula (I) have selective sigma-1 receptor agonist utility and show little or none off target effects. In another embodiment, the compounds of Formula (I) and Formula (II) have sigma-1 receptor agonist utility and in particular useful in treating diseases or disorders associated with ER stress, and also includes diseases with dysregulated Ca homeostasis as already discussed above. This in particular includes advantageously increasing pericyte function which relies on Ca2+homeostasis, where ER stress in these cells is less of an issue.

[0010] It is proposed that the compounds of Formula (I) / (II) and pharmaceutical compositions thereof enabled herein are useful in the prophylaxis and / or treatment of sigma-1 receptor associated diseases and disorders.

[0011] It is proposed that the compounds of Formula (I) / (II) and pharmaceutical compositions thereof enabled herein are useful in the prophylaxis and / or treatment of diseases and disorders associated with ER stress.

[0012] In one aspect, there is provided a method of treating a sigma- 1 receptor (SIR) associated disease or disorder in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5.

[0013] In another aspect, there is provided a method of treating a disease or disorder associated with ER stress in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0014] In one aspect, there is provided a method of treating a sigma- 1 receptor (SIR) associated disease or disorder in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, there is provided a method of treating a disease or disorder associated with ER stress in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments, the invention relates to methods of treating a sigma- 1 receptor (SIR) associated disease or disorder in a subject in need thereof wherein the disease or disorder is one associated with ER stress.

[0017] In another aspect, there is provided a method of treating a disease or disorder which would benefit from sigma-1 receptor (SIR) activation in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0018] In one aspect, there is provided a method of treating a disease or disorder which would benefit from sigma-1 receptor (SIR) activation in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0019] Further contemplated herein is a method for the treatment of a mammalian subject comprising the administration of a compound of Formula (I) or Formula (II) as defined herein or a pharmaceutically acceptable salt thereof. As noted above, it is considered that the compounds of Formula (I) and (II) (and subformulae thereof) and pharmaceutical compositions thereof enabled herein are useful in the prophylaxis and / or treatment of sigma- 1 receptor associated diseases and disorders, such as, a disease or disorder associated with ER stress.

[0020] In an embodiment, sigma-1 receptor associated diseases and disorders include but not limited to fibroproliferative disease including progressive fibrosis; lowering systolic blood pressure (treatment of isolated systolic hypertension); general anxiety disorder; Parkinson's disease associated with Parkin mutation which causes Pac-R accumulation in the ER; treating abuse of pschotropic substances (addiction treatment); or cancer (breast, lung, prostate, ovarian, colorectal or CNS).

[0021] In an embodiment, diseases and disorders associated with ER stress include,diabetes mellitus; viral infections (eg Newcastle disease virus); retinitis pigmentation (RP); Alzheimers disease (AD) associated with misfolded beta-amyloid; Parkinson's disease associated with MPTP induced ER stress; Wolfram's disease; steatosis (a metabolic syndrome) which is ER stress induced; cancer -ER stress due to hypoxia - such as: multliple myeloma, melanomas, glioblastoma, breast and cervical cancers; amyotrophic lateral sclerosis (ALS); adjunct therapy for subjects exposed to chemotherapy agents that cause ER stress (eg brefeldin A); hereditary tyrosinemia type 1; kidney disease; liver disease; ischemia; atherosclerosis; inflammation disorders caused by ER stress; treatment of pain disorders; and bipolar disorder (mood disorders).

[0022] In certain embodiments, the diseases or disorders associated with ER stress are pain disorders. There is a link between ER stress and pain (see Kawanaka, et al Int J Mol Sci. 2024 May 3;25(9):4995. The general idea is that pain signalling is amplified by SIR, so SIR antagonists of the present invention may function to dampen the pain signal. The pain disorder may be acute pain, chronic pain, neuropathic pain, nociceptive pain or radial pain.

[0023] In certain embodiments, the diseases or disorders associated with ER stress is a liver disease such as a liver disease caused by alcohol or other substance abuse or NASH (a type of non-alcoholic fatty liver disease). NASH (or nonalcoholic steatohepatitis) can damage the liver and occurs when the fat buildup in the liver leads to inflammation (hepatitis) and scarring. It is thought that ER stress evoked by alcohol activates transcription factors such as CHOP, leading to CHOP-induced apoptosis of hepatocytes. In this regard, ER stress is also thought to activate another transcription factor, SREBP, which is responsible for the upregulation of fatty acid synthesis, resulting in lipid induced apoptosis.

[0024] In certain embodiments, the disease or disorder associated with ER stress is a kidney disease such as kidney disease caused by various factors which induce renal injury. For instance, certain analgesic and antipyretic agents (eg, paracetamol) causes renal tubular injury, and ER stress-induced apoptosis is a reported mechanism involved in this process.

[0025] In certain embodiments, the disease or disorder associated with ER stress is ischemia and in particular ischemia caused by hypoxia. In an embodiment the ischemia is brain ischemia as it is thought that brain ischemia induced ER stress in neurons and activates ATF6, IREl, PERK pathways, leading to CHOP mediated apoptosis of neurons.

[0026] In certain other aspects, the compounds disclosed herein have particular utility in treating and / or prevention of specific ocular conditions and disease states, and / or amelioration of symptoms associated with said ocular conditions and disease states.

[0027] In a further aspect, there is provided a method of treating retinal blood vessel abnormalities associated with sigma- 1 receptor (SIR) in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0028] In an additional aspect, there is provided a method of treating retinal blood vessel abnormalities associated with sigma- 1 receptor (SIR) in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0029] Without wishing to be bound by theory, the present inventors believe that since the compounds of Formula (I) or Formula (II) as disclosed herein modulate the sigma-1 receptor, and the sigma-1 receptor is known to be implicated in the regulation of Ca2+levels, the compounds of Formula (I) or Formula (II) may be used in the treatment of a disease that is associated with Ca2+dysregulation. Since it is known that retinal cells express the sigma-1 receptor, the present inventors believe that the compounds disclosed herein may be used in the treatment of retinal diseases, and ocular diseases more generally, where the ocular disease is associated with Ca2+dysregulation.

[0030] The present invention therefore also provides a method for the treatment of an ocular disease associated with Ca2+dysregulation in a subject in need thereof, the method comprising administering a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5.

[0031] The present invention also provides a method for the treatment of an ocular disease associated with Ca2+dysregulation in a subject in need thereof, the method comprising administering a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5.

[0032] In some embodiments, the ocular disease is a glaucoma. In other embodiments, the ocular disease is macular degeneration. In other embodiments, the ocular disease is age-related macular degeneration. In other embodiments, the ocular disease is a cataract. In other embodiments, the ocular disease is dry eye disease. In certain embodiments, the ocular disease associated with Ca2dysregulation is a diabetic retinopathy. One skilled in the art would understand that a diabetic retinopathy may occur in a patient that has Type 1 or Type 2 diabetes.

[0033] It is known that dysregulation of calcium signalling via SOCE plays a central role in the neurodegenerative processes of glaucoma, particularly through its effects on microglialactivation and RGC survival Front. Aging Neurosci. 17: 1657590. Without wishing to be bound by theory, the present inventors believe that the present compounds may be useful in the treatment of glaucoma, given the ability of these compounds to modulate SOCE.

[0034] Patients with Type 1 or Type 2 diabetes experience various metabolic alterations, including cellular stress overload associated with compromised mitochondrial health. A primary manifestation of reduced mitochondrial health (i.e. mitochondrial dysfunction) is diabetic retinopathy, which arises due to neurovascular complications attributed to poor control of diabetes. This eventually results in the loss of vision and eventually blindness. Since retinal cells are sensitive to oxidative stress, the observation of damage to these cells is a key indicator of disease. Due to current screening methods, the disease remains undetected until irreversible damage occurs. Vascular complications attributed to diabetes often leads to progression of diabetic retinopathy to proliferative diabetic retinopathy, which may be characterized by excessive mitochondrial and retinal cell damage, chronic inflammation, neovascularization and reduction in the visual field. The ability to detect and diagnose proliferative diabetic retinopathy is also indicative of other complications associated with diabetes, including stroke.

[0035] The present inventors have shown that the compounds disclosed herein are useful in the modulation of the sigma-1 receptor, which is present in several ocular tissues (including the retina), among others. Since ligands of the sigma- 1 receptor are known to modulate cellular calcium levels, such ligands have demonstrated a neuroprotective effect in various retinal cells and may therefore be useful in the treatment of associated diseases. Without wishing to be bound by theory, the present inventors believe that the present compounds may be useful in the treatment of a retinopathy, given the presence of sigma- 1 receptors in retinal cells and ability of these compounds to modulate the activity of SIR.

[0036] The severity of diabetic retinopathy in patients can be assessed and classified in accordance with the ETDRS-DRSS rating scale, as reproduced below (see Hammes H-P, Lin J, Renner O, et al. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes. 2002; 51 ( 10) : 3107-3112 and taps . / / modenaod„wm / arttaes / 2019 j ung / ihe-fouiystages-oL di ab eti cr eti n op at hy ) :

[0037] While early diagnosis of the disease is ideal and typically leads to improved treatment outcomes, this is often not possible since early stages of the disease are typically asymptomatic. Current diagnostic methods include optical coherence tomography (OCT), fluorescein angiography (FA), and colour fundus retinal photography, which allows clinicians to determine one or more of the above pathological aspects and retinal findings. Current treatment options for diabetic retinopathy include intravitreal injections of anti -vascular endothelial growth factor (anti-VEGF) drugs, laser therapy and surgery, each of which requires high levels of cooperation from the patient and clinical resources. Since current approaches for the diagnosis and treatment of diabetic retinopathy are more relevant to later stages of the disease, there remains a need for earlier diagnosis and treatment in order to limit progression and therefore severity of the disease. The present inventors have found that since the sigma- 1receptor is active in retinal tissues, the ability to modulate activity at this receptor and subsequently affect Ca2+regulation means that the compounds disclosed herein can be used in the treatment of diabetic retinopathy.

[0038] In a further aspect, there is provided a method of treating diabetic retinopathy in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0039] In an additional aspect, there is provided a method of treating diabetic retinopathy in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma-1 receptor modulating compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0040] In certain embodiments, the diabetic retinopathy is a non-proliferative diabetic retinopathy. In certain embodiments, the diabetic retinopathy is a proliferative diabetic retinopathy.

[0041] In some embodiments, the diabetic retinopathy is a mild to moderate diabetic retinopathy. In other embodiments, the diabetic retinopathy is a severe non-proliferative diabetic retinopathy. In other embodiments, the diabetic retinopathy has progressed from a mild to moderate diabetic retinopathy. In other embodiments, the diabetic retinopathy is a severe diabetic retinopathy that has progressed from a mild to moderate diabetic retinopathy.

[0042] In a further aspect, there is provided a method of treating mild to moderate nonproliferative diabetic retinopathy associated with sigma-1 receptor (SIR) in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula(I) or a pharmaceutically acceptable salt thereof.

[0043] In an additional aspect, there is provided a method of treating mild to moderate nonproliferative diabetic retinopathy associated with sigma-1 receptor (SIR) in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula(II) or a pharmaceutically acceptable salt thereof.

[0044] In a further aspect, there is provided a method of preventing mild to moderate nonproliferative diabetic retinopathy in a subject from progressing to severe non-proliferativediabetic retinopathy thereof including the step of administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0045] In an additional aspect, there is provided a method of preventing mild to moderate non-proliferative diabetic retinopathy in a subject from progressing to severe non-proliferative diabetic retinopathy thereof including the step of administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0046] In a further aspect, there is provided a method of treating a severe non-proliferative diabetic retinopathy associated with sigma-1 receptor (SIR) in a subj ect in need thereof wherein the subject is administered with an effective amount of a compound of Formula (I) as disclosed herein or a pharmaceutically acceptable salt thereof.

[0047] In a further aspect, there is provided a method of treating a severe non-proliferative diabetic retinopathy associated with sigma- 1 receptor (SIR) in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (II) as disclosed herein or a pharmaceutically acceptable salt thereof.

[0048] In certain embodiments, the severe NPDR is characterized with a real-time Diabetic Retinopathy Severity Score Level severity scale (DRSS)-of between 47 to 61.

[0049] In certain embodiments, the subject has tested negative for the SIR polymorphisms rs 1799729 (GC-241-240TT) and rs 1800866 (Q2P).

[0050] In particular embodiments, the subject is provided with a >2-step improvement from baseline on the ETDRS DRSS at 1 year (non-inferiority to approved treatments or potentially improved outcomes when combined).

[0051] In another aspect, there is provided a method of treating a glaucoma in a subject need thereof, wherein the subject is administered with an effective amount of a compound compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0052] In another aspect, there is provided a method for treating a glaucoma in a subject need thereof, wherein the subject is administered with an effective amount of a compound compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0053] In a further aspect, there is provided a method of treating intraocular pressure in an eye associated with glaucoma in a subject need thereof, wherein the subject is administered with an effective amount of a compound compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0054] In an additional aspect, there is provided a method of treating intraocular pressure in an eye associated with glaucoma in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

[0055] In another aspect, there is provided a method of treating a retinal disease in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (I) as disclosed herein or a pharmaceutically acceptable salt thereof.

[0056] In another aspect, there is provided a method of treating a retinal disease in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (II) as disclosed herein or a pharmaceutically acceptable salt thereof.

[0057] In certain embodiments of the above aspects, the retinal disease is age-related macular degeneration, macular edema or retinal detachment.

[0058] In certain embodiments of the above aspects, the retinal disease is a retinopathy.

[0059] In certain embodiments, the retinopathy is a retinal vascular disease. In other embodiments, the retinopathy is a hypertensive retinopathy. In other embodiments, the retinopathy is a retinopathy of prematurity.

[0060] In certain embodiments of the above aspects, the effective amount of a compound of Formula (I) is in the range of from about 0.0001 pM to about 10 pM. In other embodiments, the effecrtive amount of a compound of Formula (I) is in the range of about 0.0001 pM to about 5 pM. In other embodiments, the effective amount of a compound of Formula (I) is in the range of from about 0.001 pM to about 5 pM. In other embodiments, the effective amount of a compound of Formula (I) is in the range of from about 0.001 pM to about 1 pM. In other embodiments, the effective amount of a compound of Formula (I) is in the range of from about0.01 pM to about 1 pM. In other embodiments, the effective amount of a compound of Formula(I) is in the range of from about 0.1 pM to about 1 pM.

[0061] In certain embodiments of the above aspects, the effective amount of a compound of Formula (I) is about 0.001 pM, 0.002 pM, 0.003 pM, 0.004 pM, 0.005 pM, 0.006 pM, 0.007 pM, 0.008 pM, 0.009 pM, 0.01 pM, 0.02 pM, 0.03 pM, 0.04 pM, 0.05 pM, 0.06 pM, 0.07 pM, 0.08 pM, 0.09 pM, 0.1 pM, 0.2 pM, 0.3 pM, 0.4 pM, 0.5 pM, 0.6 pM, 0.7 pM, 0.8 pM, 0.9 pM, 1 pM, 2 pM, 3 pM, 4 pM, 5 pM, 6 pM, 7 pM, 8 pM, 9 pM or 10 pM.

[0062] In certain embodiments of the above aspects, the effective amount of a compound of Formula (II) is in the range of from about 0.0001 pM to about 10 pM. In other embodiments, the effective amount of a compound of Formula (II) is in the range of from about 0.0001 pM to about 5 pM. In other embodiments, the effective amount of a compound of Formula (II) is in the range of from about 0.001 pM to about 5 pM. In other embodiments, the effective amount of a compound of Formula (II) is in the range of from about 0.001 pM to about 1 pM. In other embodiments, the effective amount of a compound of Formula (II) is in the range of from about 0.01 pM to about 1 pM. In other embodiments, the effective amount of a compound of Formula(II) is in the range of from about 0.1 pM to about 1 pM.

[0063] In certain embodiments of the above aspects, the effective amount of a compound of Formula (II) is about 0.001 pM, 0.002 pM, 0.003 pM, 0.004 pM, 0.005 pM, 0.006 pM, 0.007 pM, 0.008 pM, 0.009 pM, 0.01 pM, 0.02 pM, 0.03 pM, 0.04 pM, 0.05 pM, 0.06 pM, 0.07 pM, 0.08 pM, 0.09 pM, 0.1 pM, 0.2 pM, 0.3 pM, 0.4 pM, 0.5 pM, 0.6 pM, 0.7 pM, 0.8 pM, 0.9 pM, 1 pM, 2 pM, 3 pM, 4 pM, 5 pM, 6 pM, 7 pM, 8 pM, 9 pM or 10 pM.

[0064] Any one of the concentrations and / or ranges above may apply to any one of the compounds of Formula (I) or (II), i.e. compound UTA#35, UTA#37, UTA#42, UTA#43, UTA#47, UTA#54, UTA#55, UTA#61, UTA#62, UTA#65, UTA#66, UTA#71, UTA#72, UTA#73, UTA#74, UTA#75, UTA#76, UTA#77, UTA#78, UTA#80, UTA#81, UTA#84, UTA#88, UTA#89, UTA#91, UTA#93, UTA#94, UTA#95, UTA#97, UTA#113, UTA#115, UTA#116 or UTA#117 as depicted in Table 1 below.

[0065] In a further aspect there is provided a combination therapy for treating diabetic retinopathy said combination therapy including the step of administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, together with an VEGF inhibitor, wherein the administration of the combination can take placesequentially, concomitantly, or simultaneously.

[0066] In an additional aspect there is provided a combination therapy for treating diabetic retinopathy said combination therapy including the step of administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, together with an VEGF inhibitor, wherein the administration of the combination can take place sequentially, concomitantly, or simultaneously.

[0067] In certain embodiments the VEGF inhibitor is selected from the group consisting of bevacizumab, afilbercept, ranibizumab, sorafenpib, dasatinib, sunitinib, nilotinib, and pazopanib.

[0068] In certain embodiments the compounds of Formula (I) or (II) are administered to the eye as an eye drop formulation.

[0069] In certain embodiments the subject is monitored by optical-coherence-tomography angiography (OCT- A).

[0070] In certain embodiments the compounds of Formula (I) or (II) are administered to the eye as an eye drop formulation based on a once a day treatment regime.

[0071] It is known that pericytes form part of the vasculature in the retina and therefore have a role in controlling blood flow in the surrounding area. Specifically, pericytes are intrinsically linked to the control of cytoplasmic calcium levels, which result in the restriction or enlargement of the surrounding capillaries. The release of calcium from pericytes is triggered by ATP, meaning that any disruption of energy supply (e.g. under conditions of hypoxia) will impair regulation of calcium levels and therefore capillary blood flow. The compounds disclosed herein are known the modulate the activity of the sigma- 1 receptor, which in turn is implicated in the control of ATP -triggered calcium levels and the maintenance of mitochondrial function. Without wishing to be bound by theory, the present inventors believe that the compounds disclosed herein can modulate activity at the sigma- 1 receptor and subsequently restore calcium regulation and energy homeostasis. This activity in turn can result in the protection of pericyte function and viability. The inventors therefore believe that on the basis of the results disclosed herein, the compounds of Formula (I) or (II) may be used in methods for the protection of pericytes, may be used in the protection of pericytes and their function, bycontrolling microvascular blood flow (which can be measured, for example, by OCT-A) and to maintain capillary integrity.

[0072] In a further aspect there is provided a method of protecting pericyte function in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5.

[0073] In an additional aspect there is provided a method of protecting pericyte function in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5.

[0074] Where pericyte function is protected and / or maintained, this can in turn prevent the progression of diabetic retinopathy as conditions of hypoxia, loss of mitochondrial energy supply, ER stress and dysregulation of calcium levels are reduced, minimized or eliminated.

[0075] In an embodiment, the mammal is a human.

[0076] In certain embodiments, the subject may be a domesticated pet or farm animal such as a dog, cat, bird, horse, cattle, sheep, pigs, etc. Accordingly, the present methods extend to veterinary applications.

[0077] Further taught herein is a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) as defined herein and one or more pharmaceutically acceptable carriers, diluents and / or excipients.

[0078] Further taught herein is the use of a compound of Formula (I) / (II) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a mammalian subject with a sigma-1 receptor (SIR) associated disease or disorder. In a related embodiment enabled herein is a compound of Formula (I) / (II) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of a sigma- 1 receptor (SIR) associated disease or disorder in a mammalian subject in need of therapy. In a related embodiment enabled herein is a compound of Formula (I) / (II) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of a sigma-1 receptor (SIR) associated disease or disorder in a mammalian subject in need of therapy, wherein the disease or disorder is associated with ER stress.

[0079] Accordingly, the present invention also provides the use of a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5, in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.

[0080] In a further aspect, the present invention provides the use of a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5,in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.BRIEF DESCRIPTION OF FIGURES

[0081] Several SIR ligands are described to display non-linear dose effect responses. In HEK293 cells that have been described to lack SIR expression (Srivats et al. 2016), the agonists UTA#37, UTA#77 and the antagonist BD 1047 did not affect SOCE (Fig. 3), neither at the level of depleting ER stores of calcium, nor regarding the subsequent calcium influx into the cytoplasm (Fig. 3). In contrast, when the same cells were transfected with a SIR expression plasmid, the SOCE response was reduced as previously described (Srivats et al. 2016), while the combination of SIR expression and UTA#37 reduced the SOCE response even further as expected from a SIR agonist (see Figures 3 A and 3B).

[0082] Figure 1: Graph showing the effect of sigma-1 receptor ligands on Store Operated Calcium Entry (SOCE) in HepG2 cells: Data represents mean ± standard error of mean (SEM) for the total area under the curve (AUC) normalized to the untreated control, derived from > 3 independent experiments with at least 3 replicates / experiment for the present compounds and two independent experiments with 5 replicates each for the reference sigma- 1 receptor ligands. The data in HepG2 cells demonstrate that test compounds can both inhibit SOCE (results below the dotted line) as well as increase SOCE (results above the dotted line) comparable to the known agonists and antagonists.

[0083] Figure 2A: Effect of SCQ on Store Operated Calcium Entry (SOCE) in HEK293 cells: In HEK293 cells that have been described to lack SIR expression (Srivats et al. 2016), the agonists UTA#37, UTA#77 and the antagonist BD1047 did not affect SOCE at the level of depleting ER stores of calcium, nor regarding the subsequent calcium influx into the cytoplasm (UT = untreated control).

[0084] Figure 2B: Graph showing the effect of the present compounds on Store Operated Calcium Entry (SOCE) in HEK293 cells. In HEK293 cells that have been described to lack SIR expression (Srivats et al. 2016), the agonists UTA#37, UTA#77 and the antagonist BD1047 did not affect the subsequent calcium influx into the cytoplasm (UT = untreated control).

[0085] Figure 3A: Effect of SIR overexpression and the present compounds on SOCE.SIR was transiently overexpressed in HEK293 cells. After 48 hours of transfection, the cells were initially loaded with Fluo-4NW dye and treated with or without 10 pM of UTA#37 for 15 minutes, before measurement on the SOCE Paradigm. Data represents the mean ± standard error of mean (SEM) for the total area under the curve (AUC)

[0086] Figure 3B: Graph showing that SOCE is only reduced in the presence of recombinantly expressed SIR in HEK293 cells. The data represents % mean ± SEM for the total AUC (AUC peak-1 + AUC peak-2) for SIR transfected cells and SIR transfected cells treated with UTA#37.

[0087] Figure 4: Graph showing the comparison of present compounds against known SIR ligands in the Store Operated Ca2+- Entry (SOCE) paradigm.

[0088] Figure 5A: Graph showing the dose-dependency of SIR activation by present compounds, with results representing the AUC of the standard store operated calcium entry paradigm. This graph shows the dose dependency of SIR activation of two exemplary present compounds (UTA#37, UTA#77).

[0089] Figure 5B: Graph showing the comparison the time dependency of SIR activation by the orthosteric SIR ligand imipramine (10 pM) and present compounds (UTA#37 at 10 pM , UTA#77 at 10 nM). The present compounds activate the SIR within minutes, while the orthosteric ligand requires hours, indicative of a different mode of action.

[0090] Figure 5C. Graph comparing the duration of SIR activation after removal (i.e. wash out) of activator (Imi: Imipramine, with pre-treatment time of 3 h; UTA#77, with pretreatment time of 15 min). This graph shows that UTA#77 activates SIR over at least 21 h while the activity of the orthosteric agonist imipramine (Imi) only lasts for 3 h, which supports the proposed mode of action of the present compounds.

[0091] Figure 6A: Graph showing the lack of allosteric effect of compound #37. Compound UTA#37 does not affect the activity of the orthosteric SIR ligand imipramine (Imi).

[0092] Figure 6B: Graph showing the effect of the allosteric SIR modulator with either compound UTA#37 or orthosteric ligands. Orthosteric SIR agonist: imipramine (Imi, 10 pM); orthosteric SIR antagonist: BD1047 (10 pM); positive allosteric SIR modulator: phenytoin (Phen, 250 pM); compound UTA#37 (10 pM). Results represent the AUC of the standard storeoperated calcium entry paradigm. Significance p<0.033 (*), p<0.0021 (**), p<0.0002 (***), p<0.0001 (****) or “ns” (non-significant).

[0093] Figure 7A: Graph showing the dose-dependency of SIR activation by the representative redox-active (UTA#37) and redox-inactive (UTA# 147) compounds. Results represent the AUC of the standard store operated calcium entry paradigm.

[0094] Figure 7B: Graph showing the requirement of reductive bioactivation of a present compound (UTA#37) for SIR activation. In contrast, the orthosteric SIR ligands imipramine, SA4503 and BD1047 remain unaffected by the reductase inhibitor dicoumarol (Die). Imipramine and UTA#37 were each administered at a concentration of 10 pM. This data is indicative of a different mode of action.

[0095] Figure 7C: Graph showing the requirement of gamma-glutamyl carboxylase (GGCX) activity for the bioactivity of a present compound (UTA#37). GGCX was inhibited by 5 pM anisindione (Ani). This data is indicative of a different mode of action of the present compounds.

[0096] Figure 8: Figure showing the proposed catalytic mode of action of the present compounds featuring a quinone core. After chemical reduction of the quinone compound (Q) to the hydroquinone (QH2), the attached carboxylase (GGCX) utilises QH2 to carboxylate glutamine residues (Glu) in target proteins within the complex of SIR-BiP-VKORCl-GGCX. The modified Glu residues are referred to as Gia. The Gla-associated charge changes lead to the rapid dissociation of the SIR complex, which activates the receptor. The produced quinone intermediate (QO) is recycled by an additional reduction step back to Q that is then ready for another reduction cycle.

[0097] Figure 9: Graph showing the rescue of vision after administration of the compound UTA#77 in a rat model of type 2 diabetic retinopathy. Data of all diabetic animals was pooled between weeks 1 and 14 for a reliable course of vision loss.

[0098] Figure 10: Graph showing the effect of UTA#37 and UTA#77 on visual acuity following rotenone-induced vision loss.

[0099] Figure 11: Graph showing the dose-dependent effects of selected compounds onSOCE. Compounds UTA#37 (red circles), UTA#77 (green triangles), UTA#54 (blue squares) and UTA#88 (brown diamonds) were administered in a dilution series (10 pM, 1 pM and 0.1 pM) and the effect on the SOCE paradigm measured with the Fluo-4NW dye.

[0100] Figure 12: Graph showing the dose-dependent effects of selected compounds on SOCE. Compounds UTA#37 (red circles) and UTA#74 (blue squares) were administered in a dilution series of (0.01 - 1 pM) and UTA#77 (green triangles) was administered in a dilution series (0.001 - 1 pM) and the effect on the SOCE paradigm measured with the Fluo-4NW dye.

[0101] Figure 13: Graph showing the dose-dependent effects of reference quinones on SOCE. Vitamin KI (VK1, green, lower series) and idebenone (Ide, purple, upper series) were administered in a dilution series (0.1 pM, 1 pM and 10 pM) and the effect on the SOCE paradigm measured with the Fluo-4NW dye (UT = untreated control). Both reference quinones did not induce any significant effects.

[0102] Figure 14A: Graph showing the cytoplasmic calcium response of cells pre-treated with either SIR ligand activators (imipramine or SA4503), a SIR modulator (BD1047) or compounds of the present invention (UTA#37, UTA#77, UTA#54 or UTA#74) to a trigger of ATP. Data represents area under the curve (AUC).

[0103] Figure 14B: Graph showing the cytoplasmic calcium response of cells to a trigger of ATP, relative to a control (UT = untreated control), where cells were pre-treated with either SIR ligand activators (imipramine or SA4503), a SIR modulator (BD1047) or compounds of the present invention (UTA#37, UTA#77, UTA#54 or UTA#74). Data represents peak height and is expressed as “% control”.DETAILED DESCRIPTION

[0104] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or method step or group of elements or integers or method steps but not the exclusion of any other element or integer or method steps or group of elements or integers or method steps.

[0105] As used in the specification, the singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "abiological regulator" includes a single biological regulator, as well as two or more biological regulators; reference to "an agent" includes a single agent, as well as two or more agents; reference to "the disclosure" includes a single and multiple aspects taught by the disclosure; and so forth. Aspects taught and enabled herein are encompassed by the term "invention". All such aspects are enabled within the width of the present invention. Any variants and derivatives contemplated herein are encompassed by "forms" of the present invention.

[0106] The present invention relates generally to therapeutic methods compounds of Formula (I), and Formula (II), and subformulae thereof which modulate the sigma-1 receptor. In an embodiment, the compounds of Formula (I) or Formula (II), have utility as sigma- 1 receptor agonists.

[0107] Without wishing to be bound by any particular theory the inventors believe that the present compounds act via activation of the SIR by a novel mechanism that is not explained by allosteric modulation or binding to the orthosteric SIR binding pocket but rather represents a rapid, stable, post-translational modification within the SIR multi -protein complex, which results in faster activation of the receptor and longer activation times compared to orthosteric ligands.

[0108] The data presented herein allows the skilled person to postulate that the instant compounds work by a very specific mode of action that involves gamma-carboxy-glutamic acid (Gia) modification of target proteins. Gla-modified proteins in general are very rare (only about 20-30 have been verified; https: / / en.wikipedia.org / wiki / Gla_domain). Some of the known Vitamin K-dependent Gla-modified proteins are involved in blood coagulation, where the process of Gla-modification only occurs inside the ER lumen. Since Vitamin K does not affect SIR activity in the present system, the inventors expect a high level of restriction for the instant compounds towards the Gla-modification of compounds within the SIR complex. As a consequence of the unique activation mechanism, the instant compounds possess distinctive advantages over conventional orthosteric SIR ligands. The SIR ligand binding site is universally acknowledged, and is shown by the present inventors herein, to be quite inaccessible for orthosteric ligands. In contrast, the instant compounds do not enter the SIR ligand binding site but instead activate the receptor from the outside of the receptor complex. Therefore, full SIR activation by the instant compounds occurs in only a few minutes, while orthosteric ligands typically require several hours (see Figures 10B and 10C). In addition, Gla-modification of proteins is not described to be reversible. This suggests that activation of the SIR complex bya Gla-dependent post translational modification will activate the receptor for longer periods of time compared to orthosteric ligands that need to be continuously present at therapeutic levels to keep the receptor in the active state.

[0109] This hypothesis was confirmed in wash-out experiments where after full SIR activation by the orthosteric agonist imipramine (3h pre-incubation) and UTA#77 (15 min preincubation), the cells were washed several times to remove the compounds and then SIR activity was determined over a period of up to 24 hours.

[0110] While SIR activation by imipramine was retained for only 3 hours, UTA#77- dependent activation of SIR was detectable for up to 21 hours (see Figures 5B and 5C). This represents a major point of differentiation and advantage for treating eye diseases where the main limitation of small molecules is to continuously achieve therapeutic drug levels in the eye (Amo et al. Prog Retin Eye Res. 2017 Mar; 57: 134-185).

[0111] In practical terms, in contrast to conventional ligands, activation by the compounds of the present invention only relies on achieving a required Cmax of about 10 nM at the retina once (see Figure 5A). This pharmacological in vitro profile and mode of action allows once daily dosing of the present compounds.

[0112] Compared to orthosteric SIR ligands, another point of differentiation of the instant compounds is their catalytic nature for post-translational modification to activate SIR. While each orthosteric ligand molecule can only activate one receptor protein, each of the instant compounds can activate multiple receptor proteins. This difference is based on the reversible nature of reduction / oxidation cycles of our compounds (see Figure 13). The chemical reduction of the quinone (Q) moiety of the instant compounds by cellular reductases, such as the Vitamin K epoxide reductase 1 (VKORC1) and its paralogue the vitamin K epoxide reductase 1 like 1 (VKORC1L1), the warfarin-resistant Vitamin K reductase (FSP1 / AIFM2) and NAD(P)H quinone oxidoreductase 1 (NQO1), leads to the formation of a hydroquinone (QH2). This activated molecule serves as an energy -rich substrate for the VKORC1 -associated carboxylase (GGCX), which uses the chemical energy of QH2 to carboxylate specific glutamic acid residues (Glu) of target proteins. These post-translationally modified glutamic acids (Glu) are referred to as Gla-residues. The instant quinone compounds are then recycled from an intermediate (QO) back to the original quinone (Q) by another reduction step and are then able to engage in another cycle.

[0113] Thus, the instant compounds can repeatedly be used to Gla-modify target proteins, which reduces the required dose compared to orthosteric ligands. Gla-modified proteins are rare and only about 20-30 have been identified so far (https: / / en.wikipedia.org / wiki / Gla_domain). It is very unlikely that our compounds will lead to the Gla-modification of these known proteins as they are typically synthesised and modified in the ER lumen and subsequently exported from the cell, 4 of 23 while in contrast, the majority of the SIR / Heat Shock Protein Family A (Hsp70) Member 5 (BiP) complex is localised in the cytoplasm. There is an additional layer of steric selectivity, which is highlighted by the fact that Vitamin K, the molecule that leads to the Gia- modification of some known proteins, is unable to activate SIR in the present system. This is most likely due to the sterical characteristics of the SIR complex that hinders access of other quinone molecules. Based on the understanding of the instant structure-activity-relation (SAR) of the present compounds, access to the SIR multi -protein complex requires a combination of physicochemical characteristics involving size limitations, polarity and balanced solubility. Vitamin K is larger than the instant compounds and very lipophilic which restricts it to cellular membranes, while the instant compounds are smaller and display a balance between lipophilicity and water solubility that allows them to rapidly pass through membranes.

[0114] Accordingly, in some embodiments, the present compounds may provide one or more of the following benefits:• Topical, non-invasive treatment.• Fast onset of action.• Sustained activation over several hours in contrast to orthosteric SIR ligands.• Protection against the earliest pathology known in DR - the loss of function of the neurovascular unit (NVU).• Mechanism of action is comparable with the concomitant use of an anti-VEGF intravitreal injection and benefit is at least additive, if not synergistic.• Compounds can be used to treat subjects with mild NPDR and offer neuroprotective effects.

[0115] As used herein the term " sigma- 1 receptor modulation" or "modulate" refers to and extends to and encompasses inhibiting and / or promoting an interaction. Modulation can include, but is not limited to, normalization, enhancement or activation of the receptor or target site.

[0116] The term "alkyl" as used alone or in combination herein refers to a straight or branched chain saturated hydrocarbon group. The term "C1-C12 alkyl" refers to such a group containing from one to twelve carbon atoms and "lower alkyl" refers to Ci-Ce alkyl groups containing from one to six carbon atoms, such as methyl ("Me"), ethyl ("Et"), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like.

[0117] The term "cycloalkyl" refers to non-aromatic, saturated non-aromatic carbocycles. The term "C4-C9 cycloalkyl", for instance, refers to such a group having from 4 to 9 carbon atoms. Examples include cyclobutyl, cyclopentyl and cyclohexyl.

[0118] The term "alkenyl" refers to a straight or branched hydrocarbon containing one or more double bonds. The term "C2-C12 alkenyl", for instance, refers to such a group containing from two to twelve carbon atoms. Examples of alkenyl include allyl, prenyl, geranyl, 1- methylvinyl, butenyl, iso-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl, 1,3-butadienyl, 1,4- pentadienyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1,3 -hexadienyl, 1,4-hexadienyl, and 1,3,5- hexatrienyl.

[0119] The term "cycloalkenyl" refers to cyclic alkenyl groups having a single cyclic ring or multiple condensed rings, and at least one point of internal unsaturation, preferably incorporating 4 to 11 carbon atoms. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3 -enyl, cyclohex-4-enyl, cyclooct-3-enyl, indenyl and the like.

[0120] The term "alkynyl" refers to a straight or branched hydrocarbon containing one or more triple bonds, preferably one or two triple bonds. The term "C2-C12 alkynyl", for instance, refers to such a group containing from two to twelve carbon atoms. Examples include 2- propynyl and 2- or 3-butynyl.

[0121] The term "alkoxy" as used alone or in combination refers to a straight or branched chain alkyl group covalently bound via an oxygen linkage (-O-) and the terms "Ci-Ce alkoxy" and "lower alkoxy" refer to such groups containing from one to six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like.

[0122] The term "aryl" refers to carbocyclic (non-heterocyclic) aromatic rings or ringsystems. The aromatic rings may be mono- or bi-cyclic ring systems. The aromatic rings or ring systems are generally composed of 5 to 10 carbon atoms. Examples of suitable aryl groups include but are not limited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.

[0123] Aryl groups include phenyl, naphthyl, indenyl, azulenyl, fluorenyl or anthracenyl.

[0124] The term "heteroaryl" refers to a monovalent aromatic carbocyclic group, preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Preferably the heteroatom is nitrogen. Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl, or benzofuranyl).

[0125] The term "heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring.

[0126] Examples of 5-membered monocyclic heterocyclyl and heteroaryl groups include furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4-oxadiazolyls) thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3- and 1,3,4- triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3- and 1,3,4-thiadiazolyls).

[0127] Examples of 6-membered monocyclic heterocyclyl and heteroaryl groups include pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl and triazinyl.

[0128] Examples of 8, 9 and 10-membered bicyclic heterocyclyl and heteroaryl groups include 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl, naphthyridinyl, pteridinyl and the like.

[0129] The terms "halo" and "halogen" refers to fluoro, chloro, bromo and iodo groups.

[0130] The term "haloalkyl" group has one or more of the hydrogen atoms on an alkyl group replaced with halogens. Notable examples are -CF3 or -CF2H.

[0131] The term "aryloxy" refers to an aryl group as earlier described linked to the parent structure via an oxygen linkage (-O-). A notable example is phenoxy. Similarly, the term "heteroaryl oxy" refers to a heteroaryl group as earlier described linked to the parent structure via an oxygen group. A notable example is a 4, 6 or 7-benzo[b] furanyl oxy group.

[0132] The term "acyl" refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl- C(O)-, heteroaryl -C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are described herein.

[0133] The term "oxyacyl" refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

[0134] The term "acylamino" refers to the group -NR"C(O)R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

[0135] The term "alkylene" refers to a straight or branched divalent alkyl groups preferably having from 1 to 20 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), and the propylene isomers (e g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like.

[0136] The term "alkenylene" refers to a straight or branched divalent alkenyl group containing one or more double bonds and preferably having from 2 to 20 carbon atoms. Examples of such alkenylene groups include ethenylene (-CH=CH-), propenylene, prenenylene, geranenylene and isomers thereof.

[0137] The term "sulfamoyl" refers to the group -S(O)2NR"R" where each R" is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

[0138] The term "optionally substituted" means that a group may include one or moresubstituents. One or more hydrogen atoms on the group may be replaced by substituent groups independently selected from halogens (for example halo alkyl such as -CF3 or -CF2H), Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -(CH2)vC3-7 cycloalkyl, -(CH2)vC4-7 cycloalkenyl, -(CH2)Varyl, -(CH2)Vheterocyclyl, -(CFF heteroaryl, -C6H4S(O)qCi-6 alkyl, -C(Ph)3, -CN, -OR, -O- (CH2)I-6-R, -O-(CH2)I-6-OR, -OC(O)R, -C(O)R, -C(O)OR, -OC(O)NR'R", -NR'R", -NO2, -NRC(O)R', -NRC(O)NR'R", -NRC(S)NR'R", -NRS(O)2R', -NRC(O)OR', -C(N R)NR'R", -C(=NOR')R, -C(=NOH)NR'R", -C(O)NR'R", -C(=NCN)-NR'R", -C(=NR)NR'R", -C(=NR')SR", -NR'C(=NCN)SR", -CONRSO2R', -C(S)NR'R", - S(O)qR, -SO2NRR", -SO2NRC(O)R', -OS(O)2R, -PO(OR)2and -NO2; where v is 0-6, q is 0-2 and each R, R1and R" is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, aryl, heterocyclyl, heteroaryl, Ci-6 alkylaryl, Ci-6 alkylheteroaryl, and Ci-6 alkylheterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, Ci-6 alkylaryl, Ci-6 alkylheteroaryl, or Ci-6 alkylheterocyclyl, may be optionally substituted with one to six of same or different groups selected from halogen, hydroxy, lower alkyl, lower alkoxy, -CO2H, CF3, CN, phenyl, NH2 and -NO2; or when R1and R" are attached to the same nitrogen atom, they may, together with the atom to which they are attached, form a 5 to 7 membered nitrogen containing heterocyclic ring.

[0139] In an embodiment the optional substituents may be selected from: halogen (in particular, Cl, Br or F), Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl (in particular -CF3), Ci-6 haloalkoxy (such as -OCF3), -OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, silyl, -NH2, -NHC1.4 alkyl, -N(CI-4 alkyl)2, -CN, -NO2, mercapto, -P=O(OH)(NH2), - S(O)2NH2, -S(O)2NHCI-4 alkyl, -S(O)2N(CI-4 alkyl)2, C 1-6 alkylcarbonyl, Ci-6 alkoxycarbonyl, CO2H, -S(O)R"' (where R'" is lower alkyl or cycloalkyl) and -S(O)2R"' (where R'" is lower alkyl, cycloalkyl or OH).

[0140] Unless otherwise defined and only in respect of the ring atoms of non-aromatic carbocyclic or heterocyclic compounds, the ring atoms of such compounds may also be optionally substituted with one or two =0 groups, instead of or in addition to the above described optional substituents.

[0141] When the optional substituent is or contains an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group, the group may itself be optionally substituted with one to six of the same or different substituents selected from halogen, Ci-6 alkyl, Ci-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, Ci-6 haloalkyl (in particular -CF3), Ci-6 haloalkoxy (such as -OCF3), -OH,phenyl, benzyl, phenoxy, benzyloxy, benzoyl, -NH2, -NHC1.4 alkyl, -N(CI-4 alkyl)2, -CN, -NO2, mercapto, -P=O(OH)(NH2), -S(O)2NH2, -S(O)2NHCI.4alkyl, -S(O)2N(CI-4alkyl)2, Ci-6alkylcarbonyl, Ci-6 alkoxycarbonyl, CO2H, -S(O)R"' (where R'" is lower alkyl or cycloalkyl) and -S(O)2R"' (where R'" is lower alkyl, cycloalkyl or OH).

[0142] The structures of some of the compounds of the invention may include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates) are included within the scope of this invention. The present invention includes within its scope all of these stereoisomeric forms either isolated (in, for example, enantiomeric isolation), or in combination (including racemic mixtures and diastereomic mixtures).

[0143] The skilled person will appreciate that there are a range of techniques available to produce achiral compounds of the invention in racemic, enantioenriched or enantiopure forms. For example, enantioenriched or enantiopure forms of the compounds may be produced through stereoselective synthesis and / or through the use of chromatographic or selective recrystallisation techniques.

[0144] In certain embodiments the sigma- 1 receptor modulating compounds of the present invention are compounds of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5

[0145] In an embodiment, R5is C1-C4 alkyl, including methyl, ethyl, propyl and isopropyl. In another preferred embodiment, R5is methyl.

[0146] In an embodiment R6is H. In other preferred embodiments, R6is optionally substituted C5-C12 aryl. In other preferred embodiments, R6is optionally substituted C>, aryl. In further preferred embodiments, R6is a C5-C12 aryl substituted by one or more alkoxy groups. In other preferred embodiments, R6is a C5-C12 aryl substituted by one or more methoxy groups. In further preferred embodiments, R6is a Ce aryl substituted by two methoxy groups. In further preferred embodiments, R6is a 3,4-dimethoxy phenyl.

[0147] In further embodiments each R13is H. In further embodiments the compounds have one R13group. In further embodiments the compounds have one R13group which is selected from optionally substituted phenyl or optionally substituted benzyl.

[0148] With respect to Formula (I) compounds disclosed herein the following combinations of any one or more of the following options are contemplated:R5is methyl;R6is H; orR6is -COOH; orR6is -phenyl; orR6is -3,4-dimethoxy phenyl; orR6is heteroaryl; andR13is benzyl; orR13is phenyl.

[0149] In specific embodiments the sigma- 1 receptor modulating compound of Formula (I) is a compound of Formula (la):Formula (la) or a pharmaceutically acceptable salt thereof, wherein:R5is methyl,R6is selected from H, -COOR, -OR, optionally substituted C5-C12 aryl, optionallysubstituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5.

[0150] In specific embodiments the sigma-1 receptor modulating compound of Formula(I) is a compound of Formula (lb):Formula (lb) or a pharmaceutically acceptable salt thereof, wherein:R5is methyl,R6is selected from H, -COOR, -OH, optionally substituted C5-C12 aryl, optionally substituted C4-C12 heteroaryl,R is H or optionally substituted Ci-C4 alkyl;R13at each occurrence is independently selected from H, phenyl, and benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5.

[0151] In certain embodiments sigma- 1 receptor modulating compounds of the inventions are compounds of FormulaFormula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5.

[0152] In an embodiment and with reference to Formula (II), R5is C1-C4 alkyl, including methyl, ethyl, propyl and isopropyl. In another preferred embodiment, R5is methyl.

[0153] In an embodiment, R7is selected from H, or -OR.

[0154] With respect to Formula (II) compounds disclosed herein the following combinations of any one or more of the options below are contemplated:R5is H; orR5is methyl;R7is H; orR7is OH; orR7is -C(O)OH; orR7is -C(O)OCi-C3alkyl; orR7is optionally substituted phenyl; orR7is optionally substituted benzyl;R4is -C(O)O-Ci-C4alkyl; orR4is -CH2OH. r is 1.

[0155] In specific embodiments sigma- 1 receptor modulating compounds of the inventions are compounds of Formula (Ila):Formula (Ila) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or methyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted C1-C3 alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-Ci-C4 alkyl, -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is 1, and n is an integer selected from 1, 2, 3, 4 or 5.

[0156] In specific embodiments sigma- 1 receptor modulating compounds of the inventions are compounds of Formula (lib):Formula (lib) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or methyl,R7is selected from H, or -OH,R is H or optionally substituted C1-C3 alkyl,R4 is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O- Ci-C4 alkyl, - C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is 1, and n is an integer selected from 1, 2, 3, 4 or 5.

[0157] Representative compounds of Formula (I) and (II) include:Table 1 :

[0158] The salts of the compounds of Formula (I), Formula (II) and subformulae or the embodiments mentioned hereinbefore are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts. The salts may also be cosmetically acceptable insofar as the compounds are used topically.

[0159] It will be appreciated that the compounds of Formula (I), Formula (II) and subformulae or the embodiments mentioned hereinbefore, and the salts thereof, can be presented in the form of pharmaceutically acceptable derivatives. The term "pharmaceutically acceptable derivative" includes pharmaceutically acceptable esters, prodrugs, solvates and hydrates of the compounds of Formula (I), or Formula (II) or salts thereof. Pharmaceutically acceptable derivatives may include any pharmaceutically acceptable hydrate or any other compound or prodrug which, upon administration to a subject, is capable of providing (directly or indirectly) a compound of Formula (I), Formula (II) or an active metabolite or residue thereof.

[0160] The pharmaceutically acceptable salts include acid addition salts, base addition salts, and the salts of quaternary amines and pyridiniums. The acid addition salts are formed from a compound of the subject invention and a pharmaceutically acceptable inorganic or organic acid including but not limited to hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic, ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic, or tartaric acids. The counter ion of quaternary amines and pyridiniums include chloride, bromide, iodide, sulfate, phosphate, methansulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate. The base addition salts include but are not limited to salts such as sodium, potassium, calcium, lithium, magnesium, ammonium and alkylammonium. Also, basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. The salts may be made in a known manner, for example by treating the compound with anappropriate acid or base in the presence of a suitable solvent.

[0161] The compounds of Formula (I), Formula (II) or subformulae or embodiments mentioned hereinbefore may be in crystalline form and / or as solvates (e.g. hydrates) and it is intended that both forms be within the scope of the present invention. The term "solvate" is a complex of variable stoichiometry formed by a solute and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.

[0162] The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the subject invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters, phosphate esters and those formed from amino acids, preferably valine. Any compound that is a prodrug of a compound of Formula (I), Formula (II) or the embodiments mentioned hereinbefore is within the scope and spirit of the subject invention.

[0163] The term "pharmaceutically acceptable ester" includes biologically acceptable esters of compound of Formula (I), Formula (II), subformulae or embodiments mentioned hereinbefore, such as sulphonic, phosphonic and carboxylic acid derivatives.

[0164] Thus, in another aspect of the present invention, there is provided a prodrug or pharmaceutically acceptable ester of a compound of the subject invention or of salt thereof.

[0165] It will be appreciated that the compounds of the subject invention have at least one asymmetric centre, and therefore are capable of existing in more than one stereoisomeric form. The present invention extends to each of these forms individually and to mixtures thereof, including racemates. The isomers may be separated conventionally by chromatographic methods or using a resolving agent. Alternatively the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. Where the compound has at least one carboncarbon double bond, it may occur in Z- and E- forms with all isomeric forms of the compounds of Formula (I), Formula (II) subformulae or embodiments mentioned hereinbefore being included in the present invention.

[0166] The present invention also includes where possible a salt or pharmaceutically acceptable derivative such as a pharmaceutically acceptable ester, solvate and / or prodrug of the above mentioned embodiments of the subject invention.

[0167] In another aspect of the present invention, there is provided a pharmaceutical composition that comprises a therapeutically effective amount of one or more of the aforementioned compounds or pharmaceutically acceptable salts thereof, including pharmaceutically acceptable derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent. Still a further aspect of the subject invention is a cosmetic composition that comprises a cosmetically effective amount of one or more of the aforementioned compounds or pharmaceutically or cosmetically acceptable salts thereof, including pharmaceutically acceptable derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent. A cosmetic formulation is useful to ameliorate the effects of aging and may be referred to as an anti-aging formulation.

[0168] The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers.

[0169] The pharmaceutical compositions or formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), ocular, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.

[0170] The compounds of either Formula (I), Formula (II) or subformulae or the embodiments mentioned hereinbefore, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

[0171] Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amountof the active ingredient commensurate with the intended daily dosage range to be employed. Formulations containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.

[0172] The compounds of Formula (I), Formula (II) or subformulae or embodiments mentioned hereinbefore can be administered in a wide variety of oral, topical, ocular and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of Formula (I), Formula (II) subformulae or a pharmaceutically acceptable salt thereof.

[0173] For preparing pharmaceutical compositions from the compounds of Formula (I), Formula (II) or the embodiments mentioned hereinbefore, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, dispensable granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0174] In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component.

[0175] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

[0176] The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0177] For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneouslytherein, as by stirring. The molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.

[0178] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0179] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

[0180] Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups, elixirs, or sterile ocular solutions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.

[0181] The compounds of Formula (I), Formula (II) and subformulae or the embodiments mentioned hereinbefore may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, eg. sterile, pyrogen-free water, before use.

[0182] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.

[0183] Aqueous solutions suitable for topical administration can be prepared by dissolving the active component in water or a suitable carrier, and adding excipients as desired. Where a solution is intended for a particular route of administration, e.g. nasal, ocular, oral, etc, the nature of the excipients and the form of the solution can be modified accordingly.

[0184] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

[0185] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.

[0186] For topical administration to the epidermis the compounds according to the subject invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

[0187] Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0188] Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention a compound of Formula (I), Formula (la) or Formula (lb) may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.

[0189] Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane,trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

[0190] Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[0191] In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.

[0192] For ocular administration, the compounds according to the invention may be formulated as a sterile ocular solution or as an ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release). For ocular administration, the composition is preferably in the form of an ophthalmic composition. Ophthalmic compositions are preferably formulated as eye-drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette. Preferably, the compositions are sterile and aqueous based, using purified water. In addition to the compound of the invention, an ophthalmic composition may contain one or more of: a surfactant; thickening agents; an anti-oxidant; ethanol and other excipients such as an isotonic agent, buffer, preservative, and / or pH-controlling agent. The pH of the ophthalmic composition is desirably within the range of 4 to 8.

[0193] In some embodiments, the compounds of Formula (I) or Formula (II) are administered to the subject in the form of an eye drop formulation. Depending on the concentration, the eye drop formulation may be administered as a dosage of a single drop or multiple drops to each affected eye, for example, independently at a rate of 1, 2, 3, 4, or 5 drops per affected eye.

[0194] When desired, formulations adapted to give sustained release of the activeingredient may be employed. Furthermore, the formulations may be in a form suitable for cosmetic use to ameliorate the effects of aging.

[0195] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0196] The present invention also includes compounds of Formula (I), Formula (II) subformulae or embodiments mentioned hereinbefore in the absence of carrier where the compounds are in unit dosage form.

[0197] The amount of the compound of Formula (I), Formula (II), subformulae or the embodiments mentioned hereinbefore to be administered may be in the range from about 10 mg to 2000 mg per day, depending on the activity of the compound and the disease to be treated.

[0198] Liquids or powders for intranasal administration, tablets or capsules for oral administration and liquids for intravenous administration are the preferred compositions.

[0199] The pharmaceutical preparations of the compounds of Formula (I), Formula (II) or subformulae or embodiments mentioned hereinbefore may be co-administered with one or more other active agents in combination therapy. For example the pharmaceutical preparation of the active compound may be co-administered (for example, separately, concurrently or sequentially), with one or more other agents used to treat diseases or disorders associated with mitochondrial dysfunction. For example, pharmaceutical preparations of the compounds of the subject invention may be co-administered with other mitochondrial protective agents or antioxidant compounds or a component which modulates energy metabolism such as precursors or products of cellular respiratory. In some embodiments, a pharmaceutical composition further comprising an anti-diabetic agent as an additional active agent is provided.

[0200] Furthermore, it is envisaged that pharmaceutical preparations of compounds of Formula (I) or Formula (II) may be co-administered to treat, prevent, ameliorate or reduce negative effect a sigma-1 receptor mediated disease or disorder with the administration of otheractive agents.

[0201] For example in the treatment of viral infections examples of co-administered antivirals include abacavir, didanosine, emtricitabine, entecavir, emtricitabine, lamivudine, nevirapine, telbivudine, tenofovir, tipranavir, stavudine, zalcitabine, and zidovudine. Examples of anti-cancer agents having a negative effect on mitochondrial activity or function include arsenic trioxide, cetuximab, dacarbazine, denileukin, diftitox, flutamide, gemtuzumab, methotrexate, mitoxantrone, pentostatin, and tamoxifen. Examples of antibiotics having a negative effect on mitochondrial activity or function include antimycin A, isoniazid, chloramphenicol, ethambutol, gentamycin, ketoconazole, linezolid, streptozocin, streptomycin, tobramycin, tetracyclines, and trovafloxacin. Examples of CNS drugs having a negative effect on mitochondrial activity or function include amitriptyline, amphetamines, atomoxetin, chlorpromazine, cocaine, dantrolene, desipramine, divalproex, droperidol, felbamate, fluphenazine, imipramine, methamphetamine, naltrexone, nefazodone, pergolide, and valproic acid. Examples of non-steroidal anti-inflammatory drugs (NSAIDs) having a negative effect on mitochondrial activity or function include aspirin, celecoxib, diclofenac, diflunisal, etodolac, fenoprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, meloxicam, naproxen, nabumetone, oxaprozin, piroxicam, salsalate, sulindac, thioridazine, and tolmetin.

[0202] The term “effective amount” or "therapeutically effective amount" refers to that amount which is sufficient to effect treatment, as defined above, when administered to a subj ect, such as a mammal, including a human in need of such treatment. The therapeutically effective amount will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, and may be determined routinely by one of ordinary skill in the art. The “effective amount” a particular compound may vary in accordance with the nature (e.g. physical and chemical properties) of the compound itself. Furthermore, the amount and / or concentration of the active compound administered that is deemed “effective” may differ between subjects. Additionally, the “effective amount” of the compound is the amount of the compound that is required to provide an effect at the site at which the compound is active. Accordingly, the “effective concentration” of a particular compound is the concentration of the compound that is required to provide an effect at the site at which the compound is active.

[0203] In certain embodiments, the effective amount of a compound that is administered in accordance with a method as disclosed herein is in the range of about 0.001 pM to about 10 pM.

[0204] The term "treatment" as used herein covers any treatment of a condition or disease in an animal, preferably a mammal, more preferably a human, and includes: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e. arresting its development; (iii) relieving the disease or condition, i.e., causing regression of By "treatment" may also include cosmetic treatment.

[0205] The terms "preventing" and "prophylaxis" as used herein refer to administering a medicament beforehand to avert or forestall the appearance of one or more symptoms of a disease or disorder. The person of ordinary skill in the medical art recognizes that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, or symptom of the condition and this is the sense intended in this disclosure. As used in a standard text in the field, the Physician’s Desk Reference, the terms "prevent", "preventing" and "prevention" with regard to a disorder or disease, refer to averting the cause, effects, symptoms or progression of a disease or disorder prior to the disease or disorder fully manifesting itself. This also applies to amelioration of the effects of aging to reduce the immediate impact of aging.

[0206] The terms "administer", "administering" or "administration" in reference to a compound, composition or formulation of either Formula (I), Formula (II) or embodiments mentioned hereinbefore, means introducing the compound into the system of the animal in need of treatment. When a compound of the subject invention is provided in combination with one or more other active agents, "administration" and its variants are each understood to include concurrent and / or sequential introduction of the compound and the other active agents.

[0207] The term “dose” used in relation to the compound of Formula (I) or Formula (II), or pharmaceutically salts thereof, refers to the amount of the compound that is administered to the subject in need thereof. The “dose” of the compound may be higher than the “effective amount” or “therapeutically effective amount” of the compound to be administered. The dose of the compound that is required in order to provide an effective amount or a therapeutically effective amount of the compound will vary between compounds and is related to the site of action (i.e. where the compound is effective, for example, a receptor site), manner and / or route of administration, the susceptibility of the compound to degrade, decompose or be metabolised,and the activity of the compound at the intended site.

[0208] In certain embodiments of the aspects disclosed herein, the dose of the compound of Formula (I) or Formula (II) is provided at a concentration in the range of about 1 mM to about 30 mM. In certain embodiments, the dose of the compound of Formula (I) or Formula (II) is provided at a concentration in the range of about 1 mM to about 25 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM or about 1 mM to about 5 mM. In other embodiments, the dose of the compound of Formula (I) or Formula (II) administered provides the compound at an effective amount in the range of about 0.001 pM ro about 10 pM. In other embodiments, the dose of the compound of Formula (I) or Formula (II) administered provides the compound at an effective amount of about 0.0001 pM, 0.0002 pM, 0.0003 pM, 0.0004 pM, 0.0005 pM, 0.0006 pM, 0.0007 pM, 0.0008 pM, 0.0009 pM, 0.001 pM, 0.002 pM, 0.003 pM, 0.004 pM, 0.005 pM, 0.006 pM, 0.007 pM, 0.008 pM, 0.009 pM, 0.01 pM, 0.02 pM, 0.03 pM, 0.04 pM, 0.05 pM, 0.06 pM, 0.07 pM, 0.08 pM, 0.09 pM, 0.1 pM, 0.2 pM, 0.3 pM, 0.4 pM, 0.5 pM, 0.6 pM, 0.7 pM, 0.8 pM, 0.9 pM, 1 pM, 2 pM, 3 pM, 4 pM, 5 pM, 6 pM, 7 pM, 8 pM, 9 pM or 10 pM. Any one of the concentrations and / or ranges above may apply to any one of the compounds of Formula (I) or (II), i.e. compound UTA#35, UTA#37, UTA#42, UTA#43, UTA#47, UTA#54, UTA#55, UTA#61, UTA#62, UTA#65, UTA#66, UTA#71, UTA#72, UTA#73, UTA#74, UTA#75, UTA#76, UTA#77, UTA#78, UTA#80, UTA#81, UTA#84, UTA#88, UTA#89, UTA#91, UTA#93, UTA#94, UTA#95, UTA#97, UTA#113, UTA#115, UTA#116 or UTA#117 as depicted in Table 1 below.

[0209] In certain embodiments, the compound administered in accordance with one or more methods as disclosed herein is UTA#37, UTA#54, UTA#74, UTA#77 or UTA#88. In other embodiments, the compound administered in accordance with one or more methods as disclosed herein is UTA#37, UTA#54 or UTA#77. In other embodiments, the compound administered in accordance with one or mre methods as disclosed herein is UTA#37 or UTA#77.

[0210] In certain embodiments, the dose of the compound UTA#37 is administered at a concentration of about 1 mM to about 30 mM. In other embodiments, the dose of the compound UTA#77 is administered at a concentration of about 1 mM to about 30 mM.

[0211] In certain embodiments, the dose of the compound UTA#37 administered provides the compound at an effective amount in the range of about 0.0001 pM to about 10 pM. In certainembodiments, the dose of the compound UTA#77 administered provides the compound at an effective amount in the range of about 0.001 pM to about 10 pM. In certain embodiments, the dose of the compound UTA#37 administered provides the compound at an effective amount in the range of about 0.0001 pM to about 10 pM. In certain embodiments, the dose of the compound UTA#77 administered provides the compound at an effective amount in the range of about 0.001 pM to about 10 pM.

[0212] As discussed above, the present inventors have found that administration of the compounds of Formula (I) or Formula (II) show activation of the SIR within minutes (see Figure 5B). In contrast, the use of an orthosteric ligand shows much slower activation. Once activated by administration of the compound of Formula (I) or Formula (II), the SIR remains activated for at least 21 hours (see Figure 5C). In contrast, the duration of activation after administration of an orthosteric ligand is approximately 3 hours. Given the extended period in which the SIR remains activated (compared to the shorter duration of the orthosteric ligand), the present inventors believe that the compounds disclosed herein allow for a treatment regime that is effective with fewer doses. For example, given the shorter duration of action of the orthosteric ligand, maintaining an effective concentration of the compound to provide sufficient activation likely requires administration at least once every few hours.

[0213] The present inventors believe that the methods disclosed herein can comprise administration of a compound of Formula (I) or Formula (II) once a day, which is due to the extended duration of action of the compounds. In certain embodiments, the compound of Formula (I) or Formula (II) is administered once a day. In other embodiments, the compound of Formula (I) or (II) is administered once every 24 hours. In other embodiments, the compound of Formula (I) or (II) is administered once every 24 hours ± 3 hours. In other embodiments, the compound of Formula (I) or (II) is administered once every 24 hours ± 2 hours. In other embodiments, the compound of Formula (I) or (II) is administered once every 24 hours ± 1 hour. In other embodiments, the time between administrations of the compound of Formula (I) or (II) is in the range of about 21 hours to about 27 hours. In other embodiments, the time between administrations of the compound of Formula (I) or (II) is in the range of about 22 hours to about 26 hours. In other embodiments, the time between administrations of the compound of Formula (I) or (II) is in the range of about 23 hours to about 25 hours.

[0214] The compounds of either Formula (I), Formula (II) or subformulae or embodiments mentioned hereinbefore can also be used in research applications, such as in vitro, in vivo, orex vivo experiments in order to modulate one or more biomarkers in an experimental system. Such experimental systems can be cell samples, tissue samples, cell components or mixtures of cell components, partial organs, whole organs, or organisms. Such research applications can include, but are not limited to, use as assay reagents, elucidation of biochemical pathways, or evaluation of the effects of other agents on the metabolic state of the experimental system in the presence / absence of one or more compounds of the subject invention.

[0215] Additionally, the compounds of Formula (I), subformulae or embodiments mentioned hereinbefore can be used in biochemical tests or assays. Such tests can include incubation of one or more compounds of Formula (I), Formula (II) or embodiments mentioned hereinbefore with a tissue or cell sample from a subject to evaluate a subject's potential response (or the response of a specific subset of subjects) to administration of said one or more compounds, or to determine which compound of Formula (I), Formula (II) subformulae or embodiments mentioned hereinbefore produces the optimum effect in a specific subject or subset of subjects. Accordingly, enabled herein is an assay or screen for identifying a compound of Formula (I), Formula (II) or subformulae or an embodiment mentioned hereinbefore that modulates the activity of one or more biomarkers, the assay comprising the steps of i) obtaining a cell sample or tissue sample from a subject or set of subjects in which modulation of one or more biomarkers can be assayed; ii) administering one or more compounds of the subject invention to the cell sample(s) or tissue sample(s); and 3) quantifying the effect of the compounds on the modulation of the one or more biomarkers after administration of the one or more compounds, compared to the status of the biomarker prior to administration of the one or more compounds.

[0216] Further enabled herein is an assay or screen for identifying a compound of Formula (I), or Formula (II), or subformulae, or an embodiment mentioned hereinbefore that modulates the activity of one or more biomarkers, the assay comprising the steps of i) obtaining a cell sample or tissue sample from a subject or set of subjects in which modulation of one or more biomarkers can be assayed; ii) administering at least two compounds of the subject invention to the cell sample(s) or tissue sample(s); iii) quantifying the effect of the compounds on the modulation of the one or more biomarkers after administration of the at least two compounds, compared to the status of the biomarker prior to administration of the at least two compounds, and iv) selecting a compound for use in treatment, suppression, or modulation based on the amount of modulation determined in step iii).

[0217] In an embodiment, the biomarker is a chemokine, cytokine, growth factor or chemotactic agent. In the method of identifying a compound of Formula (I), Formula (II) or an embodiment mentioned hereinbefore which modulates the activity of one or more biomarkers, the compounds may be selected on the basis of one or more physicochemical, pharmacokinetic, biological, and / or physiological properties. Examples of such properties include, but are not limited to, binding affinity, selectivity, toxicity, efficacy, stability, lipophilicity, and / or activity, such as agonism, antagonism and / or inhibition.

[0218] The interaction with a biomarker may be detected by any convenient means such as nuclear magnetic resonance (NMR), mass spectrometry (MS), isothermal titration calorimetry (ITC), dynamic light scattering (DLS), surface plasmon resonance (SPR), dual polarization interferometry (DPI), microscale thermophoresis (MST), gel retardation, filter retardation, affinity co-electrophoresis, bioluminescent resonance energy transfer (BRET) assays, fluoresence resonance energy transfer (FRET) assays, fluorescence polarization (FP) assays, scintillation proximity assays or immobilization to biochips or other surfaces including those coupled with mass spectrometric detection.

[0219] The latter may be accomplished by first immobilizing a compound to a chip and then adding a sample. Alternatively, a given biomarker may be immobilized to a chip and used to screen for the ability of a compound to bind thereto.

[0220] There are, of course, any number of other assays, which may be used to screen for interaction between a compound of Formula (I) and biomarker. Another assay is a filter binding assay. In this assay, one of a compound, or a biomarker is labeled with a reporter molecule capable of providing an identifiable signal such as a fluorescent dye and both molecules are allowed to interact in solution. The resulting mixture is then passed through a filter capable of retarding one of components, such as the compound or the biomarker.

[0221] Different compounds will interact with different biological regulators, or different regulators will interact with different compounds or both. In addition, different compounds may interact with different biological regulator receptor chains. Accordingly, another assay involves the use of affinity columns carrying immobilized chemokines. The compounds are then passed through the column and the presence of retardation of the compounds determined. A salt gradient is conveniently used to elute bound compounds.

[0222] Other examples of assays contemplated by the present invention include functional assays such as whole cell assays. Such functional assays may provide more useful information on the effect of the tested compound than binding assays.

[0223] As used herein the expression "pharmaceutically acceptable salt" refers to the salt of a given compound, wherein the salt is suitable for administration as a pharmaceutical. For example, such salts may be formed by the reaction of an acid or a base with an amino or a carboxyl group respectively.

[0224] Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted amines, and cyclic amines, including isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-ethylpiperidine. It should also be understood that other carboxylic acid derivatives would be useful, for example carboxylic acid amides, including carboxamides, lower alkyl carboxamides, di(lower alkyl) carboxamides, and the like.

[0225] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0226] The term "protecting group" refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to re-establish the hydroxyl, thio, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blockinggroups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Protecting groups are disclosed in more detail in Greene and Wuts (1991), "Protective Groups in Organic Synthesis" 2nd Ed, John Wiley and Sons, N.Y.

[0227] Examples of removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (ALOC) and the like, which can be removed by conventional conditions compatible with the nature of the product.

[0228] Examples of removable alcohol blocking groups include conventional substituents such as ethers, including methyl ethers, t-butyl ether, silyl ethers; methoxymethyl ether (MOM), allyl ether, benzyl ethers, and esters such as acetic acid esters (AcO-) and benzoic acid esters, which can be removed by conventional conditions compatible with the nature of the product.

[0229] Examples of removable carbonyl or acid blocking groups include conventional substituents such as esters, including methyl ester, t-butyl ester, benzyl esters, which can be removed by conventional conditions compatible with the nature of the product.

[0230] "Selectivity" or "specificity" in general is a measure of the binding preferences of a ligand for different receptors and / or a measure of the binding preferences of different ligands for a receptor. The selectivity of a ligand with respect to its target receptor relative to another receptor is given by the ratio of the respective values of Ka (i.e., the dissociation constants for each ligand-receptor complex), or in cases where a biological effect is observed below the Kd, selectivity is given by the ratio of the respective ECso values (i.e. the concentrations that produce 50% of the maximum response for the ligand interacting with the two distinct receptors).

[0231] Various embodiments of the invention disclosed herein include:1. A method for the treatment of an ocular disease associated with Ca2+dysregulation in a subject in need thereof, the method comprising administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof.2. A method for the treatment of an ocular disease associated with Ca2+dysregulation in a subject in need thereof, the method comprising administering a compound of Formula (II) or a pharmaceutically acceptable salt thereof.3. A method according to claim 1 or 2, wherein the ocular disease is a glaucoma, macular degeneration, age-related macular degeneration, cataract, dry eye disease or diabetic retinopathy.4. A method according to any one of claims 1 to 3, wherein the ocular disease is diabetic retinopathy.5. A method according to claim 4, wherein the diabetic retinopathy is a mild diabetic retinopathy or a moderate diabetic retinopathy.6. A method according to claim 4, wherein the diabetic retinopathy is a nonproliferative diabetic retinopathy.7. A method according to claim 4, wherein the diabetic retinopathy is a proliferative diabetic retinopathy.8. A method according to any one of claims 1 to 7, wherein the compound of Formula (I) or Formula (II) is administered at an effective concentration in the range of from about 0.0001 pM to about 10 pM.9. A method according to any one of claims 1 to 8, wherein the compound of Formula (I) or Formula (II) is administered at an effective concentration in the range of from about 0.001 pM to about 10 pM.10. A method according to any one of claims 1 to 8, wherein the compound of Formula (I) or Formula (II) is administered as an eye drop formulation.11. A method according to any one of claims 1 to 10, wherein the compound of Formula (I) or Formula (II) is administered once a day.12. A method for combination therapy for treating diabetic retinopathy said combination therapy including the step of administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, together with an VEGF inhibitor, wherein the administration of the combination can take place sequentially, concomitantly, or simultaneously.13. A method for combination therapy for treating diabetic retinopathy said combination therapy including the step of administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof together with an VEGF inhibitor, wherein the administration of the combination can take place sequentially, concomitantly, or simultaneously.14. A method of protecting pericyte function in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.15. A method of protecting pericyte function in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.16. A method according to any one of claims 1 to 15, wherein the compound is a compound of Formula (la) or a pharmaceutically acceptable salt thereof, a compound of Formula (lb) or a pharmaceutically acceptable salt thereof, a compound of Formula (Ila) or a pharmaceutically acceptable salt thereof, or a compound of Formula (lib) or a pharmaceutically acceptable salt thereof.17. A method according to any one of claims 1 to 16, wherein the compound is selected from the group consisting of:18. A method of treating a sigma-1 receptor (SIR) associated disease or disorder in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (I) or a pharmaceutically acceptable salt thereof.19. A method of treating a disease or disorder associated with ER stress in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.20. A method of treating a sigma-1 receptor (SIR) associated disease or disorder in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (II) or a pharmaceutically acceptable salt thereof.21. A method of treating a disease or disorder associated with ER stress in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.22. A method of treating a sigma-1 receptor (SIR) associated disease or disorder in a subject in need thereof wherein the disease or disorder is one associated with ER stress.23. A method of treating a disease or disorder which would benefit from sigma- 1 receptor (SIR) activation in a subject in need thereof, wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.24. A method of treating a disease or disorder which would benefit from sigma- 1 receptor (SIR) activation in a subject in need thereof, wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (II) or a pharmaceutically acceptable salt thereof.25. A method of treating sigma- 1 receptor associated diseases and disorders include butnot limited to fibroproliferative disease including progressive fibrosis; lowering systolic blood pressure (treatment of isolated systolic hypertension); general anxiety disorder; Parkinson's disease associated with Parkin mutation which causes Pac-R accumulation in the ER; treating abuse of pschotropic substances (addiction treatment); or cancer (breast, lung, prostate, ovarian, colorectal or CNS).26. A method of treating diseases and disorders associated with ER stress including diabetes mellitus; viral infections (eg Newcastle disease virus); retinitis pigmentation (RP); Alzheimers disease (AD) associated with misfolded beta-amyloid; Parkinson's disease associated with MPTP induced ER stress; Wolfram's disease; steatosis (a metabolic syndrome) which is ER stress induced; cancer -ER stress due to hypoxia - such as: multliple myeloma, melanomas, glioblastoma, breast and cervical cancers; amyotrophic lateral sclerosis (ALS); adjunct therapy for subjects exposed to chemotherapy agents that cause ER stress (eg brefeldin A); hereditary tyrosinemia type 1; kidney disease; liver disease; ischemia; atherosclerosis; inflammation disorders caused by ER stress; treatment of pain disorders; and bipolar disorder (mood disorders).27. A method of treating a sigma-1 receptor (SIR) associated disease or disorder in a subject in need thereof wherein the subject is administered with an effective amount of a sigma- 1 receptor modulating compound of Formula (I) or a pharmaceutically acceptable salt thereof.28. A method of treating a disease or disorder associated with ER stress in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.29. A method of treating a sigma-1 receptor (SIR) associated disease or disorder in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.30. A method of treating a disease or disorder associated with ER stress in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.31. A method of treating a sigma-1 receptor (SIR) associated disease or disorder, wherein the disease or disorder is selected from fibroproliferative disease including progressivefibrosis; lowering systolic blood pressure (treatment of isolated systolic hypertension); general anxiety disorder; Parkinson's disease assosciated with Parkin mutation which causes Pac-R accumulation in the ER; treating abuse of pschotropic substances (addiction treatment); cancer (breast, lung, prostate, ovarian, colorectal or CNS); or treatment of viral infections.32. A method of treating a disease or disorder associated with ER stress, wherein the disease or disorder is selected from diabetes mellitus; viral infections; retinitis pigmentation (RP); Alzheimers disease (AD) associated with misfolded beta-amyloid; Parkinson's disease assosciated with MPTP induced ER stress; steatosis (a metabolic syndrome) which is ER stress induced; cancer -ER stress due to hypoxia - such as: multliple myeloma, melanomas, glioblastoma, breast and cervical cancers; amyotrophic lateral sclerosis (ALS); adjunct therapy for subjects exposed to chemotherapy agents that cause ER stress (eg brefeldin A); herediatary tyrosinemia type 1; kidney disease; liver disease; ischemia; atherosclerosis; inflammation disorders caused by ER stress; treatment of pain disorders; and bipolar disorder (mood disorders)33. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.34. Use of a compound of Formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.35. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.36. Use of a compound of Formula (II) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.37. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for protecting pericyte function.37. Use of a compound of Formula (II) or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for protecting pericyte function.EXAMPLESGENERAL SYNTHETIC SCHEMES AND DESCRIPTION

[0232] For convenience, many chemical moi eties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso-propyl (iPr), n-butyl (nBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), methoxy (MeO), ethoxy (EtO), trimethyl silyl (TMS), tert-butyloxycarbonyl (Boc), and acetyl (Ac).

[0233] For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), diethyl ether (Et2O), ethyl acetate (EtOAc), triethylamine (TEA), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), trifluoroethanol (TFE), dimethylformamide (DMF), sodium sulphate (Na2SC>4), tetrahydrofuran (THF), meto-chloroperoxybenzoic acid (mCPBA), hexamethyldisilazane sodium salt (NaHMDS), O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU), dimethylsulfoxide (DMSO), magnesium sulphate (MgSCU), sodium hydrogen carbonate (NaHCOs), tert-butanol (Z-BuOH), l-ethyl-3- (3 -dimethylaminopropyl) carbodiimide hydrochloride salt (EDC1.HC1), tetra-n- butylammonium fluoride (TBAF), tetra-n-butylammonium bromide (TBAB), N,N- diisopropylethylamine (DIPEA), tert-butyldimethylsilyl (TBDMS), 1 -hydroxybenzotriazole (HOBt), trans-dichlorobis(triphenylphosphine)palladium(II) (PdChfPPl^), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) tris(dibenzylideneacetone) dipalladium(O) (Pd2(dba)s), tri-t-butyl phosphonium tetrafluorob orate (Z-BU3PH.BF4), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine (PPI13), diisopropyl azodi carb oxy late (DIAD), pyridinium chlorochromate (PCC), borane dimethylsulfide (BMS), titanium isopropoxide (TiOiPn), sodium triacetoxyborohydride (NaBH(OAc)3), sodium cyanoborohydride (NaBH3(CN)), sodium borohydride (NaBHj), ammonium chloride (NH4CI), chloroform (CHCh), manganese dioxide (MnCh), potassium carbonate (K2CO3), 1,2-di chloroethane (DCE), sodium azide (NaNs), sodium nitrite (NaNCh) and di-tert-butyl dicarbonate (BOC2O).

[0234] General Procedure A: Quinone acid synthesis; Silver mediated radical decarboxylationmenadioneCarboxylic acid (2 equiv.) was added to a solution of menadione (1 equiv.) in CH3CN / H2O (3: 1) and the mixture was heated to 75 °C. To this solution, AgNOs (0.1 equiv.) was added followed by the slow addition of (NH4)2S20s (2.5 equiv.) in H2O (5 mL) over 10 mins. The resulting mixture was stirred for a further 2 h. The mixture was cooled to room temperature, extracted with dichloromethane and the organic extract washed with H2O. The organic layer was dried over MgSC , filtered and the solvent removed under reduced pressure to give the crude product, which was purified by flash chromatography (silica gel).

[0235] General Procedure B: Quinone amide couplingQuinone acid (1 equiv.) was added to anhydrous di chloromethane (5- 10ml) under an atmosphere of N2 and cooled to 0 °C. Amine (1 equiv.), dimethylaminopyridine (DMAP, 0.1 equiv.), triethylamine (EtsN, 2.5 equiv.) and a coupling agent (1.4 equiv.) were added consecutively and the reaction mixture warmed slowly to room temperature before leaving overnight. The reaction was quenched with H2O (20mL) and the organic layer washed with sat. KHSO4 solution, sat. NaHCOs solution and H2O. The organic layer was dried with MgSC , filtered and the solvent removed under reduced pressure to give a crude product, which was purified by flash chromatography (silica gel) to give the pure analogue.

[0236] General Procedure C: t-butyl ester deprotection methodThe t-butyl esters were added to 10% TFA in dichloromethane (5.0 mL) and the reaction mixture stirred at room temperature over night before the solvent was removed under reduced pressure. The crude product was obtained and purified by flash chromatography (silica gel) to give the pure analogue.

[0237] Representative ExamplesRepresentative examples of compounds of Formula (I) were generated as described under General Procedures A, B and / or C.

[0238] Intermediate Example l:4-(3-Methyl-l,4-naphthalen-2-yl)-butanoic acid (UTA#23)UTA#23 was prepared according to general procedure A from menadione (1.953 g, 11.34 mmol) and glutaric acid (3.041 g, 23.01 mmol) and purified by flash chromatography (silica gel, 100 % CH2Q2 followed by 100 % ethyl acetate) to give UTA#23 as a yellow solid in 40 % yield (1.169 g, 4.525 mmol) with a melting point of 74-78 °C.'H NMR 5 (CDCh, 400 MHz): 1.82 (quin, J =7.6 Hz, 2H), 2.20 (s, 3H), 2.46 (t, J =7.2 Hz, 2H), 2.69 (t, J= 7.9 Hz, 2H), 7.66 - 7.69 (m, 2H), 8.04 - 8.06 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.84, 23.57, 26.41, 33.89, 126.43, 126.50, 132.24, 132.28, 133.61, 133.62, 144.15, 146.27, 179.39, 184.77, 185.36; IR VmaX: 3064, 2938, 2359, 2340, 1706, 1699, 1695, 1658, 1616, 1595, 1412, 1379, 1325, 1295, 1260, 717, 692, cm'1

[0239] Intermediate Example 2: 5-(3-methyl-l,4-naphthoquinone-2-yl)propanoic acid (UTA#28)UTA#28) was prepared according to general procedure A from menadione (12) (1.995 g, 11.59 mmol) and succinic acid (2.757 g, 23.34 mmol) and the product purified by flash chromatography (100% dichloromethane followed by 100% ethyl acetate) to give UTA#28) asa crystalline yellow solid in 20 % yield (0.5607 g, 2.296 mmol) with a melting point of 68 - 72'H NMR 5 (CDC13, 400 MHz): 2.23 (s, 3H), 2.60 (t, J = 7.9 Hz, 2H), 2.98 (t, J = 7.9 Hz, 2H), 7.69 - 7.71 (m, 2H), 8.06 - 8.09 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.9, 22.7, 32.6, 126.5, 126.5, 132.2, 132.3, 133.75, 133.76, 144.7, 144.9, 177.8, 184.6, 185.2 ; IR Vmax: 2932 (- OH), 1738 (C=O), 1706 (C=O), 1658 1595, 1379, 1330, 1296, 716 cm'1

[0240] Intermediate Example 3: 5-(3-methyl-l,4-naphthoquinone-2-yl)pentanoic acid (UTA#67)UTA#67 was prepared according to general procedure A from menadione (2.1636 g, 12.566 mmol) and adipic acid (3.7242 g, 25.484 mmol) and the product purified by flash chromatography (100% di chloromethane followed by 100% ethyl acetate) to give UTA#67 as a crystalline yellow solid in 78 % yield (2.6528 g, 9.7422 mmol) with a melting point of 66 - 70 °C.XH NMR 5 (CDCh, 400 MHz): 1.49 - 1.57 (m, 2H), 1.70 - 1.77 (m, 2H), 2.17 (s, 3H), 2.40 (t, J= 7.4 Hz, 2H), 2.64 (t, J= 7.9 Hz, 2H), 7.66 - 7.68 (m, 2H), 8.03 - 8.05 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.7, 24.9, 26.7, 28.1, 33.8, 126.3, 126.4, 132.20, 132.21, 133.4, 133.5, 143.5, 146.8, 179.6, 184.7, 185.3; IR Vmax: 2939, 1705, 1658, 1618, 1595, 1379, 1327, 1294, 1261, 715 cm'1

[0241] Intermediate Example 4: 5-(3-methyl-l,4-naphthoquinone-2-yl)hexanoic acid (UTA#70)UTA#70 was prepared according to general procedure A from menadione (2.010 g, 11.676 mmol) and pimelic acid (3.720 g, 23.229 mmol) and the product purified by flash chromatography (100% di chloromethane followed by 100% ethyl acetate) to give UTA#70 as a crystalline yellow solid in 57 % yield (1.921 mg, 6.710 mmol) with a melting point of 49 - 51 °C.H NMR 5 (CDC13, 400 MHz): 1.45 - 1.51 (m, 4H), 1.69 (quin, J= 7.4 Hz, 2H), 2.18 (s, 3H), 2.36 (t, J= 7.4 Hz, 2H), 2.63 (t, J= 7.4 Hz, 2H), 7.66 - 7.69 (m, 2H), 8.05 - 8.07 (m, 2H); 'C NMR 5 (CDC13, 100 MHZ): 12.7, 24.5, 26.9, 28.4, 29.4, 33.9, 126.3, 126.4 132.2, 132.3, 133.46, 133.49, 143.4, 147.2, 179.6, 184.8, 185.4; IR Vmax: 2937 (-OH), 1707 (C=O), 1658 (C=O), 1595, 1327, 1294, 1259, 715 cm'1.

[0242] Intermediate Example 5: 4-(l,4-naphthoquinone-2-yl)butanoic acid (UTA# 59)UTA#59 was prepared according to general procedure A from naphthoquinone (1.9989 g, 12.64 mmol) and glutaric acid (0.8354 mg, 6.323 mmol) and the product purified by a Revel eris (Registered Trade Mark) X2 automated flash chromatography system (Eluent: gradient 0 - 80 % ethyl acetate in hexane, Column: Reveleris (Registered Trade Mark) Silica 24 g, Flow rate: 18 mL / min) to give UTA#59 as a brown solid in 42 % yield (0.6546 g, 2.680 mmol) with a melting point of 120 - 122 °C.'H NMR 5 (CD3OD, 400 MHz): 1.90 (quin, J= 7.6 Hz, 2H), 2.39 (t, J= 7.2 Hz, 2H), 2.62 (td, J= 7.6, 1.1 Hz, 2H), 6.85 (t, J= 1.2 Hz, 1H), 7.78 - 7.80 (m, 2H), 8.02 - 8.04 (m, 1H), 8.07 - 8.10 (m, 1H);13C NMR 5 (CD3OD, 100 MHz): 24.4, 30.0, 34.3, 126.8, 127.4, 133.4, 133.7, 134.8, 134.9, 136.0, 152.4, 186.1, 186.3 (one carbon missing or overlapped) ; IR Vmax: 2956, 1699, 1660, 1620, 1953, 1417, 1327, 1303, 1265, 1143, 783, 661.

[0243] Example 1: (R)-methyl-2(4-(3-methyl-l,4-naphthoquinone-2-yl)butamido)-3- phenylpropanoate (UTA#35)UTA#35 was prepared according to general procedure B from UTA#23 (107.7 mg, 0.4170 mmol) and (R)-phenylalanine methyl ester (90.4 mg, 0.4193 mmol). The product purified by a Reveleris (Registered Trade Mark) X2 automated flash chromatography system (Eluent: gradient 100 % Hexanes - 100 % ethyl acetate, Column: Reveleris (Registered Trade Mark) Silica 4 g, Flow rate: 18 mL / min) to give UTA#35 as a yellow oil in 29 % yield (51.3 mg, 0.1223 mmol).'H NMR 5 (CDCh, 400 MHz): 1.80 (quin, J = 8.2 Hz, 2H), 2.20 (s, 3H), 2.29 (t, J= 7.2 Hz, 2H), 2.65 (t, J= 7.9, 2H), 3.15 (qd, J= 14.0, 6.0 Hz, 2H), 3.74 (s, 3H), 6.11 (d, J = 7.8, 1H), 4.92 (q, J= 6.1 Hz, 1H), 7.12 - 7.14 (m, 2H), 7.24 - 7.31 (m, 3H), 7.70 - 7.72 (m, 2H), 8.07 - 8.10 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.9, 24.3, 26.4, 23.9, 38.1, 52.5, 53.2, 126.4, 126.5, 127.3 128.7 (two carbons), 129.4 (two carbons), 132.2, 132.3, 133.5, 133.6, 136.1, 144.2, 146.4, 172.0, 172.3, 184.9, 185.3; HRMS: For C25H25N1O5, predicted 419.17327, found 419.17403; MS m / z (EI+): 419 (M+, 45), 241 (100), 197 (50), 162 (100), 120 (45); IR Vmax : 3371, 3293, 2951, 1745, 1652, 1596, 1538, 1436, 1378, 1329, 1295, 1215, 717.

[0244] Example 2: (S)-tert-butyl-2-(4-(3-methyl-l,4-naphthoquinone-2-yl)butanamido)-3- phenylpropanoate (UTA#36)UTA#36 was prepared according to general procedure B from UTA#23 (504.2 mg, 1.9522 mmol) and L-phenylalanine t-butyl ester.HCl (489.4 mg, 1.9023 mmol) and the product purified by flash chromatography (40 % ethyl acetate / hexanes) to give UTA#36 as a yellow oil in 36 % yield (317.3 mg, 0.6875 mmol).'H NMR 5 (CDCh, 400 MHz): 1.40 (s, 9H), 1.78 (quin, J= 7.8 Hz, 2H), 2.17 (s, 3H), 2.27 (t, J= 7.4 Hz, 2H), 2.62 (t, J= 8.0 Hz, 2H), 3.04 - 3.13 (m, 2H), 4.77 (q, J= 6.2 Hz, 1H), 6.09 (d, J= 7.8 Hz, 1H), 7.14 - 7.27 (m, 5H), 7.66 - 7.69 (m, 2H), 8.04 - 8.07 (m, 2H)13C NMR 5 (CDCh, 100 MHz): 12.8, 24.3, 26.3, 28.0 (three carbons), 36.1, 38.2, 53.5, 82.4,126.3, 126.4, 127.0, 128.4 (two carbons), 129.5 (two carbons), 132.21, 132.26, 133.4, 133.5,136.3, 144.0, 146.4, 170.9, 171.8, 184.8, 185.3; [a]D20: +36.24° (c 0.91, CHCh); IR Vmax: 3420, 2978, 1732, 1658, 1595, 1525, 1367, 1329, 1294, 1257, 1226, 1155, 700.

[0245] Example 3: (S) -tert-butyl- 1-( 4-( 3-methyl-l, 4-naphthoquinone-2- yl) butanoyl)pyrrolidine-2-carboxylate (UTA# 42)UTA#42 was prepared according to general procedure B from UTA#23 (196.9 mg, 0.7623 mmol) and L-proline t-butyl ester.HCl (139.5 mg, 0.6716 mmol) and the product purified by flash chromatography (60 % ethyl acetate / hexanes) to give UTA#42 as yellow oil in 53 % yield (145.8 mg, 0.3543 mmol).XH NMR 5 (CDCh, 400 MHz): 1.44 (s, 9H), 1.82 - 1.88 (m, 2H), 1.90 - 1.96 (m, 2H), 2.04 - 2.13 (m, 2H), 2.21 (s, 3H), 2.36 - 2.48 (m, 2H), 2.67 - 2.71 (m, 2H), 3.47 - 3.52 (m, 1H), 3.59 - 3.64 (m, 1H), 4.37 (dd, J= 8.5, 3.9 Hz, 1H), 7.66 - 7.68 (m, 2H), 8.03 - 8.07 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.8, 23.7, 24.7, 26.5, 28.0 (three carbons), 29.3, 34.1, 47.1, 59.5, 81.2, 126.2 (two carbons), 132.23, 132.26, 133.3 (two carbons), 144.0, 146.7, 171.0, 171.6, 184.7, 185.3 ; [a]D20: +48.70 ° (c 0.97, CHCh); IR Vma : 2976, 2935, 1735, 1654, 1618, 1595, 1456, 1425, 1367, 1294, 1153, 719

[0246] Example 4: tert-Butyl 2-(4-(3-methyl-l,4-naphthoquinone-2- yl)butanamido)acetate (UTA#47)UTA#47 was prepared according to general procedure B from 4-(3 -methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (165 mg, 0.6381 mmol) and glycine / -butyl ester (148 mg, 0.8852 mmol) and the product purified by flash chromatography (50 % ethyl acetate / hexanes) to give UTA#47 as yellow viscous oil in 36 % yield (85 mg, 0.2294 mmol).'H NMR 5 (CDC13, 400 MHz): 1.41 (s, 9H), 1.79 (quin, J = 7.2 Hz, 2H), 2.15 (s, 3H), 2.31 (t, J = 7.2 Hz, 2H), 2.62 - 2.62 (m, 2H), 3.89 (d, J = 5.1 Hz, 2H), 6.27 - 6.29 (m, 1H), 7.60 - 7.65 (m, 2H), 7.98 - 8.01 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.7, 24.3, 26.3, 28.0, 35.8, 42.0, 82.2, 126.25, 126.29, 132.13, 132.17, 133.3, 133.4, 144.0, 146.3, 169.2, 172.4, 184.7, 185.1; IR Vmax: 3369 (N-H), 2978, 1743 (C=O), 1660 (C=O), 1595, 1521, 1369, 1329, 1294, 1224, 1157, 717 cm-1

[0247] Example 5: (S)-tert-butyl-4-methyl-2-(4-(3-methyl-l,4-naphthoquinone-2- yl)butanamido)pentanoate (UTA#53)UTA#53 was prepared according to general procedure B from 4-(3 -Methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (194 mg, 0.7496 mmol) and L-Leucine t-butyl ester.HCl (168 mg, 0.7509 mmol) and the product purified by flash chromatography (40 % ethyl acetate / hexanes) to give UTA#53 as yellow oil in 39 % yield (124 mg, 0.2898 mmol).1H NMR 5 (CDC13, 400 MHz): 0.90 (d, J = 6.5 Hz, 6H), 1.42 (s, 9H), 1.46 - 1.65 (m, 2H), 1.79 (quin, J = 7.4 Hz, 2H), 2.16 (s, 3H), 2.29 (t, J = 7.4 Hz, 2H), 2.62 - 2.66 (m, 2H), 4.49 (td, J = 8.6, 5.3 Hz, 1H), 6.16 (d, J = 8.3 Hz, 1H), 7.62 - 7.66 (m, 2H), 7.98 - 8.03 (m, 2H);13C NMR 5 (CDC13, 100 MHz):12.7, 22.1, 22.8, 24.3, 25.0, 26.4, 28.07, 36.1, 41.9, 51.4, 81.8, 126.2, 126.3, 132.1, 132.2, 133.40, 133.43, 144.0, 146.4, 171.9, 172.5, 184.8, 185.2; [a]D20: -2.620(c 1.06, CHC13); IR Vmax: 3354 (N-H), 2958, 2870, 1734 (C=O), 1718 (C=O), 1660 (C=O),1595, 1541, 1521, 1456, 1367, 1329, 1294, 1149, 717 cm-1

[0248] Example 6: (S)-tert-butyl-2-(3-(3-methyl-l,4-naphthoquinone-2-yl)propanamido)~ 3-phenylpropanoate (UTA#65)UTA#65 was prepared according to general procedure B from 3 -(3 -methyl- 1,4-naphthal en-2- yl)-propanoic acid (UTA#28) (119 mg, 0.4876 mmol) and L-phenylalanine t-butyl ester.HCl (115 mg, 0.4462 mmol) and the product purified by flash chromatography (30 % ethyl acetate / hexanes) to give UTA#65 as yellow oil in 22 % yield (45 mg, 0.0997 mmol).XH NMR 5 (CDC13, 400 MHz): 1.37 (s, 9H), 2.94 (s, 3H), 2.37 - 2.41 (m, 2H), 2.92 (t, J = 7.8 Hz, 2H), 3.05 (d, J = 6.1 Hz, 2H), 4.71 - 4.76 (m, 1H), 6.08 (d, J = 7.7 Hz, 1H), 7.09 - 7.21 (m, 5H), 7.66 - 7.68 (m, 2H), 8.02 - 8.05 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.8, 23.4, 28.0, 34.9, 38.1, 53.5, 82.4, 126.33, 126.39, 127.0, 128.4 (2 x C), 129.5 (2 x C), 132.1, 132.2, 133.50, 133.54, 136.2, 144.5, 145.4, 170.7, 171.0, 184.7, 185.0; [a]D20: +29.91° (c 0.54, CHC13); IR Vmax: 3365 (N-H), 2978, 1732(C=O), 1718 (C=O), 1660 (C=O), 1595, 1521, 1456, 1367, 1294, 1153, 700 cm-1

[0249] Example 7: (S)-tert-butyl-2-(3-(3-methyl-l,4-naphthoquinone-2-yl)pentanamido)~ 3-phenylpropanoate (UTA#71)UTA#71 was prepared according to general procedure B from 5-(3-methyl-l,4- naphthoquinone-2-yl)pentanoic acid (UTA#67) (205 mg, 0.7525 mmol) and L-phenylalanine t-butyl ester.HCl (188 mg, 0.7308 mmol) and the product purified by flash chromatography (40 % ethyl acetate / hexanes) to give UTA#71 as bright yellow oil in 69 % yield (240 mg, 0.5055 mmol).'H NMR 5 (CDC13, 400 MHz): 1.35 (s, 9H), 1.39 - 1.47 (m, 2H), 1.67 (quin, J = 7.5 Hz, 2H), 2.11 (s, 3H), 2.20 (t, J = 7.5 Hz, 2H), 2.58 (t, J = 7.9 Hz, 2H), 2.98 - 3.08 (m, 2H), 4.70 - 4.75 (m, 1H), 6.09 (d, J = 7.6 Hz, 1H), 7.09 - 7.12 (m, 5H), 7.60 - 7.64 (m, 2H), 7.98 - 8.02 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.6, 25.6, 26.5, 27.9 28.0, 36.0, 38.0, 53.4, 82.2, 126.1, 126.2, 126.8, 128.3 (2 x C), 129.4 (2 x C), 132.11, 132.12, 133.3 (2 x C), 136.2, 143.4, 146.8, 170.8, 172.1, 184.6, 185.1; [a]D20: +37.83° (c 0.92, CHC13); IR VmaX: 3306 (N-H), 2978, 2933, 1732 (C=O), 1658 (C=O), 1595, 1531, 1367, 1329, 1257, 1294, 1155, 715 cm-1

[0250] Example 8: N-(2-(lH-indol-3-yl)ethyl)-4-(3-methyl-l,4-naphthoquinone-2- yl)butanamide (UTA#73)UTA#73 was prepared according to general procedure B from UTA#23 (193.9 mg, 0.7507 mmol) and tryptamine (123.5 mg, 0.7708 mmol) and the product purified by flash chromatography (80 % ethyl acetate / hexanes) to give UTA#73 as a brown viscous oil in 42 % yield (127.3 mg, 0.3178 mmol).'H NMR 5 (CDCh, 400 MHz): 1.77 (quin, J = 7.6 Hz, 2H), 2.14 (s, 3H), 2.22 (t, J= 7. Hz, 2H), 2.59 (t, J= 7.9 Hz, 2H), 2.97 (t, J= 6.8 Hz, 2H), 3.61 (q, J= 6.2 Hz, 2H), 6.13 (t, J= 5.2 Hz, 1H), 7.01 (bs, 1H), 7.04 - 7.08 (m, 1H), 7.11 - 7.15 (m, 1H), 7.32 (d, J= 8.1 Hz, 1H), 7.56 (d, J= 7.9 Hz, 1H), 7.64 - 7.67 (m, 2H), 7.99 - 8.04 (m, 2H), 8.69 (bs, 1H);13C NMR 5 (CDCh, 100 MHz): 12.7, 24.3, 25.2, 26.3, 36.1, 39.9, 111.4, 112.7, 118.6, 119.3, 122.0, 122.2, 126.2(two carbons), 127.3, 132.02, 132.09, 133.42, 133.47, 136.4, 143.9, 146.2, 172.6, 184.8, 185.1; IR Vmax: 3392, 3294, 2935, 1705, 1653, 1595, 1527, 1458, 1332, 1296, 740, 715

[0251] Example 9: N-(4-hydroxyphenethyl)-4-(3-methyl-l,4-naphthoquinone-2- yl)butanamide (UTA#74)UTA#74 was prepared according to general procedure B from UTA#23 (235.6 mg, 0.9122 mmol) and tyramine (119.0 mg, 0.8675 mmol) and the product purified by flash chromatography (80 % ethyl acetate / hexanes) to give UTA#74 as yellow solid in 33 % yield (108.9 mg, 0.2885 mmol) with a melting point of 116 - 118 °C.'H NMR 5 (CDCh, 400 MHz): 1.76 (quin, J = 7.5 Hz, 2H), 2.12 (s, 3H), 2.24 (t, J= 7.2 Hz, 2H), 2.56 - 2.60 (m, 2H), 2.71 (t, J= 7.0 Hz, 2H), 3.47 (q, J= 6.4 Hz, 2H), 6.22 (t, J= 5.5 Hz, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.96 (d, J= 8.4 Hz, 2H), 7.62 - 7.65 (m, 2H), 7.97 - 8.00 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.7, 24.4, 16.3, 34.7, 36.1, 41.1, 115.7 (two carbons), 126.3 (two carbons), 129.8 (two carbons), 129.9, 132.0, 132.1, 133.53, 133.59, 144.2, 146.2, 155.3, 173.1, 185.0, 185.2; IR Vmax: 3365, 3306, 2935, 1654, 1616, 1595, 1541, 1516, 1375, 1330, 1296, 715

[0252] Example 10: (S)-tert-butyl-2-(6-(3-methyl-l,4-naphthoquinone-2-yl)hexanamido)~ 3-phenylpropanoate (UTA#75)UTA#75 was prepared according to general procedure B from 6-(3 -methyl- 1,4- naphthoquinone-2-yl)hexanoic acid (UTA#70) (240 mg, 0.8396 mmol) and L-phenylalanine t- butyl ester.HCl (180 mg, 0.7001 mmol) and the product purified by flash chromatography (40 % ethyl acetate / hexanes) to give UTA#75 as yellow oil in 48 % yield (166 mg, 0.3383 mmol). 'H NMR 5 (CDC13, 400 MHz): 1.40 (s, 9H), 1.41 - 1.47 (m, 4H), 1.64 (quin, J = 7.5 Hz, 2H), 2.16 (s, 3H), 2.18 - 2.29 (m, 2H), 2.60 (t, J = 7.8 Hz, 2H), 3.02 - 3.10 (m, 2H), 4.73 - 4.78 (m,1H), 6.05 (d, J = 7.7 Hz, 1H), 7.13 - 7.15 (m, 2H), 7.21 - 7.28 (m, 3H), 7.65 - 768 (m, 2H), 8.03 - 8.06 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.6, 25.2, 26.8, 27.9, 28.3, 29.4, 36.3, 38.1, 53.3, 82.3, 126.20, 126.28, 126.9, 128.3 (2 x C), 129.5 (2 x C), 132.17, 132.19, 133.32, 133.35, 134.18, 136.3, 143.2, 147.2, 170.9, 172.3, 184.6, 185.3[a]D20: +23.33° (c 0.66, CHC13); IR Vmax: 3290 (N-H), 2978, 2933, 1734 (C=O), 1718 (C=O), 1695 (C=O), 1653, 1595, 1521, 1456, 1369, 1294, 1155, 702 cm-1

[0253] Example 11: N-(3,4-dimethoxyphenethyl)-4-(3-methyl-l,4-naphthoquinone-2- yl)butanamide (UTA#77)UTA#77 was prepared according to general procedure B from UTA#23 (187.5 mg, 0.7260 mmol) and 3,4-dimethoxyphenylethylamine (146.6 mg, 0.8088 mmol) and the product purified by flash chromatography (90 % ethyl acetate / hexanes) to give UTA#77 as pale orange crystalline solid in 38 % yield (117.0 mg, 0.2776 mmol) with a melting point of 105 - 108 °C. 'H NMR 5 (CDCh, 400 MHz): 1.77 (quin, J = 7.7 Hz, 2H), 2.16 (S, 3H), 2.22 (t, J = 7.2 Hz, 2H), 2.60 (t, J= 8.0 Hz, 2H), 2.74 (t, J= 7.2 Hz, 2H), 3.48 (q, J = 6.5 Hz, 2H), 3.79 (s, 3H), 3.81 (s, 3H), 5.94 (t, J= 5.6 Hz, 1H), 6.68 - 6.76 (m, 3H), 7.63 - 7.66 (m, 2H), 7.98 - 8.02 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.7, 24.3, 26.3, 35.2, 36.1, 40.7, 55.8, 55.9, 111.4, 111.9,120.7, 126.25, 126.29, 131.4, 132.0, 132.1, 133.4, 133.5, 144.0, 146.2, 147.7, 149.0, 172.3,184.8, 185.1.; IR Vmax: 3377, 3296, 2935, 2656, 1595, 1516, 1462, 1329, 1294, 1261,1236, 1157, 1141, 1028, 717

[0254] Example 12: (S)-N-(l-hydroxy-3-phenylpropan-2-yl)-4-(3-methyl-l,4- naphthyoquinone-2-yl) butanamide (UTA# 62)UTA#62 was prepared according to general procedure B from UTA#23 (133.5 mg, 5169 mmol) and L-phenylalaninol (76.4 mg, 0.5053 mmol) and the product purified by flash chromatography (100 % ethyl acetate) to give UTA#62 as yellow / orange oil in 49 % yield (97.7 mg, 0.2496 mmol).'H NMR 5 (CDCh, 400 MHz): 1.70 - 1.78 (m, 2H), 2.15 (s, 3H), 2.25 (t, J= 7.2 Hz, 2H), 2.55 (t, J= 8.0 Hz, 2H), 2.83 - 2.94 (m, 2H), 3.03 (bs, 1H), 3.59 (dd, J = 11.2, 5.4 Hz, 1H), 3.71 (dd, J= 11.2, 3.8 Hz, 1H), 4.21 - 4.29 (m, 1H), 6.31 (d, J= 8.0 Hz, 1H), 7.15 - 7.27 (m, 5H), 7.64 - 7.69 (m, 2H), 8.00 - 8.05 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.7, 24.3, 26.2, 36.2, 37.0, 52.9, 64.1, 126.35, 126.36, 126.6, 128.6 (two carbons), 129.2 (two carbons), 132.0, 132.1, 133.5, 133.6, 137.9, 144.2, 146.2, 173.1, 185.12, 185.13; [a]D20: -21.33 °(c 1.57, CHCh); IR Vmax: 3369, 3296, 2933, 1658, 1595, 1539, 1456, 1377, 1330, 1296, 1043, 717, 702

[0255] Example 13: (R)-N-(l-hydroxy-3-phenylpropan-2-yl)-4-(3-methyl-l,4- naphthyoquinone-2-yl)butanamide (UTA# 78)UTA#78 was prepared according to general procedure B from 4-(3 -methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (180 mg, 0.6954 mmol) and D-phenylalaninol (117 mg, 0.7731 mmol) and the product purified by flash chromatography (100 % ethyl acetate) to give UTA#78 as a brown oil in 55 % yield (186 mg, 0.4300 mmol).XH NMR 5 (CDC13, 400 MHz): 1.72 - 1.78 (m, 2H), 2.17 (s, 3H), 2.25 (t, J = 6.9 Hz, 2H), 2.56 - 2.60 (m, 2H), 2.86 - 2.91 (m, 2H), 3.60 (dd, J = 11.2, 5.2 Hz, 1H), 3.74 (dd, J = 11.2, 3.5 Hz, 1H), 4.21 - 4.25 (m, 1H), 6.09 (d, J = 7.7 Hz 1H), 7.19 - 7.29 (m, 5H), 7.68 - 7.71 (m, 2H), 8.03 - 8.08 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.8, 24.3, 26.2, 36.2, 37.1, 53.0, 64.4, 126.45, 126.47, 126.7, 128.7, 129.3, 132.1, 132.2, 133.5, 133.7, 137.8, 144.3, 146.3, 173.0, 185.22, 185.27; [a]D20: -13.88° (c 0.25, CHC13); IR Vmax: 3369, 3306, 3064, 2933, 1653, 1595, 1533, 1456, 1377, 1330, 1294, 1041, 734, 702 cm-1

[0256] Example 14: (R)-N-(2-hydroxy-l-phenylethyl)-4-(3-methyl-l,4-naphthoquinone-2- yl)butanamide (UTA#80)UTA#80 was prepared according to general procedure B from 4-(3 -methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (178 mg, 0.6877 mmol) and D-phenyl glycinol (109 mg, 0.7953 mmol) and the product purified by dissolving in dichloromethane and adding hexanes dropwise until a precipitate was formed to give UTA#80 as yellow crystaline solid in 62 % yield (161 mg, 0.4266 mmol) with a melting point of 150 - 154 °C.XH NMR 5 (CDC13, 400 MHz): 1.80 - 1.90 (m, 2H) 2.29 (s, 3H), 2.36 (t, J = 7.1 Hz, 2H), 2.65 - 2.73 (m, 2H), 3.92 (d, J = 5.0 Hz, 2H), 5.10 - 5.14 (m, 1H), 6.50 (d, J = 6.8 Hz, 1H), 7.27 - 7.38 (m, 5H), 7.67 - 7.72 (m, 2H), 8.03 - 8.10 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.8, 24.4, 26.3, 36.2, 56.1, 66.8, 126.4, 126.9, 128.0, 129.0 (2 x C), 132.1, 132.3, 133.5, 133.7, 139.0, 144.4, 146.3, 172.9, 185.2, 185.3; [a]D20: -31.81° (c 0.64, CHC13); IR Vmax: 3296 (N- H), 2935, 1658 (C=O), 1595, 1541, 1456, 1377, 1330, 1294, 719, 700 cm-1

[0257] Example 15: (S)-N-(2-hydroxy-l-phenylethyl)-4-(3-methyl-l,4-naphthoquinone-2- yl)butanamide (UTA#81)UTA#81 was prepared according to general procedure B from 4-(3 -methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (187 mg, 0.7252 mmol) and L-phenyl glycinol (106 mg, 0.7690 mmol) and the product purified by dissolving in dichloromethane and adding hexanes dropwise until a precipitate was formed to give UTA#81 as yellow crystalline solid in 69 % yield (188 mg, 0.4992 mmol) with a melting point of 140 - 144 °C.XH NMR 5 (CDC13, 400 MHz): 1.80 - 1.90 (m, 2H), 2.19 (s, 3H), 2.37 (t, J = 7.1 Hz, 2H), 2.65 - 2.72 (m, 2H), 3.92 (d, J = 5.0 Hz, 2H), 5.09 - 5.14 (m, 1H), 6.53 (d, J = 6.3 Hz, 1H), 7.27 - 7.38 (m, 5H), 7.68 - 7.70 (m, 2H), 8.04 - 8.08 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 28, 24.4, 26.3, 36.1, 56.2, 66.7, 126.4, 126.9, 128.0, 128.9 (2 x C), 132.1, 132.3, 133.5, 133.7, 139.0, 144.4, 146.3, 173.0, 185.2, 185.3; [a]D20: +18.01° (c 0.66, CHC13);1 IR Vmax: 3294 (C=O), 2937, 1656 (C=O), 1595, 1535, 1454, 1377, 1330, 1294, 1070, 700 cm-1

[0258] Example 16: (S)-N-(l-hydroxy-3-phenylpropan-2-yl)-6-(3-methyl-l,4- naphthoquione-2-yl)hexanamide (UTA#84)UTA#84 was prepared according to general procedure B from 6-(3 -methyl- 1,4- naphthoquinone-2-yl)hexanoic acid (UTA#70) (148 mg, 0.5176 mmol) and L-phenylalaninol (92 mg, 0.6071 mmol) and the product purified by flash chromatography (2 % methanol / ethyl acetate) to give UTA#84 as yellow semi solid in 34 % yield (74 mg, 0.1759 mmol).'H NMR 5 (CDC13, 400 MHz): 1.34 - 1.48 (m, 4H), 1.62 (quin, J = 7.4 Hz, 2H), 2.16 (s, 3H), 2.17 (t, J = 7.5 Hz, 2H), 2.56 - 2.60 (m, 2H), 2.78 (bs, 1H), 2.81 - 2.92 (m, 2H), 3.59 (dd, J = 11.1, 5.2 Hz, 1H), 3,69 (dd, J = 11.1, 3.5 Hz, 1H), 4.16 - 4.20 (m, 1H), 5.97 (d, J = 7.0 Hz, 1H),7.19 - 7.23 (m, 3H), 7.27 - 7.31 (m, 2H), 7.67 - 7.70 (m, 2H), 8.03 - 8.07 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.8, 25.4, 26.9, 28.3, 29.3, 36.4, 37.1, 53.1, 64.4, 126.3, (2 x C), 126.8, 128.7, 129.3, 132.26, 132.28, 133.51, 133.53, 137.7, 143.4, 147.2, 174.1, 184.9, 185.4 cm-1; [a]D20: +15.15° (c 2.31, CHC13); IR Vmax: 3336 (N-H), 2935, 1695 (C=O), 1658 (C=O), 1595, 1541, 1456, 1377, 1329, 1296, 715, 702 cm-1

[0259] Example 17: N-(4-hydroxyphenethyl)-5-(3-methyl-l,4-naphthoquinone-2- yl)pentanamide (UTA#88)UTA#88 was prepared according to general procedure B from 5-(3-methyl-l,4- naphthoquinone-2-yl)pentanoic acid (UTA#67) (159 mg, 0.5831 mmol) and tyramine (77 mg, 0.5628 mmol) and the product purified by flash chromatography (85 % ethyl acetate / hexanes) to give UTA#88 as orange solid in 20 % yield (45 mg, 0.1137 mmol) with a melting point of 136 - 138 °C.XH NMR 5 (CD3OD, 400 MHz): 1.42 - 1.50 (m, 2H), 1.66 (quin, J = 7.5 Hz, 2H), 2.15 (s, 3H),2.19 (t, J = 7.3 Hz, 2H), 2.62 - 2.68 (m, 4H), 3.33 (t, J = 7.2 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 7.72 - 7.74 (m, 2H), 8.01 - 8.04 (m, 2H);13C NMR 5 (CD3OD, 100 MHz): 12.7, 27.1, 27.4, 29.1, 35.6, 36.8, 42.2, 116.1, 127.0, 127.1, 130.7 (2 x C), 131.2, 133.4, 134.5 (2 x C), 144.6, 148.0, 156.8, 175.8, 185.8, 186.3 ; IR Vmax: 3369 (N-H), 3296, 2937, 1755 (C=O), 1693 (C=O), 1653 (C=O), 1616, 1595, 1516, 1329, 1294, 1197, 734, 715 cm-1

[0260] Example 18: N-(4-hydroxyphenethyl)-6-(3-methyl-l,4-naphthoquinone-2-yl) hexanamide (UTA#89)UTA#89 was prepared according to general procedure B from 6-(3 -methyl- 1,4- naphthoquinone-2-yl)hexanoic acid (UTA#70) (1367 mg, 0.4778 mmol) and tyramine (74 mg, 0.5423 mmol) and the product purified by flash chromatography (90 % ethyl acetate / hexanes) to give UTA#89 as orange crystalline solid in 39 % yield (75 mg, 0.1842 mmol) with a melting point of 90 - 92 °C.'H NMR 5 (CD3OD, 400 MHz): 1.33 - 1.42 (m, 2H), 1.45 - 1.54 (m, 2H), 1.62 (quin, J = 7.4 Hz, 2H), 2.13 - 2.16 (m, 2H), 2.17 (s, 3H), 2.62 - 2.69 (m, 2H), 3.34 (t, J = 7.3 Hz, 2H), 6.68 - 6.70 (m, 2H), 6.99 - 7.03 (m, 2H), 7.72 - 7.78 (m, 2H), 8.02 - 8.05 M, 2H);°C NMR 5 (CD3OD, 100 MHz): 12.6, 26.6, 27.6, 29.2, 30.3, 35.7, 36.9, 42.0, 116.3, 127.00, 127.08, 130.6 (2 x C), 131.3, 133.55, 134.52, 134.54, 144.5, 148.4, 156.8, 175.9, 185.9, 186.4;IR Vmax: 3369 (N-H), 3296, 2935, 1695 (C=O), 1654 (C=O), 1595, 1541, 1516, 1329, 1296, 734, 713 cm-1

[0261] Example 19: N-butyl-4-(3-methyl-l,4-naphthoquione-2-yl)butanamide (UTA#91)UTA#91 was prepared according to general procedure B from 4-(3 -Methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (149 mg, 0.5533 mmol) and butylamine (67 mg, 0.9106 mmol) and the product purified by flash chromatography (70 % ethyl acetate / hexanes) to give UTA#91 as yellow solid in 40 % yield (73 mg, 0.2336 mmol) with a melting point of 136 - 138 °C.'H NMR 5 (CDC13, 400 MHz): 0.91 (t, J = 7.3 Hz, 3H), 1.35 (sextet, J = 7.3 Hz, 2H), 1.49 (quin, J = 7.3 Hz, 2H), 1.83 (quin, J = 7.3 Hz, 2H), 2.21 (s, 3H), 2.27 (t, J = 7.3 Hz, 2H), 2.65 - 2.69 (m, 2H), 3.24 - 3.29 (m, 2H), 5.78 (bs, 1H), 7.67 - 7.69 (m, 2H), 8.04 - 8.08 (m, 2H):13C NMR 5 (CDC13, 100 MHz): 2.8, 13.8, 20.2, 24.5, 26.5, 31.8, 36.2, 39.4, 126.40, 126.43, 132.2, 132.3, 133.5, 133.6, 144.2, 146.4, 172.2, 185.1, 185.2; IR Vmax: 302 (N-H), 2931, 2862, 1660 (C=O), 1639, 1595, 1554, 1458, 1323, 1296, 717 cm-1

[0262] Example 20: (2S,4R)-methyl-4-hydroxy-l-(4-(3-methyl-l,4-dioxo-l,4- dihydronaphthalen-2-yl)butanoyl)pyrrolidine-2-carboxylate (UTA#93)UTA#93 was prepared according to general procedure B from 4-(3 -Methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (143 mg, 0.5536 mmol) and trans-4-Hydroxy-L-proline methyl ester.HCl (103 mg, 0.5693 mmol) and the product purified by flash chromatography (90 % ethyl acetate / hexanes) to give UTA#93 as yellow viscous oil in 59 % yield (126 mg, 0.3256 mmol).3H NMR 5 (CDC13, 400 MHz): 1.77 - 1.85 (m, 2H), 2.05 (ddd, J = 13.3, 8.1, 5.0 Hz, 1H), 2.18 (s, 3H), 2.25 - 2.31 (m, 1H), 2.41 (t, J = 7.2 Hz, 2H), 2.64 - 2.68 (t, J = 7.9 Hz, 2H), 3.47 (bs, 1H), 3.54 - 3.56 (m, 1H), 3.69 (s, 3H), 3.73 - 3.76 (m, 1H), 4.56 (t, J = 8.0 Hz, 2H), 7.63 - 7.67 (m, 2H), 7.99 - 8.04 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.8, 23.5, 26.3, 34.0, 37.8, 52.4, 55.3, 57.7, 70.3, 126.3 (2 x C, 132.1, 132.2, 133.4, 133.5, 144.2, 146.5, 172.0, 172.8, 184.9, 185.3; [a]D20: -58.57° (c 1.33, CHC13); IR Vmax: 3396 (N-H), 2951, 1747 (C=O), 1716 (C=O), 1653 (C=O), 1622, 1595, 1456, 1437, 1327, 1296, 1199, 1084, 717 cm-1

[0263] Example 21: 4-(l,4-naphthoquinone-2-yl)-N-(4-hydroxyphenethyl)butanamide(UTA#113)UTA#113 was prepared according to general procedure B from 4-(l,4-naphthalen-2-yl) butanoic acid (150 mg, 0.6149 mmol) and tyramine (89 mg, 0.6502 mmol) and the product purified by flash chromatography (80 % ethyl acetate / hexanes) to give UTA#113 as a brown viscous oil in 33 % yield (109 mg, 0.2885 mmol).'H NMR 5 (CDC13, 400 MHz): 1.85 (quin, J = 7.4 Hz, 2H), 2.22 (t, J = 7.4 Hz, 2H) 2.49 - 2.53 (m, 2H), 2.72 (t, J = 6.8 Hz, 2H), 3.46 - 3.50 (m, 2H), 5.89 (t, J = 5.27 Hz, 1H), 6.71 (s, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.68 - 7.71 (m, 2H), 7.99 - 8.05 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 24.0, 29.0, 34.7, 35.9, 40.9, 115.7, 121.7, 126.1, 126.7,129.9, 132.1, 132.2, 133.8, 133.9, 150.9, 155.1, 172.6, 185.1, 185.24, 185.28;IR Vmax: 3312 (N-H), 2932, 1661 (C=O), 1594, 1539, 1455, 1302, 1265, 1042, 733, 702 cm-1

[0264] Example 22: (S)-4-(l,4-naphthoquinone-2-yl)-N-(l-hydroxy-3-phenylpropan-2-yl) butanamide (UTA# 115)UTA#115 was prepared according to general procedure B from 4-(l,4-naphthalen-2-yl)- butanoic acid (140 mg, 0.5728 mmol) and L-phenylalaninol (96 mg, 0.6349 mmol) and the product purified by flash chromatography (4 % methanol / ethyl acetate) to give UTA#115 as a dark brown semi solid in 53 % yield (115 mg, 0.3034 mmol).'H NMR 5 (CDC13, 400 MHz): 1.86 (quin, J = 7.3 Hz, 2H), 2.25 (t, J = 7.3 Hz, 2H), 2.49 - 2.53 (m, 2H), 2.89 (t, J = 7.0 Hz, 2H), 3,04 (bs, 1H), 3.59 (dd, J = 11.1, 5.1 Hz, 1H), 3.70 (dd, J =11.1, 3.6 Hz, 1H), 4.21 - 4.25 (m, 1H), 6.17 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 7.19 - 7.29 (m, 5H), 7.71 - 7.73 (m, 2H), 8.02 - 8.07 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 4.9, 28.9, 35.9,37.1, 52.8, 64.0, 126.1, 126.7, 128.6 (2 x C), 129.3 (2 x C), 132.1, 132.2, 133.8, 135.3, 137.8,150.9, 172.7, 185.1, 185.3; [a]D20: -23.09° (c 0.97, CHC13); IR Vmax: 3350 (N-H), 2947, 1733 (C=O), 1645 (C=O), 1611, 1456, 1266, 1204, 1153, 1055, 735, 702 cm-1

[0265] Example 23: (S)-methyl-2-(4-(3-methyl-l,4-naphthoquinone-2-yl)butanamido)-2- phenylacetate (UTA#95)UTA#95 was prepared according to general procedure B from 4-(3 -methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (209 mg, 0.8100 mmol) and S-(+)-phenyl glycine methyl ester.HCl (169 mg, 0.8396 mmol) and the product purified by flash chromatography (45 % ethyl acetate / hexanes) to give UTA#95 as yellow solid in 72 % yield (236 mg, 0.5826 mmol) with a melting point of 100 - 102 °C.'H NMR 5 (CDC13, 400 MHz): 1.78 - 1.85 (m, 2H), 2.13 (s, 3H), 2.35 (td, J = 7.3, 3.2 Hz, 2H), 2.63 - 2.67 (m, 2H), 3.70 (s, 3H), 5.59 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 7.28 - 7.37 (m, 5H), 7.63 - 7.66 (m, 2H), 7.99 - 8.03 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.7, 24.2,26.3, 35.8, 52.8, 56.5, 126.3, 126.4, 127.4, 128.6, 129.1, 132.1, 132.2, 133.4, 133.5, 136.5,144.1, 146.3, 171.5, 171.7, 184.9, 185.2; [a]D20: +99.11° (c 1.13, CHC13); IR Vmax: 3306 (N-H), 3030, 2953, 1743 (C=O), 1647 (C=O), 1597, 1597, 1537, 1456, 1379,1330, 1296, 1213, 1127, 754, 717, 698 cm-1

[0266] Example 24: (R)-methyl-2-(4-(3-methyl-l,4-naphthoquinone-2-yl)butanamido)-2- phenylacetate (UTA#97)UTA#97 was prepared according to general procedure B from 4-(3 -methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (202 mg, 0.7810 mmol) and R-(-)-phenyl glycine methyl ester.HCl (161 mg, 0.8396 mmol) and the product purified by flash chromatography (45 % ethyl acetate / hexanes) to give UTA#97 as yellow solid in 69 % yield (219 mg, 0.5394 mmol) with a melting point of 90 - 92 °C.'H NMR 5 (CDC13, 400 MHz): 1.78 - 1.86 (m, 2H), 2.15 (s, 3H), 2.35 (td, J = 7.3, 3.0 Hz, 2H), 2.46 - 2.68 (m, 2H), 3.71 (s, 3H), 5.60 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 7.30 - 7.36 (m, 5H), 7.64 - 7.69 (m, 2H), 8.00 - 8.06 (m, 2H);13C NMR 5 (CDC13, 100 MHz):12.7, 24.3, 26.3, 35.9, 52.9, 56.5, 126.3, 126.4, 127.4 (2 x C), 128.7, 129.1 (2 x C), 132.20, 132.27, 133.50, 133.54, 136.6, 144.1, 146.4, 171.5, 171.7, 184.9, 185.3; [a]D20: -93.58° (c 0.78, CHC13); IR Vmax: 3304 (N-H), 3032, 2953, 1743 (C=O), 1656 (C=O), 1647, 1597, 1521, 1456, 1435, 1379, 1323, 1296, 1259, 1213, 1172, 754, 717, 696 cm-1

[0267] Example 25: (S)-2-(4-(2-(hydroxymethyl)pyrrolidin-l-yl)-4-oxobutyl)-3-methyl-1, 4-naphthoquinone (UTA #61)UTA#61 was prepared according to general procedure B from UTA#23 (116.8 mg, 0.4522 mmol) and L-prolinol (159.1 mg, 0.7587 mmol) and the product purified by flash chromatography (100 % ethyl acetate) to give UTA#61 as yellow oil in 36 % yield (49.8 mg, 1459 mmol).'H NMR 5 (CDCh, 400 MHz): 1.60 (quin, J= 6.2 Hz, 2H), 1.82 - 2.02 (m, 6H), 2.21 (s, 3H), 2.39 (t, J = 7.2 Hz, 2H), 2.67 - 2.72 (m, 2H), 3.50 - 3.55 (m, 1H), 3.66 (dd, J= 11.3, 2.8 Hz, 1H), 4.15 - 4.22 (m, 1H), 7.66 - 7.68 (m, 2H), 8.03 - 8.07 (m, 2H). ;13C NMR 5 (CDCh, 100 MHz): 12.8, 23.6, 24.5, 26.4, 28.3, 34.6, 48.1, 61.2, 67.3, 126.33, 126.37, 132.1, 132.2, 133.4, 133.5, 144.1, 146.6, 173.6, 184.9, 185.3; [a]D20: -35.12 ° (c 0.41, CHCh); IR Vma : 3367, 2953, 2877, 1695, 1654, 1616, 1595, 1454, 1329, 1296, 1047, 732, 719.

[0268] Example 26: (S) -tert-butyl 2-(4-(l,4-naphthoquinone-2-yl)butanamido)-3- phenylpropanoate (UTA# 116)UTA# 116 was prepared according to general procedure B from UTA#59 (29.5 mg, 0.1208 mmol) and L-phenyl alanine t-butyl ester.HCl (34.8 mg, 0.1353 mmol) and the product purified by a Reveleris (Registered Trade Mark) X2 automated flash chromatography system (Eluent: gradient 100 % Hexanes - 80 % ethyl acetate, Column: Reveleris ® Silica 4 g, Flow rate: 18 mL / min) to give UTA#116 as brown oil in 20 % yield (10.9 mg, 0.0243 mmol).'H NMR 5 (CDCh, 400 MHz): 1.43 (s, 9H), 1.91 (quin, J= 7.6 Hz, 2H), 2.29 (td, J= 7.5, 2.9 Hz, 2H), 2.56 - 2.60 (m, 2H), 3.10 - 3.14 (M, 2H), 4.76 - 4.81 (M, 1H), 6.03 (d, J= 7.3 Hz, 1H), 7.16 -6 7.31 (m, 5H), 7.74 - 7.76 (m, 2H), 8.07 - 8.12 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 23.9, 28.1 (three carbons), 29.1, 35.8, 38.2, 53.5, 82.5, 126.2, 126.7, 127.1, 128.5 (two carbons), 129.6 (two carbons), 132.2, 132.3, 133.7, 133.8, 135.3, 136.3, 150.9, 170.9, 172.5, 185.1, 185.2; [a]D20: +38.46° (c 0.39, CHCh); IR Vma : 3309,2978, 2931, 1732, 1662, 1595, 1525, 1367, 1301, 1259, 1153, 700.

[0269] Example 27: S)-tert-butyl-3-(4-hydroxyphenyl)-2-(4-(3-methyl-l,4- naphthoquinone-2-yl) butanamido)propanoate (UTA# 55)UTA#55 was prepared according to general procedure B from 4-(3 -methyl- 1,4-naphthal en-2- yl)-butanoic acid (UTA#23) (225 mg, 0.8727 mmol) and L-tyrosine t-butyl ester.HCl (188 mg, 0.7902 mmol). The crude product was dissolved in 10 mL methanol, excess potassiumcarbonate added and the reaction left stirring at r.t for Ihour. The mixture was extracted with di chloromethane 3x 30 mL and the organic layer dried over MgSO4, filtered and the solvent removed under reduced pressure and purification by flash chromatography (50 % ethyl acetate / hexanes) gave UTA#55 as yellow oil in 20 % yield (42 mg, 0.0871 mmol).'H NMR 5 (CDC13, 400 MHz): 1.42 (s, 9H), 1.78 (quin, J = 7.5 Hz, 2H), 2.17 (s, 3H), 2.27 (t, J = 7.5 Hz, 2H), 2.61 - 2.65 (m, 2H), 2.98 (dd, J = 14.1, 6.1 Hz, 1H), 3.05 (dd, J = 14.1 Hz, 6.1 Hz, 1H), 4.72 - 4.76 (m, 1H), 6.09 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H), 7.67 - 7.72 (m, 2H), 8.05 - 8.08 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.8, 24.3, 26.4, 28.1, 36.2, 37.4, 77.3, 82.5, 115.4 (2 x C), 126.42, 126.47, 130.7 (2 x C), 132.3, 133.5, 144.2, 146.5, 154.9, 171.1, 171.9, 184.9, 185.3; [a]D20: +14.86.0(c 0.18, CHCh); IR Vmax:3367 (N-H), 2987, 2931, 1732 (C=O), 1654 (C=O), 1616, 1695, 1516, 1506, 1369, 1330, 1294, 1259, 1153, 734 cm-1

[0270] Example 28: (S)-2-(4-(3-methyl-l,4-naphthoquinone-2-yl)butanamido)-3- phenylpropanoic acid (UTA# 37)UTA#37 was prepared from the deprotection of UTA#36 (317.3 mg, 0.6875 mmol), using general procedure C. The product was purified by flash chromatography (5% methanol / ethyl acetate) to give UTA#37 as brown viscous oil in 79 % yield (219.6 mg, 0.5416 mmol).'H NMR 5 (CDCh, 400 MHz): 1.72 - 1.79 (m, 2H), 2.14 (s, 3H), 2.29 (t, J= 7.2 Hz, 2H), 2.58 (t, J = 7.8 Hz, 2H), 3.12 (dd, J= 14.0, 7.0 Hz, 1H), 3.26 (dd, J= 14.1, 5.4 Hz, 1H), 4.90 (m, 1H), 6.54 (d, J = 7.7 Hz, 1H), 7.17 - 7.28 (m, 5H), 7.66 - 7.69 (m, 2H), 8.02 - 8.05 (m, 2H), 8.92 (bs, 1H);13C NMR 5 (CDCh, 100 MHz): 12.8, 24.2, 26.2, 35.8, 37.3, 53.4, 126.4 (two carbons), 127.2, 128.7 (two carbons), 129.4 (two carbons), 132.0, 132.2, 133.5, 133.6, 135.9, 144.3, 146.2, 173.5, 174.7, 185.1, 185.2; [a]D20: +35.83 °(c 0.24, CHCh); IR Vmax: 3491, 2931, 1716, 1660, 1616, 1595, 1521, 1456, 1332, 1296, 1267, 1217, 702

[0271] Example 29: (S)-l-(4-(3-methyl-l,4-naphthoquinone-2-yl)butanoyl)pyrrolidine-2- carboxylic acid (UTA#43)UTA#43 was prepared from the deprotection of UTA#42 (113.8 mg, 0.2766 mmol), using general procedure C. The product was purified by flash chromatography (3 % methanol / ethyl acetate) to give UTA#43 as brown viscous oil in 65 % yield (63.9 mg, 0.1798 mmol)'H NMR 5 (CDCh, 400 MHz): 1.82 - 1.90 (m, 2H), 2.02 - 2.08 (m, 2H), 2.21 (s, 3H), 2.13 - 2.33 (m, 2H), 2.45 - 2 / 50 (m, 2H), .68 - 2.72 (m, 2H), 3.49 - 3.53 (m, 1H), 3.60-3.63 (m, 1H), 4.55 - 4.58 (m, 1H), 7.53 bs, 1H), 7.68 - 7.07 (m, 2H), 8.04 - 8.08 (m, 2H);13C NMR 5 (CDCh, 100 MHz): 12.8, 23.3, 24.8, 26.4, 28.0, 34.1, 47.8, 59.7, 126.34, 126.38, 132.1, 132.2, 133.51, 133.56, 144.2, 146.3, 173.4, 173.9, 184.8, 185.3; [a]D20: -65.80° (c 1.69, CHCh); IR Vma : 2976, 2956, 1732, 1658, 1616, 1595, 1456, 1329, 1294, 1188, 717

[0272] Example 30: (S)-2-(3-(3-methyl-l,4-naphthoquinone-2-yl)propanamido)-3- phenyl propanoic acid (UTA#66)UTA#66 was prepared from the deprotection of UTA#65 (18 mg, 0.0407 mmol), using general procedure C. The product purified by flash chromatography (5 % methanol / ethyl acetate) to give UTA#66 as a yellow oil in 80 % yield (13 mg, 0.0327 mmol).'H NMR 5 (CD3OD, 400 MHz): 2.08 (s, 3H), 2.37 (td, J = 7.6, 3.5 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.89 (dd, J = 13.9, 9.3 Hz, 1H), 3.17 (dd, J = 13.9, 4.9 Hz, 1H), 4.64 (dd, J = 9.3, 5.0 Hz, 1H), 7.11 - 7.17 (m, 5H), 7.72 - 7.75 (m, 2H), 8.00 - 8.02 (m, 2H);13C NMR 5 (CD3OD, 100 MHz): 12.7, 24.3, 35.1, 38.4, 55.0, 127.0, 127.7, 129.3 (2 x C), 130.1 (2 x C), 133.4, 134.590, 134.598, 138.4, 145.5, 146.4, 174.4, 185.6, 186.1; [a]D20: -3.950(c 0.45, CHC13); IR Vmax: 3306 (N-H), 2926, 1732 (C=O), 1714 (C=O), 1658 (C=O), 1595, 1454, 1330, 1296, 1195, 734, 702 cm-1

[0273] Example 31: (S)-2-(5-(3-methyl-l,4-naphthoquinone-2-yl)pentanamido)-3- phenylpropanoic acid (UTA#72)UTA#72 was prepared from the deprotection of UTA#71 (215 mg, 0.4517 mmol), using general procedure C. The product purified by flash chromatography (35 % ethyl acetate / hexane) to give UTA#72 as a brown oil in 85 % yield (161 mg, 0.3843 mmol).1H NMR 5 (CD3OD, 400 MHz): 1.26 - 1.40 (m, 2H), 1.58 (quin, J = 7.6 Hz, 2H), 2.09 (s, 3H), 2.17 - 2.22 (m, 2H), 2.55 (t, J = 7.9 Hz, 2H), 2.90 (dd, J = 14.0, 9.6 Hz, 1H), 3.19 (dd, J = 14.0, 4.8 Hz, 1H), 4.67 (dd, J = 9.6, 4.8 Hz, 2H), 7.14 - 7.21 (m, 5H), 7.70 - 7.74 (m, 2H), 7.99 - 8.02 (m, 2H);13C NMR 5 (CD3OD, 100 MHz): 12.7, 26.9, 27.4, 28.9, 36.4, 38.3, 54.8, 127.0, 127.1, 127.6, 129.3 (2 x C), 130.1 (2 x C), 133.40, 133.42, 134.5 (2 x C), 138.5, 144.5, 148.0, 174.7, 175.7, 185.7, 186.3; [a]D20:+25.16° (c 1.06, CHCh); IR Vmax:3316 (N-H), 2939, 1734 (C=O), 1716 (C=O), 1656 (C=O), 1595, 1525, 1456, 1294, 1190, 736, 702 cm-1

[0274] Example 32: (S)-2-(6-(3-methyl-l,4-naphthoquinone-2-yl)hexanamido)-3- phenylpropanoic acid (UTA#76)UTA#76 was prepared from the deprotection of UTA#75 (166 mg, 0.3382 mmol), using general procedure C. The product purified by precipitation from di chloromethane and the solvent was decanted to give UTA#76 as brown solid in 84 % yield (124 mg, 0.2854 mmol) with a melting point of 72 - 76 °C.XH NMR 5 (CD3OD, 400 MHz): 1.30 - 1.35 (m, 2H), 1.39 - 1.46 (m, 2H), 1.56 (quin, J = 7.5 Hz, 2H), 2.16 (s, 3H), 2.17 - 2.20 (m, 2H), 2.58 - 2.62 (m, 2H), 2.93 (dd, J = 14.0, 9.5 Hz, 1H), 3.22 (dd, J = 14.0, 4.9 Hz, 1H), 4.69 (dd, J = 9.5, 4.9 Hz, 1H), 7.20 - 7.28 (m, 5H), 7.74 - 7.76 (m, 2H), 8.03 - 8.05 (m, 2H);13C NMR 5 (CD3OD, 100 MHz): 12.7, 26.5, 27.6, 29.3, 30.2, 36.5, 38.4, 54.8, 127.02, 127.09, 127.7, 129.4, 130.2, 133.46, 133.49, 134.57, 134.58, 138.5, 144.4, 148.3, 174.7, 175.9, 185.8, 186.3; [a]D20: +24.710(c 0.78, CHC13); IR Vmax: 3288 (N- H), 2937, 1732 (C=O), 1716 (C=O), 1660 (C=O), 1595, 1531, 1456, 1377, 1330, 1294, 1172, 736, 702 cm-1

[0275] Example 33: (R)-2-(4-(3-methyl-l,4-naphthoquinone-2-yl)butanamido)-3- phenylpropanoic acid (UTA#94)4-(3-Methyl-l,4-naphthalen-2-yl)-butanoic acid (UTA#23) (200 mg, 0.7736 mmol) was added to anhydrous dichloromethane (10 mL) under an atmosphere of N2. Carbonyl diimidazole (145 mg, 0.8930 mmol) was added and the resulting mixture stirred for 3.5 h at room temperature. The reaction was quenched with H2O (20mL) and the organic layer washed with H2O (2 x 20 mL). The organic layer was dried with MgSCL, filtered and the solvent removed under reduced pressure to give the crude N-acylimidazole as a yellow oil (221.7 mg, 0.7190 mmol). To the crude intermediate in THF (5 mL) a solution of D-phenylalanine (650 mg, 3.937 mmol) and pyridine (0.28 mL, 3.6084 mmol) in H2O (15 mL) was added and the reaction stirred under an atmosphere of nitrogen for 6 h. The reaction mixture was quenched with 20 mL 2M HC1 and extracted DCM (3 x 20 mL) and the organic layer was dried with MgSCU, filtered and the solvent removed under reduced pressure to give a crude product, which was purified by flash chromatography (7 % methanol / ethyl acetate) to give UTA#94 as yellow oil in 14 % yield (44 mg, 0.1080 mmol).XH NMR 5 (CDC13, 400 MHz): 1.72 - 1.79 (m, 2H), 2.15 (s, 3H), 2.30 (t, J = 7.3 Hz, 2H), 2.57 - 2.61 (m, 2H), 3.13 (dd, J = 14.1, 7.0 Hz, 2H), 3.27 (dd, J = 14.1, 5.5 Hz, 2H), 4.88 - 4.93 (m, 1H), 6.51 (d, J = 7.5 Hz, 1H), 7.18 - 7.29 (m, 5H), 7.67 - 7.71 (m 2H), 8.03 - 8.07 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 12.8, 24.2, 26.2, 35.9, 37.4, 53.4, 126.4, 127.2, 128.7 (2 x C), 129.4 (2 x C), 132.1, 132.2, 133.5, 133.6, 135.9, 144.3, 146.2, 173.3, 174.8, 185.0, 185.2; [a]D20: -38.75° (c 0.16, CHC13); IR VmaX: 3370 (N-H), 2928, 1732 (C=O), 1716 (C=O), 1658 (C=O), 1595, 1527, 1456, 1330, 1294, 734, 717, 702 cm-1

[0276] Example 34: (S)-2-(4-(l,4-naphthoquinone-2-yl)butanamido)-3- phenylpropanoic acid (UTA# 117)UTA#117 was prepared from the deprotection of UTA#116 (428 mg, 0.9563 mmol), using general procedure C. The product was purified by flash chromatography (5 % methanol / ethyl acetate) to give UTA#117 as brown solid in 92 % yield (345 mg, 0.8811 mmol) with a melting point of 110 - 112 °C.'H NMR 5 (CDC13, 400 MHz): 1.86 (quin, J = 7.4 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.45 - 2.54 (m, 2H), 3.12 (dd, J = 14.0, 7.4 Hz, 1H), 3.28 (dd, J = 14.0, 5.2 Hz, 1H), 4.97 - 5.02 (m, 1H), 6.74 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 7.17 - 7.21 (m, 3H), 7.24 - 7.28 (m, 2H), 7.71 - 7.73 (m, 2H), 7.99 - 8.06 (m, 2H);13C NMR 5 (CDC13, 100 MHz): 24.0, 28.8, 35.3, 37.3, 53.5, 126.2, 126.7, 127.4, 128.8, 129.3, 131.9, 132.1, 134.0, 135.3, 135.53, 135.55, 150.7, 174.82, 174.88, 185.2, 185.6; [a]D20:+7.87° (c 0.33, MeOH) ; IR Vmax: 3301 (N-H), 2929, 1708 (C=O), 1661 (C=O), 1554, 1454, 1369, 1302, 1260, 697 cm-1

[0277] Example 35: (S)-4-methyl-2-(4-(3-methyl-l,4-naphthoquinone-2- yl)butanamido)pentanoic acid (UTA#54)UTA#54 was prepared from the deprotection of UTA#53 (109 mg, 0.2559 mmol), using general procedure C. The product purified by flash chromatography (5 % methanol / ethyl acetate) to give UTA#54 as a dark yellow viscous oil in UTA#54 % yield (58 mg, 0.1612 mmol).'H NMR 5 (CDC13, 400 MHz): 0.93 - 0.95 (m, 6H), 1.61 - 1.73 (m, 2H) 1.82 (quin, J = 7.4 Hz, 2H), 2.17 (s, 3H), 2.38 (t, J = 7.4 Hz, 2H), 2.64 - 2.68 (m, 2H), 4.59 - 4.64 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H), 7.65 - 7.67 (m, 2H), 7.99 - 8.03 (m, 2H):13C NMR 5 (CDC13, 100 MHz): 12.7, 21.8, 22.9, 24.3, 25.0, 26.3, 35.9, 41.0, 51.0, 126.3 (2 x C), 132.0, 132.1, 133.5, 133.6, 144.3, 146.2, 173.5, 176.2, 185.1, 185.2: [a]D20: -5.350(c 0.93, CHC13): IR Vmax: 3321 (N- H), 1716 (C=O), 1660 (C=O), 1618, 1595, 1539, 1506, 1330, 1294, 1207,717cm-1.Biological examples

[0278] As noted previously, SIR is known to play a role in the regulation of cellularcalcium levels. This regulatory system was used to compare quinone compounds of this invention against known SIR agonists (SA4503, Imipramine) and the antagonist BD1047 (see Figure 1). The data in HepG2 cells demonstrate that test compounds can both inhibit SOCE (results below the dotted line) as well as increase SOCE (results above the dotted line) comparable to the known agonists and antagonists (see Figure 1). Several SIR ligands are described to display non-linear dose effect responses. In HEK293 cells that have been described to lack SIR expression (Srivats et al. 2016), the agonists UTA#37, UTA#77 and the antagonist BD1047 did not affect SOCE, neither at the level of depleting ER stores of calcium, nor regarding the subsequent calcium influx into the cytoplasm (see Figure 2). In contrast, when the same cells were transfected with a S 1R expression plasmid, the SOCE response was reduced as previously described (Srivats et al. 2016), while the combination of SIR expression and UTA#37 reduced the SOCE response even further as expected from a SIR agonist (see Figures 3 A and 3B). These data illustrate that the present compounds modulate SIR activity to affect cellular SOCE.

[0279] Example 36 - Effect of sigma- 1 receptor ligands on Store Operated Calcium Entry (SOCE) in HepG2 cellsCells were seeded in 96 well plates in 100 pl of DMEM + 10% FBS at 50,000 cells / well and allowed to adhere for 24 h. Cells were loaded with Fluo-4NW dye in calcium-containing HBSS + 20 mM HEPES for 30 mins at 37 °C followed by 30 min RT. Subsequently, cells were washed with calcium-free HBSS + 20 mM HEPES to remove excess dye and treated with UTA#37 (10 pM), UTA#77 (10 nM) for 15 min and 10 pM sigma-1 receptor reference ligands for < 2.5 h (Agonists: SA4503 and Imipramine; antagonist BD1047). Fluorescence intensity was continuously measured with a plate reader (TECAN Spark) to acquire basal levels, and after stimulation with 1 pM thapsigargin for 10 min and subsequent extracellular calcium (2 mM) exposure over a total period of 5 min. Fluorescence intensity for all time points was converted to relative fluorescence by normalizing to the baseline fluorescence using MS Excel. Statistical analysis was performed using GraphPad Prism (version 9). Data represents mean ± standard error of mean (SEM) for the total area under the curve (AUC) normalized to the untreated control, derived from > 3 independent experiments with at least 3 replicates / experiment for SCQs and two independent experiments with 5 replicates each for the reference sigma- 1 receptor ligands. Results are shown in Figures 1 and 14. This data illustrates that the present compounds at an optimised concentration are activating the SIR to an extent comparable to SIR reference ligands.

[0280] Example 37 - Effect of SCQ on Store Operated Calcium Entry (SOCE) in HEK293 cellsHEK293 cells were seeded in 96 well plates in DMEM + 10% FBS at 50,000 cells / well and allowed to adhere for 24 hours. Cells were loaded with Fluo-4NW dye in calcium- containing HBSS + 20 mM HEPES for 30 min at 37 °C and 30 min at RT. Cells were washed 3x with calcium-free HBSS with 20 mM HEPES and treated 10 pM of compounds UTA#37, 10 nM UTA#77 and the sigma- 1 receptor antagonist BD1047 for 15 min. Fluorescence intensity was measured following stimulation with 1 pM thapsigargin for 10 min and subsequently 2 mM calcium using a plate reader (Tecan Spark). Fluorescence intensity for all time points was acquired and normalized to the baseline. Data was analysed using Microsoft Excel. Statistical analysis was performed using GraphPad Prism. Results are shown in Figure 2A. These results illustrate that in HEK293 cells that lack significant expression of SIR, the present compounds as well as the reference antagonist BD1047 do not affect SIR-dependent SOCE.

[0281] The area under the curve (AUC) for UTA#37, UTA#77 and BD1047 were normalized to the control from three independent experiments with at least 3 replicates / experiment. Unpaired T-Test with Welch's correction was used to compare control and treated cells; significance is indicated by asterisks (significant) p<0.033 (*), p<0.002 (**), p<0.0002 (***), p<0.0001 (****) or “ns” (non-significant). Results are shown in Figure 2B. These results illustrate that in HEK293 cells that lack significant expression of SIR, the present compounds as well as the reference antagonist BD1047do not affect SIR-dependent SOCE.

[0282] Example 38 - Effect of SIR and compounds of the present invention on SOCE HEK293 cells, transiently transfected with a sigma-1 receptor expression plasmid, were seeded in 96 well plates in 100 pl of DMEM + 10% FBS and allowed to adhere for 24 h. Cells were loaded with Fluo-4NW dye in calcium containing HBSS + 20 mM HEPES for 30 min at 37 °C and 30 min at RT. After incubation, cells were washed 3x with calcium-free HBSS + 20 mM HEPES and treated with 10 pM UTA#37. Fluorescence intensity was measured following stimulation with IpM thapsigargin for 10 mins and subsequently with 2 mM calcium using a plate reader (Tecan Spark). Fluorescence intensity was acquired for all time points and normalised to the baseline. Statistical analysis was performed using GraphPad Prism. Unpaired T-Test with Welch's correction was used to compare untreated and treated cells; significance is indicated by asterisks (significant) p<0.033 (*), p<0.0021 (**), p<0.0002 (***), p<0.0001 (****) or “ns” (non-significant). Results are shown in Figures 3 A and 3B. These results confirm that in the presence of SIR in HEK293 cells, the present compounds can reduce the cellularSOCE similar to what is known for SIR reference compounds.

[0283] Example 39 - Comparison of present compounds against known SIR ligands in the Store Operated Ca2+- Entry (SOCE) paradigmHepG2 cells were pre-treated with known SIR agonists (SA4503, Imipramine), SIR antagonist (BD1047), present compounds #37, #77 for 3 hours before measuring calcium influx. Data represents the summary from 3 independent experiments with at least 3 replicates each, (% mean ± standard error of mean (SEM) for the total area under the curve, normalised to the control). One-way ANOVA with Dunnett’s test and unpaired student’s t-test with Welch correction compares control against treatments. Significance p<0.033 (*), p<0.0021 (**), p<0.0002 (***), p<0.0001 (****) or “ns” (non-significant). Results are shown in Figure 4. This data illustrates that the present compounds are reducing cellular SOCE to an extent comparable to SIR reference ligands.

[0284] Example 40 - Rescue of vision after administration of UTA#77Significant vision loss (#) was calculated by comparing baseline values (average OKR for Week 1-4) against all weeks until Week 14. From Week 15, results of topical treatment with UTA#77 (solid black circles) are shown. Data are expressed as mean (n = 49 eyes / group for untreated eyes (Weeks 1-14), n = 9 for UTA#77-treated eyes (Weeks 14-21), n = 11 for vehicle- treated group (open circles), and n = 12 for healthy nondiabetic control (open triangles). Error bars = SEM; #, pO.OOOl (compared against baseline data, Weeks 1-4) and *p<0.05, **p<0.01 (compared against vehicle-treated eyes, open circles) using two-way repeated measure ANOVA. Baseline period (Weeks 1-4), brown area; grey area: treatment period. (Daniel et al. 2021). Results are shown in Figure 9. These results demonstrate that UTA#77 can restore visual acuity in diabetic rats.

[0285] Example 41 - Effect of UTA# 37 and UTA#77 on visual acuity following rotenone-induced vision lossExperimental design is as described previously in Heitz et al. 2012. Following intraocular rotenone injection in the left eye, visual acuity was measured once every week for both eyes. The right eye was used as internal control within each mouse. Visual acuity was quantified by scoring the number of head-turns. Treatment: 200 mg / kg p.o. Data represents mean of n = 9-11 mice. Idebenone is marketed in Europe for the treatment of Leber’s Hereditary Optic Neuropathy (LHON). Results are shown in Figure 10. These results illustrate that the present compound can restore visual acuity in a mouse model of LHON.

[0286] Example 42 - Dose-dependent effects of selected compounds on SOCEHepG2 cells were pre-treated with a dilution series (10 pM, 1 pM and 0.1 pM) of compounds UTA#37 (red circles), UTA#77 (green triangles), UTA#54 (blue squares) and UTA#88 (brown diamonds) for 15 minutes to measure their effect on the SOCE paradigm with the Fluo-4NW dye. The data represents the % mean ± SEM for the total AUC (AUC peak-1 + AUC peak-2) normalised to the UT from (n > 3) independent experiments with at least 3 replicates / experiment each. The significance is indicated by asterisks p<0.033 (*), p<0.0021 (**), p<0.0002 (***), or p<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (UT: Untreated control, SOCE: Store- operated calcium entry, SEM: standard error of the mean, AUC: Area under the curve, SCQ: Short chain quinones). Results are shown in Figure 11. These results illustrate that some of the present compounds demonstrate a non-linear dose response , which has been described for some SIR ligands.

[0287] Example 43 - Dose-dependent effects of selected compounds on SOCEHepG2 cells were pre-treated with doses of 0.01 - 10 pM for compounds UTA#37 (red circles) and UTA#74 (blue squares) and a dose range of 0.001 - 1 pM for UTA#77 (green triangles) for 15 minutes to measure their effect on the SOCE paradigm with the Fluo-4NW dye. The data represents the % mean ± SEM for the total AUC (AUC peak-1 + AUC peak-2) normalised to the UT from (n > 3) independent experiments with 5 replicates each. While doses connected with solid lines were tested in the same experiment, the dotted lines indicate the absence of measurements. The significance is indicated by asterisks p<0.033 (*), p<0.0021 (**), p<0.0002 (***), or p<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (UT: Untreated control, SOCE: Store-operated calcium entry, SEM: standard error of the mean, AUC: Area under the curve, SCQ: Short chain quinones). Results are shown in Figure 12. These results illustrate that some of the present compounds demonstrate a non-linear dose response, which has been described for some SIR ligands with maximal activity at nanomolar concentrations.

[0288] Example 44: Dose-dependent effects of reference quinones on SOCE.HepG2 cells were pre-treated with a dilution series (0.1 pM, 1 pM and 10 pM) of VK1 (green curve, lower series) and Ide (purple curve, higher series) for 15 minutes to measure their effect on the SOCE paradigm with the Fluo-4NW dye. The data represents the % mean ± SEM for the total AUC (AUC peak-1 + AUC peak-2) normalised to the UT from (n = 3) independentexperiments with 5 replicates / experiment each. The significance is indicated by asterisks p<0.033 (*), p<0.0021 (**), p<0.0002 (***), or p<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (UT: Untreated control, SOCE: Store-operated calcium entry, SEM: standard error of the mean, AUC: Area under the curve, VK1 : Vitamin KI, Ide: Idebenone). Results are shown in Figure 13. These results demonstrate that the observed effects on SOCE do not apply to all quinones but are restricted to the present compounds.

[0289] Example 45 - Effect of compounds on the ATP -triggered IP 3 pathwayHepG2 cells were pre-treated with SIR ligands (activators: Imi, SA4503 and modulator: BD1047 at 10 pM) and present compounds (10 pM #37, 0.01 pM #77, 10 pM #54, 0.5 pM #74) for 3 hours. The cells were then loaded with the Fluo-4NW dye and triggered with 100 pM of freshly reconstituted ATP to measure calcium mobilisation. Data represent the % mean ± SEM for the AUC (A) and the peak height (B) after ATP addition, normalised to UT from (n=3) independent experiments with 5 replicates per experiment. Statistical significance is indicated as p<0.033 (*), p<0.0021 (**), p<0.0002 (***), or p<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (UT: Untreated control, Imi: Imipramine, SIR: Sigma-1 receptor, IP3R: inositol 1,4,5- trisphosphate receptors, SCQ: Short chain quinones, SEM: standard error of the mean, AUC: Area under the curve). Results are shown in Figure 14A and 14B. These results illustrate that the observed effects of the present compounds on cellular calcium homeostasis also extend to additional mechanisms such as IP3 recpetor mediated calcium mobilisation, which is also controlled by SIR activity.

[0290] Example 46 - Effect of redox active and inactive compounds on SOCE.(A) HepG2 cells were pre-treated with the redox active UTA#37 and the redox inactive compounds UTA#147 (N-(3,4-dimethoxyphenethyl)-4-(3-methyl-l,4-dioxo-3,4- dihydrophthalazin-2(lH)-yl)butanamide) for 15 minutes to measure their effect on the SOCE paradigm. Data represents the % mean ± SEM for the total AUC (AUC peak-1 + AUC peak-2) normalised to the untreated control (0 pM) for (n > 3) independent experiments with at least 3 replicates each. Results are shown in Figure 7A. This result illustrates that bioactivation by enzymatic reduction of the quinone is required for their activity on SOCE.(B) Effect of dicoumarol SIR ligand-mediated effects on SOCE. HepG2 cells were pre-treated with SIR ligands (agonists: SA4503, Imi and antagonist: BD1047 at 10 pM), #74 (0.5 pM) and#37 (10 pM) in the presence or absence of 10 pM of Dicu for 3 hours. The cells were loaded with Fluo-4NW dye to measure their effect on the (SOCE) paradigm. The data represents the % mean ± SEM for the total AUC (AUC peak-1 + AUC peak-2) normalised to the untreated control from (n=3) independent experiments with 5 replicates. Results are shown in Figure 7B. This result demonstrates that inhibition of quinone reductase will inhibit the activity of the present compounds but will leave SIR reference compounds unaffected, which supports a different mode of action.(C) Effect of gamma-carboxy -glutamyl activity on SIR ligand-mediated effects on SOCE. HepG2 cells were first pre-treated with 5 pM Ani for 1 hour and treated with SIR ligands (agonist: Imi, antagonist: BD1047 at 10 pM) for 3 hours. Treatments with 10 nM of #77 were added for 15 minutes to measure their effect on the SOCE paradigm. The data represent the % mean ± SEM for the total AUC (AUC peak-1 + AUC peak-2) normalised to the untreated control from (n=3) independent experiments with 5 replicates per experiment. The significance is indicated by asterisks p<0.033 (), p<0.0021 (), p<0.0002 (), orp<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (*- comparison between treatment and the untreated control, #- pairwise comparison between treatments). (SIR: Sigma-1 receptor, AUC: Area under the curve, Ani: anisindione, SEM: Standard error of the mean, SOCE: Store-operated calcium entry). Results are shown in Figure 7C. This result illustrates that the reduced quinone serves as substrate for the gamma glutamic acid carboxylase (GGCX) to exert their effects on SOCE. In contrast, the activity of the reference compounds remains unaffected by inhibition of GGCX, which supports a different mode of action.

[0291] Example 47 - Comparative time-dependency profdes of SOCE with present compounds.(A) Dose-dependent effects (0.001-10 pM) of the present compounds on SOCE.HepG2 cells were pre-treated with doses of 0.01 - 10 pM for UTA#37 and 0.001 - 10 pM for UTA#77 for 15 minutes to measure their effect on the SOCE paradigm with the Fluo-4NW dye. Results are shown in Figure 5A. Data represents the % mean ± SEM for the total AUC normalised to the UT from (n > 3) independent experiments with 5 replicates each. While doses connected with solid lines were tested in the same experiment, the dotted lines indicate the absence of measurements. Significance is indicated by asterisks p<0.033 (*), p<0.0021 (**), p<0.0002 (***), p<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (UT: Untreated control, SOCE: Store-operatedcalcium entry, SEM: standard error of the mean, AUC: Area under the curve, SCQ: Short chain quinones). This data illustrates that the present compound can be associated with linear (UTA#37) or non-linear (UTA#77) dose-response relationships, which have been described for known SIR ligands previously.(B) Time-dependent effects on the SOCE paradigm in different time intervals between 15 mins (0.25 hours) to 72 hours for the SIR agonist (Imi, purple hexagons, 10 pM) was compared with effects of UTA#37 (10 pM, red circles) and UTA#77 (0.01 pM, green squares). Results are shown in Figure 5B. The data represents the % mean ± SEM for the total AUC=AUC peak-1 + AUC peak-2, normalised to the UT from (n=3) independent experiments with 5 replicates per experiment. This data demonstrates that the present compound activate the SIR significantly faster in a few minutes compared to the reference agonist that requires several hours.(C) Pulse-chase experiment with imipramine and compound #77.Results of this study are shown in Figure 5C. HepG2 cells were pre-incubated with the orthosteric SIR agonist Imi (purple hexagons, 10 pM, 3 hours) and UTA#77 (green squares, 10 nM, 15 minutes) (-3 to 0 hours). The treatments were removed from the system (wash out, red line at 0 hours), and their effect on the SOCE paradigm was measured after different periods (1, 2, 3, 6, 18, 21 and 24 hours) of “post- wash” incubation (0-24 h). The data represents the % mean ± SEM for the total AUC (AUC peak-l+ peak-2) normalised to the untreated cells from (n=3) independent experiments with 5 replicates. Open symbols ( ) indicate a statistically significant effect, and closed symbols (•) indicate non-significant responses compared to the untreated cells. Statistical analysis was performed using GraphPad Prism ver. 9. (UT: Untreated control, SOCE: Store-operated calcium entry, SEM: standard error of the mean, AUC: Area under the curve, Imi: imipramine). These results show that after wash-out of compound UTA#77, the activation of the SIR remains active for at least 21 hours, while after activation by the reference compound imiparamine the SIR retains its activity only for about 3 hours. This data, therefore supports a different mechanism of activation by the present compounds.

[0292] Example 48 - Effects of co-treating cells with present compounds and known SIR ligands on SOCE.(A) HepG2 cells were pre-treated with different combinations of 10 pM Imi (SIR agonist), and 10 pM UTA#37 for 3 hours and loaded with Fluo-4NW dye to measure their effect on the SOCE paradigm. Results are shown in Figure 6A. The data represent the % mean ± SEM forthe total AUC (AUC peak-1 + AUC peak-2) normalised to the untreated control from (n=3) independent experiments with 5 replicates per experiment. The significance is indicated by asterisks p<0.033 (*), p<0.0021 (**), p<0.0002 (***), or p<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (*- comparison between treatment and the untreated control, #- pairwise comparison between treatments) (SIR: Sigma-1 receptor, AUC: Area under the curve, Phe: Phenytoin, Imi; Imipramine, SEM: Standard error of the mean, SOCE: Store-operated calcium entry). These results demonstrate that the combination of the reference compound imipramine with the present compound UTA#37 does not result in additive, allosteric or synergistic effects.(B) Effect of phenytoin on present compounds-mediated effects on SOCE.HepG2 cells were pre-treated with SIR ligands (agonist: Imi and antagonist: BD1047 at 10 pM) and 1 pM of compound #37 in the presence or absence of allosteric modulator (Phe at 250 pM) for 3 hours. The cells were then loaded with Fluo-4NW dye to measure their effect on the SOCE pathway. Results are shown in Figure 6B. Data represents the % mean ± SEM for the total AUC normalised to the untreated cells from (n=3) independent experiments with 5 replicates per experiment. Significance is indicated by asterisks p<0.033 (*), p<0.0021 (**), p<0.0002 (***), or p<0.0001 (****) in accordance with the adjusted P-values. Statistical analysis was performed using GraphPad Prism ver. 9. (*-comparison between treatment and the untreated control, #- pairwise comparison between treatments). (AUC: Area under the curve, Phe: Phenytoin, Imi; Imipramine, SEM: Standard error of the mean). These results demonstrate that the combination of the reference compound imipramine or the present compound UTA#37 with the allosteric modulator phenytoin does enhance their effectivenes to reduce SOCE. In contrast, the activity of reference SIR antagonist BD1047 remains unaffected as described previously. These results demonstrate that the present compounds can be combined with allosteric SIR modulators with similar effects to SIR reference agonists and support their activities as SIR activators (Figure 6B).

[0293] Example 49 - The naphthoquinone cycleVitamin K analogues with a naphthoquinone core (Q) are reduced to their active form, the hydroquinone (QH2), by different quinone K reductases (VKR). This hydroquinone (QH2) fuels the y-Glutamyl carboxylase (GGCX) that adds carboxyl (COO-) groups to specific glutamic acid (Glu) residues of specific target proteins through y-carboxylation of form y- carb oxy glutamic acid (Gia). During this reaction, QH2 is oxidised to a quinone epoxide (QO) intermediate, which is further recycled back to its active form by another reductase step. (Figure8). The cyclic use of the present compounds in this pathway explains their activities at low concentrations. In addition, GLA modifications are regarded as stable posttranslational modifications that explain the sustained target activation observed with the present compounds (see Example 47, Figure 5C).

Claims

CLAIMS:

1. A method for the treatment of an ocular disease associated with Ca2+dysregulation in a subject in need thereof, the method comprising administering a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5.

2. A method for the treatment of an ocular disease associated with Ca2+dysregulation in a subject in need thereof, the method comprising administering a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C 12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5.

3. A method according to claim 1 or 2, wherein the ocular disease is a glaucoma, macular degeneration, age-related macular degeneration, cataract, dry eye disease or diabetic retinopathy.

4. A method according to any one of claims 1 to 3, wherein the ocular disease is diabetic retinopathy.

5. A method according to claim 4, wherein the diabetic retinopathy is a mild diabetic retinopathy or a moderate diabetic retinopathy.

6. A method according to claim 4, wherein the diabetic retinopathy is a nonproliferative diabetic retinopathy.

7. A method according to claim 4, wherein the diabetic retinopathy is a proliferative diabetic retinopathy.

8. A method according to any one of claims 1 to 7, wherein the compound ofFormula (I) or Formula (II) is administered at an effective concentration in the range of from about 0.0001 pM to about 10 pM.

9. A method according to any one of claims 1 to 8, wherein the compound ofFormula (I) or Formula (II) is administered at an effective concentration in the range of from about 0.001 pM to about 10 pM.

10. A method according to any one of claims 1 to 9, wherein the compound of Formula (I) or Formula (II) is administered as an eye drop formulation.

11. A method according to any one of claims 1 to 10, wherein the compound of Formula (I) or Formula (II) is administered once a day.

12. A method for combination therapy for treating diabetic retinopathy said combination therapy including the step of administering an effective amount of a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5; together with an VEGF inhibitor, wherein the administration of the combination can take place sequentially, concomitantly, or simultaneously.

13. A method for combination therapy for treating diabetic retinopathy said combination therapy including the step of administering an effective amount of a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C 12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5; together with an VEGF inhibitor, wherein the administration of the combination can take place sequentially, concomitantly, or simultaneously.

14. A method of protecting pericyte function in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5.

15. A method of protecting pericyte function in a subject in need thereof wherein the subject is administered with an effective amount of a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C 12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5.

16. A method according to any one of claims 1 to 15, wherein the compound is a compound of Formula (la):Formula (la) or a pharmaceutically acceptable salt thereof, wherein:R5is methyl,R6is selected from H, -COOR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5; a compound of Formula (lb):Formula (lb) or a pharmaceutically acceptable salt thereof, wherein:R5is methyl,R6is selected from H, -COOR, -OH, optionally substituted C5-C12 aryl, optionally substituted C4-C12 heteroaryl,R is H or optionally substituted Ci-C4 alkyl;R13at each occurrence is independently selected from H, phenyl, and benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5; a compound of Formula (Ila):Formula (Ila) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or methyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted C1-C3 alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-Ci-C4 alkyl, -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is 1, and n is an integer selected from 1, 2, 3, 4 or 5; or a compound of Formula (lib):Formula (lib) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or methyl,R7is selected from H, or -OH,R is H or optionally substituted C1-C3 alkyl,R4 is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O- Ci-C4 alkyl, -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is 1, and n is an integer selected from 1, 2, 3, 4 or 5.

17. A method according to any one of claims 1 to 15, wherein the compound is selected from the group consisting of:

18. Use of a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5, in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.

19. Use of a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C 12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5, in the manufacture of a medicament for the treatment of an ocular disease associated with Ca2+regulation.

20. Use of a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R6is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C2-C12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl;R13at each occurrence is independently selected from H, optionally substituted phenyl, and optionally substituted benzyl, n is an integer selected from 1, 2, 3, 4 or 5, and m is an integer selected from 1, 2, 3, 4 or 5,in the manufacture of a medicament for protecting pericyte function.

21. Use of a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt thereof, wherein:R5is selected from H or C1-C4 alkyl,R7is selected from H, -C(O)OR, -OR, optionally substituted C5-C12 aryl, optionally substituted C1-C3 alkyl, optionally substituted C2-C 12 heteroaryl,R is H or optionally substituted Ci-Ce alkyl,R4is selected from -C(O)OH, optionally substituted C1-C3 alkyl, -C(O)O-[Ci-C4 alkyl], -C(O)O-optionally substituted C5-C12 aryl, and -C(O)O-optionally substituted C2-C12 heteroaryl, r is an integer selected from 1 or 2, and n is an integer selected from 1, 2, 3, 4 or 5, in the manufacture of a medicament for protecting pericyte function.

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