WO2012094615A2

WO2012094615A2 - Use of cav3.1 selective t-type calcium channel antagonists

Info

Publication number: WO2012094615A2
Application number: PCT/US2012/020518
Authority: WO
Inventors: Eckard Weber; Tilman Oltersdorf; Martin Koller
Original assignee: Zenyaku Kogyo Kabushikikaisha
Priority date: 2011-01-07
Filing date: 2012-01-06
Publication date: 2012-07-12
Also published as: WO2012094615A3; WO2012094612A1

Abstract

The present invention is directed to heterocyclic compounds which are antagonists of T-type calcium channels and which are useful in the treatment and prevention of disorders and diseases in which T-type calcium channels are involved. The invention is also directed to methods of identifying a compound for the treatment and prevention of Alzheimer's Disease by investigating T-type calcium channel blocking activity of the compound.

Description

USE OF CAV3. 1 SELECTIVE T-TYPE CALCIUM CHANNEL

ANTAGONISTS

BACKGROUND OF THE INVENTION Field of the Invention

[0001] The present invention is directed to heterocyclic compounds which are antagonists of T- type calcium channels and which are useful in the treatment and prevention of disorders and diseases in which T-type calcium channels are involved. The invention is also directed to methods of identifying a compound for the treatment and prevention of Alzheimer's Disease by investigating T-type calcium channel antagonistic activity of the compound.

Related Art

[0002] Alzheimer's Disease (AD) is a neurodegenerative disorder for which there are only symptomatic treatments, with limited efficacy. Existing symptomatic treatments of AD enhance neurotransmitter activity. In particular, acetylcholine esterase inhibitors such as donepezil, rivastigmine, and galantamine increase the brain levels of acetylcholine which, in turn, lead to improved mental function.

[0003] Approaches other than inhibition of acetylcholinesterase have been pursued to increase brain cholinergic function, in particular the use of agonists for nicotinic and muscarinic acetylcholine receptors. However, to date, no regulatory approval of these compounds has been granted.

[0004] Thus, there remains a need in the art for compounds for use in the prevention and treatment of AD.

[0005J The compound ST101 , also know as ZSET1446, has shown pharmacological activity in rodent models of learning and memory relevant to AD after both acute (single-dose) and chronic administration. The chemical name for ST101 is spiro(imidazo(l,2-a)pyridin- 2(3H)-one-3,2'-indan).

[0006] ST101 has been shown to increase acetylcholine (ACh) levels in rodent brains and to improve learning and memory in a number of behavioral tests in animals. (Yamaguchi Y., et al., J. Pharmacol. Exp. Ther. 577: 1079-87 (2006); Ito Y., et ai, J. Pharmacol. Exp. Ther. 520:819-27 (2007)). This functional improvement was correlated with enhancement in long-term potentiation (LTP), the electrophysiological correlate of memory formation, as well as with biochemical changes that are associated with enhanced LTP, such as increased activity of protein kinase C and Ca²⁺/calmodulin- dependent protein kinase II (CaMK II) (Han, F., et al., J. Pharmacol. Exp. Ther. 326: \27- 134 (2008)).

[0007] Experiments have shown that ST101 potentiates nicotine-stimulated release of ACh, increases extracellular ACh concentrations in the cerebral cortex, and increases extracellular concentrations of both ACh and dopamine in the hippocampus. The breadth of models across which ST101 exerts its effects suggests the potential for involvement at an upstream target in the signaling pathway(s) associated with these processes.

[0008] ST101 has also demonstrated effects in the Senescence Accelerated Mouse P 8 (SAMP8), a mouse strain that develops age-related deficits in learning and memory along with accumulation of Αβ-like deposits in brain tissue. The SAMP8 mouse is discussed in Morley, J.E., Biogerontolog 3: 57-60 (2002). ST101 decreased accumulation of Αβ-like deposits and also produced an improvement in learning and memory functions, suggesting the behavioral effect of ST101 may be linked to reduction of Αβ production and/or accumulation. See US Patent Appl. Publication No. 2008/103158 Al . ST101 has also been shown to induce cleavage of amyloid precursor protein, to decrease the level of pro-ADAMlO and/or BACE protein, and to enhance the activity of the ubiquitin- proteasome system pathway. See US Patent Appl. Publication No. 2010/0168135, US Patent Appl. Publication No. 2010/0267763, and US Patent Appl. Publication No. 2010/0298348.

[0009] Ion channels are proteins which form pores within the cell membrane which allow for the passage of ions (Jain, G., et al, Current Research & Information on Pharmaceutical Sciences 70:9-15 (2009)). Some channels, termed voltage-gated channels, have portions that are sensitive to membrane potential. Voltage-gated channels consist of one or more subunits, each of which has transmembrane helices forming peptide chains. On activation, these helices move and allow the pore to open.

[0010J Control of calcium influx across the cellular membrane is partially regulated by voltage- gated calcium channels. Voltage-gated calcium channels have been classified into the following different subtypes: Ca_vl .x (L-type), Ca_v2.x (N-, P/Q-, and R-types), and Ca_v3.x (T-type) (Giordanetto, F., et al., "T-type calcium channels inhibitors: a patent review," Expert Opin. Ther. Patents, on-line posting Informa Healthcare (November 19, 2010)). The T-type class is characterized by low voltage activation, fast inactivation, and small conductance and is composed of three members based on their different main pore- forming al subunits: Ca_v3.1 (al G), Ca_v3.2 (alH), and Ca_v3.3 (al l). Ca_v3.1 and Ca_v3.3 are mainly expressed in the brain and Ca_v3.2 is found in brain and peripheral tissues.

[0011] T-type channels have been proposed as therapeutic targets for a variety of diseases including hypertension, angina pectoris, heart failure, atrial fibrillation, obesity, fertility disorders, cancer, neuropathic pain, epilepsy, insomnia, and nicotine addiction (Giordanetto, F., et al., "T-type calcium channels inhibitors: a patent review," Expert Opin. Ther. Patents, on-line posting Informa Healthcare (November 19, 2010)). Mibrefradil was launched in 1997 as an effective antihypertensive agent with a novel and unique mode of action and structurally related to previously reported calcium channel blockers. Although it was first reported as a selective T-type channel inhibitor, subsequent studies demonstrated that mibefradil, while being largely non-selective within the calcium channel family, also Inhibits sodium, potassium, and chlorine channels.

[0012] Ca_v3 T-type calcium channels and K_v4 A-type potassium channels have been shown to form a signaling complex in which T-type calcium channels provide a physiological source of calcium for modulating A-type currents in cerebellar stellate cells. (Anderson, D., et al., Nature Neuroscience 73:333-337 (2010)). K_v4 potassium channels conduct "fast, inactivating A-type potassium currents that are involved in . regulating spike frequency and timing, dendritic activity, and synaptic plasticity." Id. at page 336. K_v4 and Ca_v3 can form a macromolecular signaling complex that allows the cytoskeletal protein KChIP3 to act as a calcium sensor in the calcium nanodomain which results in T- type channel regulation of A-type potassium channel current. Id. at page 336. This calcium-dependent modulation of A-type potassium channel current has been shown to require the co-expression of not only Ca_v3 and K_v4.2 channels but also CMP3 as the critical calcium sensor. (Anderson, D., et al., Channels 4:163-167 (2010)). The authors posited that brain regions for which this signaling complex controls neuronal activity will show a dependence of KChTP3 distribution. There is no link between K_v4 and other calcium channels (Ca_vl .4, Ca_v2.1 , or Ca_v2.3).

[0013] The release of neurotransmitters at neuronal synapses is highly dependent upon the depolarization-induced influx of calcium through voltage-dependent calcium channels. (Giovanni, F., et al, British Journal of Pharmacology 136:1135-1145 (2002)). Multiple voltage-dependent calcium channel subtypes have been implicated in different synapses throughout the nervous system. For example, L-type, N-type, and P/Q-type calcium channels have been shown to play a role in acetylcholine release (Giovanni, F., et al, page 1 135) and N-type, P-type, and Q-type voltage-dependent calcium channels have been demonstrated to be involved in dopamine release in the neostriatum (Phillips, P.E.M. and Stamford, J.A., Brain Research 884: 139-146 (2000)).

[0014] T-type calcium channels are predicted to have an opposite effect on neurotransmitter release compared to high-voltage activated (HVA) calcium channels (L-type, N-type, and P-type). T-type calcium channels activate A-type potassium currents through K_v4 channels. Anderson, Channels, at page 163. A-type K⁺ currents govern the firing frequency of neurons. Potassium efflux through open potassium channels increases the membrane potential and raises the threshold for the next action potential. This directly leads to a decrease in neuronal firing frequency. Lower firing rate results in less neurotransmitter release. Anderson showed that blockage of this mechanism by an antibody against KChIP reduces A-type K⁺ currents. Anderson, Nature Neuroscience, at page 336. This reduction of A-type K⁺ currents will increase firing frequency and therefore increase neurotransmitter release. The data also suggest that reduction of A- type potassium currents by other mechanisms, including inhibition of T-type calcium currents will have the same effect.

[0015] Therefore, the need exists for an antagonist selective for T-type calcium channels, in particular the Ca_v3.1 calcium channel.

[0016] Essential tremor is a slowly progressive neurological disorder identified by an involuntary shaking movement. Current drug treatments of tremors do not offer long- term sustained efficacy but rather lower the severity of the condition. The most common and primarily prescribed treatment is a beta-blocker propranolol and primidone, a drug used to treat seizures. Additional medications that may reduce tremors include antiseizure drugs such as gabapentin and topiramate, mild tranquilizers such as alprazolam and clonazepam, and calcium-channel blockers such as flunarizine and nimodipine. In severe cases, surgery may be used to treat tremors.

[0017] Thus, there is a clear need for an effective, low risk therapy for essential tremor. BRIEF SUMMARY OF THE INVENTION

[0018] The present invention provides a method of treating or preventing a condition mediated by T-type calcium ion channels, the method comprising administering to a subject in need thereof an effective amount of a heterocyclic compound having the general Formula (I):

or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein Rj, R₂, R3, R4, R_x, and the structural unit

are as defined herein.

[0019] In one embodiment, the present invention provides a method of treating or preventing a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound which is a Ca_v3.1 calcium channel antagonist wherein the compound binds to the Ca_v3.1 calcium channel and reduces the voltage-activated calcium current in the subject.

[0020J In another embodiment, the present invention provides a method of treating or preventing a disease or condition selected from the group consisting of essential tremor, epilepsy, absence seizures, juvenile myoclonic epilepsy, migraine, neuropathic pain syndromes, sleep disorders, jet lag disorder, circadian rhythm sleep disorders, tinnitus, dystonia, familial ataxia, schizophrenia, schizoaffective disorder, hypertension, arrhythmias, atrial fibrillation, congestive heart failure, cyclical hormonal secretion under central nervous system control, and weight loss. In one embodiment, the disease or condition is essential tremor. In another embodiment, the disease or condition is epilepsy. In another embodiment, the disease or condition is absence seizure. In another embodiment, the disease or condition is neuropathic pain.

[0021] In another embodiment, the present invention provides a method of treating or preventing a disease or condition selected from the group consisting of senile dementia, Alzheimer's disease, cognitive decline, depression, manic depressive psychoses; obsessive-compulsive disorder, panic disorder, anxiety disorder, transient ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage, cerebral infarct, hypertensive encephalopathy, amyloidosis, cerebral amyloid angiopathy, cataracts, glaucoma, progression of glaucoma, age-related macular degeneration, rheumatism, osteoporosis, metabolic syndrome, wrinkles, hair loss, one or more conditions associated with senescence, ulcers, periophthalmic lesions, corneal opacity, lordokyphosis, age retardant activity, cognitive impairment, cerebrovascular disease, Lewy body dementia, Parkinson's disease, Pick's disease, Huntington's disease, Down's syndrome, psoriasis, Crohn's disease, rheumatoid arthritis, asthma, autoimmune disease, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivies, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, transplant rejection, inclusion body myositis, vasculitis, cystic fibrosis, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, contact dermatitis, conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, ulcerative colitis, mastocytosis, hyper IgE syndrome, systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, anaphylactic reaction, cancer, Paget's disease, frontotemporo lobar dementia, sporadic inclusion body myositis, cardiac dysfunction, spinobulbar muscular atrophy, spinocerebellar ataxia, macular degeneration, congestive heart failure, Haw River syndrome, polyglutamine diseases, and systemic amyloidosis.

In another embodiment, the present invention provides a method of treating or preventing a disease or condition comprising administering a compound which is an antagonist of the Ca_v3.1 calcium channel, wherein the compound administered is a compound of Formula

(I):

or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein R], R₂, R₃, R_x, and the structural unit

are as defined herein. In another embodiment, the compound is not spiro(imidazo(l ,2- a)pyridin-2(3H)-one-3,2'-indan).

[0023] In another embodiment, the present invention provides a method of treating or preventing a disease or condition comprising administering a compound which is an antagonist for the Ca_v3.1 calcium channel, wherein the compound does not antagonize the L-type, retype, P-type, Q-type, or R-type calcium channels. In another embodiment, the compound does not antagonize the Ca_v3.2 calcium channel. In another embodiment, the compound does not antagonize the Ca_v3.3 calcium channel.

[0024] In one embodiment, the present invention provides a method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting a first group of cells expressing a Ca_v3.1 calcium channel with a test compound;

(b) measuring the calcium channel antagonist activity of the first group;

(c) comparing the calcium channel antagonist activity of the first group to the calcium channel antagonist activity of a second group of said cells that have not been contacted with said test compound;

wherein a test compound that provides a greater calcium channel antagonist activity than the calcium channel antagonist activity of second group is selected. In one embodiment, the activity of the cells is measured by whole cell patch clamp. In another embodiment, the cells expressing Ca_v3.1 calcium channel are HEK 293 cells or transformed HEK 293 cells.

[0025] In one embodiment, the present invention provides a method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(b) measuring the calcium channel antagonist activity of the test compound of (a);

(c) contacting cells expressing a Ca_v3.2 calcium channel with the same test compound used in (a);

(d) measuring the calcium channel antagonist activity of the test compound of (c);

(e) comparing the activity of (b) with the activity measured in (d); wherein a test compound that provides a greater activity in (b) than the activity in (d) is selected. In one embodiment, the activity of the cells is measured by whole cell patch clamp. In another embodiment, the cells expressing Ca_v3.1 and Ca_v3.2 calcium channels are HEK 293 cells or transformed HEK 293 cells.

(0026] In one embodiment, the present invention provides a method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(c) contacting cells expressing a Ca_v3.3 calcium channel with the same test compound used in (a);

(e) comparing the activity of (b) with the activity measured in (d); wherein a test compound that provides a greater activity in (b) than the activity in (d) is selected. In one embodiment, the activity of the cells is measured by whole cell patch clamp. In another embodiment, the cells expressing Ca_v3.1 and Ca_v3.3 calcium channels are HEK 293 cells or transformed HEK 293 cells.

[0027] In one embodiment, the present invention provides a method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(e) contacting cells expressing a Ca_v3.3 calcium channel with the same test compound used in (a);

(f) measuring the calcium channel antagonist activity of the test compound of (e);

(g) comparing the activity of (b) with the activity of (d) and (f);

wherein a test compound that provides a greater activity in (b) than the activities in (d) and (f) is selected. In one embodiment, the activity of the cells is measured by whole cell patch clamp. In another embodiment, the cells expressing Ca_v3.1, Ca_v3.2, and Ca_v3.3 calcium channels are HEK 293 cells or transformed HEK 293 cells.

[0028] In another embodiment of the present invention, the compound that selectively antagonizes activity of the Ca_v3.1 calcium channel also enhances the release of a neurotransmitter. In one embodiment, the neurotransmitter is acetylcholine. In another embodiment, the neurotransmitter is dopamine.

[0029] In another embodiment of the present invention, the compound that selectively antagonizes activity of the Ca_v3.1 calcium channel also reduces amyloid beta production. In one embodiment, the disease or condition is selected from the group consisting of Alzheimer's disease, diabetes, Parkinson's disease, transmissable spongiform encephalopathy, bovine spongiform encephalopathy, Huntington's disease, medullary carcinoma of the thyroid, cardiac arrhythmias, isolated atrial amyloidosis, atherosclerosis, rheumatoid arthritis, aortic medial amyloid, prolactinomas, familial amyloid polyneuropathy, hereditary non-neuropathic systemic amyloidosis, dialysis-related amyloidosis, Finnish amyloidosis, lattice corneal dystrophy, cerebral amyloid angiopathy, systemic AL amyloidosis, inclusion body myositis, amyloidosis, cataracts, glaucoma, age-related macular degeneration, rheumatism, osteoporosis, metabolic syndrome, wrinkles, and hair loss.

[0030] In one embodiment, the present invention provides a method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

[0031] or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein Rl , R2, R3, R4, and Rx are as defined herein. In another embodiment, the compound is spiro(imidazo( 1 ,2 -a)pyridin-2(3 H)-one-3 ,2'-indan) .

[0032] In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 600 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 500 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 400 mg. In another embodiment, the compound of Formula (I) is administered at a dose of between about 10 mg and 300 mg.

[0033] In another embodiment, the compound of Formula (I) is administered orally to the subject. In another embodiment, the compound of Formula (I) is administered parenterally to the subject. In another embodiment, the compound of Formula (I) is administered intravenously, subcutaneously, or intramuscularly to the subject.

[0034] In another embodiment, the present invention provides a method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) and a therapeutic agent used to treat essential tremor. In another embodiment, the therapeutic agent used to treat essential tremor is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.

[0035] In another embodiment, the present invention provides a pharmaceutical composition comprising (a) a compound of Formula (I) and (b) a further therapeutic agent for the treatment of essential tremor. In one embodiment, the compound of Formula (I) is spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-indan). In another embodiment, the further therapeutic agent for the treatment of essential tremor is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.

[0036] In another embodiment, the compound of Formula (I) and the therapeutic agent are administered orally.

[0037] In another embodiment, the present invention provides a kit comprising spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent. In one embodiment, the therapeutic agent is selected from the group consisting of propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine. In another embodiment, the therapeutic agent is in a form suitable for oral administration.

[0038] In another embodiment, the present invention provides a kit comprising spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent, wherein spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered simultaneously.

[0039] In another embodiment, the present invention provides a kit comprising spno(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent, wherein spiro(imidazo(l ,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered separately. BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

[0040] Figure 1 describes the effects of propranolol and ST101 on harmaline-induced tremor events. Events that are significantly different from the vehicle are indicated with a *.

[0041] Figure 2 describes the effects of propranolol and ST101 on (a) harmaline-induced short tremor events at 30, 60, and 90 minutes after administration of ST101 and (b) harmaline- induced long tremor events at 30, 60, and 90 minutes after administration of ST101 (* (p<0.05) and ** (pO.01) indicate significant differences compared to vehicle for each specific time point).

[0042] Figure 3 describes the effects of propranolol and ST101 on (a) harmaline-induced total tremor events at 30, 60, and 90 minutes after administration of ST101 (* (p<0.05) and ** p<0.01) indicate significant differences compared to vehicle for each specific time point).

[0043] Figure 4 describes the effects of (a) a 60 minute pre-treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events and (b) a 90 minute pre- treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events (* (p<0.05) and ** (p<0.01) indicate significant differences compared to vehicle for each specific time point).

[0044] Figure 5 is a diagram of the inhibitory dose response of ST101 on the Ca_v3.1 calcium channel.

[0045] Figure 6 is a diagram of the current-voltage dependence (I-V) curve of the control and

ST101 (0.0429 μΜ) on the Ca_v3.1 calcium channel.

[0046] Figure 7 provides a current activation curve of the inhibitory effect of mibefradil (0.1 μΜ) and control on the Ca_v3.1 calcium channel.

[0047] Figure 8 provides a current activation curve of the inhibitory effect of 0.1 uM ST101 followed by 3 μΜ mibefradil compared to control on the Ca_v3.1 calcium channel.

[0048] Figure 9 is a diagram of the inhibitory dose response of ST101 on the Ca_v3.2 calcium channel.

[0049] Figure 10 is a diagram of the current-voltage dependence (I-V) curve of the control and

ST101 (100 μΜ) on the Ca_v3.2 calcium channel.

[0050] Figure 11 provides a current activation curve of the inhibitory effect of 3 μΜ mibefradil and control on the Ca_v3.2 calcium channel. [0051] Figure 12 provides a current activation curve of the inhibitory effect of 300 μΜ ST101 followed by 3 μΜ mibefradil compared to control on the Ca_v3.2 calcium channel.

[0052] Figure 13 is a diagram of the inhibitory dose response of ST101 on the Ca_v3.3 calcium channel.

[0053] Figure 14 is a diagram of the current-voltage dependence (I-V) curve of the control and

ST101 (100 μΜ) on the Ca_v3.3 calcium channel.

[0054] Figure 15 provides a current activation curve of the inhibitory effect of 1 μΜ mibefradil and control on the Ca_v3.3 calcium channel.

[0055] Figure 16 provides a current activation curve of the inhibitory effect of 3 uM ST101 followed by 3 μΜ mibefradil compared to the control on the Ca_v3.3 calcium channel.

[0056] Figure 17 provides (a) normalized peak amplitude against time for Ca_v3.1 transiently expressed in the HEK293 cell line at time of onset of ST101 and (b) normalized peak amplitude against time for Ca_v3.1 transiently expressed in ihe HEK293 cell line at time of offset of STlOl .

[0057] Figure 18 provides a study of the change of frequency of voltage steps at IC50 of ST101 on Ca_v3.1 transiently expressed HEK293.

[0058] Figure 19 provides (a) an IC50 determination of mibefradil on Ca_v3.1 transiently expressed in HEK293 and (b) an IC50 determination of ST101 on Ca_v3. l transiently or stably expressed in HEK293.

[0059] Figure 20 provides a current activation curve of the effect of ST101 and a control on IC90 on Ca_v3.1 transiently or stably expressed in HEK293.

[0060] Figure 21 provides a steady state inactivation of ST101 and a control on Ca_v3.1.

[0061] Figure 22 provides a proposed mechanism for the ST101 blockade of the Ca_v3.1 calcium channel which causes acetylcholine release and cognition enhancement.

[0062] Figure 23 provides a proposed mechanism for the ST101 blockade of the Ca_v3.1 calcium channel which causes γ-secretase cleavage and A-beta production.

DETAILED DESCRIPTION OF THE INVENTION

[0063] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which the invention belongs. [0064] The invention relates to compounds useful in treating conditions mediated by T-type calcium channel activity. In one embodiment, the compounds are heterocyclic compounds with structural features that enhance the T-type calcium channel blocking activity of the compounds.

[0065] The present invention is directed to a method of treating or preventing a disease or condition comprising administering a compound which is a selective antagonist for the Ca_v3.1 calcium channel.

[0066] The present invention is also directed to a method of treating or preventing a disease or condition comprising administering a compound which is a selective antagonist for the Ca_v3.1 calcium channel, wherein the compound administered is a compound of Formula

(I):

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.

[0067] In the general Formula (I), the structural unit having the general Formula (II)

may be one or more structural units selected from multiple types of structural units having the general Formula (III)

[0068] In the general Formula (I), R_x is methyl or nil. In the general Formula (I), Ri and R₂ each are one or more functional groups independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, acetylamino, benzylamino, trifluoromethyl, C C6 alkyl, C1-C6 alkoxy, C₂-C6 alkenyl, C₃-Cg cycloalkyl, benzyloxy, CH₂-Rs (wherein R₅ is phenyl (which may be substituted with Ci-C₆ alkyl, halogen, or cyano), or thienyl), and -0-(CH₂)_n-R6, wherein R6 is a vinyl, C3-C8 cycloalkyl, or phenyl, and n is 0 or 1.

[0069] In the general Formula (I), R3 and R4 each are one or more functional groups independently selected from the group consisting of hydrogen, C1-C6 alkyl, C₂-C6 alkenyl, C₃-C₈ cycloalkyl, CH2-R5 (wherein R₅ is phenyl (which may be substituted with C1-C6 alkyl, halogen, or cyano), naphthyl, or thienyl), and -CH(R$)-R7. Alternatively, R3 and R₄ together form a spiro ring having the general Formula (IV):

[0070] R₇ is one or more functional groups selected from the group consisting of a vinyl; ethynyl; phenyl optionally substituted by a C -Ce alkyl, Cj-C6 alkoxy, hydroxy, 1 or 2 halogen atoms, di C\-Ce alkylamino, cyano, nitro, carboxy, or phenyl; phenethyl; pyridyl; thienyl; and furyl. The above R₈ is a hydrogen or Ci-Ce alkyl. [0071] Furthermore, in the general Formula (IV), the structural unit B may be one or more structural units selected from multiple types of structural units having the general Formula (V). The structural unit B binds at a position marked by * in the general Formula (V) to form a spiro ring.

[0072] R.9 is one or more functional groups selected from the group consisting of hydrogen, halogen, hydroxy, Ci-Ce alkoxy, cyano, and trifluoromethyl.

[0073] When the heterocyclic compound having the general Formula (I) has asymmetric carbon atoms in the structure, its isomer from asymmetric carbon atoms and their mixture (racemic modification) is present. In such cases, all of them are included in the heterocyclic compound used in the embodiments described later.

[0074] The term "Ci-C6^M refers to 1 to 6 carbon atoms unless otherwise defined. The term "C₃- C₈" refers to 3 to 8 carbon atoms unless otherwise defined. The term "C\-Ce alkyl" includes linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n- butyl, tert-butyl, sec-butyl, n-pentyl, and n-hexyl. The term "Ci-C₆ alkoxy" includes linear or branched alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, and n-hexyloxy. The term "C3-C8 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl, and cyclooctyl. The term "halogen" includes fluorine, chlorine, bromine, and iodine.

In another embodiment, the heterocyclic compound useful in the practice of the present invention is selected from the group consisting of:

3,3-dimethylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dipropylimidazoG,2-a)pyridin-2(3H)-one,

3,3-dibutylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-diallylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-diallyl-8-benzyloxyimidazo(l,2-a)pyridin-2(3H)-one,

3,3-di(2-propinyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-methylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-5,7-dimethylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-hydroxyirnidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-methoxyimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-ethoxyimidazo(l,2-a)pyridin-2(3H)-one,

8-allyloxy-3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-isopropoxyimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-cyclopropylmethyloxyimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-cycloheptyloxyimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-6-chloroimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-6,8-dichloroimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-chloro-6-trifluoromemyHmidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-benzyloxyimidazo(l,2-a)pyridin-2(3H)-one,

8-amino-3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,

8-acetylamino-3,3-dibenzylimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibenzyl-8-benzylaminoimidazo(l,2-a)pyridin-2(3H)-one,

3,3 -bis(3 -chlorobenzyl)imidazo(l,2-a)pyridin-2(3 H)-one,

3,3-bis(3-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one, 3,3-bis(4-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(2,4-dichlorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(4-dimethylaminoben2yl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(4-methoxybenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(4-biphenylmethyl)imida2o(l,2-a)pyridin-2(3H)-one,

3 , 3 -bis(4-cyanobenzyl)imidazo(l,2-a)pyridin-2(3 H)-one,

3,3-bis(4-hydroxy-benzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(3-phenyl-l-propyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(2,4-difluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(4-nitrobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(4-carboxybenzyI)imidazo(l,2-a)pyridin-2(3H)-one,

8-benzyloxy-3,3-bis(l-phenylethyl)imidazo(l,2-a)pyridin-2(3H)-one,

8-benzyloxy-3,3-bis(3-methylbenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

8-benzyloxy-3,3-bis(4-methylbenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3-benzyl-3-(4-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

3-ethyl-3(4-fluorobenzyl)imidazo(l,2-a)pyridin-2(3H)-one,

8-methyl-3,3-bis(3-pyridylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,

8-methyl-3,3-bis(4-pyridylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(2-thienylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(2-furylmethyl)imidazo(l,2-a)pyridin-2(3H)-one,

spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-indan),

spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(2,3)dihydrophenarene), spiro(imidazo(2,l-b)thiazol-6(5H)-one-5,2'-benzo(f)indan), spiro(imidazo(l,2-b)thiazol-6(5H)-one-5,2'-ind n),

spiro(2-methylimidazo(l,2-b)thiazol-6(5H)-one-5,2'-benzo(f)indan),

5,5-bis(4-fluorobenzyl)imidazo(2,l-b)thiazol-6(5H)-one,

5,5-dibenzylimidazo(2,l-b)thiazol-6(5H)-one,

5,5-bis(4-methylbenzyl)imidazo(2,l-b)thiazol-6(5H)-one,

5,5-bis(4-cyanobenzyl)imidazo(2,l-b)thiazol-6(5H)-one,

5,5-dibenzyl-2-methylimidazo(2,l-b)thiazol-6(5H)-one,

5,5-bis(4-fluorobenzyl)-2-methyliniidazo(2,l-b)thiazol-6(5H)-one,

5,5-dicyclohexyl-2-methylimidazo(2,l-b)tliiazol-6(5H)-one, 5,5-bis(4-cyanobenzyl)-2-methylimidazo(2,l-b)thiazol-6(5H)-one,

5,5-di(2-butenyl)imidazo(2,l-b)thiazol-6(5H)-one,

5,5-dibutylimidazo(2,l-b)thiazol-6(5H)-one,

5,5-dicyclohexylimidazo(2,l-b)thiazol-6(5H)-one,

5,5-bis(2-thienylmethyl)imidazo(2,l-b)thiazol-6(5H)-one,

spiro(2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one-5,2'-benzo(f)indan),

5,5-dibutyl-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,

5,5-di(2-butenyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,

5,5-bis(4-methylbenzyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,

5,5-bis(2-thienylmethyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,

5,5-bis(4-fluorobenzyl)-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,

5,5-dibenzyl-2,3-dihydroimidazo(2,l-b)thiazol-6(5H)-one,

spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-benzo(f)indan),

2- hydroxy-3-(2-naphthylmethyl)-imidazo(l,2-a)pyridine,

3- benzylimidazo(l,2-a)pyridin-2(3H)-one,

spiro(5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one-3,2'-benzo(f)indan),

3,3-dicyclohexyl-5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one,

3,3-bis(2-thienylmethyl)-5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dibutyl-5,6,7,8-tetra ydroimidazo(l,2-a)pyridin-2(3H)-one,

3,3-dipropyl-5,6,7,8-telrahydroimidazo(l,2-a)pyridin-2(3H)-one, spiro(imidazo(l,2-a)pyrimidin-2(3H)-one-3,2'-benzo(f)indan),

3,3-di(2-butenyl)imidazo(l,2-a)pyrimidin-2(3H)-one,

3,3-bis(2-thienylmethyl)imidazo(l,2-a)pyrimidin-2(3H)-one,

3,3-bis(4-fluorobenzyl)iniidazo(l,2-a)pyrimidin-2(3H)-one,

3,3-dicyclohexylimidazo(l,2-a)pyrimidin-2(3H)-one,

3,3-bis(4-cyanobenzyl)imidazo(l,2-a)pyrimidin-2(3H)-one,

3.3- bis(4-methylbenzyl)imidazo(l,2-a)pyritnidin-2(3H)-one,

4.4- dibenzyl-l-methyl-5-oxo-4,5-dihydroimidazole,

spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(4'-fluoroindan)),

spiro(imidazo(l,2-a)pyridin-2(3IT)-one-3,2'-(5^,-methoxyindan)),

spiro(irnidazo(l,2-a)pyridin-2(3H)-one-3,2'-(5'-iodoindan)),

spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(4'-cyanoindan)), spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3,2'-indan),

spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2^,-((l,2,5-thiadiazo)(4,5-c)indan)), spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3₎2^,-((l,2,5-tbiadiazo)(4,5-c)indan)), spiro(imidazo(l,2-a)pyrimidin-2(3H)-one-3,4'-(l-cyclopentene)), spiro(imidazo(l_J2-a)pyrimidin-2(3H)-one-3,2'-indan),

spiro(irrudazo(l,2-a)pyrimidin-2(3H)-one-3,2'-((l,2,5-thiadiazo)(4,5-c) spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-(5'-trifluoromethylindan)), spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'-benzo(e)indan),

spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3,r-(3'-cyclopentene)), spiro(8-benzyloxyimidazo(l,2-a)pyridin-2(3H)-one-3,r-(3'-cyclopentene)), spiro(7,8,9,10-tetrahydroimidazo(2,l-a)isoquinolin-2(3H)-one-3,l'-cyclopentane), spiro(imidazo(2,l-a)isoquinolin-2(3H)-one-3,r-cyclopenlane), and spiro(5,6,7,8-tetrahydroimidazo(l,2-a)pyridin-2(3H)-one-3,2'-indan).

[0076] In another embodiment, the compound is spiro(imidazo(l,2-a)pyridin-2(3H)-one-3,2'- indan). In another embodiment, the method of the present invention can be practiced using any of the compounds disclosed in U.S. Patent Appl. Publication No.

2008/0103157, U.S. Patent Appl. Publication No. 2008/0103158, U.S. Patent No.

6,635,652, and U.S. Patent No. 7,141,579, each of which is incorporated by reference in its entirety.

[0077] The compounds are useful in the methods of the invention and exert their desirable effects through their ability to modulate the activity of T-type calcium channels. The present invention provides a method of treating a disease or disorder through antagonizing calcium flow through calcium channels. The term "antagonist" as used herein, refers to a compound capable of decreasing the flow of ions in a calcium channel relative to the absence of the antagonist.

[0078] The compounds are useful in the treatment of diseases and conditions including, but not limited to, senile dementia, Alzheimer's disease, cognitive decline, depression, manic depressive psychoses, obsessive-compulsive disorder, panic disorder, anxiety disorder, transient ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage, cerebral infarct, hypertensive encephalopathy, amyloidosis, cerebral amyloid angiopathy, cataracts, glaucoma, progression of glaucoma, age-related macular degeneration, rheumatism, osteoporosis, metabolic syndrome, wrinkles, hair loss, one or more conditions associated with senescence, ulcers, periophthalmic lesions, corneal opacity, lordokyphosis, age retardant activity, cognitive impairment, cerebrovascular disease, Lewy body dementia, Parkinson's disease, Pick's disease, Huntington's disease, Down's syndrome, psoriasis, Crohn's disease, rheumatoid arthritis, asthma, autoimmune disease, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivies, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, transplant rejection, inclusion body myositis, vasculitis, cystic fibrosis, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, contact dermatitis, conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, ulcerative colitis, mastocytosis, hyper IgE syndrome, systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, anaphylactic reaction, cancer, Paget's disease, frontotemporolobar dementia, sporadic inclusion body myositis, cardiac dysfunction, spinobulbar muscular atrophy, spinocerebellar ataxia, macular degeneration, congestive heart failure, Haw River syndrome, polyglutamine diseases, and systemic amyloidosis.

[0079] The compounds are useful in the treatment of diseases and conditions where modulation of T-type calcium channels is desired, including: essential tremor, Parkinson's disease, epilepsy, absence seizures, juvenile myoclonic epilepsy, migraine, neuropathic pain syndromes, sleep disorders, jet lag disorder, circadian rhythm sleep disorders, tinnitus, cognition, dystonia, familial ataxia, depression, obsessive compulsive disorder, schizophrenia, schizoaffective disorder, hypertension, arrhythmias, atrial fibrillation, congestive heart failure, cyclical hormonal secretion under central nervous system control, and weight loss. The method comprises administering, to a subject in need thereof, a therapeutically effective amount of a compound of Formula (1).

[0080] The compounds are also useful in the treatment of diseases and conditions that reduce amyloid beta production including, but not limited to, Alzheimer's disease, diabetes, Parkinson's disease, transmissable spongiform encephalopathy, bovine spongiform encephalopathy, Huntington's disease, medullary carcinoma of the thyroid, cardiac arrhythmias, isolated atrial amyloidosis, athreosclerosis, rheumatoid arthritis, aortic medial amyloid, prolactinomas, familial amyloid polyneuropathy, hereditary non- neuropathic systemic amyloidosis, dialysis-related amyloidosis, Finnish amyloidosis, lattice corneal dystrophy, cerebral amyloid angiopathy, systemic AL amyloidosis, inclusion body myositis, amyloidosis, cataracts, glaucoma, age-related macular degeneration, rheumatism, osteoporosis, metabolic syndrome, wrinkles, and hair loss.

[0081] In another embodiment, the compounds are able to selectively antagonize T-type calcium channels without antagonizing L-type, N-type, P-type, Q-type, or -type calcium channels. The method comprises administering, to a subject in need thereof, a therapeutically effective amount of a compound that selectively antagonizes the Ca_v3.1 calcium channel.

[0082] In another embodiment, the compounds are able to selectively antagonize the Ca_v3.1 calcium channel. The method comprises administering to a subject in need thereof, a therapeutically effective amount of a compound that selectively antagonizes the Ca_v3.1 calcium channel.

[0083] The term "antagonize" as used herein, refers to a compound capable of decreasing the flow of ions in a channel relative to the absence of the antagonist. The term "selectively antagonize" as used herein, refers to a compound that has a therapeutically meaningful effect on a particular channel when compared to its effect on other channels. Selectivity for the Ca_v3.1 calcium channel does mean that there is no effect on, for example, Ca_v3.1 or Ca_v3.2 calcium channels however, the effect is not therapeutically meaningful. In one embodiment, the compound "selectively antagonizes" the Ca_v3.1 calcium channel when it has an effect that is at least 10 times greater than that of another channel, in another embodiment, the compound of the invention "selectively antagonizes" the Ca_v3.1 calcium channel when it has an effect that is at least 50 times greater than that of another channel. In another embodiment, the compound of the invention "selectively antagonizes" the Ca_v3.1 calcium channel when it has an effect that is at least 100 times greater than that of another channel.

[0084] In another embodiment, the compounds are able to selectively antagonize the Ca_v3.1 calcium channel without antagonizing the Ca_v3.2 calcium channel. In another embodiment, the compounds are able to selectively antagonize the Ca_v3.1 calcium channel without antagonizing the Ca_v3.3 calcium channel. In another embodiment, the compounds are able to selectively antagonize the Ca_v3.1 calcium channel without antagonizing the Ca_v3.2 calcium channel and the Ca_v3.3 calcium channel. [0085] The invention also relates to methods of antagonizing T-type calcium channel activity using the compounds, thus treating conditions associated with T-type calcium channel activity. For example, the compounds may be used for treating conditions associated with undesired T-type calcium channel activity. Alternatively, the compounds may be used to treat a subject that may have normal T-type calcium channel function which nevertheless results in an undesirable physical or metabolic state.

[0086] T-type calcium channel activity is involved in a multiplicity of disorders, and particular types of channels are associated with particular conditions. The association of T-type calcium channels in conditions associated with neural transmission would indicate that compounds which target T-type calcium channels are most useful in these conditions. Thus, as described below, the compounds are screened for their ability to interact with T- type channels as an initial indication of desirable function. It is particularly desirable that the compounds exhibit IC50 values of <1 μΜ. The IC50 is the concentration which inhibits 50% of the calcium flux at a particular applied potential.

[0087] Classic calcium channel inhibitors, for example, L-type channel antagonists, have the opposite effect and decrease firing frequency and neurotransmitter release. They have been proposed as neuroprotective agents with the hypothesis that they prevent the "excitotoxic" neurotransmitter release that occurs for instance, after a stroke. This is opposite of the mechanism of Ca_v3.1 channels as shown in Figure 22.

[0088] It has been found that ST101 antagonism enhances neurotransmitter release and cognition enhancement as shown by the mechanism in Figure 22. It has been found that Ca_v3.1 calcium channels form a complex with Kv4 potassium channels and the. potassium channel interacting protein 3 (KChIP3). K_v4 potassium channels govern firing frequency. Ca_v3.1 currents activate K_v4 currents. Thus, it is believed that ST101 antagonism of the Ca_v3.1 calcium channel decreases K_v4 currents and thus increases the firing frequency of neurons. Functionally, ST101 is an indirect inhibitor of A-type potassium channels. This increase in the firing frequency of neurons enhances the release of neurotransmitters such as acetylcholine. While not wishing to be bound by theory, it is believed that ST101 antagonism of the Ca_v3.1 calcium channel can increase the release of neurotransmitters such as acetylcholine and thus improve mental function. In one embodiment, ST101 antagonism of the Ca_v3.1 calcium channel increases the release of a neurotransmitter. In another embodiment, antagonism of the Ca_v3.1 calcium channel increases the release of acetylcholine. In another embodiment, ST101 antagonism of the Ca_v3.1 calcium channel increases the release of dopamine. In another embodiment, antagonism of the Ca_v3.1 calcium channel increases the release of serotonin. In another embodiment, antagonism of the Ca_v3.1 calcium channel increases the release of glutamate.

[0089] It has also been found that ST101 antagonism reduces amyloid beta (Αβ) production as shown by the mechanism in Figure 23. As discussed above, Ca_v3.1 calcium channels form a complex with K_v4 potassium channels and the potassium channel interacting protein 3 (KChIP3). KChIP3 is also known as calsenilin and as DREAM (dynorphin response element-antagonist modulator) (Buxbaum, J.D., Biochem. Biophys. Res. Commun. 522:1 140-1 144 (2004)). Calsenilin binds to presenilin (a γ-secretase protein). Disruption of calsenilin, as demonstrated by knock-out mice, has been shown to decrease Αβ peptide levels and increase long-term potentiation (Lilliehook, C, et al., J. Neuroscience 25:9097-9106 (2003)). Thus, a decrease in calsenilin activity reduces the production of Αβ. While not wishing to be bound by theory, it is believed that ST101 antagonsim of the Ca_v3.1 calcium channel can decrease calsenilin activity and thus reduce the production of Αβ. ST101 decreased accumulation of Αβ-like deposits and also produced an improvement in learning and memory functions, suggesting the behavioral effect of ST101 may be linked to reduction of Αβ production and/or accumulation. See US Patent Appl. Publication No. 2008/103158 Al . ST101 has also been shown to induce cleavage of amyloid precursor protein, to decrease the level of pro- AD AM 10 and/or BACE protein, and to enhance the activity of the ubiquitin-proteasome system pathway. See US Patent Appl. Publication No. 2010/0168135, US Patent Appl. Publication No. 2010/0267763, and US Patent Appl. Publication No. 2010/0298348. Thus ST101 can work as a disease modification agent in Alzheimer's disease.

[0090] The compounds modulate the activity of calcium channels; in general, said modulation is the inhibition of the ability of the channel to transport calcium. As described below, the effect of a particular compound on calcium channel activity can readily be ascertained in a routine assay whereby the conditions are arranged so that the channel is activated, and the effect of the compound on this activation (either positive or negative) is assessed.

[0091] The need for fast and sensitive drug testing requires the implementation of rapid, highly- parallel screening techniques. Many techniques for screening ion channel drug targets are known to those of skill in the art and include fluorescence-based methods, flux assays, binding assays, and patch clamp techniques (Jain, G., et ah, Current Research & Information on Pharmaceutical Sciences 70:9-15 (2009)). In choosing a method for screening ion channels, parameters such as sensitivity, specificity, throughput, information content,^' robustness, flexibility, cost, and physiological relevance need to be considered. A useful technique for screening ion channel active drugs is patch clamp recording from cell membranes, which allows even single ion channels to be probed with great accuracy (Brueggemann, A., et ai, Current Drug Discovery Technologies 7 :91-96 (2004)).

[0092] Methods of performing these screening functions are well-known in the art. One technique involves the use of fluorescence-based methods. Fluorescence-based methods do not directly measure the ionic current, but rather measure the ionic concentration dependent change in fluorescent signals from fluorescent dyes.

[0093] Another technique involves the use of a flux assay. A flux assay uses radioactive isotopes to trace ion flux across the channels.

[0094] Another technique involves the use of a binding assay. A binding assay is an indirect approach and detects binding of a ligand to an ion channel. This technique involves tagging the ligand with a radioactive compound and measuring its activity by displacement.

[0095] A more definitive assay, the patch clamp technique, can be used to distinguish inhibitors of calcium flow which operate as open channel blockers, as opposed to those that operate by promoting inactivation of the channel or as resting channel blockers. Additionally, the patch clamp technique allows for real-time analysis of a single ion channel. In the patch clamp technique, assays for compounds capable of inhibiting or increasing divalent cation flux through T-type calcium channel proteins can be performed by application of the compounds to a bath solution containing cells expressing functional T-type calcium channels. The compounds are then allowed to contact the cells in the bath. Samples or assays that are treated with a potential T-type calcium channel antagonist are compared to control samples without the test compound, to examine the extent of modulation. Control samples (untreated with inhibitors) are assigned a relative calcium channel activity value of 100. In one embodiment, inhibition of T-type calcium channels is achieved when the calcium channel activity value relative to the control is less than 70%. In another embodiment, the calcium channel activity value relative to the control is less than 40%. In another embodiment, the calcium channel activity value relative to the control is less than 30% at a concentration of 100 μΜ. In another embodiment, the calcium channel activity value relative to the control is less than 30% at a concentration of less than 10 μΜ or less than 1 μΜ. Generally, the compounds to be tested are present in the range from about 0.1 nM to about 100 mM. In one embodiment, the compounds to be tested are present in the range from about 0.1 nM to about 3 uM.

[0096] The present invention provides a simple in vitro system for the screening of drug actions on the T-type calcium channel, which will be useful for the development of drugs for the treatment of diseases and conditions. Assays can be performed on living mammalian cells, which more closely approximate the effects of a particular serum level of drug in the body, or on microsomal extracts prepared from the cultured cell lines. In one embodiment, the cells expressing calcium channels are mammalian cells. In another embodiment, the cells expressing calcium channels are HEK 293 or transformed HEK 293 cells. HEK 293 cells that express Ca_v3 are well-known in the field and have been used for recording T-type currents. See Joksovic, P.M., et al., J. Physiol. 574.2: 415-430 (2006) and Orestes, P., et ai, Molecular Pharmacology 75:542-554 (2009).

[0097] The present invention provides a screening method for determining compounds that antagonize the Ca_v3.1 calcium channel. For example, the present invention provides a screening method for the determination of a preventive or therapeutic agent for a disease or condition, comprising:

(b) measuring the calcium channel antagonist activity of the first group;

wherein a test compound that provides a greater antagonist activity than the activity of second group is selected.

[0098] The present invention also provides a screening method for determining compounds that selectivity antagonize the Ca_v3.1 calcium channel without antagonizing the Ca_v3.2 calcium channel. For example, the present invention provides a screening method for a preventative or therapeutic agent for Alzheimer's disease comprising: (a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(e) comparing the activity of (b) with the activity measured in (d); wherein a test compound that provides a greater activity in (b) than the activity in (d) is selected.

[0099] The present invention also provides a screening method for determining compounds that selectivity antagonize the Ca_v3.1 calcium channel without antagonizing the Ca_v3.3 calcium channel. For example, the present invention provides a method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(b) measuring the calcium channel antagonist activity of the lest compound of (a);

[00100] The present invention also provides a screening method for determining compounds that selectivity antagonize the Ca_v3.1 calcium channel without antagonizing the Ca_v3.2 or Ca_v3.3 calcium channels. For example, the present invention provides a method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(e) contacting cells expressing a Ca_v3.3 calcium channel with the same test compound used in (a); (f) measuring the calcium channel antagonist activity of the test compound of (e);

(g) comparing the activity of (b) with the activity of (d) and (f);

wherein a test compound that provides a greater activity in (b) than the activities in (d) and (0 is selected.

] In one embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent No. 7,745,452:

wherein: X¹, X² and X³ are independently selected from the group consisting of:

(1 ) hydrogen,

(2) fluoro,

(3) chloro, and

(4) bromo;

R¹ is phenyl, Ci-galkyl, or C_3-6cycloalkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:

(1) halogen,

(2) Ci.6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(3) -OCi-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(4) -CN,

(5) -NR⁵R⁶, wherein R⁵ and R⁶ are independently selected from hydrogen,

Ci-6alkyl and Ci^alkyl-phenyl, and

(6) -S(0)_nCi-6alkyl, wherein n is 0, 1 or 2;

R is Ci-6alkyl, C3.6cycloalkyl, phenyl, C₂-6alkenyl, or C₂_6alkynyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of:

(1) fluoro,

(2) chloro,

(4) -S(0)_nC^alkyl, (5) -OH,

(6) =0,

(7) -CHO,

(8) -COz-Ci-ealkyl,

(9) C_3-6cycloalkyl,

(10) dioxanyl, and

(1 1) phenyl, which is unsubstituted or substituted with halogen, hydroxyl,

Ci-6alkyl or

R³ is Ci-6alkyl which is substituted with one or more fluoro, and which is optionally substituted with an additional substituent selected from the group consisting of:

(1) C_1-6alkyl,

(2) C_3-6cycloalkyl,

(3) phenyl, and

(4) pyridyl;

and pharmaceutically acceptable salt thereof and individual diastereomers thereof.

In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2010/0210671 :

wherein:

X', X² and X³ are independently selected from the group consisting of:

(1) hydrogen,

(2) fluoro,

(3) chloro, and

(4) bromo;

R¹ is phenyl, C|.e alkyl, or Ci-6 cycloalkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:

(1) halogen,

(2) C |.6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, (3)— OCi-6 alkyl, which is unsubstituted or substituted with halogen, hydroxy 1 or phenyl,

(4)— CN,

(5)— NR⁵ R⁶ , wherein R⁵ and R⁶ are independently selected from hydrogen, Ci^ alkyl and Ci^ alkyl-phenyl, and

(6)— S(0)_n C]^ alkyl, wherein n is 0, 1 or 2;

R² is Ci-6 alkyl, C_3-6 cycloalkyl, phenyl, C_2-6 alkenyl, or C_2-6 alkynyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of:

(1) fluoro,

(2) chloro,

(3)— OCi-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(4) _S(0)_n C_I-6 alkyl,

(5)— OH,

(6) =0,

(7)— CHO,

(8)— C0₂— C,_5 alkyl,

(9) C₃-6 cycloalkyl,

( 10) dioxanyl, and

(1 1) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, Ci-6 alkyl or— O— Ci-6 alkyl;

R^J is Ci-6 alkyl which is substituted with one or more fluoro, and which is optionally substituted with an additional substituent selected from the group consisting of:

(1) C_1-6 alkyl,

(2) C_3-6 cycloalkyl,

(3) phenyl, and

(4) pyridyl;

R⁴ is Cj-6 alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:

(1) halogen,

(2)—OH, (3)— OCi-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(4) -CN,

(5)— NR⁵ R⁶ , wherein R⁵ and R⁶ are independently selected from hydrogen, C|^ alkyl and Ci-6 alkyl-phenyl,

(6) phenyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:

(a) halogen,

(b) Ci-6 alkyl, unsubstituted or substituted with fluoro,

(c) C3-6 cycloalkyl,

(d)—0—C_1-6 alkyl,

(e)— OH,

(f)— (CO)O— Ci-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,

(g) triazolyl, which is unsubstituted or substituted with halogen or Ci-6 alkyl, and

00— CN,

(7) heteroaryl, which is unsubstituted or substituted with a substituent selected from the group consisting of:

(a) halogen,

(b) unsubstituted or substituted with fluoro,

(c) C_3-6 cycloalkyl,

(d)—0—C,.₆ alkyl,

(e)— OH,

(g) triazolyl, which is unsubstituted or substituted with halogen or Ci^ alkyl, and

(h)— CN, and

(8)— C0₂— C_1-6 alkyl;

or an N-oxide thereof or a pharmaceutically acceptable salt thereof. ] In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in .S. Patent Appl. Publication No. 2010/0222387:

wherein:

R¹ and R² are independently selected from the group consisting of:

(1) hydrogen, and

(2) Ci-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl, or R¹ and R² taken together form a C_3-6 cycloalkyl ring, which is unsubstituted or substituted with Ci-6 alkyl or halogen, which is unsubstituted or substituted with

alkyl or halogen;

R³ is selected from the group consisting of:

(1) phenyl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3e ,

(2) Ci_-8 alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R ^a , R^3b , R^3c , R^3d and R^3e ,

(b) halogen,

(c) hydroxyl,

(d)— O— Ci-6 alkyl,

(e)— C0₂ R⁹ , where R⁹ is independently selected from:

(i) hydrogen,

(ii)— Ci-6 alkyl, which is unsubstituted or substituted with 1 -6 fluoro,

(iii) benzyl, and

(iv) phenyl,

(f)— NR^,0 Rⁿ , wherein R¹⁰ and R^{1 1} are independently selected from hydrogen,— Ci-6 alkyl and— Ci-6 alkyl-0— Cj-6 alkyl, or R¹⁰ and R¹¹ together form a pyrrolidine, piperidine, oxazolidine or morpholine ring, which is unsubstituted or substituted with halogen, Ci-6 alkyl or halogen-substituted C]_6 alkyl. (3) C_3-io cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3e ,

(b) halogen,

(c) hydroxyl,

(d)— O— C^alkyl,

(e)— C0₂R⁹,

(f)— NR¹⁰Rⁿ ,

(4)— Ci-6 alkyl-(C_3-io cycloalkyl), which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3c ,

(b) halogen,

(c) hydroxyl,

(d)— O— Cealkyl,

(e)— C0₂R⁹,

(f)— NR^l0Rⁿ ,

(5) heteroaryl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3e , or oxo;

R^3a , R^3b , R^3c , R^3d and R^3e are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— C-ealkyl,

(5)— O— Ci_-6alkyl,

(6)— CF₃,

(7)— OCF₃,

(8)— OCHF2,

(9)— OCH₂F,

(10)— OCF₂CHF₂₎

(11)— CN, and

(12)— NR¹⁰R^U;

R⁴ and R³ are independently selected from the group consisting of

(1) hydrogen, (2) Ci-8 alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3A , R^3B , R^3C , R^3D and R^3E ,

(b) halogen,

(c) hydroxyl,

(d)— O— Ci_-6 alkyl,

(e)— C0₂ R⁹ ,

(£)— NR^{I 0 '}R" ;

(3) C3-io cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3A , R^3B , R^3C , R^3D and R^3E ,

(b) halogen,

(c) hydroxyl,

(d)— O—Ci-6 alkyl,

(e)— C0₂ R⁹ ,

(f)— NR¹⁰ R" ;

(4) phenyl, which is substituted with R^3A , R^3B , R^3E , R^3D and R^3E ;

(5) heterocycle, which is substituted with R^3A , R^3B , R^3C , R^3D and R^3E , or oxo,

(6)— CO— Cj.g alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3A , R^3B , R^3C , R^3D and R^3E ,

(b) halogen,

(c) hydroxyl,

(d)— O— C ,.₆ alkyl,

(c)— C0₂ R⁹ ,

(f)— NR^{I O} R" ;

(7)— S0₂ R⁹ ,

(8)— C0₂ R⁹ , and

(9)— CONR¹⁰ R^U ,

or R⁴ and R⁵ taken together form a C3-6 cycloalkyl ring, which is unsubstituted or substituted with C_]-6 alkyl or halogen; and N-oxides thereof, and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

] In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2010/0216841 :

wherein:

R¹ and R² are independently selected from the group consisting of:

(1) hydrogen, and

(2) Ci-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl, or

»

R¹ and R² taken together form a C_3-6 cycloalkyl ring, which is unsubstituted or substituted with C 1-6 alky 1 or halogen;

R³ is selected from the group consisting of

(1) phenyl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3c ,

(2) Ci-8 alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3e ,

(b) halogen,

(c) hydroxyl,

(d)— O— Ci-6 alkyl,

(e)— C0₂ R⁹ , where R⁹ is independently selected from:

(i) hydrogen,

(ii)— Ci-6 alkyl, which is unsubstituted or substituted with 1 -6 fluoro,

(iii) benzyl, and

(iv) phenyl,

(f)— NR¹⁰ Rⁿ , wherein R¹⁰ and R^u are independently selected from hydrogen,— Q.6 alkyl,— Ci-6 alkyl-C_3-6 cycloalkyl and— Ci.₆ alkyl-0— Ci-6 alkyl, or R¹⁰ and R¹¹ together form a pyrrolidine, pipendine, oxazolidine or morpholine ring, which is unsubstituted or substituted with one or more halogen,

or halogen-substituted Chalky.,

(a) C_1-6 alkyl,

(b) phenyl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3e ,

(c) halogen,

(f)— C0₂ R⁹ ,

(g)— NR^{10 n}

(h) oxo,

(4)— Ci- alkyl-(C3.io cycloalkyl), which is unsubstituted or substituted with one or more substituents selected from:

(a) C_1-6 alkyl,

(b) phenyl, which is substituted with R^3a , R^3b , R^3c , R^3d and R^3e ,

(c) halogen,

(d) hydroxyl,

(e)— O— Ci.₆ alkyl,

(O— C0₂ R⁹,

(g)— R¹⁰ R¹¹ ,

(h) oxo,

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— C_1-6 alkyl,

(5)— O— Ce alkyl,

(6)— Ci_-6alkyl-0— C _]-6 alkyl,

(6)— CF₃ ,

₍7) _ 0CF₃ , (8)— OCHF₂,

(9)— OCH₂F,

(10)— OCF₂CHF₂,

(11)— CN, and

(12)— NR¹⁰Rⁿ ;

(12)— N0₂,

R⁴ and R⁵ are independently selected from the group consisting of

(1) hydrogen,

(2) Ci-ioalkyl or C_2-io alkenyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3A, R^3B, R^3C, R^3dand R^3E,

(b) halogen,

(c) hydroxyl,

(d)— O— Ci-ealkyl,

(e) -C0₂R⁹,

(f)— S0₂R⁹,

(g)— NR¹⁰R^N ;

(3) C3-iocycloalkyl or C₅.iocycloalkenyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3A, R^3B, R^3C, R^3dand R^3E,

(b) halogen,

(c) hydroxyl,

(d)— O— Cj-ealkyl,

(e)— C0₂R⁹,

(f)— NR'°R" ;

(4)— Ci_ioalkyl-(C 3_iocycloalkyl) or— Ci.ioalkyl-C_5-i₀cycloalkenyl;

(5) phenyl, which is substituted with R^3A , R^3B , R^3E , R^3D and R^3E ;

(6) heterocycle, which is substituted with R^3A, R^3B, R^3C, R^3dand R^3E, or oxo,

(7)— CO— Ci-8 alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R^3A , R^3B , R^3C , R^3D and R^3E ,

(b) halogen, (c) hydroxyl,

(d)— O— C^ alkyl,

(e)— C0₂R⁹,

(f)— NR^l0Rⁿ ;

(8)— S0₂R⁹ ,

(9)— C0₂R⁹ , and

(10)— CONR¹⁰ Rⁿ ,

or R⁴ and R⁵ taken together form a C_3-s cycloalkyl ring, which is unsubstituted or substituted with

alkyl or halogen;

and N-oxides thereof, and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

An embodiment of the present invention includes compounds of the formula I, wherein: R¹ and R² are independently selected from the group consisting of

(1) hydrogen, and

(2) C,^ alkyl;

R³ is selected from the group consisting of:

(1 ) phenyl, which is substituted with R^3a , R^3b and R^3c ,

(2) C 1-8 alkyl, which is unsubstituted or substituted with phenyl, where the phenyl is substituted with R^3a , R^3b and R^3c ,

(3) C3.10 cycloalkyl, which is unsubstituted or substituted with phenyl, where the phenyl is substituted with R^3a , R^3b and R^3c , and

(4)— Ci-6 alkyl-(C3-io cycloalkyl), which is unsubstituted or substituted with phenyl, where the phenyl is substituted with R^3a , R^3b and R^3c ;

R^3a , R^3b and R^3c are independently selected from the group consisting of

(1) hydrogen,

(2) halogen,

(3)— C_w alkyl,

(4)— O— C_W alkyl,

(5)— CF₃ ,

(7)— OCHF_{2 j}

(8)— OCH₂F, (9)— OCF₂CHF₂ ,

(10)— CN, and

(1 1 )— NR¹⁰ R^N , wherein R¹⁰ and R^U are independently selected from hydrogen, — C_I-6 alkyl,— C_1-6 alkyl-C₃.₆ cycloalkyl and— Ci.₆ alkyl-O— Ci-₆ alkyl, or R¹⁰ and R^{1 1} together form a pyrrolidine, piperidine, oxazolidine or morpholine ring, which is unsubstituted or substituted with one or more halogen, Ci_-6 alkyl or halogen-substituted Ci_-6 alkyl;

R⁴ and R⁵ are independently selected from the group consisting of:

(1) hydrogen,

(2) Ci-8 allyl, which is unsubstituted or substituted with hydroxy or phenyl, where the phenyl is substituted with R^3A , R^3B and R^3C ,

(3) C_3- io cycloalkyl or C_3-io cycloalkyl, which is unsubstituted or substituted with Ci_-8 alkyl or phenyl, where the phenyl is substituted with R^3A , R^3B and R^3C ,

(4) C3-io cycloalkyl oxy, which is unsubstituted or substituted with C]_-8 alkyl or phenyl, where the phenyl is substituted with R^3A , R^3B and R^3E , and

(5)— CO— C _{) -8} alkyl, and

(6)— C0NR'° R" ;

In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent No. 7,875,636:

wherein:

A is selected from the group consisting of phenyl, napthyl and heteroaryl;

R^{L A} , R^{I B} and R^{L C} may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl, (4)— On-phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthy] is unsubstituted or substituted with one or more substituents selected from R¹³,

(5)— On-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(6)— On— Ci^ alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R ¹³ ,

(7)— O_n— C3-5 cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(8)— C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(9)— NR¹⁰Rⁿ , wherein R^l0 and R¹¹ are independently selected from the group consisting of:

(a) hydrogen,

(b) Ci-6 alkyl, which is unsubstituted or substituted with R¹³ ,

(c) C3.0 alkenyl, which is unsubstituted or substituted with R¹³ ,

(d) cycloalkyl which is unsubstituted or substituted with R¹³ ,

(e) phenyl, which is unsubstituted or substituted with R¹³ , and

(f) heterocycle, which is unsubstituted or substituted with R¹³ , or R¹⁰ and R¹ ' taken together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, azetidine or morpholine ring, which is unsubstituted or substituted with R¹³ ,

(10)— S(0)₂— NR¹⁰R" ,

(1 1)— S(0)_q— R¹² , where q is 0, 1 or 2 and where R¹² is selected from the definitions of R¹⁰ and R^{1 1} ,

(12)— C0₂H,

(13)— C0₂— R¹² ,

(14)— CN, and

(15)— N0₂ ; or R^la and R^lb taken together form a cyclopentyl, cyclohexyl, dihydrofuranyl or dihydropyranyl ring, which is unsubstituted or substituted with one or more substituents selected from— CH₃ , (=CH₂ ), keto, and hydroxyl;

R² and R³ are independently selected from the group consisting of:

(1) hydrogen,

(2) hydroxyl,

(3) halogen

(4) Ci-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(5) C3.6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(6)— O— Ci-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(7)— O— C3.6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

or R and R and the carbon atom to which they are attached form a keto group, or R and R and the carbon atom to which they are attached form a C_3-$ cycloalkyl ring, which is unsubstituted or substituted with R¹³ ;

R⁴ is selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(3)— C_3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(4) C_2-6 alkenyl, which is unsubstituted or substituted with one or more substituents selected from R ,

(5) C2-6 alkynyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(6) phenyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(7)— (C=0)— NR¹⁰ R^{1 1} , and (8)— (C=0)— O— Ci-6 alkyl, which is unsubstituted or substituted with one or

13

more substituents selected from R ,

R^5a , R^5b and R^5c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxy 1,

(4)— O_n— Ci-6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(5)— On— C3-6 cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(6)— C₂-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(7)— On-phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(8)— On-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(9)— (C=0)— NR¹⁰ R^{1 1} ,

(10)— NR^,0 Rⁿ ,

(1 1)— S(0)₂— NR¹⁰ R^U ,

(13)— S(0)_q— R¹² , where q is 0, 1 or 2 and where R¹² is selected from the definitions of R¹⁰ and R¹¹ ,

(14) ^C0₂H,

(15)— CN,

(16)— NO2 ;

(17) or R^5aand R^5b taken together form a pyrrolyl or imidazolyl ring, which is unsubstituted or substituted with— CH3 , (=CH2 ), keto, or hydroxyl;

R¹³ is selected from the group consisting of: (1) halogen,

(2) hydroxyl,

(3)— (C=0)_m— O_n— C alkyl, where m is 0 or 1 and n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present, and wherein if m is 0 and n is 0, a single bond is present) where the alkyl is unsubstituted or substituted with one or more substituents selected from

(4)— O_n— (Ci-3 )perfluoroalkyl,

(5)— (C=0)m— O_n— cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹ ,

(6)— (C=0)_m— C₂-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹⁴ ,

(7)— (C=0)_m— On-phenyl or— (C=0)_m— O_n-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹ ,

(8)— (C=0)_m— On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹⁴ ,

(9)— (C=0)— NR¹⁰ R^{1 1} ,

(10)— NR^,0 Rⁿ ,

(1 1)— S(0)₂— NR¹⁰ R" ,

(12)— S(0)_q— R¹² ,

(13)— C0₂H,

(14)— CN, and

(15)— N0₂ ;

R¹⁴ is selected from the group consisting of:

(1 ) hydroxyl,

(2) halogen,

(3) C_1-6 alkyl,

(4)— C_3-6 cycloalkyl,

(5)— O— Ci-6 alkyl,

(6)— 0(C=0)— C_l-6 alkyl,

(7)— NH— Ci-6 alkyl,

(8) phenyl,

(9) heterocycle, (10)— C0₂H, and

(1 1) -CN;

or a pharmaceutically acceptable salt thereof.

] In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2010/0216816:

wherein:

A is selected from the group consisting of phenyl, napthyl and heteroaryl;

R^,a , R^lb and R^lc may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— O_n -phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(6)— On— Ci-6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(7)— On— C3-6 cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(8)— C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³ , (9)— NR¹⁰R^U , wherein R¹⁰ and R^u are independently selected from the group consisting of:

(a) hydrogen,

(b) Ci-6 alkyl, which is unsubstituted or substituted with R¹³ ,

(c) C_3-6 alkenyl, which is unsubstituted or substituted with R¹³ ,

(d) cycloalkyl which is unsubstituted or substituted with R¹³ ,

(e) phenyl, which is unsubstituted or substituted with R¹³ , and

(f) heterocycle, which is unsubstituted or substituted with R¹³ , or R¹⁰ and R^u taken together with the nitrogen atom to which they are attached form a pyrrolidine, pipendine, azetidine or morpholine ring, which is unsubstituted or substituted with R¹³ ,

(10)— S(0)2— NR¹⁰Rⁿ ,

(11)— S(0)_q— R¹² , where q is 0, 1 or 2 and where R¹² is selected from the definitions of R¹⁰ and R¹¹ ,

(12)— C0₂H,

(13)— COz— R¹² ,

(14)— CN, and

(15)— N0₂ ;

or R^la and R^lb taken together form a cyclopentyl, cyclohexyl, dihydrofuranyl or dihydropyranyl ring, which is unsubstituted or substituted with one or more substituents selected from— CH₃, (=CH₂), keto, and hydroxyl;

R² and R³ are independently selected from the group consisting of:

(1) hydrogen,

(2) hydroxyl,

(3) halogen

(5) C₃-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(6)— O— Ci-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ , (7)— O— C_3- cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

or R² and R³ and the carbon atom to which they are attached form a keto group, or R² and R³ and the carbon atom to which they are attached form a C_3-6 cycloalkyl ring, which is unsubstituted or substituted with R¹³ ;

R⁴ is selected from the group consisting of:

(1) hydrogen,

(2) Ci-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(4) C₂-6 alkenyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(5) C_2-6 alkynyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(7)— (C=0)— NR¹⁰ R^{1 1} , and

(8)— (C=0)— O— Ci-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

R^5a , R^5b and R^5c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— O_n— C1.6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(5)— 0„— C₃^ cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(6)— C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³ _T (7)— On-phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(8)— O_n-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³,

(9)— (C=0)— NR^1DRⁿ ,

(10)— NR¹⁰ Rⁿ ,

(1 1)— S(0)₂— NR¹⁰ R^U ,

(12)— NR¹⁰— S(0)₂R^u ,

(13)— S(0)_q— ¹² , where q is 0, 1 or 2 and where R¹² is selected from the definitions ofR¹⁰ and R" ,

(14) -C0₂H,

(15)— CN,

(16)— N0₂;

(17) or R^5a and R^5b taken together form a pyrrolyl or imidazolyl ring, which is unsubstituted or substituted with— CH₃ , (=CH₂ ), keto, or hydroxy];

R¹³ is selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3)— (C=0)_m— O_n— Ci-6 alkyl, where m is 0 or 1 and n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present, and wherein if m is 0 and n is 0, a single bond is present) where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹⁴ ,

(4)— O_n— (Ci.3 )perfluoroalkyl,

(5)— (C=0)_m— O_n— C 3_6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(6)— (C=0)_m— C 2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(7)— (C=0)m— On-phenyl or— (C=0)_m— O_n-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹⁴, (8)— (C=0)_m— O_n-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹⁴ ,

(9)— {C=o - NR¹⁰ R",

(10)— NR¹⁰R" ,

(1 1)— S(0)₂— NR^l0Rⁿ,

(12)— S(0)_q-R¹²,

(13)— C0₂H,

(14)— CN, and

(15)— N0₂;

R¹⁴ is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) C,.₆ alkyl,

(4)— C3-6 cycloalkyl,

(5)— O— Ci-ealkyl,

(6)— 0(C=0)— Ci_-6 alkyl,

(7)— NH— C_1-6 alkyl,

(8) phenyl,

(9) heterocycle,

(10)— C0₂H, and

(1 1)— CM;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2010/0249176:

wherein:

A is heteroaryl;

R^lb and R^,c may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of: (1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— On-phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(5)— O_n-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³,

(6)— O_n— Ci-6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(7)— On— C3-6 cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(8)— C₂_4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³ ,

(9)— NR¹⁰R ^u, wherein R¹⁰ and R^{1 1} are independently selected from the group consisting of:

(a) hydrogen,

(b) Ci-6 alkyl, which is unsubstituted or substituted with R¹³,

(c) C_3- alkenyl, which is unsubstituted or substituted with R¹³,

(d) cycloalkyl which is unsubstituted or substituted with R¹³,

(e) phenyl, which is unsubstituted or substituted with R¹³, and

(f) heterocycle, which is unsubstituted or substituted with R¹³, or R¹⁰ and R^{1 1} taken together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, azetidine or morpholine ring, which is unsubstituted or substituted with R¹³ ,

(10)— S(0)₂— NR¹⁰ R",

(1 1)— S(0)_q— R¹² , where q is 0, 1 or 2 and where R¹² is selected from the definitions of R¹⁰ and R",

(12)— C0₂H, (13)— C0₂— R¹²,

(14)— CN, and

(15)— N0₂ ;

R² and R³ are independently selected from the group consisting of:

(1) hydrogen,

(2) hydroxyl,

(3) halogen

(4) Cj-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(5) C_3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(6)— O— Ci-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(7)— O— C₃.6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³ ,

or R² and R³ and the carbon atom to which they are attached form a keto group, or R² and R³ and the carbon atom to which they are attached form a C₃^ cycloalkyl ring, which is unsubstituted or substituted with R¹³;

R⁴ is selected from the group consisting of:

(1) hydrogen,

(2) Ci-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(3)— C_3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(4) C₂-6 alkenyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(5) C_2-6 alkynyl, which is unsubstituted or substituted with one or more substituents selected from R¹³, (6) phenyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(7)— (C=0)— NR¹⁰R^M, and

R^5A, R^5B and R^5eare independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— 0„— Ci.6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(5)— O_n— C_3-6 cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(6)— C₂- alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(7)— O_n-phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(8)— O_n heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³,

(9)— (C=0>— NR¹⁰R",

(10)— NR'V¹,

(1 1)— S(0)₂— R¹⁰R",

(12)— NR¹⁰— S(0)₂R^N,

(14)— C0₂H,

(15)— CN,

(16)— N0₂; (17) or R^5A and R^5B taken together form a pyrrolyl or imidazolyl ring, which is unsubstituted or substituted with— CH₃, (=CH₂), keto, or hydroxyl;

R¹³ is selected from the group consisting of:

(1) halogen,

(2) hydroxyl,

(3)— (C=0)_m— O_n— Cj-6 alkyl, where m is 0 or 1 and n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present, and wherein if m is 0 and n is 0, a single bond is present) where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(4)— O_n— (Ci_-3)perfluoroalkyl,

(5)— (C=0)_m— On— C_3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(6)— (C=0)_m— C₂-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(7)— (C=0)m— On-phenyl or— (C=0)_m— O_n-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(8)— (C=0)m— On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(9)— (C=0>— NR¹⁰R" ,

(10)— NR'V,

(1 1)— S(0)₂— NR¹⁰R" ,

(12)— S(0)_q— R¹²,

(13)— C0₂H,

(14)— CN, and

(15)— 0₂;

R¹⁴ is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) Ci.₆ alkyl,

(4)— C_3-6 cycloalkyl,

(5)— O— C_1-6 alkyl,

(6)— 0(C=0)— Ci.6 alkyl, (7)— NH— Ci^ alkyl,

(8) phenyl,

(9) heterocycle,

(10)— C0₂H, and

(1 1)— CN;

or a pharmaceutically acceptable salt thereof.

] In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2010/0261724:

wherein:

A is a heterocycle;

m is 0 or 1 (wherein if m is 0, a bond is present);

R , R^l and R^lc may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— O_n-phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(5)— O_n-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R ,

(6)— O_n— Ci_6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(7)— O_n— C3.6 cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³, (8)— C₂-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(9)— NR¹⁰R^N, wherein R¹⁰and R" are independently selected from the group consisting of:

(a) hydrogen,

(b) Ci-6 alkyl, which is unsubstituted or substituted with R¹³,

(c) C3-6 alkenyl, which is unsubstituted or substituted with R¹³,

(d) cycloalkyl which is unsubstituted or substituted with R¹³,

(e) phenyl, which is unsubstituted or substituted with R¹³, and

(f) heterocycle, which is unsubstituted or substituted with R¹³, or R¹⁰ and R¹¹ taken together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, azetidine or morpholine ring, which is unsubstituted or substituted with R¹³,

(11)— S(0)_q— R¹², where q is 0, 1 or 2 and where R¹² is selected from the definitions of R¹⁰ and R^U ,

(12)— C0₂H,

(13)— C0₂— R¹²,

(14)— CN. and

(15)— 0₂;

or R^LA and R^LB taken together form a cyclopentyl, cyclohexyl, dihydrofuranyl or dihydropyranyl ring, which is unsubstituted or substituted with one or more substituents selected from— CH3, (=CH₂), keto, and hydroxyl;

R² and R³ are independently selected from the group consisting of:

(1) hydrogen,

(2) hydroxyl,

(3) halogen

(5) C3.6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³, (6)— Ο— C_]-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(7)— O— C3-6 cycloallyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

or R² and R³ and the carbon atom to which they are attached form a keto group, or R² and R³ and the carbon atom to which they are attached form a C3.6 cycloalkyl ring, which is unsubstituted or substituted with R¹³;

R⁴ is selected from the group consisting of:

(1) hydrogen,

(3)— C3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(4) C_2-6 alkenyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(5) C₂.6 alkynyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

(6) phenyl, which is unsubstituted or substituted with one or more substituents

1

selected from R ,

(7)— (C=0)— NR¹⁰R", and

(8)— (C=0)— O— C1.6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R¹³,

R^5a , R^5b and R^5c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— O_n— Ci-6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from

R¹³,

(5)— O_n— C3.6 cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R , (6)— C2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(7)— On-phenyl or— O_n-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹³,

(8)— On-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹³,

(9)— (C=0)— NR¹ °R' ¹ ,

(10)— NR¹⁰R" ,

(1 1 )— S(0)₂— R¹⁰R^N ,

(12)— NR¹⁰— S(0)2R" ,

(13)— S(0)_q— R¹², where q is 0, 1 or 2 and where R¹² is selected from the definitions of R¹⁰ and R^U,

(14)— C0₂H,

(15)— CN,

(16)— N0₂;

(17) or R^5a and R⁵ taken together form a pyrrolyl or imidazolyl ring, which is unsubstituted or substituted with— CH_3: (=CH₂), keto, or hydroxyl;

R⁶ is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4)— On— Ci-6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹³, and

(5)— On— C3.6 cycloallyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹³;

R¹³ is selected from the group consisting of:

(1) halogen,

(2) hydroxyl, (3)— (C=0)_m— O_n— Ci-6 alkyl, where m is 0 or 1 and n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present, and wherein if m is 0 and n is 0, a single bond is present) where the alkyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(4)— O_n— (C i .3 )perfluoroalkyl,

(5)— (C=0)_m— O_n— C₃.<s cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(7)— (C=0)_m— O_n-phenyl or— (C=0)_m— O_n-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(8)— C=0)_m— O_n-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R¹⁴,

(9)— (C=0)— NR₁₀R^U,

(10)— NR¹⁰R",

(12)— S(0)_q— R¹²,

(13)— C0₂H,

(14)— CN, and

(15)— N0₂;

R¹⁴ is selected from the group consisting of:

(1) hydroxyl,

(2) halogen,

(3) C_w alkyl,

(4)— C_3-6 cycloalkyl,

(5)— O— C_1-6 alkyl,

(6)— 0(C=0>-C_I-6 a]k 'l,

(7)— H— Ci-6 alkyl,

(8) phenyl,

(9) heterocycle,

(10)— C0₂H, and

(11)— CN; or a pharmaceutically acceptable salt thereof.

[00109] In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2009/0270413:

or a pharmaceutically acceptable salt or conjugate thereof, wherein

R i are independently C(CH₃)₃ or C(CF₃)₃;

each R ₂ is independently selected from halo, CN, N0₂ , CF₃ , OCF₃ , COOR', CONR'2 , OR', SR', SOR', S0₂ R', NR'₂ , NR'(CO)R', NR'S0₂ R',— Si(CH₃)₃,— CH₂CN, — C(CH₃)₂CN,— C(CH₃)₂CH₂OR',— C(CH₃)₂C0₂R',— C(CH₃)₂CONHR',

— C(CH₃)₂CONR'₂, =0, and =NOR', wherein each R' is independently H or an optionally substituted group selected from alkyl (1 -6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); or R ₂ may be one or more optionally substituted groups selected from alkyl (1 -6C), alkenyl (2-6C), alkynyl (2- 6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C);

m is 0-4 and n is 0-1;

X is alkylenyl (1 -3C) or heteroalkylenyl (1-3C);

Ar is an optionally substituted aryl (6-lOC) or heteroaryl (5-12 ring members);

wherein the optional substituents on Ar are independently selected from halo, CN, N0₂ , CF₃ , OCF₃ , COOR', CONR'z , OR', SR', SOR', S0₂ R', NR'₂ , NR'(CO)R', NR'S0₂ R',— Si(CH₃)₃, — CH₂CN, — C(CH₃)₂CN, — C(CH₃)₂CH₂OR', — C(CH₃)₂C0₂R', — C(CH₃)₂CONHR', — C(CH₃)₂CONR'₂, wherein each R' is independently H or an optionally substituted group selected from alkyl (1 -6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); or the optional substituents may be one or more optionally substituted groups selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6- IOC), heteroaryl (5-12 ring members).

[00110] In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2008/0227823:

or a pharmaceutically acceptable salt or conjugate thereof, wherein

each X¹ and X² is independently an optionally substituted alkylene (1-3C), alkenylene (2-

3C), alkynylene (2-3 C), heteroalkylene (2-3 C), heteroalkenylene (2-3 C), or heteroalkynylene (2-3C);

Ar¹ is an optionally substituted phenyl ring;

AT² is an optionally substituted aromatic (6-10 membered) or heteroaromatic (5- 10 membered) ring;

each A¹ and A² are independently H or methyl;

C is an optionally substituted alkylene (1-3C), alkenylene (2-3C), alkynylene (2-3C), heteroalkylene (2-3C), heteroalkenylene (2-3C), heteroalkynylene (2-3C), aromatic (6- membered) or heteroaromatic (5-10 membered) ring;

D is H, or an optionally substituted alkylene (1 -3C), alkenylene (2-3C), alkynylene (2- 3C), heteroalkylene (2-3C), heteroalkenylene (2-3C), heteroalkynylene (2-3C), wherein either C and A¹ or C and D may optionally together form an optionally substituted 3-6 membered cyclic or heterocyclic ring;

n and m are independently 0 or 1 ; and

wherein the optional substituents on each Ar¹, Ar², X¹, X², C and D are independently selected from halo, CN, N0₂, CF₃, OCF₃, COOR', CONR'₂, OR', SR', SOR', S0₂R', NR' ₎ NR'(CO)R', and NR'S0₂R', wherein each R' is independently H or an optionally substituted group selected from alkyl (1-3C), alkenyl (2-3C), alkynyl (2-3C), heteroalkyl (2-3C) heteroalkenyl (2-3), and heteroalkynyl (2-3C); or the optional substituents may be one or more optionally substituted groups selected from alkyl (1 -3C), alkenyl (2-3C), alkynyl (2-3C), heteroalkyl (2-3C), heteroalkenyl (2-3C), or heteroalkynyl (2-3C); and wherein the optional substituent on C and D may further be selected from =0 and =NOR';

and wherein optional substituents on a cyclic or heterocyclic ring formed with C and one of A ¹ and D may independently be selected from =0, =NOR', halo, CN, N0₂, CF₃, OCF₃, COOR', CONR'2, OR', SR', SOR', S0₂R', NR'₂, NR'(CO)R', and NR'S0₂R', wherein each R' is independently H or an optionally substituted group selected from alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C) heteroalkenyl (2-8C), and heteroalkynyl (2-8C); or the optional substituents may be one or more optionally substituted groups selected from alkyl (1 -8C), alkenyl (2-8C), alkynyl (2-8C), heteroalkyl (2-8C), heteroalkenyl (2-8C), heteroalkynyl (2-8C), aromatic (6-10 membered) or heteroaromatic (6-10 membered).

] In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2009/0298834:

or a pharmaceutically acceptable salt or conjugate thereof, wherein

A is C(0)NH or NHC(0);

X is an optionally substituted alkylene (1-4C), heteroalkylene (2-4C), alkenylene (2-4C), or heteroakenylene (2-4C);

m, n and p are independently 0 or 1 ;

Ar is an optionally substituted aryl (6- IOC) or heteroaryl (5-12 ring members);

each Y is independently H, SR', SOR', S0₂R', wherein each R' is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6), heteroalkynyl (2-6C); or each Y is an optionally substituted group selected from alkyl (1-lOC), alkenyl (2- I OC), alkynyl (2-10C), heteroalkyl (2-lOC), heteroalkenyl (2-lOC), heteroalkynyl (2-lOC), aryl (6-12C)-alkyl (1- 6C) or heteroaryl (5-12 ring members)-alkyl (1 -6C); or two Y may together form an optionally substituted heterocyclic ring (4-6 ring members);

wherein the optional substituents on X, Y and Ar may be one or more halo, CN, N0₂, CF₃, OCF₃, COOR', CONR'₂, OR', SR', SOR', S0₂R', NR'₂, NR'(CO)R', and NR'S0₂R', wherein each R' is independently H or an optionally substituted group selected from alkyl (1 -6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C); or each substituent is alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); aryl (6- IOC), heteroaryl (5-12 ring members), O-aryl (6-l OC), O-heteroaryl (5-12 ring members), aryl (6-12C)- alkyl (1-6C) or heteroaryl (5-12 ring members)-alkyl (1 -6C); and wherein optional substituents on X and Y may be additionally selected from =0, =NOR'.

In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2009/0298883:

or a pharmaceutically acceptable salt or conjugate thereof, wherein

A is C(0)NR' or NR'C(O) wherein R' is H or methyl;

X is an optionally substituted alkylene (1 -4C), heteroalkylene (2-4C), alkenylene (2-4C), or heteroakenylene (2-4C);

n is 0 or 1 ;

Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12C);

B is OH or NY₂ , wherein each Y is independently H, SR", SOR", S0₂R", or each Y is an optionally substituted group selected from alkyl (1-lOC), alkenyl (2- IOC), alkynyl (2- 10C), heteroalkyl (2- I OC), heteroalkenyl (2-10C), heteroalkynyl (2- IOC); or two Y may together form an optionally substituted heterocyclic ring (4-6 ring members);

each R is independently H, halo, CN, N0₂, CF₃, OCF₃, COOR", CONR"₂, OR", SR", SOR", S0₂R", NR"₂, NR"(CO)R", and NR"S0₂R"; or each R is independently optionally substituted groups selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); or two R on the same carbon atom taken together are =0, =NOR" or =NCN; or two R together form an optionally substituted cyclic or heterocyclic ring (3-6 ring members); or if B is NY₂, one R and one Y together form an optionally substituted heterocyclic ring (4-6 ring members);

each R" is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2- 6C),

wherein the optional substituents on Y, R and R" may be one or more halo, =0, =NOR', CN, N0₂, CF₃, OCF₃, COOR', CONR'₂, OR', SR', SOR', S0₂R', N '₂ , NR'(CO)R', and NR'S0₂R', alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); wherein the optional substituents on X and Ar may be one or more halo, CN, CF₃, OCF₃, COOR", CONR"₂, OR", SR", SOR", S0₂R", alkyl (1 -6C), alkenyl (2-6C), alkynyl (2- 6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); aryl (6-10C), heteroaryl (5-12 ring members), O-aryl (6-lOC), O-heteroaryl (5-12 ring members), aryl (6-12C)-alkyl (1-6) or heteroaryl (5-12 ring members)-alkyl (1 -6C); and wherein optional substituents on X may be additionally selected from =0, =NOR", N0₂, NR"₂, NR"(CO)R", and NR"S0₂R"; and wherein two substituents on Ar or X may together form a cyclic or heterocyclic ring (4-7 ring members).

in another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent Appl. Publication No. 2008/0280900:

or a pharmaceutically acceptable salt or conjugate thereof, wherein

each Ri and R₂ are independently, H, or an optionally substituted alkyl (1 -6C), alkenyl (2- 6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6-10C), heteroaryl (5-12C), or C6-C12-aryl-Cl-C6-alkyl; or Ri and R₂ together with N to which they are attached form an optionally substituted 3-8 membered heterocyclic ring or 5-12 membered heteroaromatic ring;

each R₃ and R4 are independently H, halo or an optionally substituted alkyl (1-3C) or heteroalkyl (1 -3C);

X is an optionally substituted alkylene (1 -3C) or heteroalkylene (1 -3C);

Y is Ar or N(Rs )(Re ) wherein Ar is an optionally substituted aryl (6- IOC) or heteroaryl (5-12C) and R5 and R_¾ are independently, H, or an optionally substituted alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), aryl (6- I OC), heteroaryl (5-12C), or C6-C12-aryl-Cl-C6-alkyl; or R₅ and Ri together with to which they are attached form an optionally substituted 3-8 membered heterocyclic ring or 5-12 membered heteroaromatic ring;

wherein the optional substituents on each X, Ar, R_l3 R₂, R₃, R and R5 are independently selected from halo, CN, N0₂ , CF₃, OCF₃, COOR', CONR'₂, OR', SR', SOR, S0₂R, NR '2, NR'(CO)R', and NR'S0₂R', wherein each R' is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6C), and heteroalkynyl (2-6C); or the optional substituents may be one or more optionally substituted groups selected from alkyl (1 -6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), or heteroalkynyl (2-6C); and wherein the optional substituent on X, R¹, R², R⁵ and R⁶ may further be selected from =0 and -NOR';

and wherein optional substituents on a heterocyclic ring formed with R¹ and R² or R⁵ and R⁶ may independently be selected from =0, =NOR', halo, CN, N0₂ , CF₃, OCF₃, COOR', CONR'2, OR', SR', SOR', S0₂R', NR'₂, NR'(CO)R', and NR'S0₂R', wherein each R' is independently H or an optionally substituted group selected from alkyl (1 -6C), alkenyl (2- 6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), and heteroalkynyl (2-6C); or the optional substituents may be one or more optionally substituted groups selected from alkyl (1 -6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C), or aryl (6-lOC), heteroaryl (5-12C), or C6-C12-aryl-Cl-C6-alkyl; with the provisos that for compounds of formula (1): when Y is N(R₅)(R6), a carbon atom in X or Y that is adjacent to the N in Y is substituted by =0;

and when Y is Ar, then neither Ri nor R₂ is arylalkyl.

In another embodiment, the compound that antagonizes the Ca_v3.1 calcium channel is a compound disclosed in U.S. Patent :

enantiomers, diastereomers, solvates and salts thereof

wherein A is aryl or heteroaryl, each of which may be optionally substituted with Z^la, Z^2a and one or more Z^3a

a is a single or a double bond where R⁴ is absent;

J is alkylene, alkenylene, or alkynylene any of which may be optionally substituted with Z^lb , Z^2b and one or more Z^3b;

R¹ is hydrogen, alkyl, alkenyl or alkynyl any of which may be optionally substituted with

Z^{l c} , Z^2c and one or more Z^3c;

R² is

(a) alkyl, alkoxy or aryloxy, each group optionally substituted with Z^ld, Z^2d and one or more Z^3d;

(b) cyano or nitro; or

(c)— C(0)R⁵ or C(0)OR⁵;

R³ is

(a) cycloalkyl, aryl, heterocyclo or heteroaryl, any of which may be optionally substituted with Z^,e, Z^2e and one or more Z^3e; or

(b)— NR⁶R⁷— N(R⁶)C(0) R⁷,— N(R⁶)C(0)OR⁷,— (R⁶)C(0)— NR⁷R⁸, — OC(0)NR⁶R⁷,— NR⁶S(0)_tR⁷,— S(0),R⁶R⁷or S(0)_tR⁶ where t is 1 or 2;

R⁴ is

(a) absent;

(b) hydrogen; or

(c) alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl or (heteroaryl)alkyl any of which may be optionally substituted with Z^{l f} , Z^2f and one or more Z^3f;

R⁵ is

(a) hydrogen; or

(b) alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl or (heteroaryl)alkyl any of which may be optionally substituted with Z^lg, Z^2g and one or more Z^3g;

R^5a is

(a) hydrogen; or (b) amino, alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl,

(cycloalky!)alkyl, (heterocyclo)alkyl or (heteroaryl )alkyl any of which may be optionally substituted with Z^{l h}, Z^2h and one or more Z^3h;

R⁶, R⁷ and R⁸ are independently

(a) hydrogen;

(b) alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclo, or heteroaryl, any group of which may be optionally substituted with Z^h, Z²' and one or more Z³'; or

(c) R⁶ and R⁷ are optionally taken together to form

(i) an alkylene or alkenylene group;

(ii)— N=CR⁹— ;

(iii)— N=N— ; or

R⁹ is

(a) hydrogen; or

(b) alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl or (heteroaryl)alkyl any of which may be optionally substituted with Z^V), Z²' j and one or more Z^3j;

Ζ¹"^-1-*, Ζ^23-2·", and Z^33-3-* are optional substituents independently selected from (1) R¹⁰, where R¹⁰ is

(1) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,

(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl;

(ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or

(iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Z^la_j

(2)— OH or—OR¹⁰,

(3)— SH or— SR¹⁰,

(4)— C(0)_tH,— C(0)_tR¹⁰, or— O— C(0)R¹⁰, where t is 1 or 2,

(5)— S0₃H,— S(0)_tR¹⁰, or SO^NiR'^R¹⁰ ,

(6) halo,

(7) cyano,

(8) nitro, (9)— U¹— R¹²R¹³,

(10)— U¹— (Rⁿ>— U²— NR^I2R¹³,

(1 1)— U¹— N(R¹⁴)— U²— R¹⁰,

(12)— U¹— N(R¹⁴)— U²— H,

(13) oxo;

U¹ and U² are each independently

(1) a single bond,

(2)— U³— S(0)r-U⁴— ,

(3)— U³— C(O)— U⁴— ,

(4)— U³— C(S>— U⁴— ,

(5)— U³— O— U⁴— ,

(6)— U³— S— U⁴— ,

(7)— U³— O— C(0>— U⁴— ,

(8)— U³— C(O)— O— U⁴—

(9)— U³— C(=NR¹⁵)— U⁴— , or

(10)— U³— C(0>— C(O)— U⁴— ;

R^u, R¹², R¹³, and R¹⁵

(1) are each independently hydrogen or a group provided in the definition of Z^la~^J; or

(2) R¹² and R ¹³ may together be alkylene or alkenylene, completing a 3- to 8- membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z^la_J , or

(3) R¹² or R¹³, together with R^{1 1}, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z^la-J, or

(4) R¹² and R¹³ together with the nitrogen atom to which they are attached may combine to form a group— N=CR¹⁶R¹⁷ where R¹⁶ and R¹⁷ are each independently H or a group provided in the definition of R¹⁰; and

U³ and U⁴ are each independently

(1) a single bond, (2) alkylene,

(3) alkenylene,

(4) alkynylene.

In another embodiment, the compound is disclosed in U.S. Patent No. 7,166,603:

enantiomers, diastereomers, solvates and salts thereof,

wherein

A is aryl or heteroaryl, each of which may be optionally substituted with Z¹, Z² and/or one or more Z³;

X is oxygen or sulfur;

J is alkylene, alkenylene, or alkynylene any of which may be optionally substituted with Z^la, Z^2a and/or one or more Z^3a;

R¹ is hydrogen, alkyl, alkenyl or alkynyl any of which may be optionally substituted with Z^lb, Z^2b and or one or more Z^3b;

(a) alkyl, alkoxy or aryloxy, each group optionally substituted with Z

and/or one or more Z^3c;

(b) cyano or nitro; or

(c)— C(0)R⁵ or C(0)OR⁵;

R³ is

(a)— N(R⁶)C(0)R⁷,— N(R⁶)C(0)OR⁷,— N(R⁶)C(0)— R⁷R⁸,

-NR⁶S(0),R⁷,— S(0),NR⁶R⁷ or S(0),R⁶ where t is 1 or 2; or

(b) a group of formula

of formula

R⁴ is

(a) hydrogen; or

(b) alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl or (heteroaryl)alkyl, any of which may be optionally substituted with Z^l , Z^2e and/or one or more Z^3e;

R⁵ is

(a) hydrogen; or

(b) alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl or (heteroaryl)alkyl, any of which may be optionally substituted with Z^lf, Z^2f and/or one or more Z^3f;

R⁶, R⁷ and R⁸ are independently

(a) hydrogen;

(b) alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl or (heteroaryl)alkyl, any of which may be optionally substituted with Z'^e, Z^2g and one or more Z^3g; or

(c) R⁶ and R⁷ are optionally taken together to form

(i) an alkylene or alkenylene group;

(ii)— N=CR⁹— ;

(iii)— N=N— ; or

R⁹ is

(a) hydrogen; or

(b) alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl or (heteroaryl)alkyl, any of which may be optionally substituted with Z ^g. Z^2g and/or one or more Z³⁸;

Z^1"'⁸, Z^2"2g, and Z^3"3gare optional substituents independently selected from (1) R¹⁰, where R¹⁰ is (1) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,

(iii) a group (i) or (ii) which is independently substituted by one or more

(preferably 1 to 3) of the following groups (2) to ( 13) of the definition of Z¹,

(2)— OH or— OR¹⁰,

(3)— SH or— S¹⁰,

(4)— C(0)_TH,— C(0)_TR¹⁰, or— O— C(0)R¹⁰, where t is 1 or 2,

(5)— S0₃H,— S(0),R¹⁰, or S(0)_t (R^M)R¹⁰,

(6) halo,

(7) cyano,

(8) nitro,

(9)— U¹— R¹²R¹³,

(10)— U ¹— N(R^M )— U²— NR¹²R¹³,

( 1 1 )— U¹— N(R¹ )— U²— R¹⁰,

( 12)— U¹— N(R¹⁴)— U²— H,

(13) oxo;

U¹ and U² are each independently

(1 ) a single bond,

(2) _U³— S(0)_T— U⁴—

(3)— U³— C(O)— U⁴— ,

(4)— U³— C(S)— U⁴— ,

(5)— U³— O— U⁴— ,

(6)— U³— S— U⁴— ,

(7)— U³— O— C(O)— U⁴— ,

(8)— U³— C(O)— O— U⁴— ,

(9)— U³— C(=NR¹⁵)— U⁴— , or

(1 0)— U³— C(O)— C(0>— U⁴— ;

R" , R^{1 2}, R¹³, R^l4 and R¹⁵

( 1 ) are each independently hydrogen or a group provided in the definition of Z¹ ; or (2) R¹² and R¹³ may together be alkylene or alkenylene, completing a 3- to 8- membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z¹, or

(3) R¹² or R¹³, together with R¹¹, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the definition of Z¹, or

(4) R¹² and R¹³ together with the nitrogen atom to which they are attached may combine to form a group— N=CR¹⁶ R¹⁷ where R¹⁶ and R¹⁷ are each independently H or a group provided in the definition of R¹⁰; and

U³ and U⁴ are each independently

(1) a single bond,

(2) alkylene,

(3) alkenylene,

(4) alkynylene.

In another embodiment, the compound is disclosed in U.S. Patent No. 7,504,431 :

its stereoisomers, solvates, and salts, thereof wherein:

a is R¹, >C₃ alkyl, substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl (preferably R¹, C₄.₈ alkyl, or aryl);

R ¹ is— C(0)NR²R³ or C(0)OR⁴— ;

R² and R³ are independently

(a) hydrogen;

(b) alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl; or

(c) R² and R³ together to the atom to which they are attached form a heterocycle; b is CR¹³R¹⁴ (especially where R¹³ and R¹⁴ are, independently hydrogen or C alkyl); c is aryl or heteroaryl; d is a bond, alkylene,— OC(=0)— , — C(=0)— — C(=O)0— ,— C(=0)NR⁷— ,— NR⁷— , — S(=0>— , — SO2— , — S0₂NR⁷— , — NR⁷S(0)₂NR⁸— , — NR⁷S(0)2— , — NR⁷C(=0)— ,— NR⁷C(=0)0— , and— NR⁷C(=0)NR⁸— ;

f is hydrogen, halogen, nitro, cyano, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocyclo, — 0(CH₂)_pR⁶, — S(CH₂)_PR⁶, — OC(=0)(CH₂)_qR⁶, — C(=0)(CH₂)_qR⁶, — C(0)0(CH₂)_pR⁶,— C(=0)NR^uR¹²,— NR^{l l}R¹²,— S(=0)(CH₂)_PR⁶,— S0₂(CH₂)_qR⁶,— S0₂NRⁿR¹², — NR¹⁰S0₂NR"R¹², — NR^l0SO₂(CH₂)_qR⁶, — NR¹⁰C(=O)(CH₂)_qR⁶, — NR¹⁰C(O)O(CH₂)_pR⁶, or— NR¹⁰C(=O)NR^uR¹²;

R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² are independently hydrogen; alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl;

or R¹¹ and R¹² together to the atom to which they are attached form a heterocycle;

1, m, n, p and q are independently 0 to 4;

R_a , R¹³ and R¹⁴ are independently where valence allows hydrogen, cyano, nitro, halogen, oxo, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocyclo,— OR¹⁵,— SR¹⁵,— OC(=0)R¹⁵,— C(=0)R¹⁵,— C0₂R¹⁵,— C(=0)NR¹⁶R¹⁷,— NR¹⁶R¹⁷,— S(=0)R¹⁵, or— S0₂R¹⁵;

or R¹³ and R¹⁴ are taken together to form oxo;

R¹⁵, R¹⁶ and R¹⁷ are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl; and

R²¹ and R²² are independently hydrogen or CM alkyl;

provided that when c is phenyl and R_a is located para to the sulfoxide substituent; R_a is not chloro or— OMe; and when a is >C₃ alkyl, n is 0.

In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No. 2007/0197523:

2-(3,4-Dimethoxy-phenyl)-N-[5-(3-ethoxy-benzenesulfonyl)-thiazol-2-yl]-acetamide; 2-(3,4-Dimethoxy-phenyl)-N-[5-(3-trifluoromethoxy-benzenesulfonyl)-thiazol-2-yl]- acetamide;

2-Benzo[l,3]dioxol-5-yl-N-[5-(3-fluoro-benzenesulfonyl)-thiazol-2-ylj-acetamide;

2-(4-Chloro-phenyl)-N-[5-(3-methoxy-benzoyl)-thiazol-2-yl]-propionamide;

(l-Benzyl-piperidin-4-yl)-[5-(4-fluoro-benzenesulfonyl)-thiazol-2-yl]-amine; 5-(4-Fluoro-phenylsulfonyl)-thiazole-2-carboxylic acid 4-methoxy-benzylamide;

[2-(3-Trifluoromethoxy-phenoxy)-thiazol-5-ylmethyl]-(4-trifluororaethyl-benzyl)-am [2-(3,4-Dirnethoxy-phenyl)-ethyl]-[5-(3-ethoxy-phenyl)-thiazol-2-ylmethylJ-carbamic acid tert-butyl ester;

4-{4-[5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-pyrimidin-2-yl}-rno holi e;

[5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-[5-fluoro-2-methyl-6-(2-pyrrolidin-yl- ethoxy)-pyrimidin-4-yl]-amine;

[5-(3-£thoxy-benzenesulfonyl)-thiazol-2-ylJ-[6-(3-methoxy-prop-l -ynyl)-2-rnethyl- pyrimidin-4-ylj-amine;

[5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-[2-methyl-6-((R)-pyrrolidin-3-yloxy)- pyrimidin-4-y 1] -amine ;

N-[5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-N'-(R)-pyrrolidin-3-yl-2-trifluoromethyl- pyrimidine-4,6-diamine;

[5-(3-Ethoxy-benzenesulfonyl)-thi zol-2-yl]-(6-methoxy-2-moφholin-4-yl yrimidin-4- yl)-amine;

N*5*-[5-(3-Fluoroy-benzenesulfonyl)-thiazol-2-yl]-N*2*-(2-pyiTolidin-l-yl-elhyl)- pyridine-2,5-diamine;

2-(3,4-Dimethoxy-phenyl)-N-[5-(4-fluoro-benzenesulfonyl)-thiazol-2-yrj-acetamide

N-(5-Cyclopentylsulfanyl-thiazol-2- yl)-2-(3,4-djmethoxy-phenyl)-acetamide;

[6-(3 - Amino-3 -methy l-butyl)-2-methy l-pyrimidin-4-y l]-[5 -(3 -ethoxy-benzenesulfonyl)- thiazol-2-yl]-amine;

2-(3,4-Dimethoxy-phenyl)-N-[5-(3-ethoxy-benzenesulfonyl)-thiazol-2-yl]-N-methyl- acetamide;

1- [5-(4-Fluoro-benzenesulfonyl)-thiazol-2-yl]-3-(4-methoxy-benzyl)-urea;

2- (4-Trifluoromethoxy-phenylsulfanyl)-thiazole-5-carboxylic acid 4-methoxy- benzylamide;

3- Phenyl- 1 -[2-(4-trifluoromethoxy-benzenesulfonyl)-thiazol-5-yl]-propan- 1 -ol;

3 -(3 ,4-Dimethoxy-pheny 1)- 1 - [5 -(3 -ethoxy-benzenesulfonyl)-thiazol-2-y I ]- propan- 1 -one ; N-(2-Amino-2-methyl-propyl)-N'-[5-(3-ethoxy-benzenesulfonyl)-thiazol-2-yl]-2-methyl- pyrimidine-4,6-diamine;

(3-{6-[5-(3-Emoxy-benzenesulfonyl)-thiazol-2-ylammoJ-2-memyl-pyrimidin-4-yl}-l,l- dimethyl-prop-2-ynyl)-carbamic acid tert-butyl ester; N*2*-[5-(3-Emoxy-benzenesulfonyl)-thiazol-2-yl]-N*5*-(2^>TTolidin-l-yl-ethyl)- pyridine-2,5-diamine;

N-[5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-2-methyl-N'-(R)-pyrrolidin-3-yl- pyrimidine-4,6-diamine;

N*2*-[5-(4-Fluoro-benzenesulfonyl)-miazol-2-yl]-N*5*-(2-methoxy-ethyl)-pyridine-2,5- diamine;

[5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-(6-(2-methoxy-ethyl)-2-mo holin-4-yl- pyrimidin-4-yl)-amine.

[0106] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2007/0173504:

In the compound of Formula (I), X¹ is— S— ,— O— , or— N(R³)— . R¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R² is substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. L¹ and L² are independently a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene,

4)— , -N(R⁴)C(0)— , — N(R⁴)C(0)0— , — N(R⁴)C(0)N(R⁴)— , —

represents an nteger rom to . an are n epen ent y y rogen, su st tute or unsubstituted alky], substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0107] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2008/0070888:

or a pharmaceutically acceptable salt, solvate, hydrate, ester, prodrug or stereoisomer thereof, wherein:

Z¹ is selected from the group consisting of:— CH2— or— C(O)—

R¹ is selected from the group consisting of:

(1) H,

(2) alkyl (such as, for example, i-propyl, methyl,— (CH₂)₂CH(CH₃)2),—

CH₂CH(CH₃)2,

(3) substituted alkyl,

(4)— CR^A(aryl)_w wherein w is 2 or 3, and wherein each aryl is independently selected, and wherein R^A is selected from the group consisting of: F,— OH, H, and lower alkyl, and wherein examples of said— CR^A(aryl)_w include, for example,— CH(aryl)₂, such as, for example,— CH(phenyl)₂,

(5)— CR^A(substituted aryl)_w wherein w is 2 or 3 and wherein each substituted aryl is independently selected, and wherein R^A is selected from the group consisting of: F,— OH, H, and lower alkyl, and wherein examples of said— CR^A(substituted aryl)_w include, for example,— CH(substituted aryl)₂, such as, for example,— CH(substituted phenyl)₂,

(6) aryl (e.g., phenyl),

(7) substituted aryl (e.g., substituted phenyl) (examples of substituted aryl groups include, for example, (i) halo substituted phenyl, such as, for example, p-F-phenyl, (ii) alkoxy substituted phenyl (such as, for example, p-methoxyphenyl and m- methoxyphenyl, (iii)— CF3 substituted phenyl, such as, for example, p-CF3-phenyl, and (iv) alkyl substituted phenyl, such as, for example, p-methylphenyl-),

(8) arylalkyl- (e.g., benzyl),

(9) substituted arylalkyl-, wherein said substituted arylalkyl includes, for example, (a) (substituted aryl)-alkyl-, (b) aryl-(substituted alkyl)- and (c) (substituted aryl)- (substituted alkyl)-, and wherein examples of said substituted arylalkyl include, for example, substituted phenylalkyl, such as, for example, substituted benzyl, such as for example, halo substituted benzyl, such as, for example, o,p-di-F-benzyl, o-Cl-benzyl, and o,p-di-F-benzyl),

(10) heteroaryl,

(1 1) heteroarylalkyl,

(12) cycloalkyl (e.g., cyclopropyl), (13) cycloalkylalkyl (e.g., cyclopropyl-CH₂— ),

(14) alkenyl (e.g.,— CH₂CH=CH₂),

(15)— C(0)NQ^AQ^B,

(16) substituted heteroaryl; and

wherein the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, and (p)— P(0)(0-alkyl)₂;

wherein the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and

wherein the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)2, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— SCfe-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl;

Q^A is selected from the group consisting of: H and alkyl (e.g., Ci to Ce alkyl);

Q^B is selected from the group consisting of:

(1 ) aryl (e.g., phenyl), and

(2) substituted aryl wherein said substituted aryl is substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— <C=N— 0-alkyl)CH₃, (b)— C(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl, and wherein examples of said substituted aryl moiety include, for example, substituted phenyl, such as, for example, halo substituted phenyl, such as, for example, o,p-di-F-phenyl;

selected from the group consisting of:

(1 ) heteroaryl (e.g., pyridyl, pyrimidinyl, benzoimidazolyl-, and substituted heteroaryl (e.g., heteroaryl substituted with one or more ring system substitutents as defined herein)),

(2) heterocycloalkenyl (e.g. dihydrothiazolyl, dihydrooxazolyl, and substituted heterocycloalkcnyl (e.g., heterocycloalkenyl substituted with one or more ring system substitutents as defined herein));

(3) substituted cyclobutenedione of the formula:

wherein each R is independently selected from the group consisting of: H, alkyl (e.g., C| to alkyl, or Ci to C alkyl or Ci to C₂ alkyl), substituted alkyl (e.g., Cj to C_$ substituted alkyl, or C_\ to C₄ substituted alkyl or Ci to C₂ substituted alkyl), aryl, substituted aryl, heteroaryl and substituted heteroaryl, provided that at least one R ^B is other than H, and wherein the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— <C= — 0-alkyl)CH₃₎ (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — C(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, and (p)— P(0)(0-alkyl)₂;

wherein the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (0)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and

wherein the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— <C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂₎ (h)— CF₃, (i)—OH, G) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl;

(4) thiadiazoles of the formula:

wherein each R^B is independently selected from the group consisting of: H, alkyl (e.g., Ci to alkyl, or Q to C₄ alkyl or C\ to C₂ alkyl), substituted alkyl (e.g., C\ to Ce substituted alkyl, or Ci to C₄ substituted alkyl or Ci to C₂ substituted alkyl), aryl, substituted aryl, heteroaryl and substituted heteroaryl, provided that at least one R^B is other than H, and m is 0, 1 or 2, and

wherein the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂₎ (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂₎ and (q) alkyl; and

wherein the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)2, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and (5) substituted heteroaryl, said substituted heteroaryl substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) — <C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)2, (h)— CF₃, (i) —OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl;

R³ is selected from the group consisting of:

(1 ) alkyl,

(2) substituted alkyl,

.(3) aryl (e.g., phenyl),

(4) substituted aryl, including for example, (a) halo substituted phenyl (such as, for example, p-Cl-phenyl, p-Br-phenyl, and p-F-phenyl), and (b) phenyl substituted with CN (such as, for example, p-CN-phenyl),

(5) aryl-aryl-, such as, for example, phenyl-phenyl-,

(6) substituted aryl-aryl- (wherein one or both aryl moieties are substituted), such as substituted phenyl-phenyl-,

(7) heteroaryl-aryl-, such as, for example, heteroaryl-phenyl-, such as, for example, pyridyl-phenyl-,

(8) heteroaryl-(substituted aryl)-, such as, for example, heteroaryl-(substituted phenyl)-, such as, for example, pyridyl-(substituted phenyl)-,

(9) arylalkyl-,

(10) substituted arylalkyl- (wherein said substituted arylalkyl includes (a)

(substituted aryl)-alkyl-, (b) aryl-(substituted alkyl)- and (c) (substituted aryl)-(substituted alkyl)-,

(1 1 ) arylalkenyl-,

(12) substituted arylalkenyl-,

(13) arylalkynyl-,

(14) substituted arylalkynyl-

(15) arylalkyl-NH— ,

(16) substituted arylalkyl-NH— ,

(17) arylalkoxy-

(18) substituted arylalkoxy-, (19) arylcarbonyl-

(20) substituted arylcarbonyl-

(21) heteroaryl (e.g., pyridyl),

(22) heteroarylalkyl-,

(23) heteroarylalkenyl-,

(24) heteroarylalkynyl-, and

(25) H,

(26) substituted heteroaryl; and

wherein the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)2, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and

wherein the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— <C=N— 0-alkyl)CH₃, (b)— NC(0)NH_2> (c)— NC(0)NH(alkyl), (d) — C(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)2, and (q) alkyl;

Each occurrence of R⁴ is:

independently selected from the group consisting of: — CH₂— , — CH(alkyl)-, — C(alkyl)₂-,— C(0>— ,— CH(substituted alkyl)-,— C(substituted alkyl)₂-, and each alkyl is independently selected, and each substituted alkyl is independently selected, and examples of said alkyl moieties include, for example, Ci to G» alkyl and Ci to C₂ alkyl, and examples of said substituted alkyl moieties include, for example, substituted Cj to C₄ alkyl and substituted Cj to C₂ alkyl, and

preferably each occurrence of R⁴ is selected from the group consisting of:— CH₂— ,— CH(alkyl)-,— C(alkyl)₂, and— C(O)— , and

more preferably, when v is 1, 2 or 3, there are 0 to 1— C(O)— moieties, and preferably no— C(O)— moiety, and when said— C(O)— is present said— C(O)— moiety is preferably adjacent to the ring nitrogen, and

wherein the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, and (p)— P(0)(0-alkyl)₂;

Each occurrence of R⁵ is:

independently selected from the group consisting of: — CH₂— , — CH(alkyl)-, — C(alkyl)₂-,— C(O)— ,— CH(substituted alkyl)-,— C(substituted alkyl)₂-, and each alkyl is independently selected, and each substituted alkyl is independently selected, and examples of said alkyl moieties include, for example, Cj to C₄ alkyl and Ci to C₂ alkyl, and examples of said substituted alkyl moieties include, for example, substituted Ci to C₄ alkyl and substituted Ci to C₂ alkyl, and

preferably each occurrence of R⁵ is selected from the group consisting of:— CH₂— ,— CH(alkyl)-,— C(alkyl)₂, and— C(0— , and

wherein the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH (alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, and (p)— P(0)(0-alkyl)₂; or R⁴ and R⁵ are as defined above, and one ring carbon of R⁴ and one ring carbon of R are bound together by a— CH₂— CH₂— group (i.e., there is a C₂ bridge joining a R⁴ ring carbon and a R⁵ ring carbon, and those skilled in the art will appreciate that the bridged carbons for R⁴ and R⁵ are each independently selected from the group consisting of:— CH— ,— C(alkyl)-, and— C(substituted alkyl)- wherein alkyl and substituted alkyl are as defined in R⁴ and R⁵ );

u is an integer from 0 to 3; and

v is an integer from 0 to 3 such that the sum of u and v is from 3 to 5.

In another embodiment, the comp n U.S. Patent No. 7,638,526:

R ¹ is selected from the group consisting of: (1) H, (2) alkyl, (3) substituted alkyl, (4) cycloalkyl, (5) aryl, (6) substituted aryl, (7) arylalkyl, (8) heteroaryl, (9) substituted heteroaryl, (10) heteroarylalkyl, (1 1) diphenylmethyl, (12) cycloalkylalkyl, (13) alkenyl, (14)— C(0)NQ^B (wherein Q^B is selected from the group consisting of substituted aryl (e.g., substituted phenyl)), and (15) -alkylene-C(0)N(alkyl)2; and wherein:

the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) — (C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂₎ (h)— CF₃, (i) —OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (0)— S0₂- alkyl, and (p)— P(0)(0-alkyl)₂;

the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) — (C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i) —OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, G) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl;

R² is selected from the group consisting of: (1) H, (2) alkyl, (3) substituted alkyl, (3) cycloalkyl, (4) aryl, (5) substituted aryl, (6) arylalkyl, (7) heteroarylalkyl, (8) heterocycloalkyl, (9) heterocycloalkylalkyl, (10) R⁶-A-, (11) alkyl-O— C(O)— , (12) (alkyl)₂-N-alkylene-C(0)— , (13) (alkyl)₂-N— C(0)-alkylene-C(0)— , (14) CN-alkylene- C(O)— , (15) alkyl-O-alkylene-C(O)— , (16) alkyl-C(0)-alkylene-C(0)— , (17) alkyl- C(O)— NH-alkylene-C(O)— , (18) alkyl-NH— C(0>— , (19) alkyl-O— C(0)-alkylene- C(O)— , (20) alkyl-O— C(0)-cycloalkylene-alkylene-, (21) NH₂— C(O)— NH-alkylene- C(O)— , (22) NH₂— C(0)-alkylene-C(0)— , (23) alkyl-C(O)— NH-alkylene-S-alkylene- C(O)— , (24) alkyl-O— C(0)-alkylene-C(0)—, (25) alkyl-S-alkylene-C(O)— , (26) alkyl- C(0)-cycloalkylene-alkylene-C(0)- , (27) alkyl-S-alkylene-(— NHC(0)alkyl)-C(0)— , (28) alkyl(-C(0)Oalkyl)-NH— C(O)— , (29) alkyl-S-alkylene(— NHC(0)alkyl)-C(0)— , (30)— C(0)NHQ^A wherein Q^A is selected from the group consisting of: (a) cycloalkyl, (b) alkyl substituted with— C(O)— O-alkyl, (c) substituted aryl, (d) alkyl, (e) substituted arylalkyl, (f) substituted heterocycloalkenylbenzo, and (g) heteroaryl, (31)— C(0)NQ^cQ^D wherein Q^c and Q^D are each independently selected from the group consisting of: (a) H, (b) Q^A (wherein Q^A is as previously defined), (c) substituted aryl, and (d) arylalkyl, (32) substituted heteroarylalkyl, and

wherein Z^A is selected from the group consisting of: H and alkyl (e.g., Q to C₄ alkyl), and Q^F is selected from the group consisting of:— C(0)Oalkyl (e.g.,— C(0)0(Ci to C₄ alkyl)) and— C(0)N(X^A)₂ wherein each X^A is independently selected from the group consisting of: H and alkyl (e.g., Ci to C₄ alkyl), and wherein examples of the group (33) include, for example, alkyl(— C(0)Oalkyl)-NH— C(O)— (such as, for example,

such as, for exam]

C|

0(C,-C,)alfcyl such as, for example,

such as, for example,

such as, for example,

such as, for example,

such as, for example,

wherein:

the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) — (C=N— 0-alkyl)CH_3s (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i) —OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, and (p)— P(0)(0-alkyl)₂;

the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g. 1 to 3) substituents independently selected from the group consisting of: (a) — (C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i) —OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and

the substituted heteroarylalkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and wherein the heteroaryl portion is substituted, or the alkyl portion is substituted, or both the heteroaryl and alkyl portions are substituted; and

R³ is selected from the group consisting of: (1) H, (2) alkyl, (3) substituted alkyl, (4) cycloalkyl, (5) aryl, (6) substituted aryl, (7) arylalkyl, (8) arylalkenyl, (9) arylalkynyl (10) heteroaryl, (1 1) substituted heteroaryl, (12) heteroarylalkyl, (13) heteroarylalkenyl, and (14) heteroarylalkynyl; and wherein:

the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) — (C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH_2j (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i) —OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, and (p)— P(0)(0-alkyl)₂;

the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) — (C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)2, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i) —OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and

the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— SQ₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and

Each occurrence of R⁴ is independently selected from the group consisting of:— CH₂— , — CH(alkyl)- and— C(alkyl)₂ wherein each alkyl for each R⁴ is independently selected, and wherein examples of said alkyl group include, for example, Ci to C₄ alkyl, and Ci to C₂ alkyl;

Each occurrence of R⁵ is independently selected from the group consisting of:— CH₂— , — CH(alkyl)- and— C(alkyl)₂ wherein each alkyl for each R⁵ is independently selected, and wherein examples of said alkyl group include, for example, Ci to C₄ alkyl, and Ci to C₂ alkyl; or

R⁴ and R⁵ are as defined above, and a ring carbon of said R⁴ is bound to a ring carbon of said R⁵ by a— CH₂— CH₂— group (i.e., there is a C₂ bridge joining a R⁴ ring carbon and a R⁵ ring carbon, and those skilled in the art will appreciate that the bridged carbons for R⁴ and R⁵ are each independently selected from the group consisting of:— CH— and— C(alkyl)-);

u is an integer from 0 to 3;

v is an integer from 0 to 3, such that the sum of u and v is from 3 to 5; R⁶ is selected from the group consisting of: (1) alkyl, (2) substituted alkyl, (3) aryl, (4) substituted aryl, (4) heteroaryl, (5) substituted heteroaryl, (6) cycloalkyl, (7) cycloalkylalkyl, (8) heterocycloalkyl, (9) cycloalkenyl, (10) heterocycloalkenyl, (1 1) benzofused cycloalkyl, (12) benzo fused heterocycloalkyl, and (13) benzo fused heterocycloalkenyl; and wherein

the substituted alkyl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) — (C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)2, (h)— CF₃, (i) —OH, 0) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, and (p)— P(0)(0-alkyl)₂, and (q) alkyl;

the substituted aryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a) _.— (C=N— 0-alkyl)CH₃, (b) — NC(0)NH₂, (c) — NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)2, (h)— CF₃, (i) —OH, G) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂- alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl; and

the substituted heteroaryl moieties are each independently substituted with one or more (i.e., at least one, e.g., 1 to 3) substituents independently selected from the group consisting of: (a)— (C=N— 0-alkyl)CH₃, (b)— NC(0)NH₂, (c)— NC(0)NH(alkyl), (d) — NC(0)N(alkyl)₂, (e)— S0₂NH₂, (f)— S0₂NH(alkyl), (g)— S0₂N(alkyl)₂, (h)— CF₃, (i)—OH, (j) -halo, (k)— CN, (1) -alkoxy, (m)— C(0)0-alkyl, (n)— S(0)alkyl, (o)— S0₂-alkyl, (p)— P(0)(0-alkyl)₂, and (q) alkyl;

A is selected from the group consisting of: (1)— C(O)— , (2)— C(0)-alkylene-, (3)— C(0)-alkylene-0— , (4)— C(O)— (CH₂)_0-2— C(O)— , (5)— C(O)— CH — NH— C(O)— , (6) — C(O)— CH₂— N(alkyl)-C(0)— , (7) -alkylene-, (8) -alkenylene-, (9) — C(O)- alkenylene-, (10)— O— C(0)-alkylene-C(0>— , (11)— C(O)— NH-cycloalkylene-, (12) — C(O)— NH— , (13)— C(0>— NH-alkylene-, (14)— C(0)-alkylene(— NHC(O)alkyl)-, (15)— C(0)-alkylene-NH— C(0)-alkylene-, (16)— C(0)-alkylene-NH— C(O)— , (17)— C(0)-alkylene-0-alkylene-, (18)— C(0)-alkylene(alkoxy)-, (19)— C(0)-alkylene-S— , (20)— C(0)-alkylene(— N(alkyl)₂)— , and

In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No. 2008/0070892:

wherein said compound is selected from the group consisting of the compounds defined by Tables, 1, 2, 3a, 3b, 3c, 3d and 4a, as described below. Table 1 provides the definitions of R¹ and assigns each moiety a number that is used in Tables 3a, 3b, 3c, 3d and 4a to define the compounds represented by the structure assigned to Tables 3a, 3b, 3c, 3d and 4a. Table 2 provides the definitions of R² and assigns each moiety a number that is used in Tables 3a, 3b, 3c, _. and 3d to define the compounds represented by the structure assigned to Tables 3a, 3b, 3c, and 3d.

87

88

89

90

91

92

93

95

continued

he R² Moieties

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

TABLE 2-contiaued

Table 3a is directed to compounds of the formula (IA):

wherein R^{ and R² are as defined in Table 3 a.

An "X" in the box formed by the intersection of the R² and the R¹ row represents an R² and R¹ combination of a compound of ion ·<·.·⁾ a IA that, is included in the definition of the compounds of formula I that are useful in Hie methods of this invention. For example, compounds of formula IA wherein R is moiety 1 (see Table 2 for definition) and R¹ is moiety 2 (see Table 1 for definition) are included in the definition of formula I (there is an "X" in the box formed by the intersection of the R* column and the R row), if there is no "X" in the box, then that compound is not included in the definition of the compounds of formula I. For example, compounds of formula I A wherein moiety R^{" '} is 2 and moiety R^! is 23 (no "X" in the box formed by the intersection of the R² column and the R* row) are not. within the definition of the compounds of formula Ϊ. TABLE 3a

Rl

R2 2 3 9 10 11 14 15 23 20

1 X X X X X X X X X

2 X X X ^"X X X X X

3 X X X X X X X X

4 X X X X X X X X X

5 X X X X

6 X X X X X X X X X

7 X X X X X X X X

8 X X X X X X X X X

9 X X X X X X X X

10 X X X X X X X X X

11 X X X X X X X X X

12 X X X X X X X X X

13 X X X X X X X X

14 X X X X X X X X X

15 X X X X X X X X X

16 X X X X X X X X X

17 X X X X X X X X X

18 X X X X X X X X X

19 X X X X X X X X X

20 X X X X X X X X

21 X X X X X X X X X

22 X X X X X X X X

23 X X X X X X X X X

24 X X X X X X X X X

25 X X X X X X X X X

26 X X X X X X X X X

27 X X X X X X

28 X X X X X X X X X

29 X X X X X X X X X

30 X X X X X X X X X

31 X X X X X X X X

32 X X X X X X X X X

33 X X X X X X X X X

34 X X X X X X X X X

35 X X X X X X X X

36 X X X X X X X X X

37 X X X X X X X X X

38 X X X X X X X X X

39 X X X X X X X X

40 X X X X X X X X X

41 X X X X X X

42 X X X X X X X X X

43 X X X X X X X X X

Rl

R2 22 27 38 39 40 41 42 31 32 34 35 36 37

1 X X X X X X X X X X X X X

2 X X X X X X X X X X X X X

3 X X X X X X X X X X X X X

4 X X X X X X X X X X X X X

5 X X X X X X X X X X X

6 X X X X X X X X X X X X X

7 X X X X X X X X X X X X X

8 X X X X X X X X X X X X X

9 X X X X X X X X X X X X

10 X X X X X X X X X X X X X

11 X X X X X X X X X X X X X

12 X X X X X X X X X X X X X

13 X X X X X X X X X X X X X

14 X X X X X X X X X X X X X

15 X X X X X X X X X X X X X

16 X X X X X X X X X X X X X

17 X X X X X X X X X X X X X

18 X X X X X X X X X X X X

19 X X X X X X X X X X TABLE 3a-continued TABLE 3a-continued

X X X X X X X X X X X X X Rl

X X X X X X X X X X X X X

X X X X X X X X X X X X X R2 2 3 9 10 11 14 15 23 20

X X X X X X X X X X X X X

X X X X X X X X X X X X X 44 X X X X X X X X

X X X X X X X X X X X X X 45 X X X X X X X X X

X X X X X X X X X X X X X 46 X X X X X

47 X X X X X X X X X

X X X X X X X X X X X X X 48 X X X X X X X X X

X X X X X X X X X X X X X 49 X X X X X X X X

X X X X X X X X X X X X 50 X X X X X X X X X

X X X X X X X X X X X X X 51 X X X X X X

X X X X X X X X X X X X 52 X X X X X X X X X

X X X X X X X X X X X X 53 X X X X X X X X X

X X X X X X X X X X X 54 X X X X X X X X X

X X X X X X X 55 X X X X X X X X X

X X X X X X X X X X X X X 56 X X X X X X X X X

X X X X X X X X X X X X X 57 X X X X X X X X X

X X X X X X X X X X X X X 58 X X X X X X X X X

X X X X X X X X X X X X X 59 X X X X X X X X X

X X X X X X X X X X X 60 X X X X X X X X X

X X X X X X X X X X X X X 61 X X X X X X X X X

X X X X X X X X X X X X 62 X X X X X X X X X

X X X X X X X X X X X X 63 X X X X X X X X X

64 X X X X X X X X

Rl 65 X X X X X X X X X

66 X X X X X X X X X

30 44 45 47 49 50 51 52 7 8 13 67 X X X X X X X X X

68 X X X X X X X X

69 X X X X X X X X X

70 X X X X X X X X X

X

71 X X X X X X X X

X X X X X X X X

72 X X X X X X X X X

73 X X X X X X X X X

X X X X X X X X 74 X X X X X X X X X

X X X X

75 X X X X X X X

X X X X 76 X X X X X X X X X

X X X X 77 X X X X X X X X

X X X X 78 X X X X X X X

X X X X 79 X X X X X X X X X

X X X X 80 X X X X X X X X X

X X X X 81 X X X X X X

X X X X 82 X X X X X X X X X

X X X X 83 X X X X X

X X X X 84 X X X X X X

X X X X X X X X X X X 85 X X X X

X X X X 86 X X

X X X 87 X X X

X

88 X X X

X X X

X X X X X X X X X X X

Rl

X X X X

X X X X X X X X X X X R2 22 27 38 39 40 41 42 31 32 34 35 36 37

X X X X

X X X X 44 X X X X X X X X X X X X

X X X X 45 X X X X X X X X X X X X X

X X X X 46 X X X X X X X X

X X X 47 X X X X X X X X X X

X X X X 48 X X X X X X X X X X X X

X X X X 49 X X X X X X X X X X X X

X X X X X X X X X X X 50 X X X X X X X X X X X X X

X X X X 51 X X X X X X X X X

X X X X 52 X X X X X X X X X X X X X

X X X 53 X X X X X X X X X X X X X

54 X X X

X X X X X X X X X X X X X

X

55 X X X X X X X X X X X X X

X X X X X X X X X

56 X X

X X X X

57 X X X X X X X X X X X

X X X X

58 X X X X X X X X X X

X X X X

59 X X X X X X X X X X X X

X X X X 60 X X X X X X X X X X X X

X X X X 61 X X X X X X X X X X

X X X X 62 X X X X X X X X X X X X X

X X X X 63 X X X X X X X X X X X X X

X X X X 64 X X X X X X X X X X X X

65 X X X X X X X X X X X TABLE 3a-coB.tiiraed TABLE 3a-continued

66 X X X X X X X X X X X X Rl

67 X X X X X X X X X X X X

68 X X X X X X X X X X X R2 2 3 9 10 11 14 15 20 22

6S X X X X X X X X

70 X X X X X X X X X 133 X X X X X X X X

71 X X X X X ^:X X X X X 134 X X X X X X X X

72 X X X X X X X X X X X 135 X X X X X X X X

73 X X X X X X X X X X 136 X X X X X X X X

74 X X X X X X X X X X X 137 X X X X X X X X

75 X X X X X X X X X X X X 138 X X X X X X X X

7s X X X X X X X X X X X X 139 X X X X X X

X X X X X X X X X X X X 140 X X X X X X

141 X X X X X

79 X X X X X X X X X X X X 142 X X X X X X X X

SO X X X X X X X X X X X X 143 X X X X X X X X

SI X X X X X X X X X X X X 144 X X X X X X X

82 X X X X X X X X X X X 145 X X X X X X X

83 X X X X X X 146 X X X X X X X X

84 X X X X X X X X X X 147 X X X X X

S3 X X X X X X X X 148 X X X X X X X X

S6 X X X X X X X 149 X X X X X X X X

87 X X X X X 150 X X X X X X X X i¾S X X X X X X 151 X X X X X X X X

152 X X X X X X X X

Rl 153 X X X X X X X

154 X X X X X X X 2 30 44 45 47 49 50 51 52 7 8 13 155 X X X X X X X X

156 X X X X X X X X

44 X X X X X X X X X X X 157 X X X X X X X X

45 X X X X 158 X X X X X X X X

46 X X X X 159 X X X X X X X X

47 X X X X X X X X X X X 160 X X X X X X X X

48 X X X X X X X X X X X 161 X X X X X X X

49 X X X X 162 X X X X X X X X

50 X X X X 163 X X X X X X X X

51 X X X X 164 X X X X X X X X

52 X X X X 165 X X X X X X X

53 X X X X 166 X X X X X X X X

54 X X X X 167 X X X X X X X X

55 X X X X X X X X X X 168 X X X X X X X X

56 X X X 169 X X X

57 X X X 170 X X X

58 X X X X 171 X X X

59 X X X X X X X X X X X 172 X X X X X X X

60 X X X X X X X X X X 173 X X X X X

61 X X X X 174 X X X

62 X X X X 175 X X X X X X

176 X X X X X X X

63 X X X X

64 X X X X X X X X X X X

Rl

65 X X X X

66 X X X X

R2 44 45 47 49 50 51 52 7 8 13 17 19 21

67 X X X X

68 X X X X X X X X X X X 133 X X X X X X X

69 X X X X 134 X X X X X X X X X

70 X X X X 135 X X X X X X X X X

71 X X X X 136 X X X X X X X X X

72 X X X X 137 X X X X

73 X X X X 138 X X X X X X X X X

74 X X X X 139 X X X X X X X X X

75 X X X X 140 X X X X X X X X

76 X X X X 141 X X X X X X X X

77 X X X X 142 X X X X

78 X X X 143 X X X X

144

79 X X X X X X X X X X X X X

145 X X X X

80 X X X X

146 X X X X X X X

81 X X X X

147 X X X X

82 X X X X

148 X X X X

83 X X X X 149 X X X X

84 X X X X X X X X 150 X X X X

85 X X X X X X X X X X 151 X X X X

86 X X X 152 X X X X X X X X X

87 X X X X 153 X X X

154 X X X

155 X X X X TABLE 3a-continued TABLE 3a-continued

156 X X X X 182 X X X X X X X X X

157 X X X X X X X X X 183 X X X X X X X X X X

158 X X X X 184 X X X X X X X X

159 X X X X 185

160 X X X 186 X X X X X X X

161 X X X X 187 X X X X X X X X X X

1 2 X X X X 188 X X X X X X X X X X

163 X X X X 190 X X X X X X X X X X

164 X X X X 191 X X X X X X X X X X

165 X X X X 192 X X X X X X X X X X

166 X X X X 193 X X X X X X X X X X

167 X X X X X X X X X 194 X X X X X X X X X X

168 X X X X 195 X X X X X X X X X X

169 X X 196 X X X X X X X X X X

170 X X X 197 X X X X X X X X X X

171 X X 199 X X X X X X X X X X

172 X X X X 201 X X X X X X X

173 X X X 203 X X X X X X X X

174 X X 204 X X X X X X X X X X

175 X X X X X X X X X 205 X X X X X X X X X X

176 X X X X 206 X X X X X X X X X X

207 X X X X X X X X X X

Rl 208 X X X X X X X X X X

209 X X X X X

R2 2 3 9 10 11 14 15 23 210 X X X X X X X

211 X X X X X X X X X X

180 X X X X X X 212 X X X X X X X X

181 X X X X X X X 213 X X X X X X

213 X X X X X X 190 X X X X X X

214 X X X X X X X 191 X X X X X X X X

215 X X X X X 192 X X X X X X X

216 X X X X X X X 193 X X X X X X X X

220 X X X X X X X 194 X ^;x X X X X X X

221 X X X X X X X 195 X X X X X X X

222 X X X X X 196 X X X X X X

228 X X X X X X X 197 X X X X X X X X

229 X X X X X X X 199 X X X X X X X X

231 X X X X X X X 201 X X X X X X X X

232 X X X X X X X 203 X X X X X X X

233 X X X X X X X 204 X X X X X X X X

234 X X X X X X X 205 X X X X X X X

235 X X X X X X X 206 X X X X X X X X

„ 207 X X X X X X X

Rl 208 X X X X X X X X

209 X X X X X X X

R2 20 22 27 38 39 40 41 42 31 32 34 35 36 37 210 X X X X X X

211 X X X X X X X X

180 X X X X X X X X X X 212 X X X X X X X X

181 X X X X X X X X X X 213 X X X X X X X X TABLE 3a-continued TABLE 3a-continued

214 X X X X X X X X 247 X X X X X X X X

215 X 249 X X X X X X X

216 X X X X X X X X 250 X X X X X X X X

220 X X X X X X X 252 X X X X X X X X

221 X X X X X X X 253 X X X X X X X X

222 X X X X X 254 X X X X X X X X

228 X X X X X X X X 255 X X X X X X X X

229 X X X X X X 256 X X X X X X X X

231 X X X X X 257 X X X X X X X

232 X X X X X X X 259 X X X X X X X X

233 X X X X X X X 261 X X X X X X X X

234 X X X X X X X 262 X X X X X X X

235 X X X X X X X

Rl

R2 2 3 9 10 11 14 15 23

265

237 X X X X X X X 266 X X X X X X X X

238 X X X X X X X 267 X X X X X X X X

239 X X X X X X X 268 X X X X X X X X

240 X X X X X X X 269 X X X X X X X

241 X X X X X X X 270 X X X X X X X X

243 X X X X X X X 271 X X X X X X X

244 X X X X X X X 272 X X X X X X X

246 X X X X X X X 273 X X X X X X X

247 X X X X X X X 274 X

249 X X X X X X X 275 X X X X X X X

250 X X X X X X X 276 X X X X X X X

252 X X X X X X X 277 X X X X X X X

253 X X X X X X X 278 X X X X X X X

254 X X X X X X X 279 X X X X X X X X

255 X X X X X X X 280 X X X X X X X

256 X X X X X X X 281 X X X X X X X

257 X X X X X X X 282 X X X X X X X X

259 X X X X X X X 283 X X X X X X X

261 X X X X X X X 284 X X X X X X X X

262 X X X X X X X 285 X X X X X X X

286 X X X X

Rl 287 X X X X X

288 X X X X X X X

R2 20 22 27 38 39 40 41 42 31 32 34 35 36 37 289 X X X X X X

290 X X X X X X

237 X X X X X X X 291 X X X X X

238 X X X X X X X X 292 X X X X X X X

239 X X X X X X X X X 293 X X X X X X X

240 X X X X X X X X X 294 X X X X X

241 X X X X X X X X X X 295 X X X X X X X X

243 X X X X X X X X X X 296 X X X X X X X

244 X X X X X X X X X X 297 X X X X X X X X

246 X X X X X X X X X 298 X X X X X X X

247 X X X X X X X 299 X X X

249 X X X X X X X X X X

250 X X X X X X X X X X Rl

252 X X X X X X X X X X

253 X X X X R2 20 22 27 38 39 40 41 42 31 32 34 35 36 37

254 X X X X X X X X X X

255 X X X X X X X X X X 265

256 X X X X X X X X X X 266 X X X X X X X

257 X X X X X X X X X X 161 X X X X X X X X X X X X

259 X X X X X X X X 268 X X X X X X X X X X X X

261 X X X X X X X X X X 269 X X X X X X X X X X X X

262 X X X X X X X X X X 270 X X X X X X X X X X X

271 X X X X X X X X X X

Rl 272 X X X X X X X X X X

273 X X X X X X X X X X X X

R2 7 8 13 17 19 21 25 33 43 26 29 274 X X

275 X X X X X X X X X X X

237 X X X X X X X X 276 X X X X X X X X X X X X

238 X X X X X X X X 277 X X X X X X X X X X

239 X X X X X X X 278 X X X X X X X X X X X

240 X X X X X X X 279 X X X X X X X X X X X X

241 X X X X X X X X 280 X X X X X X X X X

243 X X X X X X X 281 X X X X X X X X X X X X

244 X X X X X X X 282 X X X X X X X X X X X X

246 X X X X X X X X 283 X X X X X X X X X X X TABLE 3a -continued TABLE 3a-conlinaed

284 X X X X X X X X X X X X 315

285 X X X X X X X X X 316 X X X X X X X

286 X X X X X X 317 X X X X X

287 X X X X X X X X 318 X X X X X X

288 X X X X X X X X X X X 319 X X X X

289 X X X X X X X X X X X 320 X X X X X X

290 X X X X X X X X X 321 X X X X X X X X

291 X X X X X X X X X X 322 X X X X X X X X

292 X X X X X X X X X X X 323 X X X X X X X X

293 X X X X X X X X X X X X 324 X X X X X

294 X X X X X X X X X X X 25 X X

295 X X X X X X X X X X X 326 X X X

296 X X X X X X X X X X X 327 X X X

297 X X X X X X X X X X X X 328

298 X X X X X X X X X X X X 330

299 X X X X 331

332

Rl 333

334 X X X X

R2 7 8 13 17 19 21 25 33 43 26 28 29 30 335

336 X X

265 337 X X X

266 X X X X X X 338 X X X X

267 X X X X X X X X X X X

268 X X X X X X X X X X X Rl

269 X X X X X X X X X

270 X X X X X X X X X X R2 20 22 27 38 39 40 41 42 31 32 34 35 36 37

271 X X X X X X X X X

272 X X X X X X X X X 300 X X X X X X X X X X X

273 X X X X X X X X X 301 X X X X X X X X X X X

274 X X X 302 X X X

275 X X X X X X X X X X 303 X X

276 X X X X X X X X 304 X X X X X X X X X X X X

277 X X X X X X X 305 X X X X X X X X X

278 X X X X X X X X X 306 X X X X X X X X X X X

279 X X X X X X X X 307 X X X X X X X X

280 X X X X X X X X X 308 X X X X X X X X X X X X

281 X X X X X X X X 309 X X X X X X X X X X

282 X X X X X X X X X X X 310 X X X X X X X X X X X X

283 X X X X X X X X 311 X X X X X X X X

284 X X X X X X X X 312 X X X X X X X X X

285 X X X X X X X 313 X X X X X X X

286 X X X X X X X X 314 X X X X X X X

287 X X X X 315

288 X X X X X X X 316 X X X X X X X X X X X X

289 X X X X X X X X 317 X X X X X X X

290 X X X X X X X X 318 X X X X X X

291 X X X X X X X 319 X X X X X X X X X X

292 X X X X X X X X 320 X X X X X X X X X X

293 X X X X X X X X 321 X X X X X X X X X X X

294 X X X X X X X X 322 X X X X X X X X X X X

295 X X X X X X X X X 323 X X X X X X X X X X X

296 X X X X X X X X X 324 X

297 X X X X X X X X X X 325

298 X X X X X X X X X X 326 X X

299 X X X X X X 327 X X

328 X X X

Rl 330 X X X X X X X X X X

331 X X X X X X X X

R2 2 3 9 10 11 14 15 23 332 X X X X X X X

333 X X X X X X X X

300 X X X X X X 334 X X X X X

301 X X X X X X X 335 X X X

302 X X X X 336 X X X

303 X X 337 X X X X

304 X X X X X X X X 338 X X X X

305 X X X

306 X X X X X Rl

307 X X X X X

308 X X X R2 13 17 19 21 25 33 43 26 28 29 30

309 X X X X X

310 X X X X X X X X 300 X X X X X X X

311 X X X X X X 301 X X X X X

312 X X X X 302 X X X

313 X X X 303 X

314 X X 304 X X X X X X TABLE 3a-contimied TABLE 3a-continued

305 X X X X X X 376 x

306 X X X X X X X X 377

307 X X X X

308 X X X X X X X E.1

309 X X X X X X X X

310 X X X X X X X X X 39 40 41 42 31 32 34

311 X X X X X X

312 X X X X 339 X X X X X

313 X X X X X X 340 X X X X X

314 X X X 341 X X X X

315 X 342 X X X X X

316 X X X X X X X X 343 X X X

317 X X X X X X X X 344 X X X X

318 X X X X X X 345 X X X X X

319 X X X X X X 346 X X X X X

320 X X X X X X X X 347 X X X X X

321 X X X X X X X X X X X 348 X X

322 X X X X X X X X X X X 349 X X X X

323 X X X X X X X X X 350 X X X X X

324 X X X X 351 X X X X

325 X X 352 X X X X X

326 X X X X X X 353 X

327 X X X X X X X 354 X X

328 X X X 355 X X X X X

330 356 X X X X X 331 X 357 X

332 X 358 X X X X

333 X 359 X X X X X 334 X 360 X

335 X 361 X X X X X 336 X 362 X X X X 337 X 363 X X

338 X 364

365

Rl 366

367

R2 2 3 9 10 11 14 23 368

369 X X X

339 X X X X 370 X X X

340 X X X 371 X X X

341 X X X X 372 X X X

342 X X X X 373 X X X

343 374 X X X

344 X X 375 X X X

345 X 376 X

346 X X X 377 X X X

347 X X X X

348 X X X X l

349 X

350 X X X 2 13 17 19 21 25 33 43 26 28 29 30

351 X X X

352 X X X 339 X

353 340 X

354 341 X

355 X X X 342 X

356 X X X X 343 X

357 X 344

358 X 345 X

359 X X X X 346 X

360 X X X 347 X

361 X X X 348 X

362 X X X 349 X

363 350 X

364 X 351 X X

352 X X

365 X X X X

353 X

366 X X

354

367 X X X

355 X

368

356 X

369 X X X

357 X

370 X X X 358 X

371 X X X 359 X

372 X 360 X

373 X X X 361 X X

374 X 362 X X

375 X X X 363 X TABLE 3a-contmued TABLE 3a-continued

364 226 X X X X X X X X X X

365 X X 227 X X X X X X X X X X

366 230 X X X X X X X X X X

367 X X 242 X X X X X X X X X X

368 245 X X X X X X X X X X

369 248 X X X X X X X X X X

370 251 X X X X X X X X X X

371 258 X X X X X X X X X X

372 260 X X X X X X X X X X

373 329 X X X X X X X X X X X

374 263 X

375 2 6 X X X X X X X X X

376

377 Rl

Rl 2 30 44 45 47 49 50 51

R2 2 3 9 10 11 14 15 23 378

379

378 X X 380

379 X X 381

380 X X 382

381 383

382 177

383 178

177 X X X X X X 179

178 X X X X X X X 264

179 X X X X X X X 189 X X X X

264 198 X X X X X X X

189 X X X X X X X 200 X X X X X X X

198 X X X X X X 202 X X X X X X X

200 X X X X 217 X X X X

202 X X X X X X 218 X X X X

217 X X X X X X X 219 X X X X

218 X X X X X X X 223 X X X X

219 X X X X X X X 224 X X X X

223 X X X X X X X 225 X X X X X X X

224 X X X X X X X 226 X X X X X X X

225 X X X X X X X 227 X X X X X X

226 X X X X X X X 230 X X X X X X X

227 X X X X X X X 242 X X X X X X X

230 X X X X X X X 245 X X X X X X

242 X X X X X X X 248 X X X X X X X

245 X X X X X X X 251 X X X X X X X

248 X X X X X X X 258 X X X X X X X

251 X X X X X X X 260 X X X X X X X

258 X X X X X X X 329 X X X X X X

260 X X X X X X X 263 X X X X X X X

329 236 X X X

263

236 X X X X X X X Rl

Rl R2 13 17 19 21 25 33 43 26 28 29

! 20 22 27 38 39 40 41 42 31 32 34 35 36 37 378

379

378 X X X 380

379 X X X 381

380 X X 382

381 X X 383

382 X 177 X X X X X 383 X X X 178 X X X X X X X X 177 X X X X X X X X X X 179 X X X X X X X 178 X X X X X X X 264

179 X X X X X 189 X X X X X X X X 264 X X X X X X X 198 X X X X X X X X 189 X X X X X X 200 X X

198 X X X X X X 202 X X X X X X X 200 X X X X X X 217 X X X X X X X 202 X X X X 218 X X X X X X X X 217 X X X X X 219 X X X X X X 218 X X X 223 X X X X X X X 219 X X X X X 224 X X X X X X X X 223 X X X X X 225 X X X X X X X X 224 X X X X X 226 X X X X X X X X 225 X X X X X X 227 X X X X X X X TABLE 3a-continued TABLE 3a-contiaoed

230 X X X X X X X X 210 X X X X X X X X X X X

242 X X X X X X X X 211 X X X X X X X X X X X X X

245 X X X X X X X X

248 X X X X X X X X Rl

251 X X X X X X X X

258 X X X X X X X R2 2 9 10 11 14 15 23 22 39 40 41 42

260 X X X X X X X X

329 212 X X X X X X X X X X X X

263 213 X X X X X X X X

236 X X X X X ^"X 214 X X X X X X X X X X X

215 X X X X X

l 216 X X X X X X X X X X X X

220 X X X X X X X X X X X X

R2 2 9 10 11 14 15 23 22 39 40 41 42 221 X X X X X X X X X X X X

222 X X X X X X X X X X

180 X X X X X X X X X X X 228 X X X X X X X X X X X X

181 X X X X X X X X X X X X 229 X X X X X X X

182 X X X X X X X X X X 231 X X X X X X X X X X X

183 X X X X X X X X X X X X 232 X X X X X X X X X X X X

184 X X X X X X X X X X X X 233 X X X X X X X X X X X X

185 X X X X X X 234 X X X X X X X X X X X X

186 X X X X X X X X 235 X X X X X X X X X X X

187 X X X X X X X X X X X X 237 X X X X X X X X X

188 X X X X X X X X X X X X 238 X X X X X X X X X X X X

190 X X X X X X X X X X X 239 X X X X X X X X X X X

191 X X X X X X X X X X X 240 X X X X X X X X X X X X

192 X X X X X X X X X X X X 241 X X X X X X X X X X X X

193 X X X X X X X X X X X 243 X X X X X X X X X X X X

194 X X X X X X X X X X X X 244 X X X X X X X X X X X X

195 X X X X X X X X X X X 246 X X X X X X X X X X

196 X X X X X X X X X X X X 247 X X X X X X X X X X X

197 X X X X X X X X X X X X 249 X X X X X X X X X X X X

199 X X X X X X X X X X X X 250 X X X X X X X X X X X X

201 X X X X X X :X 252 X X X X X X X X X X X

203 X X X X X X X X X X 253 X X X X X X X X

204 X X X X X X X X X X X X 254 X X X X X X X X X X X X

205 X X X X X X X X X X X X 255 X X X X X X X X X X X X

206 X X X X X X X X X X X 256 X X X X X X X X X X X X

207 X X X X X X X X X X X X 257 X X X X X X X X X X X X

208 X X X X X X X X X X X X 259 X X X X X X X X X X

209 X X X X X X X X 261 X X X X X X X X X X X X

210 X X X X X X X X X 262 X X X X X X X X X X X X

211 X X X X X X X X X X X X

Rl

R2 31 32 34 36 37 7 13 19 21 25 33 43 26 2 31 32 34 36 37 7 13 19 21 25 33 43 26

212 X X X X X X X X X X X

213 X X X X X X X X X X X X

180 X X X X X X X X X X X

214 X X X X X X X X X X X X

181 X X X X X X X X X X X X

215 X

182 X X X X X X X X X

216 X X X X X X X X X X X X

183 X X X X X X X X X X X X X 220 X X X X X X X X X X X X

184 X X X X X X X X X 221 X X X X X X X X X X X X

185 X X 222 X X X X X X X X X X

186 X X X X 228 X X X X X X X X X X X X X

187 X X X X X X X X X X X X X 229 X X X X X X

188 X X X X X X X X X X X X 231 X X X X X X X X X X

190 X X X X X X X X X X X 232 X X X X X X X X X X X X

191 X X X X X X X X X X X X X 233 X X X X X X X X X X X X

192 X X X X X X X X X X X X 234 X X X X X X X X X X X

193 X X X X X X X X X X X X X 235 X X X X X X X X X X X X

194 X X X X X X X X X X X X X 237 X X X X X X X X X X X X X

195 X X X X X X X X X X X X 238 X X X X X X X X X X X

239 X X X X X X X X X X X X

196 X X X X X X X X X X X

240 X X X X X X X X X X X

197 X X X X X X X X X X X X X

241 X X X X X X X X X X X X X

199 X X X X X X X X X X X X X

243 X X X X X X X X X X X X

201 X X X X X X X X X X X X X

244 X X X X X X X X X X X X

203 X X X X X X X X X X X X 246 X X X X X X X X X X X X X

204 X X X X X X X X X X X X X 247 X X X X X X X X X X X

205 X X X X X X X X X X X X 249 X X X X X X X X X X X X

206 X X X X X X X X X X X X X 250 X X X X X X X X X X X X X

207 X X X X X X X X X X X X 252 X X X X X X X X X X X X X

208 X X X X X X X X X X X X X 253 X X X X X X X X X X X

209 X X X X X X X X X X 254 X X X X X X X X X X X X X TABLE 3a-continued TABLE 3a-continued

255 X X X X X X X X X X X X X 288 X X X X X X X X X X X X

256 X X X X X X X X X X X X X 289 X X X X X X X X X X X

257 X X X X X X X X X X X X 290 X X X X X X X X X

259 X X X X X X X X X X X X X 2 1 X X X X X X X X X

261 X X X X X X X X X X X X X 292 X X X X X X X X X X X

262 X X X X X X X X X X X X 293 X X X X X X X X X X X X

294 X X X X X X X X X X X

Rl 295 X X X X X X X X X X X

296 X X X X X X X X X X 2 2 3 9 10 11 14 15 23 22 297 X X X X X X X X X X X

~» » 298 X X X X X X X X X X X X

265 299 X X X

266 X X X X X X X X 300 X X X X X X X X X X X

267 X X X X X X X X X 301 X X X X X X X X X X

268 X X X X X X X X X

269 X X X X X X X X Rl

270 X X X X X X X X X

271 X X X X X X X X R2 7 8 13 17 19 21 25 33 43 28 29

272 X X X X X X X X

273 X X X X X X X X 265

274 X X 266 X X X X X

275 X X X X X X X X 267 X X X X X X X X X X

276 X X X X X X X X 268 X X X X X X X X X X

277 X X X X X X X X 269 X X X X X X X X

278 X X X X X X X X X 270 X X X X X X X X X

279 X X X X X X X X X 271 X X X X X X X X

280 X X X X X X X X 272 X X X X X X X X

281 X X X X X X X X 273 X X X X X X X X

282 X X X X X X X X X 274 X X

283 X X X X X X X 275 X X X X X X X X X

284 X X X X X X X X X 276 X X X X X X X X

285 X X X X X X X X 277 X X X X X X X

286 X X X X 278 X X X X X X X X

287 X X X X X X 279 X X X X X X X

288 X X X X X X X X 280 X X X X X X X

289 X X X X X X 281 X X X X X X X

290 X X X X X X X 282 X X X X X X X X X X

291 X X X X X X 283 X X X X X X X

292 X X X X X X X X 284 X X X X X X X

293 X X X X X X X X 285 X X X X X X

294 X X X X X X 286 X X X X X X X

295 X X X X X X X X X 287 X X X X

296 X X X X X X X X 288 X X X X X X

297 X X X X X X X X X 289 X X X X X X X

298 X X X X X X X X 290 X X X X X X X

299 X X X X 291 X X X X X X

300 X X X X X X X 292 X X X X X X X

301 X X X X X X X X 293 X X X X X X X

294 X X X X X X X

Rl 295 X X X X X X X X

296 X X X X X X X X X

R2 38 39 40 41 42 31 32 34 35 36 37 30 297 X X X X X X X X X X

298 X X X X X X X X X

265 299 X X X X X X

266 X X X X X X X X 300 X X X X X X X

267 X X X X X X X X X X X X 301 X X X X X X

268 X X X X X X X X X X X X

269 X X X X X X X X X X X X Rl

270 X X X X X X X X X X X

271 X X X X X X X X X X R2 2 3 9 10 11 14 15 23 22

272 X X X X X X X X X X

273 X X X X X X X X X X X X 302 X X X X

274 X X 303 X X

275 X X X X X X X X X X X 304 X X X X X X X X X

276 X X X X X X X X X X X X 305 X X X X

277 X X X X X X X X X 306 X X X X X X

278 X X X X X X X X X X X 307 X X X X X X

279 X X X X X X X X X X X 308 X X X X

280 X X X X X X X X X 309 X X X X X X

281 X X X X X X X X X X X X 310 X X X X X X X X X

282 X X X X X X X X X X X X 311 X X X X X X

283 X X X X X X X X X X X 312 X X X X

284 X X X X X X X X X X X X 313 X X X

285 X X X X X X X X X 314 X X

286 X X X X X X 315

287 X X X X X X X 316 X X X X X X X X TABLE 3a-coritinued TABLE 3a-continued

317 X X X X X 319 X X X X X

318 X X X X X X X 320 X X X X X X

319 X X X X X 321 X X X X X X X X X

320 X X X X X X X 322 X X X X X X X X X X

321 X X X X X X X X X 323 X X X X X X X X

322 X X X X X X X X X 324 X X X X

323 X X X X X X X X X 325 X X

324 X X X X X 326 X X X X X

325 X X 327 X X X X X X

326 X X X X 328

327 X X X 330

328 X 331 X X

330 332 X X

331 X 333 X X

332 334

333 X

334 X X X X Rl

Rl R2 9 10 11 14 39

R2 38 39 40 41 42 31 32 34 35 36 37 3! 335 X

336 X X

302 X X X 337 X X X X

303 X X 338 X X X X X

304 X X X X X X X X X X X X 339 X X X X X

305 X X X X X X X X 340 X X X X

306 X X X X X X X X X X X 341 X X X X X

307 X X X X X X X 342 X X X X X

308 X X X X X X X X X X X X 343

309 X X X X X X X X X X 344 X X X

310 X X X X X X X X X X X X 345 X X

311 X X X X X X X X X 346 X X X X

312 X X X X X X X X X X 347 X X X X X

313 X X X X X X X X 348 X X X X X

314 X X X X X X X X 349 X X

315 350 X X X X

316 X X X X X X X X X X X X 351 X X X X

317 X X X X X X X X 352 X X X X

318 X X X X X X 353

319 X X X X X X X X X X 354

320 X X X X X X X X X X 355 X X X X

321 X X X X X X X X X X X 356 X X X X X

322 X X X X X X X X X X X 357 X

323 X X X X X X X X X X X 358 X X

324 X

325 Rl

343 X X X X X

302 X X X X 344 X X X X

303 X 345 X X X X X

304 X X X X X X X 346 X X X X X X

305 X X X X X 347 X X X X X X

306 X X X X X X X 348 X X X

307 X X X X 349 X X X X X

308 X X X X X X 350 X X X X X

309 X X X X X X X

351 X X X X X

310 X X X X X X X X

352 X X X X X X X 15 X X X X X

353 X X

X X X

354 X X

31 X X X X X

314 X X 355 X X X X X X X

315 X 356 X X X X X X

316 X X X X X X X 357 X X

317 X X X X X X X 358 X X X X

318 X X X X X TABLE 3a-continued TABLE 3a-continued

Rl 224 X X X X X X X

225 X X X X X X X

R2 30 U 14 39 226 X X X X X X X

227 X X X X X X X

359 X X X X X 230 X X X X X X X

360 X X X 242 X X X X X X X

361 X X X X 245 X X X X X X X

362 X X X X 248 X X X X X X X

363 X 251 X X X X X X X

364 X 258 X X X X X X X

365 X X X X 260 X X X X X X X

366 X X 329

367 X X X 263

368 236 X X X X X X X

369 X X X X

370 X X X X Rl

371 X X X X

372 X X R2 22 27 38 39 40 41 42 31 I 32 34 35 .

373 X X X X

374 X X 177 X X X X X X X X X

375 X X X X 178 X X X X X X

376 X X X 179 X X X X X

377 X X 264 X X X X X X X X X X

378 X X X 189 X X X X X X X X X

379 X X X 198 X X X X X X X X X

380 X X 200 X X X X X X X X X

381 202 X X X X X X X X X

382 217 X X X X X X X X X

383 218 X X X X X X X X X

219 X X X X X X X X X

Rl 223 X X X X X X X X X

224 X X X X X X X X X 2 40 42 31 34 35 30 29 225 X X X X X X X X X

226 X X X X X X X X X

359 X X X X X X X 227 X X X X X X X X X

360 X X 230 X X X X X X X X X

361 X X X X X X 242 X X X X X X X X X

362 X X X X X 245 X X X X X X X X X

363 X X 248 X X X X X X X X X

364 251 X X X X X X X X X

365 X X X 258 X X X X X X X X X

366 X 260 X X X X X X X X X

367 X X X 329 X X X X X X X X X X X

368 X 263

369 X X X 236 X X X X X X X X X

370 X X X

371 X X X Rl

372 X X X

373 X X X

HI 44 45 47 49 50 51 52

374 X X X

375 X X X

177

376 X

178

377 X X X

378 X X X 179

379 X X X 264

380 X X 189 X X X X

381 X X 198 X X X X X X X

382 X 200 X X X X X X X

383 X X X 202 X X X X X 5£ X

217 X X X X

Rl IZ 218 X X X X

219 X X X X

R2 2 9 10 11 14 15 23 20 223 X X X X

224 X X X X

177 X X X X X X X

225 X X X X X X X

178 X X X X X X X X 226 X X X X X X X

179 X X X X X X X X

227 X X X X X X

264

230 X X X X X X X

189 X X X X X X X

242 X X X X X X X

198 X X X X X X X

245 X X X X X X

200 X X X X

202 X X X X X X 248 X X X X X X X

217 X X X X X X X 251 X X X X X X X

218 X X X X X X X 258 X X X X X X X

219 X X X X X X X 260 X X X X X X X

223 X X X X X X X 329 X X X X X X TABLE 3a-continued

263 X X X X X X

236 X X X

...51._™

R2 7 13 19 21 25 33 43 26

177 X X X X X

178 X X X X X X X X

179 X X X X X X X

264

189 X X X X X X X X

198 X X X X X X X X

200 X X

202 X X X X X X X

217 X X X X X X X

218 X X X X X X X X

219 X X X X X X

223 X X X X X X X

224 X X X X X X X X

225 X X X X X X X X

226 X X X X X X X X

227 X X X X X X X

230 X X X X X X X X

242 X X X X X X X X

245 X X X X X X X X

248 X X X X X X X X

251 X X X X X X X X

258 X X X X X X X X

260 X X X X X X X X

329

263

236 X X X X X X

Rl

R2 22 44 45 47 49 50 51 52

384 X X X X X X X

385 X X X X X X X

386 X X X X X X X

387 X X X X X X X

388 X X X X X X X

389 X X X X X X X

390 X X X X X X X

391 X X X X X X X

392 X X X X X X X

393 X X X X X X X

394 X X X X X X

395 X X X X X X X

396 X X X X X X X

397 X X X X X X X

398 X X X X X X X

399 X X X X X X X

400 X X X X X X X

401 X X X X X X X

402 X X X X X X X

403 X X X X X X X

404 X X X X X X X

405 X X X X X X X

406 X X X X X X X

407 X X X X X X X

408 X X X X X X X

409 X X X X X X X

410 X X X X X X X

411 X X X X X X X

412 X X X X X X X

413 X X X X X X X

414 X X X X X X X

415 X X X X X X X

416 X X X X X X X

417 X X X X X X X

418 X X X X X

419 X X X X X X X

420 X X X X X X

421 X X X X X X TABLE 3a-continued

422 X X X X X

423 X X X X X

424 X X X X X

425 X X X X X

426 X X X X X

427 X X X X X

428 X X X X X

429 X X X X X

430 X X X X X

431 X X X X X

432 X X X X X

434 X X X X

437 X X X X

433 X X X

435 X X X

436 X X X

438 X X X

Table 3b

Table 3b is directed to compounds of the formula (IB):

1 1

wherein R and R are as defined in Table 3b.

An "X" in the box formed by the intersection of the R and the R row represents an R and R¹ combination of a compound of formula IB that is included in the definition of the compounds of formula I useful in the methods of this invention. For example, compounds of formula IB wherein R² is moiety 3 (see Table 2 for definition) and R¹ is moiety 45 (see Table 1 for definition) are included in the definition of formula I (there is an "X" in the box formed by the intersection of the R² column and the R¹ row).

If there is no "X" in the box, then that compound is not within the definition of the compounds of formula I. For example, compounds of formula IB wherein moiety R is 3 and moiety R is 44 (no "X" in the box formed by the intersection of the R column and the R¹ row) are not within the definition of the compounds of formula I.

TABLE 3b

Rl

R2 45 46 47 48 49 50 51 52

3 X X X X X X X X

5 X X X X X X X X

16 X X X X X X X

20 X X X X X X X X

22 X X X X X X X X

30 X X X X X X X X

35 X X X X X X X

44 X X X X X X X TABLE 3b-continued TABLE 3b-conlimied

R.1 R :

45 46 47 48 49 50 51 52 R2 45 46 47 48 49 50 51 44

X X X X X X X X 410 X X X X X X .X X

X X X X X X X X 411 X X X X X X X X

X X X X X X X X 412 X X X X X X X X

X X X X X X X X 413 X X X X X X X X

X X X X X X X X 414 X X X X X X X X

X X X X X X X X 415 X X X X X X X X

X X X X X X X X 416 X X X X X X X X

X X X X X X X 417 X X X X X X X X

X X X X X X X X 418 X X X X X X X X

X X X X X X X X 419 X X X X X X X X

X X X 420 X X X X X X X

X X X X X X X X 421 X X X X X X X X

X X X X X X X X 422 X X X X X X X X

X X X X X X X X 423 X X X X X X X X

X X X X X X X X 424 X X X X X X X X

X X X X X X X X 425 X X X X X X X

X X X X X X X X 426 X X X X X X X X

X X X X X X X 427 X X X X X X X X

X X X X X X X X 428 X X X X X X X X

X X X X X X X X 429 X X X X X X X X

X X X X X X X X 430 X X X X X X X X

X X X X X X X 431 X X X X X X X X

X X X X X X X X 432 X X X X X X X

X X X X X X X X 433 X X X X X X

X X X X X X X X 434 X X X X X X X X

X X X X X X X X 435 X X X X X X X

X X X X X X X X 436 X X X X X

X X X X X X X X 437 X X X X X X

X X X X X X 438 X X X X X

X X X X X X X 469 X X X X X X X X

X X X X X X 470 X X X X X X X

X X X X X X X 471 X X X X X X X X

X X X X X X X 472 X X X X X X X

X X X X X X X X 473 X X X X X X X

X X X X X X X X 474 X X X X X X X X

X X X X X X X X 475 X X X X X

X X X X X X X X 476 X X X X X X X X

X X X X X X X 477 X X X X X X X X

X X X X X X X X 478 X X X X X X X X

X X X X X X X 479 X X X X X X X X

X X X X X X X 480 X X X X X X X X

X X X X X X X X 481 X X X X X X X X

X X X X X X X X 482 X X X X X X X X

X X X X X X X X 483 X X X X X X X X

X X X X X X X X 484 X X X X X X X X

X X X X X X X X

485 X X X X X X X

X X X X X X X X

486 X X X X X X X X

X X X X X X X X

X X X X X X X X 487 X X X X X X X X

X X X X X X X 488 X X X

X X X X X X X X 489 X X X X X X X X

X X X X X X X 490 X X X X X X X X

X X X X X X X X 491 X X X X X X X X

X X X X X X X X 492 X X X X X X X X

X X X X X X X X 493 X X X X X X

X X X X X X X X 494 X X X X X X X X

X X X X X X X 495 X X X X X X X

X X X X X X X X 496 X X X X X X X

X X X X X X X X 497 X X X X X X X X

X X X X X X X X 498 X X X X X X

X X X X X X X X 500 X X X X X X X X

X X X X X X X X 501 X X X X X X X X

X X X X X X X X

502 X X X X X X X X

X X X X X X X X

503 X X X X X X X X

X X X X X X X X

504 X X X X X X X X

X X X X X X X

X X X X X X 505 X X X X X X

X X

X X X X X X X X 506 X X X X X X X X

X X X X X X X 507 X X X X X X X X

X X X X X X X X 508 X X X X X X X X

X X X X X X X X 509 X X X X X X X X

X X X X X X X X 510 X X X X X X X X TABLE 3b-continued

Rl

R2 45 46 47 4 ^■8 49 50 51 52 44

511 X X X X X X X

512 X X X X X X X X

513 X X X X X X X X

514 X X X X X X X X

515 X X X X X X X X

516 X X X X X X X X

517 X X X X X X X X

518 X X X X X X X

519 X X X X X X X X

520 X X X X X X X X

521 X X X X X X

522 X X X X X

523 X X X X X

524 X X X X X X X

525 X X X X X X X X

526 X X X X X X X X

527 X X X X X X X X

528 X X X X X X X X

529 X X X X X X X

530 X X X X X X X X

531 X X X X X X X

532 X X X X X X X

533 X X X X X X X

534 X X X X X X

535 X X X X X

536 X X X X X X

Table 3 c

Table 3c is directed to compounds of the formula (IC):

wherein R¹ and R² are as defined in Table 3c.

An "X^" the box formed by the intersection of the R and the R row represents R and R. combination of a compound of formula IC that is included in the definition of the compounds of formula I useful in the methods of this invention. For example, compounds of formula IC wherein R² is moiety 3 (see Table 2 for definition) and R¹ is moiety 44 (see Table 1 for defmition) are included in the definition of formula I (there is an "X" in the box formed by the intersection of the R" column and the R row).

If there is no "X" in the box, then that compound is excluded from the defmition of the compound of formula I For example, compounds of formula IC wherein moiety R is 3 and moiety R¹ is 50 (no "X" in the box formed by the intersection of the R² column and the R¹ row) are excluded from the defmition of the compounds of formula I. TABLE 3c-contmued

TABLE 3c

Rl

R2 44 46 47 51

44 46 47 51

402 X X X X

X X X X 403 X X X X

X X X X 404 X X X X

X X X X 405 X X X X

X X X X 406 X X X X

X X X X 407 X X X X

X X X X 40S X X X X

X X X X 409 X X X X

X X X X 410 X X X X

X X X X 411 X X X X

X X X X 412 X X X X

X X X X 413 X X X X

X X X X 414 X X

X X X X 415 X X X X

X X X X 4! 6 X X X X

X X X X 417 X X X X

X X 4!8 X X

X X X 19 X X X X

X X X 42G X X X X

X X 421 X X X X

X X X X 422 X X X X

X X X X 4/3 X X X X

X X X X 424 X X X X

X X X X 425 X X X X

X X X X 426 X X X

X X X X 427 X X X X

X X X X 428 X X X X

X X X X 42S X X X X

X X X X 430 X X X

X X X X 431 X X X X

X X X X 432 X X X X

X X X X 433 X X

X X X X 434 X X X X

X X X X X 435 X X

X X X X 436 X X

X X X X 437 X X X X

X X X X 438 X X

X X X X 469 X X X

X X X X 470 X X X X

X X X X 471 X X X X

X X X X 472 X X X X

X X X X 473 X X X X

X X X X 474 X X X X

X X X X 475 X X X X

X X X X 476 X X X

X X X X 477 X X X X

X X X X X 478 X X X X

X X X X 479 X X X X

X X X 4S0 X X X X

X X X X 481 X X X

X X X X 482 X X X X

X X X X 483 X X X X

X X X X 484 X X X X

X X X X 4SS X X X X

X X X X 486 X X X X

X X X X 4S7 X

X X X X 488 X

X X X X 489 X X X X

X X X X 490 X X X X

X X X X 491 X X X

X X X X 492 X X X X

X X X X 493 X X X X

X X X X 494 X X X X

X X X X 495 X X X X

X X X X 496 X X X

X X X 497 X X X

X X X X 498 X X X

X X X X 500 X X X X

X X X X 501 X X X X

X X X X 502 X X X X

X X X X 503 X X X X

X X X X 504 X X X X

X X X X TABLE 3c-continued

Rl_,

R2 44 46 47

505 X X X X X

506 X X X X X

507 X X X X X

508 X X X X X

509 X X X X X

510 X X X X X

511 X X X X X

512 X X X X X

513 X X X X X

514 X X X X X

515 X X X X X

516 X X X X X

517 X X X X X

518 X X X X X

519 X X X X X

520 X X X X X

521 X X X X X

522 X X X X X

523 X X X X X

524 X X X X X

525 X X X X X

526 X X X X X

527 X X X X X

52S X X X X X

529 X X X X X

530 X X X X

531 X X X X

532 X X X

533 X X X X

534 X. X X X X

535 X X X

536 X X X X

Table 3d

Table 3d is directed to compounds of the formula (ID):

wherein R¹ and R² are as defined in Table 3d.

An "X" in the box formed by the intersection of the R² and the R¹ row represents an R² and R¹ combination of a compound of formula ID that is included in the definition of the compounds of formula I useful in the methods of this invention. For example, compounds of formula ID wherein R² is moiety 3 (see Table 2 for definition) and R¹ is moiety 46 (see Table 1 for definition) are included in the definition of formula 1 (there is an "X" in the box formed by the intersection of the R² column and then that compound is excluded from the definition the R¹ row).

If there is no "X" in the box, then that compound is excluded from the definition of the compounds of formula I. For example, compounds of formula ID wherein moiety R is 83 and moiety R¹ is 46 (no "X" in the box formed by the intersection of the R² column and the R¹ row) are excluded from the definition of the compounds of formula I. TABLE 3d TABLE 3d-continued

Rl Rl

46 48 R2 46 48

X X 398 X X

X X 399 X X

X X 400 X X

X X 401 X X

402 X X

X X

403 X X

X X

404 X X

X X

405 X X

X X 406 X X

X X 407 X X

X X 408 X X

X X 409 X X

X X 410 X X

X X 411 X X

X X 412 X X

X X 413 X X

X 414 X X

X X 415 X X

X 416 X X

X 417 X X

X X 418 X X

X X 419 X X

X X 420 X X

X X 421 X

X X 422 X X

X X 423 X X

424 X X

X X

425 X X

X X

426 X X

X X 427 X X

X X 428 X X

X X 429 X X

X X 430 X X

X X 431 X X

X X 432 X X

X X 433 X

X X 434 X X

X X 435 X

X X 436 X

X X 437 X X

X 438 X

X X 469 X X

X X 470 X X

X X 471 X X

X X 472 X X

X X 473 X

X X 474 X X

X X 475 X

476 X X

X X

477 X X

X

478 X X

X X

479 X X

X X 480 X X

X X 481 X X

X X 482 X X

X X 483 X X

X X 484 X X

X X 485 X X

X X 486 X X

X X 487 X

X X 489 X X

X X 490 X X

X X 491 X X

X X 492 X X

X X 493 X X

X X 494 X

X X 495 X X

X X 496 X X

X X 497 X

X X 498 X

500 X X

X X

501 X X TABLE 3d-contimied

i

R2 46 48

502 X X

503 X X

504 X X

505 X X

506 X X

507 X X

508 X X

50P X X

510 X X

511 X X

512 X X

513 X X

514 X X

515 X X

516 X X

517 X X

518 X X

519 X X

520 X X

521 X X

522 X X

523 X X

524 X X

525 X X

526 X X

527 X X

528 X X

529 X X

530 X X

531 X X

532 X X

533 X X

534 X X

535 X

536 X

Table 4a

Table 4a is directed to compounds of the formula (IE):

Wherein R¹ is as defined in Tabic 4a.

The compounds defined by Table 4a are included in the definition of the compounds of formula I useful in the methods of this invention. TABLE 4a TABLE 4a-continued

Rl Rl

22

25

[0110] In another embodiment, the compound is disclosed in U.S. Patent No. 7,884,080:

and pharmaceutically acceptable salts, solvates, esters, prodrugs or stereoisomers thereof, wherein:

R* is H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, diphenylmethyl, cycloalkylalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or -alkylene-C(0)N(alkyl)₂, wherein an alkyl aryl or heteroaryl group can be optionally and independently substituted with one or more of the following groups: — (C=N— 0-alkyl)CH₃, — NC(0)NH₂, — NC(0)NH(alkyl),— NC(0)N(alkyl)₂,— S0₂NH₂,— S0₂NH₂,— S0₂NH(alkyl),— S0₂N(alkyl)₂, — CF₃,—OH, -halo,— CN, -alkoxy,— CO(0)-alkyl,— S(0)alkyl,— S0₂-alkyl, or -P(0)(0- alkyl)₂, and an aryl group may further be optionally and independently substituted with one or more alkyl groups;

R² is H, alkyl, cycloalkyl, aryl, arylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, R⁶-A-, alkyl-O— C(0>— , (alkyl)₂N-alkylene-C(0)— , (alkyl)₂-N— C(0 aikylene-C(O)— , CN-alkylene-C(O)— , alkyl-O-alkylene-C(O)— , alkyl-C(0)-alkylene-C(0)— , alkyl-C(OHNH-alkylene-C(0)— , alkyl-NH— C(O)— , aryl-NH— C(O)— , alkyl-O— C(0> alkylene-C(O)— , alkyl-O— C(0)-cycloalkylene-alkylene-, N¾— C(O)— NH-alkylene-C(O)— , NH₂— C(0)-alkylene-C(0)— , alkyl-C(O)— NH-alkylene-S-alkylene-C(O)— , alkyl-O— C(O)- alkylene-C(O)— , alkyl-S-alkylene-C(O)— , alkyl-C(0)-cycloalkylene-alkylene-C(0)— , alkyl-S- alkylene-, (— NHC(0)alkyl)-C(0)— , alkyl(-C(0)Oalkyl)-NH— C(O)— , or — C(0)-alkylene- N(R⁶)₂— ; or alkyl-S-alkylene(-NHC(0)alkyl)-C(0)— , wherein an alkyl or aryl group can be optionally and independently substituted with one or more of the following groups:— (C=N— O- alkyl)CH₃,— NH— C(0)NH-alkyl,— C(0)NH₂,— CN,— C(0)NH-alkyl, — C(0)0-alkyl,— C(0)H, — C(0)OH, — NC(0)NH₂, — NC(0)NH(alkyl), — NC(0)N(alkyl)₂, — S0₂NH₂, — S0₂NH(alkyl),— S0₂N(alkyl)₂,— CF₃,—OH, -halo, haloalkyl,— CN, -alkoxy,— C(0)0-alkyl, — S(0)alkyl,— S0₂-alkyl, or— P(0)(0-alkyl)₂, and an aryl group may further be optionally and independently substituted with one or more alkyl groups;

R³ is H, alkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, NH-arylalkyl, arylalkoxy, arylthio, arylalkylthio, arylcarbonyl, aryloxy, cycloalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkoxy, heteroaryloxy or heteroarylsulfonyl, wherein an alkyl or aryl group can be optionally and independently substituted with one or more of the following groups: — (C=N— 0-alkyl)CH₃, — NC(0)NH₂, — NC(0)NH(alkyl), — NC(0)N(alkyl)₂, — S0₂NH₂, — S0₂NH(alkyl), — S0₂N(alkyl)₂, — CF₃, —OH, -halo, — CN, -alkoxy,— C(0)0-alkyl,— S(0)alkyl,— S0₂-alkyl, or— P(0)(0-alkyl)₂, an aryl group can be optionally and independently substituted with one or more alkyl groups, and a heteroaryl group can be optionally and independently substituted with one or more aryl or heteroaryl groups.

each occurrence of R⁴ and R⁵ is independently— C(R⁷)₂— , wherein the ring carbon atom of one R⁴ group and the ring carbon atom of one R⁵ group may optionally be joined by a— CH₂— CH₂— group;

each occurrence of R⁶ is independently alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, benzofused cycloalkyl, benzofused heterocycloalkyl, or benzofused heterocycloalkenyl;

each occurrence of R⁷ is independently— H, -alkyl,— CN, or— OH;

A is— C(0>— ,— OC(0>— , -alkylene-C(O)— ,— O-alkylene-C(O)— ,— C(0)-alkylene-C(0)— , — C(O)— NHCH₂— C(O)— , — C(O)— N(alkyl)-CH₂— C(O)— , -alkylene-, alkenylene-, -alkenylene-C(O)— , —0— C(0)-alkylene^C(0), -cycloalkylene-NH— C(O)— , NHC(O , -alkylene-NHC(O)— , - alkylene-C(0)NH-alkylene-C(0)— , -alkylene-C(0)NH-alkylene-C(0)— , — C(0)—NH- alkylene-C(O)— , -alkylene-O-alkylene-C(O)— , -alkylene(alkoxy)-C(0)~- or — S-alkylene- C(O)— , wherein an A group is joined to the nitrogen atom to which it is attached via a terminal C(O) group;

u is an integer ranging from 0 to 3; and

v is an integer ranging from 0 to 3; such that the sum of u and V is from 3 to 5,

such that the compound of formula (I) is not a compound of formula (IA), (IB), (IC) or (ID) as set forth below:

wherein R¹ and R² are denoted using an "X" as set forth below in Table 1 , and defined below in Tables 5 and 6, respectively.

TABLE 1

n

»

«

« TABLE 1 -continued TABLE 1 -continued

Rl Ri

5

1 2 3 4 5 6 8 9 10 11 7 12 R2 1 2 3 4 5 6 8 9 10 11 7 12

X X X X X X X X 167 X X X X X X X X

X X X X X X X 168 X X X X X X X X

X X X X X X X 169 X X X X X X X X

X X X X X X X X 170 X X X X X X X X

X X X X X X X X X X X X 171 X X X X X X X

X X X X X X X X 172 X X X X X X X X X X X X

X X X X X X 173 X X X X X X X X

X X X X X X X X X X X 174 X X X X X X X

X X X X X X X X X X X X 175 X X X X X X X

X X X X X X X 176 X X X X X X X X

X X X X X X X X 15 177 X X X X X X X X X X X X

X X X X X X X 178 X X X X X X X

X X X X X X X X 179 X X X X X X X X X X X X

X X X X X X X X 180 X X X X X X X X

X X X X X X X X 181 X X X X X X X X X X X

X X X X X X X X X X X X 182 X X X X X X X X X X X X

X X X X X X X X 183 X X X X X X X X X X X

20

X X X X X X X X 184 X X X X X X X X X X X X

X X X X X X X X 185 X X X X X X X

X X X X X X X X X X X X 186 X X X X X X X X X X X X

X X X X X X X X X X X X 187 X X X X X X X

X X X X X X X X 188 X X X X X X X X X X X X

X X X X X X X X 189 X X X X X X X X X X X X

X X X X X X X X 190 X X X X X X X X X X X X

X X X X X X X X X X X X 191 X X X X X X X X X X X X

X X X X X X X X 192 X X X X X X X X X X X X

X X X X X X X X 193 X X X X X X X X

X X X X X X X X 194 X X X X X X X X X X X X

X X X X X X X X X X X X 195 X X X X X X X X X X

X X X X X X X X 196 X X X X X X X X X X X

X X X X X X X X 197 X X X X X X X X X X X X

X X X X X X X X 198 X X X X X X X

X X X X X X X X 199 X X X X X X X X X

X X X X X X X X 200 X X X X X X X X X X X

X X X X X X X X 201 X X X X X X X X X X X X

X X X X X X X X 202 X X X X X X X X X X X X

X X X X X X X X 203 X X X X X X X X X X X X

X X X X X X X X 204 X X X X X X X X X X X X

X X X X X X X X 205 X X X X X X

X X X X X X X X 206 X X X X X X

X X X X X X X X 207 X X X X X X

X X X X X X X X X X 208 X X X X X X X X

40

X X X X X X X X X X X 209 X X X X X

X X X X X X X X X X X 213 X X X X X

X X X X X X X 214 X X X X X X X

X X X X X X X X X X X X 210 X X X X X X X X X X

X X X X X X X X X X 211 X X X X X

X X X X X X 215 X X X X X X X X

X X X X X X X 216 X X X X X X X X

X X X X X X X 212 X X

X X X X X X X X 217 X X X X X X X X X X X

X X X X X X X X X X X X 218 X X X X X X X X X X X

X X X X X X X X 219 X X X X X X X X X X X X

X X X X X X X X 220 X X X X X X X X X

X X X X X X X X X X X X 221 X X X X X X X X X X X

X X X X X X X X X X X X 222 X X X X X X X X X X X

X X X X X X X X X X X 223 X X X X X

X X X X X X X 224 X X X X X

X X X X X X X X X X X X 225 X X X X

X X X X X X X X 233 X X

X X X X X X X X 55 227 X X X X X X X X

X X X X X X X X X X X X 228 X X X X X X X

X X X X X X X X X X X X 230 X X X X X X X

X X X X X X X X 232 X X X X X X

X X X X X X X X 229 X X X X X X

X X X X X X X X 231 X X X X X

X X X X X X X 234 X X X X X X

60

X X X X X X X 226 X X X X X X X

X X X X X X X X 235 X

X X X X X X X X 236 X X X X

X X X X X X X X 237 X X X X

X X X X X X X X X X X X 238 X X X X

X X X X X X X X 239 X X X X

X X X X X X X X 240 X X X X

X X X X X X X X 242 X X X X TABLE 1 -continued TABLE 1 -continued

406

40"

{IB} TABLE 5

wherein Z represents the point of a ttachment of the R group to the nitrogen atom to which it is attached; and R² in Tables 1-4 is defined in Table 6 below: 

143

147

148

151

ı53

ı55

TABLE 6-continued

2

and wherein Z represents the point of attachment of the R group to the nitorgen atom to which it is attached.

In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No. 2008/0076750:

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

R¹ and R² are defined in Tables 1-6 herein, and

R³ is -phenyl, -4-chlorophenyl, -2-pyridyl, or -3-pyridyl.

TABLE 1

R2 1 3 4 5 6 8 9 10 .1 7 12

1. X X. X X X X Xi. X X X.

V A v A. V ^'V V

Λ Λ A Λ Λ ^' ΛV

3 X X X X X X X X

4 X X X X X X X X X X X

5 X X X X X X

6 X X X X X X X X X X X X

7 X X X X X X

S X X X X X X X X.

9 X X X X X

10 X X X X X X X X

11 X X X X X X X X

12 X X X X X X X X

13 X X X X X

14 X X X X X X X

15 X X X X X X X X

16 X X x X X X X X

17 X X X X X X X

18 X X X X X X X X.

19 X X X X X .X X X

20 X X X X X X X X

2 X X X X X X X

X X X X X X X X X X X TABLE 1 -continued

Rl

2 1 2 3 4 5 6 8 9 10 11 7 12

23 X X X X X X X X

24 X X X X X X X X

25 X X X X X X X X

28 X X X X X X X X X X X X

27 X X X X X X X X

28 X X X X X X X X X X X X

29 X X X X X X X X

30 X X X X X X X X X

31 X X X X X X X X

32 X X X X X X X

33 X X X X X X X

34 X X X X X X X X

35 X X X X X X X X X X X

36 X X X X X X X X

37 X X X X X X X

38 X X X X X X X X X X X X

39 X X X X X X X X

40 X X X X. X X X X

41 X X X X X X X. X

42 X X X X X X X

43 X X X X X X X X X

44 X X X X X X X

45 X X X X X X X X

46 X X X X X X X X

47 X X X X X X X X

48 X X X X X X X

49 X X X X X X X

50 X X X X X X

51 X X X X X X. X

52 X X X X" X X X X X X X X

53 X X X X X X X X

54 X X X X X X

55 X X X X X X X X X X

56 X X X X X X X X X X X X

57 X X X X X X X

58 X X X X X X X

59 X X X X X X

60 X X X X X X X X

6.1 X X X X X X X

62 X X X X X X X X

63 X X X X X X X X X X X X

64 X X X X X X X X

65 X X X X X X X X

66 X X X X X X X X

67 X X X X X X X X X X X

68 X X X X X X X X X X X X

69 X X X X X X X

70 X X X X X X X X

71 X X X X X X X X

72 X X X X X X X X X X X

73 X' X X X X X X X

74 X X X X X X X X

75 X X X X X X X X

76 X X X ^'X X X X X X X X X

77 X X X. X X X X X

78 X X X X X X X X

79 X X X X X X X X

80 X X X X X X X X

81 X X X X X X X X

82 X X X X X X X X

S3 X X X X X X X X

84 X X X X X X X X

85 X X X X X X X X

86 X X X X X X X X

87 X X X X X X X

88 X X X X X X X X

33 X X X X X X X X X X34 X X X X X X X X X X X35 X X X X X X X X X X36 X X X X X X X

37 X X X X X X X. X X X X X38 X X X X X X X X X TABLE 1 -continued TABLE 1 -continued

Ri _¾

R2 1 2 3 4 5 6 8 9 10 11 7 12 R2 1 2 3 4 5 6 8 9 10 11 7 12

139 X X X X X X 214 X X X X X X X

140 X X X X X X X 210 X X X X X X X X X X

141 X X X X X X X 211 X X X X X

142 X X X X X X X X 215 X X X X X X X X

143 X X X X X X X X X X X X 216 X X X X X X X X

144 X X X X X X X X 212 X X

145 X X X X X X X X 217 X X X X X X X X X X X

146 X X X X X X X X X X X X 218 X X X X X X X X X X X

147 X X X X X X X X X X X X 219 X X X X X X X X X X X X

148 X X X X X X X X X X X 220 X X X X X X X X X

149 X X X X X X X 221 X X X X X X X X X X X

150 X X X X X X X X X X X X 222 X X X X X X X X X X X

151 X X X X X X X X 223 X X X X X

152 X X X X X X X X 224 X X X X X

153 X X X X X X X X X X X X 225 X X X X

154 X X X X X X X X X X X X 233 X X

155 X X X X X X X X 227 X X X X X X X X

156 X X X X X X X X 228 X X X X X X X

157 X X X X X X X X 230 X X X X X X X

158 X X X X X X X 232 X X X X X X

159 X X X X X X X 229 X X X X X X

160 X X X X X X X X 231 X X X X X

161 X X X X X X X X 234 X X X X X X

162 X X X X X X X X 226 X X X X X X X

163 X X X X X X X X X X X X 235 X

164 X X X X X X X 236 X X X X

165 X X X X X X X X 237 X X X X

166 X X X X X X X X 238 X X X X

167 X X X X X X X X 239 X X X X

168 X X X X X X X X 240 X X X X

169 X X X X X X X X 242 X X X

170 X X X X X X X X 243 X X X X

171 X X X X X X X 244 X X X X

172 X X X X X X X X X X X X 245 X X X X

173 X X X X X X X X 246 X X X X

174 X X X X X X X 247 X X X X

175 X X X X X X X 248 X X X X

176 X X X X X X X X 249 X X X X

177 X X X X X X X X X X X X 250 X X X X

178 X X X X X X X 299 X X X X

179 X X X X X X X X X X X X 251 X X X X

180 X X X X X X X X 300 X X X

181 X X X X X X X X X X X 252 X X X X

182 X X X X X X X X X X X X 253 X X X X

183 X X X X X X X X X X X 254 X X X X

184 X X X X X X X X X X X X 255 X X X X

185 X X X X X X X 256 X X X X

186 X X X X X X X X X X X X 257 X X X X

187 X X X X X X X 258 X X X X

188 X X X X X X X X X X X X 259 X X X X

189 X X X X X X X X X X X X 260 X X X X

190 X X X X X X X X X X X X 261 X X X X

191 X X X X X X X X X X X X 262 X X X X

192 X X X X X X X X X X X X 263 X X X X

193 X X X X X X X X 264 X X X X

194 X X X X X X X X X X X X 265 X X X X

195 X X X X X X X X X X 266 X X X X

196 X X X X X X X X X X X 267 X X X X

197 X X X X X X X X X X X X 268 X X X X

198 X X X X X X X 269 X X X X

199 X X X X X X X X X 270 X X X X

200 X X X X X X X X X X X 271 X X X X

201 X X X X X X X X X X X X 272 X X X X

202 X X X X X X X X X X X X 273 X X X X

203 X X X X X X X X X X X X 274 X X X

204 X X X X X X X X X X X X 276 X X X X

205 X X X X X X 277 X X X X

206 X X X X X X 278 X X X X

207 X X X X X X 279 X X X X

208 X X X X X X X X 280 X X X X

209 X X X X X 281 X X X X

213 X X X X X 282 X X X X TABLE 1 -continued TABLE 1 -continued

11. 8.1

R2 1 2 3 4 5 6 8 9 10 11 7 12 2 1 2 3 4 5 6 8 9 10 11 7 12

283 X X X X 383 X X X X X X X X X X X X

28S X X X X 384 X X X X X X X X X X X X

286 X X X X 385 X X X X X X X X X X X X

287 X X X X 386 X X X X X X X X X X X X

28B X X X X 387 X X X X X X X X X X X X

289 X X X X 388 X X X X X X X X X X X X

290 X X X X 389 X X X X X X X X X X X X

291 X X X X 390 X X X X X X X X X X X X

292 X X X X 391 X X X X X X X X X X X X

293 X X X X 392 X X X X X X X X X X X X

294 X X X X

393 X X X X X X X X X X X

295 X X X X

394 X X X X X X X X X X X X

296 X X X X

395 X X X X X X X X X X X

297 X X X X

396 X X X X X X X X X X X

298 X X X X

397 X X X X X X X X X X X X

241 X X X

X X

303 X X X 398 X X X X X X X X X X

399 X X X X X X X X X X X X

284 X X X

X X 400 X X X X X X X X X X X X

301

X X 401 X X X X X X X X X X X X

275

302 X X 402 X X X X X X X X X X X X

304 X X 403 X X X X X X X X X X X X

305 X X 404 X X X X X X X X X X X X

334 X X X X X 405 X X X X X X X X X X X X

360 X X X X 406 X X X X X X X X X X X

335 X X X X X 407 X X X X X X X X X X X X

336 X X X X X

337 X X X X X

338 X X X X X

339 X X X X

340 X X X X X

341 X X X X X

342 X X X X X

343 X X X X X

344 X X X X X

345 X X X X X

346 X X X X

347 X X X X X

348 X X X X X

349 X X X X X

350 X X X X X

351 X X X X X

352 X X X X X

3 3 X X X X X

354 X X X X X

355 X X X X X

356 X X X X

361 X X X X

362 X X X X

357 X X X X X

358 X X X X X

359 X X X X X

363 X X X

364 X X X X X X X X X X X X

365 X X X X X X X X X X X X

366 X X X X X X X X X X X X

367 X X X X X X X X X X X X

368 X X X X X X X X X X X X

369 X X X X X X X X X X X X

370 X X X X X X X X X X X X

371 X X X X X X X X X X X X

372 X X X X X X X X X X X X

373 X X X X X X X X X X X X

374 X X X X X X X X X X X X

375 X X X X X X X X X X X

376 X X X X X X X X X X X X

377 X X X X X X X X X X X

378 X X X X X X X X X X X X

379 X X X X X X X X X X X X

380 X X X X X X X X X X X X

381 X X X X X X X X X X X X

382 X X X X X X X X X X wherein R is defined below in Table 5: 161

162

ı63

ı64

165

ı66



168



171

ı73

ı75

176

TABLE 6-continued TABLE 6-continued

and wherein Z represents the bond from R² to the nitorgen atom to which it is attached. In another aspect, the present invention relates to methods for treating or preventing a Condition in a patient, comprising administering to the patient an effective amount of a compound having the formula (IB):

X X X X X X X X X X 60 X X X X X X X

X X X X X X X 61 X X X X X X X

X X X X X X X 62 X X X X X X X

X X X X X X X 63 X X X X X X X X X X X

X 64 X X X X X X X

X X X X

65 X X X X X X X

X X X X X X X X X X

66 X X X X X X X

X X X X X X X

67 X X X X X X X X X X X

X X X X X X X X X X X

68 X X X X X X X X X X X

X X X X X 69 X X X X X X X

X X X X X X X 70 X X X X X X X

X X X X X X X 71 X X X X X X X

X X X X X X X 72 X X X X X X X X X X X

X X X X X 73 X X X X X X X

X X X X X X X 74 X X X X X X X

X X X X X X X 75 X X X X X X X

X X X X X X X 76 X X X X X X X X X X X

X X X X X X X 77 X X X X X X X

X X X X X X X 78 X X X X X X X

79 X X X X X X X

X X X X X X X

80 X X X X X X X

X X X X X X X

51 X X X X X X X

X X X X X X X

82 X X X X X X X

X X X X X X X X X X X 83 X X X X X X X

X X X X X X X 84 X X X X X X X

X X X X X X X 85 X X X X X X X

X X X X X X 86 X X X X X X X

X X X X X X X X X X 87 X X X X X X X

X X X X X X X 88 X X X X X X X X

X X X X X X X X X X 133 X X X X X X X X X

X X X X X X 134 X X X X X X X X X X X

X X X X X X X X X X 135 X X X X X X X X X

X 136 X X X X X X X

X X X X X X

137 X X X X X X X X X X X

X X X X X X X

138 X X X X X X X X X X

X X X X X X X

140 X X X X X X

X X X X X X X

141 X X X X X X

X X X X X X X X X X X 142 X X X X X X X

X X X X X X X 143 X X X X X X X X X X

X X X X X X X 144 X X X X X X

X X X X X X X X X X X 145 X X X X X X X

X X X X X X X 146 X X X X X X X X X X X

X X X X X X X 147 X X X X X X X X X X X

X X X X X X X 148 X X X X X X X X X X X

X X X X X X X 150 X X X X X X X X X X

X X X X X X X X X X 151 X X X X X X

X 152 X X X X X X X

X X X X X X

153 X X X X X X X X X X

X X X X X X X

154 X X X X X X X X X

155 X X X X X X

156 X X X X X X

157 X X X X X X

159 X X X X X X

160 X X X X X X

161 X X X X X X

162 X X X X X X X

163 X X X X X X X X X

164 X X X X X X ^'CABLE 2-contimied TABLK 2-coBtiiiued

_™J¾L.

2 1 3 4 s 7 8 11 12 9 10 2 1 3 4 6 7 8 2 11 5 12

165 X X X X X X ^•36 X X X X X

166 X X X X X X 231 X X X

167 X X X X X .X 237 X X X X m X X X X X X 238 X X X X

170 X X X X X X X 239 X X X X

172 X X X X X X X X X X 240 X X. X X

173 X X X X X X 241 X X X

176 X X X X X X 242 X X X X

139 X X X X 243 X X. X X

149 X X X X 244 X X X

158 X X X X 245 X X X

169 X X X X X 246 X X X

171 X X X X X 301 X

174 X X X X X 247 X X X X

175 X X X X X 24S X X X X.

177 X X X X X X X X X X X X 249 X X X X

179 X X X X X X X X X X X 250 X X X X

180 X X X X X X X X X X 299 X X X

181 X X X X X X X X X X X 251 X X X X

182 X X X X X X X X X X 300 X X

183 X X X X X X X X X X X 252 X X X X

184 X X X X X X X. X X X 253 X X X

135 X X X X X X X X X X 254 X X X X

209 X X X X X X X X 255 X X

186 X X X X X X X X X X X 256 X X iS7 X X X X X X X X X 257 X X X X m X X X X X X X X X X X 258 X X X X

189 X X X X X X X X X 259 X X X

190 X X X X X X X .X X X 260 X X X X

191 X X X X X X X X X X X 261 X X X X.

192 X X X X X X X X 262 X X X

193 X X X X X X X X X 263 X X X X

194 X X X X X X X X X X X 264 X X X X

195 X X X X X X X X X 265 X X X X m X X X X X X X X X 266 X X X X

197 X X X X X X X X X X 267 X X X X

198 X X X X X X. X X X 268 X X X.

201 X X X X X X X X X 269 X X X X

202 X X X X X X X X X X 270 X X X

203 X X X X X X X X X X X 271 X X X X

204 X X X X X X X X X X X 272 X X. X X

205 X X X X X X X 273 X X X

210 X X X X X X X X X X X 274 X X X X

205 X X X X X X 275 X

207 X X X X X X 276 X X X

208 X X X X X. X X X 277 X X X

178 X X X X 27K X X X X

2 2 X X X X X X 279 X X X X

215 X X X X X X X X 280 X X X

199 X X X X 302 X

200 X X X X X X X X X 281 X X X X

213 X X 282 X X X

214 X X X X X X X 303 X

211 X X X X X 283 X X X X

.'leX X X X X X X 304 X an X X X X X X X X X X 284 X X X

218 X X X X X X X X X X 285 X X X.

226 X X X X X X X X X X 286 X X X

219 X X X X X X X X X 287 X X X X

220 X X X X' X X 288 X X X X

227 X X X X X X X X 289 X X X X

228 X X X X X X X X 290 X X X X

221 X X X X X X X X X 291 X X X X

222 X X X X X X X X X X 292 X X X X.

229 X X 293 X X X X

223 X X X X X X X X X X 294 X X X

224 X X X X X X X 295 X X X X

234 X X X 296 X X. X X

233 X X X X 305 X

230 X X X 297 X X X X

232 X X X X X X 2 a X X X X

225 X X X X X. X X 312 X X. TABLE 2-continued TABLE 2-continued

Rl Rl

R2 1 3 4 6 7 8 2 11 5 12 9 10 R2 1 3 4 6 7 8 2 11 5 12 9 10

324 X X X 405 X X X X X X X X X X X X

334 X X X X X 406 X X X X X X X X X X X X

360 X X X X X

407 X X X X X X X X X X X X

335 X X X X X

336 X X X X X

337 X X X X X

338 X X X X X

339 X X X X X

340 X X X X X

341 X X X X X

342 X X X X X

343 X X X X X

344 X X X X X

345 X X X X X

346 X X X X X

347 X X X X X

348 X X X X X

361 X X X X X

349 X X X X X

350 X X X X X

351 X X X X X

352 X X X X X

363 X X X X

353 X X X X X

354 X X X X X

355 X X X X X

356 X X X X X

362 X X X X X

357 X X X

358 X X X X X

359 X X X X X

364 X X X X X X X X X X X X

365 X X X X X X X X X X X X

366 X X X X X X X X X X X X

367 X X X X X X X X X X X X

368 X X X X X X X X X X X X

369 X X X X X X X X X X X X

370 X X X X X X X X X X X X

371 X X X X X X X X X X X X

372 X X X X X X X X X X X X

373 X X X X X X X X X X X X

374 X X X X X X X X X X X X

375 X X X X X X X X X X X X

376 X X X X X X X X X X X X

377 X X X X X X X X X X X X

378 X X X X X X X X X X X X

379 X X X X X X X X X X X X

380 X X X X X X X X X X X X

381 X X X X X X X X X X X X

382 X X X X X X X X X X X X

383 X X X X X X X X X X X X

384 X X X X X X X X X X X X

385 X X X X X X X X X X X X

386 X X X X X X X X X X X X

387 X X X X X X X X X X X X

388 X X X X X X X X X X X X

389 X X X X X X X X X X X X

390 X X X X X X X X X X X X

391 X X X X X X X X X X X X

392 X X X X X X X X X X X X

393 X X X X X X X X X

394 X X X X X X X X X X

395 X X X X X X X X X

396 X X X X X X X X X X

397 X X X X X X X X X X

398 X X X X X X X X X X X

399 X X X X X X X X X X X X

400 X X X X X X X X X X X

401 X X X X X X X X X X X

402 X X X X X X X X X X X X

403 X X X X X X X X X X X X

404 X X X X X X X X X X X X

In another aspect, the present invention relates to methods for treating or preventing a Condition in a patient, comprising administering to the patient an effective amount of a compound having the formula (IC):

or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, wherein R¹ is defined above in Table 5, R² is defined above in Table 6, and the identity of R¹ and R² in the compoimds of formula (IC) are denoted using an "X" as set forth below in Table 3

TABLE 3

Rl

R2 1 2 3 4 8 12 11 7 6 5 10

26 X X X X X X X X X X

30 X X X X X X X X

38 X X X X X X X X X X

43 X X X X X X X X X X

52 X X X X X X X X X X

63 X X X X X X X X X X

68 X X X X X X X X X X

217 X X X X X X

218 X X X X

219 X X

220 X X X X X X

221 X X X

222 X X X X x X X

223 X

224 X

225 X

226 X X X

227 X X X X X X

228 X X

229 X X X X

230 X X X X

231 X

232 X X X X

233 X

234 X X X X X X

236 X X

237 X X X X X X X X X X

238 X X X X X X X X X X

239 X X X X X X X X X X

240 X X X X X X X X

241 X X X X X X X X X X TABLE 3-contimied TABLE 3-conlinued

R2 1 2 3 4 8 12 V. 7 6 5 10 R2 1 2 3 4 8 12 11 7 6 5 10

242 X X X X X X X X X X 3U2 X X X X 243 X X X X X X X X X X X X X X X X X X

244 X X X X X X X X X X 304 X X X X X X X X

245 X X X X X X X X X 305 X X X X

246 X X X X X X X X X 145 X X X X X X X X X

247 X X X X X X X X X X 147 X X X X X X X X X

248 X X X X X X X X !4S X X X X X X X X X

6 X X X X X X X X X X 334 X X X X X X X X X

S X X X X X X X X X X 335 X X X X X X X X X

22 X X X X X X X X X X 533 X X X X X

28 X X X X X X X X X X 134 X X X X X X X X X

56 X X X X X X X X X !35 X X X X X X X X X

76 X X X X X X X X X X 137 X X X X X X X X X

249 X X X X X X X X X X 138 X X X X X X X X X

250 X X X X ;x X X X X X 143 X X X X X X X X X

251 X X X X X X X X X X ISO X X X X X X X X

232 X X X X X X X X X X 153 X X X X X X X X X

253 X X X X X X X X X X 554 X X X X X X X X

254 X X X X X X X X X X 153 X X X X X X X X

255 X X X X X X X X X X 172 X X X X X X X X

256 X X X X X X X X X X 336 X X X X X X X X ^7 X X X X X X X X X X 337 X X X X X X X X

258 X X X X X X X X X X 33S X X X X X X X X X

25» X X X X X X X X 339 X X X X X,

2C0 X X X X X X X X X 340 X X X X X X X X

2il X X X X X X X X X 341 X X X X X X X X

2«2 X X X X X X X X 342 X X X X X X X X X

263 X X X X X X X 343 X X X X X X X X

264 X X X X X X X X X X 344 X X X X X X X X X

265 X X X X X X X X X 345 X X X X X X X X X

266 X X X X X X X X X X .346 X X X X X X X X X

267 X X X X X X X X X X 347 X X X X X X X X X

268 X X X X X X X X X X 348 X X X X X X X X X

269 X X X X X X X X X X 349 X X X X X X X X X

270 X X X X X X X X X^" X 350 X X X X X X X X X

271 X X X X X X X X X 351 X X X X X X X X X

272 X X X X X X X X X X 352 X X X X X X X X X

273 X X X X X X X X X 353 X X X X X X X X X

274 X X X X X X X X X X 354 X X X X X X X X

275 X X X X X 355 X X X X X X X X

276 X X X X X X X X X X 3,56 X X X X X X X X X

277 X X X X X X X X X X 357 X X X X X X

273 X X X X X X X X X X 358 X X X X X X X X X

279 X X X X X X X X X X 359 X X X X X X X X X

280 X X X X X X X X X X 3S0 X X X X X X X

281 X X X X X X X X X X 36,1 X X X X X

I X X X X X X X X X 362 X X X X X X

4 X X X X X X 363 X X X

35 X X X X X X X X X X 364 X X X X X X X X X X X

55 X X X X X X X X X 365 X X X X X X X X X X X

67 X X X X X X X X X X 366 X X X X X X X X X X X

72 X X X X X X X X X 367 X X X X X X X X X X X

282 X X X X X X X X X X 368 X X X X X X X X X X X

283 X X X X X X X X X X 369 X X X X X X X X X X X

284 X X X X X X X X 370 X X X X X X X X X X X

2X5 X X X X X X X X X X 371 X X X X X X X X X X X

2S6 X X X X X X X X X 372 X X X X X X X. X X X lii X X X X X X X X X 373 X X X X X X X X X X

288 X X X X X X X X X X 374 X X X X X X X X ^'X X X

289 X X X X X X X X X X 375 X X X X X X X X X X X

290 X X X X X X X X X 376 X X X X X X X X X X X

291 X X X X X X X X X X 377 X X X X X X X x:

292 X X X X X X X X X X 378 X X X X X X X X X

293 X X X X X X X X X X 379 X X X X X X X X X X X

294 X X X X X X X X X 380 X X X X X X X X X X X

295 X X X X X X X X X 381 X X X X X X X X X X X

296 X X X X X X X X X X 382 X X X X X X X X X X X

297 X X X X X X X X X X 383 X X X X X X X X X X X

298 X X X X X X X X X X 384 X X X X ^'X X X X X X X

299 X X X X X X X X 385 X X X X X X X X X X X

300 X X X X X X X 386 X X X X X X X X X X X

301 X X X X X 387 X X X X X X X X X X TABLE 3-continued

Rl

R2 1 2 3 4 8 12 u 7 6 5 10

388 X X X X X X X X X X X

389 X X X X X X X X X X X

390 X X X X X X X X X X X

391 X X X X X X X X X X X

392 X X X X X X X X X X

393 X X X X X X X X

394 X X X X X X

395 X X X X X X X X X

396 X X X X X X X X

397 X X X X X X X X X

398 X X X X X X X X X

399 X X X X X X X X X X X

400 X X X X X X X X X X X

401 X X X X X X X X X

402 X X X X X X X X X X X

403 X X X X X X X X X X

404 X X X X X X X X X X

405 X X X X X X X X X X

406 X X X X X X X X X X

407 X X X X X X X X X X

In another aspect, the present invention relates to methods for treating or preventing a Condition in a patient, comprising administering to the patient an effective amount of a compound having the formula (ID):

Or a pharmaceutically acceptable salt, solvate, ester, prorug or stereoisomer thereof, Wherein R¹ is defined above in Table 5, R² is defined above in Table 6, and the identity of R¹ and R² in the compounds of formula (ID) are denoted using an "X" as set forth below in Table 4:

TABLE 4

TABLE 4-continued

Rl

1 3 4 6 8 10 1 11 7 12

2 1 3 4 6 8 10 2 11 7 12

X X X X X X X X X X 15 X X X X X

X X X X X 16 X X X X X

X X X X X 17 X X X X X

X X X X X X X X X 18 X X X X X

X X X X 19 X X X X X

X X X X X X X X X X 20 X X X X X

X X X X X 21 X X X X X

X X X X X X X X X 22 X X X X X X X 7, X X

23 X X X X X

X X X X

24 X X X X X

X X X X X

25 X X X X X

X X X X X 26 X X X X X X X X X X

X X X X X 27 X X X X X

X X X X 28 X X X X X X X X X X

X X X X X 29 X X X X X

30 X X X X X X X

31 X X X X X

32 X X X X X

33 X X X X X

34 X X X X X

35 X X X X X X X X X X

36 X X X X X

37 X X X X X

38 X X X X X X X X X

39 X X X X X

40 X X X X

41 X X X X X

42 X X X X X

43 X X X X X X X X X

44 X X X X X

45 X X X X X

46 X X X X

47 X X X X X

48 X X X X X

49 X X X X X

50 X X X X X

51 X X X X X

52 X X X X X X X X X X

53 X X X X X

54 X X X X X

55 X X X X X X X X X X

56 X X X X X X X X X X

57 X X X X X

58 X X X X X

59 X X X X X

60 X X X X X

61 X X X X X

62 X X X X X

63 X X X X X X X X X

64 X X X X X

65 X X X X X

66 X X X X X

67 X X X X X X X X X X

68 X X X X X X X X X

69 X X X X X

70 X X X X X

71 X X X X X

72 X X X X X X X X X X

73 X X X X X

74 X X X X X

75 X X X X X

76 X X X X X X X X X X

77 X X X X X

78 X X X X X

79 X X X X X

80 X X X X X

81 X X X X X

82 X X X X X

83 X X X X X

84 X X X X X

85 X X X X X

86 X X X X X TABLE 4-continued TABLE 4-coiitijiued

R2 1 3 4 6 8 10 2 il 12 5 R2 1 3 4 6 10 2 11 7 12

87 X X X X X 202 X X X X X X

S3 X X X X 203 X X X X X X X

133 X X X X X X X X X X 204 X X X X X X X X

134 X X X X X X X X X X 207 X X X X X

135 X X X X X X X X X X X 20$ X X X X X

537 X X X X X X X X X X 214 X X X X

13B X X X X X X X X X X 210 X X X X X X

539 X X X X X 215 X. X

140 X X X X X X S93 X X X

141 X X X X 205 X X X

142 X X X X X X 206 X X X

143 X X X X X X X X X 209 X X X

144 X X X X X X 216 X X X

145 X X X X X X 2_.17 X X X X X X X X

146 X X X X X X X X X X X 21S X X X X X X X

147 X X X X X X X X X X X 226 X X X X

J4S X X X X X X X X X X X 22 X X X X X

149 X X X X X X 221 X X X X X X X

150 X X X X X X X X X X 230 X X X

151 X X X X X X 222 X X. X X X X

152 X X X X X X 223 X X X X X

153 X X X X X X X X X X 24 X X X X

154 X X X X X X X X X 231 X X X X X

155 X X X X X X 225 X X X X X

156 X X X X X X 229 X X X X X X

157 X X X X X X 2?4 X X X X

158 X X X X X X 219 X. X X

159 X X X X X X 227 X X X

160 X X X X X 228 X X X X

161 X X X X X X 236 X X X X

162 X X X X X X 232 X X

163 X X X X X X X X X X X 233 X

154 X X X X X X 23? X X

155 X X X X X X 238 X X X X

X X X X X X 239 X X X X

157 X X X X X X 240 X X X X m X X X X X X 241 X X X X X

169 X X X X X X 242 X X X X X

170 X X X X X X 243 X X X X

171 X X X X X X 244 X X X X X

172 X X X X X X X X X X X 245 X X X X. X

1 3 X X X X X X 246 X X X x: X

174 X X X X X X 247 X X X X X

1 5 X X X X X X 248 X X X X X

176 X X X X X X 249 X X X X X

136 X X X X. 250 X X X X X

177 X X X X X X X X 251 X X. X X X

178 X X X X X X 300 X X X X

179 X X X X X X X 252 X X X X X

ISO X X X X X X 253 X X X X X

181 X X X X X X X 254 X X X X X

211 X X X X X 255 X X X X X

182 X X X X X X X X X 256 X X X X X

183 X X X X X X X 257 X X X X X

184 X X X X X X X X 258 X X X X X

212 X X X X 259 X X X X X

1.85 X X X x: X 260 X X X X

186 X X X X X X X 261 X X X X X

137 X X X X X 262 X X X X X

188 X X X X X X X X X X 2S3 X X X X X

189 X X X X X X. X 264 X X X X X

190 X X X X X X X X 245 X X X X

191 X X X X X X X X X 266 X X X X X

192 X X X X X X X 267 X X X X X

194 X X X X X X X X X 26$ X X X X X

195 X X X X X X X X X 269 X X X X X

196 X X X X X X 270 X X X X X

197 X X X X X X X X 2.71 X X X X X

198 X X X X X X X X X. X

199 X X X 273 X X X X X

200 X X X X X X 4 X X X X X

201 X X X X X X X X 276 X X X X X TABLE 4-continued TABLE 4-continued

Rl

R2 10 2 11 7 12 5 R2 1 3 4 6 8 10 2 11 7 12 5

277 X X X X X 377 X X X X X X X X 278 X X X X X 372 X X X X X X X X X X X 279 X X X X X 379 X X X X X X X X X X X 280 X X X X X 380 X X X X X X X X X X X 281 X X X X X 381 X X X X X X X X X X X 282 X X X X 3S2 X X X X X X X X X X X 283 X X X X X 383 X X X X X X X X X X X 284 X X X X X 384 X X X X X X X X X X 285 X X X X X 385 X X X X X X X X X X X 286 X X X X X 386 X X X X X X X X X X X 287 X X X X X 3S7 X X X X X X X X X X X 288 X X X X 388 X X X X X X X X X X X 289 X X X X X 359 X X X X X X X X X X X 290 X X X X X 390 X X X X X X X X X X X 2 1 X X X X X

391 X X X X X X X X X X X 292 X X X X X 392 X X X X X X X X X X X 293 X X X X X 393 X X X X X X X X X X 294 X X X X X 394 X X X X X X X X X X X 295 X X X X X

395 X X X X X X X X X X 296 X X X X X 396 X X X X X X X X 297 X X X X X

397 X X X X X X X X X X X 298 X X X X X

398 X X X X X X X X X X X 301 X X X X

399 X X X X X X X X X X 299 X X X X

400 X X X X X X X X X X X 275 X X X X

401 X X X X X X X X X X X 302 X X X X

402 X X X X X X X X X X X 303 X X X X

403 X X X X X X X X X X X 304 X X X X

404 X X X X X X X X X 305 X X X X

405 X X X X X X X X X X X 334 X X X

406 X X X X X X X X X X X 360 X X X X X

407 X X X X X X X X X X X 335 X X X X X

336 X X X X X "

337 X X X

338 X X X X X

339 X X

340 X X X X X

341 X X X X X

342 X X X X X

343 X X X X X

344 X X X X

345 X X X X

346 X X X X X

347 X X X X X

348 X X X X X

361 X X X

349 X X X X X

350 X X X X X

351 X X X X X

352 X X X X X

363 X X X

353 X X X X X

354 X X X X X

355 X X X X X

356 X X X X X

362 X X X X X

357 X X X X X

358 X X X X X

359 X X X X

364 X X X X X X X X X X X

365 X X X X X X X X X X X

366 X X X X X X X X X X X

367 X X X X X X X X X X X

368 X X X X X X X X X X X

369 X X X X X X X X X X X

370 X X X X X X X X X X X

371 X X X X X X X X X X X

372 X X X X X X X X X X X

373 X X X X X X X X X X X

374 X X X X X X X X X X X

375 X X X X X X X X X X

376 X X X X X X X X X X X In another embodiment, the compound is disclosed in International Appl. Publication No. WO 2008/050200:

The present invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R¹ and R² are each independently -H, -OH, halo, C(-C6 alkyl, C -Ce alkoxy, -CF₃, substituted Ci-C₆ alkyl, or substituted C|-C6 alkoxy;

R³ and R⁴ are each independently -H or Ci-Ce alkyl or R³ and R⁴ taken together with the carbon atom to which they are attached form Cj-Ce cycloalkyl, or cycloheteroalkyl, provided that if one of R³ and R⁴ is -H, then the other is Cj-C6 alkyl;

R⁵ is -H, Ci-C₆ alkyl, Ci-C₆ alkoxy, -(CH₂)_q-C(0)0-W, wherein W is -H or C,-C₆ alkyl and q is 1-6;

G¹ is methylene or ethylene;

G² is C(R⁶) or N, wherein R⁶ is -H_s -OH or Ci-C₆ alkyl;

Y is -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -0-, -C(O)-, -C(0)CH₂-, -S-, -S(O)-, -S(0)₂-, - NHC(O)-, -NHC(0)CH(R⁷)-, or -NHS(0)₂-, wherein R⁷ is -H or Cj-C₄ alkyl;

Ar¹ is a radical of the formulae

-0 >_.

wherein R^P1, R^P2, R^P3, R^P4, R^P5, R^p6, R^P7, R^p8, R^N1, R^N2, R^N3, and R^{Z 1} are each independently -H, -OH, C,-C₆ alkyl, C|-C₆ alkoxy, halo, -CN, -CF₃, or -NR⁸R⁹, wherein R⁸ and R⁹ are each independently -H or C,-C₆ alkyl; R^MI, R^M2, R^{B 1}, R^B2, R^B3, R^B\ R^B5, R^B6, R^XI, R^X2, R⁵⁰, R^X4, R^y R^Y2, R^Y3, R^Y4, R^Y5, and R^Y6 are each independently -H or C,- C6 alkyl; X¹ and X² are independently CH or N; X³, X⁴, and X⁵ are each independently NH, O, or S; X⁶ is CH₂ or O; Q is substituted d-C₆ alkyl, phenyl, napthyl, 2-pyridyl, or 3-pyridyl; and

n is 0 or 1 ;

provided that when Y is O, S, NHC(O), NHS(0)₂, NHC(0)CH(R⁷), or NHS(0)₂, then G² is CH.

The present invention also relates to a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the compound is disclosed in International Appl. Publication No. WO 2008/1 17148:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are each independently -H, -OH, halo, d-C6 alkyl, CiC₆ alkoxy, -CF₃, substituted

Ci-C₆ alkyl, or substituted CiC₆ alkoxy;

R³ and R⁴ are each independently -H or Ci-Ce alkyl or R³ and R⁴ taken together with the carbon atom to which they are attached form C3-C6 cycloalkyl, or cycloheteroalkyl, provided that if one of R³ and R⁴ is -H, then the other is C1-C6 alkyl;

R⁵ is -H, Ci-C₆ alkyl, Ci-C₆ alkoxy, -(CH₂)_q-C(0)0-W, wherein W is -H or CiCe alkyl and q is 1 -6;

G¹ is methylene or ethylene;

G² is C(R⁶ ) or N, wherein R⁶ is -H, -OH or C -C₆ alkyl;

Y is -CH2-, -CH₂CH₂-, -CH₂CH₂CH₂-, -0-, -C(O)-, -C(0)CH₂-, -S-, -S(O)-, -S(0)₂- -NH-, -NHC(O)-, -NHC(0)CH(R⁷)-, or -NHS(0)₂-, wherein R⁷ is -H or C, -C₄ alkyl; Ar¹ is a radical of the formulae

wherein R^P1, R^ra, R^p\ R^P4, R^P5, R^P6, R^P7, R^P8, R^{N 1}, R^N2, R^N3, and R^Z1 are each independently -H, -OH, d-C ₆ alkyl, CiC₆ alkoxy, halo, -CN, -CF₃, or -NR⁸R⁹, wherein R⁸ and R⁹ are each independently -H or C,-C₆ alkyl; R^M1, R^M2, R^B1, R^B2, R^B3, R^m, R^B5, R^B6, R^x', R*², R³⁰, R^X4' R^Y1, R^Y2, R^Y3, R^Y4, R^YS, R^Y6 are each independently -H or C,C₆ alkyl; X¹ and X² are independently CH or N; X³, X⁴, and X⁵ are each independently NH, O, or S; X⁶ is CH₂ or O; Q is substituted Q-C6 alkyl, phenyl, napthyl, 2-pyridyl, or 3- pyridyl; and n is O or i; provided that when Y is O, S, NH, NHC(O), NHS(0)₂, NHC(0)CH(R⁷), or NHS(0)₂, then G² is CH.

[0114] In another embodiment, the compound is disclosed in International Appl. Publication No. WO

[0115] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2010/0197693:

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein

one of R¹ and R² is X, and the other of R¹ and R² is Y;

X is

m and n, at each occurrence, are independently 1 or 2;

G¹ is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl, wherein G¹ is connected through the nitrogen atom of said azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl; Y is — NR^cAr', — NR^cAr²— Ar¹, — R^cCH(Ar¹)₂, — NR^CR^pAr', — NR^c(CR^aR^b)_pCH(Ar^,)₂,

(iii), (iv), (v) or (vi);

Ar¹, at each occurrence, is independently aryl or heteroaryl, wherein said aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3, or 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, halogen, or— (alkyl)₂;

Ar² is aryl or heteroaryl, wherein said aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen; G is cycloalkyl;

R^aand R^b are at each occurrence independently hydrogen, alkyl, or hydroxyalkyl;

R^c is hydrogen or alkyl;

p is 1, 2, 3, or 4; and

R³, R⁴, R⁵ and R⁶ are each independently hydrogen, alkoxy, alkyl, or halogen.

The invention is also directed to compounds of formula (Hi) or formula (IV)

L¹ is C(O) or S(0)₂;

R² is X;

X i

m and n, at each occurrence, are independently 1 or 2;

G¹ is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl, wherein G¹ is connected through the nitrogen atom of said azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or azepanyl;

R³, R⁴, R⁵ and R⁶ are each independently hydrogen, alkoxy, alkyl, or halogen;

R⁷ is — S(0)₂Ar³, — C(0)Ar³, — S(0)₂(CR^aR^b)_pAr³,

—

S(0)₂(CR^aR^b)_pCH(Ar³)₂,— C(0)(CR^aR^b)_pCH(Ar³)₂,— CCOiCHiAr³^, or— CH(Ar³)₂;

AT³ , at each occurrence, is aryl or heteroaryl, wherein said aryl and heteroaryl are unsubstiruted or substituted with 1 , 2, 3, 4, or 5 substituents selected from alkoxy, alkyl, cyano, haloalkyl, or halogen;

R^a and R^b are at each occurrence independently hydrogen, alkyl, or hydroxyalkyl;

p is 1 , 2, 3, or 4; and

R° is hydrogen or alkyl. [0116] In another embodiment, the compound is disclosed in U.S. Patent No. 7,271,260:

wherein, n is an integer ranging from 1 to 4;

Ri is;

R₂ is Ci-C 6 alkyl, phenyl; morpholinyl; piperazinyl having a C1-C4 alkyl substituent at the 4^th position; 1-pyrrolidinyl; 1-piperidinyl; or— NR6 7, wherein R$ and R₇ are each independently Ci-Ce alkyl;

R3 is C1-C6 alkyl or phenyl;

R4

wherein X is O or NH; m is an integer ranging from 1 to 4; and R5 is C1-C4 alkyl or halogen.

[0117] In another embodiment, the compound is disclosed in International Appl. Publication No.

WO 2008/007835:

wherein n is 1 or 2;

Ri is an aryl group having 6 to 10 carbon atoms which may be unsubstituted or substituted with at least one substituent selected from halogen atoms, alkyl having 1 to 15 carbon atoms, alkoxy having 1 to 15 carbon atoms and phenoxy; an alkyl group having 1 to 15 carbon atoms; or a cycloalkyl group having 1 to 15 carbon atoms;

R₂ is a saturated or unsaturated 5- to 7-membered heterocyclic ring which contains 1 to 3 hetero atoms selected from N, O and S, and which may be unsubstituted or substituted with at least one substituent selected from alkyl having 1 to 15 carbon atoms, alkylamino having 1 to 15 carbon atoms and halogen atoms.

[0118] In another embodiment, the compound is disclosed in U.S. Patent No. 7,319,098:

wherein Ri is a phenyl or a benzyl group, optionally substituted with a moiety selected from the group consisting of a halogen atom, a C1-C6 alkoxy, a Ci-Ce alkyl, and a cyano group; R₂ is a heterocyclic group selected from the group consisting of piperidinyl, pyrrolidinyl, morpholinyl, and piperazinyl groups, wherein the heterocyclic group is optionally substituted with a Ci-C₆ alkyl group; and n is 1 or 2.

[0119] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2010/0004286:

wherein, R'-R⁵ represent independently a hydrogen atom, a halogen atom, a Ci-C6 alkoxy, a Ci-C₆ alkyl, a C\-Ce haloalkyl, a nitro, a cyano or a hydroxy; and

R⁶ represents a hydrogen atom, a C1-C6 alkyl, or an aryl.

[0120] In another embodiment, the compound is disclosed in U.S. Patent No. 7,544,686:

Fom ila 1

wherein, Ri represents phenyl, X-substituted phenyl (X include nitro, methyl, chloro, methoxy, etc.; the substitution positions are ortho, meta, and para positions; and can be mono-, di-, tri-, terra- or entirely-substituted), 1,1 -diphenylmethyl, X-substituted diphenylmethyl (X represents chloro, methyl; the substitution position can be ortho, meta, and para positions; and mono, di, tri, tetra or all thereof can be substituted);

R₂ represents hydrogen, methyl or ethyl groups;

R.3 represents methyl, propyl, isobutyl, phenyl, cyclohexyl, substituted phenyl (wherein, the substituents are methyl, chloro, methoxy, etc.), naphthyl, piperidinyl groups;

R4 represents hydrogen or C e lower alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, 2-furyl, phenyl, X-substituted phenyl(X represents chloro, methyl, cyclohexyl, piperidinyl, chloro groups, the substitution positions can be ortho, meta, and para positions and mono, di, tri, tetra or all thereof can be substituted); and n represents an integer from 0 to 3.

In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No. 2010/0094006:

[f annul a 1]

In the above formula 1 ,

Y represents— (CH₂)„— C(O)— ; or— C(O)— (CH₂)_n— , wherein n is an integer of 1-4; R¹ and R² , which may be same or different, respectively represent a hydrogen atom; Ci- C₈ alkyl group; phenyl group; phenyl group substituted with a substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, amino, mercapto, thioalkyl, C)-C₈ alkyl, C|-C₈ cycloalkyl, Ci-C₈ alkoxy groups, and C₃-C₈ heterocycloalkyl group comprising at least one heteroatom selected from O and N; benzyl group; benzyl group substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, carboalkoxy, nitro, amino, mercapto, thioalkyl, Ci-C₈ alkyl, and Ci-C₈ alkoxy groups; phenethyl group; or heteroaryl group comprising at least one heteroatom selected from O, S and N; and

R³ represents a hydrogen atom; Ci-C₈ alkyl group; heteroaryl group comprising at least one heteroatom selected from O, S and N; phenyl group; phenyl group substituted with a substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, amino, mercapto, thioalkyl, Ci-C₈ alkyl, Ci-Cs cycloalkyl, Cj-C₈ alkoxy groups, and C3-C8 heterocycloalkyl group comprising at least one heteroatom selected from O and N; benzyl group; benzyl group substituted with a substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, amino, niercapto, aryl, haloaryl, C]-C₈ alkyl, Ci -C₈ alkoxy, Ci-C₈ haloalkyl, and arylcarbonyl groups.

[0122] in another embodiment, the compound is disclosed in International Appl. Publication No.

WO 2009/035307:

wherein Ri is hydrogen; straight or branched C1-C10 alkyl; CH₂-C₃-Cio cycloalkyl; or benzyl substituted or unsubstituted with one or more groups selected from the group consisting of straight or branched C1-C10 alkyl, C1-C4 alkoxy, halogen, nitro and N (CH₃)¾

CH M M-wv

w

R₂ is or NR5R6

R5 and Rf, are each independently hydroge; C6-C20 aryl substituted with one or more groups selected from p-tolyloxy and C1-C4 alkyl; or CH (C6-C20 aryl) (halogen- substituted C6-C20 aryl), and

n is an integer of 1 to 5.

[0123] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2009/325979:

IfonnuLi 1]

In the formula 1 ,

Y -N N— ^J

is or

n is an integer of from 2 to 4, m is an integer of from 1 to 4; R¹ and R², being same or different with each other, each independently represents a hydrogen atom, Ci-C₈ alkyl group, substituted or unsubstituted phenyl group, or substituted or unsubstituted benzyl group; R³ is a hydrogen atom, Ci-Cg alkyl group, C_\-C» hydroxyalkyl group, CH(substituted or unsubstituted phenyl)₂, a heteroaromatic group having one or more hetero atom selected from O and N, substituted or unsubstituted phenyl group, or substituted or unsubstituted benzyl group; the above substituted phenyl or benzyl is respectively substituted with a substituent selected from the group consisting of halo, hydroxy, carboxy, alkoxycarbonyl, nitro, amino, mercapto, Ci-C₃ alkyl, and Q-Cg alkoxy groups. In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No. 2010/0179201 :

Ri is R and R' are the same or different for each other, and independently selected from the group consisting of hydrogen atom, halogen atom, C1-C5 alkyl, alkyloxy, phenyloxy, nitro, cyano, alkoxycarbonyl, and C3-C6 cycloalkyl,

n is 0, 1, or 2,

R₂ is

NH H, N¾, or N¾.

X is halogen atom.

In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No. 2008/0293786:

wherein

Ri may be a hydrogen atom, or a C1 -C5 linear or branched alkyl group,

R₂, R₃, and R4 may be the same or different from one another, and independently selected from the group consisting of a hydrogen atom, a halogen atom, a C1-C5 linear or branched alkyl group, a C1-C5 alkyloxy group, a trifluoromethyl group, a trifluoromethoxy group, a phenyloxy group, an amino group, a methanesulfoneamino group, a paratoluenesulfoneamino group, a nitro group, a C1-C5 cyanoalkyl group, a cyano group, a C1-C6 alkoxycarbonyl group, and a C3-C12 cycloalkyl group,

R5 may be selected from the group consisting of a C1-C5 linear or branched alkyl group, a

C3-C6 cycloalkyl group, and a benzyl group,

R6 may be selected from the group consisting of a C3-C12 cycloalkyl group, a C4-C17 alkylcycloalkyl group, an adamantly group, a benzyl group, and a C8-C13 benzylalkyl group,

n and m may be independently 0 or 1 ,

HX may be present or absent, and

when HX is present, X may be a halogen atom. [0126] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No. 2010/0056545:

[Chemical Forouila 1J

Where,

X is independently or selectively one or more substitueiits selected from the group consisting of H, halogen, and a C 1-4 alkoxy,

R¹ is a CM linear or branched alkyl,

R² is

where R³ and R⁴ are independently or selectively H, a CM linear or branched alkyl, or a C 1-4 alkoxy, and

Y is C or N.

R⁵ is a C linear or branched alkyl substituted by one or more Cs^ aryl; unsubstituted, or one or more halogens, a CM linear or branched alkyl, a CM linear or branched alkyl substituted by one or more halogens, or phenyl substituted by a CM alkoxy; unsubstituted, or one or more halogens, a CM linear or branched alkyl, a C_1-4 linear or branched alkyl substituted by one or more halogens, or benzyl substituted by a C alkoxy; or unsubstituted, or one or more halogens, a C linear or branched alkyl, a CM linear or branched alkyl substituted by one or more halogens, or benzylidene substituted by a CM alkoxy.

[0127] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2008/0160009:

wherein R¹ is a halogen, R² is a lower-alkoxy-lower-alkyl carbonyloxy, X is a C₂-C₈- alkylene, and A is a benzimidazolyl optionally substituted at the N atom with 1 to 12 C atoms in the form of their free bases, their hydrates, or their pharmaceutically usable salts for the treatment, control, and prevention of cancer.

|0128j In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2008/0194669:

wherein

Ri is selected from the group consisting of Q-C4 alkyl, hydroxy and C1-C4 alkoxy;

X is selected from the group consisting of N and CH;

Z is selected from the group consisting of NH, O, S and CH₂;

R₂ is selected from the group consisting of H, halo, NH₂, C1-C4 alkyl, hydroxy and C1-C4 alkoxy; and

R3 is selected from the group consisting of H, halo, NH₂, C1-C4 alkyl, hydroxy and C1-C4 alkoxy. In one embodiment Ri is selected from the group consisting of C1-C4 alkyl, hydroxy and C1-C4 alkoxy, X is N, Z is O or CH₂, R₂ is H, halo, NH₂ or hydroxy and R₃ is

H.

[0129] In another embodiment, the compound is disclosed in U.S. Patent Appl. Publication No.

2009/234019: Formula (I)

wherein

Ri is C1-C4 alkyl, hydroxy, or C1-C4 alkoxy;

Z is NH, NCH₃, O, S, or CH₂;

Y is NH, O, or CH ₂ with the proviso that Y and Z are not the same;

R₂ is H, halo, NH₂, C1-C4 alky], hydroxy, or C1-C4 alkoxy;

m and n are independently selected from integers ranging from 1 -5 with the proviso that m+n=an integer ranging from 2-9; and

R3 is H, halo, NH₂, C1-C4 alkyl, hydroxy, or C1-C4 alkoxy.

[0130] The compounds can be administered at an effective oral dosage of 0.0005 mg per kilogram of body weight or higher. In one embodiment, the compound is administered as part of a unit dosage form containing 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.

[0131] Compositions for use in this invention include all compositions wherein the active ingredient is contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, the active ingredient may be administered to mammals, e.g. humans, orally at a dose of 0.001 to 3 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated. The active ingredient may be administered to mammals, e.g. humans, intravenously or intramuscularly at a dose of 0.001 to 3 mg/kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated. Approximately 0.001 to approximately 3 mg/kg can be orally administered to treat or prevent such disorders. If another agent is also administered, it can be administered in an amount which is effective to achieve its intended purpose.

[0132] The unit oral dose may comprise from approximately 0.001 to approximately 200 mg, or approximately 0.5 to approximately 180 mg of the composition of the invention. The unit dose may be administered one or more times daily as one or more tablets, each containing from approximately 0.1 to approximately 90 mg, conveniently approximately 10 to 180 mg of the composition or its solvates. In one embodiment, the unit oral dose can be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 150, 160, 170, or 180 mg.

[0133] In another embodiment, the dose is between about 10 mg and 600 mg, between about 10 mg and 500 mg, between about 10 mg and 400 mg, or between about 10 mg and 300 mg. In another embodiment, the dose is 270 mg, 360 mg, 450 mg, or 540 mg.

[0134] In a topical formulation, the active ingredient may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.

[0135] In addition to administering the compound as a raw chemical, the compound may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredient into preparations that can be used pharmaceutically. The preparations, particularly those preparations, which can be administered orally, such as tablets, dragees, and capsules, and also preparations, which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, can contain from approximately 0.01 to 99 percent, or from approximately 0.25 to 75 percent of active ingredient, together with the excipient.

[0136] The compounds can be in the form of hydrate or acid addition salts as a pharmaceutically acceptable salt. Possible acid addition salts include inorganic acid salts such as the hydrochloride, sulfate, hydrobromide, nitrate, and phosphate salts and organic acid salts such as acetate, oxalate, propionate, glycolate, lactate, pyruvate, malonate, succinate, maleate, fumarate, malate, tartrate, citrate, benzoate, cinnamate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and salicylate salts.

[0137] Acid addition salts are formed by mixing a solution of the particular compound with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, lactic acid, tartaric acid, carbonic acid, phosphoric acid, sulfuric acid, oxalic acid, and the like. Basic salts are formed by mixing a solution of the particular compound of the present invention with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, Tris, N-methyl- glucamine and the like. [0138] The pharmaceutical compositions may be administered to any animal or "subject," which may experience the beneficial effects of the active ingredient. Foremost among such subject animals are mammals, e.g., humans and veterinary animals, although the invention is not intended to be so limited.

[0139] The pharmaceutical compositions may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, inhalation, or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0140] The pharmaceutical preparations are manufactured in a manner, which is itself known, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid excipients, optionally grinding the resultant mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

[0141] Suitable excipients are, in particular: fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, using, e.g. maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the above- mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, e.g. silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropymethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active ingredient doses.

[0142] Other pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient in the form of granules, which may be mixed with fillers, such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient can be dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[0143] Possible pharmaceutical preparations, which can be used rectally include, e.g. suppositories, which consist of a combination of one or more of the active ingredients with a suppository base. Suitable suppository bases are, e.g. natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules, which consist of a combination of the active ingredient with a base. Possible base materials include, e.g. liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0144] Suitable formulations for parenteral administration include aqueous solutions of the compound in water-soluble form, e.g. water-soluble salts and alkaline solutions. In addition, suspensions of the compound as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include farty oils, e.g. sesame oil; or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension include, e.g. sodium carboxymethyl cellulose, sorbitol, and or dextran. Optionally, the suspension may also contain stabilizers.

[0145] Also included within the scope of the present invention are dosage forms of the compound, in which the oral pharmaceutical preparations comprise an enteric coating. The term "enteric coating" is used herein to refer to any coating over an oral pharmaceutical dosage form that inhibits dissolution of the compound in acidic media, but dissolves rapidly in neutral to alkaline media and has good stability to long-term storage. Alternatively, the dosage form having an enteric coating may also comprise a water soluble separating layer between the enteric coating and the core. [0146] The core of the enterically coated dosage form comprises a compound. Optionally, the core also comprises pharmaceutical additives and/or excipients. The separating layer may be a water soluble inert active ingredient or polymer for film coating applications. The separating layer is applied over the core by any conventional coating technique known to one of ordinary skill in the art. Examples of separating layers include, but are not limited to sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, polyvinyl acetal diethylaminoacetate and hydroxypropyl methylcellulose. The enteric coating is applied over the separating layer by any conventional coating technique. Examples of enteric coatings include, but are not limited to cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, copolymers of methacrylic acid and methacrylic acid methyl esters, such as Eudragit^®L 12,5 or Eudragit^®L 100 (Rohm Pharma), water based dispersions such as Aquateric^® (FMC Corporation), Eudragit^®L 100-55. (Rohm Pharma) and Coating CE 5142 (BASF), and those containing water soluble plasticizers such as Citroflex^® (Pfizer). The final dosage form is an enteric coated tablet, capsule or pellet.

[0147] Examples of prodrugs of the compounds include the simple esters of carboxylic acid containing compounds (e.g. those obtained by condensation with a CI -4 alcohol according to methods known in the art); esters of hydroxy containing compounds (e.g. those obtained by condensation with a C carboxylic acid, C_3-6 dioic acid or anhydride thereof (e.g. succinic and fumaric anhydrides according to methods known in the art); imines of amino containing compounds (e.g. those obtained by condensation with a CM aldehyde or ketone according to methods known in the art); and acetals and ketals of alcohol containing compounds (e.g. those obtained by condensation with chloromethyl methyl ether or chloromethyl ethyl ether according to methods known in the art).

[0148] As used herein an effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce, the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective. The amount may cure the disease but, typically, is administered in order to ameliorate the disease. Typically, repeated administration is required to achieve the desired amelioration of symptoms.

[0149] T-type calcium channel antagonists identified as preventative or therapeutic agents for diseases or conditions may be co-administered with effective doses of additional therapeutic agents. Additional therapeutic agents include, but are not limited to, galantamine, rivastigmine, donepezil, tacrine, and memantine.

[0150] Having now generally described this invention, the same will be understood by references to the following examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLES EXAMPLE 1

Effect of ST101 on harmaline-induced tremors in mice

[0151] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (0.1 , 1 , or 10 mg kg) and placed in separate holding cages. After 20 minutes, the mice were injected with harmaline (30 mg kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. After habituation, tremor activity of the mice was measured for approximately 8 minutes. The recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.

[0152] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 seconds in duration.

[0153] Data were analyzed by analysis of variance (ANOVA) followed by Fisher PLSD post-hoc analysis. An effect was considered significant if p < 0.05. Statistical outliers that fell above or below 2 standard . deviations from the mean were removed from the final analysis.

[0154] The effects of propranolol and ST101 on short, long, and total tremor events are shown in Figure 1. One way analysis of variance (ANOVA) found a significant treatment effect for all tremor measures. Propranolol and ST101 (1 and 10 mg/kg) significantly decreased harmaline-induced short, long, and total tremor events.

EXAMPLE 2

Time course of effects of ST101 on harmaline-induced tremors in mice

[0155] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg kg), or ST101 (1 , 10, or 30 mg/kg) and placed in separate holding cages. After 20 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. After habituation, tremor activity of the mice was measured for approximately 8 minutes. Mice were re-tested again at 40 and 70 minutes post-harmaline injection for a total of 3 trials each (10, 40, and 70 minute time points). During test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.

[0156] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 but less than 0.5 seconds in duration.

[0157] Data were analyzed by analysis of variance (ANOVA) followed by Fisher PLSD post-hoc analysis. An effect was considered sigiuficant if p < 0.05. Statistical outliers that fell above or below 2 standard deviations from the mean were removed from the final analysis.

[0158] The effects of propranolol and ST101 on harmaline-induced short tremor events at 30, 60, and 90 minutes after ST101 (10, 40, and 70 minutes post-harmaline) are shown in Figure 2(a). Two-way repeated measures of ANOVA found significant main effects of treatment and time, and a significant treatment based on time interaction. Propranolol and ST101 (10 and 30 mg kg) significantly decreased harmaline-induced short tremor events at all three post-harmaline time points as compared to vehicle. Additionally, the lowest dose of STIOI (1 mg/kg) decreased harmaline-induced short tremor events at 10 and 70 minutes post-harmaline administration.

[0159] The effects of propranolol and STIOI on harmaline-induced long tremor events at 30, 60, and 90 minutes after STIOI (10, 40, and 70 minutes post-harmaline) are shown in Figure 2(b). Two-way repeated measures of ANOVA found significant main effects of treatment and time, and a significant treatment based on time interaction. Propranolol and STIO I (10 and 30 mg kg) significantly decreased harmaline-induced long tremor events at all three post-harmaline time points as compared to vehicle.

[0160] The effects of propranolol and STIOI on harmaline-induced total (short and long) tremor events at 30, 60, and 90 minutes after STI OI (10, 40, and 70 minutes post-harmaline) are shown in Figure 3. Two-way repeated measures of ANOVA found significant main effects of treatment and time, and a significant treatment based on time interaction. Propranolol and STIOI (10 and 30 mg/kg) significantly decreased harmaline-induced total tremor events at all three post-harmaline time points as compared to vehicle. Additionally, the lowest dose of STI OI (1 mg/kg) decreased harmaline-induced total tremor events at 10 and 70 minutes post-harmaline administration.

EXAMPLE 3

Effects of STIOI on harmaline-induced tremors at 60 minutes pre-treatment time

[0161] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or STI OI (1 , 10, or 30 mg/kg) and placed in separate holding cages. After 50 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. Following habituation (60 minutes after initial injection), tremor activity of the mice was measured for approximately 8 minutes. During test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.

[0162] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 Hz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 but less than 0.5 seconds in duration.

[0163] Data were analyzed by analysis of variance (ANOVA) followed by Fisher PLSD post-hoc analysis. An effect was considered significant if p < 0.05. Statistical outliers that fell above or below 2 standard deviations from the mean were removed from the final analysis.

[0164] The effects of a 60 minute pre-treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events are shown in Figure 4(a). One-way ANOVA found a significant treatment effect for all tremor measures. Propranolol and ST101 (10 and 30 mg/kg) significantly decreased harmaline-induced short, long, and total tremor events compared to vehicle. The lowest dose of ST101 (1 mg kg) attenuated long and total tremor events only.

EXAMPLE 4

Effects of ST101 on harmaline-induced tremors at 90 minutes pre-treatment time

[0165] Group housed mice (ICR mice from Taconic in Germantown, NY) were brought to the experimental room for at least 1 hour of acclimation prior to testing. Mice were injected with either sterile saline, propranolol (10 mg/kg), or ST101 (1 , 10, or 30 mg/kg) and placed in separate holding cages. After 80 minutes, the mice were injected with harmaline (30 mg/kg) and placed inside the Tremor Monitor (San Diego Instruments) chamber for a 10 minute acclimation period. Following habituation (90 minutes after initial injection), tremor activity of the mice was measured for approximately 8 minutes. During test trials, the recorded frequencies (1-64 hertz) of activity and the number of tremor events were captured electronically.

[0166] Data were analyzed by the tremor monitor software (San Diego Instruments) in a two part process. Using a Fast Fourier Transform (FFT), an output is provided showing the percentage of activity (energy) recorded at each frequency. A center frequency of activity between 14 - 15 FIz is chosen, along with a bandwidth of 10 Hz. Using these parameters, tremor events were tabulated as short, long, and total events. A long event is defined as being greater than 0.5 seconds in duration, and a short event as greater than 0.3 but less than 0.5 seconds in duration. [0167] Data were analyzed by analysis of variance (ANOVA) followed by Fisher PLSD post-hoc analysis. An effect was considered significant if p < 0.05. Statistical outliers that fell above or below 2 standard deviations from the mean were removed from the final analysis.

[0168] The effects of a 90 minute pre-treatment with propranolol or ST101 on harmaline-induced short, long, and total tremor events are shown in Figure 4(b). One-way ANOVA found a significant treatment effect for all tremor measures. Propranolol and ST101 (10 and 30 mg/kg) significantly decreased harmaline-induced short, long, and total tremor events compared to vehicle. The lowest dose of ST101 (1 mg/kg) attenuated long and total tremor events only.

EXAMPLE 5

Effect of ST101 on Ca_v3.1 Channels using manual patch clamp assays

[0169] T-type calcium channel inhibitory activity of ST101 was evaluated using patch clamp screening which is known to those skilled in the art.

[0170] HEK 293 cells expressing Ca_v3.1 channels were grown in growth media which comprised: DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin (humidified atmosphere of 95% air/5% C0₂ at 37 °C in a cell culture incubator) on a 30 mm cell culture plate. Ca_v3.1 channel expression was induced by transfection with 1 μg of Ca_v3.1 expression plasmid DNA. Cells were co-transfected with 1 μg of EGFP expression plasmid DNA to allow identification of transfected cells under fluorescent light. The pipette (internal) solution contained 105 mM cesium chloride, 25 mM triethylamine chloride, 10 mM HEPES, 1 mM calcium chloride, 1 1 mM EGTA (pH = 7.2, adjusted with CsOH), and 92 mM cesium chloride. The bath solution contained 40 mM triethylamine, 1 mM magnesium chloride, 2 mM calcium chloride, lOmM HEPES, and 10 mM glucose (pH = 7.4, adjusted with cesium hydroxide). ST101 was diluted in the bath solution to the desired concentration (0.001 μΜ, 0.03 μΜ, 0.1 μΜ, 0.3 μΜ, 1 μΜ, and 10 μΜ). For control purposes, HEK 293 cells without overexpression of Ca_v3.1 were used.

[0171] Membrane current recordings were made with an Axopatch 200 recorder (Axon Instruments, Inc.) patch clamp and pClamp (Axon Instruments, Inc.) data acquisition software. Experiments were performed at 20-23 °C. The holding membrane potential was fixed at -100 mV. Ca currents through the Ca_v3.1 channels were elicited by a series of 150 msec depolarizing pulses applied from a holding potential of -100 mV to a membrane potential between -90 mV and +20 mV every 15 seconds.

[0172] Percent inhibition is calculated from the ratio of the current amplitude in the presence and absence of compound. When multiple doses of compound were tested, IC50 values are calculated by Hill equation fit. The range of concentrations tested was 0.001 μΜ to 10 μΜ. IC50 values are calculated from the fits of the Hill equation to the data.

[0173] Figures 5-8 show the results of the electrophysiological studies of ST101 on the Ca_v3.1 channel using the patch clamp screen. As seen in Figure 5, ST101 displayed an antagonistic effect on Ca_v3.1 with an IC50 ⁼ 0.0429 μΜ.

EXAMPLE 6

Effect of ST101 on Ca_v3.2 Channels using manual patch clamp assays

[0174] T-type calcium channel inhibitory activity of ST101 was evaluated using patch clamp screening which is known to those skilled in the art.

[0175] HE 293 cells expressing Ca_v3.2 channels were grown in growth media which comprised: DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin (humidified atmosphere of 95% air/5% C0₂ at 37 °C in a cell culture incubator) on a 30 mm cell culture plate. Ca_v3.2 channel expression was induced by transfection with 1 μg of Ca_v3.1 expression plasmid DNA. Cells were co-transfected with 1 μg of EGFP expression plasmid DNA to allow identification of transfected cells under fluorescent light. The pipette (internal) solution contained 105 mM cesium chloride, 25 mM triethylamine chloride, 10 mM HEPES, 1 mM calcium chloride, 11 mM EGTA (pH = 7.2, adjusted with CsOH), and 92 mM cesium chloride. The bath solution contained 40 mM triethylamine, 1 mM magnesium chloride, 2 mM calcium chloride, lOmM HEPES, and 10 mM glucose (pH = 7.4, adjusted with cesium hydroxide). ST101 was diluted in the bath solution to the desired concentration (0.001 μΜ, 0.01 μΜ, 0.1 μΜ, 1 μΜ, 10 μΜ, 100 μΜ, and 300 μΜ). For control purposes, HEK 293 cells without overexpression of Ca_v3.2 were used.

[0176] Membrane current recordings were made with an Axopatch 200 recorder (Axon instruments, Inc.) patch clamp and pClamp (Axon Instruments, Inc.) data acquisition software. Experiments were performed at 20-23 °C. The holding membrane potential was fixed at -100 mV. Ca currents through the Ca_v3.2 channels were elicited by a series of 150 msec depolarizing pulses applied from a holding potential of -100 mV to a membrane potential between -90 mV and +20 mV every 15 seconds.

[0177] Percent inhibition is calculated from the ratio of the current amplitude in the presence and absence of compound. When multiple doses of compound were tested, IC50 values are calculated by Hill equation fit. The range of concentrations tested was 0.001 μΜ to 300 μΜ. ICso values are calculated from the fits of the Hill equation to the data.

[0178] Figures 9-12 show the results of the electrophysiological studies of ST101 on the Ca_v3.2 channel using the patch clamp screen. As seen in Figure 9, ST101 did not display an antagonistic or agonistic effect on the Ca_v3.2 channel.

EXAMPLE 7

Effect of ST101 on Ca_v3.3 channels using a manual patch clamp assays

[0179] T-type calcium channel inhibitory activity of ST101 was evaluated using patch clamp screening which is known to those skilled in the art.

[0180] HEK 293 cells expressing Ca_v3.3 channels were grown in growth media which comprised: DMEM supplemented with 10% fetal bovine serum and penicillin/streptomycin (humidified atmosphere of 95% air/5% C0₂ at 37 °C in a cell culture incubator) on a 30 mm cell culture plate. Ca_v3.3 channel expression was induced by transfection with 1 μg of Ca_v3.1 expression plasmid DNA. Cells were co-transfected with 1 μg of EGFP expression plasmid DNA to allow identification of transfected cells under fluorescent light. The pipette (internal) solution contained 105 mM cesium chloride, 25 mM triethylamine chloride, 10 mM HEPES, 1 mM calcium chloride, 1 1 mM EGTA (pH = 7.2, adjusted with CsOH), and 92 mM cesium chloride. The bath solution contained 40 mM triethylamine, 1 mM magnesium chloride, 2 mM calcium chloride, lOmM HEPES, and 10 mM glucose (pH = 7.4, adjusted with cesium hydroxide). ST101 was diluted in the bath solution to the desired concentration (0.3 μΜ, 1 μΜ, 3 μΜ, 10 μΜ, and 30 μΜ). For control purposes, HEK 293 cells without overexpression of Ca_v3.3 were used.

[0181] Membrane current recordings were made with an Axopatch 200 recorder (Axon instruments, Inc.) patch clamp and pClamp (Axon Instruments, Inc.) data acquisition software. Experiments were performed at 20-23 °C. The holding membrane potential was fixed at -100 mV. Ca currents through the Ca_v3.3 channels were elicited by a series of 150 msec depolarizing pulses applied from a holding potential of -100 mV to a membrane potential between -90 mV and +20 mV every 15 seconds.

[0182] Percent inhibition is calculated from the ratio of the current amplitude in the presence and absence of compound. When multiple doses of compound were tested, IC50 values are calculated by Hill equation fit. The range of concentrations tested was 0.3 μΜ to 30 μΜ. IC₅₀ values are calculated from the fits of the Hill equation to the data.

[0183] Figures 13-16 show the results of the electrophysiological studies of ST101 on the Ca_v3.3 channel using the patch clamp screen. As seen in Figure 13, ST101 displayed an slight antagonistic effect on the Ca_v3.3 channel with an IC50 = 104.2379 μΜ.

EXAMPLE 8

Effect of ST101 on Ca_v3.1 Channels using patch clamp screen

[0184] T-type calcium channel inhibitory activity of ST101 was evaluated using patch clamp screening which is known to those skilled in the art.

[0185] HEK 293 cells expressing Ca_v3.1 channels, alpha 1 G subunit (CACNAIG), and transcript variant accession number NM 018896.3 as transfection-ready DNA were grown in growth media which comprised: DMEM supplemented with 10% fetal bovine serum and penicillin streptomycin (humidified atmosphere of 95% air/5% C0₂ at 37 °C in a cell culture incubator) on a 30 mm cell culture plate. Ca_v3.1 channel expression was transfection with 1 μg of Ca_v3.1 expression plasmid DNA. Cells were co-transfected with 1 μg of EGFP expression plasmid DNA to allow identification of transfected cells under fluorescent light. The pipette (internal) solution contained 105 mM cesium chloride, 25 mM triethyl amine chloride, 10 mM HEPES, 1 mM calcium chloride, 11 mM EGTA (pH = 7.2, adjusted with CsOH), and 92 mM cesium chloride. The bath solution contained 40 mM triethylamine, 1 mM magnesium chloride, 2 mM calcium chloride, l OmM HEPES, and 10 mM glucose (pH = 7.4, adjusted with cesium hydroxide). ST101 was diluted in the bath solution to the desired concentration (0.001 μΜ, 0.03 μΜ, 0.1 μΜ, 0.3 μΜ, 1 μΜ, and 10 μΜ). For control purposes, HEK 293 cells without overexpression of Ca_v3.1 were used.

[0186] Membrane current recordings were made with an Axopatch 200 recorder (Axon Instruments, Inc.) patch clamp and pClamp (Axon Instruments, Inc.) data acquisition software. Experiments were performed at 20-23 °C. The holding membrane potential was fixed at -100 mV. Ca²⁺ currents through the Ca_v3.1 channels were elicited by a series of 150 msec depolarizing pulses applied from a holding potential of -100 mV to a membrane potential between -90 mV and +20 mV every 15 seconds.

[0187] Percent inhibition is calculated from the ratio of the current amplitude in the presence and absence of compound. When multiple doses of compound were tested, IC50 values are calculated by Hill equation fit. The range of concentrations tested was 0.001 μΜ to 10 μΜ. ICso values are calculated from the fits of the Hill equation to the data.

[0188] Figure 17(a): Normalized peak amplitude of Ca_v3.1 currents (average data from 6 transfected cells) is plotted against a time course of 300 seconds starting directly after the application of ST101. ST101 was applied at IC50 (0.0310 μΜ, as determined in Figure 19b). Cells were held at -100 mV and then depolarized from holding potential to a testing potential on -40 mV every 15 seconds to evoke inward currents.

[0189] Figure 17(b): Normalized peak amplitude of Ca_v3.1 currents (average data from 6 transfected cells) is plotted against a time course of 300 seconds starting after the removal of ST101 by washout following ST101 incubation at 0.031 μΜ for 300 seconds. Cells were held at -100 mV and then depolarized from holding potential to a testing potential on -40 mV every 15 seconds to evoke inward currents. After washout, the T-type currents remained at about 15-20% of control levels over the 300 second testing period, suggesting a long-lasting inhibition by ST101.

[0190] Figure 18 shows the effect of the change of frequency of voltage steps of ST101 at IC50 (0.031 μΜ) on Ca_v3.1 calcium channels transiently expressed in HEK 293 cells. Cells were held at -100 mV and were depolarized from the holding potential of -100 mV to the test potential of -40 mV with a start-to-start interval of 5 seconds or 15 seconds, respectively. The total recording time was 90 seconds. As shown in Figure 18, there was no difference in the recorded current between the 5 second and 15 second intervals between depolarizations.

[0191] Figure 19 shows a side-by-side comparison of the IC₅₀ ST101 and mibefradil (a known T- type calcium channel inhibitor). Cells were held at -100 mV and were depolarized from the holding potential of -100 mV to the test potential of -40 mV. Figure 19(a) shows the IC50 of mibefradil on Ca_v3.1 calcium channels transiently expressed in HEK 293 cells. Using the Hill statistic fitting equation (3 parameter):

with b= -0.3545, c(IC₅₀) = 0.0404 μΜ, and a = 1.0203, IC90 = 21.19 μΜ. Figure 19(b) shows the IC₅₀ of ST101 on Ca_v3.1 calcium channels transiently expressed HEK 293 cells. Using the Hill statistic fitting equation (3 parameter):

La_max = (a*x^b)/(c^b+x^b)

with b= -0.3385, c(lC₅₀) = 0.0310 μΜ, and a = 1.0513, IC50 = 0.0310 μΜ and IC90 = 24.01 μΜ. Results from the Hill equation indicate that it is a negative cooperation reaction and once the drug molecule is bound to the receptor, its affinity for other molecules decreases.

[0192] Figure 20 shows an I/V plot before (o) and during (·) the application of ST101 at IC90 (24.01 μΜ) on Ca_v3.1 channels transiently expressed in HEK 293 cells. Currents were elicited by progressing from -100 to +20 mV in 10 mV increments from a holding potential of -100 mV with 15 second intervals. Using the Hill statistic fitting equation (3 parameter):

with b= -0.3385, c(IC₅₀) = 0.0310 μΜ, and a = 1.0513, IC90 = 24.01 μΜ. ST101 depressed the peak current over the range of all examined test potentials by about 90%.

[0193] Figure 21 shows the steady-state inactivation of Ca_v3.1 calcium channels transiently expressed in the HEK 293 cell line. To measure steady-state inactivation, cells were held at -100 mV. Condition pulses from -120 mV to -10 mV were applied in 10 mV increments. Then a test potential of -40 m V was applied. ST101 was used at IC50 (0.031 μΜ). Figure 21 shows currents normalized to maximal currents for control and ST101 treated cells plotted against the command potentials. A Boltzmann sigmoidal statistic fitting equation was used. The steady-state inactivation plot indicates that the fraction of inactivated channels is voltage dependent. The data suggest that ST 101 does not alter the fraction of inactivated channels at different voltages.

[0194] Having now fully described this invention, it will be understood by those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations and other parameters without affecting the scope of the invention or any embodiment thereof. All patents, patent applications, and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing a disease or condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound which is a Ca_v3.1 calcium channel antagonist wherein the compound binds to the Ca_v3.1 calcium channel and reduces the voltage-activated calcium current in the subject.

2. The method of claim 1, wherein the disease or condition is selected from the group consisting of essential tremor, epilepsy, absence seizures, juvenile myoclonic epilepsy, migraine, neuropathic pain syndromes, sleep disorders, jet lag disorder, circadian rhythm sleep disorders, tinnitus, dystonia, familial ataxia, schizoaffective disorder, hypertension, arrhythmias, atrial fibrillation, congestive heart failure, cyclical hormonal secretion under central nervous system control, and weight loss.

3. The method of claim 1, wherein the disease or condition is selected from the group consisting of senile dementia, Alzheimer's disease, cognitive decline, depression, manic depressive psychoses, obsessive-compulsive disorder, panic disorder, anxiety disorder, transient ischemic attack, cerebral hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage, cerebral infarct, hypertensive encephalopathy, amyloidosis, cerebral amyloid angiopathy, cataracts, glaucoma, progression of glaucoma, age-related macular degeneration, rheumatism, osteoporosis, metabolic syndrome, wrinkles, hair loss, one or more conditions associated with senescence, ulcers, periophthalmic lesions, corneal opacity, lordokyphosis, age retardant activity, cognitive impairment, cerebrovascular disease, Lewy body dementia, Parkinson's disease, Pick's disease, Huntington's disease, Down's syndrome, psoriasis, Crohn's disease, rheumatoid arthritis, asthma, autoimmune disease, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivies, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, transplant rejection, inclusion body myositis, vasculitis, cystic fibrosis, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, contact dermatitis, conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, ulcerative colitis, mastocytosis, hyper IgE syndrome, systemic lupus erythematus, psoriasis, acne, multiple sclerosis, allograft rejection, reperfusion injury, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, anaphylactic reaction, cancer, Paget's disease, frontotemporolobar dementia, sporadic inclusion body myositis, cardiac dysfunction, spinobulbar muscular atrophy, spinocerebellar ataxia, macular degeneration, congestive heart failure, Haw River syndrome, polyglutamine diseases, and systemic amyloidosis.

The method of claim 1, wherein the compound is not spiro(imidazo(l,2-a)pyridin-2(3H)- one-3,2'-indan).

The method of claim 2, wherein the compound administered is a compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

wherein in the general Formula (I), the structural unit having the general Formula (II)

R_x is methyl or nil;

R] and R₂ each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, Ci-C₆ alkyl group, Q-Q alkoxy group, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, benzyloxy, CH₂-R₅, and -0-(CH₂)_n-R<s;

R₃ and R4 are either

(i) each one or more functional groups independently selected from the group consisting of a hydrogen atom, Ci-C₆ alkyl group, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl group, CH₂-R₅, and -CH(R )-R₇; or

(ii) R₃ and R together form a spiro ring of Formula (IV):

(IV)

wherein B may be one or more structural units selected from structural units having the general Formula (V),

the structural unit B binds at a position marked by * in the Formula (V) to form a spiro ring; and

R.5 is naphthyl; thienyl; or phenyl, which may be substituted with Q-Q alkyl, halogen atom or cyano;

R₆ is a vinyl group, C₃-C₈ cycloalkyl group, or phenyl group, and n is 0 or 1 ;

R is one or more functional groups selected from the group consisting of a vinyl group; ethynyl group; phenyl optionally substituted by a C_\-Ce alkyl group, Ci-C^ alkoxy group, hydroxy group, 1 or 2 halogen atoms, di C!-C₆ alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;

R₈ is a hydrogen atom or Ci-C₆ alkyl group; and

R₉ is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, C]-C₆ alkoxy group, cyano group, and trifluoromethyl group.

6. The method of claim 1 , wherein the disease or condition is essential tremor.

7. The method of claim 1, wherein the disease or condition is epilepsy.

8. The method of claim 1 , wherein the disease or conditio is absence seizure.

9. The method of claim 1 , wherein the disease or condition is neuropathic pain.

10. The method of claim 1 , wherein the compound does not antagonize L-type, N-type, P- type, Q-type, or R-type calcium channels.

1 1. The method of claim 1 , wherein the compound does not antagonize the Ca_v3.2 calcium channel.

12. The method of claim 1 , wherein the compound does not antagonize the Ca_v3.3 calcium channel.

13. A method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising: (a) contacting a first group of cells expressing a Ca_v3.1 calcium channel with a test compound;

(b) measuring the calcium channel antagonist activity of the first group;

(c) comparing the calcium channel antagonist activity of the first group to the cal cium channel antagonist activity of a second group of said cells that have not been contacted with said test compound;

wherein a test compound that provides greater calcium channel antagonist activity than the activity of the second group is selected.

14. The method of claim 13, wherein the activity of the cells is measured by whole cell patch clamp.

15. The method of claim 13, wherein the cells expressing the Ca_v3.1 calcium channel are HEK 293 cells or transformed HEK 293 cells.

16. A method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

17. The method of claim 16, wherein the activity of the cells is measured by whole cell patch clamp.

18. The method of claim 16, wherein the cells expressing Ca_v3.1 or Ca_v3.2 calcium channels are HEK 293 cells or transformed HEK 293 cells.

19. A method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising: (a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(e) compare the activity of (b) with the activity measured in (d); wherein a test compound that provides a greater activity in (b) than the activity in (d) is selected.

20. The method of claim 19, wherein the activity of the cells is measured by whole cell patch clamp.

21. The method of claim 19, wherein the cells expressing Ca_v3.1 or Ca_v3.3 calcium channels are HEK 293 cells or transformed HEK 293 cells.

22. A method of screening for a preventative or therapeutic agent for Alzheimer's disease comprising:

(a) contacting cells expressing a Ca_v3.1 calcium channel with a test compound;

(g) comparing the activity of (b) with the activity of (d) and (f);

wherein a test compound that provides a greater activity in (b) than the activities in (d) and (f) is selected.

23. The method of claim 22, wherein the activity of the cells is measured by whole cell patch clamp.

24. The method of claim 22, wherein the cells expressing Ca_v3.1, Ca_v3.2, or Ca_v3.3 calcium channels are HEK 293 cells or transformed HEK 293 cells.

25. The method of claim 1, wherein the compound also enhances the release of a neurotransmitter.

26. The method of claim 25, wherein the neurotransmitter is acetylcholine.

27. The method of claim 25, wherein the neurotransmitter is dopamine.

28. The method of claim 1, wherein the compound also reduces amyloid beta production.

29. The method of claim 28, wherein the disease or condition is selected from the group consisting of Alzheimer's disease, diabetes, Parkinson's disease, transmissable spongiform encephalopathy, bovine spongiform encephalopathy, Huntington's disease, medullary carcinoma of the thyroid, cardiac arrhythmias, isolated atrial amyloidosis, athreosclerosis, rheumatoid arthritis, aortic medial amyloid, prolactinomas, familial amyloid polyneuropathy, hereditary non-neuropathic systemic amyloidosis, dialysis-related amyloidosis, Finnish amyloidosis, lattice corneal dystrophy, cerebral amyloid angiopathy, systemic AL amyloidosis, inclusion body myositis, amyloidosis, cataracts, glaucoma, age-related macular degeneration, rheumatism, osteoporosis, metabolic syndrome, wrinkles, and hair loss.

30. The method of claim 3, wherein the compound administered is not a compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

Π)

R_x is methyl or nil;

Ri and R₂ each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, Ci-C₆ alkyl group, Ci-C alkoxy group, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, benzyloxy, CH₂-R₅, and -0-(CH₂)_n-R6;

R₃ and R₄ are either

(i) each one or more functional groups independently selected from the group consisting of a hydrogen atom, Ci-C₆ alkyl group, C₂-C₆ alkenyl, C3-C8 cycloalkyl group, CH₂-R₅, and -CH(R₈)-R₇; or

(ii) R₃ and R4 together form a spiro ring of Formula (IV):

(IV)

R₅ is naphthyl; thienyl; or phenyl, which may be substituted with Q-Q alkyl, halogen atom or cyano;

¾ is a vinyl group, C₃-C₈ cycloalkyl group, or phenyl group, and n is 0 or 1 ;

R₇ is one or more functional groups selected from the group consisting of a vinyl group; ethynyl group; phenyl optionally substituted by a CrC₆ alkyl group, Q-C6 alkoxy group, hydroxy group, 1 or 2 halogen atoms, di Q-C6 alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;

R₈ is a hydrogen atom or C C alkyl group; and

R₉ is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, Ci-C₆ alkoxy group, cyano group, and trifluoromethyl group.

31. A method of treating or preventing essential tremor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

wherein

R_x is methyl or nil;

Ri and R₂ each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C_!-C₆ alkyl group, C C₆ alkoxy group, C₂-C₆ alkenyl, C3-C8 cycloalkyl, benzyloxy, CH₂-R₅, and -0-(CH₂)_n-R₆;

R₃ and R4 are either

(i) each one or more functional groups independently selected from the group consisting of a hydrogen atom, Ci-C₆ alkyl group, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl group, CH₂-R₅, and -CH(R₈)-R₇; or

(ii) R₃ and R4 together form a spiro ring of Formula (IV):

wherein B may be one or more structural units selected from structural units having the general Formula (V):

R-5 is naphthyl; thienyl; or phenyl, which may be substituted with C -Ce alkyl, halogen atom or cyano;

R₆ is a vinyl group, C₃-C cycloalkyl group, or phenyl group, and n is 0 or 1 ;

R₇ is one or more functional groups selected from the group consisting of a vinyl group; ethynyl group; phenyl optionally substituted by a Ci-C alkyl group, C_\-C alkoxy group, hydroxy group, 1 or 2 halogen atoms, di Q-C₆ alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;

Rg is a hydrogen atom or C C₆ alkyl group; and

R₉ is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, Q-C6 alkoxy group, cyano group, and trifluoromethyl group.

32. The method of claim 31 , wherein the compound is spiro(imidazo(l,2-a)pyridin-2(3H)- one-3,2'-indan).

33. The method of claim 31, wherein the compound is administered at a dose of between about 10 mg and 600 mg.

34. The method of claim 33, wherein the compound is administered at a dose of between about 10 mg and 500 mg.

35. The method of claim 33, wherein the compound is administered at a dose of between about 10 mg and 400 mg<

36. The method of claim 33, wherein the compound is administered at a dose of between about 10 mg and 300 mg.

37. The method of claim 31 , wherein the compound is administered orally to the subject.

38. The method claim 31 , wherein the compound is administered parenterally to the subject.

39. The method of claim 31, wherein the compound is administered intravenously, subcutaneously, or intramuscularly to the subject.

40. The method of claim 31, further comprising administering a therapeutic agent used to treat essential tremor.

41. The method of claim 40, wherein the therapeutic agent is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.

42. A pharmaceutical composition comprising: (a) a compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate or prodrug thereof,

wherein

R_x is methyl or nil;

Rj and R₂ each are one or more functional groups independently selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, amino group, acetylamino group, benzylamino group, trifluoromethyl group, C C₆ alkyl group, C C₆ alkoxy group, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, benzyloxy, CH₂-R₅, and -0-(CH₂)_n-R6;

R₃ and R₄ are either

(i) each one or more functional groups independently selected from the group consisting of a hydrogen atom, C_!-C₆ alkyl group, C₂-C₆ alkenyl, C₃-Cg cycloalkyl group, CH₂-R₅, and -CH(R₈)-R₇; or

(ii) R₃ and R4 together form a spiro ring of Formula (IV):

R₇ is one or more functional groups selected from the group consisting of a vinyl group; ethynyl group; phenyl optionally substituted by a C_!-C₆ alkyl group, Ci-C₆ alkoxy group, hydroxy group, 1 or 2 halogen atoms, di Q-Q alkylamino group, cyano group, nitro group, carboxy group, or phenyl group; phenethyl group; pyridyl group; thienyl group; and furyl group;

R₈ is a hydrogen atom or C C₆ alkyl group; and

R₉ is one or more functional groups selected from the group consisting of a hydrogen atom, halogen atom, hydroxy group, Ci-C₆ alkoxy group, cyano group, and trifluoromethyl group; and

(b) a further therapeutic agent for the treatment of essential tremor.

43. The pharmaceutical composition of claim 42, wherein the compound of Formula (I) is spiro(midazo(l,2-a)pyridin-2(3H)-one-3,2'-indan).

44. The pharmaceutical composition of claim 42, wherein the compound of Formula (I) and the therapeutic agent are administered orally.

45. The pharmaceutical composition of claim 42, wherein the therapeutic agent is propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.

46. A kit comprising spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and a further therapeutic agent for the treatment of essential tremor.

47. The kit of claim 46, wherein the therapeutic agent is selected from the group consisting of propranolol, primidone, gabapentin, topiramate, alprazolam, clonazepam, flunarizine, or nimodipine.

48. The kit of claim 46, wherein the therapeutic agent is in a form suitable for oral administration.

49. The kit of claim 46, wherein spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered simultaneously.

50. The kit of claim 46, wherein spiro(imidazo(l,2-a)pyridine-2(3H)-one-3,2'-indan) and the further therapeutic agent are administered separately.